US 20080299220A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0299220 A1 Tamarkin et al. (43) Pub. Date: Dec. 4, 2008

(54) HYDROPHILIC, NON-AQUEOUS filed on Nov. 29, 2006, provisional application No. PHARMACEUTICAL CARRIERS AND 60/530,015, filed on Dec. 16, 2003, provisional appli COMPOSITIONS AND USES cation No. 60/492.385, filed on Aug. 4, 2003, provi sional application No. 60/784.793, filed on Mar. 21, (76) Inventors: Dov Tamarkin, Maccabim (IL); 2006, provisional application No. 60/530,015, filed on Meir Eini, Ness Ziona (IL); Doron Dec. 16, 2003, provisional application No. 60/492, Friedman, Karmei Yosef (IL); Alex 385, filed on Aug. 4, 2003, provisional application No. Besonov, Rehovot (IL); David 60/492.385, filed on Aug. 4, 2003, provisional appli Schuz. Moshav Gimzu (IL); Tal cation No. 60/679,020, filed on May 9, 2005. Berman, Rishon LeZiyyon (IL); Jorge Danziger, Rishom Lezion Publication Classification (IL); Rita Keynan, Rehovot (IL); (51) Int. Cl. Ella Zlatkis, Rehovot (IL) A633/00 (2006.01) Correspondence Address: A6II 47/34 (2006.01) WILMERHALEABOSTON A 6LX 3L/375 (2006.01) 6O STATE STREET A 6LX 3L/355 (2006.01) BOSTON, MA 02109 (US) A63L/35 (2006.01) A6II 3/442 (2006.01) (21) Appl. No.: 12/014,088 A63L/047 (2006.01) (22) Filed: Jan. 14, 2008 A 6LX 3/57 (2006.01) Related U.S. Application Data A6IR 9/12 (2006.01) (63) Continuation-in-part of application No. 1 1/430,599, A6II 3/522 (2006.01) filed on May 9, 2006, which is a continuation-in-part A63L/35 (2006.01) of application No. 10/835,505, filed on Apr. 28, 2004, (52) U.S. Cl...... 424/600: 514/772.7: 514/474; Continuation-in-part of application No. 1 1/947,751, 514/458: 514/460, 514/345; 514/729; 514/178; filed on Nov. 29, 2007, which is a continuation-in-part 424/45; 514/263.38: 514/649 of application No. 1 1/430,599, filed on May 9, 2006, which is a continuation-in-part of application No. (57) ABSTRACT 10/835,505, filed on Apr. 28, 2004, Continuation-in A waterless composition suitable for delivery of an active part of application No. 1 1/653,205, filed on Jan. 12, agent to a body Surface or cavity includes a vehicle having 2007, which is a continuation-in-part of application about 70% to about 99% by weight of a hydrophilic polar No. 10/835,505, filed on Apr. 28, 2004, said applica Solvent, said hydrophilic solvent selected from the group tion No. 1 1/653,205 is a continuation-in-part of appli consisting of (i) a mixture of two or more different polyeth cation No. 10/911.367, filed on Aug. 4, 2004, said ylene glycols (PEGs), wherein at least one PEG is a high application No. 1 1/653.205 is a continuation-in-part of molecular weight PEG having a melting point greater than application No. 1 1/430,599, filed on May 9, 2006. 25° C.; and (ii) propylene glycol (PG); about 0% to about 10% of at least one surface active agent; about 0% to about (60) Provisional application No. 607880,434, filed on Jan. 5% of a polymeric agent; about 0% to about 30% of a sec 12, 2007, provisional application No. 60/919,303, ondary hydrophilic solvent; and about 0% to about 5% of a filed on Mar. 21, 2007, provisional application No. silicone oil; and about 3% to about 25% hydrophobic propel 60/679,020, filed on May 9, 2005, provisional appli lant. The composition is otherwise substantially free of a cation No. 60/.530,015, filed on Dec. 16, 2003, provi hydrophobic solvent and includes at least one of a surface sional application No. 60/492.385, filed on Aug. 4. active agent and a polymeric agent. The vehicle and the pro 2003, provisional application No. 60/679,020, filed on pellant are sufficiently miscible that the components may be May 9, 2005, provisional application No. 60/861,620, homogeneously distributed with mild shaking.

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HYDROPHILIC, NON-AQUEOUS 0007 External topical administration is an important PHARMACEUTICAL CARRIERS AND route for the administration of drugs in disease treatment. COMPOSITIONS AND USES Many groups of drugs, including, for example, antibiotic, anti-fungal, anti-inflammatory, anesthetic, analgesic, anti-al CROSS REFERENCE TO RELATED lergic, corticosteroid, retinoid and anti-proliferative medica APPLICATIONS tions are preferably administered in hydrophobic media, namely ointment. However, ointments often form an imper 0001. This application claims the benefit of priority under meable barrier, so that metabolic products and excreta from 35 U.S.C. S 199(e) to co-pending U.S. Provisional Applica the wounds to which they are applied are not easily removed tion No. 60/880,434 filed Jan. 12, 2007, and entitled “Hydro or drained away. Furthermore, it is difficult for the active drug philic or Waterless Vehicle and Foamable Pharmaceutical dissolved in the carrier to pass through the white petrolatum Compositions.” which is incorporated in its entirety by refer barrier layer into the wound tissue, so the efficacy of the drug CCC. is reduced. In addition, ointments and creams often do not 0002 This application claims the benefit of priority under create an environment for promoting respiration of the wound 35 U.S.C. S 199(e) to co-pending U.S. Provisional Applica tissue and it is not favorable to the normal respiration of the tion No. 60/919,303 filed Mar. 21, 2008, and entitled “Hydro skin. An additional disadvantage of petroleum jelly-based philic and Non-Aqueous Pharmaceutical Carriers and Com products relates to the greasy feeling left following their positions and Uses,” which is incorporated in its entirety by topical application onto the skin, mucosal membranes and reference. wounds. 0003. This application is a continuation-in-part applica 0008 Foams and, in particular, foams that are substan tion of co-pending U.S. patent application Ser. No. 1 1/430, tially based on non-aqueous solvents are complicated sys 599, filed on May 9, 2006, entitled “Foamable Vehicle and tems which do not form under all circumstances. Pharmaceutical Compositions Thereof which is a continu 0009. There remains an unmet need for improved, easy to ation-in-part application of co-pending U.S. patent applica use, stable and non-irritating foam formulations, intended for tion Ser. No. 10/835,505, filed on Apr. 28, 2004, entitled treatment of dermal and mucosal tissues. Particularly, there “Oleaginous Pharmaceutical and Cosmetic Foam, which remains an unmet need for improved, easy to use, stable and claims the benefit of priority under 35 U.S.C. S 119(e) to U.S. non-irritating foam formulations, with unique therapeutic Patent Application Ser. No. 60/530,015, filed on Dec. 16, properties. There is more particularly a need to develop 2003, entitled “Oleaginous Pharmaceutical Foam”, and U.S. hygroscopic carriers and compositions, foamable carriers and Patent Application Ser. No. 60/492.385, filed on Aug. 4, 2003, foamable compositions and foams with active agents, which entitled “Cosmetic and Pharmaceutical Foam;’ and which are stable, are non irritating, that facilitate penetration at a claims the benefit under 35 U.S.C. S 119(e) of U.S. Provi target, that are presentable in an easily applicable stable form, sional Patent Application No. 60/679,020, filed on May 9, that can be handled with ease thereby facilitating compliance 2005, entitled “Hygroscopic Anti-Infective Compositions: and that are adaptable where there is a need to minimize the and of U.S. Provisional Patent Application No. 60/784,793, amount of free water and in consequence, the potential break filed on Mar. 21, 2006, entitled “Polyol Foamable Vehicle and down of ingredients/agents by oxidation/hydrolysis. Pharmaceutical Compositions Thereof, which are herein 0010 Some active agents are known to be generally incorporated by reference in their entirety. unstable or susceptible to isomerization or to breakdown, 0004. This application is a continuation-in-part applica resulting in loss of activity and the use of Stabilizers, anti tion of co-pending application U.S. patent application Ser. oxidants antimicrobials and buffers and the like in aqueous No. 1 1/653,205, filed on Jan. 12, 2007, which is a continua compositions to protect active or cosmetic agents is known. tion-in-part application of co-pending U.S. patent application The problems of protecting active pharmaceutical and cos Ser. No. 10/835,505, filed on Apr. 28, 2004, both entitled metic agents in waterless environments, such as polar com “Oleaginous Pharmaceutical And Cosmetic Foam, which positions are multifold and can vary according to the type of claims the benefit of priority under 35 U.S.C. S 119(e) to U.S. waterless environment and the nature of the agent being used. Patent Application Ser. No. 60/530,015, filed on Dec. 16, It has been surprisingly found that factors like small levels of 2003, entitled “Oleaginous Pharmaceutical Foam, and acid residues in the raw materials can be significant in influ 60/492.385, filed on Aug. 4, 2003, entitled “Cosmetic and encing agent stability. Similarly, the presence of low levels of Pharmaceutical Foam’, which are herein incorporated by metal ions can act to catalyze reactions or breakdown. There reference in their entirety. is therefore a need for simple and elegant Solutions to stabilize 0005. This application is a continuation-in-part applica active ingredients in a waterless or Substantially waterless tion of co-pending U.S. patent application Ser. No. 1 1/947, environment. On one level it is far from simple or obvious to 751, filed on Nov. 29, 2007, entitled “Compositions With produce waterless foamable compositions that, when Modulating Agents', which claims the benefit under 35 U.S. released, produce foams of quality Suitable for pharmaceuti C. S 119(e) of U.S. Provisional Patent Application No. cal or cosmetic application. On a further level having realized 60/861,620, filed on Nov. 29, 2006, entitled “Foamable Com a carrier that will produce a waterless foam of quality there is positions With Modulating Agents, which is herein incorpo an additional difficulty to be overcome, namely how to adapt rated by reference in its entirety. the formula and achieve a formulation, which can accept a range of various active pharmaceutical and cosmetic agents BACKGROUND Such that the composition and active agent are stable and the foam produced remains of quality. Specifically, one of the 0006. This invention relates to hygroscopic carriers and challenges in preparing Such waterless or Substantially water compositions, foamable carriers, and foamable pharmaceuti less foamable compositions is ensuring that the active phar cal and cosmetic compositions, and the use of them. maceutical or therapeutic agent does not react, isomerizes or US 2008/0299220 A1 Dec. 4, 2008 otherwise break down to any significant extent during its about 5% by weight of at least one polymeric agent; and a storage and use. Particularly, there remains an unmet need for liquefied or compressed gas propellant at a concentration of improved, easy to use, stable and non-irritating foam formu about 3% to about 25% by weight of the total composition. lations, with unique therapeutic or beneficial properties con 0020. In another aspect, the invention provides a foamable taining a stable or stabilized active pharmaceutical or cos carrier including about 50% to about 98% by weight of a metic agent. Solvent selected from the group consisting of (1) a propylene 0011 Polyethylene glycol or derivatives or mixtures glycol or derivative and (2) a polyethylene glycol (PEG) or thereof and propylene glycol or derivatives are believed, in derivative or mixtures thereof, 0% to about 48% by weight of addition to their function as a solvent, to Support, facilitate, a secondary solvent; about 0.01% to about 10% by weight of improve or optimize the function and effect of active agents a surface-active agent; about 0.01% to about 5% by weight of and may themselves have a therapeutic effect. There is thus, at least one polymeric agent; and a liquefied or compressed also an unmet need for compositions especially foamable gas propellantata concentration of about 3% to about 25% by compositions comprising combinations of polyethylene gly weight of the total composition. cols or derivatives or mixtures thereof and polyethylene gly 0021. It was discovered that in certain embodiments it is color derivatives with an active agent, especially synergistic possible to create a hydrophilic foam with silicone. compositions. 0022. In one or embodiments there is provided a foamable hydrophilic carrier or therapeutic composition, comprising: SUMMARY 0023 a waterless solvent comprising about 25% to about 0012. This invention relates to hygroscopic carriers and 95% of at least a polar solvent selected from the group con compositions, foamable carriers, and foamable pharmaceuti sisting of (1) a propylene glycol or derivative and (2) a poly cal and cosmetic compositions, wherein the solvent includes ethylene glycol (PEG) or derivative or mixtures thereof, and a polyethylene glycol or derivative or mixtures thereof or 0024 a surface-active agent and or at least one polymeric includes a propylene glycol derivative or combinations of agent at a concentration of about 0.1% to about 5% by weight polyethylene glycols with or without propylene glycol. of the total composition, wherein the at least one polymeric 0013 This invention relates more particularly to hygro agent is selected from a bioadhesive agent, a gelling agent, a scopic glycol composition comprising a polyethylene glycol film forming agent and a phase change agent which is selected orderivatives and mixtures thereofor comprising a propylene Such that it has some surfactant properties if it is used in the glycol or derivatives at a sufficient concentration alone as a absence of Surface active agent. component in the composition or with one or more other 0025. In one or embodiments there is provided a foamable hygroscopic Substances to provide hydrophilic therapeutic composition, comprising: 0014 (a) at least one hygroscopic Substance at a suffi 0026 a waterless solvent comprising about 25% to about cient concentration to provide an AW value of the hygro 95% of at least a polar solvent selected from the group con Scopic therapeutic containing composition of less than sisting of (1) a propylene glycol or derivative and (2) a poly 0.9; and ethylene glycol (PEG) or derivative or mixtures thereof; 0015 (b) a therapeutic agent thereof or combinations 0027 0% to about 48% of a secondary waterless solvent thereof. 0028 a surface-active agent at a concentration of about 0016. In one aspect, the invention provides a hygroscopic 0.1% to less than about 10% by weight of the total composi composition comprising polyethylene glycol or derivatives tion; and or and mixtures thereof or comprising propylene glycol or 0029 at least one polymeric agent at a concentration of derivatives being or having at least one hygroscopic Sub about 0.1% to about 5% by weight of the total composition, stance at a Sufficient concentration alone or with one or more wherein the at least one polymeric agent is selected from a other hygroscopic Substances to provide an AW value of the bioadhesive agent, agelling agent, a film forming agent and a hygroscopic pharmaceutical composition (1) of about less phase change agent which is selected Such that it has some than 0.9 or (2) the Aw value is in the range of about 0.8 and surfactant properties if it is used in the absence of surface about 0.9; (3) about 0.7 and about 0.8; and (4) less than about active agent. 0.7 and an or a derivative thereof or a combinations thereof. 0030 (a) optionally a silicone and 0017. In one or more embodiments, the hygroscopic phar 0.031 (b) a liquefied or compressed gas propellant at a maceutical composition further includes at least one compo concentration of about 3% to about 25% by weight of the nent, selected from the group consisting of about 0.01% to total composition; and about 5% by weight of at least one polymeric agent selected 0.032 a therapeutically effective amount of an active from a bioadhesive agent, a gelling agent, a film forming agent; and agent and a phase change agent; and a Surface-active agent. wherein the composition is stored in anaerosol container and 0.018. In one or more embodiments, the one or more upon release expands to form a breakable foam. hygroscopic Substance is selected from the group consisting 0033. In one or more embodiments, the compositions fur of polyethylene glycols (Pegs), Surfactants comprising PEG, ther comprise co-Surfactants. polyols, monosaccharides, disaccharides, oligosaccharides 0034. In one or more embodiments, the compositions fur and Sugar alcohols in an amount to provide hygroscopic prop ther comprise up to 10% of water. erties, and honey. 0035. In one or more embodiments, the composition is 0019. In another aspect, the invention provides a foamable Substantially non-aqueous and/or substantially alcohol-free. carrier including about 25% to about 98% by weight of a 0036. In one or more embodiments, the composition is Solvent selected from the group consisting of (1) a propylene non-aqueous. glycol or derivative and (2) a polyethylene glycol (PEG) or 0037. In one or more embodiments, the composition derivative or mixtures thereof, 0% to about 48% by weight of ingredients are pretreated to reduce, remove or eliminate any a secondary solvent; a surface-active agent; about 0.01% to residual or associated or absorbed water. US 2008/0299220 A1 Dec. 4, 2008

0038. In one or more embodiments, the composition is 0051. In another aspect there is provided a foamable thera Substantially non-aqueous and/or substantially alcohol-free. peutic composition including about 50% to about 98% by 0039. In one or more embodiments, the composition fur weight of a solvent selected from the group consisting of (1) ther comprises an therapeutically effective concentration of a propylene glycolor derivative and (2) a polyethylene glycol one or more active, therapeutic, pharmaceutical or cosmetic (PEG) or derivative or mixtures thereof; 0% to about 48% by agents. weight of a secondary solvent; about 0.01% to about 10% by 0040. In one or more embodiments, the composition fur weight of a surface-active agent; about 0.01% to about 5% by ther comprises one or more modulating agents. weight of at least one polymeric agent; a therapeutic agent at 0041. In one or more embodiments, the secondary solvent a therapeutically effective concentration; and a liquefied or is a polyol selected from the group consisting of a diol, a triol compressed gas propellant at a concentration of about 3% to and a saccharide, and the triol may be selected from the group about 25% by weight of the total composition. consisting of glycerin, butane-1,2,3-triol, butane-1,2,4-triol 0052. In another aspect there is provided a foamable thera and hexane-1,2,6-triol, or the diol is selected from the group peutic composition including about 50% to about 98% by consisting of propylene glycol, butanediol, butenediol. weight of a solvent selected from the group consisting of (1) butynediol, pentanediol, hexanediol, octanediol, neopentyl a propylene glycolor derivative and (2) a polyethylene glycol glycol, 2-methyl-1,3-propanediol, diethylene glycol, trieth (PEG) or derivative or mixtures thereof; 0% to about 48% by ylene glycol, tetraethylene glycol, dipropylene glycol and weight of a secondary solvent; about 0.01% to about 10% by dibutylene glycol. weight of a surface-active agent; about 0.01% to about 5% by 0042. In one or more embodiments, the polyol consists of weight of at least one polymeric agent; a therapeutic agent at at least one diol and at least one triol, and wherein the ratio atherapeutically effective concentration; a modulating agent; between the diol and triol is between 9:1 and 1:1. and a liquefied or compressed gas propellant at a concentra tion of about 3% to about 25% by weight of the total compo 0043. In one or more embodiments, the composition sition. includes a mixture of PEGs, and the PEG may be selected 0053. In yet an additional embodiment, the foamable from the group consisting of PEG 200, PEG 300, PEG 400, therapeutic composition further contains an additional thera PEG 600, PEG 1000, PEG 1500, PEG 4000, PEG 6000 and peutic agent. PEG 8OOO. 0054. In another aspect, a method of treating, ameliorating 0044. In one or more embodiments, the composition con or preventing a disorder of mammalian Subject includes tains one or more PEGs in a concentration to provide viscos administering a foamable therapeutic composition to a target ity of less than 52,000 CPs. area, the composition comprising a therapeutically effective 0045. In one or more embodiments, the composition concentration of an active agent, about 50% to about 98% of includes a mixture of at least one polyol and at least one PEG, a solvent selected from the group consisting of (1) a propy and the PEG may be selected from the group consisting of lene glycol or derivative and (2) a polyethylene glycol (PEG) PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG or derivative or mixtures thereof; 0% to about 48% of a 1500, PEG 4000, PEG 6000 and PEG 8000. secondary solvent; about 0.01% to about 5% by weight of at 0046. In one or more embodiments, the composition least one polymeric agent; about 0.01% to about 10% by includes a secondary solvent selected from the group consist weight of a Surface-active agent; a modulating agent; and a ing of dimethyl isosorbide, tetrahydrofurfuryl alcohol poly liquefied or compressed gas propellant at a concentration of ethyleneglycol, ether, DMSO, a pyrrolidone, N-Methyl-2- about 3% to about 25% by weight of the total composition. pyrrolidone, 1-Methyl-2-pyrrolidinone, ethyl proxitol, 0055. In one or more embodiments, the target site is dimethylacetamide, a PEG-type Surfactant, an alpha hydroxy selected from the group consisting of the skin, a body cavity, acid, lactic acid and glycolic acid. a mucosal Surface, the nose, the mouth, the eye, the ear canal, 0047. In one or more embodiments, the secondary solvent the respiratory system, the vagina and the rectum. is dimethyl isosorbide. 0056. In one or more embodiments the surface active 0048. In one or more embodiments, the composition agent can be increased from about 10% up to about 15% or up includes (1) at least one solvent selected from a propylene to about 20% by weight of composition depending on the glycol and a PEG, and (2) at least one secondary solvent, and Surfactant selected. for example, the solvent comprises a mixture of at least one 0057. In one aspect, a waterless composition suitable for polyol and at least one PEG, and for example, the polyol delivery of an active agent to a body Surface or cavity includes comprises a mixture of at least two polyols. a vehicle comprising: 0049. In one or more embodiments, the ratio between the 0.058 about 70% to about 99% by weight of a hydro propylene glycol and/or PEG and the secondary solvent is philic polar solvent, said hydrophilic solvent selected between 9:1 and 1:1. from the group consisting of 0050. In another aspect there is provided a foamable thera 0059) i) a mixture of two or more different polyeth peutic composition including about 25% to about 98% by ylene glycols (PEGs), wherein at least one PEG is a weight of a solvent selected from the group consisting of (1) high molecular weight PEG having a melting point a propylene glycolor derivative and (2) a polyethylene glycol greater than 25°C.; and (PEG) or derivative or mixtures thereof; 0% to about 48% by 0060 ii) propylene glycol (PG); weight of a secondary solvent; about 0.01% to about 10% by 0061 about 0% to about 10% of at least one surface weight of a surface-active agent; about 0.01% to about 5% by active agent; weight of at least one polymeric agent; a therapeutic agent at 0062) about 0% to about 5% of a polymeric agent; a therapeutically effective concentration; and a liquefied or 0063 about 0% to about 30% of a secondary hydro compressed gas propellant at a concentration of about 3% to philic solvent; and about 25% by weight of the total composition. 0064 about 0% to about 5% of a silicone oil; and US 2008/0299220 A1 Dec. 4, 2008

0065 about 3% to about 25% hydrophobic propellant; sucrose ester, including Span 20, Span 60 and Span 80, a 0.066 wherein the composition is otherwise substan partial ester of Sorbitol, including Sorbitan monolaurate, Sor tially free of a hydrophobic solvent; bitan monolaurate, and Surphope 1811, a monoglyceride, a 0067 wherein the composition includes at least one of a diglyceride, isoceteth-20, a mono, di or trifatty acid Sucrose Surface active agent and a polymeric agent; and ester, laureth-4, glyceryl Stearate, polyoxyl-100 Stearate, 0068 wherein the vehicle and the propellant are suffi glyceryl monostearate, PEG-100 stearate, PEG-40 stearate, ciently miscible that the components may be homogeneously ceteareth-6, ceteareth-16, ceteareth-20, stearyl alcohol, myr distributed with mild shaking. 52, steareth-2, steareth-20, isosteareth-20, polyglyceryl 10 0069. In one or more embodiments, the hydrophilic sol laurate, POE (2) cetyl ether, cetearyl glucoside, cetyryl alco vent is PEG and the high molecular weight PEG is selected hol, methyl glucose sesquistearate, span 60, Sucrose Stearic from the group consisting of PEG 1000, PEG 1500, PEG acid esters, Sorbitan Stearate. Sucrose cocoate. Sucrose Stear 4000, PEG 6000 and PEG 8000, and the balance of the PEG ate, Peg 40 Stearate, isosteareth 20, methyl glucose ses is selected from the group consisting of PEG 200, PEG 300, quistearate, polyoxyl 100 Stearate, macrogel cetostearyl PEG 400, and PEG 600. ether, a polymeric emulsifier, including Permulen (TR1 or 0070. In one or more embodiments, the high molecular TR2); and liquid crystal systems, including Arlatone (2121), weight PEG comprises about 1% to about 15% of the com Stepan (Mild RM1), Nikomulese (41) and Montanov (68); position. and 0071. In one or more embodiments, the mixture of two or 0078 a combination of surfactants selected from the more different PEGs are selected to provide viscosity of the group consisting of a Brij Surfactant and a Twin Surfactant, vehicle of less than 52,000 CPs, as measured at room tem wherein the Brij surfactant is the major component of the perature at 10 rmp spindle speed, or are less than 12,000 CPs combination, combinations of polyoxyethylene alkyl ethers, or are less than 10,000 CPs. including Brij 59/Brij 10; Brij 52/Brij 10; Steareth 2/Steareth 0072. In one or more embodiments, the hydrophilic polar 20: Steareth 2/Steareth 21 (Brij 72/BRIJ 721); Myr 52/Myr solvent is PG and the components of the composition are 59, Steareth 2/Laureth 4; combinations of sucrose esters, sufficiently miscible that the vehicle and the propellant do not including Surphope 1816/Surphope 1807; combinations of phase separate upon centrifugation at 1000 rpm. sorbitan esters, including Span 20/Span 80: Span 20/Span 60; 0073. In one embodiment, the hydrophilic solvent is PG. combinations of Sucrose esters and Sorbitan esters, including the composition includes a Steareth Surface active agent and a Surphope 1811 and Span 60; and combinations of liquid hydroxypropylcellulose polymeric agent, and is substantially polysorbate detergents and PEG compounds, particularly free of silicone and a secondary hydrophilic solvent. Twin 80/PEG-40 stearate/methylglucose sequistearate, glyc 0.074. In one or more embodiments, one or both of the eryl Stearate/PEG-100 stearate; ceteareth-6/stearyl alcohol: Surface active agent and the polymeric agent are selected to cetearyl glucoside/cetyryl alcohol; Sorbitan Stearate/Sucrose increase the solubility of the propellant in the vehicle. cocoate; and polysorbate 80/PEG-40 stearate. 0075. In one or more embodiments, the a polymeric agent 0079. In one or more embodiments, silicone oil is present is present in the composition and is selected from the group in the composition and is selected from the group consisting consisting of locust bean gum, Sodium alginate, sodium of dimethicone, cyclomethicone and mixtures thereof. caseinate, egg albumin, gelatin agar, carrageenin gum, 0080. In one or more embodiments, the second hydro Sodium alginate, Xanthan gum, quince seed extract, traga philic solvent is present in the composition and is a polyol canth gum, guar gum, cationic guars, hydroxypropyl guar selected from the group consisting of a diol, a triol and a gum, starch, an amine-bearing polymer, chitosan, alginic saccharide, wherein the triol is selected from the group con acid, hyaluronic acid, a chemically modified Starch, a carbox sisting of glycerin, butane-1,2,3-triol, butane-1,2,4-triol and yvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, a hexane-1,2,6-triol, and wherein the diol is selected from the polyacrylic acid polymer, a polymethacrylic acid polymer, group consisting of propylene glycol, butanediol, butenediol. polyvinyl acetate, a polyvinyl chloride polymer, a polyvi butynediol, pentanediol, hexanediol, octanediol, neopentyl nylidene chloride polymer, methylcellulose, hydroxypropyl glycol, 2-methyl-1,3-propanediol, diethylene glycol, trieth cellulose, hydroxypropyl methylcellulose, hydroxyethyl cel ylene glycol, tetraethylene glycol, dipropylene glycol and lulose, hydroxy propylmethyl cellulose, methylhydroxyeth dibutylene glycol. ylcellulose, methylhydroxypropylcellulose, hydroxyethyl 0081. In one or more embodiments, the ratio between the carboxymethylcellulose, carboxymethyl cellulose, polyethylene glycol and the secondary hydrophilic Solvent is carboxymethylcellulose carboxymethylhydroxyethylcel between about 9:1 and about 1:1. lulose, a cationic cellulose PEG 1000, PEG 4000, PEG 6000 I0082 In one or more embodiments, the composition fur and PEG 8000, polycarbophil, carbomer, ASOS, klucel and ther comprises one or more modulating agents, and are for permulen. example, selected from the group of triethanolamine, sodium 0076. In one or more embodiments, a surface active agent citrate and citric acid. is present in the composition and is selected from the group I0083. In one or more embodiments, the composition consisting of includes an active agent and the active agent is selected from 0077 a polysorbate, including polysorbate 80 and Twin the group consisting of antiinfectives, antifungals, antivirals, 80, polyoxyethylene (20) sorbitan monostearate, polyoxyeth anesthetic analgesic, corticosteroids, non Steroid anti inflam ylene (20) Sorbitan monooleate, a polyoxyethylene fatty acid matory, retinoids, lubricating agents antiwarts, antiprolifera ester, Myri 45, Myr 49, Myri 52 and Myri 59; a polyoxyeth tive, vasoactive, keratolytic, insecticide and repellants, dicar ylene alkyl ether, including polyoxyethylene cetyl ether, boxylic acids and esters; calcium channel blockers, polyoxyethylene palmityl ether, polyethylene oxide hexade cholinergic, N-oxide doners, photodynamic, anti acne, anti cyl ether, polyethylene glycol cetyl ether, Brij 10, Brij. 21, wrinkle, antioxidants, self tanning active herbal extracts, aca Brij 38, Brij 52, Brij 56, Brij 72, Brij 721 and Brij W1, a ricides, age spot and keratose removing agents, allergen, US 2008/0299220 A1 Dec. 4, 2008

analgesics, local anesthetics, antiacne agents, antiallergic 0097. In one or more embodiments, the hydrophilic sol agents, antiaging agents, antibacterials, antibiotics, antiburn vent further comprises a polyol selected from the group con agents, anticancer agents, antidandruff agents, antidepres sisting of propylene glycol and hexylene glycol, and the ratio sants, antidermatitis agents, antiedemics, antihistamines, of butylene glycol to hexylene glycol is in the range of 1:0.5 antihelminths, antihyperkeratolyte agents, antiinflammatory to about 1:3. agents, antiirritants, antilipemics, antimicrobials, antimy 0098. In another aspect, a waterless composition suitable cotics, antiproliferative agents, antioxidants, anti-wrinkle for delivery of an active agent to a body Surface or cavity agents, antipruritics, antipsoriatic agents, antirosacea agents includes a vehicle, comprising: antiseborrheic agents, antiseptic, antiswelling agents, antivi 0099 about 70% to about 99% by weight of a hydro ral agents, antiyeast agents, astringents, topical cardiovascu philic polar solvent, said hydrophilic solvent selected lar agents, chemotherapeutic agents, corticosteroids, dicar from the group consisting of polyethylene glycols boxylic acids, disinfectants, fungicides, hair growth (PEGs) and propylene glycol (PG); regulators, hormones, hydroxy acids, immunosuppressants, 01.00 about 0.1% to about 10% of at least one surface immunoregulating agents, insecticides, insect repellents, active agent, a Surface active agent is present in the keratolytic agents, lactams, metals, metal oxides, mitocides, composition and is a mixture of a Brij Surfactant and a neuropeptides, non-steroidal anti-inflammatory agents, oxi Twin surfactant, wherein the Brij surfactant is the major dizing agents, pediculicides, photodynamic therapy agents, Surface active agent component; retinoids, Sanatives, scabicides, self tanning agents, skin 0101 about 0% to about 5% of a polymeric agent; whitening agents, asoconstrictors, vasodilators, vitamins, 0102) about 0% to about 30% of a secondary hydro vitamins A, B, C, D, E, K and derivatives, wound healing philic solvent; and agents and wart removers. 0.103 about 0% to about 5% of an unmodified silicone; 0084. In one or more embodiments, the active agent is and selected from the group consisting of Acyclovir, AZelaic 0.104) about 3% to about 25% hydrophobic propellant; acid, Benzoyl peroxide, Betamethasone 17 Valerate micron 0105 wherein the composition is otherwise substan ized, Caffeine, Calcipotriol hydrate, Ciclopiroxolamine, tially free of a hydrophobic solvent; and Diclofenac sodium, Ketoconazole, Miconazole nitrate, 0106 wherein the components of the composition are suf Minoxidil, Mupirocin, Nifedipine regular, Permethrin BPC ficiently miscible that the propellant and vehicle may be (cis:trans 25:75), Piroxicam, Salicylic acid, Terbinafine HCl, homogeneously distributed with mild shaking. estradiol hemihydrate and progesterone or combinations 0107. In another aspect, a waterless composition suitable thereof. for delivery of an active agent to a body Surface or cavity 0085. In one or more embodiments, the active agent includes: includes progesterone, estrogen, a derivative thereof or mix 0108) about 70% to about 99% by weightofa mixture of tures thereof, or the active agent includes a vitamin, Such as two or more different polyethylene glycols (PEGs), Vitamin D, retinol, retinoic acid, tocopherol, Vitamin K. Vita wherein at least one PEG is a high molecular weight min C or Vitamin B or a derivatives thereof, or a steroid, or a PEG having a melting point greater than 25°C., and mixture of a steroid and a vitamin. wherein the mixture of two or more different PEGs is I0086. In one or more embodiments, the composition com Selected to provide angel, ointment or cream; and prises a polymeric agent and the polymeric agent is selected 01.09 about 0% to about 10% of at least one surface from the group of bioadhesive polymers, and for example, the active agent; polymeric agent is selected from the group consisting of 0110 about 0% to about 5% of a polymeric agent; and hydroxypropylcellulose and carbomer. The composition has 0.111 about 0% to about 30% of a secondary hydro a bioadhesive force in the range of about -3 g to about -25 g. philic solvent; 0087. In another aspect, a waterless composition suitable 0112 wherein the composition includes at least one of a for delivery of an active agent to a body Surface or cavity Surface active agent and a polymeric agent. includes a vehicle, comprising: 0113. In one or more embodiments, the high molecular I0088 about 70% to about 99% by weight of a hydro weight PEG is present in an amount greater than about 10% philic polar solvent comprising butylene glycol (BG) by weight of the composition. 0089 about 0% to about 10% of at least one surface 0114. In one or more embodiments, the PEG is a combi active agent; nation of a high and low molecular weight PEG selected from (0090 about 0% to about 5% of a polymeric agent; the group consisting PEG6000/PEG200; PEG400/PEG1500, PEG4000/PEG200; PEG4000/PEG400, PEG 4000/PEG (0091 about 0% to about 30% of a secondary hydro 600, PEG4000/PEG400/PEG200; and the like. philic Solvent; and 0.115. In another aspect, a waterless composition suitable 0092 about 0% to about 5% of an unmodified silicone; for delivery of an active agent to a body Surface or cavity and includes a vehicle comprising: (0093 about 3% to about 25% hydrophobic propellant; 0116 about 70% to about 99% by weight of a hydro 0094 wherein the composition is otherwise substan philic polar solvent, said hydrophilic solvent comprising tially free of a hydrophobic solvent; a mixture of PEG 200 and PEG 400; 0095 wherein the composition includes at least one of a 0.117 about 0% to about 10% of at least one surface Surface active agent and a polymeric agent; and active agent; 0096 wherein the components of the composition are suf 0118 about 0% to about 5% of a polymeric agent; ficiently miscible that the vehicle and the propellant do not 0119) about 0% to about 30% of a secondary hydro phase separate upon centrifugation at about 1000 rpm for philic solvent; and about 10 mins, or at about 3000 rpm for about 10 mins. 0120 about 0% to about 5% of a silicone oil; and US 2008/0299220 A1 Dec. 4, 2008

I0121 about 3% to about 25% hydrophobic propellant; shaking together, the combination is only lightly opaque Sug 0.122 wherein the composition is otherwise substan gesting that some kind of quickly reversible micelles are tially free of a hydrophobic solvent; formed. While Surfactants and other Surface active agents can 0123 wherein the composition includes at least one of a help to stabilize the two phases, this is a challenge without the Surface active agent and a polymeric agent; and presence of an aqueous phase (for which many surfactants 0.124 wherein the vehicle and the propellant are suffi have been developed and for which the formation of water ciently miscible that the components may be homogeneously emulsions is well understood). distributed with mild shaking. 0.132. According to one or more embodiments, stable 0.125 Compositions including a polyethylene glycol sol foamable compositions including a PEG or PG or mixtures vent or derivative or mixtures thereof or includes a propylene provide a composition that is resistant to phase separation, or glycol derivative or combinations of polyethylene glycols that is easily mixed by mild agitation, e.g., by a few simple with or without propylene glycol containing an effective shakes of a pressurized container. “Mild agitation” or “lightly amount of one or more active, therapeutic, pharmaceutical or shaking refers to the force applied to a canister containing a cosmetic agents can be applied to the skin, a body cavity, a shakable foamable formulation with propellant, which is mucosal Surface, the nose, the mouth, the eye, the ear canal, raised to about the level of head height and mildly brought to the respiratory system, the vagina and the rectum. Such car about waist height and back again a few times by an average riers and compositions are adaptable to deliver active, thera adult without excessive or vigorous force. Formulations of peutic, pharmaceutical or cosmetic agents with water as a PEG and/or PG with surface active agents and/or a polymeric minor constituent or with little or no water. This can be agents that stabilize the foamable carrier when stored under convenient where agents are susceptible to oxidation and pressure with a hydrophobic propellant and which, when breakdown in solution. Vitamins may for example breakdown released from the pressurized container provide an excellent in the presence of water and may not be stable in composi quality foam, are disclosed. The Surface active agents and tions for sufficiently long periods of time to facilitate satis polymeric agents promote the formation of a waterless emul factorily cosmetic and pharmaceutical uses. sion between the hydrophilic glycol and the hydrophobic The compositions as described hereinabove can be used for propellant. treating disorders of the skin, mucosa, and body cavities as 0133. In one or more embodiments, the foamable carriers described in greater detail herein. are substantially free of additional hydrophobic solvents, as additional hydrophobic is likely to make the task of formu BRIEF DESCRIPTION OF THE DRAWING lating even harder as the formulation would need more stabi 0126 FIG. 1: The in vitro anti-infective effect of pharma lization ceutical foamable compositions as prepared as described in 0.134 One of the advantages of these hydrophilic water Example 22. less formulations, which are stored in sealed canisters, is that 0127 FIG. 2 is a plot of load vs time for the foamable they can provide a safe medium for active agents that tend to composition as prepared in Example 50, sample EST-010. break down upon exposure to one or more of water, light or 0128 FIG. 3 is a plot of load vs time for the foamable air. They can also be formulated to exhibit bioadhesive prop composition as prepared in Example 50, sample EST-011. erties and can be used for body cavity applications with minimal or no leakage. They are also of pleasant appearance DETAILED DESCRIPTION and skin feeling. 0.135 According to one or more embodiments, the foam 0129. Waterless foamable carriers are disclosed for use as able carrier, comprises: foamable vehicles and carriers for the delivery of an active A waterless composition suitable for delivery of an active agent. In various embodiments, hydrophilic solvents, such as agent to a body Surface or cavity comprising: polyethylene glycol or propylene glycol, are used as solvents in a waterless system. These hydrophilic solvents, while not 0.136 a vehicle comprising: as polara water, nonetheless provide a degree of polarity that 0137) a) about 70% to about 99% by weight of a hydro is useful in solubilizing polar or hydrophilic active agents. In philic polar solvent, said hydrophilic solvent selected addition, the use of a hydrophilic solvent provides advantages from the group consisting of over water-based formulations, in those frequent instances 0.138 i) a mixture of two or more different polyeth when an active agent is water-unstable. Active pharmaceuti ylene glycols (PEGs), wherein at least one PEG is a cal and cosmetic agents are more generally referred to as a high molecular weight PEG having a melting point therapeutic agent. greater than 25°C.; and 0130. The use of hydrophilic solvents nonetheless pre I0139 ii) propylene glycol (PG): sents some challenges. In a foamable system, it is common to 0140 b) about 0% to about 10% of at least one surface store the foamable carrier in a pressurized carrier and to active agent; charge the container with a hydrophobic propellant such as a 0.141 c) about 0% to about 5% of a polymeric agent; hydrocarbon or hydrofluorocarbon. The hydrophilic carrier 0.142 d) about 0% to about 30% of a secondary hydro on its own is usually not miscible in the propellant and the hydrophobic components, including the propellant, tend to philic solvent; and phase separate quite quickly from the hydrophilic compo 0.143 e) about 0% to about 5% of a silicone oil; and nent, including PEGs and PG. 0144) about 3% to about 25% hydrophobic propellant; 0131 PG and PEG are not as polar as water, so the pro 0145 wherein the composition is otherwise substan pellant solubility in PG or PEG should be greater than in tially free of a hydrophobic solvent; water. However, PEG and PG do not dissolve in propellant 0146 wherein the composition includes at least one of a alone and if shaken together will quickly separate. Upon Surface active agent and a polymeric agent; and US 2008/0299220 A1 Dec. 4, 2008

0147 wherein the vehicle and the propellant are suffi 0.164 e) about 0% to about 5% of an unmodified sili ciently miscible that the components may be homogeneously cone; and distributed with mild shaking. (0165) about 3% to about 25% hydrophobic propellant; 0148 All % values are provided on a weight (w/w) basis. 0166 wherein the composition is otherwise substan 0149. In one or more embodiments the surface active tially free of a hydrophobic solvent; agent ranges from about less than 0.01% up to about 5% up to 0.167 wherein the composition includes at least one of a about 10% up to about 15% or up to about 20% by weight of Surface active agent and a polymeric agent; and composition depending on the Surfactant selected or prefer 0168 wherein the components of the composition are suf ably is about 0.2% to about 10% by weight of composition ficiently miscible that the vehicle and the propellant do not more preferably 0.5% to about 5% by weight of composition. phase separate upon centrifugation at about 1000 rpm for 0150 Water, up to 25% of the composition, and more about 10 mins. preferably up to 10%, and optional ingredients can be added According to one or more embodiments, the foamable com to complete the total mass to 100%. In certain cases, the position, includes: composition contains two active agents that require different 0169. A waterless composition suitable for delivery of pH environments in order to remain stable. For example, an active agent to a body Surface or cavity comprising: corticosteroids are typically stable at acidic pH (they have a 0170 a vehicle, comprising: maximum stability at a pH of about 4-6) and vitamin D (0171 a) about 70% to about 99% by weight of a hydro analogues are typically stable at basic pH (they have a maxi philic polar solvent, said hydrophilic solvent selected mum stability at pH values above about 8). In other cases, the from the group consisting of polyethylene glycols active agent degrades in the presence of water, and therefore, (PEGs) and propylene glycol (PG); in Such cases the present of water in the composition is not (0172 b) about 0.1% to about 10% of at least one surface desirable. Thus, in certain preferred embodiments, the com active agent, a Surface active agent is present in the position is Substantially non-aqueous. The term "substan composition and is a mixture of a Brij Surfactant and a tially non-aqueous” or “substantially waterless” is intended Twin surfactant, wherein the Brij surfactant is the major to indicate that the composition has a water content below Surface active agent component; about 5%, preferably below about 2%, such as below about 0173 c) about 0% to about 5% of a polymeric agent; 1.5%. In certain other preferred embodiments the composi (0174 d) about 0% to about 30% of a secondary hydro tion is non aqueous or waterless. philic solvent; and 0151. According to one or more embodiments, the foam (0175 e) about 0% to about 5% of an unmodified sili able carrier, includes a waterless solvent, a stabilizing Surfac cone; and tant, a polymeric agent, a modulating agent and a propellant. (0176) about 3% to about 25% hydrophobic propellant; 0152. According to one or more embodiments, the foam 0.177 wherein the composition is otherwise substan able pharmaceutical or cosmetic foamable composition, tially free of a hydrophobic solvent; and includes a waterless solvent, a stabilizing Surfactant, a poly 0.178 wherein the components of the composition are suf meric agent, a modulating agent, a propellant and an active ficiently miscible that the propellant and vehicle may be pharmaceutical or cosmetic agents. homogeneously distributed with mild shaking. 0153. According to one or more embodiments, the foam 0179 Shakability means that the composition contains able carrier, includes: some or sufficient flow to allow the composition to be mixed 0154) a. a waterless solvent comprising about 25% to or remixed on shaking. That is, it has fluid or semi fluid about 98% of at least polar solvent selected from the properties. A breakable foam is that is thermally stable, yet group consisting of (1) a propylene glycol or derivative breaks under sheer force. and (2) a polyethylene glycol (PEG) or derivative or 0180. The breakable foam is not “quick breaking”, i.e., it mixtures thereof; does not readily collapse upon exposure to body temperature 0155 b. a surface-active agent; environment. Sheer-force breakability of the foam is clearly 0156 c. about 0.01% to about 5% by weight of at least advantageous over thermally induced breakability, since it one polymeric agent; and allows comfortable application and well directed administra 0157 d. a liquefied or compressed gas propellant at a tion to the target area. concentration of about 3% to about 25% by weight of the 0181. In one or more embodiments the ratio of polymeric total composition; agent to surfactant is about 1:10 to about 10:1; about 1:5 to wherein the composition is shakable; and about 5:1; about 3:7 to about 7:3; and about 2:1 to about 1:2. wherein the composition is stored in an aerosol container and 0182. The provision and selection of polymeric agent is upon release expands to form a breakable foam. however not straightforward. The polymers should be mis 0158. According to one or more embodiments, the foam cible or Swell in the waterless solvent. It has been found that able carrier, includes: in the case of modified cellulose that lower molecular weight A waterless composition suitable for delivery of an active cellulose polymer derivatives are preferable. agent to a body Surface or cavity comprising: 0183 In one embodiment the polymeric agent is hydrox 0159 a vehicle, comprising: ypropyl cellulose. (0160 a) about 70% to about 99% by weight of a hydro 0184. In another embodiment the polymeric agent is or philic polar solvent comprising butylene glycol (BG) Carbomer such as Carbopol 934(R). (0161 b) about 0% to about 10% of at least one surface 0185. According to one or more embodiments, the pre active agent; foamable carrier; the pre-foamable pharmaceutical or cos 0162 c) about 0% to about 5% of a polymeric agent; metic composition; the foamable carrier, or the foamable 0163 d) about 0% to about 30% of a secondary hydro pharmaceutical or cosmetic composition further includes philic Solvent; and 0.1% to about 75% of a secondary solvent. US 2008/0299220 A1 Dec. 4, 2008

0186. In one or more embodiments there is provided a 0.195. In one or more embodiments, the polyol is a mixture foamable vehicle that is suitable for use as a base for delivery of polyols. In one or more embodiments, the mixture of of not merely one type of active pharmaceutical ingredient polyols contains at least one diol and at least one triol. (API) but is adaptable for use with one or more API's from According to certain embodiments the ratio between the diol a wide range of different types of API's with appropriate and and triol is between 9:1 and 1:1. usually relatively minimal or minor adjustment to the vehicle. 0196. In one or more embodiments, part of mixture of For example, by altering the amount of a component or by the polyols is a saccharide. Exemplary saccharides include, but addition of a stabilizer or an antioxidant as would be appre are not limited to monosaccharide, disaccharides, oligosac ciated by a person skilled in the art. charides and Sugar alcohols. 0187. In a further embodiment the surfactant and poly 0.197 A monosaccharide is a simple sugar that cannot be meric agent and their amounts are selected so that the com hydrolyzed to smaller units. Empirical formula is (CH2O)n position is sufficiently so that foam extrusion and Substan and range in size from trioses (n-3) to heptoses (n=7). Exem tially uniform foam formation is not hampered. To this extent, plary monosaccharide compounds are ribose, glucose, fruc the maximum effective amount of Surfactant and polymeric tose and galactose. agent that may be used for a foam may be limited by the need 0198 Disaccharides are made up of two monosaccharides for shakability. For example as the level of waxy surfactants joined together, Such as Sucrose, maltose and lactose. and or polymeric agents the composition will become thicker 0199 A sugar alcohol (also known as a polyol, polyhydric until it reaches a point where it will no longer be shakable or alcohol, or polyalcohol) is a hydrogenated form of saccha flowable. And whilst for an ointment or gel the levels may be ride, whose carbonyl group (aldehyde or ketone, reducing further increased a solid non flowable composition is not Sugar) has been reduced to a primary or secondary hydroxyl suitable for foams. group. They are commonly used for replacing Sucrose in 0188 In a further embodiment the propellant is preferably foodstuffs, often in combination with high intensity artificial between about 5% to about 12% by weight of the composi Sweeteners to counter the low Sweetness. Some exemplary tion. Sugar alcohols, which are Suitable for use according to the 0189 In one or more embodiments of the pharmaceutical present invention are mannitol, Sorbitol. Xylitol, maltitol, lac or cosmetic foamable product is non-flammable. titol. (Maltitol and lactitol are not completely hydrogenated 0190. By waterless is meant that the composition contains compounds—they are a monosaccharide combined with a no or Substantially no, free or unassociated or absorbed water. polyhydric alcohol.) Mixtures of polyols, including (1) at It will be understood by a person of the art that the waterless least one polyol selected from a diol and a triol; and (2) a solvents and substances miscible with them can be hydro saccharide are contemplated within the scope. philic and can contain water in an associated or unfree or absorbed form and may absorb water from the atmosphere Polyethylene Glycol and the ability to do so is its hygroscopic water capacity. In 0200. In an embodiment, the solvent consists of a poly Some embodiments the composition ingredients are pre merized ethylene glycol, namely polyethylene glycol, which treated to reduce, remove or eliminate any residual or asso is also termed “PEG”. Exemplary PEGs are provided in the ciated or absorbed water. following table. 0191 Upon release from an aerosol container, the foam able carrier or composition forms an expanded foam Suitable for the treatment of an infected surface and for topical admin istration to the skin, a body Surface, a body cavity or a Composition AV. Molecular weight Appearance Melting point (C.) mucosal Surface. PEG 200 190-210 Oily liquid PEG 300 285-315 Oily liquid Polyol PEG 400 380-420 Oily liquid PEG 600 570-630 Oily liquid 17-22 0192 In one or more embodiments, the solvent or second PEG 1 OOO 950-1OSO Solid 35-40 ary solvent is a polyol. A polyol is an organic Substance that PEG 4OOO 38OO-44OO Solid 53-58 contains at least two hydroxy groups in its molecular struc PEG 6000 5600-64OO Solid SS-60 ture. PEG 8000 7SOO-85OO Solid 58-65 0193 In one or more embodiments, the foamable carrier contains at least one diol (a compound that contains two 0201 Thus, in an embodiment, the PEG is selected from hydroxy groups in its molecular structure). Examples of diols the group consisting of PEG 200, PEG 300, PEG 400, PEG include propylene glycol (e.g., 1,2-propylene glycol and 1.3- 600, PEG 1000, PEG 4000, PEG 6000 and PEG 8000. Poly propylene glycol), butanediol (e.g., 1.2-butanediol. 1,3-bu ethylene glycol of average molecular weight 1500 (PEG tanediol. 2,3-butanediol and 1,4-butanediol), butanediol, 1500) is a solid and melts at about 45 degrees C. In an pentanediol (e.g., pentane-1,2-diol, pentane-1,3-diol, pen embodiment the High molecular weight PEG is 1500. In one tane-1,4-diol, pentane-1,5-diol, pentane-2,3-diol and pen or more embodiments it can be used in combination with one tane-2,4-diol), hexanediol (e.g., hexane-1,6-diol hexane-2,3- or more of PEG 200; PEG 400 and PEG 600. The foamable diol and hexane-2.56-diol), octanediol (e.g., 1.8-octanediol), carrier according to the present invention can contain a single neopentylglycol, 2-methyl-1,3-propanediol, diethylene gly PEG or a mixture of two or more PEGs. PEGs having molecu col, triethylene glycol, tetraethylene glycol, dipropylene gly lar weight of more that about 1000 possess gelling properties: col and dibutylene glycol. i.e., they increase the Viscosity of a composition. Therefore, 0194 In one or more embodiments, the foamable carrier by combining PEGs with different molecular weights/melt contains at least one triol (a compound that contains three ing points, one can attain varying levels of flowability as hydroxy groups in its molecular structure), such as glycerin, desirable for the treatment of a given target site. The concen butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol. tration of the PEG should be in a level that results in viscosity, US 2008/0299220 A1 Dec. 4, 2008 prior to filling of the composition into aerosol canisters in the one hydroxyl group. Such as ethanol, propanol, isopropanol, range of 100 to 5200 cps typically measured at room tem butanol, iso-butanol, t-butanol and pentanol, are considered perature on a Brookfield Viscometer with a spindle speed of less desirable polar solvents due to their skin-irritating effect. 10 RPM. In some embodiments, the viscosity is less than 0211 Thus, in certain embodiments, the composition is 12,000 CPs, or less than 10,000 CPs. substantially alcohol-free and includes less than about 5% final concentration of lower alcohols, preferably less than Secondary Solvent about 2%, more preferably less than about 1%. However, in 0202 Optionally, a secondary solvent is added to the other embodiments, a short chain alcohol can be included in foamable composition. The secondary solvent is selected the composition, as long as the ratio between the short chain from a variety of organic solvents that are typically miscible alcohol and the polyol is less than 1:4 by weight. on both water and oil. Examples of solvent that can be con Modulating Agent tained in the foamable carrier include dimethyl isosorbide, tetrahydrofurfuryl alcohol polyethyleneglycol ether (glyco 0212. The term modulating agent is used to describe an furol), DMSO, pyrrolidones, (such as N-Methyl-2-pyrroli agent which can improve the stability of or stabilize a foam done and 1-Methyl-2-pyrrolidinone), ethyl proxitol, dim able carrier or composition and or an active agent by modu ethylacetamide (DMAc). PEG-type surfactants and alpha lating the effect of a substance or residue present in the carrier hydroxy acids, Such as lactic acid and glycolic acid. or composition. The Substance or residue may for example be 0203) Appropriate use of a secondary solvent in a water acidic or basic and potentially alteran artificial pH in a water less foam composition can help improve delivery of active less or Substantially non aqueous environment or it may be agents to a target area. Foam compositions, for which the one or more metal ions which may act as a potential catalyst Solvent includes a secondary solvent, can increase the levels in a waterless or Substantially non aqueous environment. of the active agent in the waterless composition and thus, 0213. In one or more embodiments, the modulating agent provide high delivery and improved therapy. is used to describe an agent which can affect pH in an aqueous Solution. The agent can be any of the known buffering sys Solubilization and Penetration Enhancement tems used in pharmaceutical or cosmetic formulations as would be appreciated by a man of the art. It can also be an 0204. In many cases, polyols, PEGs and polar solvents organic acid, a carboxylic acid, a fatty acid an amino acid, an possess a high solubilizing power and thus, they can enable aromatic acid, an alpha or beta hydroxyl acid an organic base increased concentrations of an active agent. Polyols, PEGs or a nitrogen containing compound. and polar solvents are also known for their skin penetration 0214. In one or more further embodiments, the modulat enhancement properties. These properties enable high drug ing agent is used to describe an agent, which is a chelating or bioavailability in the target area of treatment, resulting in an sequestering or complexing agent that is sufficiently soluble enhanced therapeutic effect. Occasionally, combinations of a or functional in the waterless solvent to enable it to “mop up' polyol, PEGs and a secondary polar solvent, exhibit an or “lock' metal ions. increased permeability across the skin, as Suggested, for 0215. In the embodiment modulating agent is used to example, in Eur J Pharm Biopharm. 1998 November; 46(3): describe an agent which can effect pH in an aqueous solution 265-71. the term modulating agent more particularly means an acid or 0205 Thus, in one or more embodiments, the foamable base or buffer system or combinations thereof, which is intro carrier contains (1) at least one polar solvent, selected from a duced into or is present in and acts to modulate the ionic or polyol (selected from a diol and a triol) and PEG, and (2) at polar characteristics and any acidity or basesity balance of a least one secondary polar solvent. waterless or Substantially non aqueous carrier, composition, 0206. In one or more embodiments, the foamable carrier foamable carrier or foamable composition or resultant foam. contains (1) a mixture of at least two polyols; and (2) at least 0216. The substance or residue can be introduced into the one secondary polar solvent. In additional embodiments, the formulation from any one or more of the ingredients, some of foamable carrier contains a mixture of at least one polyol and which themselves may have acidic or basic properties. For at least one PEG, yet in other embodiments the foamable example the polymer or solvent may contain basic residues in carrier contains (1) a mixture of at least one polyol and at least which case it may be desirable or beneficial to add an acid. one PEG and (2) at least one secondary polar solvent. Alternatively the Surfactant may contain some acid residues 0207. According to certain embodiments the ratio in which case the addition of a base may be desirable and between the polyol and/or PEG and the secondary polar sol beneficial. In some cases more than one ingredient may con vent is between 9:1 and 1:1. tain residues which may ameliorate or compound their sig 0208. In certain embodiments, the polyol is selected from nificance. For example if one ingredient provided weak acid the group consisting of propylene glycol, butylene glycol. residues and another stronger acid residues the artificial pH in hexylene glycol and glycerin (and mixtures thereof); and the a waterless environment should be lower. In contrast if one secondary polar solvent is selected from the group consisting residue was acid and the other basic the net effect in the of dimethyl isosorbide, diethylene glycol monoethyl ether, a formulation maybe significantly reduced. In an embodiment liquid polyethylene glycol and glycofurol. Sufficient modulating agent is added to achieve an artificial 0209. In certain embodiments, the foamable carrier con pH in which the active agent is preferably stable. tains (1) at least one polyol; and (2) dimethyl isosorbide. 0217. The terms pH, pKa, and pKb, buffers and the like are 0210 Short chain alcohols, such as ethanol and propanol used in classical measurements of an aqueous solution. Such are known as polar solvents, however, according to one or measurements are artificial in a waterless environment. Nev more embodiments, the composition is substantially alcohol ertheless, reference to and description below of such terms free, i.e., free of short chain alcohols. Short chain alcohols, are made for convenience and clarity, since Such terms are having up to 5 carbonatoms in their carbon chain skeleton and well defined and understood with reference to aqueous solu US 2008/0299220 A1 Dec. 4, 2008

tions and further due to the lack of an appropriate uniform are benzyl conium chloride, and cetyl pyridium chloride. Non way of describing and identifying the artificial or virtual pH, limiting examples of negative ionization agents are sodium pK etc in a waterless environment in relation to the present lauryl Sulphate, sodium lauryl lactylate and phospholipids. invention. Although predictions of artificial pH can be made 0227. In one or more embodiments the formulations using dilution techniques of measurements of waterless for described herein may further contain a modulating agent. mulations diluted in water they are formulation sensitive and specific and have to be carefully calibrated with complex MicroSponges formulas. 0228. The MicroSponges are rigid, porous and spongelike 0218 Waterless medium can be polar and protic yet it does round microscopic particles of cross-linked polymer beads not conform to classical ionic behavior. (e.g., polystyrene or copolymers thereof), each defining a 0219. A buffer, as defined by Van Slyke Van Slyke, J. substantially noncollapsible pore network. The Micro Biol. Chem. 52, 525 (1922), is “a substance which by its sponges can be loaded with an active ingredient and can presence in Solution increases the amount of acid oralkali that provide a controlled time release of the active ingredient to must be added to cause unit change in pH. skin or to a mucosal membrane upon application of the for 0220. A buffer solution is a solution of a definite pH made mulation. The slow release is intended to reduce irritation by up in Such a way that this pH alters only gradually with the the active. Microsponge R. delivery technology was devel addition of alkali or acid. Such a solution consists of a solu oped by Advanced Polymer Systems. In one or more embodi tion of a salt of the week acid in the presence of the three acid ments the composition comprises one or more active agents itself. The pH of the solution is determined by the dissociation loaded into Microponges with an aqueous carrier or with a equilibrium of the free acid. waterless carrier described herein which may comprise a 0221. An acid can be a strong acid or a weak acid. A strong modulating agent. acid is an acid, which is a virtually 100% ionized in solution. In contrast, a week acid is one which does not ionize fully. Polymeric Agent When it is dissolved in water. The lower the value for pKa, the stronger is the acid and likewise, the higher the value for pKa 0229. In one or more embodiments the composition con the weaker is the acid. tains a polymeric agent. It has been documented that the 0222 Abase can be a strong base or a weak base. A strong presence of a polymeric agent is necessary for the creation of base is something, which is fully ionic with 100% hydroxide foam, having fine bubble structure, which does not readily ions. In contrast, a weak base is one which does not convert collapse upon release from the pressurized aerosol can. The fully into hydroxide ions in solution. The lower the value for polymeric agent serves to stabilize the foam composition and pKb, the stronger is the base and likewise, the higher the value to control drug residence in the target organ. Preferably, the for pKb the weaker is the base. polymeric agent is soluble or readily dispersible in the polyol; 0223) In one or more preferred embodiments the chelating or in the mixture of a polyol and an additional polar solvent. agent is selected from the group consisting of ethylenedi 0230 Non-limiting examples of polymeric agents that are aminetetraacetic acid ("EDTA) and salts thereof such as soluble or readily dispersible in propylene glycol are Hydrox disodium EDTA, tetrasodium EDTA and calcium disodium ypropylcellulose and carbomer (homopolymer of acrylic acid EDTA; diethylenetriaminepentaacetic acid (“DTPA) and is crosslinked with anallyl etherpentaerythritol, anallyl ether salts thereof, hydroxyethylethylenediaminetriacetic acid of sucrose, or an allyl ether of propylene, such as CarbopolR) (“HEDTA) and salts thereof and nitrilotriacetic acid 934, Carbopol R 940, CarbopoR 941, Carbopol.R. 980 and (“NTA'); more preferably EDTA, HEDTA and their salts: Carbopol R 981. most preferably EDTA and its salts. 0231. Other polymeric agents are suitable for use accord 0224. In one or more embodiments a preferred non limit ing to the present invention provided that they are soluble or ing example of the chelating agent is EDTA. Typically, the readily dispersible in the polyol; or in the mixture of a polyol chelating and sequestering agent is present in the composition and an additional polar solvent, on a case by case basis. at a level of up to about 5.0%, preferably 1.0 percent, by 0232 Exemplary polymeric agents include, in a non-lim weight, of the composition. iting manner, naturally-occurring polymeric materials, such 0225. In another aspect the active agents are ideally so far as locust bean gum, Sodium alginate, sodium caseinate, egg as is possible delivered onto the skin or within a body cavity albumin, gelatin agar, carrageenin gum, Sodium alginate, at a pH of from about 3.5 to about 7.5, more preferably at a pH Xanthan gum, quince seed extract, tragacanth gum, guar gum, of about 4.5 to about 6.5. Thus in another aspect the modu cationic guars, hydroxypropyl guar gum, starch, amine-bear lating agents may help to create an artificial pH more Suited to ing polymers such as chitosan; acidic polymers obtainable the skin or mucosal membrane requirements. from natural sources, such as alginic acid and hyaluronic 0226. In one or more embodiments, the modulating agent acid; chemically modified starches and the like, carboxyvinyl may also be a preservative or an antioxidant or an ionization polymers, polyvinylpyrrolidone, polyvinyl alcohol, poly agent. Any preservative, antioxidant or ionization agents Suit acrylic acid polymers, polymethacrylic acid polymers, poly able for pharmaceutical or cosmetic application may be used. vinyl acetate polymers, polyvinyl chloride polymers, polyvi Non limiting examples of antioxidants are tocopherol Succi nylidene chloride polymers and the like. nate, propyl galate, butylated hydroxy toluene and butyl 0233. Additional exemplary polymeric agents include hydroxyanisol. In one or more embodiments the modulating semi-synthetic polymeric materials such as cellulose ethers, agent is a flavonoid. Ionization agents may be positive or may Such as methylcellulose, hydroxypropyl cellulose, hydrox be negative depending on the environment and the active ypropyl methylcellulose, hydroxyethyl cellulose, hydroxy agent or composition that is to be protected. Ionization agents propylmethyl cellulose, methylhydroxyethylcellulose, meth may for example act to protect or reduce sensitivity of active ylhydroxypropylcellulose, hydroxyethylcarboxymethylcel agents. Non limiting examples of positive ionization agents lulose, carboxymethyl cellulose, carboxymethylcellulose US 2008/0299220 A1 Dec. 4, 2008 carboxymethylhydroxyethylcellulose, and cationic cellulo surface active agent and the weighted average of their HLB ses. Polyethylene glycol, having molecular weight of 1000 or values is between about 9 and about 19. more (e.g., PEG 1,000, PEG1500 PEG4,000, PEG 6,000 and 0240 Preferably, the composition contains a non-ionic PEG 10,000) also have gelling capacity and while they are considered herein as “secondary polar solvents', as detailed Surfactant. Nonlimiting examples of possible non-ionic Sur herein, they are also considered polymeric agents. factants include a polysorbate, polyoxyethylene (20) sorbitan 0234 Mixtures of the above polymeric agents are contem monostearate, polyoxyethylene (20) Sorbitan monooleate, a plated. polyoxyethylene fatty acid ester, Myri 45, Myr 49, Myr 52 0235. The concentration of the polymeric agent should be and Myr 59; a polyoxyethylene alkyl ether, polyoxyethylene selected so that the composition, after filling into aerosol cetyl ether, polyoxyethylene palmityl ether, polyethylene canisters, is flowable, and can be shaken in the canister. In one oxide hexadecyl ether, polyethylene glycol cetyl ether, brij or more embodiments, the concentration of the polymeric 38, brij 52, brij 56 and brij W1, a sucrose ester, a partial ester agent is selected Such that the viscosity of the composition, of Sorbitol and its anhydrides, Sorbitan monolaurate, Sorbitan prior to filling of the composition into aerosol canisters, is less monolaurate a monoglyceride, a diglyceride, isoceteth-20 than 52,000 CPS, less than 12,000 CPs, and more preferably, less than 10,000 CPs. and mono-, di- and tri-esters of Sucrose with fatty acids. 0241. Non-limiting examples of non-ionic surfactants that Surface-Active Agent have HLB of about 7 to about 12 include steareth 2 (HLB-4. 0236. The composition can further contain a surface-ac 9); glyceryl monostearate/PEG 100 stearate (AV HLB-11.2): tive agent. Surface-active agents (also termed 'Surfactants”) stearate Laureth 4 (HLB-9.7) and cetomacrogol ether (e.g., include any agent linking oil and water in the composition, in polyethylene glycol 1000 monocetyl ether). Exemplary sta the form of emulsion. A surfactant's hydrophilic/lipophilic bilizing surfactants which may be suitable for use in the balance (HLB) describes the emulsifier's affinity toward present invention are found below. water or oil. HLB is defined for non-ionic surfactants. The HLB scale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic), with 10 representing an equal balance of both characteristics. Lipophilic emulsifiers form water-in-oil PEG-Fatty Acid Monoester Surfactants (w/o) emulsions; hydrophilic Surfactants form oil-in-water (ofw) emulsions. The HLB of a blend of two emulsifiers Chemical name Product example name HLB equals the weightfraction of emulsifier A times its HLB value PEG-30 Stearate Myri 51 >10 plus the weight fraction of emulsifier B times its HLB value PEG-40 laurate Crodet LAO (Croda) 17.9 (weighted average). In many cases a single Surfactant may PEG-40 oleate Crodet O40 (Croda) 17.4 Suffice. In other cases a combination of two or more Surfac PEG-45 Stearate Nikkol MYS-45 (Nikko) 18 tants is desired. As will be appreciated by a person skilled in PEG-50 Stearate Myri 53 >10 the art which Surfactant or Surfactant system is more appro PEG-1OO Stearate Myri 59, Arlacel 165 (ICI) 19 priate is related to the vehicle and intended purpose. In gen eral terms a combination of Surfactants is usually preferable where the vehicle is an emulsion. In a waterless or Substan tially waterless environment it has been discovered that the presence of a Surfactant or combination of Surfactants can be PEG-Fatty Acid Diester Surfactants significant in producing breakable forms of good quality. It has been further discovered that the generally thought con Chemical name Product example name HLB siderations for oil in water emulsions of using a Surfactant or PEG-4 dilaurate Mapeg.RTM. 200 DL (PPG), 7 sufactant combination with preferably a HLB value or aver Kessco RTMPEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo age in or towards the lipophilic side of the scale are not Chem.) binding for waterless or Substantially waterless systems as PEG-4 distearate Kessco RTM. 200 DS 5 described herein and that good quality foams can be produced (Stepan.Sub) with a surfactant or surfactant combination both where the PEG-32 dioleate Kessco RTMPEG 1540 DO 15 (Stepan) HLB values are in or towards the lipophilic side of the scale PEG-400 dioleate) Cithrol 4DO series (Croda >10 and more surprisingly where the HLB values are in or towards PEG-400 disterate Cithrol 4DS series (Croda) >10 the hydrophilic side of the scale. PEG-20 glyceryl oleate Tagat. RTM. O (Goldschmidt) >10 0237 According to one or more embodiments the compo sition contains a single Surface active agent having an HLB value between about 2 and 9, or more than one surface active agent and the weighted average of their HLB values is between about 2 and about 9. Transesterification Products of Oils and Alcohols 0238 According to one or more embodiments the compo sition contains a single Surface active agent having an HLB Chemical name Product example name HLB value between about 7 and 14, or more than one surface active PEG-30 castor oil Emalex C-30 (Nihon Emulsion) 11 agent and the weighted average of their HLB values is PEG-40 hydrogenated castor Cremophor RH 40 (BASF), 13 between about 7 and about 14. oil) Croduret (Croda), Emulgin HRE 0239 According to one or more other embodiments the 40 (Henkel) composition contains a single Surface active agent having an HLB value between about 9 and about 19, or more than one US 2008/0299220 A1 Dec. 4, 2008 12

two or more Surface active agents can be more effective than a single surfactant and provides a more stable emulsion or improved foam quality than a single Surfactant. For example Polyglycerized Fatty Acids and by way of non-limiting explanation it has been found that Chemical name Product example name LB by choosing say two surfactants, one hydrophobic and the other hydrophilic the combination can produce a more stable Polyglyceryl-6 dioleate Caprol.RTM. 6G20 (ABITEC): 8.5 emulsion than a single surfactant. Preferably, the complex PGO-62 (Calgene), PLUROL OLEIQUE CC 497 emulgator comprises a combination of Surfactants wherein (Gattefosse)Hodag there is a difference of about 4 or more units between the HLB values of the two surfactants or there is a significant differ ence in the chemical nature or structure of the two or more Surfactants. 0243 Specific non limiting examples of surfactant sys PEG-Sorbitan Fatty Acid Esters tems are, combinations of polyoxyethylene alkyl ethers. Such as Brij 59/Brij 10: Brij 52/Brij 10; Steareth 2/Steareth 20; Chemical name Product example name HLB Steareth 2/Steareth 21 (Brij 72/Brij 721); combinations of PEG-20 Sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 polyoxyethylene stearates such as Myri 52/Myri 59; combi monopalmitate (Croda) nations of sucrose esters, such as Surphope 1816/Surphope PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), Crillet 3 15 1807; combinations of sorbitan esters, such as Span 20/Span (Croda) PEG-20 Sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 80; Span 20/Span 60; combinations of sucrose esters and (Croda) sorbitan esters, such as Surphope 1811 and Span 60; combi PEG-20 Sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 nations of liquid polysorbate detergents and PEG com (Croda) pounds, such as Tween 80/PEG-40 stearate; methyl glucaso sequestrate; polymeric emulsifiers, such as Permulen (TR1 or TR2); liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1), Nikomulese (41) and Montanov (68) and the like. Polyethylene Glycol Alkyl Ethers 0244. In certain embodiments the surfactant is preferably a combination of Steareth-2 and Steareth-21; in certain other Chemical name Product example name HLB embodiments the Surfactant is a combination of polysorbate PEG-2 oleyl ether oleth-2 Brij92/93 (Atlas/ICI) 4.9 80 and PEG-40 stearate. In certain other embodiments the PEG-3 oleyl ether oleth-3 Volpo 3 (Croda) &10 surfactant is a combination of glyceryl monostearate/PEG PEG-5 oleyl ether oleth-5 Volpo 5 (Croda) &10 100 Stearate PEG-10 oleyl ether oleth-10 Volpo 10 (Croda), Brij 12 96/97 (Atlas/ICI) 0245. In certain cases, the surface active agent is selected PEG-20 oleyl ether oleth-20 Volpo 20 (Croda), Brij 15 from the group of cationic, Zwitterionic, amphoteric and 98/99 (Atlas/ICI) ampholytic Surfactants, such as sodium methyl cocoyl tau PEG-4 lauryl ether laureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23 lauryl ether laureth-23Brij 35 (Atlas/ICI) 17 rate, Sodium methyl oleoyl taurate, sodium lauryl Sulfate, PEG-10 stearyl ether Brij 76 (ICI) 12 triethanolamine lauryl sulfate and betaines. PEG-2 cetyl ether Brij 52 (ICI) 5.3 0246. Many amphiphilic molecules can show lyotropic liquid-crystalline phase sequences depending on the Volume balances between the hydrophilic part and hydrophobic part. These structures are formed through the micro-phase segre gation of two incompatible components on a nanometer scale. Sugar Ester Surfactants Soap is an everyday example of a lyotropic liquid crystal. Certain types of Surfactants tend to form lyotropic liquid Chemical name Product example name HLB crystals in emulsions interface (oil-in-water) and exert a sta Sucrose distearate Sisterna SP50, Surfope 1811 11 bilizing effect. Non limiting examples of surfactants with postulated tendency to form interfacial liquid crystals are: phospholipids, alkyl glucosides. Sucrose esters, Sorbitan esters. In certain embodiments surfactants which tend to form liquid crystals may improve the quality of foams produced Sorbitan Fatty Acid Ester Surfactants from compositions. 0247. In one or more embodiments the surfactant is a Chemical name Product example name HLB Surfactant or Surfactant combination is capable of or which Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 8.6 tends to form liquid crystals. (Croda), Arlacel 20 (ICI) 0248. In one or more embodiments the at least one surface Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 6.7 (Croda), Nikkol SP-10 (Nikko) active agent is solid, semi Solid or waxy. Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 4.3 0249. In one or more embodiments, the surface-active (Croda), Crill 50 (Croda) agent includes at least one non-ionic Surfactant. Ionic Surfac Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 4.7 tants are known to be irritants. Therefore, non-ionic Surfac (Croda), Nikkol SS-10 (Nikko) tants are preferred in applications including sensitive tissue Such as found in most mucosal tissues, especially when they 0242. In one or more embodiments the surface active are infected or inflamed. We have surprisingly found that agent is a complex emulgator in which the combination of non-ionic Surfactants alone provide formulations and foams US 2008/0299220 A1 Dec. 4, 2008 of good or excellent quality in the waterless and Substantially phase change agent which is selected Such that it has some waterless carriers and compositions. surfactant properties if it is used in the absence of surface 0250 Thus, in a preferred embodiment, the surface active active agent; and agent, the composition contains a non-ionic Surfactant. In 0260 a therapeutically effective amount of an active another preferred embodiment the composition includes a agent. mixture of non-ionic Surfactants as the sole Surface active 0261. In one or more further embodiments there is pro agent. Yet, in additional embodiments, the foamable compo vided a composition, comprising: sition includes a mixture of at least one non-ionic Surfactant 0262 a mixture of polyethylene glycol (PEG) or PEG and at least one ionic Surfactant in a ratio in the range of about derivatives, wherein the PEG mixtures is present at a concen 100:1 to 6:1. In further embodiments, surface active agent tration of about 70% to about 96.5% by weight of the total comprises a combination of a non-ionic Surfactant and an composition; ionic surfactant, at a ratio of between 1:1 and 20:1. 0263 0% to about 28% of a secondary solvent 0251. In selecting a suitable surfactant or combination 0264 a surface-active agent at a concentration of about thereof it should be borne in mind that the upper amount of 0.1% to less than about 10% by weight of the total composi surfactant that may be used may be limited by the shakability tion; and or of the composition. In general terms, as the amount of non 0265 at least one polymeric agent at a concentration of liquid surfactant is increased the shakability of the formula about 0.1% to about 5% by weight of the total composition, tion reduces until a limitation point is reached where the wherein the at least one polymeric agent is selected from a formulation becomes non shakable and unsuitable. Thus in an bioadhesive agent, agelling agent, a film forming agent and a embodiment any effective amount of Surfactant may be used phase change agent which is selected Such that it has some provided the formulation remains shakable. In the present surfactant properties if it is used in the absence of surface invention where it is desirable to use a high molecular weight active agent; and Solvent and more particularly significant amounts it may be 0266 atherapeutically effective amount of an active agent helpful to include a liquid Surfactant in addition to or in place wherein at least one PEG comprises about more than 5% of of a more waxy surfactant and or to increase the level of the high molecular weight solid PEG. Surfactant. 0267 As will be appreciated by someone skilled in the art 0252. In certain embodiments the amount of surfactant or as the levels of PEG are increased the composition will combination of surfactants is between about 0.05% to about become more Suitable foragel or ointment pharmaceutical or 20%; between about 0.05% to about 15%. or between about cosmetic composition. 0.05% to about 10%. In a preferred embodiment the concen Silicon Oil tration of surface active agent is between about 0.2% and 0268 Optionally, the foamable carrier may contain silicon about 5%. In a more preferred embodiment the concentration oil. In one or more embodiments, the silicone oils, is dime of surface active agent is between about 1% and about 4% thicone, cyclomethicone, polyalkyl siloxanes, polyaryl silox 0253) If the composition is formulated as a substantially anes, polyalkylaryl siloxanes and polyether siloxane copoly non flowing composition for use as a gel, ointment or cream, mers, polydimethylsiloxanes (dimethicones) and poly then the above limitation of shakability does not apply. Suit (dimethylsiloxane)-(diphenyl-siloxane) copolymers. able formulations include polyethylene glycol or derivatives or mixtures thereof or propylene glycol comprising higher Heumectant levels of waxy or semi Solid or solid Surfactants and/or com 0269. Aheumectant, is a substance that helps retain mois prising higher molecular weight polymers or polymer com ture and also prevents rapid evaporation. Non limiting binations which are usually waxy or Solid at room tempera examples of Suitable heumectants are propylene glycol, pro ture such as PEG 4000 or Peg 4000/400 combination with pylene glycol derivatives, and glycerin. Further examples are significant amounts of say PEG 4000 of 5% of 10% of 15% of provided elsewhere in the description. Other examples of 20% of 25% of 30% of as a basis for gels, ointments or humectants and moisturizers may be found in the Handbook creams. Other similar combinations may be envisaged of say of Pharmaceutical Additives published by Gower. Suitable PEG6000/PEG200; PEG4000/PEG200; PEG4000/PEG400/ ones for use with and soluble in the waterless and substan PEG200; and the like. tially waterless compositions may be selected as will be 0254. In one or more embodiments there is provided a appreciated by a person skilled in the art. composition, comprising: 0270. In an embodiment, the additional component is a 0255 about more than 3% of high molecular weight solid humectant. Suitable humectants include but are not limited to PEG: guanidine, urea, glycolic acid, glycolate salts, ammonium 0256 a waterless solvent comprising about 25% to about glycolate, quaternary alkyl ammonium glycolate, lactic acid, 95% of at least a polar solvent selected from the group con lactate salts, ammonium lactate, quaternary alkyl ammonium sisting of (1) a propylene glycol or derivative and (2) a poly lactate, aloe Vera, aloe Vera gel, allantoin, urazole, alkoxy ethylene glycol (PEG) or derivative or mixtures thereof; lated glucose, hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine and derivatives, esters, salts 0257 0% to about 48% of a secondary waterless solvent; and mixtures thereof. 0258 a surface-active agent at a concentration of about 0271 Pharmaceutical compositions may in one or more 0.1% to less than about 10% by weight of the total composi embodiments usefully comprise in addition a heumectant or a tion; and or moisturizer or combinations thereof. 0259 at least one polymeric agent at a concentration of about 0.1% to about 5% by weight of the total composition, Foam Adjuvant wherein the at least one polymeric agent is selected from a 0272 Optionally, a foam adjuvant is included in the foam bioadhesive agent, agelling agent, a film forming agent and a able carriers to increase the foaming capacity of Surfactants US 2008/0299220 A1 Dec. 4, 2008

and/or to stabilize the foam. In one or more embodiments, the ited to C12 to C15 alkyl benzoates, alkyl p-hydroxyben foam adjuvant agent includes fatty alcohols having 15 or Zoates, aloe Vera extract, ascorbic acid, benzalkonium chlo more carbons in their carbon chain, such as cetyl alcohol and ride, benzoic acid, benzoic acid esters of C9 to C15 alcohols, stearyl alcohol (or mixtures thereof). Other examples offatty butylated hydroxytoluene, castor oil, cetyl alcohols, chloro alcohols are arachidyl alcohol (C20), behenyl alcohol (C22), cresol, citric acid, cocoa butter, coconut oil, diazolidinyl urea, 1-triacontanol (C30), as well as alcohols with longer carbon diisopropyl adipate, dimethyl polysiloxane, DMDM hydan chains (up to C50). Fatty alcohols, derived from beeswax and toin, ethanol, fatty acids, fatty alcohols, hexadecyl alcohol, including a mixture of alcohols, a majority of which has at hydroxybenzoate esters, iodopropynyl butylcarbamate, least 20 carbon atoms in their carbon chain, are especially isononyl iso-nonanoate, jojoba oil, lanolin oil, methylpara well Suited as foam adjuvant agents. The amount of the fatty alcohol required to Support the foam system is inversely ben, mineral oil, oleic acid, olive oil, polyethers, polyoxypro related to the length of its carbon chains. Foam adjuvants, as pylene butyl ether, polyoxypropylene cetyl ether, potassium defined herein are also useful in facilitating improved spread Sorbate, silicone oils, Sodium propionate, sodium benzoate, ability and absorption of the composition. Sodium bisulfite, Sorbic acid, Stearic fatty acid, vitamin E, 0273. In one or more embodiments, the foam adjuvant Vitamin E acetate and derivatives, esters, salts and mixtures agent includes fatty acids having 16 or more carbons in their thereof. carbon chain, Such as hexadecanoic acid (C16) Stearic acid 0279. In an embodiment, the additional component is a (C18), arachidic acid (C20), behenic acid (C22), octa skin penetration enhancer. Suitable skin penetration enhanc cosanoic acid (C28), as well as fatty acids with longer carbon ers include but are not limited to acetone, acyl lactylates, acyl chains (up to C50), or mixtures thereof. As for fatty alcohols, peptides, acylsarcosinates, alkanolamine salts of fatty acids, the amount offatty acids required to support the foam system alkylbenzene Sulphonates, alkyl ether Sulphates, alkyl Sul is inversely related to the length of its carbon chain. phates, anionic Surface-active agents, benzyl benzoate, ben 0274 Optionally, the carbon atom chain of the fatty alco Zyl salicylate, butan-1,4-diol, butylbenzoate, butyl laurate, hol or the fatty acid may have at least one double bond. A butyl myristate, butyl Stearate, cationic Surface-active agents, further class of foam adjuvantagent includes a branched fatty citric acid, cocoamidopropylbetaine, decyl methyl Sulfoxide, alcohol or fatty acid. The carbon chain of the fatty acidor fatty decyloleate, dibutyl azelate, dibutyl phthalate, dibenzyl seba alcohol also can be substituted with a hydroxyl group, such as cate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, 12-hydroxy Stearic acid. dicapryladipate, didecyl phthalate, diethylene glycol, diethyl Additional Components sebacate, diethyl-m-toluamide, di(2-hydroxypropyl)ether, diisopropyl adipate, diisopropyl sebacate, N,N-dimethyl 0275. In an embodiment, a composition includes one or acetamide, dimethyl azelate, N,N-dimethyl formamide, 1.5- more additional components. Such additional components dimethyl-2-pyrrolidone, dimethyl sebacate, dimethyl sul include but are not limited to anti perspirants, anti-static phoxide, dioctyladipate, dioctyl azelate, dioctyl sebacate, 1.4 agents, buffering agents, bulking agents, chelating agents, dioxane, 1-dodecylazacyloheptan-2-one, dodecyl dimethyl cleansers, colorants, conditioners, deodorants, diluents, dyes, amine oxides, ethyl caprate, ethyl caproate, ethyl caprylate, emollients, fragrances, hair conditioners, humectants, pearl 2-ethyl-hexyl pelargonate, ethyl-2-hydroxypropanoate, ethyl escent aids, perfuming agents, permeation enhancers, pH laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicy adjusting agents, preservatives, protectants, skin penetration late, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypro enhancers, softeners, Solubilizers, Sunscreens, Sun blocking panoic acid, 2-hydroxypropionic acid, isethionates, isopropyl agents, Sunless tanning agents, and Viscosity modifiers. As is isostearate, isopropyl palmitate, guar hydroxypropyltrimo known to one skilled in the art, in some instances a specific nium chloride, hexan-2,5-diol, khellin, lamepons, lauryl additional component may have more than one activity, func alcohol, maypons, metal salts of fatty acids, methyl nicoti tion or effect. nate, 2-methyl propan-2-ol. 1-methyl-2-pyrrolidone, 5-me 0276. In an embodiment, the additional component is a pH thyl-2-pyrrolidone, methyl taurides, miranol, nonionic Sur adjusting agent or a buffering agent. Suitable buffering agents face-active agents, octyl alcohol, octylphenoxy include but are not limited to acetic acid, adipic acid, calcium polyethoxyethanol, oleic ethanolamide, pleyl alcohol, pen hydroxide, citric acid, glycine, hydrochloric acid, lactic acid, tan-2,4-diol, phenoxyethanol, phosphatidyl choline, phos magnesium aluminometasilicates, phosphoric acid, sodium phine oxides, polyalkoxylated ether glycolates, poly(dial carbonate, Sodium citrate, sodium hydroxide, Sorbic acid, lylpiperidinium chloride), poly(dipropyldiallylammonium Succinic acid, tartaric acid, and derivatives, salts and mixtures chloride), polyglycerol esters, polyoxyethylene lauryl ether, thereof. polyoxy:polyoxyethylene Stearate, polyoxypropylene 15 0277. In an embodiment, the additional component is an Stearyl ether, poly(vinyl pyridinium chloride), propan-1-ol. emollient. Suitable emollients include but are not limited to propan-2-ol, propylene glycol dipelargonate, pyroglutamic mineral oil, lanolin oil, coconut oil, cocoa butter, olive oil, acids, 2-pyrrolidone, pyruvic acids, Quaternium 5. Quater aloe Vera extract, jojoba oil, castor oil, fatty acids, fatty alco nium 18, Quaternium 19, Quaternium 23, Quaternium 31, hols, diisopropyl adipate, hydroxybenzoate esters, benzoic Quaternium 40, Quaternium 57, quartenary amine salts, acid esters of C9 to C15 alcohols, isononyl iso-nonanoate, quaternised poly (dimethylaminoethylmethacryl-ate), silicone oils, polyethers, C12 to C15 alkylbenzoates, oleic quaternised poly (vinyl alcohol), Sapamin hydrochloride, acid, Stearic fatty acid, cetyl alcohols, hexadecyl alcohol, Sodium cocaminopropionate, Sodium dioctyl Sulphonsucci dimethyl polysiloxane, polyoxypropylene cetyl ether, poly nate, sodium laurate, sodium lauryl ether Sulphate, sodium oxypropylene butyl ether, and derivatives, esters, salts and lauryl Sulphate, Sugar esters, Sulphosuccinate, tetrahydrofu mixtures thereof. ran, tetrahydrofurfural alcohol, transcutol, triethanolamine 0278. In an embodiment, the additional component is a dodecyl benzene Sulphonate, triethanolamine oleate, urea, preservative. Suitable preservatives include but are not lim water and derivatives, esters, salts and mixtures thereof. US 2008/0299220 A1 Dec. 4, 2008

0280 Lubricants may be introduced into any of the for 0290. The propellant makes up about 5-25 wt % of the mulations to reduce friction during application. This may be foamable composition. Aerosol propellants are used to gen useful for producing a good skin feeling or ease of body erate and administer the foamable composition as a foam. The cavity use. Any pharmaceutically or cosmetically acceptable total composition including propellant, foamable composi lubricant may be used. Non limiting examples of general tions and optional ingredients is referred to as the foamable categories of lubricants are; polymeric Substances such as composition. celluloses, natroSol: hyaluronic acid; glycerin; silicones (e.g. dimethicone); and oil based lubricants such as plant based Hygroscopic Property of the Composition oils (e.g. olive oil, Sweet almond oil; avocado oil and the like); 0291. A hydroscopic substance is a substance that absorbs petrolatum; and fats. In some situations it may be appropriate water readily from its surroundings. Microorganisms require to select a polymeric agent having a viscosity and also a water to grow and reproduce, and Such water requirements are lubricating effect such that it has some adherence to the site of best defined in terms of water activity of the substrate. The application but displays a reduced fricion and is easier and wateractivity of a solution is expressed as Aw-P/Po, where P more pleasant to use. is the water vapor pressure of the solution and Po is the vapor 0281. In one or more embodiments there are provided pressure of pure water at the same temperature. Addition of a compositions comprising polymeric agents which have both hygroscopic Substance to an aqueous solution in which a a viscosity and anti friction effect. microorganism is growing will have the effect of lowering the Propellants Aw, with a consequent effect upon cell growth. Every micro organism has a limiting AW, below which it will not grow, e.g., 0282. Examples of suitable propellants include volatile for Streptococci, klebsiella spp., escherichia coli, clostridium hydrocarbons such as butane, propane, isobutane and fluoro perfingens, and pseudomonas spp., the AW value is 0.95. carbon gases, or mixtures thereof. Staphylococcus aureus is most resistant and can proliferate 0283. In an embodiment the propellant is 1681, which is a with an Aw as low as 0.86. mixture of propane, isobutene and butane. In another embodi 0292. The water activity of a product can be determined ment it is AP70, which is a mixture of propane, isobutene and from the relative humidity of the air surrounding the sample butane with a higher pressure. when the air and the sample are at equilibrium. Measurement 0284. The propellant makes up about 5-25 wt % of the is performed by placing a sample in an enclosed space where foamable composition. In some circumstances the propellant this equilibrium can take place. Once this occurs, the water may be up to 35%. The propellants are used to generate and activity of the sample and the relative humidity of the air are administer the foamable composition as a foam. The total equal. The measurement taken at equilibrium is called an composition including propellant, foamable compositions equilibrium relative humidity or ERH. The relationship and optional ingredients is referred to as the foamable com between the wateractivity and ERH is in accordance with the position. following formula: 0285 Alcohol and organic solvents render foams inflam mable. It has been surprisingly discovered that fluorohydro Aw=ERH/100 carbon propellants, other than chloro-fluoro carbons 0293 Various types of wateractivity instruments are com (CMCs), which are non-oZone-depleting propellants, are par mercially available. One exemplary instrument uses chilled ticularly useful in the production of a non-flammable foam mirror dewpoint technology while other instruments measure able composition. Such propellants include, but are not lim relative humidity with sensors that change electrical resis ited to, hydrofluorocarbon (HFC) propellants. tance or capacitance. 0286. In one or more embodiments, the non inflammable 0294 Polyols, PEG's propylene glycols and other polar propellants are used in combination with the more traditional Solvents have a great affinity for water, and as such, they hydrocarbon propellants. exhibit hygroscopic properties. The concentration of the 0287. In one or more embodiments foamable composi polyol, the PEG and/or other polar solvents determines the tions comprise a combination of a HFC such as dimethyl ether Aw of the carrier. In one or more embodiments, the polyols, and a hydrocarbon propellant Such as n-butane or mixtures of the PEG and/or the secondary polar solvent is contained in the hydrocarbon propellants such as propane, isobutane and composition at a sufficient concentration to provide an Aw butane. value of the hygroscopic carrier of less than 0.9. In other 0288. In certain embodiments, fluorohydrocarbon propel embodiments, the concentration of the polyol, the PEG and/ lants, other than chloro-fluoro carbons (CMCs) which are or secondary polar solvent in the composition is selected to non-oZone-depleting propellants, are particularly useful in provide a Aw value selected from the ranges of (1) about 0.8 the production of a non-flammable foamable composition. and about 0.9; (2) about 0.7 and about 0.8; and (3) less than 0289 Such propellants include, but are not limited to about 0.7. hydrofluorocarbon (HFC) propellants, that contain no chlo 0295. As such, a composition containing a polyol, a PEG rine atoms, and as such, falls completely outside concerns with or without a secondary polar solvent can be used as about stratospheric ozone destruction by chlorofluorocarbons topical treatment of Superficial infectious conditions. or other chlorinated hydrocarbons. Exemplary non-flam 0296. The advantage of providing a hygroscopic compo mable propellants according to this aspect include propellants sition in a pressurized packaging presentation is readily per made by DuPont under the registered trademark Dymel, such ceived. The usage of all other presentations, such as Solutions, as 1,1,1,2 tetrafluoroethane (Dymel 134), and 1,1,1,2,3,3,3 creams, lotions, ointments and the like involves repeated heptafluoropropane (Dymel 227), 1.1, difluoro ethane opening of the package closure, resulting in absorption of (Dymel 152) and 1,1,1,3,3,3 hexafluoropropane. HFCs pos water from the Surrounding environment and a Subsequent sess Ozone Depletion Potential of 0.00 and thus, they are elevation of the Aw (thus lowering the hygroscopicity of the allowed for use as propellant in aerosol products. product, and therefore decreasing its anti-infective potential. US 2008/0299220 A1 Dec. 4, 2008

By contrast, a pressurized packaging does not allow for any 0308 Topically administrable foams are typically of qual humidity to be absorbed by the preparation, and therefore, the ity grade E or G, when released from the aerosol container. hygroscopic character of the composition cannot be dam Smaller bubbles are indicative of more stable foam, which aged. does not collapse spontaneously immediately upon discharge 0297. In one or more embodiments, the hygroscopic com from the container. The finer foam structure looks and feels position further contains an anti-infective agent, selected Smoother, thus increasing its usability and appeal. from the group of an antibiotic agent, an antibacterial agent, (0309 As further aspect of the foam is breakability. The an antifungal agent, an agent that controls yeast, an antiviral breakable foam is thermally stable, yet breaks under sheer agent and an antiparasitic agent. Combining the anti-infective force. Sheer-force breakability of the foam is clearly advan effect of a hygroscopic composition, which acts through a tageous over thermally induced breakability. Thermally sen dehydration mechanism, with an additional anti-infective sitive foams immediately collapse upon exposure to skin agent that acts through alternate mechanisms results in a temperature and, therefore, cannot be applied on the hand and synergistic effect and consequently higher Success rate of the afterwards delivered to the afflicted area. treatment. 0310. The foam has several advantages, when compared with hydroalcoholic foam compositions, such as described in Composition and Foam Physical Characteristics and Advan WO 2004/071479. tages 0311 Breakability. The foam is thermally stable. Unlike hydroalcoholic foam compositions of the prior art, the foam is 0298. A pharmaceutical or cosmetic composition manu not "quick breaking’, i.e., it does not readily collapse upon factured using the foamable carrier is very easy to use. When exposure to body temperature environment. Sheer-force applied onto the afflicted body Surface of mammals, i.e., breakability of the foam is clearly advantageous over ther humans or animals, it is in a foam state, allowing free appli mally induced breakability, since it allows comfortable appli cation without spillage. Upon further application of a cation and well directed administration to the target area. mechanical force, e.g., by rubbing the composition onto the 0312 1. Skin drying and skin barrier function. Short body Surface, it freely spreads on the Surface and is rapidly chain alcohols are known to dry the skin and impair the absorbed. integrity of the skin barrier. By contrast, including a film 0299 The foamable composition is stable, having an forming agent in the composition foes not cause acceptable shelf-life of at least one year, or preferably, at least unwanted skin barrier damage. two years at ambient temperature, as revealed in accelerated 0313 2. Irritability. Due to the lack of alcohol and stability tests. Organic carriers and propellants tend to impair improvement in skin barrier function, skin irritability is the stability of emulsions and to interfere with the formation eliminated. of stable foam upon release from a pressurized container. It 0314. Another property of the foam is specific gravity, as has been observed, however, that the foamable compositions measured upon release from the aerosol can. Typically, foams according to the present invention are Surprisingly stable. have specific gravity of less than 0.12 g/mL, or less than 0.10 Following accelerated stability studies, they demonstrate g/mL, or less than 0.08 g/mL, depending on their composition desirable texture; they form fine bubble structures that do not and on the propellant concentration. break immediately upon contact with a surface, spread easily on the treated area and absorb quickly. Pharmaceutical Composition 0300. The composition should also be free flowing, to 0315. The foamable composition is an ideal vehicle for allow it to flow through the aperture of the container, e.g., and Vitamins, active pharmaceutical ingredients and active cos aerosol container, and create an acceptable foam. metic ingredients. In the context, active pharmaceutical 0301 Foam quality can be graded as follows: ingredients and active cosmetic ingredients are collectively 0302 Grade E (excellent): very rich and creamy inappear termed “active agent(s) or “therapeutic agent(s)'. A foam ance, does not show any bubble structure or shows a very fine able composition, comprising an active agent has the follow (small) bubble structure: does not rapidly become dull; upon ing advantages: spreading on the skin, the foam retains the creaminess prop 0316 1. The foamable composition provides a pre erty and does not appear watery. ferred solvent for active agents, particularly water-in 0303 Grade G (good): rich and creamy in appearance, Soluble agents. very small bubble size, “dulls' more rapidly than an excellent 0317 2. The inclusion of a propylene glycol and/or a foam, retains creaminess upon spreading on the skin, and PEG and a secondary polar solvent in the foamable does not become watery. composition facilitates a co-solvent effect, resulting 0304 Grade FG (fairly good): a moderate amount of increased concentrations of soluble active agent in the creaminess noticeable, bubble structure is noticeable; upon dosage form, thus facilitating enhanced skin penetration spreading on the skin the product dulls rapidly and becomes of the active agent. In many cases, increased penetration Somewhat lower in apparent viscosity. is positively correlated with improved clinical outcome. 0305 Grade F (fair): very little creaminess noticeable, In certain case, attaining an increased drug penetration larger bubble structure than a “fairly good' foam, upon into the target site of action enables a decrease of treat spreading on the skin it becomes thin in appearance and ment frequency, for example, from twice or three times watery. daily to once daily. 0306 Grade P (poor): no creaminess noticeable, large 0318. 3. Polyols and PEGs; and combinations of a bubble structure, and when spread on the skin it becomes very polyol and/or PEG with a secondary polar solvent are thin and watery in appearance. known as skin penetration enhancers, thus, increasing 0307 Grade VP (very poor): dry foam, large very dull drug residence in the target area and increasing clinical bubbles, difficult to spread on the skin. efficacy, as detailed above. US 2008/0299220 A1 Dec. 4, 2008

0319 4. The fact that the composition contains no (0341 c) about 0% to about 5% of a polymeric water, substantially no water or up to 10% water or up to agent, 25% water and is hydrophilic minimizes the probability (0342 d) about 0% to about 30% of a secondary of degradation of water-sensitive active agents. Further hydrophilic solvent; and more, as exemplified herein, a foam containing a polyol (0343 e) about 0% to about 5% of an unmodified and/or PEG with no water at all can be formed in accor silicone; and dance with the composition and process. Such compo 0344) about 3% to about 25% hydrophobic propel sitions ensure high stability of water sensitive active lant; agents. O345 Whereinhereinth the COmoOS1t1Onposition is1S otherwiOtherW1Se SubStanb 0320 5. Combining the anti-infective effect of a hygro tially free of a hydrophobic solvent; Scopic composition, which acts through a dehydration 0346 wherein the composition includes at least one mechanism, with an additional anti-infective agent, of a Surface active agent and a polymeric agent; and Selected from the group of an antibiotic agent, an anti 0347 wherein the components of the composition bacterial agent, an antifungal agent, an agent that con are sufficiently miscible that the vehicle and the pro trols yeast, an antiviral agent and an antiparasitic agent, pellant do not phase separate upon centrifugation at that acts through alternate mechanisms results in a syn about 1000 rpm for about 10 mins. ergistic effect and consequently higher Success rate of 0348. In another preferred embodiment, the composition the treatment. includes at least one active agent being a therapeutically 0321) 6. The foamable polyol composition in contained effective concentration of at least one active agent, and in an impermeable pressurized packaging presentation 0349. A waterless composition suitable for delivery of is impermeable and thus, the active agent is not exposed an active agent to a body Surface or cavity comprising: to environmental degradation factors, such as light and 0350 a vehicle, comprising: oxidating agent during storage. 0351) a) about 70% to about 99% by weight of a 0322 Thus, in a preferred embodiment, the composition hydrophilic polar solvent, said hydrophilic solvent includes at least one active agent being a therapeutically Selected from the group consisting of polyethylene effective concentration of at least one active agent; and glycols (PEGs) and propylene glycol (PG); 0323 A waterless composition suitable for delivery of 0352 b) about 0.1% to about 10% of at least one an active agent to a body Surface or cavity comprising: Surface active agent, a Surface active agent is 0324 a vehicle comprising: present in the composition and is a mixture of a Brij 0325 a) about 70% to about 99% by weight of a surfactant and a Twin surfactant, wherein the Brij hydrophilic polar solvent, said hydrophilic solvent Surfactant is the major Surface active agent compo selected from the group consisting of: nent; 0326 i) a mixture of two or more different poly 0353 c) about 0% to about 5% of a polymeric ethylene glycols (PEGs), wherein at least one PEG agent, is a high molecular weight PEG having a melting 0354 d) about 0% to about 30% of a secondary point greater than 25°C.; and hydrophilic solvent; and 0327 ii) propylene glycol (PG): 0355 e) about 0% to about 5% of an unmodified 0328 b) about 0% to about 10% of at least one sur silicone; and face active agent; 0356) about 3% to about 25% hydrophobic propel 0329 c) about 0% to about 5% of a polymeric agent; lant; 0357 wherein the compositionp is otherwise substan 0330 d) about 0% to about 30% of a secondary tially free of a hydrophobic solvent; and hydrophilic solvent; and 0358 wherein the components of the composition 0331 e) about 0% to about 5% of a silicone oil; and are sufficiently miscible that the propellant and 0332 about 3% to about 25% hydrophobic propel vehicle may be homogeneously distributed with mild lant; shaking. 0333 wherein the composition is otherwise substan 0359. In another preferred embodiment, the composition tially free of a hydrophobic solvent; includes at least one active agent being a therapeutically 0334 wherein the composition includes at least one of a effective concentration of at least one active agent, and Surface active agent and a polymeric agent; and 0360 A waterless composition suitable for delivery of 0335 wherein the vehicle and the propellant are suffi an active agent to a body Surface or cavity comprising: ciently miscible that the components may be homoge 0361 a vehicle comprising: neously distributed with mild shaking. 0362 a) about 70% to about 99% by weight of a 0336. In another preferred embodiment, the composition hydrophilic polar solvent, said hydrophilic solvent includes at least one active agent being a therapeutically comprising a mixture of PEG 200 and PEG 400; effective concentration of at least one active agent; and 0363 b) about 0% to about 10% of at least one 0337. A waterless composition suitable for delivery of Surface active agent; an active agent to a body Surface or cavity comprising: 0364 c) about 0% to about 5% of a polymeric 0338 a vehicle, comprising: agent, 0339 a) about 70% to about 99% by weight of a 0365 d) about 0% to about 30% of a secondary hydrophilic polar solvent comprising butylene gly hydrophilic solvent; and col (BG) 0366 e) about 0% to about 5% of a silicone oil; and (0340 b) about 0% to about 10% of at least one 0367 about 3% to about 25% hydrophobic propel Surface active agent; lant; US 2008/0299220 A1 Dec. 4, 2008 18

0368 wherein the composition is otherwise substan agent is an antifungal agent, and more preferably the tially free of a hydrophobic solvent; anti-infective agent is terbinafine. 0369 wherein the composition includes at least one of a Surface active agent and a polymeric agent; and Active Agents 0370 wherein the vehicle and the propellant are suf 0381 Active agents can be used on their own or in com ficiently miscible that the components may be homo bination with other agents. Suitable therapeutic agents geneously distributed with mild shaking. include but are not limited to active herbal extracts, acari cides, age spot and keratose removing agents, allergen, anal 0371. In the context of combining a hygroscopic carrier gesics, local anesthetics, antiacne agents, antiallergic agents, according to the present invention and an anti-infective active antiaging agents, antibacterials, antibiotics, antiburn agents, agent, a pharmaceutical composition is provided, including: anticancer agents, antidandruff agents, antidepressants, anti 0372 a. a hygroscopic Substance at a sufficient concen dermatitis agents, antiedemics, antihistamines, antihelm tration to provide an AW value of the hygroscopic carrier inths, antihyperkeratolyte agents, antiinflammatory agents, of less than 0.9. The concentration of the hygroscopic antiirritants, antilipemics, antimicrobials, antimycotics, anti Substance in the composition can be designed to provide proliferative agents, antioxidants, anti-wrinkle agents, anti a Aw value selected from the ranges of (1) about 0.8 and pruritics, antipsoriatic agents, antirosacea agents antisebor about 0.9; (2) about 0.7 and about 0.8; and (3) less than rheic agents, antiseptic, antiswelling agents, antiviral agents, about 0.7: antiyeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, 0373) b. about 0.2% to about 5% by weight of a surface disinfectants, fungicides, hair growth regulators, hormones, active agent; hydroxy acids, immunosuppressants, immunoregulating 0374 c. about 0.01% to about 5% by weight of at least agents, insecticides, insect repellents, keratolytic agents, lac one polymeric agent selected from a bioadhesive agent, tams, metals, metal oxides, mitocides, neuropeptides, non agelling agent, a film forming agent and a phase change steroidal anti-inflammatory agents, oxidizing agents, pedicu agent, licides, photodynamic therapy agents, retinoids, Sanatives, 0375 d. a therapeutically effective concentration of an Scabicides, self tanning agents, skin whitening agents, aso anti-infective agent, and constrictors, vasodilators, vitamins, vitamin D derivatives, 0376 e. a liquefied or compressed gas propellant at a wound healing agents and wart removers. AS is known to one concentration of about 3% to about 25% by weight of the skilled in the art, in some instances a specific active agent may total composition. have more than one activity, function or effect. 0382. In an embodiment, the therapeutic agent is an active 0377. An exemplary case for the inclusion of an anti herbal extract. Suitable active herbal extracts include but are infective agent in a hygroscopic composition is provided not limited to angelica, anise oil, astragali radix, azalea, ben herewith. It has been Surprisingly discovered that combining Zyl acetate, birch tar oil, bornyl acetate, Cacumen biotae, an antifungal agentina hygroscopic composition results in an camphor, cantharidin, capsicum, cineole, cinnamon bark, anti-infective effect on Strains that are not supposed to be cinnamon leaf, citronella, citroneliol, citronellyl acetate, cit affected by the said antifungal agent. For example, terbinafine ronellyl formate, eucalyptus, eugenyl acetate, flos Carthami, is know to be highly effective against dermatophite patho fructus mori, garlic, geraniol, geranium, geranyl acetate, gens, but not against candida. In-vitro studies have revealed, habanera, isobutyl angelicate, lavender, ledum latifolium, however that terbinafine, dissolved in a hygroscopic carrier, ledum palustre, lemongrass, limonene, linalool, linallyl effectively inhibited the spreading of candida albicans, while acetate, methyl anthranilate, methyl cinnamate, meZereum, a control preparation, comprising the same concentration of neem, nerol, neryl acetate, nettle root extract, oleum ricini, terbinafine in an emulsion base was not effective. Thus, com oregano, pinenes, alpha.-pinene..beta-pinene, radix angeli bining an antifungal agent in a hygroscopic composition caesinesis, radix paenoiae rubra, radix polygoni multiflori, results in an expansion of the spectrum of infective strains that radix rehmanniae, rhizoma pinelliae, rhizoma Zingiberis can benefit form the therapy, and furthermore, in can render recens, sabadilla, Sage, Sandalwood oil, saw palmetto extract, an improved effect of such a composition on mixed infections semensesami nigrum, staphysagria, tea tree oil, terpene alco or in infections that are not accurately diagnosed. hols, terpene hydrocarbons, terpene esters, terpinene, terpin 0378 Consequently, in another aspect, a pharmaceutical eol, terpinyl acetate and derivatives, esters, salts and mixtures composition, which possesses an improved antifungal activ thereof. In an embodiment, the active agent is an acaricide. ity or that possesses an antifungal activity on an expanded Suitable acaricides include but are not limited to amitraz, spectrum of pathogens, is provided, including: flumethrin, fluvalinate and derivatives, esters, salts and mix 0379 a. a hygroscopic composition, comprising a tures thereof. hygroscopic Substance at a Sufficient concentration to 0383. In an embodiment, the therapeutic agent is an age provide an Aw value of the hygroscopic carrier of less spot and keratoses removing agent. Suitable age spot and than 0.9. The concentration of the hygroscopic sub keratoses removing agent include but are not limited to stance in the composition can be designed to provide a hydroxy acids, azelaic acid and other related dicarboxylic Aw value selected from the ranges of (1) about 0.8 and acids, retinoids, kojic acid, arbutin, nicotinic, ascorbic acid, about 0.9; (2) about 0.7 and about 0.8; and (3) less than hydroquinone and derivatives, esters, salts and mixtures about 0.7; and thereof. Certain nonsteroidal anti-inflammatory agents, such 0380 b. an anti-infective agent, selected from the group as diclofenac are also useful for the treatment of keratoses. of an antibiotic agent, an antibacterial agent, an antifun 0384. In an embodiment, the therapeutic agent is an anal gal agent, an agent that controls yeast, an antiviral agent gesic. Suitable analgesics include but are not limited to ben and an antiparasitic agent. Preferably, the anti-infective Zocaine, butamben picrate, dibucaine, dimethisoquin, dyclo US 2008/0299220 A1 Dec. 4, 2008

nine, lidocaine, pramoxine, tetracaine, salicylates and water. The reaction of a dicarboxylic acid with one alcohol derivatives, esters, salts and mixtures thereof. molecule results in a mono ester of said dicarboxylic acid, and 0385. In an embodiment, the therapeutic agent is a local the reaction of a dicarboxylic acid with two alcohol molecules anesthetic. Suitable local anesthetics include but are not lim results in a diester of the dicarboxylic acid. ited to benzocaine, benzyl alcohol, bupivacaine, butamben 0394 The alcohol molecule, to be linked to the dicarboxy picrate, chlorprocaine, cocaine, dibucaine, dimethisoquin, lic acid, can be selected from the group of an alkyl an aryl dyclonine, etidocaine, hexylcaine, ketamine, lidocaine, alcohol. Exemplary alcohol, Suitable according to the present mepivacaine, phenol, pramoxine, procaine, tetracaine, Sali invention include methyl alcohol, ethyl alcohol, propyl alco cylates and derivatives, esters, salts and mixtures thereof. hol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, t-butyl 0386. In an embodiment, the therapeutic agent is an anti alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, decyl acne agent. Suitable antiacne agents include but are not lim alcohol, capryl alcohol, phenol, benzyl alcohol and the like. ited to N-acetylcysteine, adapalene, azelaic acid, benzoyl 0395. In one or more embodiments, the alcohol is a bio peroxide, cholate, clindamycin, deoxycholate, erythromycin, logically active alcohol. In an embodiment, biologically flavinoids, glycolic acid, meclocycline, metronidazol, mupi active alcohol possesses keratolytic activities. Examples of rocin, octopirox, phenoxy ethanol, phenoxy proponol, pyru keratolytically active alcohol Suitable according to the Vic acid, resorcinol, retinoic acid, Salicylic acid, Scymnol present invention include ortho-, meta- and para-hydroxy Sulfate, Sulfacetamide-sulfur, Sulfur, tazarotene, tetracycline, alkylbenzoate, salicylic acid, ortho-, meta-, and para-dihy tretinoin triclosan and derivatives, esters, salts and mixtures droxybenzene, ortho-, meta-, and para-hydroxytoluene, thereof. alpha-hydroxy acid, retinol, and derivatives thereof Such as 0387. In an embodiment, the therapeutic agent is an anti provided in U.S. Pat. No. 6, 180,669. 22. In an embodiment, aging agent. Suitable antiaging agents include but are not the biologically active alcohol is selected from the group limited to Sulfur-containing D and L amino acids, alpha consisting of steroidal hormones, Steroidal anti-inflammatory hydroxy acids S, beta-hydroxy acids (e.g. salicylic acid), urea, agents, vitamin E and vitamin D, such as provided in U.S. Pat. hyaluronic acid, phytic acid, lipoic acid; lysophosphatidic Appl. 20040191196. acid, skin peel agents (e.g., phenol, resorcinol and the like), Vitamin B3 compounds (e.g., niacinamide, nicotinic acid and Antibiotics nicotinic acid salts and esters, including non-vasodilating esters of nicotinic acid (Such as tocopheryl nicotinate), nic 0396. In an embodiment, the therapeutic agent is an anti otinyl amino acids, nicotinyl alcohol esters of carboxylic biotic. The terms “antibiotic” as used herein shall include, but acids, nicotinic acid N-oxide and niacinamide N-oxide), Vita is not limited to, any substance being destructive to or inhib min B5 and retinoids (e.g., retinol, retinal, retinoic acid, reti iting the growth of bacteria or any Substance having the nyl acetate, retinyl palmitate, retinyl ascorbate) skin barrier capacity to inhibit the growth of or to destroy bacteria. 0397. In one or more embodiments, the antibiotic agent is forming agents, melatonin and derivatives, esters, salts and selected from the group consisting of a beta-lactamantibiotic, mixtures thereof. an aminoglycoside, an ansa-type antibiotic, an Dicarboxylic Acid and Esters Thereof. anthraquinone, an azole, an antibiotic glycopeptide, a mac rolide, an antibiotic nucleoside, an antibiotic peptide, an anti 0388. In an embodiment, the organic carrier comprises an biotic polyene, an antibiotic polyether, an antibiotic qui ester of a dicarboxylic acid. In the context, a dicarboxylic acid nolone, an antibiotic steroid, a Sulfonamide, an antibiotic is an organic material, having two carboxylic acid moieties on metal, an oxidizing agent, a periodate, a hypochlorite, a per its carbon atom skeleton. They have the general molecular manganate, a Substance that release free radicals and/or active formula HOOC-(CH), COOH. oxygen, a cationic antimicrobial agent, a quaternary ammo 0389. In an embodiment, the dicarboxylic acid is a short nium compound, a biguanide, a triguanide, a bisbiguanide, a chain dicarboxylic acid. The simplest Short-chaindicarboxy polymeric biguanide, and analogs, derivatives, salts, ions and lic acid are oxalic acid (n=0), malonic acid (n=1). Succinic complexes thereof. acid (n=2) and glutaric acid (n-3). 0398 Suitable antibiotics include but are not limited to 0390 Additional members of dicarboxylic acid group are amanfadine hydrochloride, amanfadine Sulfate, amikacin, derived from natural products or from synthesis, having “n” arnikacin Sulfate, aminoglycosides, amoxicillin, amplicillin, value from 4 up to 21. In one or more embodiments, the ansamycins, bacitracin, beta-lactams, candicidin, capreomy dicarboxylic acid is selected from the group consisting of cin, carbenicillin, cephalexin, cephaloridine, cephalothin, adipic acid (hexanedioic acid; n=4), pimelic acid (hep cefazolin, cephapirin, cephradine, cephaloglycin, chloram tanedioic acid; n=5), Suberic acid (octanedioic acid; n=6), phenicols, chlorhexidine, chlorhexidine gluconate, chlo aZelaic acid (nonanedioic acid; n=7), sebacic acid (de rhexidine hydrochloride, chloroxine, chlorquinaldol, chlo canedioic acid; n=8) and dodecanedioic acid (n=10). rtetracycline, chlortetracycline hydrochloride, ciprofloxacin, 0391. In an additional embodiment, the dicarboxylic acid circulin, clindamycin, clindamycin hydrochloride, clotrima contains 10 to 32 carbonatoms in their carbonatom skeleton, Zole, cloxacillin, demeclocycline, dicloSXacillin, diiodohy Such as brassylic acid (n=11), thapsic acid (n=14), 14-meth droxyquin, doxycycline, ethambutol, ethambutol hydrochlo ylnonacosanedioic acid (C29) and 14,15-dimethyltriacon ride, erythromycin, erythromycin estolate, erythromycin tanedioic acid (C30). Stearate, farnesol, floxacillin, gentamicin, gentamicin Sulfate, 0392 The carbon atom skeleton of the dicarboxylic acid gramicidin, griseofulvin, haloprogin, haloquinol, hexachlo can be saturated or unsaturated. Such as in the case of maleic rophene, iminocyldline, iodate, iodine, iodochlorhydrox acid and fumaric acid. ycuin, kanamycin, kanamycin Sulfate, lincomycin, lineomy 0393 An ester of a dicarboxylic acid is a chemical com cin, lineomycin hydrochloride, macrollides, meclocycline, pound produced by the reaction between a dicarboxylic acid methacycline, methacycline hydrochloride, methenamine, and at least one alcohol, with the elimination of a molecule of methenamine hippurate, methenamine mandelate, methicil US 2008/0299220 A1 Dec. 4, 2008 20 lin, metronidazole, miconazole, miconazole hydrochloride, 04.01 Aminoglycosides include, but are not limited to, microcrystalline and nanocrystalline particles of silver, cop 1,2'-N-DL-isoseryl-3',4'-dideoxykanamycin B, 1,2'-N-DL per, Zinc, mercury, tin, lead, bismuth, cadmium and chro isoseryl-kanamycin B, 1.2-N-(S)-4-amino-2-hydroxybu mium, minocycline, minocycline hydrochloride, mupirocin, tyryl-3',4'-dideoxykanamycin B, 1,2'-N-(S)-4-amino-2- nafcillin, neomycin, neomycin Sulfate, netilmicin, netilmicin hydroxybutyryl-kanamycin B, 1-N-(2- Sulfate, nitrofuraZone, norfloxacin, nystatin, octopirox, ole Aminobutanesulfonyl) kanamycin A, 1-N-(2- andomycin, orcephalosporins, oxacillin, oxytetracycline, aminoethanesulfonyl)3',4'-dideoxyribostamycin, 1-N-(2- oxytetracycline hydrochloride, parachlorometa Xylenol, Aminoethanesulfonyl)3'-deoxyribostamycin, 1-N-(2- paromomycin, paromomycin Sulfate, penicillins, penicillin aminoethanesulfonyl)3'4'-dideoxykanamycin B, 1-N-(2- G. penicillin V, pentamidine, pentamidine hydrochloride, aminoethanesulfonyl)kanamycin A, 1-N-(2- phenethicillin, polymyxins, quinolones, streptomycin Sul aminoethanesulfonyl)kanamycin B, 1-N-(2- fate, tetracycline, tobramycin, tolnaftate, triclosan, trifampin, aminoethanesulfonyl)ribostamycin, 1-N-(2- rifamycin, rollitetracycline, spectinomycin, spiramycin, aminopropanesulfonyl)3'-deoxykanamycin B, 1-N-(2- streptomycin, Sulfonamide, tetracyclines, tetracycline, tobra aminopropanesulfonyl)3'4'-dideoxykanamycin B, 1-N-(2- mycin, tobramycin Sulfate, triclocarbon, triclosan, trimetho aminopropanesulfonyl)kanamycin A 1-N-(2- prim-sulfamethoxazole, tylosin, Vancomycin, yrothricin and aminopropanesulfonyl)kanamycin B, 1-N-(L-4-amino-2- derivatives, esters, salts and mixtures thereof. hydroxy-butyryl)2,3'-dideoxy-2'-fluorokanamycin A, 1-N- (L-4-amino-2-hydroxy-propionyl)2,3'-dideoxy-2'- 0399. 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 antibiot isoserylkanamycin B, 1-N-DL-isoserylkanamycin, 1-N-DL ics, aminoglycosides, ansa-type antibiotics, anthraquinones, isoserylkanamycin B, 1-N-L-(-)-(alpha-hydroxy-gamma antibiotic azoles, antibiotic glycopeptides, macrollides, anti aminobutyryl)-XK-62-2,2',3'-dideoxy-2'-fluorokanamycin biotic nucleosides, antibiotic peptides, antibiotic polyenes, A.2-hydroxygentamycin A3.2-hydroxygentamycin B, 2-hy antibiotic polyethers, quinolones, antibiotic steroids, Sulfona droxygentamycin B1.2-hydroxygentamycin JI-20A 2-hy mides, tetracycline, dicarboxylic acids, antibiotic metals, oxi droxygentamycin JI-20B, 3"-N-methyl-4"-C-methyl-3',4'- dizing agents, Substances that release free radicals and/or dodeoxy kanamycin A, 3"-N-methyl-4"-C-methyl-3',4'- active oxygen, cationic antimicrobial agents, quaternary dodeoxy kanamycin B, 3"-N-methyl-4"-C-methyl-3',4'- ammonium compounds, biguanides, triguanides, bisbigu dodeoxy-6'-methyl kanamycin B, 3',4'-Dideoxy-3'-eno anides and analogs and polymers thereof and naturally occur ribostamycin.3',4'-dideoxyneamine.3',4'- ring antibiotic compounds. dideoxyribostamycin, 3'-deoxy-6'-N-methyl-kanamycin 0400 Beta-lactam antibiotics include, but are not limited B.3'-deoxyneamine.3'-deoxyribostamycin, 3'-oxysaccharo to, 2-(3-alanyl)clavam, 2-hydroxymethylclavam, 8-epi-thie cin,3,3'-nepotrehalosadiamine, 3-demethoxy-2"-N-formim namycin, acetyl-thienamycin, amoxicillin, amoxicillin idoylistamycin B disulfate tetrahydrate, 3-demethoxyistamy Sodium, amoxicillin trihydrate, amoxicillin-potassium clavu cin B.3-O-demethyl-2-N-formimidoylistamycin B, 3-O- lanate combination, amplicillin, amplicillin sodium, amplicillin demethylistamycin B,3-trehalosamine,4", trihydrate, amplicillin-Sulbactam, apalcillin, aspoxicillin, azi 6'-dideoxydibekacin, 4-N-glycyl-KA-6606VI, 5"-Amino-3', docillin, azlocillin, aztreonam, bacampicillin, biapenem, car 4',5'-trideoxy-butirosin A, 6'-deoxydibekacin,6'-epifortimi benicillin, carbenicillin disodium, carfecillin, carindacillin, cin A, 6-deoxy-neomycin (structure 6-deoxy-neomycin B),6- carpetimycin, cefacetril, cefaclor, cefadroxil, cefalexin, cefa deoxy-neomycin B, 6-deoxy-neomycin C, 6-deoxy loridine, cefalotin, cefamandole, cefamandole, cefapirin, paromomycin, acmimycin, AHB-3',4'-dideoxyribostamycin, cefatrizine, cefatrizine propylene glycol, cefazedone, cefazo AHB-3'-deoxykanamycin B, AHB-3'-deoxyneamine. AHB lin, cefbuperaZone, cefcapene, cefcapene pivoxilhydrochlo 3'-deoxyribostamycin, AHB-4'-6"-dideoxydibekacin, AHB ride, cefdinir, cefditoren, cefditoren pivoxil, cefepime, cefe 6'-deoxydibekacin, AHB-dideoxyneamine. AHB-kanamycin tamet, cefetamet pivoxil, cefixime, cefimenoXime, B, AHB-methyl-3'-deoxykanamycin B, amikacin, amikacin cefnetazole, cefiminox, cefiminox, cefimolexin, cefodizime, Sulfate, apramycin, arbekacin, astromicin, astromicin Sulfate, cefonicid, cefoperaZone, ceforanide, cefoselis, cefotaxime, bekanamycin, bluenSomycin, boholmycin, butirosin, cefotetan, cefotiam, cefoxitin, cefoZopran, cefpiramide, cef butirosin B, catenulin, coumamidine gammal, coumamidine pirome, cefpodoxime, cefpodoxime proxetil, cefprozil, gamma2.D.L-1-N-(alpha-hydroxy-beta-aminopropionyl)- cefauinome, cefradine, cefroxadine, cefsulodin, ceftazidime, XK-62-2, dactimicin.de-O-methyl-4-N-glycyl-KA-6606VI, cefteram, cefteram pivoxil, ceftezole, ceftibuten, cefti de-O-methyl-KA-6606I, de-O-methyl-KA-7038I.destomy Zoxime, ceftriaxone, cefuroxime, cefuroxime axetil, cepha cin A, destomycin B, di-N6'O3-demethylistamycin A, losporin, cephamycin, chitinovorin, ciclacillin, clavulanic dibekacin, dibekacin Sulfate, dihydrostreptomycin, dihydros acid, clometocillin, cloxacillin, cycloserine, deoxy pluraci treptomycin Sulfate, epi-formamidoylglycidylfortimicin B, domycin, dicloxacillin, dihydro pluracidomycin, epicillin, epihygromycin, formimidoyl-istamycin A, formimidoyl-is epithienamycin, ertapenem, faropenem, flomoxef, fluclox tamycin B, fortimicin B, fortimicin C, fortimicin D, fortimi acillin, hetacillin, imipenem, lenampicillin, loracarbef, cin KE, fortimicin KF, fortimicin KG, fortimicin KG 1 (ste mecillinam, meropenem, metampicillin, meticillin, mezlocil reoisomer KG1/KG2), fortimicin KG2 (stereoisomer KG1/ lin, moxalactam, nafcillin, northienamycin, oxacillin, KG2), fortimicin KG3, framycetin, framycetin sulphate, panipenem, penamecillin, penicillin, phenethicillin, piper gentamicin, gentamycin Sulfate, globeomycin, hybrimycin acillin, taZobactam, pivampicillin, pivoefalexin, pivmecilli A1, hybrimycin A2, hybrimycin B1, hybrimycin B2, hybri nam, pivmecillinam hydrochloride, pluracidomycin, propi mycin C1, hybrimycin C2, hydroxystreptomycin, hygromy cillin, Sarmoxicillin, Sulbactam, Sulbenicillin, talampicillin, cin, hygromycin B, isepamicin, isepamicin Sulfate, istamy temocillin, terconazole, thienamycin, ticarcillin and analogs, cin, kanamycin, kanamycin Sulphate, kasugamycin, salts and derivatives thereof. lividomycin, marcomycin, micronomicin, micronomicin Sul US 2008/0299220 A1 Dec. 4, 2008 fate, mutamicin, myomycin, N-demethyl-7-O-demethyl epiroprim, flucytosine, gougerotin, mildiomycin, nikkomy celesticetin, demethylcelesticetin, methanesulfonic acid cin, nucleocidin, oxanosine, oxanosine, puromycin, pyrazo derivative of istamycin, nebramycin, nebramycin, neomycin, mycin, showdomycin, sinefungin, sparsogenin, Spicamycin, netilmicin, oligostatin, paromomycin, quintomycin, ribosta tunicamycin, uracil polyoxin, Vengicide and analogs, salts mycin, saccharocin, seldomycin, Sisomicin, Sorbistin, specti and derivatives thereof. nomycin, streptomycin, tobramycin, trehaloSmaine, trestatin, 0408 Antibiotic peptides include, but are not limited to, validamycin, Verdamycin, Xylostasin, Zygomycin and ana actinomycin, aculeacin, alaZopeptin, amfomycin, amythia logs, salts and derivatives thereof. mycin, antifungal from Zalerion arboricola, antrimycin, apid, 0402 Ansa-type antibiotics include, but are not limited to, apidaecin, aspartocin, auromomycin, bacileucin, bacillomy 21-hydroxy-25-demethyl-25-methylthioprotostreptovaricin, cin, bacillopeptin, bacitracin, bagacidin, berninamycin, beta 3-methylthiorifamycin, ansamitocin, atropisostreptovaricin, alanyl-L-tyrosine, bottromycin, capreomycin, caspofungine, awamycin, halomicin, maytansine, naphthomycin, rifabutin, cepacidine, cerexin, cillofungin, circulin, colistin, cyclodep rifamide, rifampicin, rifamycin, rifapentine, rifaximin, rubra sipeptide, cytophagin, dactinomycin, daptomycin, decapep dirin, Streptovaricin, tolypomycin and analogs, salts and tide, desoxymulundocandin, echanomycin, echinocandin B, derivatives thereof. echinomycin, ecomycin, enniatin, etamycin, fabatin, ferri 0403 Antibiotic anthraquinones include, but are not lim mycin, ferrimycin, ficellomycin, fluoronocathiacin, fusarici ited to, auramycin, cinerubin, ditrisarubicin, ditrisarubicin C, din, gardimycin, gatavalin, globopeptin, glyphomycin, figaroic acid fragilomycin, minomycin, rabelomycin, rudol gramicidin, herbicolin, iomycin, iturin, iyomycin, iZupeptin, fomycin, Sulfurmycin and analogs, salts and derivatives janiemycin, janthinocin, jolipeptin, katanosin, killertoxin, thereof. lipopeptide antibiotic, lipopeptide from Zalerion sp., lyso 0404 Antibiotic azoles include, but are not limited to, bactin, lysozyme, macromomycin, magainin, melittin, aZanidazole, bifonazole, butoconazol, chlormidazole, chlor mersacidin, mikamycin, mureidomycin, mycoplanecin, midazole hydrochloride, cloconazole, cloconazole monohy mycosubtilin, neopeptifluorin, neoviridogrisein, metropsin, drochloride, clotrimaZol, dimetridazole, econazole, econa nisin, nocathiacin, nocathiacin 6-deoxyglycoside, nosihep Zole nitrate, enilconazole, fenticonazole, fenticonazole tide, octapeptin, pacidamycin, pentadecapeptide, peptiflu nitrate, fezatione, fluconazole, flutrimazole, isoconazole, iso orin, permetin, phytoactin, phytostreptin, planothiocin, plus conazole nitrate, itraconazole, ketoconazole, lanoconazole, bacin, policillin, polymyxin antibiotic complex, polymyxin B, metronidazole, metronidazole benzoate, miconazole, polymyxin B1, polymyxin F. preneocarzinostatin, quinomy miconazole nitrate, neticonazole, nimorazole, niridazole, cin, quinupristin-dalfopristin, Safracin, salmycin, salmycin, omoconazol, omidazole, oxiconazole, oxiconazole nitrate, salmycin, Sandramycin, Saramycetin, siomycin, sperabillin, propenidazole, secnidazol, Sertaconazole, Sertaconazole sporamycin, a streptomyces compound, Subtilin, teicoplanin nitrate, Sulconazole, Sulconazole nitrate, tinidazole, tiocona aglycone, telomycin, thermothiocin, thiopeptin, thiostrepton, Zole, Voriconazole and analogs, salts and derivatives thereof. tridecaptin, tsushimycin, tuberactinomycin, tuberactinomy 04.05 Antibiotic glycopeptides include, but are not limited cin, tyrothricin, valinomycin, viomycin, Virginiamycin, Zer to, acanthomycin, actaplanin, avoparcin, balhimycin, bleo Vacin and analogs, salts and derivatives thereof. mycin B (copper bleomycin), chloroorienticin, chlo 04.09. In one or more embodiments, the antibiotic peptide ropolysporin, demethylvancomycin, enduracidin, galacar is a naturally-occurring peptide that possesses an antibacte din, guanidyl fungin, hachimycin, demethylvancomycin, rial and/or an antifungal activity. Such peptide can be N-nonanoyl-teicoplanin, phleomycin, platomycin, ristocetin, obtained from a herbal or a vertebrate source. staphylocidin, talisomycin, teicoplanin, Vancomycin, Victo 0410 Polyenes include, but are not limited to, amphoteri mycin, Xylocandin, Zorbamycin and analogs, salts and deriva cin, amphotericin, aureofungin, ayfactin, azalomycin, blasti tives thereof. cidin, candicidin, candicidin methyl ester, candimycin, can 04.06 Macrollides include, but are not limited to, acetylleu dimycin methyl ester, chinopricin, filipin, flavofungin, comycin, acetylkitasamycin, angolamycin, azithromycin, fradicin, hamycin, hydropricin, levorin, lucensomycin, luc bafilomycin, brefeldin, carbomycin, chalcomycin, cirramy knomycin, mediocidin, mediocidin methyl ester, mepartricin, cin, clarithromycin, concanamycin, deisovaleryl-niddamy methylamphotericin, natamycin, niphimycin, nystatin, nysta cin, demycinosyl-mycinamycin, Di-O-methyltiacumicidin, tin methyl ester, oxypricin, partricin, pentamycin, perimycin, dirithromycin, erythromycin, erythromycineStolate, erythro pimaricin, primycin, proticin, rimocidin, sistomycosin, Sor mycin ethyl Succinate, erythromycin lactobionate, erythro angicin, trichomycin and analogs, salts and derivatives mycin Stearate, flurithromycin, focusin, foromacidin, hateru thereof. malide, haterumalide, josamycin, josamycin ropionate, 0411 Polyethers include, but are not limited to, 20-deoxy juvenimycin, juvenimycin, kitasamycin, ketotiacumicin, epi-narasin, 20-deoxysalinomycin, carriomycin, dianemy lankavacidin, lankavamycin, leucomycin, machecin, marido cin, dihydrolonomycin, etheromycin, ionomycin, iso-la mycin, megalomicin, methyleucomycin, methymycin, salocid, lasalocid, lenoremycin, lonomycin, lysocellin, midecamycin, miocamycin, mycaminosyltylactone, mycino monensin, narasin, oxolonomycin, a polycyclic ether antibi mycin, neutramycin, niddamycin, nonactin, oleandomycin, otic, Salinomycin and analogs, salts and derivatives thereof. phenylacetyldeltamycin, pamamycin, picromycin, rokitamy 0412 Quinolones include, but are not limited to, an alkyl cin, rosaramicin, roXithromycin, Sedecamycin, shincomycin, methylendioxy-4(1H)-oxocinnoline-3-carboxylic acid, ala spiramycin, Swalpamycin, tacrolimus, tellithromycin, trofloxacin, cinoxacin, ciprofloxacin, ciprofloxacin hydro tiacumicin, tilmicosin, treponemycin, troleandomycin, chloride, danofloxacin, dermofongin A, enoxacin, tylosin, Venturicidin and analogs, salts and derivatives enrofloxacin, fleroxacin, flumequine, gatifloxacin, gemi thereof. floxacin, grepafloxacin, levofloxacin, lomefloxacin, lom 0407 Antibiotic nucleosides include, but are not limited efloxacin, hydrochloride, miloxacin, moxifloxacin, nadi to, amicetin, angustmycin, azathymidine, blasticidin S. floxacin, nalidixic acid, nifuroquine, norfloxacin, ofloxacin, US 2008/0299220 A1 Dec. 4, 2008 22 orbifloxacin, oxolinic acid, paZufloxacine, pefloxacin, port systems upon absorption into bacterial or fungal cells. pefloxacin mesylate, pipemidic acid, piromidic acid, prema Anti-microbial metal ions of silver, copper, Zinc, and gold, in floxacin, roSoxacin, rufloxacin, sparfloxacin, temafloxacin, particular, are considered safe for in vivo use. Anti-microbial to Sufloxacin, trovafloxacin and analogs, salts and derivatives silver and silver ions are particularly useful due to the fact that thereof. they are not substantially absorbed into the body. 0413 Antibiotic steroids include, but are not limited to, 0418. Thus, in one or more embodiment, the antibiotic aminosterol, ascosteroside, cladosporide A, dihydrofusidic metal consists of an elemental metal, selected from the group acid, dehydro-dihydrofusidic acid, dehydrofusidic acid, consisting of silver, copper, Zinc, mercury, tin, lead, bismutin, fusidic acid, squalamine and analogs, salts and derivatives cadmium, chromium and gold, which is Suspended in the thereof. composition as particles, microparticles, nanoparticles or col 0414 Sulfonamides include, but are not limited to, chloramine, dapsone, mafenide, phthalylsulfathiazole, Succi loidal particles. The antibiotic metal can further be interca nylsulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlo lated in a chelating Substrate. rpyridazine, Sulfadiazine, Sulfadiazine silver, Sulfadicramide, 0419. In further embodiments, the antibiotic metal is Sulfadimethoxine, Sulfadoxine, Sulfaguanidine, Sulfalene, ionic. The ionic antibiotic metal can be presented as an inor SulfamaZone, Sulfamerazine, Sulfamethazine, Sulfame ganic or organic salt (coupled with a counterion), an organo thizole, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfa metallic complex or an intercalate. Non binding examples of monomethoxine, Sulfamoxol, Sulfanilamide, Sulfaperine, Sul counter inorganic and organic ions are sulfadiazine, acetate, faphenazol, Sulfapyridine, Sulfaquinoxaline, benzoate, carbonate, iodate, iodide, lactate, laurate, nitrate, SulfaSuccinamide, Sulfathiazole, Sulfathiourea, Sulfatola oxide, palmitate, a negatively charged protein. In preferred mide, Sulfatriazin, Sulfisomidine, Sulfisoxazole, Sulfisoxazole embodiments, the antibiotic metal salt is a silver salt, such as acetyl, Sulfacarbamide and analogs, salts and derivatives silver acetate, silver benzoate, silver carbonate, silver iodate, thereof. silver iodide, silver lactate, silver laurate, silver nitrate, silver 0415 Tetracyclines include, but are not limited to, dihy oxide, silver palmitate, silver protein, and silver Sulfadiazine. drosteffimycin, demethyltetracycline, aclacinomycin, akrobomycin, baumycin, bromotetracycline, cetocyclin, 0420. In one or more embodiments, the antibiotic metal or chlortetracycline, clomocycline, daunorubicin, demeclocy metal ion is embedded into a substrate, such as a polymer, a cline, doxorubicin, doxorubicin hydrochloride, doxycycline, mineral (such as Zeolite, clay and silica). lymecyclin, marcellomycin, meclocycline, meclocycline Sul 0421 Oxidizing agents and substances that release free fosalicylate, methacycline, minocycline, minocycline hydro radicals and/or active oxygen. In one or more embodiments, chloride, musettamycin, oxytetracycline, rhodirubin, rollitet the antibiotic agent comprises strong oxidants and free radi racycline, rubomycin, serirubicin, Steffimycin, tetracycline cal liberating compounds, such as oxygen, hydrogen peroX and analogs, salts and derivatives thereof. ide, benzoyl peroxide, elemental halogen species, as well as 0416 Dicarboxylic acids, having between about 6 and oxygenated halogen species, bleaching agents (e.g., Sodium, about 14 carbon atoms in their carbon atom skeleton are calcium or magnesium hypochloride and the like), perchlorite particularly useful in the treatment of disorders of the skin and species, iodine, iodate, and benzoyl peroxide. Organic oxi mucosal membranes that involve microbial. Suitable dicar dizing agents are also included in the definition of “oxidizing boxylic acid moieties include, but are not limited to, adipic agent according to the present invention, Such as quinones. acid, pimelic acid, Suberic acid, azelaic acid, sebacic acid, Such agents possess a potent broad spectrum activity 1.11-undecanedioic acid, 1,12-dodecanedioic acid, 1,13 tridecanedioic acid and 1,14-tetradecanedioic acid. Thus, in 0422. In one or more embodiments the antibiotic agent is one or more embodiments, dicarboxylic acids, having a cationic antimicrobial agent. The outermost Surface of bac between about 6 and about 14 carbon atoms in their carbon terial cells universally carries a net negative charge, making atom skeleton, as well as their salts and derivatives (e.g., them sensitive to cationic Substances. Examples of cationic esters, amides, mercapto-derivatives, anhydraides), are use antibiotic agents include: quaternary ammonium compounds ful immunomodulators in the treatment of disorders of the (QAC’s)—QAC's are surfactants, generally containing one skin and mucosal membranes that involve inflammation. AZe quaternary nitrogen associated with at least one major hydro laic acid and its salts and derivatives are preferred. It has phobic moiety; alkyltrimethyl ammonium bromides are mix antibacterial effects on both aerobic and anaerobic organ tures of where the alkyl group is between 8 and 18 carbons isms, particularly propionibacterium acnes and Staphylococ long, such as cetrimide (tetradecyltrimethylammonium bro cus epidermidis, normalizes keratinization, and has a cyto mide); benzalkonium chloride, which is a mixture of n-alky toxic effect on malignant or hyperactive melanocytes. In a ldimethylbenzyl ammonium chloride where the alkyl groups preferred embodiment, the dicarboxylic acid is azelaic acid in (the hydrophobic moiety) can be of variable length; dialkyl a concentration greater than 10%. Preferably, the concentra methyl ammonium halides; dialkylbenzyl ammonium tion of azelaic acid is between about 10% and about 25%. In halides; and QAC dimmers, which bear bi-polar positive Such concentrates, azelaic acid is Suitable for the treatment of charges in conjunction with interstitial hydrophobic regions. a variety of skin disorders, such as acne, rosacea and hyper 0423. In one or more embodiments, the antibiotic agent is pigmentation. selected from the group of biguanides, triguanides, bisbigu 0417. In one or more embodiments, the antibiotic agent is anides and analogs thereof. an antibiotic metal. A number of metals ions been shown to 0424 Guanides, biguanides, biguanidines and triguanides possess antibiotic activity, including silver, copper, Zinc, mer are unsaturated nitrogen containing molecules that readily cury, tin, lead, bismutin, cadmium, chromium and ions obtain one or more positive charges, which make them effec thereof. It has been theorized that these antibiotic metal ions tive antimicrobial agents. The basic structures a guanide, a exert their effects by disrupting respiration and electron trans biguanide, a biguanidine and a triguanide are provided below. US 2008/0299220 A1 Dec. 4, 2008 23

aabomycin, acetomycin, acetoxycycloheximide, acetylnan aomycin, an actinoplanes sp. Compound, actinopyrone, afl 4 2 astatin, albacarcin, albacarcin, albofungin, albofungin, alisa HN NH mycin, alpha-R.S.-methoxycarbonylbenzylmonate, ull altromycin, amicetin, amycin, amycin demanoyl compound, HN HN NH2 amycine, amycomycin, anandimycin, anisomycin, anthra Biguanide 2 mycin, anti-Syphilis imune Substance, anti-tuberculosis NH imune Substance, antibiotic from Escherichia coli, antibiotics 4 6 from Streptomyces refitineus, anticapsin, antimycin, aplas l Y N H NH2 momycin, aranorosin, aranorosinol, arugomycin, ascofura HN HN r none, ascomycin, ascosin, Aspergillus flavus antibiotic, NH asukamycin, aurantinin, an Aureolic acid antibiotic Sub 5 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 7 ul 5 l 3 ls diplanecin, carumonam, carzinophilin, celesticetin, cepacin, HN HN HN NH2 cerulenin, cervinomycin, chartreusin, chloramphenicol, Triguanide chloramphenicol palmitate, chloramphenicol Succinate Sodium, chlorflavonin, chlorobiocin, chlorocarcin, chromo mycin, ciclopiroX, ciclopiroX olamine, citreamicin, cla 0425. In one or more preferred embodiments, the guanide, dosporin, claZamycin, clecarmycin, clindamycin, coliformin, biguanide, biguanidine or triguanide, provide bi-polar con collinomycin, copiamycin, corallopyronin, corynecandin, figurations of cationic and hydrophobic domains within a coumermycin, culpin, cuprimyxin, cyclamidomycin, cyclo single molecule. heximide, dactylomycin, danomycin, danubomycin, delami 0426 Examples of guanides, biguanides, biguanidines nomycin, demethoxyrapamycin, demethylscytophycin, der and triguanides that are currently been used as antibacterial madin, desdamethine, dexylosyl-benanomycin, agents include chlorhexidine and chlorohexidine salts, ana pseudoaglycone, dihydromocimycin, dihydronancimycin, logs and derivatives, such as chlorhexidine acetate, chlorhexi diumycin, dnacin, dorrigocin, dynemycin, dynemycin triac dine gluconate and chlorhexidine hydrochloride, picloxy etate, ecteinascidin, efrotomycin, endomycin, ensanchomy dine, alexidine and polihexanide. Other examples of cin, equisetin, ericamycin, esperamicin, ethylmonate, everni guanides, biguanides, biguanidines and triguanides that can nomicin, feldamycin, flambamycin, flavensomycin, conceivably be used according to the present invention are florfenicol, fluvomycin, fosfomycin, fosfonochlorin, frederi chlorproguanil hydrochloride, proguanil hydrochloride (cur camycin, frenolicin, fumagillin, fumifungin, funginon, fusa rently used as antimalarial agents), metforminhydrochloride, candin, fusafungin, gelbecidine, glidobactin, grahamimycin, phenformin and buformin hydrochloride (currently used as granaticin, griseofulvin, griseoviridin, grisonomycin, antidiabetic agents). hayumicin, hayumicin, haZymicin, hedamycin, heneicomy 0427. In one or more embodiments, the cationic antimi cin, heptelicid acid, holomycin, humidin, isohematinic acid, crobial agent is a polymer. karnatakin, kaZusamycin, kristenin, L-dihydrophenylala 0428 Cationic antimicrobial polymers include, for nine, a L-isoleucyl-L-2-amino-4-(4-amino-2',5'-cyclohexa example, guanide polymers, biguanide polymers, or poly dienyl) derivative, lanomycin, leinamycin, leptomycin, liba mers having side chains containing biguanide moieties or nomycin, lincomycin, lomofungin, lysolipin, magnesidin, other cationic functional groups, such as benzalkonium manumycin, melanomycin, methoxycarbonylmethylmonate, groups or quarternium groups (e.g., quaternary amine methoxycarbonylethylmonate, methoxycarbonylphenylimo groups). It is understood that the term “polymer as used nate, methyl pseudomonate, methylmonate, microcin, mito herein includes any organic material comprising three or malcin, mocimycin, moenomycin, monoacetyl cladosporin, more repeating units, and includes oligomers, polymers, monomethyl cladosporin, mupirocin, mupirocin calcium, copolymers, block copolymers, terpolymers, etc. The poly mycobacidin, myriocin, myxopyronin, pseudoaglycone, nan merbackbone may be, for example a polyethylene, polypro aomycin, nancimycin, nargenicin, neocarcinostatin, neoen pylene or polysilane polymer. actin, neothramycin, nifurtoinol, nocardicin, nogalamycin, 0429. In one or more embodiments, the cationic antimi novobiocin, octylmonate, olivomycin, orthosomycin, oude crobial polymer is a polymeric biguanide compound. When mansin, oxirapentyn, oxoglaucine methiodide, pactacin, pac applied to a Substrate, such a polymer is known to form a tamycin, papulacandin, paulomycin, phaeoramularia fungi barrier film that can engage and disrupt a microorganism. An cide, phenelfamycin, phenyl, cerulenin, phenylmonate, exemplary polymeric biguanide compound is polyhexameth pholipomycin, pirlimycin, pleuromutilin, a polylactone ylene biguanide (PHMB) salts. Other exemplary biguanide derivative, polynitroXin, polyoxin, porfiromycin, pradimicin, polymers include, but are not limited to poly(hexamethyl prenomycin, prop-2-enylmonate, protomycin, pseudomonas enebiguanide), poly(hexamethylenebiguanide) hydrochlo antibiotic, pseudomonic acid, purpuromycin, pyrinodemin, ride, poly(hexamethylenebiguanide) gluconate, poly(hexam pyrrolnitrin, pyrrolomycin, amino, chloro pentenedioic acid, ethylenebiguanide) stearate, or a derivative thereof. In one or rapamycin, rebeccamycin, resistomycin, reuterin, reveromy more embodiments, the antimicrobial material is Substan cin, rhizocticin, roridin, rubiflavin, naphthyridinomycin, tially water-insoluble. saframycin, Saphenamycin, Sarkomycin, Sarkomycin, sclo 0430. Yet, in one or more embodiment, the antibiotic is a pularin, selenomycin, siccanin, Spartanamicin, spectinomy non-classified antibiotic agent, including, without limitation, cin, Spongistatin, Stravidin, streptolydigin, streptomyces are US 2008/0299220 A1 Dec. 4, 2008 24 nae antibiotic complex, Streptonigrin, streptothricins, to chlorcyclizine, diphenhydramine, mepyramine, methapy streptovitacin, Streptozotocine, a strobilurin derivative, rilene, tripelennamine and derivatives, esters, salts and mix stubomycin, Sulfamethoxazol-trimethoprim, Sakamycin, tures thereof. teeramycin, terpentecin, tetrocarcin, thermorubin, ther moZymocidin, thiamphenicol, thioaurin, thiolutin, thiomar Antifungal inol, thiomarinol, tirandamycin, tolytoxin, trichodermin, 0437. In an embodiment, the therapeutic agent is an anti trienomycin, trimethoprim, trioxacarcin, tyrissamycin, mycotic, also termed antifungal agent. The terms “antimy umbrinomycin, unphenelfamycin, urauchimycin, usnic acid, cotic' and “antifungal as used herein include, but is not uredolysin, variotin, Vermisporin, Verrucarin and analogs, limited to, any Substance being destructive to or inhibiting the salts and derivatives thereof. growth of fungi and yeast or any substance having the capac 0431. In one or more embodiments, the antibiotic agent is ity to inhibit the growth of or to destroy fungi and/or yeast. a naturally occurring antibiotic compound. As used herein, 0438. In one or more embodiments, the antifungal agent is the term “naturally-occurring antibiotic agent” includes all an agent that is useful in the treatment of a Superficial fungal antibiotic that are obtained, derived or extracted from plant or infection of the skin, dermatophytosis, microsporum, tricho vertebrate sources. Non-limiting examples of families of phyton and epidermophyton infections, candidiasis, oral can naturally-occurring antibiotic agents include phenol, resorci didiasis (thrush), candidiasis of the skin and genital mucous nol, antibiotic aminoglycosides, anamycin, quinines, membrane, candida paronychia, which inflicts the nail and anthraquinones, antibiotic glycopeptides, azoles, macrollides, nail bed and genital and vaginal candida, which inflict geni avilamycin, agropyrene, cnicin, aucubin antibioticsaponin talia and the vagina. Thus, in one or more embodiments, the antifungal agent is selected from the group including but not fractions, berberine (isoquinoline alkaloid), arctiopicrin (ses limited to, azoles, diazoles, triazoles, miconazole, flucona quiterpene lactone), lupulone, humulone (bitter acids), alli Zole, ketoconazole, clotrimazole, itraconazole, Climbazole, cin, hyperforin, echinacoside, coniosetin, tetramic acid, ima griseofulvin, ciclopiroX, ciclopiroX-olamine, amorolfine, ter nine and novoimanine. binafine, Amphotericin B, potassium iodide and flucytosine 0432 CiclopiroX and ciclopiroXolamine possess fungi (5FC) at a therapeutically effective concentration. cidal, fungistatic and sporicidal activity. They are active 0439 AZoles are pharmaceutically active compounds that against a broad spectrum of dermatophytes, yeasts, moulds are unsaturated five member ring heterocyclic compound, and other fungi. Such as trichophyton species, microsporum wherein one, two or three members of the ring are nitrogen species, epidermophyton species and yeasts (candida albi atoms, as exemplified in a non-limiting way and illustrated in cans, candida glabrata, other candida species and cryptococ the following schemes: cus neoformans). Some aspergillus species are sensitive to ciclopiroX as are some penicillium. Likewise, ciclopiroX is effective against many gram-positive and gram-negative bac Azole Imidazole 1.2.4 Triazole 12.3 Triazole teria (e.g., escherichia coli, proteus mirabilis, pseudomonas N N N N aeruginosa, Staphylococcus and Streptococcus species), as well as mycoplasma species, trichomonas vaginalis and acti \ / \, f; ,\ /) (\ || . N N N nomyces. Thiadiazole Pyrazole 0433 Plant oils and extracts which contain antibiotic S N agents are also useful. Non limiting examples of plants that contain agents include thyme, perilla, lavender, tea tree, ter fezia clayeryi, Micromonospora, putterlickia Verrucosa, S.N S. putterlickia pyracantha, putterlickia retroSpinosa, Maytenus ilicifolia, maytenus evonymoides, maytenus aquifolia, faenia 0440 The azole is a compound including an unsaturated interjecta, cordyceps sinensis, couchgrass, holy thistle, plan five member ring heterocyclic compound, wherein one, two tain, burdock, hops, echinacea, buchu, chaparral, myrrh, red or three members of the ring are nitrogen atoms. clover and yellow dock, garlic and St. John's wort. 0441 Examples of therapeutic azoles include, but are not 0434 Mixtures of these antibiotic agents may also be limited to, azanidazole, bifonazole, butoconazol, chlormida employed according to the present invention. Zole, climbazole, cloconazole, clotrimazole, dimetridazole, 0435. In an embodiment, the therapeutic agent is an anti econazole, enilconazole, fenticonazole, fezatione, flucona dandruff agent. Suitable antidandruff agents include but are Zole, flutrimazole, isoconazole, itraconazole, ketoconazole, not limited to aminexil, benzalkonium chloride, benzetho lanoconazole, metronidazole, metronidazole benzoate, nium chloride, 3-bromo-1-chloro-5,5-dimethyl-hydantoin, miconazole, neticonazole, nimorazole, niridazole, omocona chloramine B, chloramine T. chlorhexidine, N-chlorosuccin Zol, ornidazole, oxiconazole, posaconazole, propenidazole, imide, climbazole-, 1,3-dibromo-5,5-dimethylhydantoin, raVuconazole, secnidazol, Sertaconazole, Sulconazole, thia 1,3-dichloro-5,5-dimethyl-hydantoin, betulinic acid, betu bendazole, tinidazole, tioconazole, Voriconazol and salts and lonic acid, celastrol, crataegolic acid, cromakalin, cyproter derivatives thereof. Such azoles are mainly used as antifungal one acetate, dutasteride, finesteride, ibuprofen, ketoconozole, agents, yet several of them also possess other therapeutic oleanolic acid, phenyloin, picrotone olamine, Salicylic acid, benefits, such as anti-inflammatory, antibacterial and antivi Selenium Sulphides, triclosan, triiodothyronine, ursolic acid, ral effects. Zinc gluconate, Zincomadine, Zinc pyrithione and derivatives, 0442. Additional non-limiting exemplary classes ofazoles esters, salts and mixtures thereof. include oxazoles, thiazoles, thiadiazoles and thiatriazoles, 0436. In an embodiment, the therapeutic agent is an anti benzimidazoles, and salts and derivatives thereof. histamine. Suitable antihistamines include but are not limited 0443. In an embodiment, the azole is metronidazole. US 2008/0299220 A1 Dec. 4, 2008

0444. In one or more embodiments, the antifungal agent is in the composition as particles, microparticles, nanoparticles a peptide. or colloidal particles. The anti-microbial metal can further be 0445. In certain embodiments, antifungal agent is a natu intercalated in a chelating Substrate. rally-occurring peptide that possesses an antibacterial and/or 0456. In further embodiments, the anti-microbial metal is an antifungal activity. Such peptide can be obtained from a ionic. The ionic antibiotic metal can be presented as an inor herbal or a vertebrate source. ganic or organic salt (coupled with a counterion), an organo 0446. In an embodiment, the antifungal agent is a polyene. metallic complex or an intercalate. Non binding examples of Polyene compounds are so named because of the alternating counter inorganic and organic ions are sulfadiazine, acetate, conjugated double bonds that constitute a part of their mac benzoate, carbonate, iodate, iodide, lactate, laurate, nitrate, rollide ring structure. Polyenes include, but are not limited to, oxide, palmitate, a negatively charged protein. In preferred amphotericin, aureofungin, ayfactin, azalomycin, blasticidin, embodiments, the antibiotic metal salt is a silver salt, such as candicidin, candicidin methyl ester, candimycin, candimycin silver acetate, silver benzoate, silver carbonate, silver iodate, methyl ester, chinopricin, filipin, flavofungin, fradicin, hamy silver iodide, silver lactate, silver laurate, silver nitrate, silver cin, hydropricin, levorin, lucensomycin, lucknomycin, oxide, silver palmitate, silver protein, and silver Sulfadiazine. mediocidin, mediocidin methyl ester, mepartricin, methy 0457. Yet, in another embodiment, the antifungal agent is lamphotericin, natamycin, niphimycin, nystatin, oxypricin, an oxidizing agent or a substance that releases free radicals partricin, pentamycin, perimycin, pimaricin, primycin, proti and/or active oxygen. Exemplary oxidizing agents are hydro cin, rimocidin, sistomycosin, Sorangicin, trichomycin and gen peroxide, benzoyl peroxide, elemental halogen species analogs, salts and derivatives thereof. (compounds), as well as oxygenated halogen species (com 0447. In an embodiment, the antifungal agent is a pyrimi pounds), bleaching agents (e.g., Sodium, calcium or magne dine, such as Flucytosine. sium hypochloride and the like), perchlorite species (com 0448. In an embodiment, the antifungal agent is an ally pounds), iodine and iodate compounds. Organic oxidizing lamine, Such as terbinafine and naftifine. agents are also included in the definition of “oxidizing agent' 0449 In an embodiment, the antifungal agent is a morpho according to the present invention, Such as quinones. Such line derivative, Such as amorolfine. agents possess a potent broad spectrum activity 0450. In an embodiment, the antifungal agent is selected 0458 In further embodiments the antibiotic agent is a from the group consisting of CiclopiroX, ciclopiroXolmine, cationic antimicrobial agent. The outermost Surface of bacte griseofulvin. rial and fungal cells universally carries a net negative charge, 0451. In an embodiment, the antifungal agent is a Thio making them sensitive to cationic substances. Examples of carbamate, Such as tolnaftate. cationic antibiotic agents include: quaternary ammonium 0452. In an embodiment, the antifungal agent is a Sulfona compounds, such as alkyltrimethyl ammonium bromides, mide, Such as Mafenide and Dapsone. benzalkonium chloride, dialkylbenzyl ammonium halides, 0453. In an embodiment, the antifungal agent consists of a and dimmers thereof, which bear bi-polar positive charges in plant oil or a plant extract possessing antifungal activity; or a conjunction with interstitial hydrophobic regions. plant oil or extract which contains antifungal agents. Non 0459. In one or more embodiments, the antifungal agent is limiting examples of plants containing agents include, but are an agent that is useful in the treatment of a Superficial fungal not limited to, anise, basil, bergemont, burdock, buchu, chap infection of the skin, dermatophytosis, microsporum, tricho arral, camphor, cardamom, carrot, canola, Cassia, catnip, phyton and epidermophyton infections, candidiasis, oral can cedarwood, citronella, clove, couchgrass, cypress, echinacea, didiasis (thrush), candidiasis of the skin and genital mucous eucalyptus, faenia interjecta, garlic, ginger, grapefruit, holy membrane, candida paronychia, which inflicts the nail and thistle, hops, hyssop, jasmine, jojova, lavender, lavandin, nail bed and genital and vaginal candida, which inflict geni lemon, lime, mandarin, marigold, marjoram, maytenus ilici talia and the vagina. folia, maytenus evonymoides, maytenus aquifolia, 0460 Suitable antimycotics include but are not limited to micromonospora, myrrh, neroli, nutmeg, orange, Ordyceps allylamines, amorolfine, amphotericin B. azole compounds, Sinensis, peppermint, perilla, petitgrain, plantain, putter bifonazole, butoconazole, chloroxine, clotrimazole, ciclo lickia verrucosa, putterlickia pyracantha, putterlickia retro piroX olamine, clotrimazole, econazole, elubiol, fenticona spinosa, rosemary, sage, spearmint, star anise, St. John's Zole, fluconazole, flucytosine (5FC), griseofulvin, itracona wort, red clover, tangerine, tea tree, terfezia clayeryi, thyme Zole, ketoconazole, mafenide acetate, miconazole, naftifine, vanilla, verbena, white clover and yellow dock. natamycin, tolnaftate, nystatin, polyenes, oxiconazole, Sul 0454. In an embodiment, the antifungal agent is an anti bentine, Sulconazole, terbinafine, terconazole, tioconazole, microbial metal. A number of metals ions been shown to undecylenic acid and derivatives, esters, salts and mixtures possess antibiotic activity, including silver, copper, Zinc, mer thereof. cury, tin, lead, bismutin, cadmium, chromium and ions thereof. It has been theorized that these anti-microbial metal Vasoactive, Calcium Channel Blocker and Cholinergic Agent ions exert their effects by disrupting respiration and electron Vasoactive transport systems upon absorption into bacterial or fungal cells. Anti-microbial metal ions of silver, copper, Zinc, and 0461 In the context, a vasoactive agent is a Substance that gold, in particular, are considered safe for in Vivo use. Anti changes the diameter of a blood vessel. microbial silver and silver ions are particularly useful due to 0462. In one or more embodiments, the vasoactive agentis the fact that they are not substantially absorbed into the body. a vasodilator. A vasodilator is any of various agents that relax 0455 Thus, in one or more embodiment, the anti-micro or widen blood vessels and thereby maintain or lower blood bial metal consists of an elemental metal, selected from the pressure. group consisting of silver, copper, Zinc, mercury, tin, lead, 0463 Alteration in the release and action of endothelium bismutin, cadmium, chromium and gold, which is suspended derived vasoactive factors is responsible for changes in vas US 2008/0299220 A1 Dec. 4, 2008 26 cular reactivity early in the course of vascular disease. These 0469. In one or more embodiments, the vasoactive agent is factors include nitric oxide, eicosanoids, endothelium-de selected from the group of vasodilator peptides and proteins. rived hyperpolarizing factor, endothelin, and angiotensin II. Non-limiting examples of vasodilator paprides include, but 0464 Nitric oxide (NO) has been recognized as an impor are not limited to bradykinin, bradykinin-like peptide I, tant messenger molecule having a broad spectrum of func bradykinin-like peptide III Phyllokinin (bradykinyl-isole tions in many biological systems ranging from physiological ucyl-tyrosine O-sulfate), megaScoliakinin (Thr6bradyki control to pathological cytotoxic effect1-3. Along with pros nin-Lys-Ala), lysyl-bradykinin-like waspkinin, lysyl-brady kinin, maximakinin (Bombinakinin M), bombinakinin-GAP, tacyclin, NO is responsible for endothelium derived tonic kininogen-1 associated peptides, kininogen-2 associated pep relaxation of all types of blood vessels. NO is formed from tides, T-kinin, thiostatin, prolixin-S, Vespulakinin 2, Vespaki L-arginine through the action of a family of isoenzymes, the nin X, relaxin, adrenomedullin, ghrelin, maxadilan, Sub nitric oxide synthases (NOS). Thus, in one or more embodi stance P, calcitonin gene-related peptide (CGRP), Natriuretic ments, the vasoactive agent is selected from the group of peptides (NPs), e.g., atrial natriuretic peptide (ANP), C-type therapeutic agents that modulate the production of nitric natriuretic peptide (CNP), and adrenomedulin (ADM), oxide or otherwise modulate or activate the effect of nitric adrenomedullin, Ovine corticotropin-releasing factor, sau oxide. In one or more embodiments, the vasoactive agent is vagine, urotensin and salts, isomers, analogs and derivatives selected from the group of therapeutic agents that modulate thereof. the activity of the enzyme nitric oxide synthase. In one or 0470. In one or more embodiments, the vasoactive agent is more embodiments, the vasoactive agent is selected from the selected from the group of therapeutic agents that induce the group of therapeutic agents that enhance the effect of NO by production of a vasodilator peptide or otherwise enhance or inhibiting enzymes from the phosphodiesterase group. Such activate the effect of a vasodilator peptide. as phosphodiesterase type 5 (PDE5). 0471. In one or more embodiments, the vasoactive agent is 0465. In one or more embodiments, the vasoactive agent is a Substance derived or extracted from herbs having a vasodi selected from the group including nitrites, nitrates and their lator effect. Non limiting examples of herbs that contain analogs, esters and salts. In one or more embodiments the vasoactive agents include achillea millefolium (Yarrow), vasoactive agent possesses a moiety selected from the group allium sativum (garlic), amoracia rusticana (horseradish), consisting of ONO, and ONO2. berberis vulgaris (barberry), cimicifiiga racemosa (black 0466 Exemplary vasodilators include, but are not limited cohosh), Coleus forskholii (coleus), Coptis (Goldenthread), to, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobu crataegus (hawthorn), eleutherococcus senticosus (Siberian tyl nitrite, glyceryl trinitrate, also known as nitroglycerin, ginseng), ginkgo biloba (ginkgo), melissa officinalis (lemon octyl nitrite, sodium nitrite, sodium nitroprusside, clonitrate, balm), Olea europaea (olive leaf), panax ginseng (Chinese erythrity1 tetranitrate, isosorbide mononitrate, isosorbide ginseng), petroselinum crispum (parsley), scutellaria dinitrate, mannitol hexanitrate, pentaerythritol tetranitrate, baicalensis (baical skullcap), tilia europaea (linden flower), penetrinitol, triethanolamine trinitrate, troInitrate phosphate trigonella foenum-graecum (fenugreek), urtica dioica (triethanolamine trinitrate diphosphate), propatylnitrate, (nettles), valeriana officinalis (Valerian), viburnum (cramp, nitrite esters of Sugars, nitrite esters of polyols, nitrate esters bark, blackhaw), veratrum viride (American hellebore), ver of Sugars, nitrate esters of polyols, nicorandil, apresoline, bena officinalis (vervain), xanthoxylum americanum (prickly diazoxide, hydralazine, hydrochlorothiazide, minoxidil, pen ash), Zingiber officinale (ginger), rauwolfia serpentina (In taerythritol, tolaZoline, scoparone (6.7-dimethoxycoumarin) dian Snakeroot), viscum album, wildyam, sasparilla, licorice, and salts, isomers, analogs and derivatives thereof. damiana, yucca, saw palmetto, gotu kola (centella asiatica), 0467. In one or more embodiments, the vasoactive agent yohimbine and salts, hazelnut, brazil nut, walnut and analogs belongs to a class of drugs that are known of possess vasodi and derivatives thereof. lator properties. Non limiting examples of drug classes that 0472. According to one or more embodiments, the foam possess vasodilator properties include, but are not limited to, able composition includes a vasodilator and a vasoactive beta-adrenergic blockers, alpha-adrenoceptor blockers, pros agent such that the vasodilator can have a synergistic effect by taglandin and prostaglandin-like compounds, inhibitors of readily facilitating facile penetration of the vasoactive agent. type 5 phosphodiesterase (PDE-5), angiotensin converting 0473. In one or more embodiments, the vasoactive agent is enzyme inhibitors, calcium antagonists, angiotensin II recep a vasoconstrictor. A vasoconstrictor is any of various agents tor antagonists, direct acting Smooth muscle vasodilators, that narrow blood vessels and thereby maintain or increase adrenergic inhibitors, endothelin antagonists, mineralocorti blood pressure, and/or decrease blood flow. There are many coid receptor antagonists, vasopeptidase inhibitors and renin disorders that can benefit from treatment using a vasocon inhibitors. Active agents belonging to Such drug classes, as strictor. For example, redness of the skin (e.g., erythema or well as active agents belonging to other classes, which cause cuperose), which typically involves dilated blood vessels, a vasodilator effect are also included in the scope of vasoac benefit from treatment with a vasoconstrictor, which shrinks tive agents according to the present invention. the capillaries thereby decreasing the untoward redness. 0468. Non-nitrate vasodilators from different classes 0474. Other descriptive names of the vasoconstrictor include, but are not limited to sildenafil, dipyridamole, cat group include vasoactive agonists, vasopressor agents and echolamine, isoproternol, furosemide, prostaglandin, prosta vasoconstrictor drugs. Certain vasoconstrictors act on spe cyclin, enalaprilat (ACE-inhibitor), morphine (opiate), cific receptors, such as vasopressin receptors or adrenorecep acepromazine (C.-blocker), praZosin (C-blocker), enalapril tOrS. (ACE-inhibitor), captopril (ACE-inhibitor), amlodipine (Ca 0475. In one or more embodiments, the vasoconstrictor is channel blocker), minoxidil, tadalafil. Vardenafil, phenyleph a calcium channel agonist. Calcium channel agonists are rine, etilefein, caffeine, capsaicin and salts, isomers, analogs agents that increase calcium influx into calcium channels of and derivatives thereof. excitable tissues, thereby causing vasoconstriction. US 2008/0299220 A1 Dec. 4, 2008 27

0476 Non limiting examples of vasoconstrictors include nitrendipine, perhexyline, tiapamil, Verapamil, pharmaceuti ephedrine, epinephrine, phenylephrine, angiotensin, vaso cally acceptable salts, isomers, analogs and derivatives pressin, and analogs and derivatives thereof. thereof. 0477. In one or more embodiments, the vasoactive agent is a Substance derived or extracted from herbs, having a vaso Cholinergic Drugs constrictor effect. 0487 Cholinergic drugs produce the same effects as ace 0478 Thus, in one or more embodiments, the vasoactive tylcholine. Acetylcholine is the most common neurohormone agent is a Substance derived or extracted from a herbal source, of the parasympathetic nervous system, the part of the periph selected from the group including ephedra sinica (mahuang), eral nervous system responsible for the every day work of the polygonum bistorta (bistort root), hamamelis virginiana body. A cholinergic agent, also known as a parasympathomi (witch hazel), hydrastis Canadensis (goldenseal), lycopus vir metic agent, is a chemical which functions to enhance the ginicus (bugleweed), aspidosperma quebracho (quebracho effects mediated by acetylcholine in the central nervous sys blanco), Cytisus scoparius (Scotch broom), cypress and salts, tem, the peripheral nervous system, or both. These include isomers, analogs and derivatives thereof. acetylcholine receptor agonists muscarine and nicotine, as 0479. Yet, in additional embodiments, the vasoactive well as anticholinesterases. agent is a metal oxide or a mineral. Such as Zinc oxide and 0488 Suitable cholinergic drugs in accordance with the bismuth Subgallate. present invention are selected from a cholinergic agonist of 0480. The McKenzie vasoconstrictor assay, as described, acetylcholine, bethanechol, carbachol, methacholine, and for example, in the British Journal of Dermatology 1975; pilocarpine, or an anticholinesterase of ambenonium, neo 93:563-71 and versions thereof, has been the primary method Stigmine, physostigmine, pyridostigmine, dyflos, and ecothi used for classifying the strength of a vasoconstrictor clinical nopate, and pharmaceutically acceptable salts, isomers, ana efficacy. Thus, in one or more embodiments, the vasoactive logs and derivatives thereof. agent is an agent that positively affects the vasoconstrictor assay. Nitric Oxide Donors 0481 Mixtures of these vasoactive agents may also be 0489 Nitric oxide is an inorganic free radical, which has employed according to the present invention. the chemical formula of N=O and abbreviated to NO, and is a 0482 Solubility of the vasoactive agent is an important remarkably versatile biological messenger. The chemical factor in the development of a stable foamable composition properties of NO are crucial in defining its biological roles, according to the present invention. both as a transcellular signal in the cardiovascular and ner Vous systems and as a cytotoxicantipathogenic agent released Calcium Channel Blockers during an inflammatory response. Endogenous NO is synthe sized from the amino acid L-arginine by three isoforms of the 0483 Calcium channel blockers are a chemically and enzyme NO synthase (NOS). The endothelial (eNOS) and pharmacologically heterogeneous group of drugs, but physi neuronal (nNOS) isoforms that synthesize NO for transcel ologically they all share the ability to selectively antagonize lular signaling are constitutively expressed tightly regulated the calcium ion movements that are responsible for the exci by a number of cofactors. These NOS isoforms typically tation-contraction coupling in the cardiovascular system. synthesize small amounts of NO and require activation by Beyond their cardiovascular effects, calcium channel block Ca"-calmodulin, making them sensitive to agents and pro ers are known to possess other effects, such as inhibition of cesses that increase intracellular calcium levels. The NO gen the growth and proliferation of vascular Smooth muscle cells erated diffuses to neighboring target cells where it acts pri and fibroblasts, inhibition of the synthesis of extracellular marily through activation of soluble guanylate cyclase (sGC) matrix proteins, immunomodulation, inhibition of mast cell to generate coiMP from GTP, and bring about the cellular degranulation and platelet aggregation and Suppression of response through a reduction in intracellular calcium levels. neutrophil adhesion and Superoxide anion (O-2) production. 0490. In an embodiment, the nitric oxide donors can be Some calcium channel blockers also have analgesic effects. selected from several classes, including, but not limited to 0484 Current therapeutic uses of calcium channel block inorganic nitrites and nitrates (e.g., sodium nitrite), organic ers include (but are not limited to) hypertension, angina, nitrites and nitrates, Sodium nitroprusside, molsidomine and arrhythmia and Subarachnoid hemorrhage. Calcium channel its metabolites, diazeniumdiolates, S-nitrosothiols, blockers may further relieve or prevent reactive vasodilation mesoionic oXatriazole and derivatives thereof iron-Sulphur of migraine Sufferers by inhibiting the vasoconstriction dur nitrosyls. Sinitrodil, FK-409 (4-Ethyl-2-(Z)-hydroxyimi ing the prodromal phase. nol-5-nitro-3(E)-hexeneamide) and derivatives thereof and 0485 There are two main classes of calcium channel hybrid NO donor drugs. blockers: dihydropyridines (e.g., nifedipine, nicardipine, 0491. In an embodiment, the organic nitric oxide donor amlodipine, felodipine and nimodipine) and nondihydropy includes at least one organic nitrate, which includes esters of ridines which include diltiazem (a benzothiazepine) and Vera nitric acid and may be an acyclic or cyclic compound. For pamil (a phenylalkylamine). Flunarizine is an antihistamine instance, the organic nitrate may be ethylene glycol dinitrate; with calcium channel blocking activity. isopropyl nitrate; amyl nitrite, amyl nitrate, ethyl nitrite, butyl 0486 In an embodiment, the calcium channel blocker can nitrite, isobutyl nitrite, octyl nitrite, glyceryl-1-mononitrate, be selected from the group consisting of an amlodipine, glyceryl-1,2-dinitrate, glyceryl-1,3-dinitrate, nitroglycerin, anipamil, bamidipine, benidipine, bepridil, darodipine, dilt butane-1,2,4-triol-trinitrate; erythrityl tetranitrate; pen iazem, efonidipine, felodipine, isradipine, lacidipine, lercani taerythrity1 tetranitrate; sodium nitroprusside, clonitrate, dipine, lidoflazine, manidipine, mepirodipine, nicardipine, erythrity1 tetranitrate, isosorbide mononitrate, isosorbide nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine, dinitrate, mannitol hexanitrate, pentaerythritol tetranitrate, US 2008/0299220 A1 Dec. 4, 2008 28 penetrinitol, triethanolamine trinitrate, trolnitrate phosphate betamethsone, betamethasone benzoate, betamethasone dex (triethanolamine trinitrate diphosphate), propatylnitrate, amethasone-phosphate, dipropionate, betamethasone Valer nitrite esters of sugars, nitrate esters of Sugars, nitrite esters of ate, budesonide, chloroprednisone, chlorprednisone acetate, polyols, nitrate esters of polyols, nicorandil, apresoline, dia clescinolone, clobetasol, clobetasol propionate, clobetasol Zoxide, hydralazine, hydrochlorothiazide, minoxidil, pen Valerate, clobetaSone, clobetaSone butyrate, clocortelone, taerythritol, tolaZoline, scoparone (6.7-dimethoxycoumarin) cortisone, cortodoxone, craposone butyrate, desonide, des and pharmaceutically acceptable salts, isomers, analogs and oxymethasone, dexamethasone, desoxycorticosterone derivatives thereof. acetate, dichlorisone, diflorasone diacetate, diflucortolone 0492. In one embodiment, vasoactive drugs that act via Valerate, difluorosone diacetate, diflurprednate, fluadre eNOS activity enhancement, such as sildenafil. Vardenafiland nolone, flucetonide, flucloronide, fluclorolone acetonide, flu tadalafil are also regarded “nitric oxide donors.” cortine butylesters, fludroxycortide, fludrocortisone, flu 0493. In an embodiment, the active agent is an antipruritic. methasone, flumethasone pivalate, flumethasone pivalate, Suitable antipruritics include but are not limited to menthol, flunisolide, fluocinolone, fluocinolone acetonide, fluocinon methdilazine, trimeprazine, urea and derivatives, esters, salts ide, fluocortin butyl, fluocortolone, fluorometholone, fluosi and mixtures thereof. nolone acetonide, fluperolone, fluprednidene acetate, flu 0494. In an embodiment, the therapeutic agent is an addi prednisolone hydrocortamate, fluradrenolone, tional antipsoriatic agent. Suitable additional antipsoriatic fluradrenolone acetonide, flurandrenolone, fluticasone, halci agents include but are not limited to 6-aminonicotinamide, nonide, halobetasol, hydrocortisone, hydrocortisone acetate, 6-aminonicotinic acid, 2-aminopyrazinamide, anthralin, hydrocortisone butyrate, hydrocortisone cyclopentylpropi 6-carbamoylnicotinamide, 6-chloronicotinamide, 2-carbam onate, hydrocortisone Valerate, hydroxyltriamcinolone, oylpyrazinamide, corticosteroids, 6-dimethylaminonicotina medrysone, meprednisone, alpha.-methyl dexamethasone, mide, dithranol, 6-formylaminonicotinamide, 6-hydroxy methylprednisolone, methylprednisolone acetate, mometa nicotinic acid, 6-substituted nicotinamides, 6-substituted Sone furoate, paramethasone, prednisolone, prednisone, nicotinic acid, 2-substituted pyrazinamide, tazarotene, pregnenolone, progesterone, Spironolactone, triamcinolone, thionicotinamide, trichothecene mycotoxins and derivatives, triamcinolone acetonide and derivatives, esters, salts and esters, salts and mixtures thereof. mixtures thereof. 0495. In an embodiment, the active agent is an antirosacea 0500. The steroid according to the present invention is agent. Suitable antirosacea agents include but are not limited selected from the group consisting of: to azelaic acid, metronidazole, Sulfacetamide and derivatives, 0501 (i) a steroid compound containing a cyclopenta esters, salts and mixtures thereof. Certain nonsteroidal anti aphenanthrene skeleton; inflammatory agents, such as Salicylic acid, Salycilates, 0502 (ii) a steroid compound containing a cyclopenta piroxicam and diclofenac are also useful for the treatment of aphenanthrene skeleton carrying one or more func Rosacea. tional groups selected from halogens, alkyl groups, aryl 0496. In an embodiment, the therapeutic agent is an anti groups, benzyl groups, carboxy groups and alkoxy seborrheic agent. Suitable antiseborrheic agents include but groups: are not limited to glycolic acid, Salicylic acid, selenium Sul 0503 (iii) a steroid compound selected from the fami fide, Zinc pyrithione, a dicarboxylic acid, such as azelaic acid lies of (a) cardanolides, (b) bufanolides, (c) spirostans, and derivatives, esters, salts and mixtures thereof. (d) furostans, (e) steroid alkaloids, (f) steroid lactones, 0497. In an embodiment, the therapeutic agent is an anti (g) oxo-steroids, (h) steroid-alcohols and (i) steroid viral agent. Suitable antiviral agents include but are not lim amines: ited to acyclovir, gancyclovir, ribavirin, amantadine, riman 0504 (iv) a steroid compound, where one or more of the tadine nucleoside-analog reverse transcriptase inhibitors, cyclopentalaphenanthrenerings is contracted by loss of Such as zidovudine, didanosine, Zalcitabine, tavudine, lami an unsubstituted methylene group; Vudine and Vidarabine, non-nucleoside reverse transcriptase 0505 (v) a steroid compound, where one or more of the inhibitors, such as nevirapine and delavirdine, protease cyclopentalaphenanthrene rings is expanded by inclu inhibitors, such as Saquinavir, ritonavir, indinavir and nelfi sion of a methylene group; navir, and interferons and derivatives, esters, salts and mix 0506 (vi) a steroid compound containing a cyclopenta tures thereof. aphenanthrene skeleton and a carbocyclic or heterocy 0498. In an embodiment, the therapeutic agent is a chemo clic ring component fused to it; therapeutic agent. Suitable chemotherapeutic agents include 0507 (vii) a compound, wherein two or more steroid but are not limited to daunorubicin, doxorubicin, idarubicin, molecules are linked together covalently: amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, 0508 (viii) a compound selected from the group con teniposide, vinblastine, Vincristine, mitomycin C, 5-FU, sisting of 5C.-pregnane, 53-pregnane, 5C-cholane (allo paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, cholane), 53-cholane, 5C-cholestane, 53-cholestane, irinotecan, gemcitabine cyclosporin, Verapamil, Valspodor, 5C.-ergostane, 5B-ergostane, 5C.-campestane, probenecid, MK571, GF120918, LY335979, biricodar, ter 5B-campestane, 5C-poriferastane, 53-poriferastane, fenadine, quinidine, pervilleine A, XR9576 and derivatives, 5C.-StigmaStane, 5B-stigmastane, 5C.-gorgostaneacri esters, salts and mixtures thereof. hellin, actodigin, alfacalcidol, aldosterone, androster one, betamethasone, brassinolide, calcidiol, calciol, cal Steroids citriol, canrenone, clomegestone, cholesterol, cholic 0499. In an embodiment, the therapeutic agent is a corti acid, corticosterone, cortisol, cortisolacetate, cortisone, costeroid. Suitable corticosteroids include but are not limited cortisone acetate, cyproterone, deoxycorticosterone, to alclometasone dipropionate, amcinafel, amcinafide, amci dexamethasone, disogluside, ecdysone, ercalciol, ergos nonide, beclomethasone, beclomethasone dipropionate, terol, estradiol, estriol, estrone, ethinylestradiol, fluaza US 2008/0299220 A1 Dec. 4, 2008 29

cort, fluocortin, fusidic acid, gestrinone, gonane, halom 0521 (xxi) a vitamin D; etaSone, hydrocortisone, lanosterol, lithocholic acid, 0522 (xxii) a steroid that exhibits qualitatively the bio mebolazine, medroxyprogesterone, meproscillarin, logical activity of calciol; mespirenone, mestranol, naflocort, norenthisterone, norgesterone, norgestrel, Oxandrolone, oxymetholone, 0523 (xxiii) a vitamin D selected from the group con pancuronium bromide, prednisolone, prednisone, sisting of cholecalciferol, 25-hydroxycholecalciferol, progesterone, proscillardin, pseudotigogenin, roxi 1C.25-dihydroxycholecalciferol, ergocalciferol, 1C.25 bolone, Sarsasapogenin, Smilagenin, spironolactone, dihydroxyergocalciferol, 22.23-dihydroergocalciferol, timobesone, testosterone, tigogenin triamcinolone, 1,24,25-trihydroxycholecalciferol, previtamin D, tach urSodeoxycholic acid; ysterol (also termed tacalciol); 0509 (ix) an anti-inflammatory steroid: 0524 (xxiv) a vitamin D3 analogue: 0510 (X) a steroid possessing immunomodulating and/ 0525 (XXV) isovitamin D, dihydrotachysterol, (1S)- or anti-inflammatory properties; hydroxycalciol, (24R)-hydroxycalcidiol, 25-fluorocal 0511 (xi) a steroid, selected from the group of low ciol, ercalcidiol, ertacalciol, (5E)-isocalciol, 22.23-di potency anti-inflammatory steroids, medium potency hydroercalciol, (24S)-methylcalciol, (5E)-(10S)-10, 19 anti-inflammatory steroids and high potency anti-in dihydroercalciol, (24S)-ethylcalciol and (22E)-(24R)- flammatory steroids; ethyl-22.23-didehydrocalciol; 0512 (xii) an anti-inflammatory steroid, selected from the group consisting of hydrocortisone, hydrocortisone 0526 (XXvi) a vitamin D analogue selected from cal acetate, desonide, betamethasone Valerate, clobetaSone cipotriol, tacalcitol, maxacalcitol, and calcitriol; 17-butyrate, flucinonide, fluocinolone acetonide, 0527 (XXvii) a phytosteroid or a phytosterol: alcometasone dipropionate, mometaSone furoate, pred 0528 (XXviii) a steroid derived or extracted from one of nicarbate, triamcinolone acetonide, betamethasone-17 the families of phytosteroids, phytosterols, phy benzoate, methylprednisolone aceponate, betametha to stanols, ecdysones, withanolids, sterines, Steroid Sone dipropionate, halcinonide, triamcinolone Saponins and Soflavonoids; acetonide, halobetasol, clobetasol-17-propionate; 0529 (xxix) a steroid selected from the group consist 0513 (xiii) a steroid that positively affects the McKen ing of alpha-sitosterol, beta-sitosterol, StigmaStanol, Zie vasoconstrictor assay; campesterol, alpha-sitostanol, beta-sitostanol, Stigmas 0514 (xiv) a steroid hormone; tanol, campestanol, avenosterol, brassicasterol, desmo 0515 (XV) a steroid hormone, selected from the group sterol, chalinosterol, beta-ecdysone, whithaferin A, consisting of an androgen, an estrogen and a progesto beta-sitosterine, Stigmasterine, campesterine, ergoster gen, ine, diosgenin, daidzein, glycitein, genistein, murister 0516 (xvi) an androgen, selected from the group con one, poriferasterol, clionasterol, campestanol, and sisting of testosterone, testosterone cipionate, testoster cycloartenol; one decanoate, testosterone enantate, testosterone iso caproate, testosterone phenylpropionate, testosterone 0530 (XXX) a plant oil or a plant extract, which contains propionate, testosterone undecylate, 5C-dihydrotest a steroid; osterone, dehydroepiandrosterone (also termed praster 0531 (XXXi) a plant oil or a plant extract, selected from one and DHEA), androstenedione, androstanediol, the group consisting of nuts seeds, sprouted seeds and androsterone, androstenolone, prasterone enantate, grains (such as alfalfa), St. Mary's thistle, ginkgo biloba, prasterone sodium Sulfate, ormeloxifene, mesterolone, saw palmetto, panax, Siberian ginseng, foeniculum vul fluoxymesterone, methyltestosterone, gestrinone, del gare, cinicifiiga racemosa, licorice root, red clover, madinone, delmadinone acetate, chlormadinone, chlor Sage, Sarsaparilla, Sassafras, angelica Sinensis achilea madinone acetate, danazol and testolactone; millefolium, anemone pratensis, angelica sinensis, gly 0517 (xvii) an estrogen selected from the group con cyrrhiza glabra, hypericum perforatum, larrea, panax, sisting of estradiol, estradiol benzoate, estradiol cipi piscidia erythrina, plantago psyllium, Serenoa repens, onate, estradiol dipropionate, estradiol enantate, estra Symphytum, taraxacum officinale, trifolium pratense, diol hexahydrobenzoate, estradiol phenylpropionate, turnera spp., tussilago farfara, Valeriana officinalis, estradiol Valerate, polyestradiol phosphate, estriol, viburnum prunifolium, calendula officinalis, estriol sodium Succinate, estriol Succinate, polyestriol 0532 (XXXii) any one of the compounds exemplified in phosphate, quinestradol, ethinylestradiol, estraproni the present specification; and salts thereof. cate, mestranol, estrapronicate and equilin; 0533. In the context, steroids are compounds possessing 0518 (xviii) a progestogen, selected from the group the skeleton of cyclopentaalphenanthrene or a skeleton consisting of progesterone, norethisterone, norethister derived therefrom by one or more bond scissions or ring one acetate, norethisterone enantate, medroxyprogester expansions or contractions. Methyl groups are normally one acetate, delmadinone acetate, flugestone acetate, present at C-10 and C-13. An alkyl side chain may also be dydrogesterone, desogestrel, norgestrel, levonorgestrel, present at C-17. Sterols are steroids carrying a hydroxyl dydrogesterone, gestodene, chlormadinone acetate, group at C-3 and most of the skeleton of cholestane. Addi dienogest, drospirenone, lynestrenol, tybolone, cyprot tional carbon atoms may be present in the side chain. erone acetate, megestrol acetate, nomegestrol acetate; 0534 Steroids are numbered and rings are lettered as in 0519 (xix) an inhibitor of a steroid hormone: formula 1. If one of the two methyl groups attached to C-25 is 0520 (XX) an inhibitor of a steroid hormone selected substituted it is assigned the lower number (26); if both are from the group consisting of finasteride, dutasteride and substituted, that carrying the substituent cited first in the spironolactone; alphabetical order is assigned the lower number. US 2008/0299220 A1 Dec. 4, 2008 30

-continued (1) (7)

(22E)-(24R)-24-Methylcholesta-5,7,22-trien-3?-ol or (22E)-ergosta-5,722-trien-3?-ol trivial name ergosterol 0535 The steroids can have substituents on the steroid side chain as exemplified in formula 4-7: 0536 The steroids can have the formalae as exemplified in

(4) formula 9-18. In one or more embodiments, the steroid or sterol has no Substitution at C-17, as exemplified by gonane, H e.g., formulae 9 and 10, estrange (also termed oestrane), e.g. OH formulae 11 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.

HO H

(20R)-5C-Pregnane-3f20-diol (9) (5)

OH

H

OH

HO H (20S)-5C-Pregnane-3f,20.21-triol (10)

(6)

(11)

HO US 2008/0299220 A1 Dec. 4, 2008 31

-continued -continued

(12) (18)

(13)

44,14-Trimethyl

TABLE 1

Hydrocarbons with side chain at C-17

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

2 5C-pregnane 5P-pregnane HC (allopregnane)

17s.

21 H 5C-cholane 5P-cholane H3C CH (allocholane) (15) '2, 17

21 H 5C-cholestane 5P-cholestane H3C, CH3 (coprostane) 20

Y. CH3 7 (16) 5C-ergostane 5P-ergostane

5C-campestane 5P-campestane (17)

CH3 5C-poriferastane 5P-poriferastane

44,14-Trimethyl US 2008/0299220 A1 Dec. 4, 2008 32

TABLE 1-continued -continued

(22) Hydrocarbons with side chain at C-17 Side chain 5C-Series (15) 5P-Series (16) 5C-StigmaStane 5P-stigmastane

Hot H 5 B.133,143-Pregna-6,8,11-trien-20-yn-3C-ol

0538. The stereochemistry of double bonds in the side 5C-gorgostane 5P-gorgostane chain is indicated using the E.Z convention. The same applies to the seco compounds of the vitamin D series (example in formula 23). In certain cases, the steroid has two carbon chains attached at position 17, e.g. 17-methyl-5C-pregnane 24, 17-methyl-5C, 173-pregnane 25, and 17-ethyl-5-choles tane and 17-(2-bromoethyl)-5C, 17C.-cholestane 26. Other examples of a steroid that has two carbon chains attached at position 17, are 17,17-dimethyl-5C.-androstane 27 and 17 B 0537 Examples of unsaturated Steroids and sterols are methyl-17C-propyl-5C.-androstane 28. In certain embodi provided in formulae 19-22: ments, the carbon skeleton of a steroid a carbon atom is replaced by a hetero atom, as exemplified by 17 B-hydroxy 4-oxaandrost-5-en-3-one 29. Yet, in additional embodiments, an additional ring is formed by means of a direct link between any two carbon atoms of the steroid ring system or the (19) attached side chain, as exemplified by formulae 30, 31 and 32.

(23)

CH3

Estra-1,3,5(10)triene

(20) C) O (24) Estra-1,3,7,9-pentaene

(21) 17-Methyl-5C (25) OH x. xxxx

5C-Androst-1-en-163-ol 17-Methyl-5C US 2008/0299220 A1 Dec. 4, 2008 33

-continued -continued (26) (32) Br H 2

(27) (20K)-18.21-Cyclo-5C

0539 Many important naturally occurring steroids con tain one or more additional heterocyclic ring(s), fused or (28) attached to ring D, formed by modifications of the side chain. These steroids can be grouped into the following families: (a) cardanolides, e.g., 5 B-cardanolide 33, 3?,14-dihydroxy-5f card-20(22)-enolide (digitoxigenin) 34 and 3 B.5,14-trihy droxy-19-oxo-5B-card-20(22)-enolide (strophanthidin) 35, as well as epoxycardanolides, containing a 14.21- or a 16.21 17B-Methyl oxygen bridge, as shown in 36, (b) bufanolides, e.g., struc (29) tures 37-39, (c) spirostans, e.g., structures 40-43, (d) furo OH Stans, e.g., structures 44-45, and (e) steroid alkaloids.

(33) O O 17B-Hydroxy-4- (30) H 'o H

OH 3C-Cyclo-5C-cholestan-6B

(31) (34)

OH

HO 5.7c-Cyclo-5C-cholestan-1C.- US 2008/0299220 A1 Dec. 4, 2008 34

-continued -continued

(35) (39) O O 2 H

OHC

OH

HO H

(36) 3|B. H-D (40)

(37) (41)

23

(42)

(38)

(43)

US 2008/0299220 A1 Dec. 4, 2008 35

-continued -continued (44) (48) COOH

5 B-A (49) (45)

5 B-Hydroxy-1B HO s H

(0540 Several biologically important steroids are deriva- (50) tives of the parent hydrocarbons carrying various functional -OOC COOCH groups. Some of the common functional groups include but are not limited to halogens, alkyl groups, aryl groups, benzyl groups, carboxy groups and alkoxy groups. 0541. 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 formulae 50 and 51. In one or more embodiments, the steroid HO is a lactone, as exemplified in formulae 52-54. H 24-Methyl 3,3-hydroxy-5C (51) (46) 2 I /-coch 3 COOH

OH

HO Methyl

(52) (47)

HO ''

HO H US 2008/0299220 A1 Dec. 4, 2008 36

-continued -continued (58) O (53) FO

O just2 H

H 5C (59) HO COONat O (54)

HO H Sodium 3C,12C

0542. In one or more embodiments, the steroid is an ester of a steroid alcohol, as exemplified by 5-cholestan-3-yl (55) acetate, 5-cholestane-3,12-diyl diacetate, 3-oxoandrost-4- en-17-yl acetate (trivial name testosterone acetate), 17-hy 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. 0543. In one or more embodiments, the steroid is an oxo O compound. The oxo compound can be an aldehde, as exem CsHoCO| 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 5f-Cholestane-3C, exemplified by 5-androstan-3-one, pregn-5-ene-320-dione (56) and 11-oxo-5-cholan-24-oic acid.

0544. In one or more embodiment, the steroid is an alcohol as exemplified by 5-cholestane-3,11-diol, 3-hydroxy-5-an drostan-17-one (trivial name: androsterone) and by formulae 59. 0545. 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, O (20S)-3,17.20-trimethoxy-5-pregnane, (20S)-3,17 w dimethoxy-5-pregnan-20-ol. 21-O-methylcortisol and for H mula 61, an acetal or a ketal of an oxosteroid (also named as 12C-Hydroxy-5f-cholestane-3C dialkoxy steroids) as exemplified by 3.3-dimethoxycholest (57) 4-ene, 2.3-(methylenedioxy)pregn-5-ene and formula 62.

US 2008/0299220 A1 Dec. 4, 2008 37

0547. Additional non-limiting examples of steroids that -continued are applicable according to the present invention are provided COOH in formulae 63-79. H

(63)

O 17B-Hydroxyandrost-4-en-3-one ( (64) 9H

0546. Examples of trivial names retained for important O steroid derivatives, these being mostly natural compounds of -17B-Hydroxyandrost-4-en-3-one ( 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 11B,21-dihydroxy-3,20-dioxopregn-4-en 18-all or 11B, 18-epoxy-183,21-dihydroxypregn-4-ene-3,20 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-3?-ol Cholic acid 3C,7c.,12C-trihydroxy-5f-cholan-24-oic acid Corticosterone 11 B,21-dihydroxypregn-4-ene-3,20-dione Cortisol 11 B,17.21-trihydroxypregn-4-ene-3,20-dione Cortisolacetate 21-O-acetylcortisol Cortisone 17,21-dihydroxypregn-4-ene-3,11,20-trione Cortisone acetate 21-O-acetylcortisone Deoxycorticosterone 21-hydroxypregn-4-ene-3,20-dione (i.e. the 11-deoxy derivative of corticosterone) Ecdysone (22R)-2B.3?,14C.22,25-pentahydroxy-5f-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-17B estra-1,3,5(10)-triene-3,17B-diol Estriol estra-1,3,5(10)-triene-3,16C, 17B-triol Estrone 3-hydroxyestra-1,3,5(10)-trien-17-one Lanosterol lanosta-8.24-dien-3?-ol Lithocholic acid 3C-hydroxy-5f-cholan-24-oic acid Progesterone pregn-4-ene-320-dione Pseudotigogenin (25R)-5C-furost-20(22)-ene-3f,26-diol Sarsasapogenin (25S)-5f-spirostan-3?-ol Smilagenin Testosterone (63) 17B-hydroxyandrost-4-en-3-one Tigogenin US 2008/0299220 A1 Dec. 4, 2008 38

-continued -continued (65) (71)

(66)

N E (72)

(67)

(73)

(68)

(74)

(69)

(75)

5 B-Cholestane-3C, (70)

(76) US 2008/0299220 A1 Dec. 4, 2008 39

-continued -continued

(77) (82)

(78) (83)

(79) (84)

0548. In one or more embodiments according to the (85) present invention, the steroid is a compound, in which one or more of the cyclopentalaphenanthrene rings is contracted by loss of an unsubstituted methylene group, as exemplified by 4-nor-5-androstane (78), where C-4 is missing. In other embodiments one or more of the cyclopentalaphenanthrene rings is expanded by inclusion of a methylene group, as exemplified by formulae 80-86.

(86)

(80)

0549. In one or more embodiments, the steroid contains (81) 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 7 adjacent ring positions as exemplified by formulae 99-102. 0550. In one or more embodiments, the steroid contains a I6 15 cyclopentalaphenanthrene skeleton and a carbocyclic or het erocyclic ring component fused to it, as exemplified by for HO mulae 103-111, and in other embodiments, an additional ring 5-Hydroxy-17a,17b is linked to the cyclopentalaphenanthrene skeleton through a spiro system, as exemplified by formula 1 12. US 2008/0299220 A1 Dec. 4, 2008 40

-continued 99

O (99) (105)

(100) (106)

(101) (107)

N

(108)

O C4H5 (102)

is H

Ot. { # (109) ow (103)

(110) (104)

US 2008/0299220 A1 Dec. 4, 2008 42

TABLE 3-continued Exemplary steroids that are useful according to the present invention.

Molecular Trivial name Chemical name formula Medroxyprogesterone 17-hydroxy-6C.-methylpregn-4-ene-3,20-dione Meproscillarin 3f-(6-deoxy-4-O-methyl-C-L-mannopyranosyloxy)-14 hydroxybufa-4.20,22-rienolide Mespirenone 7c-acetylthio-15C, 16C.-dihydro-3-oxo-3'H- 300S cyclopropa 151-17C-pregna- -1,4-diene-21,17 carbolactone Mestranol 3-methoxy-19-nor-17C-pregna-1,3,5(10)-trien-20-yn-17 26O2 ol Nafiocort 9-fluoro-1',4'-dihydro-11B,21-dihydroxy-16bH HFO naphtho2',3':16,17prena- -1,4-diene-3,20-dione Norenthisterone 17-hydroxy-19-nor-17C-pregn-4-en-20-yn-3-one Norgesterone 17-hydroxy-19-nor-17C-pregna-5(10).20-dien-3-one Norgestrel rac-17-hydroxy-18C-homo-19-nor-17C-pregn-4-en-20 yin-3-one Oxandrolone 17B-hydroxy-17C.-methyl-2-oxa-5C-androstan-3-one Oxymetholone 17B-hydroxy-2-(hydroxymethylene)-17C.-methyl-5C.- androstan-3-one Pancuronium 1,1'-(3C,17B-diacetoxy-5C-androstane-2B,16B bromide diyl)bis(-methylpiperidinium) dibromide Prednisolone 11B, 17.21-trihydroxypregna-1,4-diene-3,20-dione Prednisone 17,21-dihydroxypregna-1,4-diene-3,11,20-trione Proscillardin 33-(6-deoxy-C-L-mannopyranosyloxy)-14-hydroxybufa 4.20.22-trienolide Roxibolone 11B,17B-dihydroxy-17C.-methyl-3-oxoandrosta-1,4- diene-2-carboxylic acid Spironolactone 7c-acetylthio-3-oxo-17C-pregn-4-ene-21, 17 C24 H32 OS carbolactone Timobesone S-methyl 9-fluoro-11B,17C-dihydroxy-16B-methyl-3- oxoandrosta- -1,4-diene-17B-carbothioate Triamcinolone 9-fluoro-11B,16C, 17.21-tetrahydroxypregna-1,4-diene 3.20-dione Ursodeoxycholic 3C,7B-dihydroxy-5f-cholan-24-oic acid acid

0553 Mixtures of these steroids may also be employed according to the present invention. TABLE 0554. The steroid is included in the composition in a con Exemplary anti-inflammatory steroids centration that provides a desirable ratio between the efficacy Typical concentration and safety. Typically, Steroids are included in the composition Relative Potency Generic Name in topical products in a concentration between about 0.005% and about 12%. Low Potency Hydrocortisone O.S96-190 However, in Some embodiments, the concentration is hydrocortisone acetate O.S.-1.0% between about 0.005% and about 0.5%, in other embodiment Desonide O.O2-0.2% between about 0.5% and about 2%, and in additional embodi Medium Potency Betamethasone valerate O.05%-0.1% ments between about 2% and about 5% or between about 5% Prednicarbate O.O2-0.2% Clobetasone-17-butyrate O.05% and about 12%. Flucinonide O.01%-0.05% Fluocinolone acetonide O.O1-0.01% 0555. In one or more embodiments, the steroid possesses AlcometaSone dipropionate O.01% immunomodulating and/or anti-inflammatory properties. Mometasome furoate O.1% Without being bound to a specific theory, immunomodulating Triamcinolone acetonide O.025%-0.1% High Potency Betamethasone-17-benzoate O.025% and/or anti-inflammatory steroids act, among other mecha Methylprednisolone aceponate O.1% nisms, through inhibition of the activity of phospholipase A. Betamethasone dipropionate 0.025%, 0.05% They also may have anti-proliferative effects on keratinocytes Halcinonide O.1% Triamcinolone acetonide O.S9/o and other cell types. They can Suppress collagen synthesis by Highest Potency Halobetasol O.05% fibroblasts, but this may lead to adverse effects. Anti-inflam Clobetasol-17-propionate O.05% matory steroids are roughly grouped according to relative anti-inflammatory activity, but activity may vary consider 0556. In one or more embodiments, the steroid is selected ably depending upon the vehicle, the site of application, dis from the group of low-potency anti-inflammatory steroids, ease, the individual patient and whether or not an occlusive medium potency anti-inflammatory steroids and high dressing is used, as exemplified in the Table below. potency anti-inflammatory steroids. US 2008/0299220 A1 Dec. 4, 2008

0557. In one or more embodiments, the anti-inflammatory female hormones/estrogens include estradiol, estradiol ben steroid is included in the composition at a concentration Zoate, estradiol cipionate, estradiol dipropionate, estradiol between about 0.005% and about 1%. enantate, estradiol hexahydrobenzoate, estradiol phenylpro 0558. The McKenzie vasoconstrictor assay, as described, pionate, estradiol Valerate, polyestradiol phosphate, estriol, for example, in the British Journal of Dermatology 1975; estriol Sodium Succinate, estriol Succinate, polyestriol phos 93:563-71 and versions thereof, has been the primary method phate, quinestradol, ethinylestradiol, estrapronicate, mestra used for classifying the potency of a product, containing an nol, estrapronicate and equilin. anti-inflammatory steroids. Thus, in one or more embodi 0562. In one or more embodiments, the steroid hormone is ments, the anti-inflammatory steroid is a steroid that posi a progestogen. Non-limiting examples of progestogens tively affects the vasoconstrictor assay. include progesterone, norethisterone, norethisterone acetate, 0559. In one or more embodiments, the steroid is a hor norethisterone enantate, medroxyprogesterone acetate, del mone. Hormones are known to affect a variety of biological madinone acetate, flugestone acetate, dydrogesterone, processes in any organism, and thus, their inclusion in the desogestrel, norgestrel, levonorgestrel, dydrogesterone, composition, which is intended for local treatment of the skin, gestodene, chlormadinone acetate, dienogest, drospirenone, the vagina, the rectum as well as other body Surfaces and lynestrenol, tybolone, cyproterone acetate, megestrol acetate, cavities provided an advantageous treatment modality. Such nomegestrol acetate. compositions containing hormones can be further adminis 0563 Yet, in additional embodiments, the steroid an tered systemically, via the transdermal or transmucosal route, inhibitor of a steroid hormone. Non-limiting examples of in order to alleviate a disorder that is affected by the specific Such inhibitors are finasteride, dutasteride and spironolac hormone, or in order to tune the hormonal balance of the body tOne. in order to attain certain effects controlled by hormones, such 0564. In one or more embodiments, the steroid is a vitamin as contraception and birth induction. D. The term vitamin D is used to describe all steroids that 0560. In one or more embodiments, the steroid hormone is exhibit qualitatively the biological activity of calciol (vitamin a male hormone or an androgen. Non-limiting examples of D). Non limiting examples of vitamin D compounds are male hormones?androgens include testosterone, testosterone provided in Table 5. cipionate, testosterone decanoate, testosterone enantate, tes 0565. Yet, in additional embodiments, the steroid is a vita tosterone isocaproate, testosterone phenylpropionate, test min D analogue. Exemplary vitamin D analogs include osterone propionate, testosterone undecylate, 5C.-dihydrotes calcipotriol, tacalcitol, maxacalcitol, and calcitriol, with cal tosterone, dehydroepiandrosterone (also termed prasterone cipotriol being especially preferred. Vitamin D analogues and DHEA), androstenedione, androstanediol, androsterone, and derivatives are known to degrade at low pH levels. There androstenolone, prasterone enantate, prasterone sodium Sul fore, in certain preferred embodiments, the steroid is a vita fate, ormeloxifene, mesterolone, fluoxymesterone, methylt min D. or an analogue or a derivative thereof, the pH is estosterone, gestrinone, delmadinone, delmadinone acetate, adjusted to the range between about 7 and about 10, or chlormadinone, chlormadinone acetate, danazoland testolac between about 7.5 and about 9. In one or more embodiments, tOne. the pH is adjusted using a buffering agent, Suitable of main 0561. In one or more embodiments, the steroid hormone is taining a pH level between about 7 and about 10, or between a female hormone or an estrogen. Non-limiting examples of 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-5,7,10(19).22 ercalcitriol) 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-3- (6Z)-tacalciol) 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-cholestadien dihydroercalciol) 3-ol US 2008/0299220 A1 Dec. 4, 2008 44

0566 Further examples of vitamin D compounds include, tion, contributes to the clinical activity of the steroid. Thus, in but are not limited to (1S)-Hydroxycalciol (also termed one or more embodiments, the foamable composition further 1O-hydroxycholecalciferol and alfacaleidol), (24R)-Hy includes at least one additional therapeutic agent, in a thera droxycalcidiol (also termed 24(R).25-dihydroxycholecalcif peutically effective concentration. erol), 25-Fluorocalciol (also termed 25-fluorocholecalcif 0571. In one or more embodiments, the at least one addi erol), Ercalcidiol (also termed 25-hydroxyergocalciferol), tional non-steroidal therapeutic agent is selected from the Ertacalciol (also termed tachysterol, (5E)-Isocalciol (also group consisting of an anti-infective, an antibiotic, an anti termed isovitamin D, 22.23-Dihydroercalciol), (24S)-meth bacterial agent, an antifungal agent, an antiviral agent, an ylcalciol (also termed vitamin D), (5E)-(10S)-10,19-Dihy antiparasitic agent, a nonsteroidal anti-inflammatory drug, an droercalciol, (also termed dihydrotachysterol, hytakerol, immunosuppressive agent, an immunomodulator, an immu and dihydrotachysterol), (24S)-Ethylcalciol (also termed noregulating agent, a hormonal agent, vitaminA, a vitamin A vitamin Ds) and (22E)-(24R)-Ethyl-22.23-didehydrocalciol, derivative, vitamin B, a vitamin B derivative, vitamin C, a (also termed vitamin D). vitamin C derivative, vitamin E, a vitamin E derivative, vita 0567. In one or more embodiments, the steroid is a phy min F, a vitamin F derivative, vitamin K, a vitamin K deriva tosteroid or a phytosterol. As used herein, the term “phy tive, a wound healing agent, a disinfectant, an anesthetic, an tosteroid' or “phytosterol includes all steroids that are antiallergic agent, an alpha hydroxyl acid, lactic acid, gly obtained, derived or extracted from plant sources. Non-lim colic acid, a beta-hydroxy acid, a protein, a peptide, a neu iting examples of families of phytosteroids and phytosterols ropeptide, a allergen, an immunogenic Substance, a haptene, include ecdysones, withanolids, Sterines, steroid saponins an oxidizing agent, an antioxidant, a dicarboxylic acid, aze and Soflavonoids. Non-limiting examples of phytosteroid and laic acid, sebacic acid, adipic acid, fumaric acid, a retinoid, an phytosterol compounds include alpha-sitosterol, beta-sito antiproliferative agent, an anticancer agent, a photodynamic sterol, Stigmastanol, campesterol, alpha-sitostanol, beta-sito therapy agent, an anti-wrinkle agent, a radical scavenger, a stanol, Stigmastanol, campestanol, avenosterol, brassicast metal oxide (e.g., titanium dioxide, Zinc oxide, Zirconium erol, desmosterol, chalinosterol, beta-ecdysone, whithaferin oxide, iron oxide), silicone oxide, an anti wrinkle agent, askin A, beta-sitosterine, Stigmasterine, campesterine, ergosterine, whitening agent, a skin protective agent, a masking agent, an diosgenin, daidzein, glycitein, genistein, muristerone, anti-wart agent, a refatting agent, a lubricating agent and poriferasterol, clionasterol, campestanol, and cycloartenol, as mixtures thereof. well as all natural or synthesized forms and derivatives 0572. In certain cases, the disorder to be treated involves thereof, such as fatty acid esters, such as ferulic acid esters, unaesthetic lesions that need to be masked. For example, oleoyl esters, and cinnamic acid esters, including isomers. rosacea involves papules and pustules, which can be treated 0568 Plant oils and extracts which contain steroids are with a steroid, as well as erythema, telangiectasia and red also useful. Non limiting examples of plants that contain ness, which do not respond to treatment with a steroid. Thus, steroids include nuts seeds, sprouted seeds and grains (such as in one or more embodiments, the additional active agent is a alfalfa), St. Mary's thistle, ginkgo biloba, saw palmetto, masking agent, i.e., a pigment. Non limiting examples of panax, Siberian ginseng, foeniculum vulgare, Cimicifiiga suitable pigments include brown, yellow or red iron oxide or racemosa, licorice root, red clover, Sage, Sarsaparilla, Sassa hydroxides, chromium oxides or hydroxides, titanium oxides fras, angelica sinensis achillea millefolium, anemone praten or hydroxides, zinc oxide, FD&C Blue No. 1 aluminum lake, sis, angelica sinensis, glycyrrhiza glabra, hypericum perfo FD&C Blue No. 2 aluminum lake and FD&C Yellow No. 6 ratum, larrea, panax, piscidia erythrina, plantago psyllium, aluminum lake. serenoa repens, symphytum, taraxacum officinale, trifolium 0573. In an embodiment, the active agent is a hair growth pratense, turnera spp., tussilago farfara, valeriana officina regulator. Suitable hair growth regulators include but are not lis, viburnum prunifolium, calendula officinalis limited to N-acetylgalactosamine, N-acetylglucosamine, 0569. In one or more embodiments, the steroid is a com N-acetylmannosamine, acitretin, aminexil, ascomycin, asi pound that is positively identified using a laboratory method, atic acid, azelaic acid, benzalkonium chloride, benzethonium Suitable of detecting a steroid. chloride, benzydamine, benzyl nicotinate, benzoyl peroxide, Steroids in Combination with Other Agents benzyl peroxide, betulinic acid, betulonic acid, calcium pan 0570. Several disorders of the skin, a body cavity or tothenate, celastrol, cepharanthine, chlorpheniramine male mucosal Surface (e.g., the mucosa of the nose, mouth, eye, ate, clinacycin hydrochloride, crataegolic acid, cromakalin, ear, vagina or rectum) involve a combination of inflammation, cyproterone acetate, diaZoxide, diphenhydramine hydrochlo cell proliferation and differentiation abnormalities, and other ride, dutasteride, estradiol, ethyl-2-hydroxypropanoate, fin biological abnormalities that can be effected by a steroid; and asteride, D-fucono-1,5-lactone, furoate, L-galactono-1.4-lac other etiological factors that require an additional therapeutic tone, D-galactosamine, D-glucaro-1,4-lactone, modality. For example, psoriasis involves inflammation as D-glucosamine-3-sulphate, hinokitiol, hydrocortisone, 2-hy well as excessive cell proliferation and inadequate cell differ droxypropionic acid, isotretinoin, itraconazole, ketocona entiation. Atopic dermatitis involves inflammation, skin dry Zole, latanoprost, 2-methylpropan-2-ol, minocyclin, minoxi ness and keratinocyte growth abnormality. Bacterial, fungal dil, mipirocin, mometaSone, oleanolic acid, panthenol, 1.10 and viral infections involve pathogen colonization at the phenanthroline, phenyloin, prednisolone, progesterone, affected site and inflammation. Likewise, hair growth disor propan-2-ol, pseudoterins, resorcinol, selenium sulfide, taZ ders and other pilosebaceous disorders involve an impaired arotene, triclocarbon, triclosan, triiodothyronine, ursolic hormonal balance (which can be affected by a steroid hor acid, Zinc pyrithione and derivatives, esters, salts and mix mone or a steroid hormone antagonist), together with other tures thereof. etiological factors, that can be affected a non-steroidal active 0574. In an embodiment, the therapeutic agent is a hor agent. Hence, in many cases, the inclusion of an additional mone. Suitable hormones include but are not limited to meth therapeutic agent in the foamable pharmaceutical composi yltestosterone, androsterone, androsterone acetate, andros US 2008/0299220 A1 Dec. 4, 2008

terone propionate, androsterone benzoate, androsteronediol. absorbed from vaginal tablets and rings, limited data are androsteronediol-3-acetate, androsteronediol-17-acetate, available regarding long-term safety of vaginally adminis androsteronediol 3-17-diacetate, androsteronediol-17-ben tered estrogen. Zoate, androsteronedione, androstenedione, androstenediol. 0581 Estrogens also are used in the treatment of a variety dehydroepiandrosterone, Sodium dehydroepiandrosterone of other conditions associated with a deficiency of estrogenic Sulfate, dromostanolone, dromostanolone propionate, ethyl hormones, including female hypogonadism and castration estrenol, fluoxymesterone, nandrolone phenpropionate, nan and primary ovarian failure. In addition, estrogens also may drolone decanoate, nandrolone furylpropionate, nandrolone be used in the treatment of abnormal uterine bleeding caused cyclohexane-propionate, nandrolone benzoate, nandrolone by hormonal imbalance not associated with organic pathol cyclohexanecarboxylate, androsteronediol-3-acetate-1-7- ogy; however, progestin's are usually preferred. benzoate, Oxandrolone, oxymetholone, stanozolol, testoster 0582 Estrogen replacement therapy (ERT) is effective for one, testosterone decanoate, 4-dihydrotestosterone, 5a-dihy the prevention of osteoporosis in women and has been shown drotestosterone, testolactone, 17a-methyl-19 to reduce bone resorption and retard or halt bone loss associ nortestosterone, desogestrel, dydrogesterone, ethynodiol ated with estrogen deficiency in postmenopausal women. diacetate, medroxyprogesterone, levonorgestrel, medroX Oral estrogens (e.g., estradiol, estropipate, conjugated estro yprogesterone acetate, hydroxyprogesterone caproate, nore gens) and transdermal estrogens (e.g., estradiol) are used thindrone, norethindrone acetate, norethynodrel, allylestre adjunctively with other therapeutic measures (e.g., diet, cal nol. 19-nortestosterone, lynoestrenol, quingestanol acetate, cium, vitamin D, weight-bearing exercise, physical therapy) medrogestone, norgestrienone, dimethisterone, ethisterone, to retard further bone loss and the progression of osteoporosis cyproterone acetate, chlormadinone acetate, megestrol in postmenopausal women. acetate, norgestimate, norgestrel, desogrestrel, trimegestone, 0583. Estrogen replacement therapy has been effective in gestodene, nomegestrol acetate, progesterone, 5a-pregnan the treatment of osteoporosis in postmenopausal women and 3b.20a-diol sulfate, 5a-pregnan-3b.20b-diol sulfate, 5a-preg has been recommended as first-line therapy for women with nan-3b-ol-20-one, 16.5a-pregnen-3b-ol-20-one, 4-pregnen osteoporosis. 20b-ol-3-one-20-Sulfate, acetoxypregnenolone, anagestone 0584) Estrogens have been used in a limited number of acetate, cyproterone, dihydrogesterone, fluorogestone anorexic women with chronic amenorrhea to reduce calcium acetate, gestadene, hydroxyprogesterone acetate, hydroxym lost and, thereby, reduce the risks of osteoporosis. ethylprogesterone, hydroxymethyl progesterone acetate, 0585 Some data from observational studies indicate that 3-ketodesogestrel, megestrol, melengestrol acetate, norethis prior use of hormone replacement therapy (HRT), but not terone, progestins and derivatives, esters, salts and mixtures current HRT unless such use exceeds 10 years, is associated thereof. with reduced risk of Alzheimer's disease 0575. In addition to what is stated above in relation to 0586 Estrogens are used in the palliative treatment of steroid hormones there is now provided particular description advanced, inoperable, metastatic carcinoma of the breast in of estrogens, progesterone and progestins and their uses. A postmenopausal women and in men. Estrogens are one of main source of information is AHFS Drug Information 2007 several second-line agents that can be used in certain post published by the American Society of Health-System Phar menopausal women with metastatic breast cancer. macists. 0587. In males, estrogens are used for the palliative treat ment of advanced carcinoma of the prostate. Estrogens 0588 Estrogen is also used in the therapy of vaginal atro 0576 Estrogens are naturally occurring hormones or syn phy, hypoestrogenism (as a result of hypogonadism, castra thetic steroidal and nonsteroidal compounds with estrogenic tion, or primary ovarian failure), amenorrhea, dysmenorrhea, activity. and oligomenorrhea. Estrogens can also be used to suppress 0577 Estrogens are used for the treatment of moderate to lactation after childbirth. severe vasomotor symptoms and other symptoms, including 0589 Hormone-receptor-positive breast cancers are Vulvar and vaginal atrophy, associated with menopause and treated with drugs which suppress production in the body of for the prevention and treatment of osteoporosis. When estro estrogen. This technique, in the context of treatment of breast gens are used alone. Such therapy is referred to as estrogen cancer, is know variously as hormonal therapy, hormone replacement therapy (ERT); when estrogens are used in com therapy, or anti-estrogen therapy (not to be confused with bination with progestin's, Such therapy usually is referred to hormone replacement therapy). as hormone replacement therapy (HRT) or postmenopausal 0590 At one time, estrogen was used to induce growth hormone therapy. attenuation in tall girls. 0578 Estrogen or estrogen/progestin therapy is effective 0591) Estrogen has been used in experimental research as for the management of certain menopausal symptoms and for a way to treat patients suffering from bulimia nervosa. the prevention and treatment of osteoporosis. 0592 Estrogens also are used in combination with 0579 Estrogen or estrogen/progestin therapy is the most progestins for ovulation control in the prevention of concep effective therapy for the relief of vasomotor symptoms such tion and for the treatment of moderate acne Vulgaris; estro as hot flushes (flashes) and sleep disturbances. Estrogen or gen-progestin combinations also are used in short-course, estrogen/progestin therapy also is effective in the treatment of high-dose regimens in women for the prevention of contra genitourinary symptoms such as vaginal dryness; however, ception after unprotected intercourse (postcoital contracep the use of topical vaginal preparations should be considered tion, "morning-after pills') as emergency contraceptives. when only vulvar and vaginal symptoms are being treated. 0593 Estrogens may be administered orally, parenterally, 0580 For symptoms such as vaginal dryness, topical intravaginally, or topically. administration of estrogen alone usually is effective. 0594 Dosage equivalencies for estrogens have not been Although only limited amounts of estrogen are systemically clearly established, and reported comparative values vary US 2008/0299220 A1 Dec. 4, 2008 46 greatly. The dosage range of estrogens is generally wide, and tions and pain sometimes produced upon injection have led to dosage should be individualized according to the condition the synthesis of chemical derivatives that are effective orally, being treated and the response and tolerance of the patient. To are more potent, more specific in action, or have a longer minimize the risk of adverse effects, the lowest possible duration of action. effective dosage should be used. 0602 Progesterone administration topically for example 0595 Estrogen therapy is administered in a continuous intravaginally may be a useful alternative to injection and for daily regimen or, alternatively, estrogens are administered example may be desirable if the vagina or uterus is a target for cyclically. When estrogens are administered cyclically, the its effect. Progesterone absorbance for topical and body cav drugs are usually given once daily for 3 weeks, followed by 1 ity applications may be assisted for example by a penetration week without the drugs, and then this regimen is repeated as enhancer Such as cylodextrins, isopropyl myristate, mineral necessary. While estrogen therapy alone may be appropriate oil or propylene glycol in women who have undergone a hysterectomy, a progestin 0603 Progesterone is used to control anovulatory bleed generally is added to estrogen therapy in women with an ing. It is also used to prepare uterine lining in infertility intact uterus. Addition of a progestin for 10 or more days of a therapy and to support early pregnancy. Patients with recur cycle of estrogen administration or daily with estrogen in a rent pregnancy loss due to inadequate progesterone produc continuous regimen reduces the incidence of endometrial tion may receive progesterone. hyperplasia and the attendant risk of endometrial carcinoma 0604 Progesterone is being investigated as potentially in women with an intact uterus. beneficial in treating multiple Sclerosis, since the character 0596. The most frequent adverse dermatologic reaction istic deterioration of nerve myelin insulation halts during associated with estrogen therapy is chloasma or melasma. pregnancy, when progesterone levels are raised; deterioration Women who have had melasma during pregnancy appear to commences again when the levels drop. be most Susceptible. Irregular brown macules may develop 0605 Progesterone is used in hormone therapy for trans slowly on the face within 1 month to 2 years following ini sexual women, and some Intersex women—especially when tiation of estrogen therapy. The macules fade more slowly synthetic progestins have been ineffective or caused side than in melasma gravidarum and may be permanent. effects—since normal breast tissue cannot develop except in 0597 Other dermatologic reactions include erythema the presence of both progestogen and estrogen. Mammary multiforme, erythema nodosum, and hemorrhagic eruption. glandular tissue is otherwise fibrotic, the breast shape conical Hirsutismandalopecia have also occurred. Porphyriacutanea and the areola immature. Progesterone can correct those even has reportedly been adversely affected in some women after years of inadequate hormonal treatment. Research usu receiving estrogen therapy. ally cited against Such value was conducted using Provera, a 0598. Estrogens are readily absorbed through the skin and synthetic progestin. Progesterone also has a role in skin elas mucous membranes. Depending on the amount of estrogen ticity and bone strength, in respiration, in nerve tissue and in applied, systemic as well as local effects may occur following female sexuality, and the presence of progesterone receptors topical application. Penetration may be assisted by penetra in certain muscle and fat tissue may hint at a role in sexually tion enhancers for example like propylene glycolorisopropyl dimorphic proportions of those. myristate. 0606 Progesterone receptor antagonists, or selective 0599 Estrogens are naturally occurring hormones or syn progesterone receptor modulators (SPRM)s, such as RU-486 thetic steroidal and nonsteroidal compounds with estrogenic (Mifepristone), can be used to prevent conception or induce activity. The estrogens can be divided into 2 groups based on medical abortions. their chemical structures: Steroidal and nonsteroidal com 0607 Ethisterone was the first synthetic progestin devel pounds. All naturally occurring estrogens are steroids that oped; the drug is not currently available. 19-Nor, 17-acetoxy, contain a cyclopentanoperhydrophenanthrene ring structure and 6-methyl derivatives, which exhibit interesting struc with an unsaturated A ring, a methyl group at the C 13 posi tural-pharmacologic relationships, have been synthesized. tion, a phenolic hydroxyl group at the C 3 position, and a Some estrogenic or androgenic activity, anabolic effects, ketone or hydroxyl group at the C 17 position. Only a limited nitrogen retention, and weight gain are exhibited by the number of changes can be made in this basic steroid structure 19-nor derivatives. The 17-hydroxy or acetoxy compounds, without losing estrogenic activity. These changes are limited on the other hand, elicit responses more nearly resembling to an interconversion of the hydroxyl and ketone groups or the those of progesterone. They have little or no estrogenic or addition of various side chains at the C3 and C 17 positions. androgenic activity and may produce catabolic and slight 0600 The natural steroidal estrogens (estradiol, estrone, diuretic effects. The 19-nor derivatives are more effective in estriol, equilin, and equilenin) and their conjugates are usu postponing the normal menstrual period. ally obtained from pregnant mares' urine or prepared syn 0608 Progestins elicit, to varying degrees, all the pharma thetically. The natural steroidal estrogens, both those cologic responses usually produced by progesterone: induc obtained exclusively from natural Sources and those prepared tion of secretory changes in the endometrium, increase in synthetically, are insoluble in water but when conjugated as basal body temperature (thermogenic action), production of the Sulfates or glucuronides, these hormones become water histologic changes in vaginal epithelium, relaxation of uter soluble. Synthetic derivatives of the natural steroidal estro ine Smooth muscle, stimulation of mammary alveolar tissue gens were previously available. The nonsteroidal estrogens growth, pituitary inhibition, and production of withdrawal include diethylstilbestrol (DES) and dienestrol. bleeding in the presence of estrogen. Progesterone 0609 Progestin's are used in the treatment of functional uterine bleeding caused by hormonal imbalance and involv 0601 The use of progesterone, a hormone secreted by the ing a hyperplastic nonsecretory endometrium and the absence corpus luteum, is well established in medicine. Its relative of underlying organic pathology Such as fibroids or uterine inactivity following oral administration and the local reac cancer, and for the treatment of primary and secondary amen US 2008/0299220 A1 Dec. 4, 2008 47 orrhea in the presence of estrogen. Medroxyprogesterone and saccharic acid, talaric acid, tartaric acid, tartronic acid, hydroxyprogesterone also are used in the adjunctive and pal threaric acid, tropic acid, uronic acids, Xylaric acid and liative treatment of some cancers. Some progestin's are used derivatives, esters, salts and mixtures thereof. alone or in combination with estrogens for the prevention of 0616 Yet, another preferred keratolytic agent is urea, as conception. Medroxyprogesterone prevents follicular matu well as derivatives thereof. Urea possesses both keratolytic ration and ovulation following IM administration, and the and skin-hydration properties which are beneficial to the drug has been used parenterally for contraception. damaged tissue of the skin. 0610 Progestin's (e.g., drospirenone, medroxyprogester 0617. Another preferred group of keratolytic agents, suit one, norethindrone acetate, norgestimate) are used to reduce able for inclusion in the therapeutic composition according to the incidence of endometrial hyperplasia and the attendant the present invention is beta-hydroxy acids, such as salicylic risk of endometrial carcinoma in postmenopausal women acid (o-hydroxybenzoic acid). Beta hydroxyl acids are kera receiving estrogen replacement therapy. tolytic, and they are also have anti-inflammatory and antibac 0611 Progestin's have been used beginning in the first terial properties. trimester of pregnancy to prevent habitual abortion or to treat 0618. Short chain carboxylic acids (carboxylic acids hav threatened abortion. ing up to 6 carbonatoms in their skeleton) are also suitable for inclusion in the therapeutic composition as keratolytic Hydroxyacid agents. Examples of short chain carboxylic acid include, but are not limited to formic acid, acetic acid, propionic acid, 0612. In an embodiment, the therapeutic agent is a butyric acid (Butanoic acid), Valeric acid (pentanoic acid) and hydroxyacid. Suitable hydroxy acids include but are not lim caproic acid (hexanoic acid). In the context, di-carboxylic ited to agaricic acid, aleuritic acid, allaric acid, altraric acid, acids having up to 6 carbon atoms in their skeleton are also arabiraric acid, ascorbic acid, atrolactic acid, benzilic acid, suitable under the definition of short chain carboxylic acids citramalic acid, citric acid, dihydroxytartaric acid, erythraric having up to 6 carbon atoms in their skeleton. Non-limiting acid, galactaric acid, galacturonic acid, glucaric acid, glucu examples of Suitable dicarboxylic acids are malonic acid ronic acid, glyceric acid, glycolic acid, gularic acid, gulonic (propanedioic acid). Succinic acid (butanedioic acid), glutaric acid, hydroxypyruvic acid, idaric acid, isocitric acid, lactic acid (Pentanedioic acid) and adipic acid (Hexanedioic acid). acid, lyxaric acid, malic acid, mandelic acid, mannaric acid, Also suitable under the definition of short chain carboxylic methyllacetic acid, mucic acid, phenylacetic acid, pyruvic acid are unsaturated short chain carboxylic acids, i.e., short acid, quinic acid, ribaric acid, ribonic acid, Saccharic acid, chain carboxylic acids, having one or more double bonds in talaric acid, tartaric acid, tartronic acid, threaric acid, tropic their carbon skeleton; and halogenated short chain carboxylic acid, uronic acids, Xylaric acid and derivatives, esters, salts acids, such as fluoroethanoic acid (CH2FCO2H), chloroetha and mixtures thereof. noic acid (CH2ClCO2H) and dichloroethanoic acid (CHCl2CO2H). Dicarboxylic acids, having between about 6 Keratolytic and about 14 carbonatoms in their carbon atom skeleton also 0613. In an embodiment, the active agent is a keratolytic possess leratolytic properties. Suitable dicarboxylic acid agent. The term "keratolytic agent' is used herein to mean a moieties include, but are not limited to, adipic acid, pimelic compound which loosens and removes the stratum corneum acid, Suberic acid, azelaic acid, sebacic acid, 1.11-unde of the skin, or alters the structure of the keratin layers of skin. canedioic acid, 1,12-dodecanedioic acid, 1,13-tridecanedioic Keratolytic agents are used in the treatment of many derma acid and 1,14-tetradecanedioic acid. tological disorders, which involve dry skin, hyperkeratiniza 0619. Another group of keratolytic agents include phenol tion (such as psoriasis), skin itching (such as Xerosis), acne and Substituted phenolic compounds. Such compounds are and rosacea. Suitable keratolytic agents include but are not known to dissolve and loosen the intracellular matrix of the limited to N-acetylcysteine, azelaic acid, cresols, dihydroxy hyperkeratinized tissue. Dihydroxybenzene and derivatives benzene compounds, such as resorcinol and hydroquinone, thereof have been recognized as potent keratolytic agents. alpha-hydroxy acids, Such as lactic acid and glycolic acid, Resorcinol (m-dihydroxybenzene) and derivatives thereof phenol, pyruvic acid, resorcinol, Sulfur, salicylic acid, ret are used in anti-acne preparations. Hydroquinone (p-dihy inoic acid, isoretinoic acid, retinol, retinal, urea and deriva droxybenzene), besides its anti-pigmentation properties, is tives, esters, salts and mixtures thereof. also keratolytic. 0614 The term “keratolytic agent” refers herein to a com 0620. Vitamin A and its derivatives, such as retinol, reti pound which loosens and removes the stratum corneum of the nal, retinoic acid, retinyl acetate, retinyl palmitate, retinyl skin, or alters the structure of the keratin layers of skin. ascorbate, isotretinoin, tazarotene, adapalene, 13-cis-retinoic 0615 Suitable keratolytic agents also include alpha-hy acid, acitretin all-trans beta carotene, alpha carotene, lyco droxy acids. Alfa hydroxy acids are keratolytic, and they are pene, 9-cis-beta-carotene, lutein and Zeaxanthin are another also capable of trapping moisture in the skin and initiating the class of keratolytic agents, which alter the structure of the formation of collagen. Suitable hydroxy acids include but are skin and promote peeling. not limited to agaricic acid, aleuritic acid, allaric acid, altraric 0621. In certain embodiments, the keratolytic agent acid, arabiraric acid, ascorbic acid, atrolactic acid, benzilic includes at least two keratolytic agents. At least two or more acid, citramalic acid, citric acid, dihydroxytartaric acid, keratolytic agents in the therapeutic composition, a safe and erythraric acid, galactaric acid, galacturonic acid, glucaric effective peeling agent is attained, which breaks down the acid, glucuronic acid, glyceric acid, glycolic acid, gularic keratin layer of the skin, where the microorganisms reside. As acid, gulonic acid, hydroxypyruvic acid, idaric acid, isocitric a result of such breaking down of the keratin layer, the micro acid, lactic acid, lyxaric acid, malic acid, mandelic acid, organisms cannot further Survive in the infected area. The mannaric acid, methylacetic acid, mucic acid, phenyllacetic combination of at least two keratolytic agents enables a selec acid, pyruvic acid, quinic acid, ribaric acid, ribonic acid, tive breaking down of keratin in infected skin areas, while US 2008/0299220 A1 Dec. 4, 2008 48 non-infected skin areas are not affected. This phenomenon is of cyclooxygenase are known today: the constitutive explained by the fact that the keratin layer in infected skin cyclooxygenase (COX-1); and the inducible cyclooxygenase areas is deformed and thus it is more vulnerable to keratolytic (COX-2), which is proinflammatory. Thus, in one or more disintegration. Furthermore, combining at least two kera embodiments, the NSAID is selected from the group consist tolytic agents facilitates use of each agent in a Substantially ing of a COX-1 inhibitor, a COX-2 inhibitor or a non-selective minimally-irritating concentration, thus decreasing the over NSAID, which simultaneously inhibits both COX-1 and all irritation of the therapeutic composition. COX-2. 0622. In one or more embodiments, the keratolytic agent 0628. The term “selective COX-2 inhibitor relates o a includes at least two keratolytic agents, from different fami compound able to inhibit cyclooxygenase-2 without signifi lies of chemicals. Thus, in preferred embodiments, the kera cant inhibition of COXe-1. Typically, it includes compounds tolytic agent includes at east two agents, from different that have a COX-2 ICs of less than about 0.2 micro molar, chemical families, selected from the group consisting of: (1) and also have a selectivity ratio of COX-2 inhibition over an alpha-hydroxy acid; (2) a beta-hydroxy acid; (3) a short COX-1 inhibition of at least 50, and more typically, of at least chain carboxylic acid; (4) a hydroxylbenzene; (5) a vitamin A 100. Inhibitors of the cyclooxygenase pathway in the metabo derivative; and (6) urea. As detailed above, each of these lism of arachidonic acid used in the present invention may keratolytic agent families possess, in addition to their kera inhibit enzyme activity through a variety of mechanisms. By tolytic property, additional therapeutically-beneficial feature, the way of example, and without limitation, the inhibitors Such as anti-inflammatory, skin hydration and antibacterial used in the methods described herein may block the enzyme properties for readily contributing to the overall therapeutic activity directly by acting as a Substrate for the enzyme. benefit of the therapeutic composition. 0629 Selective COX-2 Inhibitors include, in an exem 0623. In an embodiment, the active agent is a lactam. plary manner diaryl-substituted furanones (e.g., Rofecoxib); Suitable lactams include but are not limited to L-galactono diaryl-substituted pyrazoles (e.g., Celecoxib); indole acetic 1.4-lactam, L-arabino-1,5-lactam, D-fucono-1,5-lactam, acids (e.g., Etodolac); and Sulfonanilides (e.g., NimeSulide) D-glucaro-1,4-lactam, D-glucurono-6.3-lactam, 2.5-tri-O- and salts and derivatives thereof. acetyl-D-glucurono-6.3-lactam, 2-acetamido-2-deoxyglu 0630. In one or more embodiments, the selective COX-2 cono-1,5-1-actam, 2-acetamido-2-deoxygalactono-1,5-lac inhibitor is selected from the group consisting of celecoxib, tam, D-glucaro-1,4:6.3-dilactam-, L-idaro-1,5-lactam, 2.3.5. deracoxib, Valdecoxib, rofecoxib, lumiracoxib, etoricoxib, tri-O-acetyl-D-glucaro-1,4-lactam, 2,5-di-O-acetyl-D- meloxicam, parecoxib, 4-(4-cyclohexyl-2-methyloxazol-5- glucaro-1,4:6.3-dilactam, D-glucaro-1,5-lactam methyl yl)-2-fluorobenzenesulfonamide, 2-(3,5-difluorophenyl)-3- ester, 2-propionoamide-2-deoxyglucaro-1,5-lactam and (4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one, N-2-(cy derivatives, esters, salts and mixtures thereof. clohexyloxy)-4-nitrophenylmethanesulfonamide, 2-(3,4- difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-4- Nonsteroidal Anti-Inflammatory Agent (methylsulfonyl)-phenyl-3(2H)-pyridazinone, 2-(2,4- 0624. In an embodiment, the therapeutic agent is a non dichloro-6-methylphenyl)amino-5-ethyl-benzeneacetic steroidal anti-inflammatory agent. acid, (3Z)-3-(4-chlorophenyl)-4-(methylsulfonyl)phenyl 0625 Inflammation is defined as "redness, swelling, and met-hylenedihydro-2(3H)-furanone, and (S)-6,8-dichloro fever in a local area of the body, often with pain and disturbed 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid. function, in reaction to an infection or to a physical or chemi 0631. In additional embodiments, the selective COX-2 cal injury' (Random House Webster's Dictionary). Typical inhibitor is selected from the group consisting of ibuprofen, symptoms of disorders of the skin, body Surfaces, body cavi naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ties and mucosal Surfaces (e.g., the mucosa of the nose, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, mouth, eye, ear, respiratory system, vagina or rectum) that prapoprofen, miroprofen, tioxaprofen, Suprofen, alminopro involve inflammation, as at least one of their etiological fac fen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, tors, include redness (rash, erythema), tissue thickening and/ Sulindac, tolmetin, Zomepirac, diclofenac, fenclofenec, or Swelling (oedema), itch (pruritus), blistering and exudate. alclofenac, ibufenac, isoxepac, furofenac, tiopinac, Inflammatory disorders can by short term or long term Zidometacin, acetyl salicylic acid, indometacin, piroxicam, (chronic). Inflammation typically involves overproduction of tenoxicam, nabumetone, ketorolac, azapropaZone, mefe pro-inflammatory cytokines, such as TNF-alpha, TNF-beta, namic acid, tolfenamic acid, diflunisal, podophyllotoxin interleukin-1, interleukin-4, interleukin-6, interleukin-10, derivatives, acemetacin, droxicam, floctafenine, oxyphenb interleukin-12, IFN-gamma from T cells, or increased release utaZone, phenylbutaZone, proglumetacin, acemetacin, fen of cytokines and pro-inflammatory mediators from mast tiazac, clidanac, oxipinac, mefenamic acid, meclofenamic cells. acid, flufenamic acid, niflumic acid, flufenisal, Sudoxicam, 0626. In the context, a nonsteroidal immunomodulating etodolac, piprofen, Salicylic acid, choline magnesium trisali agent (also termed herein “nonsteroidal anti-inflammatory cylate, salicylate, benorylate, fentiazac, clopinac, feprazone, agent” and “NSAID) is a pharmaceutically active com isoxicam, and 2-fluoro-a-methyl 1, 1'-biphenyl-4-acetic pound, other than a corticosteroid, which affects the immune acid, 4-(nitrooxy)butyl ester. system in a fashion that results in a reduction, inhibition, 0632. In one or more embodiments, the NSAID is salicylic prevention, amelioration or prevention of an inflammatory acid a salicylic acid derivatives. Exemplary Salicylic acid process and/or the symptoms of inflammation and or the derivative include, in a non limiting fashion, aspirin, sodium production pro-inflammatory cytokines and other pro-in salicylate, choline magnesium trislicylate, Salsalate, flammatory mediators, thereby treating or preventing a dis diflunisal, salicylsalicylic acid, SulfaSalazine, olsalazine, ease that involves inflammation. esters of Salicylic acid with a carboxylic acid, esters of Sali 0627. In one or more embodiments, the NSAID is an cylic acid with a dicarboxylic acid, esters of Salicylic acid inhibitor of the cyclooxygenase (COX) enzyme. Two forms with a fatty acid, esters of salicylic acid with a hydroxyl fatty US 2008/0299220 A1 Dec. 4, 2008 49 acid, esters of salicylic acid with an essential fatty acid, esters according to the present invention. Such agents are chemi of salicylic acid with a polycarboxylic acid, and any com cally or biologically-derived agents that modify the immune pound wherein Salicylic acid is linked to an organic moiety response or the functioning of the immune system (as by the through a covalent bond. stimulation of antibody formation or the inhibition of white 0633. In one or more embodiments, the NSAID is para blood cell activity). Immunosuppressant agents and immu aminophenol (e.g., acetaminophen) and salts and derivatives nomodulators include, among other options, cyclic peptides, thereof. Such as cyclosporine, tacrolimus, tresperimus, pimecrolimus, 0634. In one or more embodiments, the NSAID is an Sirolimus (rapamycin), Verolimus, laflunimus, lacquinimod indole oran indole-acetic acid derivative (e.g., indomethacin, and imiquimod. In one or more embodiments, the non steroi Sulindac, etodolac) and salts and derivatives thereof. dal immunomodulating agent is a calcineurin Inhibitor. 0635. In one or more embodiments, the NSAID is an aryl 0.645. In one or more embodiments, the NSAID is a nitric acetic acids (e.g., tolmetin, diclofenac, ketorolac) and salts oxide inhibitor. Nitric oxide (NO) is a potent secondary mes and derivatives thereof. senger that is both highly reactive and highly diffusible. It is 0636. In one or more embodiments, the NSAID is an aryl generated physiologically by a family of enzymes, referred to propionic acid and salts and derivatives thereof. Exemplary as NO synthases (NOS). Overproduction of NO plays a key arylpropionic acid derivative include, in a non limiting fash role in the pathology of a wide range of disorders including ion, are ibuprofen, naproxen, flubiprofen, ketoprofen, feno disorders that involve inflammation, and NOS inhibitors have profen, oxaprozin. been suggested as anti-inflammatory agents. Agents that neu 0637. In one or more embodiments, the NSAID is anthra tralize NO (also called “NO scavengers') are considered as nilic acids or an anthranilic acid derivative, also termed potential anti-inflammatory agents as well. “fenamates' (e.g., mefenamic acid, meclofenamic acid) and 0646. Also useful are compounds that inhibit or slow salts and derivatives thereof. down the migration of leucocytes (white blood cell), e.g., 0638. In one or more embodiments, the NSAID is selected macrophages, neutrophils, and monocytes towards an from the group of enolic acids, enolic acid salts, enolic acid afflicted skin Surface or mucosal membrane, which is known esters, amides, anhydrides and salts and derivatives thereof. to accelerate the inflammatory process. Non-limiting examples of enolic acid derivatives include oxi 0647. Among other inhibitors of leucocyte chemoaxis, cams (piroXicam, tenoxicam) and pyrazolidinediones (phe dicarboxylic acids, having between about 6 and about 14 nylbutaZone, oxyphenthratraZone) carbon atoms in their carbon atom skeleton are particularly 0639. Yet, in additional embodiments, the NSAID is an useful in the treatment of disorders of the skin and mucosal alkanone (e.g., nabumetone). membranes that involve inflammation. Suitable dicarboxylic 0640 Certain imidazole drugs (e.g., ketoconazole) also acid moieties include, but are not limited to, adipic acid, possess anti-inflammatory properties, (See: JAm Acad. Der pimelic acid, Suberic acid, azelaic acid, Sebacic acid, 1.11 matol. 1991 August; 25(2 Pt 1):257-61). undecanedioic acid, 1,12-dodecanedioic acid, 1,13-tride 0641 Another group of nonsteroidal immunomodulating canedioic acid and 1,14-tetradecanedioic acid. Thus, in one or agents includes agents, which inhibit pro-inflammatory more embodiments, dicarboxylic acids, having between cytokines, such as TNF-alpha, TNF-beta, interleukin-1, inter about 6 and about 14 carbon atoms in their carbon atom leukin-4, interleukin-6, interleukin-10, interleukin-12 and skeleton, as well as their salts and derivatives (e.g., esters, IFN-gamma from T cells, which are especially important in amides, mercapto-derivatives, anhydraides), are useful the induction of inflammation or inhibit the release of cytok immunomodulators in the treatment of disorders of the skin ines and pro-inflammatory mediators from mast cells. and mucosal membranes that involve inflammation. AZelaic 0642 Agents that are used to affect the untoward influence acid and its salts and derivatives are preferred. of pro-inflammatory cytokines are chemically or biologi 0648 Certain preferred dicarboxylic acid derivatives cally-originated materials that Suppress the pro-inflammatory include a dicarboxylic acid wherein at least one ester moiety effect of a pro-inflammatory cytokine via various mecha of the compound comprises a keratolytic agent, selected from nisms, including, but not limited to (a) inhibiting the forma the group consisting of alpha-hydroxy acids and derivatives tion of a pro-inflammatory cytokine; (b) Suppressing the thereof, beta-hydroxy acids and derivatives thereof, hydroxy interaction of a pro-inflammatory cytokine with its receptors; benzoic acid and their ester, anhydride and amine derivatives, or (c) neutralization the proinflammatory cytokine by direct alkylhydroxybenzoate, dihydroxy benzene and their ester, or indirect interaction. anhydride and amide derivatives, cresols and their ester, 0643. Examples of chemical anti TNF-C. agents are known anhydride and amide derivatives. Keratolytic agents also pharmaceutical materials, such as pentoxifylline, pro include alcohol derivatives of Vitamin A (retinoic acid), e.g., pentofylline, torbafylline (and other related Xanthines), retinol and derivatives thereof, as provided in U.S. Pat. No. amiloride, chloroquine, thalidomide and structural analogs 6,180.669. Additional preferred dicarboxylic acid derivatives thereof. Examples for biological anti-TNF-C. agents are anti comprise at least one ester of a active alcohol moiety, selected TNF-C. antibodies and soluble TNF-C. receptors. Additional from the groups of steroid hormones, corticosteroids, vitamin compounds are those that impair the signal transduction cas E and vitamin D, as provided in US Patent Application cade from the receptor to other functional organs of the living 2004O191196. cell. Such active agents, as well additional compounds, which 0649. In one or more embodiments, the NSAID is an ion are capable of inhibiting the production or otherwise Sup channel modulator. Ion channels are protein macromolecules pressing the pro-inflammatory effects of TNF-C. can be used located in the cell membranes that enable the selective move in the composition. ment of sodium, potassium, and calcium from outside the cell 0644 Immunosuppressant agents, immunoregulating to inside the cell and Vice-versa. agents and immunomodulators constitute an additional class 0650. In one or more embodiments, the NSAID is a potas of nonsteroidal anti-inflammatory agents, which are used sium ion channel modulator. It has been shown that the potas US 2008/0299220 A1 Dec. 4, 2008 50 sium ion channel modulator play important roles in control piperidinyl)-4-pyrimidinyl-1-piperazinylpregna-4.9(11)- ling T-cell activation and thus, they can be used to control diene-320-dione, 21-4-2,6-bis(diethylamino)-b4 inflammation. pyrimidinyl)-4-pyrimidinyl-1-piperazinyl-1-piperazinyl 0651. In one or more embodiments, the potassium ion 17 O.-hydroxy-16 C.-methylpregna-1,4,9(11)-triene-320 channel modulator is selected from the group consisting of dione, 17 O-hydroxy-21-4-2,6-bis(4-methyl-1-piperazinyl dendrotoxin, dendrotoxin I, dendrotoxin K, alpha-dendro pregna-4.9(11)-diene-3,20-dione, 17 O.-hydroxy-6 C.-methyl toxin, beta-dendrotoxin, gamma-dendrotoxin, margatoxin, 21 4-2,6-bis-(1-pyrrolidinyl-4-pyrimidinyl-1-piperazinyl Stichodactyla toxin, tityustoxin K, apamin, charylotoxin, clo pregna-1,4,9(11)-triene-320-dione, 21-4-2,6-bis trimazole, dequalinium chloride, iberiotoxin, kaliotoxin, (diethylamino)-4-pyrimidinyl-1-piperazinyl-1-1 C, 17 neuropeptide Y, noxiustoxin, tolbutamide, chlorpropamide, C.-dihydroxypregn-4-ene-320-dione, 21-4-2,6-bis(diethy glibenclamide, glipizide, nategliniide, repagliniide, gly lamino)-4-pyrimidinyl-1 piperazinyl-17 C-hydroxypregn buride, tolaZamide, nicorandil, fampiridine and penitrem A, or 4-ene-3,20-dione, 21-4-2,6-bis(diethylamino)-4-pyrimidi is a pharmaceutically acceptable salt or prodrug thereof. nyl-1-piperazinyl-17 C-hydroxy-6 C.-methylpregna-14.9 0652. In an embodiment, the potassium ion channel (11)-triene-320-dione, 17 O-hydroxy-21-4-2,6-bis(1- modulator is selected from the list of potassium ion channel pyrrolidinyl)-4-pyrimidinyl-1-piperazinylpregna-4.9(11)- modulators, provided in WO 2004/093895. diene-320-dione, 21-4-2,6-bis(diethylamino)-4- 0653. In one or more embodiments, the NSAID is a pyrimidinyl-1-piperazinyl-11 C-hydroxypregn-4-ene-3, Sodium ion channel modulator. In one or more embodiments, 20-dione, 21-4-2,6-bis(diethylamino)-4-pyrimidinyl)-1- the Sodium ion channel blocker is selected from the group piperazinyl-11 C, 17 O.-dihydroxypregn-4-ene-3,20-dione, consisting of disopyramide, procainimide, quinidine, tocam 17 O-hydroxy-16 C.-methyl-21-4-2,6-bis-(1-pyrrolidinyl)- ide, mexiletene, lidocane, phenyloin, fosphenyloin, flecam 4-pyrimidinyl-1-piperazinylpregna-1,4,9(-11)-triene-3,20 ide, propafenone, morcizine, lubeluzole, carbamazepine, dione, 17O-hydroxy-21-4-2,6-bis(1-pyrrolidinyl)-4-pyrim sipatrigine, riluzole, tetrodotoxin, spheroidine, maculotoxin, idinyl-1-piperazinylpregna-1,4,9(11)-triene-320-dione, Vinpocetine, anthopleurin-c, lamotrigine, crobenetine, 21-4-2,6-bis(diethylamino)-4-pyrimidinyl-1-piperazi lifarizine, lanodipine, lomerizine, encamide, and flunarizine nyl-17 C.-hydroxypregna-1,4,9(11)-triene-3,20-dione, 21 or is an isomer, a pharmaceutically acceptable salt, ester, or 4-4,6-bis(diethylamino)-2-pyrimidinyl-11-piperazinyl prodrug thereof. 17O-hydroxypregna-1,4,9(11)-triene-320-dione, 21-4-2, 0654. In an embodiment, the potassium ion channel 6-bis(diethylamino)-4-pyrimidinyl-1-piperazinyl-16 modulator is selected from the list of potassium ion channel C.-methylpregna-1,4,9(11)-triene-320-dione, 21-4-2,6-bis modulators, provided in U.S. Pat. Appl. 20040224940 and (diethylamino)-4-pyrimidinyl-1-piperazinyl-11. alpha.-hy 2004O22O187. droxy-16 C-methylpregna-1,4-diene-320-dione, 21-4-2,6- 0655. In one or more embodiments, the NSAID is a modu bis(diethylamino)-4-pyrimidinyl-1-piperazinyl-1-6 lator of serotonin (5-hydroxytryptamine, 5-HT) activity. C.-methylpregna-1,4-diene.3.20-dione, 16 C.-methyl-21-4- 5-HT is known to affect inflammation through its modulation 2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl-1-piperazinylpre effect on cytokine production (Cloéz-Tayarani et al. Int. gna-1,4,9(11)-triene-3,2-0-dione, 11 C-hydroxy-16 C21-4- Immunol. 2003, 15233). In certain embodiments, the sero 2,6-bis(1-pyrrolidinyl)-4-pyrimidinylpiperazinylpregna tonin activity modulator is a serotonin reuptake inhibitor. It 1,4-diene-3,20-dione, 16 C.-methyl-21-4-2,6-bis(1- has been shown that serotonin reduces inflammation and pyrrolidinyl)-4-pyrimidinyl-1-piperazinylpregna-1,4- assists healing of experimental skin wounds, and thus, sero diene-320-dione, 16.alpha.-methyl-21-4-2,6-bis(4- tonin reuptake inhibitor can be used to control inflammation morpholino)-4-pyrimidinyl-1-piperazinylpregna-1,4,9 and associated disorders. (11)-triene-320-dione, 11 O-hydroxy-16 C.-methyl-21-4-2, 0656. In one or more embodiments, the serotonin reuptake 6-bis(4-morpholino)-4-pyrimidinyl-1-piperazinylpregna inhibitor is selected from the group consisting of citalopram, 1,4-diene-3,20-dione, 16.alpha.-methyl-21-4-2-,6-bis(4- fluoxetine, fluvoxamine, paroxetine, escitalopram oxalate, morpholino(4-pyrimidinyl-1-piperazinylpregna-1,4-diene sertraline, norfluoxetine and N-demethylsertraline. 3.20-dione, 21-4-2,6-bis(allylamino)-4-pyrimidinyl)-1- 0657. In an embodiment, the serotonin reuptake inhibitor piperazinyl-16 C.-methylpregna-1,4,9(11)-triene-320 is selected from the list of potassium ion channel modulators, dione, 21-4-2,6-bis(allylamino)-4-pyrimidinyl)-1- provided in US Pat Appl. 2004.0171664. piperazinyl-11 C-hydroxy-16 C.-methylpregna-1,4-ene-3,2- 0658. In one or more embodiments, the NSAID is an anti O-dione, 21-4-2,6-bis(allylamino)-4-pyrimidinyl)-1- oxidant. Reactive oxygen species play an important role in piperazinyl-16 C.-methylpregna-1,4-ene-3,20-dione, 21-4- mediating skin inflammation, and antioxidants may provide 2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl-1-piperazinyl protection. pregn-4-ene-3,11,20-trione, 21-4-2,6-bis(1-pyrrolidinyl)- 0659 Non-limiting examples of antioxidant agents 4-pyrimidinyl-1-piperazinylpregna-4.9(11)-diene-320 include 21-4-2-amino-6-(diethylamino)-4-pyrimidinyl)-1- dione, 21-4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1- piperazinyl-17C.-hydroxypregna-4.9(11)-diene-3,20-dione, piperazinylpregna-1,4-diene-3,20-dione, 21-4-(2,6-bis(1- 17 C.-hydroxy-21-4-2,6-bis(dimethylamino)-4-pyrimidi pyrrolidinyl)-4-pyrimidinyl)-1-piperazinylpregna-4.9(11)- nyl-1-piperazinylpregna-4.9(11)-diene-320-dione, 21-4- diene-320-dione, 21-4-(2,6-bis(4-morpholino)-4- 2-(diethylamino)-6-(1-pyrrolidinyl)-4-pyrimidinyl-1-pip pyrimidinyl)-1-piperazinyl-17 C-hydroxypregna-4.9(11)- erazinyl-17C.-hydroxypregna-4.9(11)-diene-320-dione, 17 diene-320-dione, 21-4-(2,6-bis(1-pyrrolidinyl)-4- C-hydroxy-21-4-2-(diethylamino)-6-(4-methyl-1-piper pyrimidinyl)-1-piperazinylpregna-4-en-3-one, 21-4-(2,6- azinyl(4-pyrimidinyl)-1-piperazinylpregna-4.9(11)-diene bis(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazinylpregn-4- 3.20-dione, 17 O-hydroxy-21-4-2,6-bis(diethylamino)-4- en-3-one, 16 O-methyl-21-4-2,6-bis(1-pyrrolidinyl)-4- pyrimidinyll-piperazinylpregna-4.9(11)-diene-3,20 pyrimidinyl-1-piperazinylpregna-1,4,9(11)-triene-320 dione, 1 O-hydroxy-21-4-2-(diethylamino-)-6-(1- dione, 21-4-(2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl)-1-

US 2008/0299220 A1 Dec. 4, 2008 52 antagonists are known to affect inflammation and pain, as monene, nicotine, pyrethrins, cinerins, jasmolin, quassia, shown, for example in J Pharmacol Exp. Ther: 2003 October; rotenone, ryania and Sabadilla. 307(1):17-23. Epub 2003 Aug. 27. 0672. In one or more embodiments, the insecticide is a 0663. In certain embodiments, the angiotensin II receptor carbamate insecticide. Examples of carbamate insecticides antagonist is selected from the group consisting of cande include bendiocarb, carbaryl, benzofuranyl methylcarbamate Sartan, eprosartan, irbesartan, losartan, olmesartan, tasosar insecticides, such as benfuracarb, carbofuran, carbosulfan, tan, telmisartan, Valsartan, Saralasin, and 1-4-(dimethy decarbofuran and furathiocarb, dimethylcarbamate insecti lamino)-3-methylphenyl)methyl-5-(diphenylac-etyl)-4,5,6, cides, such as dimetan, dimetilan, hyduincarb and pirimicarb, 7-tetrahydro-1H-imidazo[4,5-cpyridine-6-carboxylic acid Oxime carbamate insecticides, such as alanycarb, aldicarb, ditrifluoroacetate, or an isomer, a pharmaceutically accept aldoxycarb, butocarboxim, butoxycarboxim, methomyl, nit able salt, ester, or prodrug thereof. rilacarb, oxamyl, tazimcarb, thiocarboxime, thiodicarb and 0664. In one or more embodiments, the NSAID is an thiofanoX, and phenyl methylcarbamate insecticides, such as UDP-glucuronosyltransferase inhibitor (UGT inhibitor). allyxycarb, aminocarb, bufencarb, butacarb, carbanolate, clo 0665. In certain embodiments, the UGT inhibitor is ethocarb, dicresyl, dioxacarb, ethiofencarb, fenethacarb, selected from the group consisting of epicatechin gallate, fenobucarb, isoprocarb, methiocarb, metolcarb, mexacar epigallocatechin gallate, octyl gallate, propyl gallate, querce bate, promacyl, promecarb, propoXur, trimethacarb and tin, tannic acid, benzoin gum, capsaicin, dihydrocapsaicin, xylylcarb. eugenol, gallocatechin gallate, geraniol, menthol, menthyl 0673. In one or more embodiments, the insecticide is a acetate, naringenin, allspiceberry oil, N-Vanillylnonanamide, dinitrophenol insecticides. Examples of dinitrophenol insec clovebud oil, peppermint oil, silibinin and silymarin. ticides include dinex, dinopropand dinosam. 0.666 Mixtures of these non-steroidal immunomodulators 0674. In one or more embodiments, the insecticide is a may also be employed according to the present invention. fluorine insecticide. Such as barium hexafluorosilicate, cryo 0667 Suitable non-steroidal anti-inflammatory agent lite, sodium fluoride, sodium hexafluorosilicate and sulflura include but are not limited to azelaic acid, oxicams, piroxi mid. cam, isoxicam, tenoxicam, Sudoxicam, CP-14.304, Salicy 0675. In one or more embodiments, the insecticide is a lates, aspirin, disalcid, benorylate, trilisate, Safapryn, Solprin, formamidine insecticide. Such as amitraz, chlordimeform, diflunisal, fendosal, acetic acid derivatives, diclofenac, fen formetanate and formparanate. clofenac, indomethacin, Sulindac, tolmetin, isoxepac, furo 0676 In one or more embodiments, the insecticide is an fenac, tiopinac, Zidometacin, acematacin, fentiazac, Zomepi insect growth regulator. Examples of insect growth regulators rac, clindanac, oxepinac, felbinac, ketorolac, fenamates, include chitin synthesis inhibitors, such as bistrifluoron, mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic buprofezin, chlorfluaZuron, cyromazine, diflubenZuron, acids, propionic acid derivatives, ibuprofen, naproxen, flucycloXuron, flufenoXuron, hexaflumuron, lufenuron, nov benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fen aluron, noviflumuron, penfluoron, teflubenzuron and triflu bufen, indopropfen, pirprofen, carprofen, oxaprozin, prano muron, juvenile hormone mimics, such as epolfenonane, profen, miroprofen, tioxaprofen, Suprofen, alminoprofen, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxy tiaprofen, pyrazoles, phenylbutaZone, oxyphenbutaZone, fen and triprene, juvenile hormones, moulting hormone ago feprazone, azapropaZone, trimethaZone and derivatives, nists, such as chromafenozide, halofenozide, methoxy esters, salts and mixtures thereof. fenozide and tebufenozide, moulting hormones, such as C-ecdysone and ecdysterone, moulting inhibitors, such as Insecticide diofenolan, precocenes, and dicyclanil. 0668. In an embodiment, the therapeutic agent is insecti 0677. In one or more embodiments, the insecticide is a cide. In the context of one or more embodiments “insecticide, nereistoxin analogue insecticide. Such as benSultap, cartap, is used herein to mean a compound which kills, inhibits the thiocyclam and thiosultap. growth of impeded the proliferation of or repels insects or to 0678. In one or more embodiments, the insecticide is a kill or prevent the growth of parasite arthropods, such as nicotinoid insecticide. Examples of nicotinide insecticides insects, arachnids and crustaceans, or a compound used to include flonicamid, nitroguanidine insecticides, such as repel or prevent infestation by these parasite arthropods. clothianidin, dinotefuran, imidacloprid and thiamethoxam, 0669. The term insecticides include, for example, agents nitromethylene insecticides, such as nitenpyram and nithiaz that can kill lice, flees, ticks, mites, Scabies and mousquitos, ine, and pyridylmethylamine insecticides, such as acetami as well as agents that repel Such insects. Suitable insecticides prid, imidacloprid, nitenpyram and thiacloprid. include but are not limited to DDT, lindane, malathion, per 0679. In one or more embodiments, the insecticide is an methrin, allethrin, biopermethrin, transpermethrin, pheno organochlorine insecticide. Examples of organochlorine thrin, diethyl-m-toluamide, dimethyl phthalate, piperonyl insecticides include bromo-DDT, camphechlor, DDT, lin butoxide, pyrethroids and derivatives, esters, salts and mix dane, methoxychlor, pentachlorophenol, cyclodiene insecti tures thereof. cides, such as aldrin, bromocyclen, chlorbicyclen, chlordane, 0670. In one or more embodiments, the insecticide is an chlordecone, dieldrin, dilor, endosulfan, endrin, heptachlor, antibiotic insecticide. Examples of antibiotic insecticides isobenzan, isodrin, kelevan and mirex. include allosamidin, thuringiensin, spinosad, avermectin 0680. In one or more embodiments, the insecticide is an insecticides, such as abamectin, doramectin, emamectin, organophosphorus insecticide. Examples of organophospho eprinomectin, ivermectin and Selamectin, milbemycin insec rus insecticides include organophosphate insecticides such as ticides, such as lepimectin, milbemectin, milbemycin Oxime bromfenVinfos, chlorfenvinphos, crotoxyphos, dichlorvos, and moxidectin, and arsenical insecticides. dicrotophos, dimethylvinphos, fospirate, heptenophos, 0671. In one or more embodiments, the insecticide is a methocrotophos, mevinphos, monocrotophos, naftalofos, botanical insecticide. Such as anabasine, azadirachtin, d-li phosphamidon, propaphos and tetrachlorvinphos, organ US 2008/0299220 A1 Dec. 4, 2008

othiophosphate insecticides, such as dioxabenzofos, foSme theta-cypermethrin, Zeta-cypermethrin, cyphenothrin, delta thilan, phenthoate, acethion, amiton, cadusafos, chlorethoxy methrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin, fos, chlormephos, demephion, demephion, demeton, fempirithrin, fempropathrin, fenvalerate, esfenvalerate, disulfoton, ethion, ethoprophos, isothioate, malathion, meth flucythrinate, fluvalinate, furethrin, imiprothrin, metof acrifos, oxydemeton-methyl, Oxydeprofos, oxydisulfoton, luthrin, permethrin, biopermethrin, transpermethrin, pheno phorate, Sulfotep, terbufos and thiometon, aliphatic amide thrin, prallethrin, profluthrin, pyresmethrin, resmethrin, organothiophosphate insecticides, such as amidithion, cyan bioresmethrin, cismethrin, tefluthrin, terallethrin, tet thoate, dimethoate, ethoate-methyl, formothion, mecarbam, ramethrin, tralomethrin and transfluthrin, and pyrethroid omethoate, prothoate, Sophamide and vamidothion, oxime ether insecticides, such as etofenproX, flufenproX, halfen organothiophosphate insecticides, such as chlorphoxim, prox, protrifenbute and silafluofen. phoxim and phoxim-methyl, heterocyclic organothiophos 0685. In one or more embodiments, the insecticide is a phate insecticides, such as azamethiphos, coumaphos, pyrimidinamine insecticide. Such as flufenerim and pyrimid coumithoate, dioxathion, endothion, menazon, morphothion, ifen. phosalone, pyraclofos, pyridaphenthion and quinothion, ben 0686. In one or more embodiments, the insecticide is a Zothiopyran organothiophosphate insecticides, such as dithi pyrrole insecticide. Such as chlorfenapyr. crofos and thicrofos, benzotriazine organothiophosphate 0687. In one or more embodiments, the insecticide is a insecticides, such as azinphos-ethyl and azinphos-methyl, tetronic acid insecticide. Such as spiromesifen and spirotet isoindole organothiophosphate insecticides, such as dialifos ramat. and phosmet, isoxazole organothiophosphate insecticides, Such as isoxathion and Zolaprofos, pyrazolopyrimidine orga 0688. In one or more embodiments, the insecticide is a nothiophosphate insecticides, such as chlorpraZophos and thiourea insecticide. Such as diafenthiuron. pyrazophos; pyridine organothiophosphate insecticides. Such 0689. In one or more embodiments, the insecticide is a as chlorpyrifos and chlorpyrifos-methyl, pyrimidine organ urea insecticide, such as flucofuron and Sulcofuron. othiophosphate insecticides, such as butathiofos, diazinon, 0690. Yet, in additional embodiments, the insecticide is an etrimfos, lirimfos, pirimiphos-ethyl, pirimiphos-methyl, unclassified insecticide. Such as closantel, crotamiton, primidophos, pyrimitate and tebupirimfos, quinoxaline orga fenaZaflor, fenoxacrim, flubendiamide, hydramethylnon, iso nothiophosphate insecticides, such as quinallphos and quinal prothiolane, malonoben, metaflumizone, metoxadiaZone, phos-methyl, thiadiazole organothiophosphate insecticides, nifluridide, pyridaben, pyridalyl, rafoxanide, triarathene and Such as athidathion, lythidathion, methidathion and prothi triazamate. dathion, triazole organothiophosphate insecticides, such as 0.691. The above listed insecticides, as well as others not isazofos and triazophos, phenyl organothiophosphate insec listed, are suitable for use in the composition. It is preferred to ticides. Such as azothoate, bromophos, bromophos-ethyl, car use insecticides that are approved by the FDA or other health bophenothion, chlorthiophos, cyanophos, cythioate, dicap authorities for the treatment of animals and humans. thon, dichlofenthion, etaphos, famphur, fenchlorphos, 0692. Non-limiting examples of approved insecticides fenitrothion, fensulfothion, fenthion, fenthion-ethyl, hetero include hexachlorobenzene, carbamate, naturally occurring phos, jodfenphos, mesulfenfos, parathion, parathion-methyl, pyrethroids, permethrin, allethrin, bioalethrin, phenothrin, phenkapton, phosnichlor, profenofos, prothiofos, Sulprofos, malathion and piperonylbutoxide. In a preferred embodiment temephos, trichlorimetaphos-3 and trifenofos, phosphonate the insecticide is selected from the group consisting of insecticides, such as butonate and trichlorfon, phosphono hexachlorobenzene, carbamate, naturally occurring pyre thioate insecticides Such as mecarphon, phenyl eth throids, permethrin, allethrin, bioalethrin, phenothrin, ylphosphonothioate insecticides, such as fonofos and trichlo malathion and piperonylbutoxide. ronat, phenyl phenylphosphonothioate insecticides, such as 0693. In one or more embodiments, the insecticide is a cyanofenphos, EPN and leptophos, phosphoramidate insec naturally occurring insecticide compound. As used herein, ticides, such as crufomate, fenamiphos, fosthietan, mephos the term “naturally-occurring insecticide' includes all insec folan, phosfolan and pirimetaphos, phosphoramidothioate ticides that are obtained, derived or extracted from plant or insecticides, such as acephate, isocarbophos, isofenphos, vertebrate sources. methamidophos and propetamphos, and phosphorodiamide 0694. In the context, an agent that kills or otherwise affects insecticides, such as dimefox, mazidox, mipafox and parasites, such as protozoa is also termed an insecticide (for Schradan. the purpose of this application terminology only). Exemplary 0681. In one or more embodiments, the insecticide is an antiparasites are mebendazole, thiabendazole, metronida oxadiazine insecticide, such as indoxacarb. Zole, and praziquantel. 0682. In one or more embodiments, the insecticide is a 0695 Mixtures of these insecticides may also be phthalimide insecticide. Such as dialifos, phosmet and tet employed according to the present invention. ramethrin. 0696. The insecticide is included in the composition in a 0683. In one or more embodiments, the insecticide is a concentration that provides a desirable ratio between the effi pyrazole insecticide, such as acetoprole, ethiprole, fipronil. cacy and safety. Typically, insecticides are included in the pyrafluprole, pyriprole, tebufenpyrad, tolfenpyrad and Vanil composition in a concentration between about 0.05% and iprole. about 12% by weight, depending on their potency against the 0684. In one or more embodiments, the insecticide is a parasitic arthropod to be eradicated. In some embodiments, pyrethroid insecticide. Examples of pyrethroid insecticides the concentration is between about 0.5% and about 2% by include pyrethroid ester insecticides, such as acrinathrin, weight; in other embodiment the concentration is between allethrin, bioallethrin, barthrin, bifenthrin, bioethanomethrin, about 2% and about 5% by weight; and in other embodiments cyclethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalo the concentration is between about 5% and about 12% by thrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, weight. US 2008/0299220 A1 Dec. 4, 2008 54

0697. In one or more embodiments, the insecticide and the head-to-tail manner, and derivatives, salts, structural analogs silicone work together for example the former by killing eggs and functional analogs thereof, as reviewed herein in a non and the latter by discouraging them from Sticking to a surface. limiting fashion. Typically, retinoids may beformally derived 0698. In one or more embodiments, the insecticide is from a monocyclic parent compound containing five carbon encapsulated in particles, microparticles, nanoparticles, carbon double bonds and a functional group at the terminus of microcapsules, spheres, microspheres, nanocapsules, nano the acyclic portion. spheres, liposomes, niosomes, polymer matrix, nanocrystals or microSponges, and may be manufactured according to 0703 Suitable, but non-limiting, retinoids for use in the known methods. present invention are listed below. 0704. It is convenient to omit the explicit representation of Vasodilators C and H atoms in the parent skeletal structure of retinoids as follows: 0699. In an embodiment, the therapeutic agent is a vasodi lator. Suitable vasodilators include but are not limited to agents that modulate the activity of the enzyme nitric oxide synthase, nicotinic acid, ethyl nicotinate, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobutyl nitrite, glyceryl trinitrate, octyl nitrite, sodium nitrite, Sodium nitroprusside, clonitrate, erythrity1 tetranitrate, isosorbide mononitrate, isosorbide dinitrate, mannitol hexanitrate, pentaerythritol tet ranitrate, penetrinitol, triethanolamine trinitrate, troInitrate phosphate (triethanolamine trinitrate diphosphate), pro patylnitrate, nitrite esters of Sugars, nitrite esters of polyols, 0705 (1) R=CH-OH (6) R=CH-NH, nitrate esters of Sugars, nitrate esters of polyols, nicorandil, apresoline, diazoxide, hydralazine, hydrochlorothiazide, (0706 (2) R-CHO (7) R-CH=NOH minoxidil, pentaerythritol, tolaZoline, scoparone, a beta-adr 0707 (3) R-COH (8) R=CH=NCHLCHNHCOH energic blocker, an alpha-adrenoceptor blocker, a prostaglan 0708 (4) R=CH (9) R=COCH din, sildenafil, dipyridamole, catecholamine, isoproternol, furosemide, prostaglandin, prostacyclin, enalaprilat, mor (0709 (5) R-CHOCOCH, phine, acepromazine, prazosin (C.-blocker), enalapril, Capto pril, amlodipine, minoxidil, tadalafil. Vardenafil, phenyleph (10) R- = COOH rin, etilefein, caffeine, capsaicin, an extract capsicum, O achillea millefolium (Yarrow), allium sativum (garlic), amo HO HO O-CO racia rusticana (horseradish), berberis vulgaris (barberry), cinicifiiga racemosa (black cohosh), colleus forskholii (co OH leus), Coptis (goldenthread), Crataegus (hawthorn), eleuth erococcus senticosus (Siberian ginseng), ginkgo biloba 0710 Compound (1) (2E,4E,6E.8E)-3,7-dimethyl-9-(2,6, (ginkgo), melissa officinalis (lemon balm), Olea europaea 6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol is (olive leaf), panax ginseng (Chinese ginseng), petroselinum also known as vitamin A, vitamin A alcohol, retinal, vitamin crispum (parsley), scutellaria baicalensis (baical skullcap), A. vitaminA, alcohol, axerophtholoraxerol. Compound (2) tilia europaea (linden flower), trigonella foenum-graecum also known as vitamin A aldehyde, Vitamin A aldehyde, (fenugreek), urtica dioica (nettles), valeriana officinalis (Valerian), viburnum (cramp, bark, black haw), veratrum retinene or retinene and retinal or, if liable to be confused viride (American hellebore), verbena officinalis (vervain), with the adjective retinal (pertaining to the retina), retinalde xanthoxylum americanum (prickly ash), Zingiber officinale hyde. Compound (3) also known as tretinoin (see note), Vita (ginger), rauwolfia serpentina (Indian Snakeroot), viscum min Aacid or vitamin A acid should be designated retinoic album, wild yam, sasparilla, licorice, damiana, yucca, saw acid. Compound (4), is known as axerophthene. Functional palmetto, gotu kola (centella asiatica), yohimbine and salts, substitution at the 15 position of the basic hydrocarbon is hazelnut, brazil nut and walnut, and derivatives, esters, salts denoted by the use of the group names retinyl (Ris CH ) or and mixtures thereof. retinylidene (R is CH=), with retention of the original num 0700. In an embodiment, the therapeutic agent is a vaso bering of the basic hydrocarbon. For example (5) is retinyl constrictor. Suitable vasodilators include but are not limited acetate and (6) is retinylamine. Derivatives of retinal include to ephedrine, epinephrine, phenylephrine, angiotensin, vaso for example Compound (7)—retinal oXime and Compound pressin; an extract ephedra sinica (ma huang), polygonum (8)—N 6-retinylidene-L-lysine. Other derivatives of retinoic bistorta (bistort root), hamamelis virginiana (witch hazel), acid, named as carboxylic acid derivatives Compound (9)— hydrastis Canadensis (goldenseal), lycopus virginicus (bu ethyl retinoate and Compound (10)—1-O-retinoyl-b-D-glu gleweed), aspidosperma quebracho (quebracho blanco), copyranuronic acid. cytisus scoparius (Scotchbroom) and cypress and and deriva 0711 Retinoids that differ in hydrogenation level from the tives, esters, salts and mixtures thereof. parent structure (displayed above) are named by use of the prefixes hydro and dehydro together with locants specify Retinoid ing the carbon atoms at which hydrogen atoms have been added or removed. Examples of Such retinoid compounds are 0701. In an embodiment, the active agent is a retinoid. Compound (11)—3,4-Didehydroretinol (also known as 0702. In the context, a retinoids is a compound a class of dehydroretinol or vitamin A) and Compound (12) 4.5-Di compounds consisting of four isoprenoid units joined in a dehydro-5,6-dihydroretinol (also known as alpha-vitaminA). US 2008/0299220 A1 Dec. 4, 2008 55

Compound (11) Compound (12)

N1N1 N1 N. OH N1N1 N1 N. OH

Compound (13) Compound (14) OCHs

O N1 N1 N1 N. OH PollsF Compound (15) Compound (16)

N N1 N1 N1 N1 N. OH

R = NHCHs Compound (18)

Compound (19) Compound (20)

15 4N4N4N4N- 2n-4N4N4N OCOCH

5 4 4

Compound (21) Compound (22)

R = COCH Compound (23) Compound (24)

13 15 N N N N 4 6 21 21 21 21 14 n N

R CH US 2008/0299220 A1 Dec. 4, 2008 56

-continued Compound (25) Compound (26) S-C COOH COOH

HCO

Compound (27) O

21 OCH2CH3 N 2 N

S Compound (28)

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

Compound (29) OH S1s1s1s1s1s1s1s1s

HO

0712 Substituted derivatives of retinoids are exemplified 0713 Arotinoids or retinoidal benzoic acid derivatives by Compound (13)—5,6-Epoxy-5,6-dihydroretinol (also contain, aromatic rings replacing either the basic B-ionone known as hepaxanthin) and Compound (14)—Ethyl 12-fluo type ring structure or unsaturated bonds of the tetraene side roretinoate. Seco Retinoids are exemplified by Compound chain of the parent retinoid skeleton, as exemplified by Com (15)—1.6-Seco-1,2-didehydroretinol, also known as g-vita pound (25) and Compound (26)—6-3-(1-adamantyl)-4- minA, and Nor Retinoids, which result from the elimination methoxyphenyl-2-naphthoic acid, also known as adapalene. of a CH, CH, CH or C group from a retinoid are exemplified by Compound (16) N-Ethyl-3-methoxy-2-methyl-17-nor Several artinoids, possessing potent retinoid properties, 1,2,3,4-tetradehydroretinamide (also known as motretinide), including but not limited to short retinoids, short heterocyclic Compound (17)—Ethyl 3-methoxy-2-methyl-17-nor-1.2.3, retinoids, isoxazole-containing retinoids, heterocyclic isox 4-tetradehydroretinoate (also known as etretinate), acitretin azole-containing retinoids, isoxazoline-containing retinoids, (Compound (17), wherein R—H) and Compound (18)—5- stilbene retinoid analogs, are disclosed in Pure Appl. Chem. Acetyl-4,18-dinor-retinoic acid. Retro Retinoids are exem Vol. 73, No. 9, pp. 1437-1444, 2001. plified by Compound (19) 4,5-Didehydro-15.5-retro-deox 0714 Tazarotene (Ethyl 6-2-(4,4-dimethylthiochroman yretinol (also known as anhydro Vitamin A and Compound 6-yl)ethynylnicotinate) is exemplary to a retinoid precur (20)—4, 14-retro-Retinyl acetate. Stereoisomers of retinoids sor Compound (27), suitable as retinoid for use in the are exemplified by Compound (21)—(3R)-3-Hydroxyretinol present invention. and Compound (22)—(3R)-3-Acetoxyretinol. Other stere 0715 Yet, other non-limiting exemplary retinoid precur ochemical isomers can are exemplified by Compound (23)— sors are carotenes, such as all-trans beta carotene Com 13-cis-Retinoic acid or (7E9E, 11E,13Z)-retinoic acid (also pound (28), alpha carotene, lycopene and 9-cis-beta-caro known as isotretinoin) and Compound (24)—(6E.8E,10E, tene, as well as Xanthophils (also termed “oxicarotenoids’), 12E. 15Z)-4,14-retro-Retinaloxime. Such as lutein and Zeaxanthin Compound (29). US 2008/0299220 A1 Dec. 4, 2008 57

0716 Salts and derivatives of retinoid compounds are also two main components in foods are retinol and the caro suitable as “retinoid for use in the present invention. tenoids. Retinoid refers to the chemical entity retinol or 0717 Retinoid compounds can be ascertained recognized other closely related naturally occurring derivatives. These and identified by methods known in the art. One method include: retinal (retinaldehyde); retinoic acid; and retinyl involves the use of competitive nuclear retinoic acid (RA and esters (e.g. retinyl acetate, retinyl palmitate, retinyl propi RX) receptor binding assays for identifying compounds onate). Retinoids also include structurally related synthetic which bind directly to the receptors. For instance, J. J. Repa et analogues which may or may not have retinol-like activity. al., “All-trans-retinol is a ligand for the retinoic acid recep Vitamin A (in the form of retinal) is essential for normal tors', Proc. Natl. Acad. Sci. USA, Vol. 90, pp. 7293-7297, function of the retina and particularly for visual adaptation to 1993, discloses a competitive RA receptor binding assay darkness. Other forms (retinol, retinoic acid) are necessary based on human neuroblastoma cell nuclear extracts. H. for maintenance of the structural and functional integrity of Torma et al. (1994) “Biologic activities of retinoic acid and epithelial tissue and the immune system, cellular differentia 3,4-dehydroretinoic acid in human keratinoacytes are similar tion and proliferation, bone growth, testicular and ovarian and correlate with receptor affinities and transactivation prop function and embryonic development. It may act also as a erties.J. Invest. Dermatology, Vol. 102, pp. 49-54) discloses co-factor in biochemical reactions. Deficiency can amongst assays for measuring binding affinities for the nuclear retinoic other things result in skin dryness and papular eruptions. acid receptors and for measuring transcriptional activation Vitamin A and its derivatives have the ability to normalize induction. M. F. Boehm et al. (1994) “Synthesis of high keratinization. Note that vitamin C may ameliorate the toxic specific activity. Sup.3H-9-cis-retinoic acid and its applica effects of vitamin A; that large doses increase the need for tion for identifying retinoids with unusual binding proper Vitamin E; and that Vitamin E protects against the oxidative ties.J. Med. Chem. Vol. 37, pp. 408-414) discloses a ligand binding assay and a receptor/reporter cotransfection assay for destruction of vitamin A. Retinol is susceptible to breakdown monitor regulation of gene expression. EP 0552 612 A2, from oxygen and light. Synthetic retinoids may be used for published Jul. 28, 1993, describes ligand-binding trapping skin problems (e.g. acne). assays based on incubation of radiolabeled compounds with 0725. According to certain embodiments the retinoid is transfected COS-1 cells which express RA and RX receptors. selected from the group consisting of: (1) a compound con 0718 Mixtures of these retinoids may also be employed sisting of four isoprenoid units joined in a head-to-tail man according to the present invention. ner, a compound having the formula: 0719 Suitable retinoids include but are not limited to ret inol, retinal, retinoic acid, all-trans retinoic acid, isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein and Zeaxanthin. 0720. In an embodiment, the therapeutic agent is selected from the group consisting of an immunosuppressants and immunoregulating agents. Suitable immunosuppressants and immunoregulating agents include but are not limited to cyclic peptides, such as cyclosporine, tacrolimus, tresperimus, pimecrolimus, Sirolimus (rapamycin), Verolimus, laflunimus, 0726 where R is selected from the group consisting of H, laquinimod, imiquimod derivatives, esters, salts and mixtures alkyl, aryl, alkenyl, benzyl, CH2OH, CH2NH2, CHO, thereof. In one or more embodiments, the immunomodulator CH=NOH, CO2H, CH-NCH2)4-CHNH2CO2H, CH3, is a calcineurin Inhibitor. CO2C2H5, CH2OCOCH3, a heteroatom, a saccharide and a 0721. In an embodiment, the therapeutic agent is a wart polysaccharide; (2) a compound selected from the group con remover. Suitable wart removers includebut are not limited to sisting of a hydro retinoid, a dehydro retinoid, 3,4-Didehy imiquimod, podophyllotoxin and derivatives, esters, salts and droretinol, 4.5-Didehydro-5,6-dihydroretinol, a substituted mixtures thereof. derivative of a retinoid, 5,6-epoxy-5,6-dihydroretinol, ethyl 12-fluororetinoate, a seco retinoid, 1.6-Seco-1,2-didehy Vitamin droretinol, a nor retinoid, (3) a compound which results from the elimination of a CH3, CH2, CH or C group from a retin 0722. The term vitamin includes those vitamins and oid, N-ethyl-3-methoxy-2-methyl-17-nor-1,2,3,4-tetradehy derivatives thereof (including salts) which are officially rec droretinamide, ethyl 3-methoxy-2-methyl-17-nor-1,2,3,4- ognized as vitamins, and those vitamins which were once tetradehydroretinoate, 5-acetyl-4,18-dinor-retinoic acid, a recognized or designated as vitamins but are now classified in retro retinoid, 4,5-didehydro-15.5-retro-deoxyretinol, 4,14 another way (e.g. vitamin F) and pseudo Vitamins including retro-retinyl acetate, a stereoisomer of a retinoid, (3R)-3- those Substances which are a member of a group or complex hydroxyretinol, (3R)-3-Acetoxyretinol, (7E9E, 11E. 13Z)- but are not formally recognized (e.g. para-aminobenzoic acid retinoic acid, (6E.8E, 10E, 12E. 15Z)-4,14-retro (PABA), which is claimed to prevent greying hair and to be retinaloxime, an arotinoids, a retinoidal benzoic acid useful as an anti aging Supplement) and also vitamin mimet derivative, 6-3-(1-adamantyl)-4-methoxyphenyl-2-naph ics, which have vitamin like properties or effects. thoic acid, a short retinoid, a short heterocyclic retinoid, an 0723 Suitable vitamins include vitaminA, vitamins of the isoxazole-containing retinoids, a heterocyclic isoxazole-con B complex B1, B2, B3, B5, B6, B7, B9, B12, vitamin C, taining retinoid, an isoxazoline-containing retinoid, a stil vitamins D1-D4, vitamin E, vitamin Kand so called vitamin bene retinoid analog, a retinoid precursor, (ethyl 6-2-(4.4- F and a derivative thereof and combinations thereof. dimethylthiochroman-6-yl)ethynylnicotinate, a carotene, a 0724 Vitamin A is a fat-soluble vitamin and describes Xanthophil and an oxicarotenoid; (4) a compound selected compounds that exhibit the biological activity of retinol. The from the group consisting of retinol, retinal, retinoic acid, US 2008/0299220 A1 Dec. 4, 2008

all-trans retinoic acid, isotretinoin, tazarotene, adapalene, 0732 Vitamin B6 is water soluble vitamin. Vitamin B6 a 13-cis-retinoic acid, acitretin, all-trans beta carotene, alpha generic term used to describe the compounds that exhibit the carotene, lycopene, 9-cis-beta-carotene, lutein and Zeaxan biological activity of pyridoxine. It occurs in food as pyridox thin; (5) a compound that is positively identified using a ine, pyridoxal and pyridoxamine. Vitamin B6 is converted in laboratory method, Suitable of detecting a retinoid, and salts erythrocytes to pyridoxal phosphate and, to a lesser extent, and derivatives thereof. pyridoxamine phosphate. It acts as a co-factor for enzymes 0727 Vitamin B is known as the vitamin B complex and which are involved in more than 100 reactions that affect comprises B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 protein, lipid and carbohydrate metabolism. Pyridoxal phos (pantothenic acid), B6 (pyridoxine), B7 (biotin), B9 (folic phate is also involved in: the synthesis of several neurotrans acid) and B12 (cyanocobalamin). Adequate amounts of all B mitters; the metabolism of several vitamins (e.g. the conver Vitamins are required for optimal functioning; deficiency or sion of tryptophan to niacin); haemoglobin and sphingosine excess of one B may lead to abnormalities in the metabolism formation. Lack of Vitamin B6 may affect vitamin C. of another. Examples are pyridoxine hydrochloride and pyridoxine dio 0728. Thiamine is a water soluble vitamin and is also Ctanate. known as aneurine and functions as a co-enzyme in the oxi 0733 Biotin is a water soluble vitamin which was for dative decarboxylation of alpha ketoacids (involved in energy merly known as vitamin H or co-enzyme R. Biotin functions production) and in the transketolase reaction of the pentose as an integral part of the enzymes that transport carboxyl units phosphate pathway (involved in carbohydrate metabolism). and fix carbon dioxide. Biotin enzymes are important in car Thiamine is also important in nerve transmission (indepen bohydrate and lipid metabolism, and are involved in gluco dently of co-enzyme function). It may also act as an insect neogenesis, fatty acid synthesis, propionate metabolism and repellant. the catabolism of amino acids. Biotin has been claimed to be 0729 Riboflavin is a water soluble vitamin and functions of value in the treatment of brittle finger nails, acne, sebor as a component of two flavin co-enzymes—flavin mono rhoeic dermatitis, hair fragility and alopecia. nucleotide (FMN) and flavin adenine dinucleotide (FAD). It 0734. Folic acid (pteroylglutamic acid) is a water soluble participates in oxidation-reduction reactions in numerous Vitamin and is the parent compound for a large number of metabolic pathways and in energy production. Examples derivatives collectively known as folates. Folate is the generic include: the oxidation of glucose, certain amino acids and term used to describe the compounds that exhibit the biologi fatty acids; reactions with several intermediaries of the Krebs cal activity of folic acid; it is the preferred term for the vitamin cycle; conversion of pyridoxine to its active co-enzyme; and present in foods which represents a mixture of related com conversion of tryptophantoniacin. Riboflavin has a role as an pounds (folates). Folates are involved in a number of single antioxidant. It may be involved in maintaining the integrity of carbon transfer reactions, especially in the synthesis of erythrocytes. Common forms are riboflavin, riboflavin purines and pyrimidines (and hence the synthesis of DNA), butyrate and flavin adenine dinucleotide. glycine and methionine. They are also involved in some 0730 Niacin is a water-soluble vitamin and describes the amino acid conversions and the formation and utilization of compounds that exhibit the biological properties of nicotina formate. Deficiency leads to impaired cell division (effects mide. It occurs as nicotinamide and nicotinic acid. It is some most noticeable in rapidly regenerating tissues). times known as niacinamide. An example of a derivative is 0735. Vitamin B12 is a water-soluble vitamin and it is the benzyl nicotinate. Niacin functions as a component of two generic term used to describe the compounds that exhibit the co-enzymes, nicotinamide adenine dinucleotide (NAD) and biological activity of cyanocobalamin. It includes a range of nicotinamide adenine dinucleotide diphosphate (NADP). cobalt-containing compounds, known as cobalamins. Cyano These co-enzymes participate in many metabolic processes cobalamin and hydroxocobalaminare the two principal forms including glycolysis, tissue respiration, lipid, amino acid and in clinical use. Vitamin B12 is involved in the recycling of purine metabolism. It has been shown to have antiinflamma folate co-enzymes and the degradation of valine. It is also tory properties that result in the improvement of acne. Topi required for nerve myelination, cell replication, haemato cally it has showed benefit for various skin conditions includ poiesis and nucleoprotein synthesis. ing psoriasis and rosacea. It has also been said to have a photo 0736 Vitamin C is a water-soluble vitamin and describes protection role, perhaps through anti-oxidant activity and the compounds that exhibit the biological activity of ascorbic reduces or prevents UV damage to cells and UV induced acid. These include L-ascorbic acid (ascorbic acid) and L-de disorders. hydroascorbic acid (dehydroascorbic acid). The functions of 0731 Pantothenic acid is also a water soluble vitamin and Vitamin C are based mainly on its properties as a reducing functions mainly as a component of co-enzyme A and acyl agent. It is required for: the formation of collagen and other carrier protein. Co-enzyme A has a central role as a co-factor organic constituents of the intercellular matrix in bone, teeth for enzymes involved in the metabolism of lipids, carbohy and capillaries; and the optimal activity of several enzymes— drates and proteins; it is also required for the synthesis of it activates certain liver-detoxifying enzyme systems (includ cholesterol, Steroid hormones, acetylcholine and porphyrins. ing drug-metabolizing enzymes) and is involved in the Syn As a component of acyl carrier protein, pantothenic acid is thesis of carnitine and norepinephrine (noradrenaline) and in involved in various transfer reactions and in the assembly of the metabolism of folic acid, histamine, phenylalanine, tryp acetate units into longer-chain fatty acids. Pantothenic acid tophan and tyrosine. Vitamin C also acts: as an antioxidant has been used for a wide range for disorders such as acne, (reacting directly with aqueous free radicals)-which is impor alopecia, allergies, burning feet, asthma, grey hair, dandruff, tant in the protection of cellular function; and to enhance the and cholesterol lowering. Panthenol the alcoholic form func absorption of non-haem iron. It can function as a whitening tions as a humetic. Examples of pantothenic acid derivatives agent. Vitamin C may assist with wound healing. Vitamin C are calcium pantothenate, D-pantothenyl alcohol, pantoth can spare vitamin E and vice versa and it may reduce toxic enyl ethyl ether, and acetylpentothenyl ethyl ether. effects of vitamin A. Vitamin C is unstable in solution espe US 2008/0299220 A1 Dec. 4, 2008 59 cially alkaline solution and readily undergoes oxidation on qualitatively the biological activity of phytomenadione. The exposure to air. Oxidation is accelorated by light and heat. form of vitamin K present in foods is phytomenadione (vita Cosmetic forms include calcium ascorbate, magnesium min K). The Substances synthesized by bacteria are known as ascorbate, sodium ascorbate, Sodium ascorbyl phosphate, menaquinones (vitamin K). The parent compound of the ascorbyl palmitate, magnesium ascorbyl phosphate, L-ascor vitamin K series is known as menadione (vitamin Ks); it is not bic acid and magnesium-L-ascorbyl-2-phosphate., L-ascor natural Substance and is not used in humans. Menadiol bic acid palmitate, L-ascorbic acid 2-sulfate, L-ascorbic acid sodium phosphate is water-soluble derivative of menadione. phosphate, and DL-.alpha.-tocopherol-L-ascorbic acid phos Vitamin K is an essential co-factor for the hepatic synthesis of phate diester dipotassium. L-ascorbic acid is the most bioac proteins involved in the regulation of blood clotting. These tive form and has been found to have many skin benefits but it is unstable in the presence of water and oxygen. Inclusion of are: prothrombin (factor II), factors VII, IX, X and proteins C, ascorbic acid in the vitamin carrier, wherein the composition S and Z. Vitamin K is responsible for the carboxylation of the does not contain or is essentially free of water or wherein bone protein, osteocalcin, to its active form. Osteocalcin water is not freely available due to the hygroscopic properties regulates the function of calcium in bone turnover and min of the composition randor is not exposed to air during Storage eralisation. Vitamin K is also required for the biosynthesis of makes it possible to derive stable products with the most Some other proteins found in plasma and the kidney. It is bioactive form of vitamin C. reported to speed up resolution of bruising to decrease future 0737 Vitamin D is a fat-soluble vitamin and describes all bruising and correct aspects of photoaging. sterols that exhibit the biological activity of cholecalciferol. 0740 Pseudo vitamins: Vitamin F was the designation These include: vitamin D (calciferol), vitamin D (ergocal originally given to essential fatty acids that the body cannot ciferol) vitamin D (cholecalciferol), 1 (OH)D (1 Hydroxy manufacture. They were “de-vitaminized' because they are cholecalciferol; alfacalcidol), 25(OH)D (25 Hydroxychole fatty acids. Fatty acids are a major component of fats which, calciferol; calcifediol), 1.25(OH),D, (1.25, like water, are needed by the body in large quantities and thus Dihydroxycholecalciferol; calcitriol), 24.25(OH)D (24.25. do not fit the definition of vitamins which are needed only in Dihydroxycholecalciferol) and dihydrotachysterol, calcipot trace amounts. Herbalists and naturopaths have named vari riene, 25-hydroxycholecalciferol, 1C.,25-dihydroxycholecal ous therapedic chemicals “vitamins’, even though they are ciferol, 1C.25-dihydroxyergocalciferol, 22.23-dihydroergo not, including vitamin T. S.-Methylmethionine (vitamin U) calciferol, 1,24,25-trihydroxycholecalciferol, previtamin D, and vitamin X. Some authorities say that ubiquinone, also tachysterols (also termed tacalciol), isovitamin D, dihydro called coenzyme Q10, is a vitamin. Ubiquinone is manufac tachysterol, (1S)-hydroxycalciol, (24R)-hydroxycalcidiol, tured in small amounts by the body, like vitamin D. Pangamic 25-fluorocalciol, ercalcidiol, ertacalciol, (5E)-isocalciol, acid, vitamin B15; the related substance dimethylglycine is 22.23-dihydroercalciol, (24S)-methylcalciol, (5)-(10S)-10, quite wrongly referred to as vitamin B15 but also labeled B16. 19-dihydroercalciol, (24S)-ethylcalciol and (22E)-(24R)- The toxins laetrile and amygdaline are sometimes referred to ethyl-22.23-didehydrocalciol. Vitamin D is essential for pro as vitamin B17. Both pangamic acid and laetrile were first moting the absorption and utilisation of calcium and proposed as vitamins by Ernst T. Krebs; neither are recog phosphorus, and normal calcification of the skeleton. Along nized by the medical community. Flavonoids are sometimes with parathyroid hormone and calcitonin, it regulates serum called vitamin P. Animal, bird, and bacterial growth factors calcium concentration by altering serum calcium and phos have been designated vitamins such as para-aminobenzoic phate blood levels, as needed, and mobilizing calcium from acid (PABA) vitamin Bo, the folacin (see folic acid) pteryl bone. It maintains neuromuscular function and various other heptaglutamic acid vitamin B or vitamin Bc-conjugate and cellular processes, including the immune system. Calcipot orotic acid as vitamin B. A few substances were once riene, as well as other vitamin C forms is useful in the treat thought to be B-complex vitamins and are referred to as ment of psoriasis. B-vitamins in older literature, including B (adenine) and Bs 0738 Vitamin E is a fat-soluble vitamin and describes all (adenylic acid), but are no longer recognized as Such. An tocopherol and tocotrienol derivatives that exhibit the bio antitumor pterin phosphate named Vitamin B-14 and later logical activity of alpha tocopherol. Those used commer abandoned. cially are d-alpha tocopherol (natural vitamin E), d-alpha 0741. Vitamins as antioxidants. The antioxidant vitamins tocopherol acetate, d-alpha tocopherol Succinate, d.l-alpha can be divided into those that are water-soluble and exist in tocopherol (synthetic vitamin E), d.l-alpha tocopherol acetate aqueous Solution primarily vitamin C and those that are and d.l-alpha tocopherol Succinate. Vitamin E is an antioxi fat-soluble and exist in membranes or lipoproteins—Vitamin dant, protecting polyunsaturated fatty acids in membranes E and betacarotene. Lipid membranes are particularly Vulner and other critical cellular structures from free radicals and able to oxidative breakdown by free radicals. Vitamin E pro products of oxidation. It works in conjunction with dietary tects cell membranes from destruction by undergoing prefer Selenium (a co-factor for glutathione peroxidase), and also ential oxidation and destruction. Some quinones, such as with vitamin C and other enzymes, including Superoxide ubiquinone (co-enzyme Q) also appear to have antioxidant dismutase and catalase. Vitamin E is not very stable. It may properties. All these Substances can act as free radical scav have an anti-inflammatory effect and some studies state that it engers and can react directly with free radicals. Riboflavin improves immune function in the elderly. It is also said to also has a role as an antioxident. reduce oxidative damage and to improve lung function. Vita 0742 They are believed to protect against certain diseases min E can spare vitamin Cand Vice versa. It is said to be photo by preventing the deleterious effects of free-radical-mediated protective and to have an anti aging effect on skin showing processes in cell membranes and by reducing the Susceptibil reduced wrinkles and tumors ity of tissues to oxidative stress. An article by MP Ludo 0739 Vitamin K is a fat soluble vitamin and describes entitled "Antioxidants and Vitamins in Cosmetics' Clinics in 2-methyl-1,4-naphthaquinone and all derivatives that exhibit Dermatology (2001): 19:467-473 discusses the benefits of US 2008/0299220 A1 Dec. 4, 2008 60

Vitamins and derivatives in cosmetics. Note that carotenoids 0764. In an embodiment the vitamin is vitamin E or a and flavonoids also act as antioxidants derivative thereof or combinations thereof. 0743) Synergism between vitamins is known, for example, 0765. In an embodiment the vitamin is the vitamin is vita synergism between vitamin A and vitamin E is described by min F or a derivative thereof or combinations thereof. Gallarate, Carlotti, Trotta, and Bovo in the International Jour 0766. In one or more embodiments the vitamin is a com nal of Pharmacuetics 188 (1999) 233-241 discussing a study bination of two or more vitamins selected from the group on the stability of ascorbic acid. Any synergism known in the comprising vitamin A, B3, C. K. E. and F and a derivative literature between vitamins to potentiate or facilitate their thereof. action can be used in the present invention. Details of the solubility of vitamins can be found for example in the Merck 0767. In an embodiment the vitaminor a derivative thereof Index and other similar reference works and databases. or combinations thereof comprises an antioxidant. 0744. According to one or more embodiments a hygro 0768. In another embodiment the vitamin or a derivative scopic Vitamin containing composition comprises: thereof or combinations thereof improves stimulates or pro 0745 (a) at least one hygroscopic substance at a suffi motes target site metabolism. cient concentration to provide an AW value of the hygro 0769. In a still further embodiment the vitaminor a deriva Scopic vitamin containing composition of less than 0.9; tive thereof or combinations thereof alleviates, ameliorates, and treats, prevents, retards or otherwise has a beneficial effect on 0746 (b) a vitamin or a derivative thereof or a combi a skin or boy cavity condition. nations thereof. (0770. In an embodiment the skin condition is selected 0747 According to one or more embodiments a foamable from the group consisting of skin pigmentation, dry skin, a Vitamin composition comprises: Wound, acne, psoriasis and skin aging. 0748 a. a therapeutically effective concentration of a 0771. In one or more embodiments the vitamin is a com Vitamin; bination of two or more vitamins selected from the group 0749 b. about 50% to about 98% of a solvent selected comprising vitamin B3, E and C and a derivative thereof. from the group consisting of (1) a propylene glycol or 0772. In an embodiment, the therapeutic agent is a photo derivative; and (2) a polyethylene glycol or derivatives dynamic therapy (PDT) agent. Suitable PDT agents include and mixtures thereof; but are not limited to modified porphyrins, chlorins, bacterio (0750 c. 0% to about 48% of a secondary solvent; chlorins, phthalocyanines, naphthalocyanines, pheophor (0751 d. a surface-active agent; bides, purpurins, m-THPC, mono-L-aspartyl chlorin e6, bac (0752 e. about 0.01% to about 5% by weight of at least teriochlorins, phthalocyanines, benzoporphyrin derivatives, one polymeric agent; and as well as photosensitiser precursors, such as aminolevulinic 0753 f. a liquefied or compressed gas propellant at a acid and derivatives, esters, salts and mixtures thereof. concentration of about 3% to about 25% by weight of the 0773. In an embodiment, the therapeutic agent is an anti total composition. oxidant or a radical scavenger. Suitable antioxidants and radi cal scavengers agents include but are not limited to ascorbic 0754. In one or more embodiments there is provided a acid, ascorbylesters offatty acids, magnesiumascorbyl phos method of treating a disorder or condition of mammalian phate, sodium ascorbyl phosphate, ascorbyl Sorbate, toco Subject, comprising: administering a foamable vitamin com pherol, tocopheryl Sorbate, tocopheryl acetate, butylated position to a target site, the composition comprising one or hydroxy benzoic acid, 6-hydroxy-2,5,7,8-tetramethylchro more of the foamable compositions described here: man-2-carboxylic acid, gallic acid, propyl gallate, uric acid, 0755. In one or more embodiment the surface active agent Sorbic acid, lipoic acid, diethylhydroxylamine, amino-guani can range from about less than 0.1% up to about 15% or up to dine, glutathione, dihydroxy fumaric acid, lycine pidolate, about 20% by weight of composition depending on the sur arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, factant selected or preferably is about 0.2% to about 0.5% by curcumin, lysine, methionine, proline, Superoxide dismutase, weight of composition. silymarin, tea extracts, grape skin/seed extracts, melanin, and 0756. In one or more embodiments the vitamin is selected polyunsaturated oils, containing omega-3 and omega-6 fatty from the group consisting of vitamin A, B1, B2, B3, B5, B6, acids (e.g., linoleic and linolenic acid, gamma-linoleic acid, B7, B9, B12, PABA, C, D1-D4, E, K and F and a derivative eicosapentaenoic acid and docosahexaenoic acid and deriva thereof. tives, esters, salts and mixtures thereof. 0757. In another embodiment the vitamin or a derivative 0774. In an embodiment, the therapeutic agent is a self thereof is susceptible to oxidation. tanning agent, such as dihydroxyacetone. 0758. In a further embodiment the vitamin or a derivative 0775. In an embodiment, the therapeutic agent is an agent, thereof is soluble in water. capable of treating hyperhidrosis. Suitable hyperhidrosis 0759. In another embodiment the vitamin is selected from agents include but are not limited to anticholinergic drugs, the group consisting of vitamin B1, B2, B3, B5, B6, B7, B9, boric acid, tannic acid, resorcinol, potassium permanganate, B12, PABA and C and a derivative thereof. formaldehyde, glutaraldehyde, methenamine, a Lewis acid, 0760. In an embodiment the vitamin is vitamin B3 or a aluminum chloride, aluminum chlorohydrates, Zirconium derivative thereof or combinations thereof. chlorohydrates, aluminum-zirconium-Glycine (AZG) com 0761. In an embodiment the vitamin is vitamin C or a plex, aluminum hydroxybromide, a glycopyrrolate com derivative thereof or combinations thereof. pound, a 5-alpha-reductase inhibitor, finasteride, epristeride, 0762. In an embodiment the vitamin is the vitamin is vita flutamide, Spironolactone, saw palmetto extract, cholestan-3- min K or a derivative thereof or combinations thereof. one, a mono- and dicarboxylic acid having 4 to 18 carbon 0763. In an embodiment the vitamin is vitamin A or a atoms, botulinum toxin, a 5-HT2C receptor antagonist, a derivative thereof or combinations thereof. 5-HT2C receptor antagonist, ketanserin, ritanserin, US 2008/0299220 A1 Dec. 4, 2008 mianserin, meSulergine, cyproheptadine, fluoxetine, mirtaza the composition has a water content below about 5%, prefer pine, olanzapine and Ziprasidone. ably below about 2%, such as below about 1.5%. 0776. In an embodiment, the additional therapeutic agent is a Sunscreen agent. Suitable Sunscreen agents include but Fields of Applications are not limited to titanium dioxide, Zinc oxide, Zirconium 0780. The foamable carrier is suitable for treating any oxide, iron oxide, p-aminobenzoic acid and its derivatives infected surface. In one or more embodiments, foamable (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic carrier is suitable for administration to the skin, a body sur acid); anthranilic acid derivatives (i.e., o-amino-benzoates, face, a body cavity or mucosal Surface, e.g., the cavity and/or methyl, menthyl, phenyl, benzyl, phenylethyl, linallyl, terpi the mucosa of the nose, mouth, eye, ear, respiratory system, nyl, and cyclohexenyl esters); Salicylates (amyl, phenyl, vagina or rectum (severally and interchangeably termed octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol herein “target site'). esters); cinnamic acid derivatives (menthyl and benzyl esters, 0781. By selecting a suitable active agent, or a combina a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); dihy tion of at least two active agents, the foamable composition is droxycinnamic acid derivatives (umbelliferone, methylum useful in treating an animal or a human patient having any one belliferone, methylaceto-umbelliferone); trihydroxy-cin of a variety of dermatological disorders, including dermato namic acid derivatives (esculetin, methylesculetin, logical pain, dermatological inflammation, acne, acne Vul daphnetin, and the glucosides, esculin and daphnin); hydro garis, inflammatory acne, non-inflammatory acne, acne full carbons (diphenylbutadiene, stilbene): dibenzalacetone and minans, nodular papulopustular acne, acne conglobata, benzalacetophenone; naphtholsulfonates (sodium salts of dermatitis, bacterial skin infections, fungal skin infections, 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic viral skin infections, parasitic skin infections, skin neoplasia, acids); di-hydroxynaphthoic acid, o- and p-hydroxybiphe skin neoplasms, pruritis, cellulitis, acute lymphangitis, lym nyldisulfonates, coumarin derivatives (7-hydroxy, 7-methyl, phadenitis, erysipelas, cutaneous abscesses, necrotizing Sub 3-phenyl), diazoles (2-acetyl-3-bromoindazole, phenylben cutaneous infections, Scalded skin syndrome, folliculitis, ZOxazole, methylnaphthoxazole, quinine salts (bisulfate, Sul furuncles, hidradenitis Suppurativa, carbuncles, paronychial fate, chloride, oleate, and tannate); quinoline derivatives infections, rashes, erythrasma, impetigo, eethyma, yeast skin (8-hydroxyquinoline salts, 2-phenylduinoline); hydroxy- or infections, warts, molluscum contagiosum, trauma or injury methoxy-Substituted benzophenones; uric and violuric acids; to the skin, post-operative or post-Surgical skin conditions, tannic acid and its derivatives (e.g., hexaethylether); (butyl Scabies, pediculosis, creeping eruption, eczemas, psoriasis, carbotol) (6-propyl piperonyl)ether; hydroquinone; ben pityriasis rosea, lichen planus, pityriasis rubra pilaris, edema Zophenones (oxybenzene, Sulisobenzone, dioxybenzone, tous, erythema multiforme, erythema nodosum, grannuloma benzoresorcinol, 2,2,4,4-tetrahydroxybenzophenone, 2,2'- annulare, epidermal necrolysis, Sunburn, photosensitivity, dihydroxy-4,4'-dimethoxybenzophenone, octabenzone; pemphigus, bullous pemphigoid, dermatitis herpetiformis, 4-isopropyldibenzoylmethane; butylmethoxydibenzoyl keratosis pilaris, callouses, corns, ichthyosis, skin ulcers, methane: etocrylene; octocrylene; 3-(4-methylbenzylidene ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi's bornan-2-one), terephthalylidene dicamphor Sulfonic acid sarcoma, melanoma, malignant melanoma, basal cell carci and 4-isopropyl-di-benzoylmethane. noma, squamous cell carcinoma, poison ivy, poison oak, con tact dermatitis, atopic dermatitis, rosacea, purpura, monilia 0777. In an embodiment, the additional therapeutic agent sis, candidiasis, baldness, alopecia, Behcet’s syndrome, is a figure-forming agent and an agent, capable of treating cholesteatoma, Dercum disease, ectodermal dysplasia, gus cellulite. Suitable such agents include but are not limited to tatory Sweating, nail patella syndrome, lupus, hives, hair loss, baldderwack extract, butcher's broom, cayenne, dandelion, Hailey-Hailey disease, chemical or thermal skin burns, scle red clover, ginkgo biloba, horse chestnut, witch hazel and roderma, aging skin, wrinkles, Sun spots, necrotizing fascii borage oil, caffeic acid, nicotinic acid, theophiline and pen tis, necrotizing myositis, gangrene, Scarring, and Vitiligo. toxyphilline and salts and derivatives thereof. 0782. Likewise, the foamable composition is suitable for (0778. Several disorders of the skin, body cavity or treating a disorder of a body cavity or mucosal Surface, e.g., mucosal Surface (e.g., the mucosa or the cavity of the nose, the mucosa of the nose, mouth, eye, ear, respiratory system, mouth, eye, ear, vagina or rectum) involve a combination of vagina or rectum. Non limiting examples of Such conditions etiological factors. For example, fungal and bacterial infec include chlamydia infection, gonorrhea infection, hepatitis B. tions and that are inflamed and have symptoms of redness herpes, HIV/AIDS, human papillomavirus (HPV), genital and/or itching warrant therapy that combines an anti-infective warts, bacterial vaginosis, candidiasis, chancroid, granuloma agent and an anti-inflammatory agent. Thus, in several cases, Inguinale, lymphogranloma Venereum, mucopurulent cervi combining at least two active agents that treat different etio citis (MPC), molluscum contagiosum, nongonococcal ure logical factors results in a synergistic effect and consequently thritis (NGU), trichomoniasis, Vulvar disorders, vulvodynia, higher Success rate of the treatment. Vulvar pain, yeast infection, Vulvar dystrophy, Vulvar 0779. In certain cases, the composition contains two active intraepithelial neoplasia (VIN), contact dermatitis, pelvic agents, where each of the active agents require a different pH inflammation, endometritis, Salpingitis, oophoritis, genital environment in order to remain stable. For example, corticos cancer, cancer of the cervix, cancer of the Vulva, cancer of the teroids are typically stable at acidic pH values (they have a vagina, vaginal dryness, dyspareunia, anal and rectal disease, maximum stability at a pH of about 4-6) and of vitamin D anal abscess/fistula, anal cancer, anal fissure, anal warts, analogues are typically stable at basic pH values (they have a Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecal maximum stability at pH values above about 8). In order to incontinence, constipation, polyps of the colon and rectum. circumvent the problem of instability in such cases it is pre 0783. In an embodiment, the composition is useful for the ferred that the composition is Substantially non-aqueous. The treatment of an infection. In one or more embodiments, the term 'substantially non-aqueous” is intended to indicate that composition is suitable for the treatment of an infection, US 2008/0299220 A1 Dec. 4, 2008 62 selected from the group of a bacterial infection, a fungal PRISING ONE OR MORE OF A CHANNEL AGENT, A infection, a yeast infection, a viral infection and a parasitic CHOLINERGIC AGENT, A NITRIC OXIDE DONOR, infection. AND RELATED AGENTS AND THEIR USES: U.S. patent 0784. In an embodiment, the composition is useful for the application Ser. No. 1 1/825,406, filed on Jul. 5, 2007, entitled treatment of wound, ulcer and burn. This use is particularly DICARBOXYLIC ACID FOAMABLE VEHICLE AND important since the composition creates a thin, semi-occlu PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. sive layer, which coats the damaged tissue, while allowing patent application Ser. No. 1 1/900,072, filed on Sep. 10, exudates to be released from the tissue. 2006, entitled FOAMABLE VEHICLE AND VITAMIN 0785. The composition is also suitable for administering a AND FLAVONOID PHARMACEUTICAL COMPOSI hormone to the skin or to a mucosal membrane or to a body TIONS THEREOF; and U.S. patent application Ser. No. cavity, in order to deliver the hormone into the tissue of the 11/947,751, filed Nov. 29, 2007, entitled COMPOSITIONS target organ, in any disorder that responds to treatment with a WITH MODULATINGAGENTS, all of which are incorpo hormone. rated herein by reference in their entirety. More particularly 0786. In light of the hygroscopic nature of the composi any of the active ingredients; the solvents; the Surfactants; tion, it is further suitable for the treatment and prevention of foam adjuvants; polymeric agents, penetration enhancers; post-Surgical adhesions. Adhesions are Scars that form abnor preservatives, humectants; moisturizers; and other excipients mal connections between tissue surfaces. Post-Surgical adhe as well as the propellants and methods listed therein can be sion formation is a natural consequence of Surgery, resulting applied herein and are incorporated by reference. when tissue repairs itself following incision, cauterization, 0789. The invention is described with reference to the Suturing, or other means of trauma. When comprising appro following examples. This invention is not limited to these priate protective agents, the foam is Suitable for the treatment examples and experiments. Many variations will Suggest or prevention of post Surgical adhesions. The use of foam is themselves and are within the full intended scope of the particularly advantageous because foam can expand in the appended claims. body cavity and penetrate into hidden areas that cannot be 0790. A “stable foam is defined herein as a composition, reached by any other alternative means of administration. which upon release from an aerosol can, creates a foam mass, which is Sustained on a Surface for at least one minute, more Substantially Alcohol-Free preferably at least two minutes, and yet more preferably for at least 5 minutes. A period of minutes is regarded as a short 0787. According to one or more embodiments, the foam term, but nevertheless it allows a good and more than Suffi able composition is substantially alcohol-free, i.e., free of cient period of time for a Subject to receive foam dispensed on short chain alcohols. Short chain alcohols, having up to 5 a body surface and to spread it or to transfer it to another carbonatoms in their carbon chain skeleton and one hydroxyl region and to spread it. group, such as ethanol, propanol, isopropanol, butaneol, iso 0791. In terms of spreadability and absorption an accept butaneol, t-butaneol and pentanol, are considered less desir able foam is one, that does not readily collapse upon dispens able solvents or solvents due to their skin-irritating effect. ing on the skin; spreads easily on a skin Surface; at least Thus, the composition is Substantially alcohol-free and partially absorbed following rubbing onto the skin, and more includes less than about 5% final concentration of lower preferably, substantially absorbed following rubbing on the alcohols, preferably less than about 2%, more preferably less skin. than about 1%. 0788. Other foamable compositions are described in: U.S. 0792. In terms of tactile properties an acceptable foam is Publication No. 05-0232869, published on Oct. 20, 2005, one, that: creates a pleasant feeling after application; leaves entitled NONSTEROIDAL IMMUNOMODULATING KIT minimal oily residue; and leaves minimal shiny residual look. AND COMPOSITION AND USES THEREOF; U.S. Publi Shakability cation No. 05-0205086, published on Sep. 22, 2005, entitled RETINOIDIMMUNOMODULATINGKITAND COMPO 0793 Shakability means that the composition contains SITION AND USES THEREOF; U.S. Publication No. some or sufficient flow to allow the composition to be mixed 06-0018937, published on Jan. 26, 2006, entitled STEROID or remixed on shaking. That is, it has fluid or semi fluid KIT AND FOAMABLE COMPOSITION AND USES properties. In some very limited cases it may still be possible THEREOF; U.S. Publication No. 05-0271596, published on to have a foamable composition which is flowable but not Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSI apparently shakable. TION AND USES THEREOF; U.S. Publication No. 06-0269485, published on Nov.30, 2006, entitled ANTIBI Breakability OTIC KIT AND COMPOSITION AND USES THEREOF: U.S. Publication No. 07-0020304, published on Jan. 25, 0794. A breakable foam is thermally stable or substan 2007, entitled NON-FLAMMABLE INSECTICIDE COM tially so, yet breaks under sheer force. The breakable foam of POSITION AND USES THEREOF; U.S. Publication No. the present invention is not "quick breaking’, i.e., it does not 06-0193789, published on Aug. 31, 2006, entitled FILM readily collapse upon exposure to body temperature environ FORMING FOAMABLE COMPOSITION: U.S. patent ment. Sheer-force breakability of the foam is clearly advan application Ser. No. 1 1/732,547, filed on Apr. 4, 2007, tageous over thermally induced breakability, (due to, for entitled ANTI-INFECTION AUGMENTATION OF FOAM example, the presence of alcohol) since it allows comfortable ABLE COMPOSITIONS AND KITANDUSESTHEREOF: application and well directed administration to the target area. U.S. patent application Ser. No. 1 1/732,547, filed on Apr. 4, Foam Collapse 2007, KERATOLYTIC ANTIFUNGAL FOAM: U.S. patent application Ser. No. 1 1/767,442, filed on Jun. 22, 2007, 0795. A further aspect of the foam is breakability. Ther entitled FOAMABLE COMPOSITIONS AND KITS COM mally sensitive foams immediately collapse upon exposure to US 2008/0299220 A1 Dec. 4, 2008

skin temperature and, therefore, cannot be applied on the 0807 Waterless Foam hand and afterwards delivered to the afflicted area. 0808 1. Dissolve the polymers in the main solvent with 0796. The foam of the present invention has several heating or cooling as appropriate for specific polymer. notable advantages, when compared with hydroalcoholic Add the all other ingredients and heat to 75° C. to melt foam compositions. Such as and dissolve the various ingredients. 0797 Breakability. The foam of the present invention is (0809 2. Cool to below 40° C. and add sensitive ingre thermally stable and breakable under sheer force but is not dients with mild mixing. “quick breaking which allows comfortable application and 0810) 3. Cool to room temperature. well directed administration to the target area. 0811 Oily Waterless Foam 0798 Skin drying and skin barrier function. Short chain 08.12 1. Mix all ingredients excluding polymers and alcohols are known to dry the skin and impair the integrity of heat to 75° C. to melt and dissolve and obtain homoge the skin barrier. By contrast, including a film forming agent in neous mixture. the composition of the present invention foes not cause 0813 2. Mix well and cool to below 40° C. and add the unwanted skin barrier damage. polymers and sensitive ingredients with moderate mix 0799. Irritability. Due to the lack of lower alcohols (C1 1ng. C5) and improvement in skin barrier function, skin irritability 0814 3. Cool to room temperature. is eliminated. 0815 Silicone in Glycol Emulsion 0800 Another property of the foam is specific gravity, as 0816) 1 Mix main solvent emulsifiers and foam adju measured upon release from the aerosol can. Typically, foams vants and heat to 75° C. to melt and dissolve the various have specific gravity of less than 0.12 g/mL, or less than 0.10 ingredients with vigorous mixing. g/mL, or less than 0.08 g/mL, depending on their composition 0817 2 Homogenize the formulation with vigorous and on the propellant concentration. mixing. 0818 4. Add the silicones at 60°C. with vigorous mix EXAMPLES ing. 0819 5. Cool to below 40° C. and add sensitive ingre 0801. The invention is described with reference to the dients with mild mixing. following examples. This invention is not limited to these 0820. Formulations with Silicones and HPMC examples and experiments. Many variations will suggest 0821. This methodology is suitable, for all formulations themselves and are within the full intended scope of the described comprising HPMC (Where the formulation is with appended claims, For example although examples are pro out polymer the production starts at section 2). vided below with specific active agents they may be replaced 0822. 3 Dissolve the polymers in the main solvent with by other active agents in effective concentrations withor with heating or cooling as appropriate for specific polymer out appropriate changes as will be appreciated by someone in and with vigorous mixing. the art. 0823 4Add to main solvent emulsifiers and foam adju 0802 All % values are provided on a weight (w/w) basis. vants and heat to 75° C. to melt and dissolve the various 0803. In some cases the formulations are expressed in ingredients with vigorous mixing. amounts up to 100% including the propellant. In other cases 0824 5 Homogenize the formulation with vigorous the formulations are expressed in amounts up to 100% not mixing. including the propellant, which is then added to the compo 0825 6. Add the silicones at 60°C. with vigorous mix sition. ing. 0826 7. Cool to below 40° C. and add sensitive ingre General Methodology dients with mild mixing. 0804. The formulas of the present invention may be made 0827 8. Cool to room temperature. in the following general way with appropriate adjustments for 0828 Formulations with Silicones and ASOS each formulation as will be appreciated by someone skilled in 0829. This methodology is suitable, for all formulation the art. Polymers, ifany, are mixed, swelled and solubilized in described above comprising ASOS the waterless medium, when necessary, with appropriate heat 0830) 1. Add to main solvent emulsifiers and foam adju until it forms a clear solution. Stabilizing surfactants added vants and heat to 75° C. to melt and dissolve the various usually with heat, until a homogeneous mixture is obtained, ingredients with vigorous mixing. the mixture is then allowed to cool. The remainder of the 0831 2. Homogenize the formulation with vigorous ingredients, are then added with mixing until they have dis mixing Solved in the medium. The active agent is usually added at the 0832. 3. Add the silicones at 60°C. with vigorous mix end once the modulating agent, if present, has been incorpo ing rated. For foam the canisters are then filled with the above 0833 4. Cool to below 40° C. and add sensitive ingre waterless formula, sealed and crimped with a valve and pres dients with mild mixing. surized with the propellant. 0834 5. Cool to room temperature. 0805. A general procedure for preparing foamable com 0835. Formulations with Silicones and Carbopol. positions is set out in WO 2004/037225, which is incorpo 0836. This methodology is suitable, for all formulation rated herein by reference. described comprising Carbopol. 0806. In one or more various embodiments the composi 0837. 1 Separate part fro the solvent and add the car tions can be prepared according to the general methodology bopol set out herein with appropriate changes as would be well 0838 2. Homogenize the carbopol at RT for few min appreciated by a man of the art. utes until complete. US 2008/0299220 A1 Dec. 4, 2008 64

0839. 3. Add to the rest of main solvent emulsifiers and of the material to compression is measured by a calibrated foam adjuvants and heat to 75° C. to melt and dissolve load cell and reported in units of grams on the texture analyzer the various ingredients with vigorous mixing. instrument display. Preferably at least three repeat tests are 0840 4. Homogenize the formulation with vigorous made. The textural characteristics of a dispensed foam can mixing affect the degree of dermal penetration, efficacy, spreadability 0841 5. Add the silicones at 60°C. with vigorous mix and acceptability to the user. The results can also be looked at ing as an indicator of softness. Note: the foam sample is dis 0842) 6. Cool to below 40° C. and mix with carbopol pensed into an aluminum sample holder and filled to the top of mixture with vigorous mixing. the holder. 0843. 7. Cool to room temperature. Collapse Time Production Under Vacuum 0850 Collapse time (CT) is examined by dispensing a 0844 Optionally, the foamable formulation may be pro given quantity of foam and photographing sequentially its duced under nitrogen and under vacuum. Whilst the whole appearance with time during incubation at 36°C. It is useful process can be carried out under an oxygen free environment, for evaluating foam products, which maintain structural sta it can be sufficient to apply a vacuum after heating and mixing bility at skin temperature for at least 1 min. all the ingredients to obtain an emulsion or homogenous liquid. Preferably the production chamber is equipped to Viscosity apply a vacuum but if not the formulation can be for example placed in a dessicator to remove oxygen prior to filing and 0851 Viscosity is measured with Brookfield LVDV-II+ crimping. PRO with spindle SC4-25 at ambient temperature and 10, 5 and 1 RPM. Viscosity is usually measured at 10 RPM. How Canisters Filling and Crimping ever, at about the apparent upper limit for the spindle of 0845 Each aerosol canister is filled with PFF and crimped ->50,000 CP, the viscosity at 1 RPM may be measured, with valve using vacuum crimping machine. The process of although the figures are of a higher magnitude. applying a vacuum will cause most of the oxygen present to be eliminated. Addition of hydrocarbon propellant may with FTC (Freeze Thaw Cycles) out being bound by any theory further help to reduce the likelihood of any remaining oxygen reacting with the active 0852. To check the foam appearance under extreme con ingredient. It may do so, without being bound by any theory, ditions of repeated cycles of cooling, heating, (first cycle) by one or more of dissolving in the oil or hydrophobic phase cooling, heating (second cycle) etc., commencing with -100° of the formulation, by dissolving to a very limited extent in C. (24 hours) followed by +400°C. (24 hours) measuring the the aqueous phase, by competing with Some oxygen from the appearance and again repeating the cycle for up to three times. formulation, by diluting out any oxygen, by a tendency of oxygen to occupy the dead space, and by oxygen occupying Chemical Stability part of the space created by the vacuum being the unfilled 0853. The amount of active agent present is analyzed in Volume of the canister or that remaining oxygen is rendered foam expelled from various pressurized canisters containing substantially ineffective in the formulation. foam formulations using HPLC. Analysis is carried out at Zero time and at appropriate time intervals thereafter. The Pressurizing canisters are stored in controlled temperature incubators at 5° Propellant Filling C., at 25°C., at, 40° C. and at 50° C. At appropriate time intervals canisters are removed and the amount of active agent 0846 Pressurizing is carried out using a hydrocarbon gas in the foam sample is measured. orgas mixture. Canisters are filled and then warmed for 30sec in a warm bath at 50° C. and well shaken immediately there Creaming by Centrifugation after. Principle of Test Closure Integrity Test. 0854. The centrifugation used in this procedure serves as a 0847 Each pressurized canister is subjected to bubble and stress condition simulating the aging of the liquid dispersion crimping integrity testing by immersing the canister in a 60° under investigation. Under these conditions, the centrifugal C. water bath for 2 minutes. Canisters are observed for leak force applied facilitates the coalescence of dispersed globules age as determined by the generation of bubbles. Canisters or sedimentation of dispersed solids, resulting in loss of the releasing bubbles are rejected. desired properties of the formulated dispersion.

Foam Tests Procedure 0848. By way of non limiting example the objectives of 0855 Following preparation of the experimental formula hardness, collapse time and FTC stability tests are briefly set tion/s, allow to stand at room temperature for 224 h. Handle out below as would be appreciated by a person of the art. pentane in the chemical hood. Add to each experimental formulation in a 20-mL glass vial a quantity of pentane Hardness equivalent to the specified quantity of propellant for that 0849 LFRA100 instrument is used to characterize hard formulation, mix and allow formulation to stand for at least 1 ness. A probe is inserted into the test material. The resistance h and not more than 24 h. US 2008/0299220 A1 Dec. 4, 2008

0856 Transfer each mixture to 1.5 mL microtubes. Tap each microtube on the table surface to remove entrapped air -continued bubbles. TECH TECH TECH 0857 Place visually balanced microtubes in the centrifuge PG-014 PG-01S PG-O16 rotor and operate the centrifuge at one or more of 10,000 rpm Ingredient 9% WW 9% WW 9% WW for 10 min, 3,000 rpm for 10 minor at 1,000 rpm for 10 min. Glyceryl Stearate and PEG-100 4.OO 4.OO 3.00 stearate (Simulsol 165) Bubble Size PEG 4OOO 1O.OO Glycerin anhydrous 33.00 0858. Foams are made of gas bubbles entrapped in liquid. Hydroxypropylcellulose (Klucel EF) 2.OO 2.00 2.OO The bubble size and distribution reflects in the visual texture and smoothness of the foam. Foam bubbles size is determined Total 1OOOO 100.00 1OOOO by dispensing a foam sample on a glass slide, taking a picture of the foam Surface with a digital camera equipped with a macro lens. The diameter of about 30 bubbles is measured 0862 The following observation on the preparation and manually relatively to calibration standard template. Statisti property of the foam samples were made: cal parameters such as mean bubble diameter, standard devia 0863 The compositions are substantially non-aqueous tion and quartiles are then determined. Measuring diameter 0864. In order to create a foam, a propellant can be may also be undertaken with image analysis Software. The added at a concentration of about 3% to about 25%. camera used was a Nikon D40X Camera (resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 0865 Composition TECH PG-015 contains the mini mm F2.8 EX DG HSM). Pictures obtained are cropped to mum number of components that constitute a foamable keep a squared region of 400 pixelsx400 pixels. composition, which upon release from an aerosol pres surized container affords foam of Good or Excellent Foam Satisfaction Tests quality. It contains a diol (PG), a polymeric agent 0859 Compositions of the present invention were sepa (Klucel EF), and a non-ionic surface active agent (PEG rately applied to clean skin of a group of human Subjects. 100 stearate and Laureth 4) After 5 minutes tested Subjects were asked to provide a gauge 0866 Composition TECH PG-014 demonstrates that of their satisfaction relating to the following parameters: Ease the addition of 10% PEG (secondary polar solvent) of application, skin absorption, Stickiness, odor, oily residue, maintains Good foam quality. skin Surface shiny appearance, composition stability; overall 0867 Composition TECH PG-016 demonstrates that a satisfaction; sensation change. Such as cooling, relaxing, mixture of two polyols (PG and glycerin maintains heating etc. The Subjects gauged their response according to Good foam quality. This composition possesses high the following scoring system: skin hydration effect. 1—very bad feeling 2 Bad feeling Example 2 3 feels “OK” 4—Feels good Foamable Carriers Containing Polyols 5—Feels excellent, want more The scores assigned by the Subjects were added and an aver 0868 age result was recorded. Examples TECH TECH TECH 0860. The invention is described with reference to the PG-021 PG-024 PG-O2S following examples. This invention is not limited to these Ingredient 9% WW 9% WW 9% WW examples and experiments. Many variations will suggest Propylene glycol (PG) 91.OO S8.00 43.OO themselves and are within the full intended scope of the Stearyl alcohol 2.OO 1.00 1.OO appended claims. Laureth-4 2.OO 2.00 2.OO Glyceryl Stearate and PEG-100 3.00 3.00 3.00 Section A stearate (Simulsol 165) Glycerin 33.00 33.00 Hydroxypropylcellulose (Klucel EF) 2.OO 3.00 3.00 Example 1 Dimethyl isosorbide (DMI) 1S.OO

Foamable Carriers Containing Polyols Total 1OOOO 100.00 1OOOO 0861) 0869. The following procedure was employed when the compositions of Example 2 were produced. TECH TECH TECH PG-014 PG-01S PG-O16 Step 1: Preparation of Phase A Ingredient 9% WW 9% WW 9% WW Propylene glycol (PG) 82.OO 92.00 6O.OO 0870) 1. Heat Propylene glycol and stearyl alcohol to Laureth-4 2.OO 2.00 2.OO 80-850 C. 0871 2. Add Klucel while mixing. US 2008/0299220 A1 Dec. 4, 2008 66

0872. 3. Cool to 70-75° C. Add all other ingredients Example 4 while mixing. Agitation continues until solution unifor Additional Foamable Carriers Containing Polyols, mity is reached Having Excellent Foam Structure 0873. 4. Cool solution to 30°C. with moderate mixing. 0885 Step 2: Canisters Filling and Crimping

0874) 1. Each aerosol canister 35x70 mm is filled with TECH- TECH- TECH- TECH 30+5%g of the composition PG TECH-PG PG PG PG 0875 2. Each canister was closed with an aerosol valve, O29 O3O O31 O32 O33 using a vacuum crimping machine. Ingredient % Wiw % wiw % wiw % wiw % Wiw Propylene Glycol 91.O 58.0 43.O 46.0 78.O Step 3: Pressurizing Stearyl Alcohol 2.0 1.O 1.O 1.O 1.O Glycerin 33.0 33.0 33.0 0876 Propellant (mix of propane, butane and isobutane) Klucel EF 2.0 3.0 3.0 1.5 1.5 was added to each of the canisters Laureth-4 2.0 2.0 2.0 2.O 2.0 Simulso 165 3.0 3.0 3.0 1.5 0877. The following observation on the preparation and Dimethyl Isosorbide 1S.O 1S.O 1S.O properties of the foam were made: Macrogol Cetostearyl 1.5 0878 Composition TECH PG-021, 24 and 25 demon Ether strates that the addition of 1-2% stearyl alcohol (foam Glyceryl Stearate 1.O adjuvant) facilitates the formation of foam with Excel lent quality. Substituting Stearyl alcohol with stearic acid results in an excellent foam too. Example 5 0879 Composition TECH PG-025 demonstrates that Additional Foamable Carriers which can be Used for the addition of 15% DMI (foam adjuvant) facilitates the Vitamins with and without an Active Agent formation of foam with Excellent quality. This compo sition possesses high skin penetration enhancing prop 0886 erties. 0880. In order to create a foam, a propellant can be added at a concentration of about 3% to about 25%. Gel Phase Gel Phase Gel Phase Gel Phase OO1 OO2 OO3 OO4 Example 3 Propylene glycol 88.00 78.00 46.00 78.00 Glycerin anhydrous 33.00 1O.OO Stearyl Alcohol 2.00 1.OO 1.00 2.OO Foamable Carriers Containing Polyols Hydroxypropyl Cellulose 2.00 1...SO 1...SO 2.OO Laureth-4 2.00 2.OO 2.00 2.OO 0881 Glyceyl Monostearate? 1...SO PEG 1 OO Stearate GMSNE 2.00 1.OO 2.OO Macrogol Cetostearyl 1.00 1...SO 1.OO TECH TECH TECH ether PG-026 PG-027 PG-028 PPG-15 stearyl ether 3.00 3.00 Ingredient 9% WW 9% WW 9% WW Dimethyl isosorbide 1S.OO 1S.OO Stearyl alcohol 2.OO 1.00 1.OO Total: 100.00 1OOOO 100.00 1OOOO Propylene glycol (PG) 76.OO 46.00 78.00 Laureth-4 2.OO 2.00 2.OO Glyceryl Stearate (and) PEG-100 1...SO 0887. The polar solvents of the composition including stearate (Simulsol 165) propylene glycol, glycerin and dimethyl isosorbide act as Glycerin anhydrous 33.00 Hydroxypropylcellulose (Klucel EF) 2.OO 1...SO 1...SO penetration enhancers for the vitamins and optional addi Dimethyl isosorbide (DMI) 1S.OO 1S.OO 1S.OO tional therapeutic agents. Glyceryl Stearate 1.OO 1.OO Ceteareth-6 (and) stearyl alcohol 2.OO 1...SO Example 6 (Macrogol cetostearyl ether) Foamable Ascorbic Acid Compostions Total 100.00 100.00 100.00 0888 Ascorbic acid was added to the carrier compositions Foam quality Excellent Excellent Excellent of example 5, as follows.

0882. The following observation on the preparation and properties of the foam were made: WAS OO1. WASOO2 WAS OO3 WAS OO4 0883 Composition TECH PG-027 demonstrates that a Gel Phase Stock 001 95.00% mixture of two polyols (PG and glycerin, plus DMI Gel Phase Stock 002 95.00% (secondary polar solvent) maintains Exellent foam qual Gel Phase Stock 003 95.00% ity. This composition possesses high skin hydration Gel Phase Stock 004 95.00% effect. It further possesses high skin penetration enhanc Ascorbic Acid S.OO% S.OO% S.00% S.00% ing properties. Total: 100.00 100.00 100.00 100.00 0884. In order to create a foam, a propellant can be added at a concentration of about 3% to about 25%. US 2008/0299220 A1 Dec. 4, 2008 67

0889. The following observation on the preparation and 0899. The following observation on the preparation and properties of the foam were made: properties of the foam were made: 0890. In order to create a foam, a propellant can be 0900. In order to create a foam, a propellant can be added at a concentration of about 3% to about 25%. added at a concentration of about 3% to about 25%. 0891. Following addition of a propellant to the compo 0901. Following addition of a propellant to the compo sition, foamable composition, which upon release from sition, foamable composition, which upon release from an aerosol pressurized container affords foam of Good an aerosol pressurized container affords foam of Good or Excellent quality. or Excellent quality. 0892 Following application of each of the foams on facial skin is favorable. The foam is easily spread and Example 9 immediately absorbed into the skin with no extensive Foamable Niacinamide Compositions rubbing. 0902. Niacinamide was added to the carrier compositions Example 7 of example 5, as follows. Foamable Ascorbic Acid and Nicinamide Composi tions WNIOO1 WNIOO2 0893 Ascorbic acid and niacinamide were concurrently Gel Phase Stock 001 96.00% added to the carrier compositions of example 5, as follows. Gel Phase Stock 002 96.00% Niacinamide 4.00% 4.00%

Control: 1OOOO 1OOOO WAN OO1. WAN OO2 WAN OO3 WAN OO4 Gel Phase Stock 001 93.00% 0903. The following observation on the preparation and Gel Phase Stock 002 93.00% properties of the foam were made: Gel Phase Stock 003 93.00% Gel Phase Stock 004 93.00% 0904. In order to create a foam, a propellant can be Ascorbic Acid S.00% S.00% S.00% S.00% added at a concentration of about 3% to about 25%. Niacinamide 2.00% 2.00% 2.00% 2.00% 0905 Following addition of a propellant to the compo sition, foamable composition, which upon release from Total: 100.00 100.00 100.00 100.00 an aerosol pressurized container affords foam of Good or Excellent quality. 0894. The following observation on the preparation and Example 10 properties of the foam were made: 0895. In order to create a foam, a propellant can be Foamable Ascorbic Acid and Alpha Tocopherol added at a concentration of about 3% to about 25%. Compositions 0896. Following addition of a propellant to the compo 0906 Ascorbic acid and alpha tocopherol were concur sition, foamable composition, which upon release from rently added to the carrier compositions of example 5, as an aerosol pressurized container affords foam of Good follows. or Excellent quality. 0897. Following application of each of the foams on facial skin is favorable. The foam is easily spread and immediately absorbed into the skin with no extensive WAT OO1 WATOO2 WAT OO3 WAT OO4 rubbing. Gel Phase Stock 001 94.00% Gel Phase Stock 002 94.00% Example 8 Gel Phase Stock 003 94.00% Gel Phase Stock 004 94.00% Foamable Ascorbic Acid and Tocopheryl Acetate Ascorbic Acid S.OO% S.OO% S.00% S.00% Compositions Alpha Tocopherol 1.00% 1.00% 1.00% 1.00% 0898 Ascorbic acid and tocopheryl acetate were concur Total: 100.00 100.00 100.00 100.00 rently added to the carrier compositions of example 5, as follows. 0907. The following observation on the preparation and properties of the foam were made: 0908. In order to create a foam, a propellant can be added at a concentration of about 3% to about 25%. WAT OO1 WAT OO2 WAT OO3 WAT OO4 0909. Following addition of a propellant to the compo Gel Phase Stock 001 94.00% sition, foamable composition, which upon release from Gel Phase Stock 002 94.00% an aerosol pressurized container affords foam of Good Gel Phase Stock 003 94.00% or Excellent quality. Gel Phase Stock 004 94.00% Ascorbic Acid S.00% S.00% S.00% S.00% Example 11 Tocopheryl Acetate 1.00% 1.00% 1.00% 1.00% a) Foamable Polyols Compositions, Containing a Total: 100.00 100.00 100.00 100.00 Steroid Drug 0910. The following steroids were included in formula tions TECH-PG 30, 31 and 33 (see Example 4): betametha US 2008/0299220 A1 Dec. 4, 2008

sone Valerate 0.12%, clobetasol propionate 0.05%, betamethasone dipropionate 0.05%, fluocinolone acetonide -continued 0.025%, hydrocortisone acetate 0.5% and hydrocortisone butyrate 0.1%. All samples were stored at 50° C. for 4 weeks, FXCLB1 FXCLB2 in order to assess their stability. The following table provides Ingredient 9% WW 9% WW the results of this short-term stability study, which indicated Glyceryl Stearate 1.00 high compatibility between the polyol composition and the Dimethyl isosorbide 1S.OO Calcipotriol O.OOS O.OOS steroid drugs, which are known to be temperature-sensitive. Betamethasone Dipropionate O.OS O.OS

0914. The following observation on the preparation and % Degradation after properties of the foam were made: 4 weeks at 50° C. (0915 Composition FXCLB 1 and FXCLB2 contain TECH-PG 032 TECH-PG. O33 two active agents (a corticosteroid and a vitamin D Bethamethasone Valerate 0.12% 1.8% 1.7% derivative, which are known to exert a synergistic thera Clobetasol Propionate 0.05% 4.2% S.O% peutic effect in psoriasis. These compositions contribute Bethamethasone Dipropionate 0.05% O O to enhanced skin penetration of the active agents. Fluocinolone Acetonide 0.025% 1.3% 1.7% Hydrocortison Acetate 0.5% 1.6% 2.1% 0916. The liquefied or gas propellant can be added at a Hydrocortison Butyrate 0.1% 2.6% 2.8 concentration of about 3% to about 25%. Example 13 0911 b) Foamable polyols compositions, containing a Vitamin and a steroid drug Foamable Compositions Containing Polyethylene 0912. Additionally, one or more of the following vitamins Glycol can be included informulations TECH-PG30, 31 and 33 (see Example 4): vitamin C (ascorbic acid) between 0.1 and 5% 0917

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

PEG4OO 87.50 91.50 87.50 89.5O 87.50 87.50 87.50 Klucel MX (hydroxypropyl cellulose) O.SO O O.SO O OSO O OSO Klucel LF (hydroxypropyl cellulose) O OSO O OSO O O.SO O Lipocol C2 (POE (2) cetyl ether) 2.00 2.OO O O O O O Myri 52 O O 2.OO 2.00 O O O Steareth-2 O O O O 2.OO 2.00 O Dermofeel G1OL (Polyglyceryl-10 O O O O O O 2.OO Laurate) Propellant 10 6 10 8 10 10 10 Density O.O60 OO63 0.063 O.OSS O.OS2 O.OSO 0.075 say, 0.1% 1%, 2%. 3%, 4%, or 5%, vitamin C (magnesium 0918. The following observation on the preparation and ascorbyl phosphate) 3%, retinol 1%, retinoic acid 0.1%, properties of the foam were made: niacinamide 2% and tocopherol 1% and Vitamin K. between 0919. The liquefied or gas propellant can be added at a 0.1 and 2% say, 0.1% or 1% or 2%, and are made up as concentration of about 3% to about 25%. indicted in Example 18. 0920. The foams of this example have a non-ionic sur face active agentata concentration of 2%. Total amounts Example 12 of Surface active agent foam adjuvant and polymeric Foamable Polyol Pharmaceutical Composition Com agent is in the range of 2.5%. prising a Combination of Betamethasone Dipropi 0921. The compositions are useful as carriers of various onate and Calcipotriol active therapeutic active agents. 0913 Example 14 Comparison Between Polyethylene-Based Foamable Compositions with and without Gelling Agent FXCLB1 FXCLB2 0922. The compositions of the test articles are provided in Ingredient 9% WW 9% WW the following table. All foams were dispensed on a warm Propylene glycol 90.945 77.945 surface (38°C.), and the time to full collapse of the foam was Stearyl alcohol 2.OO 1.00 Klucel EF 2.OO 1...SO measured. As shown in the table, it has been Strikingly dem Laureth-4 2.OO 2.00 onstrated that foam compositions without a gelling agent Simulsol 165 3.00 exhibit a 100% breakdown within 30 seconds, while foams Macrogol Cetostearyl Ether 1...SO containing gelling agent remained, with and without Surfac tant, were stable for several minutes. This is relevant from the US 2008/0299220 A1 Dec. 4, 2008 69 usability point of view, since a foam that is unstable at skin temperature cannot be applied to large areas effectively. TABLE 1 Exemplary Concentrations of Examples of Active Agents Additional Exemplary Formulation with therapeutic agent Formulations without gelling agent gelling agent Concentration Exemplary Use Hydrocortisone 196 Steroid responsive inflammation and PG33 PG34 PG35 PG36 TEC49 PG29 acetate % Wiw % wiw % wiw % wiw % wiw % Wiw Betamethasone O.1% psoriasis or atopic dermatitis valerate PEG 400 87.25 93.OO 91.OO 92.OO 90.50 93.50 Clobetasol O.05% Klucel GF O.SO OSO propionate (gelling agent) Acyclovir 59 Viral infection, herpes Ceteareth-16 2.OO 1.00 Ciclopirox 196 Fungal infection, seborrhea, Emulsiying 18O dandruff, Wax NF Clindamycin 296 Bacterial infection, acne, rosacea, Steareth-10 O4O OSO AZelaic acid 15% Acne, rosacea, PEG-40 1.35 pigmentation disorder and various Stearate dermatoses Steareth-2 O.6O 1.OO OSO 1.00 Metronidazol O.25%-296 Rosacea, bacterial infections and Span 60 2.70 parasite infestations Polysorbate 60 O.90 Diclofenac 196 Osteoarthritis, joint pain Propellant 6.OO 6.OO 6.OO 6.OO 8.00 6.OO Tacrolimus O.2% Atopic dermatitis, eczema and Collapse time &30 &30 &30 3O 240 >300 inflammation (Seconds; Benzoyl peroxide 1%-10% Acne 38° C.) Alpha-hydroxy 1%-20% Aging, wrinkles acids Salicylic acid 1%-10% Acne Hydroquinone 190-10% Pigmentation disorders Example 15 Caffeine 190-10% Cellulite Coenzyme Q10 0.1%-10% Aging, pigmentation Foamable Hygroscopic Composition Containing Polyethylene Glycol with no Surfactant 0923 0926 The above examples represent different drug classes and it is to be understood that other drugs belonging to each of the classes represented above may be included and used in the % Wiw compositions in a safe and effective amount.

PEG 400 93.50 Klucel GF OSO Example 17 Propellant (Butane?propane) 6.OO Foam quality E Additional Foamable Carriers which can be Used for Density O.09 Vitamins with and without an Active Agent 0927 a) Foamable vitamin carriers are made up with PEG or hexylene glycol or butylene glycol instead of glycerin anhydrous by weight of composition and added Example 16 to any of the compositions illustrated in Examples 5-10 0928 b) Foamable vitamin carriers are made up with Foamable Vitamin Compositions with an Additional PEG or hexylene glycol or butylene glycol instead of Therapeutic Agent propylene glycol by weight of composition and added to any of the compositions illustrated in Examples 5-10. 0924. Foamable vitamin compositions are made up with an active agent at either say 1%, 2%.3%, 4%, or 5%, by Example 18 weight of composition and added to any of the compositions illustrated in Examples 5-10 wherein the percentage amount More Foamable Vitamin Compositions with an Addi of one or both polar solvents is reduced by an approximately equivalent amount by weight in the composition. tional Active Agent 0925 More particularly exemplary concentrations of 0929. Foamable vitamin compositions are made up with additional therapeutic agents in foamable compositions are an active agent at either say 1%, 2%.3%, 4%, or 5%, by set out in Table 1. Each active agent is added into, for weight of composition and added to any of the compositions example, any of the carriers listed in any of Examples 5-10 illustrated in Example 19 wherein the percentage amount of above in a therapeutically effective concentration and one or both polar solvents is reduced by an approximately amount. The methodology of addition is well known to those equivalent amount by weight in the composition. More par of the art. The composition is adjusted in each case so that it ticularly examples of additional active agents areas described is made up to 100% w/w as appropriate by polar solvent. in Example 19 above. Dec. 4, 2008 70

Example 19 of Surface active agent foam adjuvant and polymeric agent is in the range of 2.5% (w/w). Foamable Polyol Pharmaceutical Composition Com prising Acyclovir Example 21 Foamable Hygroscopic Compositions Containing 0930 Terbinafine 0939. The following table exemplifies the use of PEG as a hygroscopic Substance, which also serves as an effective sol Ingredient 9% WW vent for terbinafine, which is hard to dissolve in common Acyclovir S.OO formulation excipients. Propylene Glycol 43.70 Stearyl Alcohol O.95 Glycerin 31.35 Hydroxypropyl cellulose 1.43 % ww % Wiw % Wiw Laureth-4 1.90 Glyceryl Monostearate/PEG 100 Stearate 1.43 Terbinafine 2.OO 2.00 6.OO Dimethyl Isosorbide 14.25 PEG400 89.50 89.50 89.50 Hydroxypropyl cellulose OSO O.SO OSO Steareth-2 2.OO 1.00 O 0931. The following observation on the preparation and Polyglyceryl-10 2.OO Laurate properties of the foam were made: Propellant (Propane?butane)* 6.O 6.O 6.O 0932. The composition contains acyclovir, which is not Density O.O60 O.O60 O.062 fully soluble in the polyol and DMI mixture. However, due to the unique composition, the acyclovir does not readily precipitate and does not undergo caking. Fur Example 22 thermore, thanks to the low viscosity of the composition, upon shaking the active agent readily re-disperses in the Comparative In-Vitro Activity of a Hygroscopic composition, resulting in full formulation uniformity. Composition Containing Terbinafine 0933. The combination of polyols and dimethyl isosor 0940. A comparative in-vitro study was set to evaluate the bide contributes to enhanced skin bioavailability of the effect of Composition A, consisting of 2% terbinafine, 95.3% active agent. gr. polyethylene glycol, 0.5% hydroxypropyl cellulose and 0934. The liquefied or gas propellant can be added at a 2.2% steareth-2, in comparison with Composition B (an oil in concentration of about 3% to about 25%. water emulsion containing 2% terbinafine) and Composition C a commercial 1% bifonazole cream. 0941 Three fungal strains (microsporum canis, tricho Example 20 phyton mentagrophytes and trichophyton rubrum) and one Foamable Hygroscopic Compositions Containing yeast (candida albicans) were seeded in the center of a Petri Mupirocin dish, and then, were surrounded by a film containing each of the compositions, using a Swab, soaked with each of the compositions. The proliferation and spreading of the micro 0935. The following table exemplifies the use of PEG as a organisms was followed up for 14 day by visual and photo hygroscopic Substance, which also serves as an effective sol graphic observations. vent for Mupirocin, which is practically insoluble in mineral 0942. As shown in FIG. 1, Composition A inhibited the oil and other commonly used ointment solvents. Note that proliferation and spreading of all the fungal and yeast strains Mupirocin is incompatible with most solvents and thus, a effectively. By contrast, both Compositions B and C failed to foam comprising PEG as the sole solvent is highly valuable. inhibit the growth of candida. Composition C was also inef fective in the inhibition of microsporum canis and Trichophy ton rubrum. % Wiw % Wiw % Wiw Example 23 Mupirocin 2.OO 2.00 2.OO PEG400 89.50 89.50 89.50 Hygroscopic Antifungal Compositions Hydroxypropyl cellulose OSO OSO OSO Steareth-2 2.OO 1.00 O Polyglyceryl-10 2.OO 0943 Laurate Propellant (Propane?butane)* 6.O 6.O 6.O Density O.O60 O.O60 O.062 Ointment Type Lacquer Type 0936. The following observation on the preparation and % Wiw % wiw % wiw % wiw % wiw % Wiw properties of the foam were made: PEG 400 92.OO 92.00 93.00 54.OO 46.OO 0937. The liquefied or gas propellant can be added at a PEG 4OOO 6.OO PEG 6000 6.OO 6.OO 1O.OO 8.00 concentration of about 3% to about 25%. Ethyl acetate? 30.00 3O.OO 30.00 0938. The foams of this example have a non-ionic sur Isopropanol face active agentata concentration of 2%. Total amounts US 2008/0299220 A1 Dec. 4, 2008

-continued -continued Ointment Type Lacquer Type Ingredient name Concentration (INCI, CTFA) (% w/w) % Wiw % wiw % wiw % wiw % wiw % Wiw Polyethylene 27 Urea 10.00 glycol 200 Terbinafine 2.OO 2.00 2.00 4.OO Ciclopi 1.OO 4.OO Propylene glycol 4.895 1cloprox Hydroxypropyl 1.5 cellulose 0944. The lacquer type compositions are suitable for the thin 8. treatment of infected cornified tissues, and particularly the nail. It will be appreciated that in the specific embodiment where the solvent is a polyethylene glycol or derivative or mixtures thereof where there is a significant level of high molecular weight PEG then the formulations can be used to Results T-0 produce an ointment a gel or a cream composition. Quality Good Color White Example 24 Odor No odor Density O.096 A Waterless Vitamin D3 Derivative Foamable Com position where the Modulating Agent is Triethoano (0947 Part C Where the waterless solvent is propylene lamine glycol: 0945 The components of these waterless foamable com positions and the results of measurements of the properties of the resultant foams and of the stability of the active agent are Ingredient set out below: name (INCI, Concentration CTFA) (% w/w) Calcipotriol O.OOS Propylene 87.895 :Ingredient name Concentration glycol (INCI, CTFA) (% w/w) Stearyl alcohol 2 Hydroxypropyl 2 Calcipotriol O.OOS cellulose Polyethylene 65 Laureth-4 2 glycol 400 Glyceryl 2 Polyethylene 32.925 monoStearate glycol 200 Ceteareth-20 1 Hydroxypropyl O.S cellulose PPG-15 Stearyl 3 ether Steareth-2 Triethanolamine O.1 Triethanolamine

Part A. Where the waterless solvent is a combination of two polyethylene glycols. Results T-0 Quality Good Results T-0 Color White Odor No odor Quality Good Density O.064 Color White Odor No odor Density O.096 0948 Comment: The above three formulations demon strate waterless breakable foams of good quality in which the 0946 Part B. Where the waterless solvent is a combina active ingredient is sensitive to the presence of water and light tion of two polyethylene glycols and propylene glycol: and is stabilized by the absence of water coupled with the presence of a modulating agent triethanolamine. As will be appreciated from the results the physical characteristics are little varied following variations in the waterless solvent. Ingredient name Concentration (INCI, CTFA) (% w/w) Moreover, it can be seen that waterless foamable pharmaceu tical and cosmetic compositions of good quality can be Calcipotriol O.OOS Polyethylene 65 achieved with minimal ingredients comprising a waterless glycol 400 Solvent, a Surfactant, a polymeric agent, a propellant and an effective amount of an active ingredient. US 2008/0299220 A1 Dec. 4, 2008 72

Formulation using two different polyethylene glycols 0950 Comment: this carrier produces an excellent foam. Thus, it is predicted that addition of an active agent such as active steroids in low concentrations of the order of 0.01 to 0.5% for example BMV at 0.12% w/w. together with a modu Concentration (% ww lating agent should have minimal effect on the physical char CLX-043- CLX-044 acteristics of the resultant foam. Likewise, it is predicted Ingredient name O61212 O61214 addition of an active agent Such as active steroids in low Calcipotriol O.OOS O.OOS concentrations of about the order of 0.001 to 0.5% w/w, for Polyethylene glycol 65 65 example Estradiol hemihydrate at about 0.005.1% w/w. 400 optionally together with a modulating agent for example Polyethylene glycol 27 32.925 sodium citrate and citric acid say at about 0.2% and 0.4% 200 Propylene glycol 4.895 respectively should have minimal effect on the physical char Hydroxypropyl 1.5 O.S acteristics of the resultant foam. For body cavity application cellulose about for example 0.005% w/w can be used. For topical use Steareth-2 1.5 1.5 approximately a tenfold higher concentration of estradiol Triethanolamine O.1 O.O7 hemihydrate at about say 0.05% w/w may be incorporated. Results Note propylene glycol can act as a penetration enhancer of Calcipotriol TO O.OO48 O.0049 estrogens and perhaps progesterone. concentration T O.OO45 O.OO46 (% w/w) 2. 25o C. Example 26 Foam TO Good Good Quality T Good Good Demonstration of Excellent Tri-Ingredient Foams 2. Produced with Two Different Surfactants Steareth 2 25o C. Density TO O.O70 O.O85 and Montanov 68 (Cetearyl Alcohol and Cetearyl T O.O60 O.O70 Glucoside) 2. 25o C. 0951. The components of these waterless foamable com Hardness TO SO.O 42.7 positions and the results of measurements of the properties of T 46.9 42.8 2. the resultant foams and of the stability of the active agent are 25o C. set out below: Collapse TO >300 >3OO time T >300 >3OO 2. 25°C Material chemical name 9% WW 9% WW 9% WW Shakability TO Shakable Shakable T Shakable Shakable Propylene glycol 96.OO 95.28 97.50 2. Hydroxypropyl cellulose 2.OO 2.OO O.SO 25°C Steareth 2 2.OO 2.OO Citric acid OSO Sodium citrate O.10 Cetearyl Glucoside and 2.00 Comments: The combination was found to be stable physi Cetearyl Alcohol cally and chemically for 12 months at 25 degrees C. The PEG Betamethasone 17-Valerate O.12 200 alters the formulation to provide a lower viscosity. Results Example 25 Total 100.00 1OOOO 100.00 A Tri-Ingredient Waterless Carrier quality excellent excellent excellent color white white white 0949. The components of this waterless foamable compo odor no odor no odor no odor sition and the results of measurements of the properties of the shakability shakable shakable shakable resultant foam and of the stability of the active agent are set out below: 0952 Comments: the above formulations demonstrate the preparation of excellent quality foams using two different non ionic surfactants and that the addition of buffer or active agent Material chemical name 9% WW has no significant effect on foam quality. Propylene glycol 96.OO Hydroxypropyl cellulose 2.00 Example 27 Steareth 2 2.00 Examples of Foams Containing a Steroid Active Total 100.00 Agent with Carbomer (Synthetic High Molecular Results Weight Crosslinked Polymers of Acrylic Acid) as the Quality excellent Polymeric Agent Color white Odor no odor 0953. The components of these waterless foamable com positions and the results of measurements of the properties of the resultant foams and of the stability of the active agent are set out below: US 2008/0299220 A1 Dec. 4, 2008

Material % % % % % % % chemical name WW WW WW WW WW WW WW 9, WW Propylene glycol 97.50 97.45 97.6O 97.575 97.50 97.45 97.60 97.60 Steareth 2 2.OO 2.OO 2.00 2.OO Carbomer 934 OSO O.SO O.20 O.2O O.SO OSO O.2O O.20 triethanolamine O.20 O.2O O.2O O.20 Cetearyl 2.00 2.OO Glucoside and Cetearyl Alcohol Methylglucose 2.OO sesquistearate Span 60 2.00 Clobetasol O.OS O.OS propionate Flucinolone O.O2S acetonide

Total 1OOOO 10O.OO 10O.OO 10O.OO 100.OO 100.00 Results

Quality E E E E E E G G E = excellent G = good color White white White white white white white white odor no odor no odor no odor no odor no odor no odor no odor no odor shakability yes. yes ..yes ..yes ..yes ..yes ..yes yes

0954 Comments: the above formulations demonstrate the preparation of excellent quality foam using Carbomer (Syn thetic high molecular weight crosslinked polymers of acrylic acid). Carbomer is acidic in nature and can stabilize an active agent alone or in combination with an organic base Such as triethanolamine. Example 29 Hydrophilic PEG Containing Compositions with Various Active Agents Stock Solution: 0955

Ingredient

PEG-400 97.50 Hydroxypropyl OSO cellulose Steareth 2 2.OO

Total 1OOOO

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 US 2008 /0299220 A1 Dec. 4, 2008

-continued Calcipotriol O.OOS hydrate Ciclopiroxolamine 2.00 Diclofenac sodium 1.OO

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

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 2.OO regular 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

0956 Comments: formulations based on PEG-400, poly meric agent and a surfactant, produced good (G) to excellent (E), white (W) to light yellow, No odor (N.O.) and shakable foams. The propellant can be added at a concentration of about 3% to about 25% or more. Example 29 Hydrophilic Propylene Glycol Containing Composi tions with Various Active Agents Ex 30 Part A Stock Solution: 0957)

Propylene glycol 91.OO Stearyl alcohol 2.OO Klucel EF 2.OO Laureth-4 2.OO Glyceryl Monostearate? 3.00 PEG 1 OO Stearate

Total 100.00

Part Bi Formulations with Various Active Agents

Propylene glyc ol 95.00 8S.OO 95.00 99.88 95.00 99.995 98.00 98.00 Stearyl alcohol US 2008/0299220 A1 Dec. 4, 2008

-continued Klucel EF Laureth-4 Glyceryl Monostearatef PEG 1 OO

S.OO 1S.OO Benzoyl peroxide S.OO Betametha-sone O.12

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 G E G E G E E COLOR W W 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

Part Bii Formulations with Various Active Agents

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 G G G E E E E COLOR W W Light O.W O.W O.W W Yellow ODOR N.O N.O N.O No No No No No Odor Odor Odor Odor Odor Odor Odor SHAKABILITY Yes Yes Yes Yes Yes Yes Yes Yes US 2008/0299220 A1 Dec. 4, 2008 76

0958 Comments: formulations based on Propylene gly col, polymeric agent a Surfactant and co-Surfactant, produced good (G) to excellent (E), white (W) to light yellow, no odor (N.O.) and shakable foams. 0959. The co emulsifiers are non essential and can be omitted although some adjustment may be needed to the Surfactant combination as will be appreciated by someone skilled in the art. The propellant can be added at a concentra tion of about 3% to about 25% or m. Example 30 Hydrophilic Propylene Glycol Containing Composi tions with Another Solvent DMI and Various Active Agents EX 31 Part A Stock Solution: 0960|

Propylene glycol 46.OO Glycerin anhydrous 33.00 Stearyl alcohol 1.OO Hydroxypropyl cellulose 1...SO Laureth-4 2.OO Glyceryl Monostearate? 1...SO PEG 1 OO Stearate Dimethyl isosorbide 1S.OO

Total 100.00

Part Bi Formulations with Various Active Agents

Propylene glycol 95.00 85.OO 95.00 99.88 95.OO 99.995 98.00 98.00 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 100 1OO 1OO 100 1OO 1OO 100 100 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 US 2008/0299220 A1 Dec. 4, 2008 77

Part Bii Formulations with Various Active Agents

Propylene glycol 99.00 95.00 98.00 98.00 95.00 99.00 98.OO 99.00 Glycerin anhydrous Stearyl alcohol Hydroxypropyl cellulose Laureth-4 Glyceryl Monostearate PEG 1OO Stearate Dimethyl isosorbide Ketoconazole 1.OO Minoxidi S.OO Mupirocin 2.OO Nifedipine 2.OO regular Permethrin BPC S.OO (cis:trans 25:75) Piroxicam 1.OO Salicylic acid 2.00 Terbinafine HCI 1.OO

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

QUALITY G G G G E E E G COLOR W W W Light O.W O.W O.W W Yello 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

0961 Comments: formulations based on Propylene gly col, polymeric agent, a solvent, a Surfactant and co-surfactant, -continued produced good (G) to excellent (E), white (W) to light yellow, ODOR No Odor No Odor nodor (N.O.) and shakable foams. SHAKABILITY Yes Yes 0962. The co emulsifiers are non essential and can be omitted although some adjustment may be needed to the 0964 Comments: formulations based on a polyethylene Surfactant combination as will be appreciated by someone glycol mixture, polymeric agent Surfactant, and a silicone skilled in the art. The propellant can be added at a concentra produced good (G) white (W) No odor (N.O.) and shakable tion of about 3% to about 25% or more. foams. The propellant can be added at a concentration of about 3% to about 25% or more. Example 31 Example 32 Hydrophilic PEG200/400 Mixtures Containing Hydrophilic Propylene Glycol Containing Composi Compositions with a Polymeric (Gelling) Agent: a tions with Another Polymeric (Gelling) Agent and Silicone Combination and Various Active Agents Various Active Agents 0965 0963

PROPYLENE GLYCOL 97.38 95.50 92.50 82.50 PEG 400 40.38 38.50 Steareth-2 2.00 2.OO 2.00 2.OO PEG 200 39.50 39SO CARBOMER 934 O.SO OSO O.SO OSO DIMETHICONE 3.00 3.00 Betamethasone 17 O.12 Cyclomethicone 1...SO 1...SO Valerate micronized ASOS 3.00 3.00 Mupirocin 2.OO Stearic acid 9.00 9.OO Minoxidi S.OO Steareth-2 3.SO 3.SO AZelaic acid 1S.OO Betamethasone 17 valerate O.12 micronized total 100.00 1OOOO 100.00 1OOOO Mupirocin 2.OO RESULTS, APPEARANCE

total 100.00 1OOOO QUALITY Good Good Good Good RESULTS, APPEARANCE COLOR White White White White ODOR No Odor No Odor No Odor No Odor QUALITY Good Good SHAKABILITY Good Good Good Good COLOR White White US 2008/0299220 A1 Dec. 4, 2008 78

0966 Comments: formulations based on propylene gly col, polymeric agent and a surfactant, produced good (G), -continued white (W) No odor (N.O.) and shakable foams. The propel SURFACTANTHLB lant can be added at a concentration of about 3% to about 25% O. O. CETEARYLALCOHOL 12.5 (estimated 3.00 (and) CETEARYL between 11&15.5) Example 33 GLUCOSIDE Total 1OO.OO 100.00 Hydrophilic PEG Containing Compositions with RESULTS Various Surfactants and Polymeric (Gelling) Agents APPEARANCE QUALITY Good Good COLOR White White 0967 A) ASOS ODOR No Odor No Odor DENSITY O.176 O.099 COLLAPSE TIME (sec.) >3OO >300 SURFACTANTHLB HARDNESS 55.72 66.82 PEG-400 94.00 94.00 ALUMINUM STARCH 3.00 3.00 0968 Comments: formulations based on PEG-400, poly OCTENYLSUCCINATE meric agent and a Surfactant, produced stable, good, white, (ASOS) No odor and shakable foams. The propellant can be added at Steareth 2 4.9 3.00 a concentration of about 3% to about 25% or more. 0969 B) CARBOMER

SURFACTANTHLB PCSOO1 PCSOO2 PCSOO3

PEG-400 97.50 97.50 97.50 Carbomer 934 OSO O.SO OSO Steareth 2 4.9 2.OO CETEARYLALCOHOL (and) 12.5 (estimated 2.00 CETEARYL, GLUCOSIDE between 11&15.5) PEG-40 Stearate 17.3 2.00 RESULTS

APPEARANCE QUALITY Good Good Good COLOR White White White ODOR No Odor No Odor No Odor DENSITY O.139 O.100 O.088 COLLAPSE TIME (sec.) >3OO 250 >3OO HARDNESS 60.30 SO.83

0970 Comments: formulations based on PEG-400, poly meric agent and a Surfactant, produced stable, good, white, No odor and shakable foams. The propellant can be added at a concentration of about 3% to about 25% or more. Example 34 Hydrophilic PEG Containing Compositions with Polymeric (Gelling) Agent and with and without Various Surfactants Ex 34 Part A 0971

SURFACTANT HLB

PEG-400 99.SO 98.OO 98.OO 98.OO 98.00 Hydroxypropyl O.SO cellulose Laureth 4 9.7 2.OO Steareth 2 4.9 2.00 Sorbitan 4.7 2.OO nonOStearate US 2008/0299220 A1 Dec. 4, 2008

-continued

SURFACTANT HLB

CETEARYL 12.5 2.OO ALCOHOL (estimated between (and) 11&15.5) CETEARYL GLUCOSIDE

Total 1OO 100 1OO 100 100 RESULTS

APPEARANCE QUALITY G G E E COLOR W W W W ODOR N.O. N.O. N.O. N.O. N.O. DENSITY 0.137 O.123 O.O73 0.103 0.077 COLLAPSE 75.00 NR 300 120.00 1SO.OO TIME (sec.) HARDNESS 19.29 NR 42.24 1870 44.17

Ex 34 Part B topical use approximately a tenfold higher concentration of estradiol hemihydrate at about say 0.05% w/w may be incor 0972 porated. Note: The propellant can be added at a concentration of about 3% to about 25% or more. SURFAC TANT HLB Example 35 PEG-400 98.00 98.00 98.00 97.50 Hydrophilic PEG 1500/400 Mixture Containing a Hydroxypropyl OSO cellulose Surfactant and Polymeric (Gelling) Agent Sucrose Stearic 11.0 2.00 acid esters 0974 D-1811 SORBITAN 6.O 2.00 PEG 1500 (Solid) 12.SO STEARATE PEG 400 (Liquid) 86.OO AND Hydroxypropyl cellulose OSO SUCROSE Steareth 2 1.OO COCOATE PEG-40 Stearate 17.3 2.OO Total 100 Isostearath 20 15.7 2.OO Propellant 8.OO RESULTS, APPEARANCE Total 100 100 100 100 RESULTS QUALITY G COLOR W APPEARANCE QUALITY G E G E ODOR N.O. COLOR W W W W SHAKABILITY Good ODOR N.O. N.O. N.O. N.O. DENSITY O.109 O.103 O.O94 COLLAPSE >300 120.00 6O.OO TIME (sec.) 0975 Formulation based on PEG-1500/PEG 400, and HARDNESS 27.42 12.99 19.28 relatively low levels of Surfactant and polymeric agent pro duced a good quality white shakable foam. This carrier pro duces an excellent foam. Thus, it is predicted that addition of 0973 Comments: Formulations based on PEG-400, poly an active agent such as active steroids in low concentrations of meric agent and a Surfactant, produced stable, good or exce the order of 0.01 to 0.5% for example BMV at 0.12% w/w. lent, white, no odor and shakable foams. This carrier pro together with a modulating agent should have minimal effect duces an excellent foam. Thus, it is predicted that addition of on the physical characteristics of the resultant foam. Like an active agent such as activesteroids in low concentrations of wise, it is predicted addition of an active agent such as active the order of 0.01 to 0.5% for example BMV at 0.12% w/w. steroids in low concentrations of about the order of 0.001 to together with a modulating agent should have minimal effect 0.5% w/w, for example Estradiol hemihydrate at about on the physical characteristics of the resultant foam. Like 0.005.1% w/w. optionally together with a modulating agent wise, it is predicted addition of an active agent such as active for example sodium citrate and citric acid say at about 0.2% steroids in low concentrations of about the order of 0.001 to and 0.4% respectively should have minimal effect on the 0.5% w/w, for example Estradiol hemihydrate at about physical characteristics of the resultant foam. For body cavity 0.0051% w/w. optionally together with a modulating agent application about for example 0.005% w/w can be used. For for example sodium citrate and citric acid say at about 0.2% topical use approximately a tenfold higher concentration of and 0.4% respectively should have minimal effect on the estradiol hemihydrate at about say 0.05% w/w may be incor physical characteristics of the resultant foam. For body cavity porated. The propellant can be added at a concentration of application about for example 0.005% w/w can be used. For about 3% to about 25% or more. US 2008/0299220 A1 Dec. 4, 2008 80

Example 36 0.5% for example BMV at 0.12% w/w. together with a modu lating agent should have minimal effect on the physical char Hydrophilic High Molecular Weight Peg 4000/400 acteristics of the resultant foam. Likewise, it is predicted Mixtures Containing Surfactant with and without a addition of an active agent Such as active steroids in low Polymeric (Gelling) Agent that are Suitable for Gels concentrations of about the order of 0.001 to 0.5% w/w, for and Ointments example Estradiol hemihydrate at about 0.005.1% w/w. optionally together with a modulating agent for example 0976 sodium citrate and citric acid say at about 0.2% and 0.4% respectively should have minimal effect on the physical char PEG 4OOO 8O.OO 80.00 1O.OO S.OO S.OO acteristics of the resultant foam. For body cavity application PEG 400 2.OO 8.00 87.50 93.50 93.50 about for example 0.005% w/w can be used. For topical use Ethanol 95% 17.00 approximately a tenfold higher concentration of estradiol PPG 15 10.00 hemihydrate at about say 0.05% w/w may be incorporated. Stearyl The propellant can be added at a concentration of about 3% to Ether about 25% or more. Hydroxypropyl OSO O.SO OSO Cellulose CETEARYL 2.00 1.OO 2.00 2.OO 1.00 Section B ALCOHOL Example 38 (and) CETEARYL A Tri-Ingredient Waterless Prophetic Formulation GLUCOSIDE Steareth 2 1.OO with Progesterone and Estrogen 0980 Total 100 100 1OO 100 1OO 100

0977 All the above formulations produced an ointment. chemical name 9% WW 9% WW 9% WW Example 37 Propylene glycol 92.00 95.9049 91.9049 Hydroxypropyl cellulose 2.OO 2.OO 2.00 Hydrophilic PEG 400 Containing a Polymeric Agent Steareth 2 2.OO 2.OO 2.00 with and without a Surfactant Progesterone 4.OO 4.OO Estradiol hemihydrate O.OOS1 O.OOS1 Stock Gel: Total 100.00 100 1OO 0978 Propellant* 8 8 8 *Propellant is for example a mix of propane, butane and isobutane WW 9% STOCKGEL 0981. Thus it is predicted addition of an active agent such HYDROXYPROPYL CELLULOSE 2.00 98.00 as active steroids in low concentrations of about the order of PEG 400 98.00 98.00 0.001 to 0.5% w/w, for example Estradiol hemihydrate at about 0.005.1% w/w. optionally together with a modulating agent for example sodium citrate and citric acid say at about 0.2% and 0.4% respectively should have minimal effect on the physical characteristics of the resultant foam. For body cavity application about for example 0.005% w/w can be STOCK FOAM used. For topical use approximately a tenfold higher concen W/W 9% GEL HLB QUALITY tration of estradiol hemihydrate at about say 0.05% w/w may STEARETH2O 2.OO 98.OO 15.3 G be incorporated. Note propylene glycol can act as a penetra CETEARETH2O 2.OO 98.OO 15.7 G tion enhancer of estrogens and perhaps progesterone. The PEG 40-STEARATE 2.OO 98.OO 16.9 G ISOSTEARETH2O 2.OO 98.OO 15.7 G propellant can be added at a concentration of about 3% to SUCROSE STEARATE 2.OO 98.OO 11.0 G about 25% or more. METHYL GLUCOSE 2.OO 98.00 12.0 G SESQUISTEARATE Example 39 WITHOUT SURFACTANT O.OO 100.00 G A Hydrophilic PEG Containing Prophetic Formula tion with Progesterone and Estrogen with Polymeric 0979 Formulations based on PEG-400, polymeric agent (Gelling) Agent and with and without Various Sur and a Surfactant, produced stable, good, white, No odor and factants shakable foams. This carrier produces an excellent foam. Thus, it is predicted that addition of an active agent such as EX 39 Part A active steroids in low concentrations of the order of 0.01 to 0982)

SURFACTANT HLB

PEG-400 95.SO 94.OO 94.OO 94.OO 93.9049 Hydroxypropyl O.SO cellulose US 2008/0299220 A1 Dec. 4, 2008 81

-continued

SURFACTANT HLB Laureth 4 9.7 2.OO Steareth 2 4.9 2.00 Sorbitan 4.7 2.OO nonOStearate CETEARYL 12.5 2.OO ALCOHOL (estimated between (and) 11&15.5) CETEARYL GLUCOSIDE Progesterone 4.OO 4.OO 4.OO 4.OO 4.OO Estradiol O.OOS1 hemihydrate

Total 1OO 100 1OO 100 100 Propellant* 8 8 8 8 *Propellant is for example a mix of propane, butane and isobutane

EX 39 Part B Example 40 Hydrophilic PEG 1500/400 Mixture Prophetic For 0983 mulation with Progesterone and Estrogen Containing a Surfactant and Polymeric (Gelling) Agent 0985 SUR FACTANT HLB

PEG-400 94.00 94.00 93.9049 93.50 PEG 1500 (Solid) 8.50 8.4049 12.4049 Hydroxypropyl OSO PEG 400 (Liquid) 86.OO 86.OO 86.00 cellulose Hydroxypropyl cellulose O.SO OSO O.SO Sucrose Stearic 11.0 2.00 Steareth 2 1.OO 1.OO 1.00 acid esters Progesterone 4.OO 4.OO D-1811 Estradiol hemihydrate O.OOS1 O.OS1 SORBITAN 6.O 2.OO STEARATE Total 1OO 100 1OO AND Propellant* 8.OO 8.OO 8.00 SUCROSE COCOATE *Propellant is for example a mix of propane, butane and isobutane PEG-40 Stearate 17.3 2.OO Isostearath 20 15.7 2.OO 0986 Thus, it is predicted addition of an active agent such Progesterone 4 4 4 4 as active steroids in low concentrations of about the order of Estradiol O.OOS1 0.001 to 0.5% w/w, for example Estradiol hemihydrate at hemihydrate about 0.005.1% w/w. optionally together with a modulating Total 1OO 100 1OO 100 agent for example sodium citrate and citric acid say at about Propellant* 8 8 8 8 0.2% and 0.4% respectively should have minimal effect on the physical characteristics of the resultant foam. For body *Propellant is for example a mix of propane, butane and isobutane cavity application about for example 0.005% w/w can be used. For topical use approximately a tenfold higher concen 0984 Thus, it is predicted addition of an active agent such tration of estradiol hemihydrate at about say 0.05% w/w may as active steroids in low concentrations of about the order of be incorporated. 0.001 to 0.5% w/w, for example Estradiol hemihydrate at 0987. Note: The propellant can be added at a concentra about 0.005.1% w/w. optionally together with a modulating tion of about 3% to about 25% or more. agent for example sodium citrate and citric acid say at about 0.2% and 0.4% respectively should have minimal effect on Example 41 the physical characteristics of the resultant foam. For body Hydrophilic High Molecular Weight PEG 4000/400 cavity application about for example 0.005% w/w can be Mixtures Prophetic Formulation with Progesterone used. For topical use approximately a tenfold higher concen and Estrogen Containing Surfactant with and without tration of estradiol hemihydrate at about say 0.05% w/w may a Polymeric (Gelling) Agent that are Suitable for be incorporated. The propellant can be added at a concentra Gels and Ointments tion of about 3% to about 25% or more. 0988

PEG 4OOO 76.OO 76.00 76.OO S.9049 1.OO 1.OO PEG 400 3.00 2.00 8.OO 87.50 93.50 93.50 US 2008/0299220 A1 Dec. 4, 2008 82

-continued Ethanol 95% 1S.OO 17.00 PPG 15 earyl Ether 1O.OO Hydroxypropyl Cellulose O.SO OSO CETEARYLALCOHOL 2.OO 1.00 2.OO 2.00 1.OO (and) CETEARYL, GLUCOSIDE Steareth 2 1.00 Progesterone 4.OO 4.OO 4.OO 4.OO 4.OO 4.OO Estradiol hemihydrate O.OOS1

Total 1OO 1OO 100 1OO 100

0989 Thus, it is predicted addition of an active agent such 0991 Thus, it is predicted addition of an active agent such as active steroids in low concentrations of about the order of as active steroids in low concentrations of about the order of 0.001 to 0.5% w/w, for example Estradiol hemihydrate at 0.001 to 0.5% w/w, for example Estradiol hemihydrate at about 0.005.1% w/w. optionally together with a modulating about 0.005.1% w/w. optionally together with a modulating agent for example sodium citrate and citric acid say at about agent for example sodium citrate and citric acid say at about 0.2% and 0.4% respectively should have minimal effect on 0.2% and 0.4% respectively should have minimal effect on the physical characteristics of the resultant foam. For body the physical characteristics of the resultant formulation. For cavity application about for example 0.005% w/w can be body cavity application about for example 0.005% w/w can used. For topical use approximately a tenfold higher concen tration of esrtadiol hemihydrate at about say 0.05% w/w may be used. For topical use approximately a tenfold higher con be incorporated. centration of estradiol hemihydrate at about say 0.05% w/w 0992. Note: The propellant can be added at a concentra may be incorporated. tion of about 3% to about 25% or more. Example 43 Example 42 PEG/PG Estrogen Prophetic Formulation with Poly C Hydrophilic PEG 400 Prophetic Formulation with Progesterone and Estrogen Containing a Polymeric 0993 Agent with and without a Surfactant Ingredients % Wiw

PEG 400 73.935 Stock Gel: Propylene glycol 2O.OO Peg 100 stearate 2.OO 0990 Stearyl alcohol 3.00 Methylcellulose O.10 Carbomer 934P O4O TEA (for “neutralization') O.S6 WW 9% Estradiol hemihydrate O.OOS

HYDROXYPROPYL CELLULOSE 2.OO Total 1OOOO PEG 400 98.00 Propellant* 8 *Propellant is for example a mix of propane, butane and isobutane

STOCK WW96 GEL PROGESTERONE HLB PROPELLANT:

STEARETH2O 2.OO 92.00 6.OO 15.3 CETEARETH2O 2.OO 94.OO 4.OO 15.7 PEG 40-STEARATE 2.OO 94.OO 4.OO 16.9 ISOSTEARETH2O 2.OO 94.OO 4.OO 15.7 SUCROSE STEARATE 2.OO 94.OO 4.OO 11.O METHYL GLUCOSE 2.OO 94.OO 4.OO 12.O SESQUISTEARATE WITHOUT O.OO 98.00 2.OO SURFACTANT

*Propellant is for example a mix of propane, butane and isobutane US 2008/0299220 A1 Dec. 4, 2008

0994) Note: propylene glycol may act as a penetration enhancer. -continued

Ingredients HNACO2O-0801.09 HNACO21-08O109 Example 44 butylene glycol O.O1 48.50 PEG with Surfactant and Silicone and Estradiol Estradiol hemihydrate O.O1 Total 100.00 100.00 0995 Propellent (AP-70) 8.OO 8.OO Results PFF

Estrodiol Viscosity 10669.72 13357.15 Ingredient WW 9% Centrifgation 1 K stable stable PEG-400 87.474 Centrifgation 3K stable stable Cetyl S.OO FOAM dimethicone Estrodiol O.O26 Quality G G Steareth 2 7.5 Color White White Odor no odor no odor Total 1OO Collapse time (Sec.) >300G >300G Propellant* 8.OO Density (griml) 0.055 0.057 RESULT Shakability 2 2 Foam Good Bubble size (Lm) 49 53 Quality Bubble size O O (%-above 500 m) *Propellant is for example a mix of propane, butane and isobutane 0998. In general terms propylene glycol formulations are 0996. Formulation based on PEG-400, and a surfactant, sensitive to centrifugation. For example the hydrophobic pro produced good foam with an estrogen. Thus, it is predicted pellant separates from the hydrophilic propylene glycol. In that addition of an active agent Such as active steroids in low contrast it has been unexpectedly discovered that propylene concentrations of the order of 0.01 to 0.5% for example BMV glycol formulations are stable even at 3000 rpm for 10 min at 0.12% w/w. together with a modulating agent should have utes. It was also found to be possible to combine propylene minimal effect on the physical characteristics of the resultant glycol and butylenes glycol in a centrifugation stable formu foam. Likewise, it is predicted addition of an active agent lation. Such as active steroids in low concentrations of about the order of 0.001 to 0.5% w/w, for example Estradiol hemihy 0999 Part B butylene glycol based formulation drate at about 0.051% w/w. optionally together with a modu lating agent for example sodium citrate and citric acid say at about 0.2% and 0.4% respectively should have minimal effect HNACO)10-071226 on the physical characteristics of the resultant foam. For body Hydroxypropyl cellulose (EF) 1.00 cavity application about for example 0.005% w/w can be Steareth-2 2.00 used. For topical use approximately a tenfold higher concen butylene glycol 96.99 tration of estradiol hemihydrate at about say 0.05% w/w may Estradiol hemihydrate O.O1 be incorporated. The propellant can be added at a concentra Total 100.00 tion of about 3% to about 25% or more. N/R=Not recorded. Propellent (AP-70) 8.00 Results PFF Section C Centrifugation Stable Formulations Viscosity 7422.41 Centrifugation 1 K stable Example 45 Centrifugation 3K stable FOAM Waterless Propylene and or Butylene Glycol Formu Quality G lations Color White Odor v.fodor 0997 Part A: propylene glycol based formulation with and Collapse time (Sec.) >300G Density (griml) O.OS8 without butylene glycol. Shakability 2 Bubble size (Lm) 58 Bubble size O (%-above 500 m) Ingredients HNACO2O-0801.09 HNACO21-08O109 Hydroxypropyl cellulose (EF) 1.OO 1.00 Steareth-2 2.OO 2.00 1000. It has also been unexpectedly discovered that buty Propylene glycol 96.99 48.49 lene glycol formulations are stable even at 3000 rpm for 10 minutes. US 2008/0299220 A1 Dec. 4, 2008

Example 46 Waterless Hexylene Glycol and Butylene Glycol Based Formulations 1001

HNACO12- HNACO13- HNACO16- HNACO14- HNACO17 O71226 O71226 O71226 O71226 O71226 Hydroxypropyl 1.OO 3.00 3.00 3.00 3.00 cellulose (EF) Steareth-2 2.OO 6.OO 4.OO 6.OO 6.OO Polysorbate 80 2.OO Peg 100 stearate 3.00 2.OO CETEARETH2O 2.OO Hexylene glycol 7O.OO 6S.OO SO.OO 46.00 3O.OO butylene glycol 26.99 25.99 35.99 44.99 58.99 Progesterone Estradiol O.O1 O.O1 O.O1 O.O1 O.O1 hemihydrate

Total 1OOOO 1OOOO 100.00 1OOOO 1OOOO Propellent (AP-70) 8.OO 8.00 8.OO 8.00 8.OO Results PFF

Viscosity 857.82 19211.9 Centrifugation 1 K stable stable Centrifugation 3K stable stable FOAM Quality P FG (Fafter FG (Fafter G- G ~10 sec.) ~10 sec.) Color White White Odor v.fodor v.fodor Collapse time (Sec.) 2OP 16O.F Density (griml) O.102 O.115 Shakability 2 1 Bubble size (Lm) 125 87 Bubble size (%- O O above 500 m)

1002. As can be noted from the above hexylene glycol appears to act as a defoamerand that we were able to formu -continued late a composition that generated good quality foam only after the amount ofbutylenes glycol approached that of hexy HNACOO7-071217 lene glycol. Not only were such compositions suitable for Ex. 42 producing good quality foam but unexpectedly they were also Propellent (AP-70) 8.00 stable to centrifugation. Results PFF Example 47 Centrifugation 1 K 50% Cream. + 5% Preci. Waterless Estradiol with PEG-400 and Propylene Centrifugation 3K 50% Cream. + 5% Preci. Glycol Based Formulation FOAM 1003 Quality G Color White Collapse time (Sec.) >300 FG Density (griml) O.14 HNACOO7-071217 Shakability 2 Ex. 42 Bubble size (Lm) 146 Bubble size (%-above 500 m) O PEG-400 74.59 Carbomer 934P O40 PegStearyl 100 alcohol stearate 2.003.00 1004. By combining PEG and PG it was possible to for Propylene glycol 2O.OO mulate a vehicle that generates a good quality foam that has a Estradiol hemihydrate O.O1 collapse time in excess of 5 minutes and shows some resis Total 100.00 tance to creaming. The formulation is Suitable to deliver an estrogen or progesterone. US 2008/0299220 A1 Dec. 4, 2008

Example 48 Waterless PEG-400 Based Formulations with and without PEG1500 1005

HNACOO1 - HNACOO2- HNACOO4- HNACOO3 O71212 O71212 O71212 O71212 Ex. 40 Ex. 40 Ex. 41 Ex. 41

PEG-400 95.50 93.50 89.99 86.04 PEG-1500 1245 Hydroxypropyl cellulose (EF) O.SO OSO 2.00 OSO Steareth-2 2.OO 1.OO CETEARETH2O 2.00 Progesterone 4.OO 4.OO 6.OO Estradiol hemihydrate O.O1 O.O1

Total 100.00 1OOOO 100.00 1OOOO Propellent (AP-70) 8.OO 8.OO 8.00 8.OO Results PFF

Viscosity 168.96 6638.58 3O8.93 28345.95 Centrifugation 1 K stable 10% Cream. 50% Cream. Stable Centrifugation 3K stable 10% Cream. 50% Cream. Stable FOAM

Quality G G G G Color White White White White Odor Collapse time (sec.) 17OF >300G 13OF >300G Density (griml) O.097 O.062 O.083 O.12 Shakability 2 2 2 O Bubble size (Lm) 60 59 92 66 Bubble size (%-above O O O O 500 m)

1006. As can be seen from the above whilst foam quality is an important criteria there are other factors as well which help -continued determine the suitability of the formulation. By making changes to the composition for example by adding Surfactant HNACOO1- HNACOO2 HNACO19 O71212 O71212 O8O106 or by adding a small amount of PEG 1500 it was possible to cf Ex 40 Ex. 40 Ex. 42 extend the collapse time to about almost double. All the formulations showed resistance to creaming. And two CETEARYL showed no creaming. No correlation was noted between vis- gest 4.OO 4.OO 4.OO cosity, bubble size or density and resistance to creaming. Estradiol O.10 hemihydrate Example 49 Total 1OOOO 1OOOO 100.00 Waterless PEG-400 PEG 1500 and PEG-4000 Con- Propellent (AP 8.OO 8.OO 8.OO taining Formulations 70)Results Part A PFF 1007 Viscosity 168.96 6638.58 S1166.90 Centrifgation 1 K stable 10% Cream. 3% flotation Centrifgation 3K stable 10% Cream. 3% flotation FOAM

HNACOO1- HNACOO2- HNACO19- Quality G G G O71212 O71212 O8O106 Color White White White cf Ex. 40 Ex. 40 Ex. 42 Odor no odor PEG-400 95.50 93.50 9240 Collapse time 17OF >300G 150 FG PEG-4OOO 2.00 (sec.) Hydroxypropyl O.SO OSO OSO Density (gr/ml) O.097 O.062 O.O83 cellulose (EF) Shakability 2 2 1 Steareth-2 2.OO Bubble size (Lm) 60 59 Bubbles observed CETEARYL 1.00 but not ALCOHOL (and) measured US 2008/0299220 A1 Dec. 4, 2008

However, the presence of PEG 1500, which raised substan -continued tially the viscosity, appeared to account for the improved the resistance and also the approximately doubled collapse time. HNACOO1- HNACOO2- HNACO19 O71212 O71212 O8O106 As can be seen from Part A with 2% PEG-4000 it is possible cf Ex. 40 Ex. 40 Ex. 42 still to generate foam. However, once the level was increased to 6%, the formulation resulted in a semi solid like ointment. Bubble size (%- O O Increasing the level of PEG-4000 to 50% and to 76% resulted above 500 m) in solid like ointment formulations. These semi solid and *Too small for accurate measurement solid ointment formulations were not sufficiently miscible with the propellant and were not suitable to make foams. 1008 The two PEG-400 formulations were resistant to creaming. The addition of steareth 2, a Surfactant, produced a Section D more stable foam and approximately doubled the collapse time. Both formulations showed resistance to creaming but Example 50 the presence of the Surfactant Surprisingly lowered slightly Bioadhesive Waterless Formulations of Estradiol the resistance. The addition of a small (2%) but significant Hemihydrate amount of PEG-4000 greatly increased the viscosity of the formulation. Surprisingly it was noted that although the den 1011 Bioadhesion (adhesive force) is an important prop sity of the expelled formulation was in keeping with that of a erty which needs to be examined for the selection of the foam foam the bubbles appeared smaller and about at the limits of formulation prototype. Adhesiveness is defined as the force detection. (g) needed to overcome attraction between two vaginal tis Sue-surfaces after being in contact. An animal model system Part B for measuring adhesiveness using pig vaginal tissues was developed for this purpose. Measurements make use of the 1009 LFRA Brookfield Texture Analyzer. Two sections of pig vagi nal tissue (2x2 cm) are used; one is positioned in the center of a Petri dish and the other is attached to the base of texture HNACOO4- HNACO18- HNACOO3 analyzer probe. A PFF sample is spread uniformly on the O71212 O8O106 O71212 tissue section on the Petridish. The probe is moved down and cf Ex. 41 EX. 42 Ex. 41 up, first bringing the two sections into contact, followed by PEG-400 89.99 87.40 86.04 separation. The Texture Analyzer enables the measurement of PEG-1500 1245 the force for separating the tissue sections. PEG-4OOO 6.OO Hydroxypropyl 2.00 OSO OSO 1012 Measurement of bioadhesion was performed on for cellulose (EF) mulations EST-010 and 011, which showed suitable physical Steareth-2 1.00 and chemical properties at T-0 and after storage for 3 weeks at CETEARETH 2.00 25° C., 40° C., and 50° C. (See Table 5 below) Adhesive 2O properties of three marketed products (a cream and a gel) CETEARYL 2.OO ALCOHOL were tested in parallel to serve as a reference. Comparative (and) results of the tests performed are shown in Table 1 and in CETEARYL FIGS. 2 and 3 (graphic presentation of results). The first part GLUCOSIDE Progesterone 6.OO 4.OO of each graph is the load applied to the foam and the second Estradiol O.O1 O.10 O.O1 part shows measurement of the adhesive force used to sepa hemihydrate rate the probe. TABLE 1 Total 100.00 1OOOO 1OOOO Propellent (AP- 8.00 8.OO 8.00 Adhesiveness Test Results for Selected Estradiol PFF 70) Formulations and Reference Product. Replens Gel. Results Formulation Adhesive force (g)* PFF semi-solid like ointment ESTO10 -5.87 Viscosity 3O8.93 28345.95 ESTO11 -6.12 Centrifgation 1 K 50% Cream. Stable Replens Gel For vaginal -12.13 Centrifgation 3K 50% Cream. Stable lubrication) FOAM *results, average of three determinations Quality G G Color White White Odor TABLE 2 Collapse time 13 OF >300G (sec.) Composition of the Hydrophilic Solvent-Based Formulation Density (griml) O.083 O.12 EST-010 with carbomer as main mucoadhesive agent and Shakability 2 O methylcellulose as a Second polymer. Bubble size (Lm) 92 66 Bubble size (%- O O Ingredients % ww above 500 m) PEG 400 62.36 Propylene glycol 2O.OO 1010 The formulations with PEG on its own and in com PEG-1OO Stearate 2.OO bination with PEG-1500 showed resistance to creaming. US 2008/0299220 A1 Dec. 4, 2008

TABLE 2-continued TABLE 4-continued Composition of the Hydrophilic Solvent-Based Formulation Results at T-0, PFFs of Group 3, Hydrophilic Solvent-Based EST-010 with carbomer as main mucoadhesive agent and Preparations methylcellulose as a second polymer. Test Ingredients % Wiw Material in Closure Test Results, T-0 Stearyl alcohol 4.0 Methylcellulose (Methocel A4) O.1 System Parameter ESTO1 O EST-011 Carbomer 934P O.20 Purified water 1O.OO pH 3.97 4.36 Estradiol hemihydrate in PG stock solution* O.OOS (undiluted) TEA (for neutralization of carbomer solution) C.S. pH (diluted 2.75 2.90 Lactic acid (for adjustment of pH to 4.0-4.5) C.S. 1:5 with purified Total for PFF 100.00 water) Propellant AP-70** 12.00 Centrifugation at: 1) 3,000 rpm: 3000 rpm. - 3000 rpm. - 15% creaming 35% creaming TABLE 3 2) 10,000 rpm: 10,000 rpm: 10,000 rpm. - (% .10% 15% creaming Composition of the Hydrophilic Solvent-Based Formulation creaming) creaming EST-011 with Polycarbophil as main mucoadhesive agent Viscosity 1678 2179 (cPs) ESTO11 Microscopic no crystals no crystals % Wiw examination observed observed (x200) PEG 400 62.36 Homogeneity not not Stearyl alcohol 4.OO of contents homogeneous, homogeneous, Polyoxyl 100 stearate 2.OO * but * but Polycarbophil O.20 redispersible redispersible Lactic acid Triethanolamine (to pH 4.0-4.5) after shaking after shaking Propylene glycol 2O.OO Estradiol hemihydrate stock O.OOS when the formulations including propellant were observed in closed glass solution bottles under pressure it was noted that after a relatively short period of time Purified water to 100.00 10.10 the formulations started to reveal creaming. Propellant AP-70** 12.00 1014 Abbreviations & Explanations: RT: retention time; ND: not detected; detection limit for 1013 The adhesive force seen with Polycarbophil was estrone is 0.074 ug/mL; NR: not recorded slightly greater than with carbomer. Both polymers are NE: not established (for information only), specified limits crosslinked and the difference in result was not considered to not yet established; be significant. In order to increase the mucoadesiveness the 1015 Creaming is the formation of an opaque, white amounts of crosslinked polymer should be increased. It may upper layer and less opaque?transparent lower layer; % also be effective to use a combination of the two crosslinked creaming indicates the relative Volume of the upper layer. polymers with or without a second non crosslinked polymer for example like methocellulose. TABLE 5 TABLE 4 Physical and Chemical Properties. After Three Weeks at Different Storage Conditions Results at T-0, PFFs of Group 3, Hydrophilic Solvent-Based Preparations Test Material in Clos. Tes Storage Results, 3 weeks Test Material in Sys. Parameter Conditions ESTO1 O ESTO11 Closure Test Results, T-0 Pressurized AP TO conforms Conforms System Parameter ESTO1 O ESTO11 formulation in identification 25°C. conforms Conforms aluminum RT of 40° C. conforms Conforms Unpressurized Identification RT of RT of canister estradiol 50° C. conforms Conforms formulations of estradiol estradiol peak estradiol peak peak in (PFF) (PFFs) in in Sample in Sample sample glass vials Solution Solution Solution corresponds to corresponds to corresponds that from that from to that from stand. Solution stand. standard Solution Solution HPLC assay O.004O O.OO44 HPLC assay TO O.OO3S O.0043 (% w/w): ND ND (% w/w): ND ND estradiol: estradiol: 25o C. O.OO43 O.OO46 estrone estrone: ND ND (degrad. 40° C. O.OO42 O.OO48 prod.) ND ND US 2008/0299220 A1 Dec. 4, 2008

Section E TABLE 5-continued Example 51 Physical and Chemical Properties. After Three Weeks at Propylene Glycol (PG) or PEG and Surfactant Ratios Different Storage Conditions and Propellant Test Material in Clos. Test Storage Results, 3 weeks Part A PG Sys. Parameter Conditions ESTO1 O ESTO11 1018

50° C. O.0043 O.OO48 (PFF) ND ND 50° C. O.0034 O.OO44 Propylene Glycol 89% (PFF in ND ND Brij 21 8% glass Polysorbate 80 3% bottles) Propellant AP46 (propane, butane and 8% Appearance: TO Gf white NO G, white NO isobutane mixture) Quality: FTC Gf white NO G, white NO Hardness 19.78 g G = Good 25o C. Gf white NO G, white NO Adhessive Force* -14.58 Color: 40° C. Gf white NO G, white NO Odor:NO = Measured by applying the foam to a metal Surface and testing with a tex No Odor ture analyzer as described in Example 51 Density TO O.063 O.O82 (g/mL) FTC O.045 0.077 1019 Foam quality with AP46 is Good to Excellent. The 25o C. O.045 0.075 40° C. O.O38 O.O68 foam maintains its shape well and can be extruded to form pH diluted TO 2.78 2.92 different shapes and maintain them prior to application. The 1:5 in FTC 2.81 2.99 high surfactant level and the ratio of about 8 to 3 of the two purified 25o C. 2.88. 3.00 Surfactants appears to contribute to the dissolution of the Water 40° C. 2.85 2.93 hydrophobic propellant in the hydrophilic solvent. Replacing Texture, TO 81.48 100.88 hardness (g) Bij 21 with Brij 2 did not help. Brij 21 or Brij 2 on their own Expansion TO 32 18 are less satisfactory, although Brij 21 is preferred. When the time (Sec) ratio was the reverse foam quality was only fairly good. The Collapse TO >3OO >300 adhesive force and hardness of the PG is more than satisfac time (Sec) Pressurized Shakability TO good Moderate tory. formulation shakability shakability in aluminum FTC good good Part B. PEG canister shakability shakability 25o C. good good 1020 shakability shakability 40° C. good good shakability shakability Microscopic TO no crystals no crystals PEG 200 89% examination FTC no crystals no crystals Brij 21 8% (x200) 25o C. no crystals no crystals Polysorbate 80 3% 40° C. no crystals no crystals Propellant AP46 (propane, butane and 8% PFF in Corrosion TO conforms Conforms isobutane mixture) aluminum and 50° C. conforms Conforms Hardness 84.65 g canister Deterioration Adhessive Force* -66.59 Pressurized Homogeneity T-0 Oil Non formulation in of homo- homo Measured by applying the foam to a metal Surface and testing with a tex gl. Vessel contents geneous, geneous, redispersible redispersible ture analyzer as described in Example 51 after shaking after shaking 1021 Foam quality with AP46 is Good, but extrudes with 25o C. Oil Non homo- homo a less defined shape. The high surfactant level and the ratio of geneous, geneous, about 8 to 3 of the two surfactants appears to contribute to the redispersible redispersible dissolution of the hydrophobic propellant in the hydrophilic after shaking after shaking solvent. Replacing Bij21 with Brij 2 did not help. Brij 21 or when the formulations including propellant were observed in closed glass Brij 2 on their own are less satisfactory, although Brij 21 is bottles under pressure it was noted that after a relatively short period of time preferred. When the ratio was the reverse foam quality was the formulations started to reveal creaming. only fairly good. Interestingly, PEG contributes to adhesive 1016. Abbreviations & Explanations: force and increases hardness when compared to PG. RT: retention time; ND: not detected; detection limit for 1022 All references to patents, patent publications, and estrone is 0.074 ug/mL; published articles are hereby incorporated in their entirety by NE: not established (for information only), specified limits reference. not yet established: What is claimed is: E, G, FG (grades of foam quality): excellent, good, fairly 1. A waterless composition suitable for delivery of an good; active agent to a body Surface or cavity comprising: VFO, NO: very faint odor, no odor a vehicle comprising: 1017 Creaming is the formation of an opaque, white a) about 70% to about 99% by weight of a hydrophilic polar upper layer and less opaque?transparent lower layer; % Solvent, said hydrophilic solvent selected from the group creaming indicates the relative Volume of the upper layer. consisting of: US 2008/0299220 A1 Dec. 4, 2008 89

i) a mixture of two or more different polyethylene gly ethylcellulose, a cationic cellulose PEG 1000, PEG 4000, cols (PEGs), wherein at least one PEG is a high PEG 6000 and PEG 8000, polycarbophil, carbomer, ASOS, molecular weight PEG having a melting point greater klucel and permulen. than 25°C.; and 10. The composition of claim 1, wherein a surface active ii) propylene glycol (PG); agent is present in the composition and is selected from the b) about 0% to about 10% of at least one surface active group consisting of a agent, a. polysorbate, including polysorbate 80 and Twin 80, c) about 0% to about 5% of a polymeric agent; polyoxyethylene (20) Sorbitan monostearate, polyoxy d) about 0% to about 30% of a secondary hydrophilic ethylene (20) sorbitan monooleate, a polyoxyethylene Solvent; and fatty acid ester, Myrj45, Myriq9, MyrS2 and Myr 59: e) about 0% to about 5% of a silicone oil; and a polyoxyethylene alkyl ether, including polyoxyethyl about 3% to about 25% hydrophobic propellant; ene cetyl ether, polyoxyethylene palmityl ether, polyeth wherein the composition is otherwise substantially free of ylene oxide hexadecyl ether, polyethylene glycol cetyl a hydrophobic solvent; ether, Brij 10, Brij, 21, Brij 38, Brij 52, Brij56, Brij 72, wherein the composition includes at least one of a Surface Brij 721 and Brij W1, a sucrose ester, including Span 20, active agent and a polymeric agent; and Span 60 and Span 80, apartial ester of sorbitol, including wherein the vehicle and the propellant are sufficiently mis Sorbitan monolaurate, Sorbitan monolaurate, and Sur cible that the components may be homogeneously dis phope 1811, a monoglyceride, a diglyceride, isoceteth tributed with mild shaking. 20, a mono, di or trifatty acid Sucrose ester, laureth-4, 2. The composition of claim 1, wherein the hydrophilic glyceryl Stearate, polyoxyl-100 Stearate, glyceryl solvent is PEG and the high molecular weight PEG is selected monostearate, PEG-100 stearate, PEG-40 stearate, cet from the group consisting of PEG 1000, PEG 1500, PEG eareth-6, ceteareth-16, ceteareth-20, stearyl alcohol, 4000, PEG 6000 and PEG 8000. myr 52, Steareth-2, Steareth-20, isosteareth-20, polyg 3. The composition of claim 2, wherein the balance of the lyceryl 10 laurate, POE (2) cetyl ether, cetearyl gluco PEG is selected from the group consisting of PEG 200, PEG side, cetyryl alcohol, methyl glucose sesquistearate, 300, PEG 400, and PEG 600. span 60, Sucrose Stearic acid esters, Sorbitan Stearate, 4. The composition of claim 1, wherein the hydrophilic Sucrose cocoate, Sucrose Stearate, Peg 40 stearate, isos solvent is PEG and the high molecular weight PEG comprises teareth 20, methylglucose sesquistearate, polyoxyl 100 about 1% to about 15% of the composition. Stearate, macrogel cetostearyl ether, a polymeric emul 5. The composition of claim 1, wherein mixture of two or sifier, including Permulen (TR1 or TR2); and liquid more different PEGs are selected to provide viscosity of the crystal systems, including Arlatone (2121), Stepan vehicle of less than 52,000 CPs, as measured at room tem (Mild RM1), Nikomulese (41) and Montanov (68); and perature at 10 rmp spindle speed. ... a combination of Surfactants selected from the group 6. The composition of claim 1, wherein the hydrophilic consisting of a Brij Surfactant and a Twin Surfactant, polar solvent is PG and the components of the composition wherein the Brij surfactant is the major component of the are sufficiently miscible that the vehicle and the propellant do combination, combinations of polyoxyethylene alkyl not phase separate upon centrifugation at 1000 rpm. ethers, including Brij 59/Brij 10; Brij 52/Brij 10; Ste 7. The composition of claim 6, wherein the hydrophilic areth 2/Steareth 20: Steareth 2/Steareth 21 (Brij72/BRIJ solvent is PG, the composition includes a steareth surface 721); Myri 52/Myr 59, Steareth 2/Laureth 4; combina active agent and a hydroxypropylcellulose polymeric agent, tions of sucrose esters, including Surphope 1816/Sur and is Substantially free of silicone and a secondary hydro phope 1807; combinations of sorbitan esters, including philic solvent. Span 20/Span 80: Span 20/Span 60; combinations of 8. The composition of claim 1, wherein one or both of the Sucrose esters and Sorbitan esters, including Surphope Surface active agent and the polymeric agent are selected to 1811 and Span 60; and combinations of liquid polysor increase the solubility of the propellant in the vehicle. bate detergents and PEG compounds, particularly Twin 9. The composition of claim 1 wherein the a polymeric 80/PEG-40 stearate/methyl glucose sequestrate, glyc agent is present in the composition and is selected from the eryl Stearate/PEG-100 stearate; ceteareth-6/stearyl alco group consisting of locust bean gum, sodium alginate, hol; cetearyl glucoside/cetyryl alcohol, Sorbitan Stear Sodium caseinate, egg albumin, gelatin agar, carrageenin ate/Sucrose cocoate; and polysorbate 80/PEG-40 gum, Sodium alginate, Xanthan gum, quince seed extract, Stearate. tragacanth gum, guar gum, cationic guars, hydroxypropyl 11. The composition of claim 1, wherein silicone oil is guar gum, starch, an amine-bearing polymer, chitosan, alg present in the composition and is selected from the group inic acid, hyaluronic acid, a chemically modified Starch, a consisting of dimethicone, cyclomethicone and mixtures carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alco thereof. hol, a polyacrylic acid polymer, a polymethacrylic acid poly 12. The composition of claim 1 wherein the second hydro mer, polyvinyl acetate, a polyvinyl chloride polymer, a poly philic solvent is present in the composition and is a polyol vinylidene chloride polymer, methylcellulose, selected from the group consisting of a diol, a triol and a hydroxypropyl cellulose, hydroxypropyl methylcellulose, saccharide, wherein the triol is selected from the group con hydroxyethyl cellulose, hydroxy propylmethyl cellulose, sisting of glycerin, butane-1,2,3-triol, butane-1,2,4-triol and methylhydroxyethylcellulose, methylhydroxypropylcellu hexane-1,2,6-triol, and wherein the diol is selected from the lose, hydroxyethylcarboxymethylcellulose, carboxymethyl group consisting of propylene glycol, butanediol, butenediol. cellulose, carboxymethylcellulose carboxymethylhydroxy butynediol, pentanediol, hexanediol, octanediol, neopentyl US 2008/0299220 A1 Dec. 4, 2008 90 glycol, 2-methyl-1,3-propanediol, diethylene glycol, trieth 23. The composition of claim 20, wherein the active agent ylene glycol, tetraethylene glycol, dipropylene glycol and includes a steroid. dibutylene glycol. 24. The composition of claim 1, wherein the composition 13. The composition of claim 1, wherein the ratio between comprises a polymeric agent and the polymeric agent is the polyethylene glycol and the secondary hydrophilic Sol selected from the group of bioadhesive polymers. vent is between about 9:1 and about 1:1. 25. The composition of claim 24, wherein the composition 14. The composition of claim 1 wherein the composition has a bioadhesive force in the range of about -3 g to about -25 further comprises one or more modulating agents. 9. 15. The composition of claim 14, wherein the modulating 26. The composition of claim 24 wherein the polymeric agent is selected from the group of triethanolamine, sodium agent is selected from the group consisting of hydroxypropy citrate and citric acid. lcellulose and carbomer. 16. The composition of claim 1, further comprising an 27. A waterless composition suitable for delivery of an active agent. active agent to a body Surface or cavity comprising: 17. The composition of claim 16, wherein the active agent a vehicle, comprising: is selected from the group consisting of antiinfectives, anti a) about 70% to about 99% by weight of a hydrophilic polar fungals, antivirals, anesthetic analgesic, corticosteroids, non Solvent comprising butylene glycol (BG) steroid anti inflammatory, retinoids, lubricating agents anti b) about 0% to about 10% of at least one surface active warts, antiproliferative, vasoactive, keratolytic, insecticide agent, and repellants, dicarboxylic acids and esters; calcium channel c) about 0% to about 5% of a polymeric agent; blockers, cholinergic, N-oxide doners, photodynamic, anti d) about 0% to about 30% of a secondary hydrophilic acne, anti wrinkle, antioxidants, self tanning active herbal Solvent; and extracts, acaricides, age spot and keratose removing agents, e) about 0% to about 5% of an unmodified silicone; and allergen, analgesics, local anesthetics, antiacne agents, anti about 3% to about 25% hydrophobic propellant; allergic agents, antiaging agents, antibacterials, antibiotics, wherein the composition is otherwise substantially free of antiburn agents, anticancer agents, antidandruff agents, anti a hydrophobic solvent; depressants, antidermatitis agents, antiedemics, antihista wherein the composition includes at least one of a surface mines, antihelminths, antihyperkeratolyte agents, antiinflam active agent and a polymeric agent; and matory agents, antiirritants, antilipemics, antimicrobials, wherein the components of the composition are suffi antimycotics, antiproliferative agents, antioxidants, anti ciently miscible that the vehicle and the propellant do wrinkle agents, antipruritics, antipsoriatic agents, antirosacea not phase separate upon centrifugation at about 1000 agents antiseborrheic agents, antiseptic, antiswelling agents, rpm for about 10 mins. antiviral agents, antiyeast agents, astringents, topical cardio 28. The composition of claim 27, wherein the hydrophilic vascular agents, chemotherapeutic agents, corticosteroids, Solvent further comprises a polyol selected from the group dicarboxylic acids, disinfectants, fungicides, hair growth consisting of propylene glycol and hexylene glycol. regulators, hormones, hydroxy acids, immunosuppressants, 29. The composition of claim 28, wherein the ratio of immunoregulating agents, insecticides, insect repellents, butylene glycol to hexylene glycol is in the range of 1:0.5 to keratolytic agents, lactams, metals, metal oxides, mitocides, about 1:3. neuropeptides, non-steroidal anti-inflammatory agents, oxi 30. The composition of claim 27, wherein the components dizing agents, pediculicides, photodynamic therapy agents, of the composition are sufficiently miscible that the vehicle retinoids, Sanatives, scabicides, self tanning agents, skin and the propellant do not phase separate upon centrifugation whitening agents, asoconstrictors, vasodilators, vitamins, at about 3000 rpm for about 10 mins. vitamins A, B, C, D, E, K and derivatives, wound healing 31. A waterless composition suitable for delivery of an agents and wart removers. active agent to a body Surface or cavity comprising: 18. The composition of claim 16, wherein the active agent a vehicle, comprising: is selected from the group consisting of Acyclovir, AZelaic a) about 70% to about 99% by weight of a hydrophilic polar acid, Benzoyl peroxide, Betamethasone 17 Valerate micron Solvent, said hydrophilic solvent selected from the group ized, Caffeine, Calcipotriol hydrate, Ciclopiroxolamine, consisting of polyethylene glycols (PEGs) and propy Diclofenac sodium, Ketoconazole, Miconazole nitrate, lene glycol (PG); Minoxidil, Mupirocin, Nifedipine regular, Permethrin BPC b) about 0.1% to about 10% of at least one surface active (cis:trans 25:75), Piroxicam, Salicylic acid, Terbinafine HCl, agent, a Surface active agent is present in the composi estradiol hemihydrate and progesterone or combinations tion and is a mixture of a Brij Surfactant and a Twin thereof. Surfactant, wherein the Brij Surfactant is the major Sur 19. The composition of claim 16, wherein the active agent face active agent component; includes progesterone, estrogen, a derivative thereof or mix c) about 0% to about 5% of a polymeric agent; tures thereof. d) about 0% to about 30% of a secondary hydrophilic 20. The composition of claim 16, wherein the active agent Solvent; and includes a vitamin. e) about 0% to about 5% of an unmodified silicone; and 21. The composition of claim 20, wherein the vitamin about 3% to about 25% hydrophobic propellant; selected from the group consisting of a Vitamin D, retinol, wherein the composition is otherwise substantially free of retinoic acid, tocopherol, Vitamin KVitamin C or Vitamin B a hydrophobic solvent; and or a derivatives thereof. wherein the components of the composition are suffi 22. The composition of claim 16 wherein the active agent ciently miscible that the propellant and vehicle may be includes a steroid. homogeneously distributed with mild shaking. US 2008/0299220 A1 Dec. 4, 2008

32. A hygroscopic glycol composition comprising a poly wherein the composition includes at least one of a surface ethylene glycol or derivatives and mixtures thereof or com active agent and a polymeric agent. prising a propylene glycol or derivatives at a sufficient con 35. The composition of claim 34, wherein the high molecu centration alone as a component in the composition or with lar weight PEG is present in an amount greater than about one or more other hygroscopic Substances to provide 10% by weight of the composition. (a) at least one hygroscopic Substance at a sufficient con 36. The composition of claim 34, wherein the PEG is a centration to provide an AW value of the hygroscopic combination of a high and low molecular weight PEG therapeutic containing composition of less than 0.9; and selected from the group consisting PEG6000/PEG200; (b) a therapeutic agent thereof or a combinations thereof. PEG400/PEG1500, PEG4000/PEG200; PEG4000/PEG400, 33. The composition of claim 32, wherein the composition PEG 4000/PEG 600, PEG4000/PEG400/PEG200; and the further comprises at least one component selected from the like. group consisting of 37. A waterless composition suitable for delivery of an (a) about 0.01% to about 5% by weight of at least one active agent to a body Surface or cavity comprising: polymeric agent selected from a bioadhesive agent, a a vehicle comprising: gelling agent, a film forming agent and a phase change a) about 70% to about 99% by weight of a hydrophilic polar agent; and Solvent, said hydrophilic Solvent comprising a mixture (b) a surface active agent, of PEG 200 and PEG 400; wherein the polymeric agent is selected Such that it has b) about 0% to about 10% of at least one surface active Some surfactant properties if it is used in the absence agent, of a Surface active agent. c) about 0% to about 5% of a polymeric agent; 34. A waterless composition suitable for delivery of an d) about 0% to about 30% of a secondary hydrophilic active agent to a body Surface or cavity comprising: Solvent; and a) about 70% to about 99% by weight of a mixture of two e) about 0% to about 5% of a silicone oil; and or more different polyethylene glycols (PEGs), wherein about 3% to about 25% hydrophobic propellant; at least one PEG is a high molecular weight PEG having wherein the composition is otherwise substantially free of a melting point greater than 25° C., and wherein the a hydrophobic solvent; mixture of two or more different PEGs is selected to wherein the composition includes at least one of a surface provide angel, ointment or cream; and active agent and a polymeric agent; and b) about 0% to about 10% of at least one surface active wherein the vehicle and the propellant are sufficiently mis agent, cible that the components may be homogeneously dis c) about 0% to about 5% of a polymeric agent; and tributed with mild shaking. d) about 0% to about 30% of a secondary hydrophilic solvent; c c c c c