US 20080069779A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0069779 A1 Tamarkin et al. (43) Pub. Date: Mar. 20, 2008

(54) FOAMABLE VEHICLE AND VITAMIN AND (60) Provisional application No. 60/843,140, filed on Sep. FLAVONOID PHARMACEUTICAL 8, 2006. Provisional application No. 60/784,793, filed COMPOSITIONS THEREOF on Mar. 21, 2006. Provisional application No. 60/679, 020, filed on May 9, 2005. Provisional application (75) Inventors: Dov Tamarkin, Maccabim (IL); Doron No. 60/530,015, filed on Dec. 16, 2003. Provisional Friedman, Karmei Yosef (IL); Meir application No. 60/492.385, filed on Aug. 4, 2003. Eini, Ness Ziona (IL); Tal Berman, Rishon LeZiyyon (IL); David Schuz, Publication Classification Moshav Gimzu (IL) (51) Int. Cl. Correspondence Address: A6IR 9/12 (2006.01) WILMERHALEABOSTON A6IP 37/00 (2006.01) 6O STATE STREET (52) U.S. Cl...... 424/45 BOSTON, MA 02109 (US) (73) Assignee: Foamix Ltd., Ness Ziona (IL) (57) ABSTRACT (21) Appl. No.: 11/900,072 Vitamin and flavonoid containing compositions are provided (22) Filed: Sep. 10, 2007 that are stable to degradation. Stabilized compositions include one or more features including a hygroscopic Sol Related U.S. Application Data vent at a sufficient concentration to provide an Aw value of the hygroscopic Vitamin and or flavonoid containing com (63) Continuation-in-part of application No. 11/430,599, position of less than 0.9, antioxidant flavonoids that are filed on May 9, 2006, and which is a continuation preferentially oxidized before the vitamin, preservatives, in-part of application No. 10/835,505, filed on Apr. and hydrocarbon propellants selected to reduce the oxidation 28, 2004. potential of the composition. US 2008/0069779 A1 Mar. 20, 2008

FOAMABLE VEHICLE AND VITAMIN AND left following their topical application onto the skin, FLAVONOID PHARMACEUTICAL mucosal membranes and wounds. COMPOSITIONS THEREOF 0004 Foams and, in particular, foams that are substan CROSS REFERENCE TO RELATED tially based on non-aqueous solvents are complicated sys tems which do not form under all circumstances. Whilst APPLICATIONS aqueous foam formulations are better known, they are also 0001) This application claims the benefit under 35 U.S.C. complicated and similarly do not form under all circum S119(e) of U.S. Provisional Patent Application No. 60/843, StanceS. 140, filed on Sep. 8, 2006, and U.S. Provisional Patent Application No. TBA, filed on Sep. 4, 2007, each of which 0005 Antioxidants can be protective. Flavonoids are said is entitled "Foamable Vehicle and Vitamin Pharmaceutical to have high antioxidant activity and many health promoting Compositions Thereof.” This application is also a continu effects, including anti-inflammatory and anti-allergic effects ation-in-part application of co-pending U.S. patent applica as well as reducing the risk of cancer and pulmonary disease, tion Ser. No. 11/430,599 filed on May 9, 2006, which claims improved cardiovascular health and prevention of damage the benefit under 35 U.S.C. S 119(e) of U.S. Provisional from free radicals. The use of flavonoids for protecting Patent Application No. 60/679,020, filed on May 9, 2005, ascorbic acid and ascorbyl compounds has been proposed in entitled Hygroscopic Anti-Infective Compositions, and U.S. respect of lotions creams and gels Provisional Patent Application No. 60/784,793, filed on 0006 By using specialized delivery systems like micro Mar. 21, 2006, entitled Polyol Foamable Vehicle and Phar sponges it may be possible to incorporate hydrophobic maceutical Compositions Thereof, and which is also a active ingredients within the microSponges, which active continuation-in-part application of co-pending U.S. patent ingredients are released when the microSponges come into application Ser. No. 10/835,505, filed on Apr. 28, 2004, mechanical contact with the skin. which claims the benefit of priority under 35 U.S.C. S 119(e) to U.S. Provisional Patent Application No. 60/.530,015, filed SUMMARY on Dec. 16, 2003, and U.S. Provisional Patent Application 0007 Compositions containing vitamins and/or fla No. 60/492.385, filed on Aug. 4, 2003, all entitled “Oleagi vonoids or derivative thereof using non-aqueous and aque nous Pharmaceutical Foam; all of which are hereby incor ous carriers and foamable compositions containing them and porated in their entirety by reference. methods of treatment are described. 0008 Hygroscopic and aqueous stable vitamin contain BACKGROUND ing compositions and foamable therapeutic vitamin compo 0002 Vitamins are an essential component of the bodies sitions with and without additional active agents may be daily requirements and they are needed in various metabolic used for treatment of dermal and mucosal tissues are stable. pathways and to maintain good health. Some vitamins are They are non irritating, facilitate penetration at a target, are believed to support, facilitate, improve or optimize the presentable in an easily applicable stable form, can be function and effect of other vitamins and or active agents. handled with ease thereby facilitating compliance and either Compositions which can be applied to the skin, a body minimize or eliminate the amount of free water and in cavity, a mucosal Surface, the nose, the mouth, the eye, the consequence, the potential breakdown of vitamin by oxida ear canal, the respiratory system, the vagina and the rectum tion/hydrolysis, or provide an aqueous environment where that contain an effective amount of one or more vitamins they can resist or are protected from said potential break would be useful. Some vitamins are susceptible to oxidation down. and breakdown in Solution. Vitamins may for example 0009. In one or more embodiments, topical and body breakdown in the presence of water and may not be stable cavity foam formulations containing flavonoids on their own in compositions for Sufficiently long periods of time to and in combination with one or more vitamins are described. facilitate satisfactorily cosmetic and pharmaceutical uses. 0010. In one or more embodiments, topical and body Vitamin absorption is on the other hand also retarded by cavity foam formulations containing microSponges compris Substances like paraffin's and by certain pharmaceuticals. ing one or more active ingredients are provided. In particu 0003 External topical administration is an important lar, the microSponges comprise one or more vitamins or one route for the administration of drugs in disease treatment. or more flavonoids alone or in combination and also with Many groups of drugs, including, for example, antibiotic, other active ingredients. anti-fungal, anti-inflammatory, anesthetic, analgesic, anti allergic, corticosteroid, retinoid and anti-proliferative medi 0011. In other embodiments, the use of flavonoids on cations are preferably administered in hydrophobic media, their own, Synergistically, and in combination with other namely ointment. However, ointments often form an imper active agents is disclosed. meable barrier, so that metabolic products and excreta from 0012. In one or more aspects there is provided a hygro the wounds to which they are applied are not easily removed scopic Vitamin and or flavonoid containing composition or drained away. Furthermore, it is difficult for the active comprising: drug dissolved in the carrier to pass through the white petrolatum barrier layer into the wound tissue, so the effi 0013 a. at least one agent selected from the group cacy of the drug is reduced. In addition, ointments and consisting of Vitamins and flavonoids; creams often do not create an environment for promoting 0014) b. at least one hygroscopic solvent at a sufficient respiration of the wound tissue and it is not favorable to the concentration to provide an AW value of the hygroscopic normal respiration of the skin. An additional disadvantage of Vitamin and or flavonoid containing composition of less than petroleum jelly-based products relates to the greasy feeling 0.9; US 2008/0069779 A1 Mar. 20, 2008

0.015 c. a foam stabilizer selected from the group con 0.01% to about 5% by weight of at least one polymeric agent sisting of at least one surface-active agent; at least one selected from a bioadhesive agent, a gelling agent, a film polymeric agent selected from the group consisting of a forming agent and a phase change agent; and a Surface bioadhesive agent, a gelling agent, a film forming agent and active agent. a phase change agent and mixtures thereof, and 0033. In one or more embodiments, the hygroscopic 0016 d. a propellant at a concentration of about 3% to Substance is selected from the group consisting of polyeth about 25% by weight of the total composition, ylene glycols (PEGs), Surfactants comprising PEG, polyols, 0017 wherein the composition is contained in a pressur monosaccharides, disaccharides, oligosaccharides and Sugar ized container, is substantially flowable and provides a foam alcohols in an amount to provide hygroscopic properties, upon release. and honey. 0018. In one or more aspects there is provided a foamable 0034. In one or more embodiments there is provided a hygroscopic vitamin and or flavonoid containing composi foamable composition comprising a stabilized-vitamin, tion comprising: comprising: 0019 a. at least one agent selected from the group 0035) a water-unstable vitamin; consisting of Vitamins and flavonoids; 0036) an optional flavonoid; and 0020 b. at least one hygroscopic solvent at a sufficient 0037) a foamable carrier comprising: concentration to provide an AW value of the hygro 0038 i. water; Scopic Vitamin and or flavonoid containing composi 0039) ii. a foam stabilizer selected from the group tion of less than 0.9; consisting of at least one surface-active agent; at least 0021 c. a foam stabilizer selected from the group one polymeric agent selected from the group consisting consisting of at least one surface-active agent; and at of a bioadhesive agent, a gelling agent, a film forming least one polymeric agent selected from the group agent and a phase change agent and mixtures thereof; consisting of a bioadhesive agent, a gelling agent, a 0040 iii. about 0.005% to about 5% conservational film forming agent and a phase change agent and agent; and mixtures thereof 0041) iv. a propellant at a concentration of about 3% to 0022 d. a hydrocarbon propellant at a concentration of about 25% by weight of the total composition, about 3% to about 25% by weight of the total compo 0042 where said foamable carrier reduces the destabiliz sition; and ing effect of water on the vitamin, and 0023 wherein the composition is contained in a pressur 0043 wherein the composition is contained in a pressur ized container to which a vacuum was applied prior to filling ized container, is substantially flowable and provides a foam with a hydrocarbon propellant, is substantially flowable and upon release. provides a foam upon release, and 0044) In one or more embodiments there is provided a 0024 wherein applying a vacuum to and filling a canister method of treating a disorder or condition of mammalian containing the composition with hydrocarbon propellant Subject, comprising: contributes to stabilize the agent against degradation. 0045 administering a foam produced from a foamable 0025. In one or more aspects, the hygroscopic vitamin Vitamin and or flavonoid composition to a target site, foam and or flavonoid containing composition optionally may able composition comprising a stabilized-vitamin, compris further comprise: 1ng: 0026 i. about 50% to about 98% of a polar solvent; 0046) a water-unstable vitamin; 0027 ii. 0% to about 48% of a secondary polar solvent; 0047) an optional flavonoid; and a foamable carrier comprising: 0028 iii. a foam adjuvant; 0048) 0049) i. water, 0029) iv. 0% to about 5% by weight of at least one 0050 ii. a foam stabilizer selected from the group polymeric agent; and consisting of at least one surface-active agent; at 0030 V. 0% to about 5% of a conservation agent. least one polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a 0031. In one aspect, a hygroscopic vitamin and or fla film forming agent and a phase change agent and vonoid containing composition including at least one hygro mixtures thereof; scopic Substance at a sufficient concentration to provide an Aw value of the hygroscopic pharmaceutical composition of 0051) iii. about 0.005% to about 5% conservational less than 0.9; or the Aw value is in the range of about 0.8 and agent; and about 0.9; (2) about 0.7 and about 0.8; and (3) less than 0052 iv. a propellant at a concentration of about 3% about 0.7 and a vitamin or a derivative thereof or a combi to about 25% by weight of the total composition, nations thereof. The composition may be substantially free 0053 where said foamable carrier reduces the destabiliz of water. ing effect of water on the vitamin, and 0032. In one or more embodiments, the hygroscopic 0054 wherein the composition is contained in a pressur pharmaceutical composition further includes at least one ized container, is substantially flowable and provides a foam component, selected from the group consisting of about upon release. US 2008/0069779 A1 Mar. 20, 2008

0055. In one or more embodiments, the vitamin or fla about 48% of a secondary polar solvent; a surface-active vonoid or combinations thereof are loaded into micro agent; about 0.01% to about 5% by weight of at least one Sponges. polymeric agent; and a liquefied or compressed gas propel lant at a concentration of about 3% to about 25% by weight 0056. In one or more embodiments there is provided a of the total composition. method of treating a disorder or condition of mammalian Subject, comprising: 0077. In one or more embodiments, the compositions 0057 administering a foam produced from a foamable further comprise up to 10% of water. Vitamin and or flavonoid composition to a target site, foam 0078. In one or more embodiments, the composition is able composition comprising: Substantially non-aqueous and/or Substantially alcohol-free. 0.058 a. a vitamin and/or flavonoid; and 0079. In one or more embodiments, the composition further comprises a therapeutically effective concentration 0059 b. a substantially non-aqueous carrier, the carrier of one or more vitamins. In an additional embodiment, the comprising composition further contains a therapeutically effective con 0060) i. about 50% to about 98% of a polar solvent centration of one or more additional therapeutic agents. Selected from the group consisting of polyols and 0080. In one or more embodiments, the polyol is selected polyethylene glycols (PEGs); from the group consisting of a diol, a triol and a saccharide, and the triol may be selected from the group consisting of 0061 ii. 0% to about 48% of a secondary polar solvent; glycerin, butane-1,2,3-triol, butane-1,2,4-triol and hexane 12,6-triol, or the diol is selected from the group consisting 0062) iii. a surface-active agent or foam adjuvant; of propylene glycol, butanediol, butenediol, butynediol. 0063) iv. 0% to about 5% by weight of at least one pentanediol, hexanediol, octanediol, neopentyl glycol, polymeric agent; 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and dibuty 0064 v. 0% to about 5% of a conservation agent; and lene glycol. 0065 vi. a proppropellant at a concentration of about 3% to 0081. In one or more embodiments, the polyol consists of about 25% by weight of the total composition. at least one diol and at least one triol, and wherein the ratio between the diol and triol is between 9:1 and 1:1. 0066. In one or more embodiments there is provided a method of treating a disorder or condition of mammalian 0082 In one or more embodiments, the composition Subject, comprising: includes a mixture of at least one polyol and at least one PEG, and the PEG may be selected from the group consist 0067 administering to a target site a foam produced by ing of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, release of a foamable vitamin and flavonoid composition PEG 4000, PEG 6000 and PEG 8000, or the composition from a pressurized canister containing a composition to contains one or more PEGs in a concentration to provide which a vacuum was applied prior to filling with a hydro viscosity of less than 12,000 CPs. carbon propellant, the composition comprising: 0083. In one or more embodiments, the composition 0068 a. a vitamin and/or flavonoid; and includes a secondary polar solvent selected from the group consisting of dimethyl isosorbide, tetrahydrofurfuryl alcohol 0069 b. a substantially non-aqueous carrier, the carrier polyethyleneglycol, ether, DMSO, a pyrrolidone, N-Methyl comprising 2-pyrrolidone, 1-Methyl-2-pyrrolidinone, ethyl proxitol, 0070) i. about 50% to about 98% of a polar solvent dimethylacetamide, a PEG-type surfactant, an alpha Selected from the group consisting of polyols and hydroxy acid, lactic acid and glycolic acid, or the secondary polyethylene glycols (PEGs); polar solvent is dimethyl isosorbide. 0071 ii. 0% to about 48% of a secondary polar solvent; 0084. In one or more embodiments, the composition includes (1) at least one polar solvent selected from a diol, 0072 iii. a surface-active agent or foam adjuvant; a triol and PEG, and (2) at least one secondary polar solvent, and for example, the polar solvent comprises a mixture of at 0073) iv. 0% to about 5% by weight of at least one least one polyol and at least one PEG, and for example, the polymeric agent; polyol comprises a mixture of at least two polyols. 0074 v. 0% to about 5% of a conservation agent; and 0085. In one or more embodiments, the ratio between the polyol and/or PEG and the secondary polar solvent is O075 V1.i. a propellpropellant at a COncentrat1On Offab about 3/o3% tO between 9:1 and 1:1. about 25% by weight of the total composition, 0086. In yet an additional embodiment, the foamable wherein applying a vacuum and filling the canister con Vitamin composition further contains an additional thera taining the composition with hydrocarbon propellant peutic agent. contributes to stabilize the vitamin against degradation. 0087. In another aspect, a method of treating a disorder of 0076. In another aspect, a foamable vitamin and or fla mammalian Subject includes administering a foamable vonoid carrier is provided including about 50% to about therapeutic composition to a target area, the composition 98% of a polar solvent selected from the group consisting of comprising a therapeutically effective concentration of an (1) a polyol and (2) a polyethylene glycol (PEG); 0% to active agent, about 50% to about 98% of a polar solvent US 2008/0069779 A1 Mar. 20, 2008 selected from the group consisting of (1) a polyol; and (2) a ictyol, cyanidin, delphinidin, malvidin, pelargonidin, peoni polyethylene glycol; 0% to about 48% of a secondary polar din, petunidin, catechin, gallocatechin, epicatechin, and epi solvent; about 0.01% to about 5% by weight of at least one gallocatechin. polymeric agent; a Surface-active agent; and a liquefied or 0101. In one or more embodiments there is provided a compressed gas propellant at a concentration of about 3% to composition wherein the flanonoid is a synergistic combi about 25% by weight of the total composition. nation of two or more flavonoids selected from the group 0088. In one or more embodiments, the target site is consisting of benzquercin, dioSmin, ethoxazorutoside, fla selected from the group consisting of the skin, a body cavity, Vodate, sodium hesperidin, leucocianido, monoxerutin, a mucosal Surface, the nose, the mouth, the eye, the ear oXerutin, quercetin, rutoside, roSmarinic acid, kaempferol, canal, the respiratory system, the vagina and the rectum. myricetin apigenin, luteolin, hesperetin, naringenin, eriod ictyol, cyanidin, delphinidin, malvidin, pelargonidin, peoni 0089. In one or more embodiments, the surface active din, petunidin, catechin, gallocatechin, epicatechin, and epi agent ranges from about less than 0.1% up to about 15% or gallocatechin. up to about 20% by weight of composition depending on the surfactant selected or preferably is about 0.2% to about 0.5% 0102) In one or more embodiments there is provided a by weight of composition. composition wherein the flanonoid is quercitin and or ros marinic acid and the vitamin is vitamin A, and or C and or DETAILED DESCRIPTION D (D1, D2, D3, D4, or D5) and or E or a derivative thereof. 0090. In one or more embodiments there is provided a 0103) In one or more embodiments there is provided a hygroscopic vitamin and or flavonoid containing composi composition, wherein the vitamin, flavonoid or a derivative tion comprising: thereof or combinations thereof comprises an antioxidant. 0091 a. at least one hygroscopic substance at a suffi 0104. In one or more embodiments there is provided a cient concentration to provide an Aw value of the composition wherein the vitamin, flavonoid or a derivative hygroscopic Vitamin and or flavonoid containing com thereof or combinations thereof improves stimulates or position of less than 0.9; and promotes target site metabolism. 0105. In one or more embodiments there is provided a 0092 b. a vitamin and or flavonoid or a derivative composition wherein the vitamin, flavonoid or a derivative thereof or a combinations thereof. thereof or combinations thereof alleviates, ameliorates, 0093. In one or more embodiments there is provided a treats, prevents, retards or otherwise has a beneficial effect composition wherein the Vitamin is selected from the group on a skin or body cavity condition. consisting of vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, 0106. In one or more embodiments there is provided a PABA, C, D1, D2, D3, D4, D5, E, K and F and a derivative composition wherein the skin condition is selected from the thereof or combinations thereof. group consisting of skin pigmentation, dry skin, a wound, 0094. In one or more embodiments there is provided a acne, psoriasis and skin aging. composition, wherein the vitamin, flavonoid or a derivative 0.107. In one or more embodiments there is provided a thereof is susceptible to oxidation. composition wherein the vitamin is a combination of two or more vitamins selected from the group comprising vitamin 0.095. In one or more embodiments there is provided a B3, E and C and a derivative thereof. composition, wherein the vitamin, flavonoid or a derivative thereof is soluble in water. 0108. In one or more embodiments there is provided a composition further comprising a preservative and or modu 0096. In one or more embodiments there is provided a lating agent. composition, wherein the vitamin, flavonoid or a derivative 0.109. In one or more embodiments there is provided a thereof is soluble in a hydrophobic solvent. composition wherein the preservative is selected from the 0097. In one or more embodiments there is provided a group consisting of disodium metabisulfate and sharomix composition wherein the Vitamin is a combination of two or 824 and the modulating agent is EDTA and or optionally a more vitamins selected from the group consisting of vitamin buffering agent. A, B3, C, K, E, and F and a derivative thereof. 0110. In one or more embodiments there is provided a 0098. In one or more embodiments there is provided a composition, wherein the vitamin and or flavonoid act also composition wherein the Vitamin is a combination of two or as modulating agents. more vitamins selected from the group consisting of vitamin 0111. In one or more embodiments there is provided a A, C, D1, D2, D3, D4, and D5 and a derivative thereof. composition further comprising an additional therapeutic 0099. In one or more embodiments there is provided a agent in addition to the vitamin, flavonoid, a derivative composition, wherein the flavonoid is selected from the thereof or combinations thereof. group consisting of flavonols; flavones flavonones flavan 0.112. In one or more embodiments there is provided a 3-ols anthocyanins and proanthocyanidins. composition, further comprising at least one component, 0100. In one or more embodiments there is provided a selected from the group consisting of: composition wherein the flavonoid is selected from the 0113 a. about 0.01% to about 5% by weight of at least group consisting of benzquercin, dioSmin, ethoxazorutoside, one polymeric agent selected from a bioadhesive agent, flavodate, sodium hesperidin, leucocianido, monoxerutin, a gelling agent, a film forming agent and a phase oXerutin, quercetin, rutoside, roSmarinic acid, kaempferol, change agent; and myricetin apigenin, luteolin, hesperetin, naringenin, eriod 0114 b. a surface-active agent. US 2008/0069779 A1 Mar. 20, 2008

0115) In one or more embodiments there is provided a 0.137 In one or more embodiments there is provided a composition, wherein the hygroscopic Substance is selected foamable composition comprising a stabilized-vitamin, from the group consisting of comprising: 0116 a. polyethylene glycols (PEGs); 0.138) a water-unstable vitamin; 0.117 b. surfactants comprising PEG: 0139) an optional flavonoid; and 0118 c. polyols; 0140 a foamable carrier comprising: 0141 i. water; 0119 d. monosaccharides, disaccharides, oligosaccha rides and Sugar alcohols in an amount to provide 0.142 ii. a foam stabilizer selected from the group hygroscopic properties; and consisting of at least one surface-active agent; at least one polymeric agent selected from the group consisting 0120 e. honey. of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent and mixtures thereof; 0121. In one or more embodiments there is provided a composition, wherein the Aw value of the composition is 0143 iii. about 0.005% to about 5% conservational selected from the ranges of (1) about 0.8 and about 0.9; (2) agent; and about 0.7 and about 0.8; and (3) less than about 0.7. 0144) iv. a propellant at a concentration of about 3% to 0122) In one or more embodiments there is provided a about 25% by weight of the total composition, composition, further comprising up to 10% of water. 0145 where said foamable carrier reduces the destabiliz 0123. In one or more embodiments there is provided a ing effect of water on the vitamin, and composition, wherein the composition is Substantially non 0146 wherein the composition is contained in a pressur aqueous and or Substantially alcohol-free. ized container, is substantially flowable and provides a foam 0.124. In one or more embodiments there is provided a upon release. composition, wherein the vitamin and or flavonoid or 0.147. In one or more embodiments the vitamin, fla derivative thereof or combinations thereof are loaded into vonoid, stabilizer, conservational agent, and solvent to the microSponges. extent they are present are selected to provide a composition 0125. In one or more aspects there is provided a hygro that is Substantially resistant to aging. scopic Vitamin and or flavonoid containing composition 0.148. In one or more embodiments the flavonoid and or comprising: conservational agent can Substantially conserve or stabilize the vitamin. 0126 a. at least one agent selected from the group consisting of vitamins and flavonoids; and 0149. In one or more embodiments the formulation com prises water, and the flavonoid and or conservational agent 0127 b. at least one hygroscopic solvent at a sufficient can Substantially conserve or stabilize the vitamin and concentration to provide an AW value of the hygroscopic further the vitamin, flavonoid, stabilizer, conservational Vitamin and or flavonoid containing composition of less than agent, and solvent provide a composition that is substan 0.9; tially resistant to aging. 0128 c. a foam stabilizer selected from the group con 0150. In one or more embodiments there is provided a sisting of at least one surface-active agent; at least one foamable composition wherein the Aw value of the compo polymeric agent selected from the group consisting of a sition is selected from the ranges of (1) about 0.8 and about bioadhesive agent, a gelling agent, a film forming agent and 0.9; (2) about 0.7 and about 0.8; and (3) less than about 0.7. a phase change agent and mixtures thereof, and 0151. In one or more embodiments there is provided a 0129 d. a propellant at a concentration of about 3% to foamable composition wherein the Surface active agent is about 25% by weight of the total composition, about 0.2% to about 5% by weight of composition. 0130 wherein the composition is contained in a pressur 0152. In one or more embodiments there is provided a ized container, is substantially flowable and provides a foam foamable composition wherein the polar solvent is a polyol upon release. is selected from the group consisting of a diol, a triol and a saccharide. 0131). In one or more aspects, the hygroscopic vitamin and or flavonoid containing composition optionally may 0153. In one or more embodiments there is provided a further comprise: foamable composition wherein the diol is selected from the group consisting of propylene glycol, butanediol, butene 0132) i. about 50% to about 98% of a polar solvent diol, butynediol, pentanediol, hexanediol, octanediol, neo pentyl glycol, 2-methyl-1,3-propanediol, diethylene glycol, 0133) ii. 0% to about 48% of a secondary polar solvent; triethylene glycol, tetraethylene glycol, dipropylene glycol 0134) iii. a foam adjuvant; and dibutylene glycol and, wherein the triol is selected from the group consisting of glycerin, butane-1,2,3-triol, butane 0135) iv. 0% to about 5% by weight of at least one 1,2,4-triol and hexane-1,2,6-triol. polymeric agent; and 0154) In one or more embodiments there is provided a 0136 v. 0% to about 5% of a conservation agent. foamable composition wherein the polar solvent is a PEG is US 2008/0069779 A1 Mar. 20, 2008

selected from the group consisting of PEG 200, PEG 300, selected from the group consisting of a polysorbate, poly PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000 and oxyethylene (20) Sorbitan monostearate, polyoxyethylene PEG 8OOO. (20) Sorbitan monooleate, a polyoxyethylene fatty acid ester, Myri 45, Myr 49, Myri 52 and Myri 59, a polyoxyethylene 0155 In one or more embodiments there is provided a alkylyl ether, polyoxyethylene cetyl ether, polyoxyethylene foamable composition wherein the carrier composition com palmityl ether, polyethylene oxide hexadecyl ether, polyeth prises a polar solvent mixture of at least one polyol and at ylene glycol cetyl ether, brij 38, brij 52, brij 56 brij 72, brij least one PEG. 721 and bri W1, a sucrose ester, a partial ester of sorbitol, 0156. In one or more embodiments there is provided a Sorbitan monolaurate, Sorbitan monolaurate a monoglycer foamable composition, which is non aqueous or Substan ide, a diglyceride, isoceteth-20, a Sucrose ester, or selected tially non aqueous wherein the secondary polar solvent is from the group consisting of Steareth 2, glyceryl monostear selected from the group consisting of dimethyl isosorbide, ate/PEG 100 stearate, Glyceryl Stearate, Steareth-21, peg 40 tetrahydrofurfuryl alcohol polyethyleneglycol, ether, stearate, polysorbate 60, polysorbate 80, sorbitan stearate, DMSO, a pyrrolidone, N-Methyl-2-pyrrolidone, 1-Methyl laureth 4, Sorbitan monooleate, ceteareth 16 ceteareth 20, 2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG steareth 10, steareth 20, ceteth 20, Macrogol Cetostearyl type surfactant, an alpha hydroxy acid, lactic acid and Ether, ceteth 2, PEG-30 Dipolyhydroxystearate, sucrose glycolic acid. distearate, polyoxyethylene (100) stearate, PEG 40 stearate, PEG 100 stearate, laureth 4, cetomacrogol ether, Cetearyl 0157. In one or more embodiments there is provided a alcohol, Cetearyl glucoside, Oleyl alcohol, Steareth-2, foamable composition, which is non aqueous or Substan Diisopropyl adipate, Capric/caprilic triglicerides, Polysor tially non aqueous wherein the carrier composition com bate 20; Polysorbate 80, Montanov 68 (cetearyl alcohol prises (1) at least one polar solvent selected from a diol, a (and) cetearyl glucoside.), Simusol 165 (Glyceryl Stearate triol and PEG, and (2) at least one secondary polar solvent. and PEG-100 stearate). Methyl glucose sequistearate, Peg 0158. In one or more embodiments there is provided a 30 dipolyhydroxy Stearate. Sucrose Stearic acid esters, Sorbi foamable composition, which is non aqueous or Substan tan laureth, Sorbitan Stearate, polyglyceryl-10 laurate, epik tially non aqueous wherein the concentration of the polar uuron 80, span 80 and mixtures thereof. Solvent and the secondary polar solvent is sufficient to 0163. In one or more embodiments there is provided a provide an AW value of the hygroscopic pharmaceutical foamable composition, further comprises a hydrophobic composition of less than 0.9. solvent. 0159. In one or more embodiments there is provided a 0164. In one or more embodiments there is provided a foamable composition, which is non aqueous or Substan foamable composition, wherein the hydrophobic solvent is tially non aqueous wherein the AW value of the composition selected from the group consisting of mineral oil, isopropyl is selected from the ranges of (1) about 0.8 and about 0.9; (2) palmitate, isopropyl isostearate, diisopropyl adipate, diiso about 0.7 and about 0.8; and (3) less than about 0.7. propyl dimerate, maleated Soybean oil, octyl palmitate, cetyl 0160 In one or more embodiments there is provided a lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lano foamable composition, wherein the polymeric agent is lin alcohol, cetyl acetate, phenyl trimethicone, glyceryl selected from the group consisting of locust bean gum, oleate, tocopheryl linoleate, wheat germ glycerides, Sodium alginate, Sodium caseinate, egg albumin, gelatin arachidyl propionate, myristyl lactate, decyl oleate, ricino agar, carrageenin gum, Sodium alginate, Xanthan gum, leate, isopropyl lanolate, pentaerythrityl tetrastearate, neo quince seed extract, tragacanth gum, guar gum, cationic pentylglycol dicaprylate/dicaprate, isononyl isononanoate, guars, hydroxypropyl guar gum, starch, an amine-bearing isotridecyl isononanoate, myristyl myristate, triisocetyl cit polymer, chitosan, alginic acid, hyaluronic acid, a chemi rate, octyl dodecanol, unsaturated or polyunsaturated oils, cally modified Starch, a carboxyvinyl polymer, polyvi Such as olive oil, corn oil, Soybean oil, canola oil, cottonseed nylpyrrolidone, polyvinyl alcohol, a polyacrylic acid poly oil, coconut oil, sesame oil, Sunflower oil, borage seed oil, mer, a polymethacrylic acid polymer, polyvinyl acetate, a syZigium aromaticum oil, hempseed oil, herring oil, cod polyvinyl chloride polymer, a polyvinylidene chloride poly liver oil, Salmon oil, flaxseed oil, wheat germ oil, evening mer, methylcellulose, hydroxypropyl cellulose, hydroxypro primrose oils; essential oils; and silicone oils, such as pyl methylcellulose, hydroxyethyl cellulose, hydroxy pro dimethicone, cyclomethicone, polyalkyl siloxane, polyaryl pylmethyl cellulose, methylhydroxyethylcellulose, siloxane, polyalkylaryl siloxane, a polyether siloxane methylhydroxypropylcellulose, hydroxyethylcarboxymeth copolymer and a poly(dimethylsiloxane)-(diphenyl-silox ylcellulose, carboxymethyl cellulose, carboxymethylcellu ane) copolymer. lose carboxymethylhydroxyethylcellulose, a cationic cellu lose PEG 1000, PEG 4000, PEG 6000 and PEG 8000 of 0.165. In one or more embodiments there is provided a Carbopol.R. 934, Carbopol R 940, Carbopol.R. 941, Car foamable composition, further comprising a foam adjuvant bopol R 980, Carbopol R 981. hydroxypropylcellulose and selected from the group consisting of a fatty alcohol, a fatty carbomer. acid and a hydroxyl fatty acid or liquid wax. 0166 In one or more embodiments there is provided a 0161 In one or more embodiments there is provided a foamable composition, further comprising an additional foamable composition, wherein the polymeric agent is dis component selected from the group consisting of an anti persible in the polyol or in the mixture of a polyol and an perspirant, an anti-static agent, a buffering agent, a bulking additional polar solvent. agent, a chelating agent, a colorant, a conditioner, a deodor 0162. In one or more embodiments there is provided a ant, a diluent, a dye, an emollient, fragrance, a humectant, an foamable composition, wherein the Surface active agent is occlusive agent, a penetration enhancer, a perfuming agent, US 2008/0069779 A1 Mar. 20, 2008 a permeation enhancer, a pH-adjusting agent, a preservative, 0188 iv. a propellant at a concentration of about a skin penetration enhancer, a Sunscreen, a Sun blocking 3% to about 25% by weight of the total compo agent, and a Sunless tanning agent. sition, 0167. In one or more embodiments there is provided a 0189 where said foamable carrier reduces the destabiliz foamable composition, further comprising at least one addi ing effect of water on the vitamin, and tional therapeutic agent in addition to the vitamin, and or 0.190 wherein the composition is contained in a pressur flavanoid, a derivative thereof or combinations thereof in a ized container, is substantially flowable and provides a foam therapeutically effective concentration. upon release. 0168 In one or more embodiments there is provided a foamable composition, wherein the vitamin and or flavonoid 0191 In one or more embodiments there is provided a or derivative thereof or combinations thereof are loaded into method, wherein the target site is selected from the group microSponges. consisting of the skin, a body cavity, a mucosal Surface, the nose, the mouth, the eye, the ear canal, the respiratory 0169. In one or more embodiments there is provided a system, the vagina and the rectum. method of treating a disorder or condition of mammalian Subject, comprising: 0.192 In one or more embodiments there is provided a method, wherein the disorder is selected from the group 0170 administering a foam produced by release of a consisting of dermatological pain, dermatological inflam foamable vitamin and flavonoid composition from a pres mation, acne, acne Vulgaris, inflammatory acne, non-inflam Surized canister to a target site, the composition comprising: matory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal 0171 a. a vitamin and/or flavonoid; and skin infections, viral skin infections, parasitic skin infec 0172 b. a substantially non-aqueous carrier, the carrier tions, skin neoplasia, skin neoplasms, pruritis, cellulitis, comprising acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing Subcutaneous infections, Scalded skin 0173 i. about 50% to about 98% of a polar solvent syndrome, folliculitis, furuncles, hidradenitis Suppurativa, Selected from the group consisting of polyols and carbuncles, paronychial infections, rashes, erythrasma, polyethylene glycols (PEGs); impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, post-operative or 0174 ii. 0% to about 48% of a secondary polar solvent; post-Surgical skin conditions, Scabies, pediculosis, creeping 0.175 iii. a surface-active agent or foam adjuvant; eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, 0176) iv. 0% to about 5% by weight of at least one erythema nodosum, grannuloma annulare, epidermal polymeric agent; necrolysis, Sunburn, photosensitivity, pemphigus, bullous pemphigoid, dermatitis herpetiformis, keratosis pilaris, cal 0.177 v. 0% to about 5% of a conservation agent; and louses, corns, ichthyosis, skin ulcers, ischemic necrosis, 0.178 vi. a proppropellant at a concentration of about 3% to miliaria, hyperhidrosis, moles, Kaposi's sarcoma, mela about 25% by weight of the total composition. noma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact dermatitis, 0179. In other embodiments, a method of treating a atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, disorder or condition of mammalian Subject, includes: baldness, alopecia, Behcet’s syndrome, cholesteatoma, Der cum disease, ectodermal dysplasia, gustatory Sweating, nail 0180 administering a foam produced from a foamable patella syndrome, lupus, hives, hair loss, Hailey-Hailey Vitamin and or flavonoid composition to a target site, the disease, chemical or thermal skin burns, Scleroderma, aging composition comprising: skin, wrinkles, Sun spots, necrotizing fasciitis, necrotizing 0181 a foamable composition comprising a stabilized myositis, gangrene, Scarring, and vitiligo, chlamydia infec Vitamin, comprising: tion, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vagi 0182 a therapeutically effective amount of a water nosis, candidiasis, chancroid, granuloma Inguinale, lym unstable vitamin; phogranloma Venereum, mucopurulent cerviciitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU). 0183) an optional flavonoid; and trichomoniasis, Vulvar disorders, Vulvodynia, Vulvar pain, a foamable carrier comprising: yeast infection, Vulvar dystrophy, Vulvar intraepithelial neo 0184 plasia (VIN), contact dermatitis, pelvic inflammation, 0185 i. water; endometritis, Salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer of the Vulva, cancer of the vagina, 0186 ii. a foam stabilizer selected from the group vaginal dryness, dyspareunia, anal and rectal disease, anal consisting of at least one surface-active agent; at abscess/fistula, anal cancer, anal fissure, anal warts, Crohn's least one polymeric agent selected from the group disease, hemorrhoids, anal itch, pruritus ani, fecal inconti consisting of a bioadhesive agent, a gelling agent, nence, constipation, polyps of the colon and rectum; and a film forming agent and a phase change agent and wherein the active agent is Suitable for treating said disorder. mixtures thereof 0193 In one or more embodiments there is provided a 0187 iii. about 0.005% to about 5% conserva method, wherein the at least one additional therapeutic agent tional agent; and is selected from the group consisting of active herbal US 2008/0069779 A1 Mar. 20, 2008 extracts, acaricides, age spot and keratose removing agents, group consisting of a polyene, natamycin, nystatin; an allergen, analgesics, local anesthetics, antiacne agents, anti allylamine, naftifine, terbinafine; an imidazole, bifonazole, allergic agents, antiaging agents, antibacterials, antibiotics, clotrimazole, econazole, fenticonazole, ketocanazole, antiburn agents, anticancer agents, antidandruff agents, anti miconazole, oxiconazole; a diazole, a triazoles, fluconazole, depressants, antidermatitis agents, antiedemics, antihista itraconazole, terconazole, tolnaftate, ciclopirox, undecylenic mines, antihelminths, antihyperkeratolyte agents, antiin acid, Sulbentine, griseofulvin, Amphotericin B, flucytosine flammatory agentS, antiirritants, antilipemics, (5FC), a morpholine compound, amorolfine, and the related antimicrobials, antimycotics, antiproliferative agents, anti oxidants, anti-wrinkle agents, antipruritics, antipsoriatic morpholines and analogs, derivatives and salts thereof, and agents, antirosacea agents antiseborrheic agents, antiseptic, any combination thereof at a therapeutically effective con antiswelling agents, antiviral agents, anti-yeast agents, centration. astringents, topical cardiovascular agents, chemotherapeutic 0.198. In one or more embodiments there is provided a agents, corticosteroids, dicarboxylic acids, disinfectants, method, wherein the antibacterial agent is selected from the fungicides, hair growth regulators, hormones, hydroxy group consisting of a beta-lactam antibiotic, an aminogly acids, immunosuppressants, immunoregulating agents, coside, an ansa-type antibiotic, an anthraquinone, an azole, insecticides, insect repellents, keratolytic agents, lactams, metals, metal oxides, mitocides, neuropeptides, non-steroi metronidazole, an antibiotic glycopeptide, a macrollide, dal anti-inflammatory agents, oxidizing agents, pediculi erythromycin, clindamycin, an antibiotic nucleoside, an cides, photodynamic therapy agents, retinoids, Sanatives, antibiotic peptide, polymyxin B, an antibiotic polyene, an Scabicides, self tanning agents, skin whitening agents, aso antibiotic polyether, an antibiotic quinolone, an antibiotic constrictors, vasodilators, wound healing agents and wart steroid, fucidic acid, mupirocin, chloramphenicol, a Sulfona COWS. mide, tetracycline, an antibiotic metal, silver, copper, Zinc, mercury, tin, lead, bismuth, cadmium, chromium, an oxi 0194 In one or more embodiments there is provided, dizing agent, iodine, iodate, a periodate, a hypochlorite, a wherein the at least one active agent is selected from the permanganate, a Substance that release free radicals and/or group consisting of alclometasone dipropionate, amcinafel, active oxygen, a cationic antimicrobial agent, a quaternary amcinafide, amcinonide, beclomethasone, beclomethasone ammonium compound, a biguanide, chlorohexidine, a dipropionate, betamethsone, betamethasone benzoate, triguanide, a bisbiguanide, a polymeric biguanide, a natu betamethasone dexamethasone-phosphate, dipropionate, rally occurring antibiotic compound and analogs, deriva betamethasone Valerate, budesonide, chloroprednisone, chlorprednisone acetate, clescinolone, clobetasol, clobetasol tives, salts, ions and complexes thereof. propionate, clobetasol Valerate, clobetaSone, clobetaSone 0199. In one or more embodiments there is provided a butyrate, clocortelone, cortisone, cortodoxone, craposone method, wherein the vitamin or at least one additional butyrate, desonide, desoxymethasone, dexamethasone, des therapeutic agent is unstable in the presence of water. oxycorticosterone acetate, dichlorisone, diflorasone diac etate, diflucortolone Valerate, difluorosone diacetate, diflur 0200. In one or more embodiments there is provided a prednate, fluadrenolone, flucetonide, flucloronide, method, comprising (1) at least one vitamin; and (2) at least fluclorolone acetonide, flucortine butylesters, fludroxy one additional therapeutic agent selected from the group of cortide, fludrocortisone, flumethasone, flumethasone piv an antifungal agent, an antimicrobial agent, an antiviral alate, flumethasone pivalate, flunisolide, fluocinolone, fluo agent, an anti-acne agent, an antipsoriasis agent, a kera cinolone acetonide, fluocinonide, fluocortin butyl, tolytic agent and an antiacne agent. fluocortolone, fluorometholone, fluosinolone acetonide, flu perolone, fluprednidene acetate, fluprednisolone hydrocor 0201 In one or more embodiments there is provided a tamate, fluradrenolone, fluradrenolone acetonide, flurandre method, wherein the additional therapeutic agent comprises nolone, fluticasone, halcinonide, halobetasol, a combination of (1) a corticosteroid; and (2) and active hydrocortisone, hydrocortisone acetate, hydrocortisone agent selected from the group of an anti-infective agent, an butyrate, hydrocortisone cyclopentylpropionate, hydrocorti antifungal agent, an antimicrobial agent, an antiviral agent, Sone Valerate, hydroxyltriamcinolone, medrysone, mepred an anti-acne agent, a retinoid, a vitamin D, a vitamin D3 nisone, alpha.-methyl dexamethasone, methylprednisolone, derivative, calcipotriol, calcitriol and antipsoriasis agent, a methylprednisolone acetate, mometaSone furoate, keratolytic agent, an anti-proliferative agent, an anti-cancer paramethasone, prednisolone, prednisone, pregnenolone, agent, a non-steroidal anti-inflammatory agent, an immuno progesterone, spironolactone, triamcinolone, triamcinolone modulator, an immunosuppressant and an anti-rosacea acetonide and derivatives, esters and salts thereof. agent. 0.195. In one or more embodiments there is provided a 0202) In one or more embodiments there is provided a method, wherein the at least one additional therapeutic agent method, wherein the additional therapeutic agent comprises is an anti-infective agent. a combination of (1) a keratolytic agent; and (2) and active 0196. In one or more embodiments there is provided a agent selected from the group of a corticosteroid, an anti method, wherein the at least one anti-infective agent is infective agent, an antifungal agent, an antimicrobial agent, selected from the group consisting of an antibiotic agent, an an antiviral agent, an anti-acne agent, a retinoid, a vitamin antibacterial agent, an antifungal agent, an agent that con D, a vitamin D3 derivative, calcipotriol, calcitriol and antip trols yeast, an antiviral agent and an antiparasitic agent. Soriasis agent, an anti-proliferative agent, an anti-cancer agent, a non-steroidal anti-inflammatory agent, an immuno 0197). In one or more embodiments there is provided a modulator, an immunosuppressant and an anti-rosacea method, wherein the antifungal agent is selected from the agent. US 2008/0069779 A1 Mar. 20, 2008

0203 According to one or more embodiments, the foam diol (e.g., 1,3-butanediol and 1,4-butenediol), butynediol, able vitamin and flavonoid carrier, comprises: pentanediol (e.g., pentane-1,2-diol, pentane-1,3-diol, pen tane-1,4-diol, pentane-1,5-diol, pentane-2,3-diol and pen 0204 a. about 50% to about 98% of a polar solvent tane-2,4-diol), hexanediol (e.g., hexane-1,6-diol hexane-2, Selected from the group consisting of (1) a polyol and 3-diol and hexane-2.56-diol), octanediol (e.g., 1.8- (2) a polyethylene glycol (PEG); octanediol), neopentyl glycol, 2-methyl-1,3-propanediol. 0205 b. 0% to about 48% of a secondary polar solvent; diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and dibutylene glycol. 0206 c. a surface-active agent; 0217. In one or more embodiments, the foamable carrier 0207 d. about 0.01% to about 5% by weight of at least contains at least one triol (a compound that contains three one polymeric agent; and hydroxy groups in its molecular structure), such as glycerin, 0208 e. a liquefied or compressed gas propellant at a butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol. concentration of about 3% to about 25% by weight of 0218. In one or more embodiments, the polyol is a the total composition. mixture of polyols. In one or more embodiments, the mix ture of polyols contains at least one diol and at least one triol. 0209 All % values are provided on a weight (w/w) basis. According to certain embodiments the ratio between the diol 0210. In one or more embodiments, the surface active and triol is between 9:1 and 1:1. agent ranges from about less than 0.1% upto about 15% or 0219. In one or more embodiments, part of mixture of upto about 20% by weight of composition depending on the polyols is a saccharide. Exemplary Saccharides include, but surfactant selected or preferably is about 0.2% to about 0.5% are not limited to monosaccharide, disaccharides, oligosac by weight of composition. charides and Sugar alcohols. 0211 Water, up to 25% of the composition, and more 0220 A monosaccharide is a simple sugar that cannot be preferably up to 10%, and optional ingredients are added to hydrolyzed to smaller units. Empirical formula is (CH2O)n complete the total mass to 100%. In certain cases, the and range in size from trioses (n=3) to heptoses (n=7). composition contains two active agents that require different Exemplary monosaccharide compounds are ribose, glucose, pH environments in order to remain stable. For example, fructose and galactose. corticosteroids are typically stable at acidic pH (they have a maximum stability at a pH of about 4-6) and vitamin D 0221) Disaccharides are made up of two monosaccha analogues are typically stable at basic pH (they have a rides joined together. Such as Sucrose, maltose and lactose. maximum stability at pH values above about 8). In other 0222 A Sugar alcohol (also known as a polyol, polyhy cases, the active agent degrades in the presence of water, and dric alcohol, or polyalcohol) is a hydrogenated form of therefore, in Such cases the present of water in the compo saccharide, whose carbonyl group (aldehyde or ketone, sition is not desirable. Thus, in certain preferred embodi reducing Sugar) has been reduced to a primary or secondary ments, the composition is substantially non-aqueous. hydroxyl group. They are commonly used for replacing Sucrose in foodstuffs, often in combination with high inten 0212. Upon release from an aerosol container, the foam sity artificial sweeteners to counter the low sweetness. Some able carrier forms an expanded foam suitable for the treat exemplary Sugar alcohols, which are Suitable for use are ment of an infected Surface and for topical administration to mannitol, sorbitol, xylitol, maltitol, lactitol. (Maltitol and the skin, a body Surface, a body cavity or a mucosal Surface. lactitol are not completely hydrogenated compounds—they Polar Solvent are a monosaccharide combined with a polyhydric alcohol). Mixtures of polyols, including (1) at least one polyol 0213. A “polar solvent' is an organic solvent, typically selected from a diol and a triol; and (2) a saccharide are soluble in both water and oil. Certain polar solvents, for contemplated. example propylene glycol and glycerin, possess the benefi Polyethylene Glycol cial property of a humectants. 0223) In an embodiment, the polar solvent consists of a 0214) The identification of a “polar solvent, as used polymerized ethylene glycol, namely polyethylene glycol, herein, is not intended to characterize the solubilization which is also termed “PEG”. Exemplary PEGs are provided capabilities of the solvent for any specific active agent or any in the following table. other component of the foamable composition. Rather, Such information is provided to aid in the identification of mate rials suitable for use as a part in the foamable compositions described herein. Av. Molecular Composition weight Appearance Melting point (C.) Polyol PEG 200 190-210 Oily liquid 0215. In an embodiment, the polar solvent is a polyol. A PEG 300 285-315 Oily liquid polyol is an organic Substance that contains at least two PEG 400 380-420 Oily liquid PEG 600 570-630 Oily liquid 17-22 hydroxy groups in its molecular structure. PEG 1 OOO 950-1050 Solid 35-40 0216) In one or more embodiments, the foamable carrier PEG 4OOO 3800-4400 Solid 53-58 contains at least one diol (a compound that contains two PEG 6000 5600-6400 Solid SS-60 hydroxy groups in its molecular structure). Examples of PEG 8000 7SOO-85OO Solid 58-65 diols include propylene glycol (e.g., 1,2-propylene glycol and 1,3-propylene glycol), butanediol (e.g., 1,2-butanediol. 0224 Thus, in an embodiment, the PEG is selected from 1,3-butanediol. 2,3-butanediol and 1,4-butanediol), butane the group consisting of PEG 200, PEG 300, PEG 400, PEG US 2008/0069779 A1 Mar. 20, 2008

600, PEG 1000, PEG 4000, PEG 6000, PEG 8000 and PEG isosorbide, diethylene glycol monoethyl ether, a liquid poly 10,000. The foamable carrier can contain a single PEG or a ethylene glycol and glycofurol. mixture of two or more PEGs. PEGs having molecular weight of more that about 1000 possess gelling properties: 0231. In certain embodiments, the foamable carrier con i.e., they increase the Viscosity of a composition. Therefore, tains (1) at least one polyol; and (2) dimethyl isosorbide. by combining PEGs with different molecular weights/melt 0232 Other Non limiting examples include dimethyl ing points, one can attain varying levels of flowability as isosorbide polyols, diethylene glycol, propylene glycol n-al desirable for the treatment of a given target site. Small kanols, terpenes, di-terpenes, tri-terpenes, limonene, ter amounts of high molecular weight PEG added to low pene-ol. 1-menthol, dioxolane, ethylene glycol, other gly molecular weight PEG can substantially add to the viscosity. cols, oleyl alcohol, alpha-hydroxy acids, Such as lactic acid Thus, the amount of high molecular weight PEG that may and glycolic acid, Sulfoxides, such as dimethylsulfoxide usefully be added to foamable compositions is such that the (DMSO), dimethylformanide, methyl dodecyl sulfoxide, composition remains flowable and does not form a block. dimethylacetamide, aZone (1-dodecylazacycloheptan-2- The concentration of the PEG should ideally be in a level one), 2-(n-nonyl)-1,3-dioxolane, alkanols, such as dialky that results in Viscosity, prior to filling of the composition lamino acetates, and admixtures thereof. In certain preferred into aerosol canisters, of less than 12,000 CPs, and more embodiments, the polar solvent is selected from the group preferably, less than 10,000 CPs. consisting of dimethyl isosorbide glycerol (glycerin), pro pylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, Secondary Polar Solvent lactic acid and glycolic acid. 0225 Optionally, a secondary polar solvent is added to 0233 Short chain alcohols, such as ethanol and propanol the foamable composition. The secondary polar solvent is are known as polar solvents, however, according to one or selected from a variety of organic solvents that are typically more embodiments, the composition is substantially alco miscible on both water and oil. Examples of polar solvent hol-free, i.e., free of short chain alcohols. Short chain that can be contained in the foamable carrier include dim alcohols, having up to 5 carbon atoms in their carbon chain ethyl isosorbide, tetrahydrofurfuryl alcohol polyethyleneg skeleton and one hydroxyl group, such as ethanol, propanol, lycol ether (glycofurol), DMSO, pyrrolidones, (such as isopropanol, butanol, iso-butanol, t-butanol and pentanol, N-Methyl-2-pyrrolidone and 1-Methyl-2-pyrrolidinone), are considered less desirable polar solvents due to their ethyl proxitol, dimethylacetamide (DMAc), PEG-type sur skin-irritating effect. factants and alpha hydroxy acids, such as lactic acid and glycolic acid. 0234 Thus, in certain embodiments, the composition is substantially alcohol-free and includes less than about 5% Solubilization and Penetration Enhancement final concentration of lower alcohols, preferably less than about 2%, more preferably less than about 1%. However, in 0226. In many cases, polyols, PEGs and polar solvents other embodiments, a short chain alcohol can be included in possess a high solubilizing power and thus, they can enable the composition, as long as the ratio between the short chain increased concentrations of an active agent. Polyols, PEGs alcohol and the polyol is less than 1:4 by weight. and polar solvents are also known for their skin penetration enhancement properties. These properties enable high drug Polymeric Agent bioavailability in the target area of treatment, resulting in an 0235. The composition contains a polymeric agent. The enhanced therapeutic effect. Occasionally, combinations of a presence of a polymeric agent can be necessary for or polyol, PEGs and a secondary polar solvent, exhibit an enhance the creation of foam, having fine bubble structure, increased permeability across the skin, as Suggested, for which does not readily collapse upon release from a pres example, in Eur J Pharm Biopharm. 1998 November; Surized aerosol can. The polymeric agent can serve to 46(3):265-71. stabilize the foam composition and to control drug residence in the target organ. Although it has been Surprisingly 0227 Thus, in one or more embodiments, the foamable observed that in compositions with very high oil or wax or carrier contains (1) at least one polar solvent, selected from fatty acid or fatty alcohol content the presence of polymeric a polyol (selected from a diol and a triol) and PEG; and (2) agent can decrease foam quality. Preferably, the polymeric at least one secondary polar solvent. agent is soluble or readily dispersible in the polyol; or in the 0228. In one or more embodiments, the foamable carrier mixture of a polyol and an additional polar solvent. contains (1) a mixture of at least two polyols; and (2) at least 0236 Non-limiting examples of polymeric agents that one secondary polar solvent. In additional embodiments, the are soluble or readily dispersible in propylene glycol are foamable carrier contains a mixture of at least one polyol Hydroxypropylcellulose and carbomer (homopolymer of and at least one PEG; yet in other embodiments the foamable acrylic acid is crosslinked with an allyl ether pentaerythritol, carrier contains (1) a mixture of at least one polyol and at an allyl ether of Sucrose, or an allyl ether of propylene, Such least one PEG and (2) at least one secondary polar solvent. as Carbopol.R. 934, Carbopol R 940, Carbopol.R. 941, Car 0229. According to certain embodiments the ratio bopol.R. 980 and Carbopol R 981. between the polyol and/or PEG and the secondary polar 0237 Other polymeric agents are suitable for use pro solvent is between 9:1 and 1:1. vided that they are soluble or readily dispersible in the 0230. In certain embodiments, the polyol is selected from polyol; or in the mixture of a polyol and an additional polar the group consisting of propylene glycol, hexylene glycol Solvent, on a case by case basis. and glycerin (and mixtures thereof); and the secondary polar 0238 Exemplary polymeric agents include, in a non Solvent is selected from the group consisting of dimethyl limiting manner, naturally-occurring polymeric materials, US 2008/0069779 A1 Mar. 20, 2008

Such as locust bean gum, sodium alginate, sodium caseinate, system is more appropriate is related to the vehicle and egg albumin, gelatin agar, carrageenin gum, Sodium algi intended purpose. In general terms a combination of Surfac nate, Xanthan gum, quince seed extract, tragacanth gum, tants is usually preferable where the vehicle is an emulsion. guar gum, cationic guars, hydroxypropyl guar gum, starch, In an emulsion environment a combination of Surfactants amine-bearing polymers such as chitosan; acidic polymers can be significant in producing breakable forms of good obtainable from natural Sources, such as alginic acid and quality. It has been further discovered that the generally hyaluronic acid; chemically modified Starches and the like, thought considerations for HLB values for selecting a sur carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl factant or Surfactant combination are not always binding for alcohol, polyacrylic acid polymers, polymethacrylic acid emulsions and that good quality foams can be produced with polymers, polyvinyl acetate polymers, polyvinyl chloride a surfactant or surfactant combination both where the HLB polymers, polyvinylidene chloride polymers and the like. values are in or towards the lipophilic side of the scale and 0239). Additional exemplary polymeric agents include where the HLB values are in or towards the hydrophilic side semi-synthetic polymeric materials such as cellulose ethers, of the scale. Surfactants also play a role in foam formation Such as methylcellulose, hydroxypropyl cellulose, hydrox where the foamable formulation is a single phase composi ypropyl methylcellulose, hydroxyethyl cellulose, hydroxy tion. propylmethyl cellulose, methylhydroxyethylcellulose, 0244. According to one or more embodiments the com methylhydroxypropylcellulose, hydroxyethylcarboxymeth position contains a single Surface active agent having an ylcellulose, carboxymethyl cellulose, carboxymethylcellu HLB value between about 2 and 9, or more than one surface lose carboxymethylhydroxyethylcellulose, and cationic cel active agent and the weighted average of their HLB values luloses pemulen and aluminum starch octenylsuccinate is between about 2 and about 9. Lower HLB values may in (ASOS). Polyethylene glycol, having molecular weight of certain embodiments be more applicable to water in oil 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and emulsions. PEG 10,000) also have gelling capacity and while they are 0245 According to one or more embodiments the com considered herein as “secondary polar solvents', as detailed position contains a single Surface active agent having an herein, they are also considered polymeric agents. HLB value between about 7 and 14, or more than one 0240. In one or more embodiments the polymeric agents surface active agent and the weighted average of their HLB have emulsifying properties. In certain preferred embodi values is between about 7 and about 14. Mid range HLB ments the polymeric agent is a derivatized hydrophilic values may in certain embodiments be more suitable for oil polymer with hydrophobic alkyl moieties. Other types that in water emulsions. may also a similar stabilizing effect are silicone copolymers 0246 According to one or more other embodiments the and derivatized starch ASOS. composition contains a single Surface active agent having an 0241 Mixtures of the above polymeric agents are con HLB value between about 9 and about 19, or more than one templated. surface active agent and the weighted average of their HLB values is between about 9 and about 19. In a waterless or 0242. The concentration of the polymeric agent should be substantially waterless environment a wide range of HLB selected so that the composition, after filling into aerosol values may be suitable. canisters, is flowable, and preferably can be shaken in the canister. In one or more embodiments, the concentration of 0247 Preferably, the composition contains a non-ionic the polymeric agent is selected Such that the viscosity of the Surfactant. Nonlimiting examples of possible non-ionic Sur composition, prior to filling of the composition into aerosol factants include a polysorbate, polyoxyethylene (20) sorbi tan monostearate, polyoxyethylene (20) Sorbitan canisters, is less than 12,000 CPs, and more preferably, less monooleate, a polyoxyethylene fatty acid ester, Myri 45. than 10,000 CPs. Myr 49, Myri 52 and Myri 59; a polyoxyethylene alkyl Surface Active Agent ether, polyoxyethylene cetyl ether, polyoxyethylene palmi 0243 The composition further contains a surface-active tyl ether, polyethylene oxide hexadecyl ether, polyethylene agent. Surface-active agents (also termed 'Surfactants”) glycol cetyl ether, Steareths such as Steareth 2, bril 21, bri include any agent linking oil and water in the composition, 721, brij 38, brij 52, brij 56 and brij W1, a sucrose ester, a in the form of emulsion. A surfactants hydrophilic/lipo partial ester of Sorbitol and its anhydrides, Sorbitan mono philic balance (HLB) describes the emulsifiers affinity laurate, Sorbitan monolaurate, a monoglyceride, a diglycer toward water or oil. HLB is defined for non-ionic surfac ide, isoceteth-20 and mono-, di- and tri-esters of Sucrose tants. The HLB scale ranges from 1 (totally lipophilic) to 20 with fatty acids. In certain embodiments, Suitable Sucrose (totally hydrophilic), with 10 representing an equal balance esters include those having high monoester content, which of both characteristics. Lipophilic emulsifiers form water have higher HLB values. in-oil (w/o) emulsions; hydrophilic Surfactants form oil-in 0248. In certain embodiments, surfactants are selected water (ofw) emulsions. The HLB of a blend of two emul which can provide a close packed Surfactant layer separating sifiers equals the weight fraction of emulsifier A times its the oil and water phases. To achieve Such objectives com HLB value plus the weight fraction of emulsifier B times its binations of at least two surfactants are selected. Preferably, HLB value (weighted average). In many cases a single they should be complex emulgators and more preferably Surfactant may suffice. In other cases a combination of two they should both be of a similar molecular type. For or more surfactants is desired. Reference to a surfactant in example, a pair of ethers like Steareth 2 and Steareth 21, or the specification can also apply to a combination of Surfac a pair of esters for example, PEG-40 stearate and polysor tants or a surfactant system. As will be appreciated by a bate 80. In certain circumstances POE esters cannot be used person skilled in the art which surfactant or surfactant and a combination of Sorbitan laurate and Sorbitan Stearate US 2008/0069779 A1 Mar. 20, 2008

or a combination of Sucrose Stearic acid ester mixtures and Sodium laurate may be used. All these combinations due to -continued their versatility and strength may also be used satisfactorily and effectively with solutions and with solid/crystalline Chemical name Product example name HLB Suspensions, although the amounts and proportion may be varied according to the formulation and its objectives as will PEG-40 oleate Crodet O40 (Croda) 17.4 be appreciated by a man of the art. PEG-45 Stearate Nikkol MYS-45 (Nikko) 18 PEG-50 Stearate Myri 53 >10 0249. It has been discovered also that by using a deriva PEG-1OO Stearate Myri 59, Arlacel 165 (ICI) 19 tized hydrophilic polymer with hydrophobic alkyl moieties as a polymeric emulsifier Such as pemulen it is possible to stabilize the emulsion better about or at the region of phase reversal tension. Other types of derivatized polymers like 0255 PEG-Fatty Acid Diester Surfactants: silicone copolymers, derivatized starch Aluminum Starch Octenylsuccinate (ASOS)/DRY-FLO AF Starch), and derivatized dexrin may also a similar stabilizing effect. Chemical name Product example name HLB PEG-4 dilaurate Mapeg RTM. 200 DL (PPG), 7 0250) A series of dextrin derivative surfactants prepared Kessco RTMPEG 20O DL by the reaction of the propylene glycol polyglucosides with (Stepan), LIPOPEG 2-DL (Lipo a hydrophobic oxirane-containing material of the glycidyl Chem.) ether are highly biodegradable. Hong-Rong Wang and PEG-4 distearate Kessco RTM. 200 5 DS (Stepan.Sub) Keng-Ming Chen, Colloids and Surfaces A: Physicochemi PEG-32 dioleate Kessco RTMPEG 1540 DO 15 cal and Engineering Aspects Volume 281, Issues 1-3, 15 Jun. (Stepan) 2006, Pages 190-193). PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series (Croda) >10 0251 Non-limiting examples of non-ionic surfactants PEG-20 glyceryl oleate Tagat RTM. O (Goldschmidt) >10 that have HLB of about 7 to about 12 include steareth 2 (HLB-4.9); glyceryl monostearate/PEG 100 stearate (AV HLB-11.2); stearate Laureth 4 (HLB-9.7) and cetomac 0256 Transesterification Products of Oils and Alcohols rogol ether (e.g., polyethylene glycol 1000 monocetyl ether). 0252) Non-limiting examples of preferred surfactants, which have a HLB of 4-19 are set out in the Table below: Chemical name Product example name HLB PEG-30 castor oil Emalex C-30 (Nihon Emulsion) 11 PEG-40 hydrogenated castor oil Cremophor RH 40 (BASF), 13 Croduret (Croda), Emulgin Surfactant HLB HRE 40 (Henkel) steareth 2 ~4.9 glyceryl monostearate/PEG 100 stearate Av -11.2 Glyceryl Stearate ~4 0257 Polyglycerized Fatty Acids, such as: Steareth-21 -15.5 peg 40 stearate ~16.9 polysorbate 80 -15 sorbitan Stearate ~4.7 laureth 4 --97 Chemical name Product example name LB Sorbitan monooleate (span 80) ~4.3 ceteareth 20 -15.7 Polyglyceryl-6 dioleate Caprol.RTM. 6G20 (ABITEC): 8.5 steareth 20 -15.3 PGO-62 (Calgene), PLUROL ceteth 20 -15.7 OLEIQUE CC 497 Macrogol Cetostearyl Ether -15.7 (Gattefosse)Hodag ceteth 2 (Lipocol C-2) --53 PEG-30 Dipolyhydroxystearate --55 sucrose distearate (Sisterna SP30) -6 polyoxyethylene (100) stearate ~18.8 0258 PEG-Sorbitan Fatty Acid Esters

0253 More exemplary stabilizing surfactants which may Chemical name Product example name HLB be suitable for use are found below. PEG-20 Sorbitan Tween-20 (Atlas/ICI), Crillet 1 17 monolaurate (Croda), DACOL MLS 20 0254 PEG-Fatty Acid Monoester Surfactants (Condea) PEG-20 Sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 Monopalmitate (Croda) PEG-20 Sorbitan Tween-60 (Atlas/ICI), Crillet 3 15 Chemical name Product example name HLB nonOStearate (Croda) PEG-20 Sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 PEG-30 Stearate Myri 51 >10 monooleate (Croda) PEG-40 laurate Crodet L40 (Croda) 17.9 US 2008/0069779 A1 Mar. 20, 2008 13

0259 Polyethylene Glycol Alkyl Ethers mulen (TR1 or TR2); liquid crystal systems, such as Arla tone (2121), Stepan (Mild RM1), Nikomulese (41) and Montanov (68) and the like. Chemical name Product example name HLB 0264. In certain embodiments the surfactant is preferably one or more of the following: a combination of steareth-2 PEG-2 oleyl ether oleth-2 Brij92/93 (Atlas/ICI) 4.9 PEG-3 oleyl ether oleth-3 Volpo 3 (Croda) &10 and Steareth-21 on their own or in combination with glyceryl PEG-5 oleyl ether oleth-5 Volpo 5 (Croda) &10 monostearate (GMS); in certain other embodiments the PEG-10 oleyl ether oleth-10 Volpo 10 (Croda), Brij 12 surfactant is a combination of polysorbate 80 and PEG-40 96/97 (Atlas/ICI) Stearate. In certain other embodiments the Surfactant is a PEG-20 oleyl ether oleth-20 Volpo 20 (Croda), Brij 15 combination of glyceryl monostearate/PEG 100 stearate. In 98/99 (Atlas/ICI) PEG-4 lauryl ether laureth-4Brij 30 (Atlas/ICI) 9.7 certain other embodiments the Surfactant is a combination of PEG-23 lauryl ether laureth-23Brij 35 (Atlas/ICI) 17 two or more of stearate 21, PEG 40 stearate, and polysorbate PEG-10 stearyl ether Brij 76 (ICI) 12 80. In certain other embodiments the surfactant is a combi PEG-2 cetyl ether Brij 52 (ICI) 5.3 nation of two or more of laureth 4, span80, and polysorbate 80. In certain other embodiments the surfactant is a combi nation of two or more of GMS and ceteareth. In certain other 0260 Sugar Ester Surfactants embodiments the Surfactant is a combination of two or more of steareth 21, ceteareth 20, ceteth 2 and laureth 4. In certain other embodiments the Surfactant is a combination of cet eareth 20 and polysorbate 40 stearate. In certain other Chemical name Product example name HLB embodiments the Surfactant is a combination of span 60 and Sucrose distearate Sisterna SP50, Surfope 1811 11 GMS. 0265. In certain other embodiments the surfactant is one or more of Sucrose Stearic acid esters, Sorbitan laureth, and 0261 Sorbitan Fatty Acid Ester Surfactants Sorbitan Stearate. 0266. In one or more embodiments the stability of the composition can be improved when a combination of at least Chemical name Product example name HLB one non-ionic surfactant having HLB of less than 9 and at Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 8.6 least one non-ionic Surfactant having HLB of equal or more (Croda), Arlacel 20 (ICI) than 9 is employed. The ratio between the at least one Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 6.7 non-ionic surfactant having HLB of less than 9 and the at (Croda), Nikkol SP-10 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 4.3 least one non-ionic Surfactant having HLB of equal or more (Croda), Crill 50 (Croda) than 9, is between 1:8 and 8:1, or at a ratio of 4:1 to 1:4. The Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 4.7 resultant HLB of such a blend of at least two emulsifiers is (Croda), Nikkol SS-10 (Nikko) preferably between about 9 and about 14. 0267 Thus, in an exemplary embodiment, a combination 0262. In one or more embodiments the surface active of at least one non-ionic Surfactant having HLB of less than agent is a complex emulgator in which the combination of 9 and at least one non-ionic Surfactant having HLB of equal two or more surface active agents can be more effective than or more than 9 is employed, at a ratio of between 1:8 and 8:1, a single surfactant and provides a more stable emulsion or or at a ratio of 4:1 to 1:4, wherein the HLB of the combi improved foam quality than a single Surfactant. For example nation of emulsifiers is preferably between about 5 and and by way of non-limiting explanation it has been found about 18. that by choosing say two Surfactants, one hydrophobic and 0268. In certain cases, the surface active agent is selected the other hydrophilic the combination can produce a more from the group of cationic, Zwitterionic, amphoteric and stable emulsion than a single surfactant. Preferably, the ampholytic Surfactants, such as sodium methyl cocoyl tau complex emulgator comprises a combination of Surfactants rate, Sodium methyl oleoyl taurate, Sodium lauryl Sulfate, wherein there is a difference of about 4 or more units triethanolamine lauryl sulfate and betaines. between the HLB values of the two surfactants or there is a 0269. Many amphiphilic molecules can show lyotropic significant difference in the chemical nature or structure of liquid-crystalline phase sequences depending on the Volume the two or more Surfactants. balances between the hydrophilic part and hydrophobic part. 0263 Specific non limiting examples of surfactant sys These structures are formed through the micro-phase seg tems are, combinations of polyoxyethylene alkyl ethers, regation of two Many amphiphilic molecules can show such as Brij 59/Brij 10: Brij 52/Brij 10; Steareth 2/Steareth lyotropic liquid-crystalline phase sequences depending on 20: Steareth 2/Steareth 21 (Brij 72/Brij 721); combinations the volume balances between the hydrophilic part and of polyoxyethylene stearates such as Myri 52/Myri 59: hydrophobic part. These structures are formed through the combinations of sucrose esters, such as Surphope 1816/ micro-phase segregation of two incompatible components Surphope 1807; combinations of sorbitan esters, such as on a nanometer scale. Soap is an everyday example of a Span 20/Span 80: Span 20/Span 60; combinations of sucrose lyotropic liquid crystal. Certain types of Surfactants tend to esters and Sorbitan esters, such as Surphope 1811 and Span form lyotropic liquid crystals in emulsions interface (oil-in 60; combinations of liquid polysorbate detergents and PEG water) and exert a stabilizing effect. compounds, such as Tween 80/PEG-40 stearate; methyl 0270. In one or more embodiments the surfactant is a glucaso sequistearate; polymeric emulsifiers, such as Per Surfactant or Surfactant combination is capable of or which US 2008/0069779 A1 Mar. 20, 2008

tends to form liquid crystals. Surfactants which tend to form and polymeric agents which have high molecular weight and liquid crystals may improve the quality of foams. Non are very viscous or solid or waxy (e.g., Peg 1500, 2000, etc. limiting examples of Surfactants with postulated tendency to or petrolatum) can exacerbate the effect of a waxy or solid form interfacial liquid crystals are: phospholipids, alkyl Surfactant on shakability or flowability In general terms, as glucosides, Sucrose esters, Sorbitan esters. the amount of non-liquid Surfactant is increased the shak ability of the formulation reduces until a limitation point is 0271 In one or more embodiments the at least one reached where the formulation becomes non shakable and Surface active agent is liquid. unsuitable. Thus in one embodiment, an effective amount of 0272. In one or more embodiments the at least one Surfactant may be used provided the formulation remains Surface active agent is solid, semi solid or waxy. shakable. In other certain exceptional embodiments the upper limit may be determined by flowability such as in 0273. It should be noted that HLB values may not be so circumstances where the composition is marginally or applicable to non ionic Surfactants, for example, with liquid apparently non-shakable. The formulation is sufficiently crystals or with silicones. Also HLB values may be of lesser flowable to be able to flow through an actuator valve and be significance in a waterless or Substantially non-aqueous released and still expand to form a good quality foam. environment. 0279. In certain embodiments, the amount of surfactant 0274. In one or more embodiments the surfactant can be, or combination of surfactants is between about 0.05% to a Surfactant system comprising of a surfactant and a co about 20%; between about 0.05% to about 15%. or between Surfactant, a waxy emulsifier, a liquid crystal emulsifier, an about 0.05% to about 10%. In a preferred embodiment the emulsifier which is solid or semi solid at room temperature concentration of surface active agent is between about 0.2% and pressure, or combinations of two or more agents in an and about 8%. In a more preferred embodiment the concen appropriate proportion as will be appreciated a person tration of surface active agent is between about 1% and skilled in the art. Where a solid or semi solid emulsifier about 6%. combination is used it can also comprise a solid or semi Solid emulsifier and a liquid emulsifier. 0280. In some embodiments, it is desirable that the sur face active agent does not contain a polyoxyethylene (POE) 0275. In one or more embodiments, the surface-active moiety, such as polysorbate surfactants, POE fatty acid agent includes at least one non-ionic Surfactant. Ionic Sur esters, and POE alkyl ethers, because the active agent is factants are known to be irritants. Therefore, non-ionic incompatible with such surface active agents. For example, surfactants are preferred in applications including sensitive the active agent pimecrolimus is not stable the presence of tissue Such as found in most mucosal tissues, especially POE moieties, yet benefits greatly from the use of dicar when they are infected or inflamed. Non-ionic surfactants boxylic esters as penetration enhancers. In Such cases, alone can provide formulations and foams of good or alternative surface active agents are employed. In an exem excellent quality in the carriers and compositions. plary manner, POE-free surfactants include non-ethoxylated 0276 Thus, in a preferred embodiment, the surface active Sorbitan esters, such as Sorbitan monopalmitate, Sorbitan agent, the composition contains a non-ionic Surfactant. In monostearate, Sorbitan tristearate, Sorbitan monooleate, Sor another preferred embodiment the composition includes a bitan trioleate, Sorbitan monolaurate and Sorbitan sesqui mixture of non-ionic Surfactants as the sole Surface active oleate; glycerol fatty acid esters, such as glycerol monostear agent. Yet, in additional embodiments, the foamable com ate and glycerol monooleate; mono-, di- and tri-esters of position includes a mixture of at least one non-ionic Surfac Sucrose with fatty acids (Sucrose esters). Sucrose Stearate, tant and at least one ionic Surfactant in a ratio in the range Sucrose distearate Sucrose palmitate and Sucrose laurate; and of about 100:1 to 6:1. In one or more embodiments, the alkyl polyglycosides, such as lauryl diglucoside. non-ionic to ionic Surfactant ratio is greater than about 6:1, 0281) If the composition as formulated is a substantially or greater than about 8:1; or greater than about 14:1, or non shakable composition it is nevertheless possible for the greater than about 16:1, or greater than about 20:1. In further formulation to be flowable to a sufficient degree to be able embodiments, Surface active agent comprises a combination to flow through an actuator valve and be released and still of a non-ionic Surfactant and an ionic Surfactant, at a ratio of expand to form a good quality foam. This Surprising and between 1:1 and 20:1. unusual exception may be due one or more of a number of 0277. In one or more embodiments, a combination of a factors such as the high viscosity, the softness, the lack of non-ionic Surfactant and an ionic Surfactant (such as sodium crystals, the pseudoplastic or semi pseudo plastic nature of lauryl Sulphate and cocamidopropylbetaine) is employed, at the composition and the dissolution of the propellant into the a ratio of between 1:1 and 20:1, or at a ratio of 4:1 to 10:1; composition. for example, about 1:1, about 4:1, about 8:1, about 12:1, 0282. In one or more embodiments, the surface-active about 16:1 and about 20:1 or at a ratio of 4:1 to 10:1, for agent includes mono-, di- and tri-esters of Sucrose with fatty example, about 4:1, about 6:1, about 8:1 and about 10:1. acids (sucrose esters), prepared from Sucrose and esters of 0278 In selecting a suitable surfactant or combination fatty acids or by extraction from sucro-glycerides. Suitable thereof it should be borne in mind that the upper amount of Sucrose esters include those having high monoester content. surfactant that may be used may be limited by the shakabil ity of the composition. If the Surfactant is non liquid, it can Phase Inversion and Tension make the formulation to viscous or solid. This can be 0283 Phase inversion is a factor in the preparation and particularly significant if the formulation has high molecular stabilization of emulsions and can be both an aid and a weight, e.g., a high molecular weight PEG or polymeric detriment. Phase inversion involves the change of emulsion agents or petroleum or if the Surfactants are large. Solvents type from of w to w/o or vice versa. Prior to phase inversion US 2008/0069779 A1 Mar. 20, 2008

occurring there is a tension in the emulsion which if desta Breakability bilized or driven will lead to phase inversion and if con trolled or ameliorated or dissipated will result in a more 0288 A breakable foam is one that is thermally stable, yet stable emulsion. The occurrence of phase inversion during breaks under sheer force. preparation can be a sign of instability. If controlled, it can 0289. The breakable foam, described according to one or result in a finer product but if due to other factors after the more embodiments, is not "quick breaking’, i.e., it does not emulsion was prepared it can cause problems. Inversion can readily collapse upon exposure to body temperature envi occur by for example adding calcium chloride to an ofw ronment. Sheer-force breakability of the foam is clearly emulsion stabilized with sodium stearate to form calcium advantageous over thermally induced breakability, since it Stearate. Inversion can also occur as the product of changes allows comfortable application and well directed adminis to the phase-volume ratio. For example if a small amount of tration to the target area. water is added to Surfactant mixed with oil and agitated aw?o emulsion is formed AS the amount of water added is gradu Modulating Agent ally increased a point will be reached where the water and 0290 The term modulating agent is used to describe an emulsifier envelop the oil as small droplets to form an ofw agent which can improve the stability of or stabilize a emulsion. The amount of each ingredient including the foamable carrier or composition and or an active agent by Surfactants will have their part to play in the phenomenon. modulating the effect of a Substance or residue present in the Substantially Alcohol-Free carrier or composition. 0284. According to one or more embodiments, the foam 0291. In one or more embodiments the modulating agent able composition is substantially alcohol-free, i.e., free of is used in a water in oil or oil in water emulsion. In one or short chain alcohols. Short chain alcohols, having up to 5 more other embodiments the modulating agent is used in a carbon atoms in their carbon chain skeleton and one unique waterless emulsion. hydroxyl group. Such as ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol, are consid 0292. In certain embodiments, the substance or residue ered less desirable solvents or polar solvents due to their may for example be acidic or basic and potentially alter pH skin-irritating effect. Thus, the composition is Substantially in an emulsion environment or it may be one or more metal alcohol-free and includes less than about 5% final concen ions which may act as a potential catalyst in an emulsion tration of lower alcohols, preferably less than about 2%, environment. more preferably less than about 1%. 0293. In certain other embodiments, the substance or Substantially Non Aqueous residue may for example be acidic or basic and potentially alter an artificial pH in a waterless or substantially non 0285) In certain cases, the active agent degrades in the aqueous environment or it may be one or more metal ions presence of water, and therefore, in Such cases the present of which may act as a potential catalyst in a waterless or water in the composition is not desirable. Thus, in certain Substantially non aqueous environment. preferred embodiments, the composition is substantially non-aqueous. The term 'substantially non-aqueous” or 'sub 0294. In one or more embodiments, the modulating agent stantially waterless” is intended to indicate that the compo is used to describe an agent which can affect pH in an sition has a water content below about 5%, preferably below aqueous solution. The agent can be any of the known about 2%, such as below about 1.5%. In certain other buffering systems used in pharmaceutical or cosmetic for preferred embodiments the composition is non aqueous or mulations as would be appreciated by a man of the art. It can waterless. also be an organic acid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid 0286 By non aqueous or waterless is meant that the an organic base or a nitrogen containing compound. composition contains no or Substantially no, free or unas sociated or absorbed water. It will be understood by a person 0295). In one or more further embodiments, the modulat of the art that the waterless solvents and substances miscible ing agent is used to describe an agent, which is a chelating with them can be hydrophilic and can contain water in an or sequestering or complexing agent that is sufficiently associated or unfree or absorbed form and may absorb water soluble or functional in the solvent to enable it to “mop up' from the atmosphere and the ability to do so is its hygro or “lock' metal ions. scopic water capacity. It is intended that essentially non 0296. In an embodiment, modulating agent is used to aqueous formulations are included within its scope such that describe an agent which can effect pH in an aqueous solution the formulations may have present a small amount of water. the term modulating agent more particularly means an acid In some embodiments the composition ingredients are pre or base or buffer system or combinations thereof, which is treated to reduce, remove or eliminate any residual or introduced into or is present in and acts to modulate the ionic associated or absorbed water. or polar characteristics and any acidity or basicity balance of Shakability an emulsion carrier, composition, foamable carrier or foam 0287 Shakability means that the composition contains able composition or resultant foam. some or sufficient flow to allow the composition to be mixed 0297. In other embodiments, modulating agent is used to or remixed on shaking. That is, it has fluid or semi fluid describe an agent which can effect pH in an aqueous solution properties. In some very limited cases possibly aided by the the term modulating agent more particularly means an acid presence of silicone it may exceptionally be possible to have or base or buffer system or combinations thereof, which is a foamable composition which is flowable but not appar introduced into or is present in and acts to modulate the ionic ently shakable. or polar characteristics and any acidity or basicity balance of US 2008/0069779 A1 Mar. 20, 2008

a waterless or Substantially non aqueous carrier, composi hydroxide ions. In contrast, a weak base is one which does tion, foamable carrier or foamable composition or resultant not convert fully into hydroxide ions in solution. The lower foam. the value for pKb, the stronger is the base and likewise, the 0298 The substance or residue can be introduced into the higher the value for pKb the weaker is the base. formulation from any one or more of the ingredients, some 0305. In one or more embodiments, the modulating agent of which themselves may have acidic or basic properties. comprises an organic compound. For example the polymer or solvent may contain basic residues in which case it may be desirable or beneficial to 0306 In one or more preferred embodiments the chelat add an acid. Alternatively the Surfactant may contain some ing agent is selected from the group consisting of ethylene acid residues in which case the addition of a base may be diaminetetraacetic acid (EDTA), diethylenetriaminepen desirable and beneficial. In some cases more than one taacetic acid (DTPA), hydroxyethylenediaminetriacetic acid ingredient may contain residues which may ameliorate or (HEDTA), nitrilotriacetic acid (NTA), O.O'-bis(2-aminoet compound their significance. For example if one ingredient hyl)ethyleneglycol-N.N.N',N'-tetraacetic acid (EGTA), provided weak acid residues and another stronger acid trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid residues the pH in an emulsion environment (or artificial pH (CyDTA) or a pharmaceutically acceptable salt thereof (nor in a waterless environment) should be lower. In contrast if mally as a sodium salt), more preferably EDTA, HEDTA and one residue was acid and the other basic the net effect in the their salts; most preferably EDTA and its salts. formulation maybe significantly reduced. In some circum 0307 In one or more embodiments, a preferred non stances the active ingredient may favoran acidic pH or more limiting example of the chelating agent is EDTA. Typically, significantly may need to be maintained at a certain acidic the chelating and sequestering agent is present in the com pH otherwise it may readily isomerize, chemically react or position at a level of up to about 5.0%, preferably 1.0 breakdown, in which case introducing acidic components percent, by weight, of the composition. Such as an acidic polymer might be of help. In an embodi ment Sufficient modulating agent is added to achieve a pH in 0308. In one or more embodiments, the modulating agent which the active agent is preferably stable. In another may also be a preservative or an antioxidant or an ionization embodiment Sufficient modulating agent is added to achieve agent. Any preservative, antioxidant or ionization agents an artificial pH in which the active agent is preferably stable. Suitable for pharmaceutical or cosmetic application may be used. Non limiting examples of antioxidants are tocopherol 0299) The terms pH, pKa, and pKb, buffers and the like Succinate, propyl galate, butylated hydroxy toluene and are used in classical measurements of an aqueous solution. butyl hydroxy anisol. Ionization agents may be positive or Such measurements are artificial in a waterless environment. may be negative depending on the environment and the Nevertheless, reference to and description below of such active agent or composition that is to be protected. Ioniza terms are made for convenience and clarity, since Such terms tion agents may for example act to protect or reduce sensi are well defined and understood with reference to aqueous tivity of active agents. Non limiting examples of positive Solutions and further due to the lack of an appropriate ionization agents are benzyl conium chloride, and cetyl uniform way of describing and identifying the artificial or pyridium chloride. Non limiting examples of negative ion virtual pH, pK etc in a waterless environment in relation to ization agents are sodium lauryl Sulphate, Sodium lauryl the present invention. Although predictions of artificial pH lactylate and phospholipids. can be made using dilution techniques of measurements of waterless formulations diluted in water they are formulation Hydrophobic Solvent sensitive and specific and have to be carefully calibrated 0309 Optionally, the foamable carrier further contains at with complex formulas. least one hydrophobic solvent. The identification of a 0300 Waterless medium can be polar and protic yet it “hydrophobic solvent, as used herein, is not intended to does not conform to classical ionic behavior. characterize the solubilization capabilities of the solvent for any specific active agent or any other component of the 0301) A buffer, as defined by Van Slyke Van Slyke, J. foamable composition. Rather, such information is provided Biol. Chem. 52, 525 (1922), is “a substance which by its to aid in the identification of materials suitable for use as a presence in Solution increases the amount of acid or alkali that must be added to cause unit change in pH.” part in the foamable compositions described herein. 0302) A buffer solution is a solution of a definite pH made 0310. A “hydrophobic solvent as used herein refers to a up in Such a way that this pH alters only gradually with the material having solubility in distilled water at ambient addition of alkali or acid. Such a solution consists of a temperature of less than about 1 gm per 100 mL, more solution of a salt of the week acid in the presence of the three preferable less than about 0.5gm per 100 mL, and most acid itself. The pH of the solution is determined by the preferably less than about 0.1 gm per 100 mL. dissociation equilibrium of the free acid. 0311. In one or more embodiments, the hydrophobic organic carrier is an oil. Such as mineral oil, isopropyl 0303 An acid can be a strong acid or a weak acid. A palmitate, isopropyl isostearate, diisopropyl adipate, diiso strong acid is an acid, which is a virtually 100% ionized in propyl dimerate, maleated Soybean oil, octyl palmitate, cetyl Solution. In contrast, a week acid is one which does not lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lano ionize fully. When it is dissolved in water. The lower the lin alcohol, cetyl acetate, phenyl trimethicone, glyceryl value for pKa, the stronger is the acid and likewise, the oleate, tocopheryl linoleate, wheat germ glycerides, higher the value for pKa the weaker is the acid. arachidyl propionate, myristyl lactate, decyl oleate, propy 0304. A base can be a strong base or a weak base. A lene glycol ricinoleate, isopropyl lanolate, pentaerythrityl strong base is something, which is fully ionic with 100% tetraStearate, neopentylglycol dicaprylate/dicaprate, US 2008/0069779 A1 Mar. 20, 2008

isononyl isononanoate, isotridecyl isononanoate, myristyl agents include but are not limited to acetic acid, adipic acid, myristate, triisocetyl citrate, octyl dodecanol, unsaturated or calcium hydroxide, citric acid, glycine, hydrochloric acid, polyunsaturated oils, such as olive oil, corn oil, soybean oil, lactic acid, magnesium aluminometasilicates, phosphoric canola oil, cottonseed oil, coconut oil, sesame oil, Sunflower acid, sodium carbonate, sodium citrate, sodium hydroxide, oil, borage seed oil, SyZigium aromaticum oil, hempseed oil, Sorbic acid, Succinic acid, tartaric acid, and derivatives, salts herring oil, cod-liver oil, Salmon oil, flaxseed oil, wheat and mixtures thereof. germ oil, evening primrose oils; essential oils; and silicone oils, such as dimethicone, cyclomethicone, polyalkyl silox 0317. In an embodiment, the additional component is an anes, polyaryl siloxanes, polyalkylaryl siloxanes and poly emollient. Suitable emollients include but are not limited to ether siloxane copolymers, polydimethylsiloxanes (dimethi mineral oil, lanolin oil, coconut oil, cocoa butter, olive oil, cones) and poly(dimethylsiloxane)-(diphenyl-siloxane) aloe Vera extract, jojoba oil, castor oil, fatty acids, fatty copolymers. alcohols, diisopropyl adipate, hydroxybenzoate esters, ben Zoic acid esters of C9 to C15 alcohols, isononyl iso Foam Adjuvant nonanoate, silicone oils, polyethers, C12 to C15 alkylben 0312 Optionally, a foam adjuvant is included in the Zoates, oleic acid, Stearic fatty acid, cetyl alcohols, foamable carriers to increase the foaming capacity of Sur hexadecyl alcohol, dimethyl polysiloxane, polyoxypropy factants and/or to stabilize the foam. In one or more embodi lene cetyl ether, polyoxypropylene butyl ether, and deriva ments, the foam adjuvant agent includes fatty alcohols tives, esters, salts and mixtures thereof. having 15 or more carbons in their carbon chain, such as 0318. In an embodiment, the additional component is a cetyl alcohol and stearyl alcohol (or mixtures thereof). Other humectant, a Substance that helps retain moisture and also examples of fatty alcohols are arachidyl alcohol (C20), prevents rapid evaporation. Suitable humectants include but behenyl alcohol (C22), 1-triacontanol (C30), as well as are not limited to guanidine, urea, glycolic acid, glycolate alcohols with longer carbon chains (up to C50). Fatty salts, ammonium glycolate, quaternary alkyl ammonium alcohols, derived from beeswax and including a mixture of glycolate, lactic acid, lactate salts, ammonium lactate, qua alcohols, a majority of which has at least 20 carbon atoms ternary alkyl ammonium lactate, aloe Vera, aloe Vera gel. in their carbon chain, are especially well Suited as foam allantoin, urazole, alkoxylated glucose, hyaluronic acid, adjuvant agents. The amount of the fatty alcohol required to lactamide monoethanolamine, acetamide monoethanola Support the foam system is inversely related to the length of mine and derivatives, esters, salts and mixtures thereof. its carbon chains. Foam adjuvants, as defined herein are also Other non limiting examples are propylene glycol, propy useful in facilitating improved spreadability and absorption lene glycol derivatives, glycerin, hydrogenated Starch of the composition. hydrosylate, hydrogenated lanolin, lanolin wax, D manitol, 0313. In one or more embodiments, the foam adjuvant Sorbitol, Sodium 2-pyrrolidone-5-carboxylate, Sodium lac agent includes fatty acids having 16 or more carbons in their tate, sodium PCA, soluble collagen, dibutyl phthalate, and carbon chain, Such as hexadecanoic acid (C16) Stearic acid gelatin. Additional examples may be found in the Handbook (C18), arachidic acid (C20), behenic acid (C22), octa of Pharmaceutical Additives published by Gower. cosanoic acid (C28), as well as fatty acids with longer carbon chains (up to C50), or mixtures thereof. As for fatty 0319. In an embodiment, the additional component is a alcohols, the amount of fatty acids required to Support the moisturizer, is a Substance that helps retain moisture or add foam system is inversely related to the length of its carbon back moisture to the skin. Examples are allantoin, petrola tum, urea, lactic acid, Sodium PCV, glycerin, shea butter, chain. caprylic/capric/stearic triglyceride, candelilla wax, propy 0314 Optionally, the carbon atom chain of the fatty lene glycol, lanolin, hydrogenated oils, squalene, sodium alcohol or the fatty acid may have at least one double bond. hyaluronate and lysine PCA. Other examples may be found A further class of foam adjuvant agent includes a branched in the Handbook of Pharmaceutical Additives published by fatty alcohol or fatty acid. The carbon chain of the fatty acid Gower. or fatty alcohol also can be substituted with a hydroxyl group, such as 12-hydroxy Stearic acid. 0320 Pharmaceutical compositions may in one or more embodiments usefully comprise in addition a heumectant or Additional Components a moisturizer or combinations thereof. 0315. In an embodiment, a composition includes one or more additional components. Such additional components 0321) In an embodiment the additional component is a include but are not limited to anti perspirants, anti-static conservational agent, which can be a preservative, quasi agents, buffering agents, bulking agents, conservational preservative or a modulating agent or combinations thereof agents, chelating agents, cleansers, colorants, conditioners, that can substantially conserve or stabilize the vitamin. By deodorants, diluents, dyes, emollients, fragrances, hair con substantially conserve or stabilize the vitamin is meant that ditioners, humectants, pearlescent aids, perfuming agents, it acts to inhibit, restrain or delay breakdown or reaction of permeation enhancers, pH-adjusting agents, preservatives, the vitamin in the carrier or foamable composition so that protectants, skin penetration enhancers, softeners, solubiliz most of the vitamin remains available for use in the foam ers, Sunscreens, Sun blocking agents, Sunless tanning agents, formulation. Viscosity modifiers, antioxidants like flavonoids and pheno 0322. In an embodiment, the additional component is a lics. AS is known to one skilled in the art, in some instances preservative. Suitable preservatives include but are not lim a specific additional component may have more than one ited to C12 to C15 alkyl benzoates, alkyl p-hydroxyben activity, function or effect. Zoates, aloe Vera extract, ascorbic acid, benzalkonium chlo 0316. In an embodiment, the additional component is a ride, benzoic acid, benzoic acid esters of C9 to C15 alcohols, pH adjusting agent or a buffering agent. Suitable buffering butylated hydroxytoluene, castor oil, cetyl alcohols, chloro US 2008/0069779 A1 Mar. 20, 2008 cresol, citric acid, cocoa butter, coconut oil, diazolidinyl 0333. In an embodiment of the present invention, the urea, diisopropyl adipate, dimethyl polysiloxane, DMDM additional component is a skin penetration enhancer. Suit hydantoin, ethanol, fatty acids, fatty alcohols, hexadecyl able skin penetration enhancers include but are not limited alcohol, hydroxybenzoate esters, iodopropynyl butylcar to acetone, acyl lactylates, acyl peptides, acylsarcosinates, bamate, isononyl iso-nonanoate, jojoba oil, lanolin oil, alkanolamine salts of fatty acids, alkylbenzene Sulphonates, methylparaben, mineral oil, oleic acid, olive oil, polyethers, alkyl ether Sulphates, alkyl Sulphates, anionic Surface-active polyoxypropylene butyl ether, polyoxypropylene cetyl ether, agents, benzyl benzoate, benzyl salicylate, butan-1,4-diol. potassium Sorbate, silicone oils, Sodium propionate, sodium butylbenzoate, butyl laurate, butyl myristate, butyl stearate, benzoate, sodium bisulfite, disodium metabisulfite, sorbic cationic Surface-active agents, citric acid, cocoamidopropy acid, Stearic fatty acid, vitamin E. Vitamin E acetate and 1betaine, decyl methyl sulfoxide, decyl oleate, dibutyl aze derivatives, esters, salts and mixtures thereof. late, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl Suberate, dibutyl Succinate, dicapryl adipate, didecyl 0323 In an embodiment the preservative comprises an phthalate, diethylene glycol, diethyl sebacate, diethyl-m- antioxidant. toluamide, di(2-hydroxypropyl)ether, diisopropyl adipate, 0324. In one or more embodiments flavonoids, as strong diisopropyl sebacate, N,N-dimethyl acetamide, dimethyl antioxidants, may act as a quasi preservative of a vitamin in aZelate, N,N-dimethyl formamide, 1,5-dimethyl-2-pyrroli a formulation by, without being bound by any theory, being done, dimethyl sebacate, dimethyl Sulphoxide, dioctyl adi more reactive in a formulation than the vitamin or derivative pate, dioctyl azelate, dioctyl sebacate, 1.4 dioxane, 1-dode and thereby sparing the vitamin or derivative from reaction. cylazacyloheptan-2-one, dodecyl dimethyl amine oxides, As certain flavonoids can be water soluble and certain others ethyl caprate, ethyl caproate, ethyl caprylate, 2-ethyl-hexyl hydrophobic, they can be selected to offer protection both in pelargonate, ethyl-2-hydroxypropanoate, ethyl laurate, ethyl non-aqueous an in aqueous formulations. In a preferred myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl lau embodiment a combination of one or more water soluble rate, 2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, flavonoids with one or more hydrophobic flavonoids may be 2-hydroxypropionic acid, isethionates, isopropyl isostearate, used. For example, quercetin combined with roSmarinic isopropyl palmitate, guar hydroxypropyltrimonium chlo acid. ride, hexan-2,5-diol, khellin, lamepons, lauryl alcohol, may pons, metal salts of fatty acids, methyl nicotinate, 2-methyl 0325 In an embodiment the preservative comprises at propan-2-ol. 1-methyl-2-pyrrolidone, 5-methyl-2-pyrroli least disodium metabisulfite or a derivative. In a further done, methyl taurides, miranol, nonionic Surface-active embodiment it is used in combination with another preser agents, octyl alcohol, octylphenoxy polyethoxyethanol, Vative, and or a modulating agent and or a flavonoid oleic ethanolamide, pleyl alcohol, pentan-2,4-diol, phenoxy Sodium Metabisulfite (Disodium Metabisulfite) and Deriva ethanol, phosphatidyl choline, phosphine oxides, poly tives alkoxylated ether glycolates, poly(diallylpiperidinium chlo 0326 Sodium metabisulfite is used as an antioxidant in ride), poly(dipropyldiallylammonium chloride), (primarily acidic) pharmaceutical formulations, at concen polyglycerol esters, polyoxyethylene lauryl ether, polyoxy trations of 0.01-1.0% w/v., preparations and can also be used :polyoxyethylene Stearate, polyoxypropylene 15 Stearyl as a preservative having some antimicrobial activity ether, poly(vinyl pyridinium chloride), propan-1-ol, propan although for alkaline preparations, sodium sulfite is usually 2-ol, propylene glycol dipelargonate, pyroglutamic acids, preferred 2-pyrrolidone, pyruvic acids, Quaternium 5. Quaternium 18, Quaternium 19, Quaternium 23, Quaternium 31, Quater 0327. On exposure to air and moisture, sodium met nium 40, Quaternium 57, quartenary amine salts, quater abisulfite is slowly oxidized to sodium sulfate In water, nised poly (dimethylaminoethylmethacrylate), quaternised sodium metabisulfite is immediately converted to sodium poly (vinyl alcohol), Sapamin hydrochloride, sodium (Na") and bisulfite (HSO) ions. Aqueous sodium met cocaminopropionate, Sodium dioctyl Sulphonsuccinate, abisulfite solutions also decompose in air, and are more Sodium laurate, sodium lauryl ether Sulphate, sodium lauryl Susceptible in the presence of dextrose. Sulphate, Sugar esters, Sulphosuccinate, tetrahydrofuran, tet 0328 Sodium metabisulfite reacts with sympathomimet rahydrofurfural alcohol, transcutol, triethanolamine dodecyl ics and other drugs that are ortho- or para-hydroxybenzyl benzene Sulphonate, triethanolamine oleate, urea, water and alcohol derivatives to form sulfonic acid derivatives pos derivatives, esters, salts and mixtures thereof. sessing little or no pharmacological activity is incompatible 0334. A “penetration enhancer, can be an organic sol with chloramphenicol and inactivates cisplatin in Solution. vent, typically soluble in both water and oil. Further, examples of penetration enhancer include polyols, such as 0329 Sodium metabisulfite is used as an antioxidant at glycerol (glycerin), propylene glycol, hexylene glycol, low pH, sodium bisulfite at intermediate pH, and sodium diethylene glycol, propylene glycol n-alkanols, terpenes, sulfite at higher pH values. di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol. 0330. In an embodiment the preservative comprises 1-menthol, dioxolane, ethylene glycol, hexylene glycol, EDTA other glycols, Sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, 0331 In an embodiment the preservative comprises dimethylacetamide, dimethylisosorbide, monooleate of sharonmix 824. ethoxylated glycerides (with 8 to 10 ethylene oxide units), 0332. In an embodiment, the additional component is a aZone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3- wax Such as bees wax, a wax like Substance like Stearic acid dioxolane, esters, such as isopropyl myristate/palmitate, or a liquid wax like jojoba oil, isostearic acid or oleyl alcohol ethyl acetate, butyl acetate, methyl proprionate, capric/ and similar fatty acids and fatty alcohols. caprylic triglycerides, octylmyristate, dodecyl-myristate; US 2008/0069779 A1 Mar. 20, 2008

myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate for which the solvent includes a potent solvent, increase the ketones; amides, such as acetamide oleates Such as triolein; levels of the active agent in Solution and thus, provide high various alkanoic acids such as caprylic acid; lactam com delivery and improved therapy. pounds, such as aZone; alkanols, such as dialkylamino 0341 Potent solvents, as defined herein, are usually liq acetates, and admixtures thereof. uid. Formulations comprising potent solvents and active 0335). According to one or more embodiments, the pen agents are generally disadvantageous as therapeutics, since etration enhancer is a polyethylene glycol (PEG) or PEG their usage involves unwanted dripping and inconvenient derivative that is liquid at ambient temperature. method of application; resulting in inadequate dosing. Sur prisingly, the foams, which are drip-free, provide a Superior 0336. In one or more embodiments, the foamable com vehicle for Such active agents, enabling convenient usage position includes a potent solvent, in addition to or in place and accurate effective dosing. of one of the hydrophobic solvents, polar solvents or emol lients of the composition. A potent solvent is a solvent other 0342. In one or more embodiments the present invention than mineral oil that solubilizes a specific active agent the foamable pharmaceutical composition may additionally substantially better than a hydrocarbon solvent such as include a mixture of two or more of the solvents selected mineral oil or petrolatum. For example, a potent solvent from the group of hydrophobic solvents, silicone oils, emol solubilizes the active agent 5 fold better than a hydrocarbon lients, polar solvents and potent solvents in an appropriate solvent; or even solubilizes the active agent 10-fold better proportion as would be appreciated to a person skilled in the than a hydrocarbon Solvent. art. 0337. In one or more embodiments, the composition 0343. In one or more embodiments, PPG alkyl ether may includes at least one active agent in a therapeutically effec act as a potent solvent. tive concentration; and at least one potent solvent in a Microemulsions and Nanoemulsions sufficient amount to substantially solubilize the at least one active agent in the composition. The term "substantially 0344) Microemulsions and nanoemulsion are translucent soluble” means that at least 95% of the active agent has been (or transparent) dispersions of oil and water. Compared to solubilized, i.e., 5% or less of the active agent is present in conventional emulsions, microemulsions and nanoemulsion a solid state. In one or more embodiments, the concentration are more thermodynamically stable, making them a favor of the at least one potent solvent is more than about 40% of able vehicle for pharmaceutical compositions, which have to the at least one solvent of the composition; or even more maintain stability for long periods of time. Microemulsions than about 60%. are used, for example, for controlled release of pharmaceu tical agents. In contrast to microemulsions they are in a 0338) Non-limiting examples of pairs of active agent and meta-stable state having very fine oil in water dispersions potent solvent include: Betamethasone Valerate: Practically with diameters of <100 nm with good sensorial and bio insoluble in mineral oil (<0.01%); soluble more than 1% in physical properties such as improved penetration and glycofurol; Hydrocortisone butyrate: Practically insoluble in hydrating power respectively. They and a method of manu mineral oil (<0.01%); soluble more than 1% in glycofurol; facture are more particularly described in US2006/0233721 Metronidazole: Practically insoluble in mineral oil which is incorporated herein by reference in its entirety. As (<0.01%); soluble more than 1% in dimethyl isosorbide: will be appreciated by a man of the art the methodology may Ketoconazole: Practically insoluble in mineral oil (<0.01%); be adapted according to the type of carrier composition. soluble more than 1% in glycofurol, propylene glycol and dimethyl isosorbide; Mupirocin: Practically insoluble in 0345. In one or more embodiments the composition com mineral oil (<0.01%); soluble more than 1% in glycofurol, prises microemulsions or nano-emulsions in which the sta hexylene glycol, dimethyl isosorbide, propylene glycol and bility and or delivery/penetration of the vitamins and or polyethylene glycol 400 (PEG 400); Meloxicam, a nonste flavonoids and or active ingredients are modified or roidal anti-inflammatory agent: Practically insoluble in min improved when compared to that seen with regular emul eral oil (<0.001%); soluble in propylene glycol: 0.3 mg/mL.; S1O.S. and in PEG 400: 3.7 mg/mL, and Progesterone: Practically 0346. In one or more embodiments the composition com insoluble in mineral oil (<0.001%); soluble in PEG 400: prises microemulsions or nano-emulsions and the vitamins 15.3 mg/mL. and or flavonoids and or active ingredients are loaded in 0339. A non-limiting exemplary list of solvents that can microSponges which are dispersed in the composition. be considered as potent solvents includes polyethylene gly Aging col, propylene glycol, hexylene glycol, butanediols and 0347 In order to project the potential shelf life and isomers thereof, glycerol, benzyl alcohol, DMSO, ethyl stability of the compositions and their ingredients particu oleate, ethyl caprylate, diisopropyl adipate, dimethylaceta larly active or benefit agents the compositions can Subjected mide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, to a number of tests, including centrifugation to look for polyvinylpyrrolidone, isosorbide derivatives, such as dim resistance to creaming, phase separation; one or more freeze ethyl isosorbide, glycofurol and ethoxydiglycol (transcutol) thaw cycles, standing at room and higher temperatures as an and laurocapram. indicator of resistance to aging. 0340. The use of a potent solvent in a foam composition Propellants provides an improved method of delivering poorly soluble therapeutic agents to a target area. It is known that low drug 0348 Suitable propellants include volatile hydrocarbons solubility results in poor bioavailability, leading to Such as butane, propane, isobutane and fluorocarbon gases, decreased effectiveness of treatment. Foam compositions, or mixtures thereof. US 2008/0069779 A1 Mar. 20, 2008 20

0349 The propellant makes up about 5-25 wt % of the vonoid is also present which is more reactive to oxidation foamable composition. The propellants are used to generate than the vitamin then it is postulated that the flavonoid will and administer the foamable composition as a foam. The react whilst allowing the vitamin to remain unoxidized. total composition including propellant, foamable composi Likewise the presence of another conservative agent can tions and optional ingredients is referred to as the foamable further help preserve the vitamin. composition. Hygroscopic Property of the (Substantially) Non-Aqueous 0350 Alcohol and organic solvents render foams inflam Composition mable. It has been surprisingly discovered that fluorohydro carbon propellants, other than chloro-fluoro carbons 0355. A hydroscopic substance is a substance that (CMCs), which are non-ozone-depleting propellants, are absorbs water readily from its Surroundings. Microorgan particularly useful in the production of a non-flammable isms require water to grow and reproduce, and Such water foamable composition. A test according to European Stan requirements are best defined in terms of water activity of dard prEN 14851, titled “Aerosol containers—Aerosol foam the substrate. The water activity of a solution is expressed as flammability test” revealed that compositions containing an Aw-P/Po, where P is the water vapor pressure of the solution and Po is the vapor pressure of pure water at the same organic carrier that contains a hydrophobic organic carrier temperature. The of a hygroscopic Substance to a solution in and/or a polar solvent, which are detected as inflammable which a vitamin is present containing some water will have when a hydrocarbon propellant is used, become non-flam the effect of lowering the Aw, with a postulated consequent mable, while the propellant is an HFC propellant. effect of reducing the availability of water to facilitate 0351. Such propellants include, but are not limited to breakdown of the vitamin and in parallel effect upon cell hydrofluorocarbon (HFC) propellants, that contain no chlo growth of microorganisms, if present. Also, where the rine atoms, and as such, falls completely outside concerns composition is Substantially non aqueous, it is postulated about stratospheric ozone destruction by chlorofluorocar that the water that is present in the composition will be at bons or other chlorinated hydrocarbons. Exemplary non least to the most part be associated with hygroscopic solvent flammable propellants according to this aspect of the inven so that it will have a consequent effect of reducing the tion include propellants made by DuPont under the availability of water to facilitate breakdown of the vitamin registered trademark Dymel. Such as 1.1.1.2 tetrafluorethane Every microorganism has a limiting Aw, below which it will (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel not grow, e.g., for streptococci, klebsiella spp., escherichia 227), 1.1, difluoro ethane (Dymel 152) and 1,1,1,3,3,3 coli, clostridium perfingens, and pseudomonas spp. the Aw hexafluoropropane. HFCs possess Ozone Depletion Poten value is 0.95. Staphylococcus aureus is most resistant and tial of 0.00 and thus, they are allowed for use as propellant can proliferate with an Aw as low as 0.86. in aerosol products. 0356. The water activity of a product can be determined 0352. Notably, the stability of foamable emulsions from the relative humidity of the air surrounding the sample including HFC as the propellant can be improved in com when the air and the sample are at equilibrium. Measure parison with the same composition made with a hydrocarbon ment is performed by placing a sample in an enclosed space propellant. where this equilibrium can take place. Once this occurs, the 0353. In one or more embodiments foamable composi water activity of the sample and the relative humidity of the tions comprise a combination of a HFC and a hydrocarbon air are equal. The measurement taken at equilibrium is called propellant Such as n-butane or mixtures of hydrocarbon an equilibrium relative humidity or ERH. The relationship between the water activity and ERH is in accordance with propellants such as propane, isobutane and butane. the following formula: 0354) In one or more embodiments the propellant when added to the pre foam foamable composition can dissolve in Aw-ERH100 the formulation to improve flowability and shakability and 0357 Various types of water activity instruments are reduce viscosity. An additional effect of the propellants commercially available. One exemplary instrument uses particularly when filled under vacuum may be that, without chilled-mirror dewpoint technology while other instruments being bound by any theory, they can compete with, replace, measure relative humidity with sensors that change electri or dilute out the Small or tiny amounts of remaining oxygen cal resistance or capacitance. so that remaining oxygen is rendered Substantially ineffec 0358 Polyols, PEGs and other polar solvents have a great tive. In this connection, any remaining oxygen in the for affinity for water, and as such, they exhibit hygroscopic mulation may have an increased tendency to evaporate to properties. The concentration of the polyol, the PEG and/or occupy the canister dead space compared to the hydrocarbon other polar solvents determines the Aw of the carrier. In one propellant. In consequence of these factors, the oxidation or more embodiments, the polyols, the PEG and/or the potential of the composition is reduced. This is primarily secondary polar solvent is contained in the composition at a facilitated and assisted by filling under vacuum, and further, optionally, by prior production under an inert gas and sufficient concentration to provide an Aw value of the Subsequently under vacuum. For formulations with a hydro hygroscopic carrier of less than 0.9. In other embodiments, phobic phase and some solubility of the vitamin in the the concentration of the polyol, the PEG and/or secondary hydrophobic phase, the hydrophobic propellant may be to an polar solvent in the composition is selected to provide a Aw extent, without being bound by any theory, directly protec value selected from the ranges of (1) about 0.8 and about tive of the vitamin, and even where the vitamin is water 0.9; (2) about 0.7 and about 0.8; and (3) less than about 0.7. soluble it may still offer a protective synergy. In conse 0359. As such, a composition containing a polyol, a PEG quence, the foam formulation may be less Susceptible to with or without a secondary polar solvent can be used as oxidative breakdown of the vitamin. To the extent a fla topical treatment of Superficial infectious conditions. US 2008/0069779 A1 Mar. 20, 2008

0360 The advantage of providing a hygroscopic compo very fine (small) bubble structure: does not rapidly become sition in a pressurized packaging presentation is readily dull; upon spreading on the skin, the foam retains the perceived. The usage of all other presentations, such as creaminess property and does not appear watery. Solutions, creams, lotions, ointments and the like involves repeated opening of the package closure, resulting in absorp 0368 Grade G (good): rich and creamy in appearance, tion of water from the Surrounding environment and a very small bubble size, “dulls' more rapidly than an excel Subsequent elevation of the Aw (thus lowering the hygro lent foam, retains creaminess upon spreading on the skin, scopicity of the product, and therefore decreasing its anti and does not become watery. infective potential. By contrast, a pressurized packaging 0369 Grade FG (fairly good): a moderate amount of does not allow for any humidity to be absorbed by the creaminess noticeable, bubble structure is noticeable; upon preparation, and therefore, the hygroscopic character of the spreading on the skin the product dulls rapidly and becomes composition cannot be damaged. Somewhat lower in apparent viscosity. 0361. In one or more embodiments, the presence of a 0370 Grade F (fair): very little creaminess noticeable, hygroscopic solvent in the formulation helps to ameliorate, larger bubble structure than a “fairly good' foam, upon reduce or prevent breakdown of a vitamin into a non active spreading on the skin it becomes thin in appearance and form. In a preferred embodiment, the formulation containing watery. hygroscopic Solvent is Substantially nonaqueous. In another preferred embodiment, the formulation containing hygro 0371 Grade P (poor): no creaminess noticeable, large scopic solvent is non aqueous, such that any water which bubble structure, and when spread on the skin it becomes might be absorbed from the atmosphere during preparation very thin and watery in appearance. will be closely associated with the hygroscopic solvent Such 0372 Grade VP (very poor): dry foam, large very dull that it is not expected to be available, to facilitate significant bubbles, difficult to spread on the skin. breakdown of vitamin. 0373 Topically administrable foams are typically of 0362. In one or more embodiments, the hygroscopic quality grade E or G, when released from the aerosol composition further contains an anti-infective agent, container. Smaller bubbles are indicative of more stable selected from the group of an antibiotic agent, an antibac foam, which does not collapse spontaneously immediately terial agent, an antifungal agent, an agent that controls yeast, upon discharge from the container. The finer foam structure an antiviral agent and an antiparasitic agent. Combining the looks and feels Smoother, thus increasing its usability and anti-infective effect of a hygroscopic composition, which appeal. acts through a dehydration mechanism, with an additional anti-infective agent that acts through alternate mechanisms, 0374. As further aspect of the foam is breakability. The results in a synergistic effect and consequently higher suc breakable foam is thermally stable, yet breaks under sheer force. Sheer-force breakability of the foam is clearly advan cess rate of Such treatment. tageous over thermally induced breakability. Thermally sen Composition and Foam Physical Characteristics and Advan sitive foams immediately collapse upon exposure to skin tages temperature and, therefore, cannot be applied on the hand 0363 A pharmaceutical or cosmetic composition manu and afterwards delivered to the afflicted area. factured using the foamable carrier is very easy to use. When 0375. The foam has several advantages, when compared applied onto the afflicted body Surface of mammals, i.e., with hydroalcoholic foam compositions, such as described humans or animals, it is in a foam state, allowing free in WO 2004/071479: application without spillage. Upon further application of a mechanical force, e.g., by rubbing the composition onto the 0376 (1) Breakability. The foam is thermally stable. body Surface, it freely spreads on the Surface and is rapidly Unlike hydroalcoholic foam compositions of the prior art, absorbed. the foam is not "quick breaking’, i.e., it does not readily collapse upon exposure to body temperature environment. 0364 The foamable composition is stable, having an Sheer-force breakability of the foam is clearly advanta acceptable shelf-life of at least one year, or preferably, at geous over thermally induced breakability, since it allows least two years at ambient temperature, as revealed in comfortable application and well directed administration accelerated Stability tests. Organic carriers and propellants to the target area. tend to impair the stability of emulsions and to interfere with the formation of stable foam upon release from a pressurized 0377 (2) Skin drying and skin barrier function. Short container. It has been observed, however, that the foamable chain alcohols are known to dry the skin and impair the compositions according to the present invention are surpris integrity of the skin barrier. By contrast, including a film ingly stable. Following accelerated stability studies, they forming agent in the composition foes not cause unwanted demonstrate desirable texture; they form fine bubble struc skin barrier damage. tures that do not break immediately upon contact with a Surface, spread easily on the treated area and absorb quickly. 0378 (3) Irritability. Due to the lack of alcohol and improvement in skin barrier function, skin irritability is 0365. The composition should also be free flowing, to eliminated. allow it to flow through the aperture of the container, e.g., and aerosol container, and create an acceptable foam. 0379 Another property of the foam is specific gravity, as measured upon release from the aerosol can. Typically, 0366 Foam quality can be graded as follows: foams have specific gravity of less than 0.12 g/mL, or less 0367 Grade E (excellent): very rich and creamy in than 0.10 g/mL, or less than 0.08 g/mL, depending on their appearance, does not show any bubble structure or shows a composition and on the propellant concentration. US 2008/0069779 A1 Mar. 20, 2008 22

Pharmaceutical Composition 0388 a. a therapeutically effective concentration of an active agent; and 0380 The foamable composition is an ideal vehicle for Vitamins, flavonoids, active pharmaceutical ingredients and 0389 b. about 50% to about 98% of a polar solvent, active cosmetic ingredients. It is also suitable for using Selected from the group consisting of a polyol and a microSponges to deliver, one or more of vitamins, fla polyethylene glycol; vonoids, active pharmaceutical ingredients and active cos metic ingredients to a target in a controlled way. In the 0390) c. 0% to about 48% of a secondary polar solvent; context herein, active pharmaceutical ingredients and active 0391) d. about 0.2% to about 5% by weight of a cosmetic ingredients including vitamins are collectively Surface-active agent; termed “active agent” or “active agents’. A foamable com position, comprising an active agent has the following 0392 e. about 0.01% to about 5% by weight of at least advantages: one polymeric agent; and 0393 f. a liquefied or compressed gas propellant at a 0381 1. The foamable composition provides a pre concentration of about 3% to about 25% by weight of ferred solvent for active agents, particularly water the total composition. insoluble agents. 0394. In the context of combining a hygroscopic carrier 0382 2. The inclusion of a polyol and/or a PEG and a according to the present invention, a vitamin and or a secondary polar solvent in the foamable composition flavonoid and an anti-infective active agent, a pharmaceu facilitates a co-solvent effect, resulting increased con tical composition is provided, including: centrations of soluble active agent in the dosage form, thus facilitating enhanced skin penetration of the active 0395 a. a vitamin and or a flavonoid; agent. In many cases, increased penetration is posi 0396 b. a hygroscopic substance at a sufficient con tively correlated with improved clinical outcome. In centration to provide an AW value of the hygroscopic certain case, attaining an increased drug penetration carrier of less than 0.9. The concentration of the hygro into the target site of action enables a decrease of Scopic Substance in the composition can be designed to treatment frequency, for example, from twice or three provide a Aw value selected from the ranges of (1) times daily to once daily. about 0.8 and about 0.9; (2) about 0.7 and about 0.8; 0383 3. Polyols and PEGs; and combinations of a and (3) less than about 0.7: polyol and/or PEG with a secondary polar solvent are known as skin penetration enhancers, thus, increasing 0397) c. about 0.2% to about 5% by weight of a drug residence in the target area and increasing clinical Surface-active agent; efficacy, as detailed above. 0398 d. about 0.01% to about 5% by weight of at least one polymeric agent selected from a bioadhesive agent, 0384 4. The fact that the composition contains no a gelling agent, a film forming agent and a phase water, or up to 25% and more preferably up to 10% change agent; water minimizes the probability of degradation of water-sensitive active agents. Furthermore, as exempli 0399 e. a therapeutically effective concentration of an fied herein, a foam containing a polyol and/or PEG with anti-infective agent; and no water at all can be formed in accordance with the 0400 f. a liquefied or compressed gas propellant at a composition and process. Such compositions ensure concentration of about 3% to about 25% by weight of high stability of water sensitive active agents. the total composition. 0385) 5. Combining the anti-infective effect of a 04.01. In addition to the quasi protective effect of a hygroscopic composition, which acts through a dehy hygroscopic compound in a formulation to ameliorate, dration mechanism, with an additional anti-infective reduce or inhibit the breakdown of a vitamin in the presence agent, selected from the group of an antibiotic agent, an of water an exemplary case for the additional inclusion of an antibacterial agent, an antifungal agent, an agent that anti-infective agent in a hygroscopic composition is pro controls yeast, an antiviral agent and an antiparasitic vided herewith. It has been surprisingly discovered that agent, that acts through alternate mechanisms results in combining an antifungal agent in a hygroscopic composition a synergistic effect and consequently higher success results in an anti-infective effect on Strains that are not rate of the treatment. Supposed to be affected by the said antifungal agent. For 0386 6. The foamable polyol composition in con example, terbinafine is know to be highly effective against tained in an impermeable pressurized packaging pre dermatophite pathogens, but not against candida. In-vitro sentation is impermeable and thus, the active agent is studies have revealed, however that terbinafine, dissolved in not exposed to environmental degradation factors, such a hygroscopic carrier, effectively inhibited the spreading of as light and oxidizing agent during storage. candida albicans, while a control preparation, comprising the same concentration of terbinafine in an emulsion base 0387 Thus, in a preferred embodiment, the composition was not effective. Thus, combining an antifungal agent in a includes at least one active agent. In the context of herein the hygroscopic composition results in an expansion of the at least one active agent is a vitamin and or a flavonoid, a spectrum of infective strains that can benefit form the combination of Vitamins and or flavonoids, or a combination therapy; and furthermore, in can render an improved effect of at least one vitamin and or at least one flavonoid and at of Such a composition on mixed infections or in infections least one additional active agent, as defined herewith. that are not accurately diagnosed. US 2008/0069779 A1 Mar. 20, 2008

0402 Consequently, in another aspect, a pharmaceutical the need for vitamin E; and that vitamin E protects against Vitamin and or flavonoid composition, which possesses an the oxidative destruction of vitamin A. Retinol is susceptible improved antifungal activity or that possesses an antifungal to breakdown from oxygen and light. Synthetic retinoids activity on an expanded spectrum of pathogens, is provided, may be used for skin problems (e.g. acne). including: 04.09 According to certain embodiments the retinoid is 0403 a. a hygroscopic composition, comprising a selected from the group consisting of: (1) a compound hygroscopic Substance at a Sufficient concentration to consisting of four isoprenoid units joined in a head-to-tail provide an AW value of the hygroscopic carrier of less manner, a compound having the formula: than 0.9. The concentration of the hygroscopic sub

stance in the composition can be designed to provide a Aw value selected from the ranges of (1) about 0.8 and about 0.9; (2) about 0.7 and about 0.8; and (3) less than about 0.7: 0404 b. an anti-infective agent, selected from the group of an antibiotic agent, an antibacterial agent, an antifungal agent, an agent that controls yeast, an anti viral agent and an antiparasitic agent. Preferably, the anti-infective agent is an antifungal agent, and more preferably the anti-infective agent is terbinafine. 0410 where R is selected from the group consisting of H, alkyl, aryl, alkenyl, benzyl, CH2OH, CH2NH2, CHO, 0405. In another aspect, at least one anti-infective agent, CH=NOH, CO2H, CH=NICH2)4CHNH2CO2H, CH3, Vitamins and or flavonoids are loaded into microSponges and CO2C2H5, CH2OCOCH3, a heteroatom, a saccharide and a are delivered in a foam formulation to a target. polysaccharide; (2) a compound selected from the group consisting of a hydro retinoid, a dehydro retinoid, 3,4- Active Agents Didehydroretinol, 4.5-Didehydro-5,6-dihydroretinol, a sub Vitamins stituted derivative of a retinoid, 5,6-epoxy-5,6-dihydroret 0406. The term vitamin includes those vitamins and inol, ethyl 12-fluororetinoate, a seco retinoid, 1,6-Seco-1,2- derivatives and analogs thereof (including salts) which are didehydroretinol, a nor retinoid, (3) a compound which officially recognized as vitamins, and those vitamins which results from the elimination of a CH3, CH2, CH or C group were once recognized or designated as vitamins but are now from a retinoid, N-ethyl-3-methoxy-2-methyl-17-nor-1.2.3, classified in another way (e.g. vitamin F) and pseudo Vita 4-tetradehydroretinamide, ethyl 3-methoxy-2-methyl-17 mins including those Substances which are a member of a nor-1,2,3,4-tetradehydroretinoate, 5-acetyl-4,18-dinor-ret group or complex but are not formally recognized (e.g. inoic acid, a retro retinoid, 4,5-didehydro-15.5-retro para-amino benzoic acid (PABA), which is claimed to deoxyretinol. 4, 14-retro-retinyl acetate, a stereoisomer of a prevent greying hair and to be useful as an anti aging retinoid, (3R)-3-hydroxyretinol, (3R)-3-Acetoxyretinol, (7E.9E,11E,13Z)-retinoic acid, (6E.8E,10E, 12E.15Z)-4,14 Supplement) and also vitamin mimetics, which have vitamin retro-retinaloxime, an arotinoids, a retinoidal benzoic acid like properties or effects. derivative, 6-3-(1-adamantyl)-4-methoxyphenyl-2-naph 04.07 Suitable vitamins include vitamin A, vitamins of thoic acid, a short retinoid, a short heterocyclic retinoid, an the B complex B1, B2, B3, B5, B6, B7, B9, B12, vitamin C, isoxazole-containing retinoids, a heterocyclic isoxazole vitamins D1-D4, vitamin E, vitamin Kand so called vitamin containing retinoid, an isoxazoline-containing retinoid, a F and a derivative thereof and combinations thereof. stilbene retinoid analog, a retinoid precursor, (ethyl 6-2-(4. 0408 Vitamin A is a fat-soluble vitamin and describes 4-dimethylthiochroman-6-yl)ethynylnicotinate, a carotene, compounds that exhibit the biological activity of retinol. The a Xanthophil and an oxicarotenoid; (4) a compound selected two main components in foods are retinol and the caro from the group consisting of retinol, retinal, retinoic acid, tenoids. Retinoid refers to the chemical entity retinol or all-trans retinoic acid, isotretinoin, tretinoin, tazarotene, other closely related naturally occurring derivatives. These adapalene, 13-cis-retinoic acid, acitretin, all-trans beta caro include: retinal (retinaldehyde); retinoic acid; and retinyl tene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein esters (e.g. retinyl acetate, retinyl palmitate, retinyl propi and Zeaxanthin; (5) a compound that is positively identified onate). Retinoids also include structurally related synthetic using a laboratory method, Suitable of detecting a retinoid, analogues which may or may not have retinol-like activity. and salts and derivatives thereof. Vitamin A (in the form of retinal) is essential for normal 0411 Vitamin B is known as the vitamin B complex and function of the retina and particularly for visual adaptation comprises B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 to darkness. Other forms (retinol, retinoic acid) are neces (pantothenic acid), B6 (pyridoxine), B7 (biotin), B9 (folic sary for maintenance of the structural and functional integ acid) and B12 (cyanocobalamin). Adequate amounts of all B rity of epithelial tissue and the immune system, cellular Vitamins are required for optimal functioning; deficiency or differentiation and proliferation, bone growth, testicular and excess of one B may lead to abnormalities in the metabolism ovarian function and embryonic development. It may act of another. also as a co-factor in biochemical reactions. Deficiency can amongst other things result in skin dryness and papular 0412. Thiamine is a water soluble vitamin and is also eruptions. Vitamin A and its derivatives have the ability to known as aneurine and functions as a co-enzyme in the normalize keratinization. Note that Vitamin C may amelio oxidative decarboxylation of alpha ketoacids (involved in rate the toxic effects of vitamin A; that large doses increase energy production) and in the transketolase reaction of the US 2008/0069779 A1 Mar. 20, 2008 24 pentose phosphate pathway (involved in carbohydrate 0417 Biotin is a water soluble vitamin which was for metabolism). Thiamine is also important in nerve transmis merly known as vitamin H or co-enzyme R. Biotin functions sion (independently of co-enzyme function). It may also act as an integral part of the enzymes that transport carboxyl as an insect repellant. units and fix carbon dioxide. Biotin enzymes are important 0413 Riboflavin is a water soluble vitamin and functions in carbohydrate and lipid metabolism, and are involved in as a component of two flavin co-enzymes—flavin mono gluconeogenesis, fatty acid synthesis, propionate metabo nucleotide (FMN) and flavin adenine dinucleotide (FAD). It lism and the catabolism of amino acids. Biotin has been participates in oxidation-reduction reactions in numerous claimed to be of value in the treatment of brittle finger nails, metabolic pathways and in energy production. Examples acne, seborrhoeic dermatitis, hair fragility and alopecia. include: the oxidation of glucose, certain amino acids and 0418 Folic acid (pteroylglutamic acid) is a water soluble fatty acids; reactions with several intermediaries of the Vitamin and is the parent compound for a large number of Krebs cycle; conversion of pyridoxine to its active co derivatives collectively known as folates. Folate is the enzyme; and conversion of tryptophan to niacin. Riboflavin generic term used to describe the compounds that exhibit the has a role as an antioxidant. It may be involved in main biological activity of folic acid; it is the preferred term for taining the integrity of erythrocytes. Common forms are the vitamin present in foods which represents a mixture of riboflavin, riboflavin butyrate and flavin adenine dinucle related compounds (folates). Folates are involved in a num otide. ber of single carbon transfer reactions, especially in the 0414 Niacin is a water-soluble vitamin and describes the synthesis of purines and pyrimidines (and hence the synthe compounds that exhibit the biological properties of nicoti sis of DNA), glycine and methionine. They are also involved namide. It occurs as nicotinamide and nicotinic acid. It is in some amino acid conversions and the formation and Sometimes known as niacinamide. An example of a deriva utilization of formate. Deficiency leads to impaired cell tive is benzyl nicotinate. Niacin functions as a component of division (effects most noticeable in rapidly regenerating two co-enzymes, nicotinamide adenine dinucleotide (NAD) tissues). and nicotinamide adenine dinucleotide diphosphate 0419 Vitamin B12 is a water-soluble vitamin and it is the (NADP). These co-enzymes participate in many metabolic generic term used to describe the compounds that exhibit the processes including glycolysis, tissue respiration, lipid, biological activity of cyanocobalamin. It includes a range of amino acid and purine metabolism. It has been shown to cobalt-containing compounds, known as cobalamins. have anti-inflammatory properties that result in the improve Cyanocobalamin and hydroxocobalamin are the two princi ment of acne. Topically it has showed benefit for various pal forms in clinical use. Vitamin B12 is involved in the skin conditions including psoriasis and rosacea. It has also recycling of folate co-enzymes and the degradation of been said to have a photo protection role, perhaps through valine. It is also required for nerve myelination, cell repli anti-oxidant activity and reduces or prevents UV damage to cation, haematopoiesis and nucleoprotein synthesis. cells and UV induced disorders. 0420 Vitamin C is a water-soluble vitamin and describes 0415 Pantothenic acid is also a water soluble vitamin and the compounds that exhibit the biological activity of ascor functions mainly as a component of co-enzyme A and acyl bic acid. These include L-ascorbic acid (ascorbic acid) and carrier protein. Co-enzyme A has a central role as a co-factor L-dehydroascorbic acid (dehydroascorbic acid). The func for enzymes involved in the metabolism of lipids, carbohy tions of vitamin C are based mainly on its properties as a drates and proteins; it is also required for the synthesis of reducing agent. It is required for: the formation of collagen cholesterol, Steroid hormones, acetylcholine and porphyrins. and other organic constituents of the intercellular matrix in As a component of acyl carrier protein, pantothenic acid is bone, teeth and capillaries; and the optimal activity of involved in various transfer reactions and in the assembly of several enzymes—it activates certain liver-detoxifying acetate units into longer-chain fatty acids. Pantothenic acid enzyme systems (including drug-metabolizing enzymes) has been used for a wide range for disorders such as acne, and is involved in the synthesis of carnitine and norepineph alopecia, allergies, burning feet, asthma, grey hair, dandruff, rine (noradrenaline) and in the metabolism of folic acid, and cholesterol lowering. Panthenol the alcoholic form histamine, phenylalanine, tryptophan and tyrosine. Vitamin functions as a humetic. Examples of pantothenic acid C also acts: as an antioxidant (reacting directly with aqueous derivatives are calcium pantothenate, D-pantothenyl alco free radicals)—which is important in the protection of hol, pantothenyl ethyl ether, and acetylpentothenyl ethyl cellular function; and to enhance the absorption of non-haem ether. iron. It can function as a whitening agent. Vitamin C may 0416 Vitamin B6 is water soluble vitamin. Vitamin B6 a assist with wound healing. Vitamin C can spare vitamin E generic term used to describe the compounds that exhibit the and vice versa and it may reduce toxic effects of vitamin A. biological activity of pyridoxine. It occurs in food as pyri Vitamin C is unstable in solution especially alkaline solution doxine, pyridoxal and pyridoxamine. Vitamin B6 is con and readily undergoes oxidation on exposure to air. Oxida verted in erythrocytes to pyridoxal phosphate and, to a lesser tion is accelerated by light and heat. Cosmetic forms include extent, pyridoxamine phosphate. It acts as a co-factor for calcium ascorbate, magnesium ascorbate, Sodium ascorbate, enzymes which are involved in more than 100 reactions that Sodium ascorbyl phosphate, ascorbyl palmitate, magnesium affect protein, lipid and carbohydrate metabolism. Pyridoxal ascorbyl phosphate, L-ascorbic acid and magnesium-L- phosphate is also involved in: the synthesis of several ascorbyl-2-phosphate, L-ascorbic acid palmitate, L-ascorbic neurotransmitters; the metabolism of several vitamins (e.g. acid 2-sulfate, L-ascorbic acid phosphate, and DL-alpha.- the conversion of tryptophan to niacin); haemoglobin and tocopherol-L-ascorbic acid phosphate diester dipotassium. sphingosine formation. Lack of Vitamin B6 may affect L-ascorbic acid is the most bioactive form and has been vitamin C. Examples are pyridoxine hydrochloride and found to have many skin benefits but it is unstable in the pyridoxine dioctanate. presence of water and oxygen. Inclusion of ascorbic acid in US 2008/0069779 A1 Mar. 20, 2008

the vitamin carrier, wherein the composition does not con factors VII, IX, X and proteins C, S and Z. Vitamin K is tain or is essentially free of water or wherein water is not responsible for the carboxylation of the bone protein, osteo freely available due to the hygroscopic properties of the calcin, to its active form. Osteocalcin regulates the function composition r and or is not exposed to air during Storage of calcium in bone turnover and mineralization. Vitamin K makes it possible to derive stable products with the most is also required for the biosynthesis of some other proteins bioactive form of vitamin C. found in plasma and the kidney. It is reported to speed up 0421 Vitamin D is a fat-soluble vitamin and describes all resolution of bruising to decrease future bruising and correct sterols that exhibit the biological activity of cholecalciferol. aspects of photoaging. These include: vitamin D (calciferol), vitamin D (ergocal 0424 Pseudo vitamins: Vitamin F was the designation ciferol) vitamin D (cholecalciferol), 1 (OH)D (1 Hydroxy originally given to essential fatty acids that the body cannot cholecalciferol; alfacalcidol), 25(OH)D (25 Hydroxychole manufacture. They were “de-vitaminized' because they are calciferol; calcifediol), 1.25(OH),D, (1.25, fatty acids. Fatty acids are a major component of fats which, Dihydroxycholecalciferol; calcitriol), 24.25(OH), D (24.25. like water, are needed by the body in large quantities and Dihydroxycholecalciferol) and dihydrotachysterol, calcipo thus do not fit the definition of vitamins which are needed triene, 25-hydroxycholecalciferol, 1C.25-dihydroxychole only in trace amounts. Herbalists and naturopaths have calciferol, 1C.25-dihydroxyergocalciferol, 22.23-dihydroer named various therapeutic chemicals “vitamins’, even gocalciferol, 1,24,25-trihydroxycholecalciferol, previtamin though they are not, including vitamin T. S.-Methylmethion D., tachysterol (also termed tacalciol), isovitamin D, dihy ine (vitamin U) and vitamin X. Some authorities say that drotachysterol, (1S)-hydroxycalciol, (24R)-hydroxycal ubiquinone, also called coenzyme Q10, is a vitamin. cidiol, 25-fluorocalciol, ercalcidiol, ertacalciol, (5E)-isocal Ubiquinone is manufactured in Small amounts by the body, ciol, 22.23-dihydroercalciol, (24S)-methylcalciol, (5E)- like vitamin D. Pangamic acid, vitamin B15; the related (10S)-10,19-dihydroercalciol, (24S)-ethylcalciol and (22E)- Substance dimethylglycine is quite wrongly referred to as (24R)-ethyl-22.23-didehydrocalciol. Vitamin D is essential vitamin B15 but also labeled B16. The toxins laetrile and for promoting the absorption and utilization of calcium and amygdaline are sometimes referred to as vitamin B17. Both phosphorus, and normal calcification of the skeleton. Along pangamic acid and laetrile were first proposed as vitamins with parathyroid hormone and calcitonin, it regulates serum by Ernst T. Krebs; neither are recognized by the medical calcium concentration by altering serum calcium and phos community. Flavonoids are sometimes called vitamin P. phate blood levels, as needed, and mobilizing calcium from Animal, bird, and bacterial growth factors have been des bone. It maintains neuromuscular function and various other ignated vitamins such as para-aminobenzoic acid (PABA) cellular processes, including the immune system. Calcipot Vitamin Bo, the folacin (see folic acid) pteryl-heptaglutamic riene, as well as other vitamin C forms is useful in the acid vitamin B, or vitamin Bc-conjugate and orotic acid as treatment of psoriasis. vitamin B. A few substances were once thought to be 0422 Vitamin E is a fat-soluble vitamin and describes all B-complex vitamins and are referred to as B-vitamins in tocopherol and tocotrienol derivatives that exhibit the bio older literature, including B (adenine) and Bs (adenylic logical activity of alpha tocopherol. Those used commer acid), but are no longer recognized as such. An antitumor cially are d-alpha tocopherol (natural vitamin E), d-alpha pterin phosphate named Vitamin B-14 and later abandoned. tocopherol acetate, d-alpha tocopherol Succinate, d.l-alpha 0425 Vitamins as antioxidants. The antioxidant vitamins tocopherol (synthetic vitamin E), d.l-alpha tocopherol can be divided into those that are water-soluble and exist in acetate and d.l-alpha tocopherol Succinate. Vitamin E is an aqueous Solution primarily vitamin C and those that are antioxidant, protecting polyunsaturated fatty acids in mem fat-soluble and exist in membranes or lipoproteins—Vitamin branes and other critical cellular structures from free radicals E and betacarotene. Lipid membranes are particularly Vul and products of oxidation. It works in conjunction with nerable to oxidative breakdown by free radicals. Vitamin E dietary selenium (a co-factor for glutathione peroxidase), protects cell membranes from destruction by undergoing and also with vitamin C and other enzymes, including preferential oxidation and destruction. Some quinones. Such Superoxide dismutase and catalase. Vitamin E is not very as ubiquinone (co-enzyme Q) also appear to have antioxi stable. It may have an anti-inflammatory effect and some dant properties. All these Substances can act as free radical studies state that it improves immune function in the elderly. Scavengers and can react directly with free radicals. Ribo It is also said to reduce oxidative damage and to improve flavin also has a role as an antioxidant. lung function. Vitamin E can spare vitamin C and vice versa. 0426. They are believed to protect against certain dis It is said to be photo protective and to have an anti aging eases by preventing the deleterious effects of free-radical effect on skin showing reduced wrinkles and tumors. mediated processes in cell membranes and by reducing the 0423 Vitamin K is a fat soluble vitamin and describes susceptibility of tissues to oxidative stress. An article by MP 2-methyl-1,4-naphthaquinone and all derivatives that Ludo entitled "Antioxidants and Vitamins in Cosmetics’ exhibit qualitatively the biological activity of phytomena Clinics in Dermatology (2001): 19: 467-473 discusses the dione. The form of vitamin K present in foods is phytom benefits of vitamins and derivatives in cosmetics. enadione (vitamin K). The Substances synthesized by bac teria are known as menaquinones (vitamin K). The parent 0427 Note that carotenoids and flavonoids also act as compound of the vitamin K series is known as menadione antioxidants. (vitamin Ks); it is not natural Substance and is not used in 0428 Synergism between vitamins is known, for humans. Menadiol sodium phosphate is water-soluble example, synergism between Vitamin A and vitamin E is derivative of menadione. Vitamin K is an essential co-factor described by Gallarate, Carlotti, Trotta, and Bovo in the for the hepatic synthesis of proteins involved in the regula International Journal of Pharmaceutics 188 (1999) 233-241 tion of blood clotting. These are: prothrombin (factor II), discussing a study on the stability of ascorbic acid. Any US 2008/0069779 A1 Mar. 20, 2008 26 synergism known in the literature between vitamins to 0447 Flavonoids appear to potentiate or facilitate their action can be used in the present invention. Details of the solubility of vitamins can be found 0448 act as scavengers of free radicals, including for example in the Merck Index and other similar reference Superoxide anions, singlet oxygen, and lipid peroxyl works and databases. radicals (they have antioxidant properties); 0429. In one or more embodiments the vitamin is selected 0449) sequester metal ions; from the group consisting of vitamin A, B1, B2, B3, B5, B6, 0450 inhibit in vitro oxidation of LDL cholesterol; B7, B9, B12, PABA, C, D1-D4, E, K and F and a derivative thereof. 0451 inhibit cyclo-oxygenase, leading to lower plate 0430. In another embodiment the vitamin is selected from let aggregation, decreased thrombotic tendency and the group consisting of vitamin B1, B2, B3, B5, B6, B7, B9, reduced anti-inflammatory activity; B12, PABA and C and a derivative thereof. 0452 inhibit histamine release; 0431. In an embodiment the vitamin is vitamin B3 or a 0453 improve capillary function by reducing fragility derivative thereof or combinations thereof. of capillary walls and thus preventing abnormal leak 0432. In an embodiment the vitamin is vitamin C or a age; and derivative thereof or combinations thereof. 0454 inhibit various stages of tumor development 0433. In an embodiment the vitamin is the vitamin is (animal studies only). vitamin K or a derivative thereof or combinations thereof. 0455 The activities of flavonoids are dependent on their 0434 In an embodiment the vitamin is vitamin A or a chemical structure. Estimates of dietary flavonoid intake derivative thereof or combinations thereof. vary from 10 to 100 mg daily, but may be several hundreds 0435. In an embodiment the vitamin is vitamin E or a of milligrams a day. Dietary Supplements of quercetin and derivative thereof or combinations thereof. rutin provide around 500 mg in a single dose. 0436. In an embodiment the vitamin is the vitamin is 0456 Flavonoids may have a potential role in the pre vitamin F or a derivative thereof or combinations thereof. vention of CVD, cancer and cataracts and possibly other diseases, for anti-viral activity, and they may be useful in 0437. In one or more embodiments the vitamin is a treating ulcers. include hemorrhoids, allergy, asthma, meno combination of two or more vitamins selected from the pausal symptoms and the prevention of habitual abortion. group comprising vitamin A, B3, C. K. E. and F and a derivative thereof. Quercetin 0438. In one or more embodiments the vitamin is a 0457. As a dietary supplement, quercetin is promoted for combination of two or more vitamins selected from the prevention and treatment of atherosclerosis and hyperlipi daemia, diabetes, cataracts, hay fever, peptic ulcer, inflam group comprising vitamin B3, E and C and a derivative mation, prevention of cancer and for treating prostatitis. A thereof. preliminary, double-blind, placebo-controlled trial in Flavonoids chronic non-bacterial prostatitis showed that quercetin 0439 Flavonoids (or bioflavonoids) are a large group of reduced pain and improved quality of life, but had no effect polyphenolic antioxidant compounds, which often occur as on Voiding dysfunction. glycosides and are ubiquitously present in foods of plant Rutin origin. Some flavonoids (e.g. quercetin, rutin) are available as dietary supplements. Flavonoids can be further subdi 0458 As a dietary supplement, rutin is used to reduce vided into: capillary permeability and treat symptoms of varicose veins. In combination with bromelain and trypsin, rutin is used to 0440 flavonols (e.g. kaempferol, quercetin and treat osteoarthritis. myricetin) 0459. A non limiting list of flavonoid compounds is: 0441 flavones (e.g. apigenin and luteolin) benzquercin, dioSmin, ethoxazorutoside, flavodate, sodium hesperidin, leucocianido, monoxerutin, oxerutin, quercetin, 0442 flavonones (e.g. hesperetin, maringenin, eriodic rutoside, roSmarinic acid. The above information was noted tyol) from Dietary Supplements, Electronic Version, Pharmaceu 0443 flavan-3-ols (e.g. (+)-catechin, (+)-gallocat tical Press 2007. echin, (-)-epicatechin, (-)-epigallocatechin) 0460. In an embodiment a single flavonoid is provided and in a further embodiment a combination of two or more 0444 anthocyanins (e.g. cyanidin, delphinidin, malvi flavonoid are provided. In certain embodiments the fla din, pelargonidin, peonidin, petunidin) vonoids act synergistically. In an embodiment water soluble 0445 proanthocyanidins. flavonoids are combined with water insoluble flavonoids. It is known for example that whole polyphenolic extracts have 0446 More than 4000 flavonoids have been identified, greater antioxidant effect than their known individual com and many have been studied. Most are colorless but some ponents. In an embodiment flavonoids are used in combi are responsible for the bright colors of many fruit and nation with other phenolics. In an embodiment one or more vegetables. Flavonoids are distinguished from the caro flavonoids are provided in combination with one or more tenoids. vitamins. In an embodiment flavonoids are provided that are US 2008/0069779 A1 Mar. 20, 2008 27 more reactive than the vitamins. In an embodiment the flavonoids act as a conservational agent. -continued MicroSponges Preferred compositions 0461 The MicroSponges are rigid, porous and spongelike Minimal ingredients with round microscopic particles of cross-linked polymer beads Hydrophilic Hydrophilic solvent Combination of solvents Stabilizer (surfactant or Surfactants and (e.g., polystyrene or copolymers thereof), each defining a Polymer) gelling agents substantially noncollapsible pore network. The Micro Solvents Polyols such as: Propylene sponges can be loaded with an active ingredient and can type glycol, butylenes glycol, hexylene glycol provide a controlled time release of the active ingredient to Polyethylene glycols (PEG) skin or to a mucosal membrane upon application of the Glycofurol formulation. The slow release is intended to reduce irritation Special solvents DMI, Transcutol, Ethanol, by the active. Microsponge R. delivery technology was Glycerin, PPG15 stearyl developed by Advanced Polymer Systems. ether, Liquid Wax Liquid waxes like jojoba oil, Solid waxes can isostearic acid and oley be added 0462 Microsponges have a size range in between 5 to alcohol and other wax like 300 um depending upon the degree of Smoothness or after liquid fatty acids or fatty feel required for the end formulations and can reduce alcohols which perceived oiliness. 0463 Wide ranges of uses for microsponges incorporated in foamable compositions are Suggested aiming to provide 0465. In an embodiment the amount of microsponges increased efficacy for delivery of active agents topically and may be varied from about 1% to about 25% of the formu in a body cavity with enhanced control, spreadability, safety, lation, preferably about 5% to 15%. stability and improved aesthetic properties. Microspheres 0466 In an embodiment any active agent suitable for can store an active agent until its release is triggered by loading in microSponges may be used. Such as benzyl application to the skin Surface Such as through rubbing and peroxide (BPO), tretinoin, hydroquinone, kotoprofen, ret or higher than-ambient skin temperature. MicroSponge do inol, fluconazole, ibuprofen, trolamine and the like not pass through the skin but collect on the skin Surface and slowly release the entrapped agent. The empty spheres are 0467. In an embodiment the microsponges are loaded washed away with cleansing. with one or more vitamins or with one or more flavonoids or combinations thereof. In another embodiment the vitamins 0464 MicroSponges may be incorporated in wide ranges and or flavonoids are fat soluble. In another embodiment of foam formulations. Non limiting outline examples are they are water soluble. listed in the Table below and are exemplified in the prophetic examples in Section C of the Examples: 0468. In an embodiment the vitamin is a retinoid, pref erably a vitamin A, more preferably, retinoic acid or isore tinoic acid.

Preferred compositions 0469. In an embodiment the vitamin is preferably a Minimal ingredients with vitamin D, a derivative or analogue thereof, more preferably calcipotriol or calcitriol or tacalcitol with or without a Oil in water type corticosteroid such as betmethasone or its esters (eg brmv), foams flucinonide, hydrocortisone or clobetasol proprionate High oil Oil Foam adjuvant content Stabilizing Surfactant Gelling agents 0470. In an embodiment, since retinoids and BPO can dry Water the skin, water Soluble humectants, e.g., urea, Sodium PCA, Low oil Oil Foam adjuvant content Stabilizing Surfactant Gelling agents alpha-hydroxy acids, glycerin and other polyols may be Water added. Oils types Triglycerides Fatty acid esters or ethers 0471. As can be noted from above and herein different Silicone types of active agents may be loaded into the microSponges. Mineral Specials: Jojoba Accordingly the foam formulation selected in which to Unsaturated oils disperse the microSponges should be adapted so that the Water in oil Oil Foam adjuvant active agent remains Substantially entrapped in the micro foams Stabilizing Surfactant Gelling agents sponges. In another embodiment the active agent is present Water both in the foam formulation and in the microSponges so that Oils type Some of the active agent is available for immediate penetra Oily foams Oils fatty acid or alcohols Stabilizing Surfactants tion on application of the foam and that other amounts of Oils type Mineral oils active agent are provided by slow or controlled release from Vaseline (regular or the microSponges now sitting on the topical Surface. Sofematic) Triglycerides Silicones 0472. Where the active agent is oil soluble but not water Fatty acid esters or ethers soluble then formulations with minimal or no oil are pre Unsaturated oils ferred where the active agent is primarily to be located in the Specials: Jojoba microSponges. So in an embodiment there is no oil in the formulations, only gels. In another embodiment, there are no US 2008/0069779 A1 Mar. 20, 2008 28 significant amounts of true oils that solubilize the active agents, pediculicides, photodynamic therapy agents, retin ingredients and extract them from the microSponges. oids, Sanatives, scabicides, self tanning agents, skin whit ening agents, asoconstrictors, vasodilators, vitamins, Vita 0473. In an embodiment where the active ingredient is min D derivatives, wound healing agents and wart removers. insoluble in water and is entrapped in the microSponges As is known to one skilled in the art, in some instances a there is provided true oil in water emulsion, where the active specific active agent may have more than one activity, ingredient is only exposed to the external water phase and function or effect. does not access the internal oil phase. This may be achieved in an embodiment by formulating an aqueous oil gel with 0478. In an embodiment, the additional therapeutic agent Substantial water content. is an active herbal extract. Suitable active herbal extracts include but are not limited to angelica, anise oil, astragali 0474. In an embodiment the foam formulation comprises radix, azalea, benzyl acetate, birch tar oil, bornyl acetate, a large amount of hydrophobic Surfactant or hydrophobic cacumen biotae, camphor, cantharidin, capsicum, cineole, complex emulgators which can form a tight close Surfactant cinnamon bark, cinnamon leaf citronella, citroneliol, cit layer Surrounding the oil droplets sitting in the water phase ronellyl acetate, citronellyl formate, eucalyptus, eugenyl to separate but still holding the water and oil phases together acetate, flos carthami, fructus mori, garlic, geraniol, gera as an emulsion, thereby preventing or at least Substantially nium, geranyl acetate, habanera, isobutyl angelicate, laven reducing any leakage of active agent into the oil phase. In a der, ledum latifolium, ledum palustre, lemongrass, further embodiment there is provided a gel where the gelling limonene, linalool, linallyl acetate, methyl anthranilate, agent is not fat soluble so as to prevent or at least Substan methyl cinnamate, meZereum, neem, nerol, neryl acetate, tially reduce leakage. nettle root extract, oleum ricini, oregano, pinenes, alpha.- 0475. The methodology of loading microsponges with pinene, ..beta.-pinene, radix angelicae sinesis, radix paenoiae active agent and amounts that can be loaded are described in rubra, radix polygoni multiflori, radix rehmanniae, rhizoma WO 01/85102, which is incorporated herein by way of pinelliae, rhizoma Zingiberis recens, sabadilla, Sage, sandal reference. Where Drug Microsponge X% w/w is provided wood oil, saw palmetto extract, semen sesami nigrum, it refers to the microSponges including the trapped drug and staphysagria, tea tree oil, terpene alcohols, terpene hydro any other ingredients incorporated when loading the micro carbons, terpene esters, terpinene, terpineol, terpinyl acetate and derivatives, esters, salts and mixtures thereof. In an Sponges. embodiment, the active agent is an acaricide. Suitable aca Additional Therapeutic Agent ricides include but are not limited to amitraz, flumethrin, fluvalinate and derivatives, esters, salts and mixtures 0476. Several conditions involve a combination of etio thereof. logical factors, Some of which is affected by a vitamin; and other etiological factors that require an additional therapeu 0479. In an embodiment, the additional therapeutic agent tic modality. For example, psoriasis may be treated by a is an age spot and keratoses removing agent. Suitable age vitamin D as well as a steroid drug, and therefore combined spot and keratoses removing agent include but are not treatment would be beneficial. Likewise, acne, which limited to hydroxy acids, azelaic acid and other related involves a microbial infection, excessive keratin production, dicarboxylic acids, retinoids, kojic acid, arbutin, nicotinic, excessive sebum production and inflammation, can benefit ascorbic acid, hydroquinone and derivatives, esters, salts from treatment with a combination of a vitamin A, and an and mixtures thereof. Certain nonsteroidal anti-inflamma additional therapeutic agent, selected from the group con tory agents. Such as diclofenac are also useful for the sisting of an anti-inflammatory agent, an antibiotic agent, a treatment of keratoses. Sebostatice agent and a keratolytic agent. Hence, in many 0480. In an embodiment, the additional therapeutic agent cases, the inclusion of an additional therapeutic agent in the is an analgesic. Suitable analgesics include but are not composition, contributes to the clinical activity of the vita limited to benzocaine, butamben picrate, dibucaine, dime 1. thisoquin, dyclonine, lidocaine, pramoxine, tetracaine, Sali 0477 Suitable additional therapeutic agents include but cylates and derivatives, esters, salts and mixtures thereof. are not limited to active herbal extracts, acaricides, age spot 0481. In an embodiment, the additional therapeutic agent and keratose removing agents, allergen, analgesics, local is a local anesthetic. Suitable local anesthetics include but anesthetics, antiacne agents, antiallergic agents, antiaging are not limited to benzocaine, benzyl alcohol, bupivacaine, agents, antibacterials, antibiotics, antiburn agents, antican butamben picrate, chlorprocaine, cocaine, dibucaine, dime cer agents, antidandruff agents, antidepressants, antiderma thisoquin, dyclonine, etidocaine, hexylcaine, ketamine, titis agents, antiedemics, antihistamines, antihelminths, anti lidocaine, mepivacaine, phenol, pramoxine, procaine, tetra hyperkeratolyte agents, antiinflammatory agents, caine, Salicylates and derivatives, esters, salts and mixtures antiirritants, antilipemics, antimicrobials, antimycotics, anti thereof. proliferative agents, antioxidants, anti-wrinkle agents, anti 0482 In an embodiment, the additional therapeutic agent pruritics, antipsoriatic agents, antirosacea agents antisebor is an antiacne agent. Suitable antiacne agents include but are rheic agents, antiseptic, antiswelling agents, antiviral agents, not limited to N-acetylcysteine, adapalene, azelaic acid, antiyeast agents, astringents, topical cardiovascular agents, benzoyl peroxide, cholate, clindamycin, deoxycholate, chemotherapeutic agents, corticosteroids, dicarboxylic erythromycin, flavonoids, glycolic acid, meclocycline, met acids, disinfectants, fungicides, hair growth regulators, hor ronidazol, mupirocin, octopirox, phenoxy ethanol, phenoxy mones, hydroxy acids, immunosuppressants, immunoregu proponol, pyruvic acid, resorcinol, retinoic acid, salicylic lating agents, insecticides, insect repellents, keratolytic acid, Scymnol Sulfate, Sulfacetamide-Sulfur, Sulfur, tazaro agents, lactams, metals, metal oxides, mitocides, neuropep tene, tetracycline, tretinoin triclosan and derivatives, esters, tides, non-steroidal anti-inflammatory agents, oxidizing salts and mixtures thereof. US 2008/0069779 A1 Mar. 20, 2008 29

0483. In an embodiment, the additional therapeutic agent streptomycin Sulfate, tetracycline, tobramycin, tolnaftate, is an antiaging agent. Suitable antiaging agents include but triclosan, trifampin, rifamycin, rollitetracycline, spectinomy are not limited to Sulfur-containing D and L amino acids, cin, spiramycin, Streptomycin, Sulfonamide, tetracyclines, alpha-hydroxy acids S, beta-hydroxy acids (e.g. salicylic tetracycline, tobramycin, tobramycin Sulfate, triclocarbon, acid), urea, hyaluronic acid, phytic acid, lipoic acid; lyso triclosan, trimethoprim-sulfamethoxazole, tylosin, Vanco phosphatidic acid, skin peel agents (e.g., phenol, resorcinol mycin, yrothricin and derivatives, esters, salts and mixtures and the like), Vitamin B3 compounds (e.g., niacinamide, thereof. nicotinic acid and nicotinic acid salts and esters, including 0486 In an embodiment, the additional therapeutic agent non-vasodilating esters of nicotinic acid (such as tocopheryl is an antidandruff agent. Suitable antidandruff agents include nicotinate), nicotinyl amino acids, nicotinyl alcohol esters of but are not limited to aminexil, benzalkonium chloride, carboxylic acids, nicotinic acid N-oxide and niacinamide benzethonium chloride, 3-bromo-1-chloro-5,5-dimethyl-hy N-oxide), vitamin B5 and retinoids (e.g., retinol, retinal, dantoin, chloramine B, chloramine T. chlorhexidine, N-chlo retinoic acid, retinyl acetate, retinyl palmitate, retinyl ascor rosuccinimide, climbazole-, 1,3-dibromo-5,5-dimethylhy bate) skin barrier forming agents, melatonin and derivatives, dantoin, 1.3-dichloro-5,5-dimethyl-hydantoin, betulinic esters, salts and mixtures thereof. acid, betulonic acid, celastrol, crataegolic acid, cromakalin, 0484. In an embodiment, the additional therapeutic agent cyproterone acetate, dutasteride, finesteride, ibuprofen, is an antibiotic. The terms “antibiotic” as used herein shall ketoconozole, oleanolic acid, phenyloin, picrotone olamine, include, but is not limited to, any Substance being destruc salicylic acid, selenium Sulphides, triclosan, triiodothyro tive to or inhibiting the growth of bacteria or any substance nine, ursolic acid, Zinc gluconate, Zinc omadine, Zinc having the capacity to inhibit the growth of or to destroy pyrithione and derivatives, esters, salts and mixtures thereof. bacteria. In one or more embodiments, the antibiotic agent is selected from the group consisting of a beta-lactam 0487. In an embodiment, the additional therapeutic agent antibiotic, an aminoglycoside, an ansa-type antibiotic, an is an antihistamine. Suitable antihistamines include but are anthraquinone, an azole, an antibiotic glycopeptide, a mac not limited to chlorcyclizine, diphenhydramine, rolide, an antibiotic nucleoside, an antibiotic peptide, an mepyramine, methapyrilene, tripelennamine and deriva antibiotic polyene, an antibiotic polyether, an antibiotic tives, esters, salts and mixtures thereof. quinolone, an antibiotic steroid, a Sulfonamide, an antibiotic 0488. In an embodiment, the additional therapeutic agent metal, an oxidizing agent, a periodate, a hypochlorite, a is an antimycotic Also termed antifungal agent. The terms permanganate, a Substance that release free radicals and/or “antimycotic' and “antifungal as used herein include, but is active oxygen, a cationic antimicrobial agent, a quaternary not limited to, any Substance being destructive to or inhib ammonium compound, a biguanide, a triguanide, a bisbigu iting the growth of fungi and yeast or any Substance having anide, a polymeric biguanide, and analogs, derivatives, salts, the capacity to inhibit the growth of or to destroy fungi ions and complexes thereof. and/or yeast. 0485 Suitable antibiotics include but are not limited to 0489. In one or more embodiments, the antifungal agent amanfadine hydrochloride, amanfadine Sulfate, amikacin, is an agent that is useful in the treatment of a Superficial arnikacin Sulfate, aminoglycosides, amoxicillin, amplicillin, fungal infection of the skin, dermatophytosis, microsporum, ansamycins, bacitracin, beta-lactams, candicidin, capreomy cin, carbenicillin, cephalexin, cephaloridine, cephalothin, trichophyton and epidermophyton infections, candidiasis, cefazolin, cephapirin, cephradine, cephaloglycin, chloram oral candidiasis (thrush), candidiasis of the skin and genital phenicols, chlorhexidine, chlorhexidine gluconate, chlo mucous membrane, candida paronychia, which inflicts the rhexidine hydrochloride, chloroxine, chlorquinaldol, chlo nail and nail bed and genital and vaginal candida, which rtetracycline, chlortetracycline hydrochloride, ciprofloxacin, inflict genitalia and the vagina. circulin, clindamycin, clindamycin hydrochloride, clotrima 0490 Suitable antimycotics include but are not limited to Zole, cloxacillin, demeclocycline, dicloSXacillin, diiodohy allylamines, amorolfine, amphotericin B. azole compounds, droxyquin, doxycycline, ethambutol, ethambutol hydrochlo bifonazole, butoconazole, chloroxine, clotrimazole, ciclo ride, erythromycin, erythromycin estolate, erythromycin piroX olamine, clotrimazole, econazole, elubiol, fenticona Stearate, farnesol, floxacillin, gentamicin, gentamicin Sul Zole, fluconazole, flucytosine (5FC), griseofulvin, itracona fate, gramicidin, griseofulvin, haloprogin, haloquinol, Zole, ketoconazole, mafenide acetate, miconazole, naftifine, hexachlorophene, iminocyldline, iodate, iodine, iodochlo natamycin, tolnaftate, nystatin, polyenes, oxiconazole, Sul rhydroxyquin, kanamycin, kanamycin Sulfate, lincomycin, bentine, Sulconazole, terbinafine, terconazole, tioconazole, lineomycin, lineomycin hydrochloride, macrollides, meclo undecylenic acid and derivatives, esters, salts and mixtures cycline, methacycline, methacycline hydrochloride, meth thereof. enamine, methenamine hippurate, methenamine mandelate, methicillin, metronidazole, miconazole, miconazole hydro 0491 In an embodiment, the active agent is an antipru chloride, microcrystalline and nanocrystalline particles of ritic. Suitable antipruritics include but are not limited to silver, copper, Zinc, mercury, tin, lead, bismuth, cadmium menthol, methdilazine, trimeprazine, urea and derivatives, and chromium, minocycline, minocycline hydrochloride, esters, salts and mixtures thereof. mupirocin, nafcillin, neomycin, neomycin Sulfate, netilmi 0492. In an embodiment, the additional therapeutic agent cin, netilmicin Sulfate, nitrofuraZone, norfloxacin, nystatin, is an additional antipsoriatic agent. Suitable additional antip octopirox, oleandomycin, orcephalosporins, oxacillin, Soriatic agents include but are not limited to 6-aminonico oxytetracycline, oxytetracycline hydrochloride, parachlo tinamide, 6-aminonicotinic acid, 2-aminopyrazinamide, rometa Xylenol, paromomycin, paromomycin Sulfate, peni anthralin, 6-carbamoylnicotinamide, 6-chloronicotinamide, cillins, penicillin G, penicillin V, pentamidine, pentamidine 2-carbamoylpyrazinamide, corticosteroids, 6-dimethylami hydrochloride, phenethicillin, polymyxins, quinolones, nonicotinamide, dithranol, 6-formylaminonicotinamide, US 2008/0069779 A1 Mar. 20, 2008 30

6-hydroxy nicotinic acid, 6-substituted nicotinamides, nisone, alpha.-methyl dexamethasone, methylprednisolone, 6-substituted nicotinic acid, 2-substituted pyrazinamide, taZ methylprednisolone acetate, mometaSone furoate, arotene, thionicotinamide, trichothecene mycotoxins and paramethasone, prednisolone, prednisone, pregnenolone, derivatives, esters, salts and mixtures thereof. progesterone, spironolactone, triamcinolone, triamcinolone 0493. In an embodiment, the active agent is an antirosa acetonide and derivatives, esters, salts and mixtures thereof. cea agent. Suitable antirosacea agents include but are not 0498. In an embodiment, the active agent is a hair growth limited to azelaic acid, metronidazole, Sulfacetamide and regulator. Suitable hair growth regulators include but are not derivatives, esters, salts and mixtures thereof. Certain non limited to N-acetylgalactosamine, N-acetylglucosamine, steroidal anti-inflammatory agents, such as Salicylic acid, N-acetylmannosamine, acitretin, aminexil, ascomycin, asi salycilates, piroXicam and diclofenac are also useful for the atic acid, azelaic acid, benzalkonium chloride, benzetho treatment of Rosacea. nium chloride, benzydamine, benzyl nicotinate, benzoyl peroxide, benzyl peroxide, betulinic acid, betulonic acid, 0494. In an embodiment, the additional therapeutic agent calcium pantothenate, celastrol, cepharanthine, chlorphe is an antiseborrheic agent. Suitable antiseborrheic agents niramine maleate, clinacycin hydrochloride, crataegolic include but are not limited to glycolic acid, salicylic acid, acid, cromakalin, cyproterone acetate, diaZoxide, diphenhy Selenium sulfide, Zinc pyrithione, a dicarboxylic acid, Such dramine hydrochloride, dutasteride, estradiol, ethyl-2-hy as azelaic acid and derivatives, esters, salts and mixtures droxypropanoate, finasteride, D-fucono-1,5-lactone, thereof. furoate, L-galactono-1.4-lactone, D-galactosamine, D-glu 0495. In an embodiment, the additional therapeutic agent caro-1,4-lactone, D-glucosamine-3-sulphate, hinokitiol, is an antiviral agent. Suitable antiviral agents include but are hydrocortisone, 2-hydroxypropionic acid, isotretinoin, itra not limited to acyclovir, gancyclovir, ribavirin, amantadine, conazole, ketoconazole, latanoprost, 2-methyl propan-2-ol. rimantadine nucleoside-analog reverse transcriptase inhibi minocyclin, minoxidil, mipirocin, mometaSone, oleanolic tors, such as zidovudine, didanosine, Zalcitabine, tavudine, acid, panthenol. 1,10-phenanthroline, phenyloin, predniso lamivudine and Vidarabine, non-nucleoside reverse tran lone, progesterone, propan-2-ol, pseudoterins, resorcinol, Scriptase inhibitors, such as nevirapine and delavirdine, Selenium sulfide, tazarotene, triclocarbon, triclosan, triiodot protease inhibitors, such as saquinavir, ritonavir, indinavir hyronine, ursolic acid, Zinc pyrithione and derivatives, and nelfinavir, and interferons and derivatives, esters, salts esters, salts and mixtures thereof. and mixtures thereof. 0499. In an embodiment, the additional therapeutic agent 0496. In an embodiment, the additional therapeutic agent is a hormone. Suitable hormones include but are not limited is a chemotherapeutic agent. Suitable chemotherapeutic to methyltestosterone, androsterone, androsterone acetate, agents include but are not limited to daunorubicin, doxoru androsterone propionate, androsterone benzoate, androster bicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitox onediol, androsteronediol-3-acetate, androsteronediol-17 antrone, etoposide, teniposide, vinblastine, Vincristine, mito acetate, androsteronediol 3-17-diacetate, androsteronediol mycin C, 5-FU, paclitaxel, docetaxel, actinomycin D, 17-benzoate, androsteronedione, androstenedione, colchicine, topotecan, irinotecan, gemcitabine cyclosporin, androstenediol, dehydroepiandrosterone, sodium dehydroe Verapamil, Valspodor, probenecid, MK571, GF120918, piandrosterone sulfate, dromoStanolone, dromostanolone LY335979, biricodar, terfenadine, quinidine, pervilleine A, propionate, ethylestrenol, fluoxymesterone, nandrolone XR9576 and derivatives, esters, salts and mixtures thereof. phenpropionate, nandrolone decanoate, nandrolone furyl propionate, nandrolone cyclohexane-propionate, nandrolone 0497. In an embodiment, the additional therapeutic agent benzoate, nandrolone cyclohexanecarboxylate, and roster is a corticosteroid. Suitable corticosteroids include but are onediol-3-acetate-1-7-benzoate, Oxandrolone, not limited to alclometasone dipropionate, amcinafel, oxymetholone, stanozolol, testosterone, testosterone amcinafide, amcinonide, beclomethasone, beclomethasone decanoate, 4-dihydrotestosterone, 5a-dihydrotestosterone, dipropionate, betamethsone, betamethasone benzoate, testolactone, 17a-methyl-19-nortestosterone, desogestrel, betamethasone dexamethasone-phosphate, dipropionate, dydrogesterone, ethynodiol diacetate, medroxyprogester betamethasone Valerate, budesonide, chloroprednisone, one, levonorgestrel, medroxyprogesterone acetate, hydrox chlorprednisone acetate, clescinolone, clobetasol, clobetasol yprogesterone caproate, norethindrone, norethindrone propionate, clobetasol Valerate, clobetaSone, clobetaSone acetate, norethynodrel, allylestrenol. 19-nortestosterone, butyrate, clocortelone, cortisone, cortodoxone, craposone lynoestrenol, quingestanol acetate, medrogestone, norg butyrate, desonide, desoxymethasone, dexamethasone, des estrienone, dimethisterone, ethisterone, cyproterone acetate, oxycorticosterone acetate, dichlorisone, diflorasone diac chlormadinone acetate, megestrol acetate, norgestimate, etate, diflucortolone Valerate, difluorosone diacetate, diflur norgestrel, desogrestrel, trimegestone, gestodene, nomege prednate, fluadrenolone, flucetonide, flucloronide, strol acetate, progesterone, 5a-pregnan-3b.20a-diol Sulfate, fluclorolone acetonide, flucortine butylesters, fludroxy 5a-pregnan-3b.20b-diol sulfate, 5a-pregnan-3b-ol-20-one, cortide, fludrocortisone, flumethasone, flumethasone piv 16.5a-pregnen-3b-ol-20-one, 4-pregnen-20b-ol-3-one-20 alate, flumethasone pivalate, flunisolide, fluocinolone, fluo Sulfate, acetoxypregnenolone, anagestone acetate, cyproter cinolone acetonide, fluocinonide, fluocortin butyl, one, dihydrogesterone, fluorogestone acetate, gestadene, fluocortolone, fluorometholone, fluosinolone acetonide, flu hydroxyprogesterone acetate, hydroxymethylprogesterone, perolone, fluprednidene acetate, fluprednisolone hydrocor hydroxymethyl progesterone acetate, 3-ketodesogestrel, tamate, fluradrenolone, fluradrenolone acetonide, flurandre megestrol, melengestrol acetate, norethisterone, progestins nolone, fluticasone, halcinonide, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone and derivatives, esters, salts and mixtures thereof. butyrate, hydrocortisone cyclopentylpropionate, hydrocorti 0500. In an embodiment, the additional therapeutic agent Sone Valerate, hydroxyltriamcinolone, medrysone, mepred is a hydroxyacid. Suitable hydroxy acids include but are not US 2008/0069779 A1 Mar. 20, 2008

limited to agaricic acid, aleuritic acid, allaric acid, altraric lindane, malathion, permethrin, allethrin, biopermethrin, acid, arabiraric acid, ascorbic acid, atrolactic acid, benzilic transpermethrin, phenothrin, diethyl-m-toluamide, dimethyl acid, citramalic acid, citric acid, dihydroxytartaric acid, phthalate, piperonyl butoxide, pyrethroids and derivatives, erythraric acid, galactaric acid, galacturonic acid, glucaric esters, salts and mixtures thereof. acid, glucuronic acid, glyceric acid, glycolic acid, gularic acid, gulonic acid, hydroxypyruvic acid, idaric acid, isocitric 0505. In an embodiment, the additional therapeutic agent acid, lactic acid, lyxaric acid, malic acid, mandelic acid, is a vasodilator. Suitable vasodilators include but are not mannaric acid, methylacetic acid, mucic acid, phenyllacetic limited to agents that modulate the activity of the enzyme acid, pyruvic acid, quinic acid, ribaric acid, ribonic acid, nitric oxide synthase, nicotinic acid, ethyl nicotinate, amyl saccharic acid, talaric acid, tartaric acid, tartronic acid, nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobutyl threaric acid, tropic acid, uronic acids, Xylaric acid and nitrite, glyceryl trinitrate, octyl nitrite, sodium nitrite, derivatives, esters, salts and mixtures thereof. Sodium nitroprusside, clonitrate, erythrityl tetranitrate, isos orbide mononitrate, isosorbide dinitrate, mannitol hexani 0501. In an embodiment, the active agent is a keratolytic trate, pentaerythritol tetranitrate, penetrinitol, triethanola agent. The term "keratolytic agent' is used herein to mean mine trinitrate, trolnitrate phosphate (triethanolamine a compound which loosens and removes the stratum cor trinitrate diphosphate), propatyinitrate, nitrite esters of Sug neum of the skin, or alters the structure of the keratin layers ars, nitrite esters of polyols, nitrate esters of Sugars, nitrate of skin. Keratolytic agents are used in the treatment of many esters of polyols, nicorandil, apresoline, diaZOxide, hydrala dermatological disorders, which involve dry skin, hyperk Zine, hydrochlorothiazide, minoxidil, pentaerythritol, tola eratinization (Such as prSoriasis), skin itching (Such as Zoline, scoparone, a beta-adrenergic blocker, an alpha Xerosis), acne and rosacea. Suitable keratolytic agents adrenoceptor blocker, a prostaglandin, sildenafil. include but are not limited to N-acetylcysteine, azelaic acid, dipyridamole, catecholamine, isoproternol, furosemide, cresols, dihydroxy benzene compounds, such as resorcinol prostaglandin, prostacyclin, enalaprilat, morphine, acepro and hydroquinone, alpha-hydroxy acids, such as lactic acid mazine, prazosin (C-blocker), enalapril, Captopril, amlo and glycolic acid, phenol, pyruvic acid, resorcinol, Sulfur, dipine, minoxidil, tadalafil. Vardenafil, phenylephrin, salicylic acid, retinoic acid, isoretinoic acid, retinol, retinal, etillefein, caffeine, capsaicin, an extract capsicum, achillea urea and derivatives, esters, salts and mixtures thereof. millefolium (Yarrow), allium sativum (garlic), amoracia rusticana (horseradish), berberis Vulgaris (barberry), cimic 0502. In an embodiment, the active agent is a lactam. ifuga racemosa (black cohosh), coleus forskholii (coleus), Suitable lactams include but are not limited to L-galactono coptis (goldenthread), crataegus (hawthorn), eleutherococ 1.4-lactam, L-arabino-1,5-lactam, D-fucono-1,5-lactam, cus senticosus (Siberian ginseng), ginkgo biloba (ginkgo). D-glucaro-1,4-lactam, D-glucurono-6.3-lactam, 2.5-tri-O- melissa officinalis (lemon balm), olea europaea (olive leaf), acetyl-D-glucurono-6.3-lactam, 2-acetamido-2-deoxyglu panax ginseng (Chinese ginseng), petroselinum crispum cono-1,5-lactam, 2-acetamido-2-deoxygalactono-1,5-lac (parsley), Scutellariabaicalensis (baical skullcap), tilia euro tam, D-glucaro-1,4:6.3-dilactam-, L-idaro-1,5-lactam, 2.3.5. paea (linden flower), trigonella foenum-graecum tri-O-acetyl-D-glucaro-1,4-lactam, 2,5-di-O-acetyl-D- (fenugreek), urtica dioica (nettles), Valeriana officinalis glucaro-1,4:6.3-dilactam, D-glucaro-1,5-lactam methyl (Valerian), Viburnum (cramp, bark, black haw), Veratrum ester, 2-propionoamide-2-deoxyglucaro-1,5-lactam and viride (American hellebore), verbena officinalis (vervain), derivatives, esters, salts and mixtures thereof. Xanthoxylum americanum (prickly ash), Zingiber officinale 0503. In an embodiment, the additional therapeutic agent (ginger), rauwolfia serpentina (Indian Snakeroot), Viscum is a non-steroidal anti-inflammatory agent. Suitable non album, wild yam, Sasparilla, licorice, damiana, yucca, saw steroidal anti-inflammatory agent include but are not limited palmetto, gotu kola (centella asiatica), yohimbine and salts, to azelaic acid, oxicams, piroxicam, isoxicam, tenoxicam, hazelnut, brazil nut and walnut, and derivatives, esters, salts Sudoxicam, CP-14.304, Salicylates, aspirin, disalcid, beno and mixtures thereof. rylate, trilisate, Safapryn, Solprin, diflunisal, fendosal, acetic 0506. In an embodiment, the additional therapeutic agent acid derivatives, diclofenac, fenclofenac, indomethacin, is a vasoconstrictor. Suitable vasodilators include but are not Sulindac, tolmetin, isoxepac, furofenac, tiopinac, Zidometa limited to ephedrine, epinephrine, phenylephrine, angio cin, acematacin, fentiaZac, Zomepirac, clindanac, oxepinac, tensin, Vasopressin; an extract ephedra sinica (ma huang), felbinac, ketorolac, fenamates, mefenamic, meclofenamic, polygonum bistorta (bistort root), hamamelis Virginiana flufenamic, niflumic, tolfenamic acids, propionic acid (witch hazel), hydrastis canadensis (goldenseal), lycopus derivatives, ibuprofen, naproxen, benoxaprofen, flurbipro Virginicus (bugleweed), aspidosperma quebracho (quebra fen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirpro fen, carprofen, oxaprozin, pranoprofen, miroprofen, tioX cho blanco), cytisus scoparius (Scotch broom) and cypres aprofen, Suprofen, alminoprofen, tiaprofen, pyrazoles, sand and derivatives, esters, salts and mixtures thereof. phenylbutaZone, oxyphenbutaZone, feprazone, azapropa 0507. In an embodiment, the active agent is a retinoid. Zone, trimethaZone and derivatives, esters, salts and mix Suitable retinoids include but are not limited to retinol, tures thereof. retinal, retinoic acid, all-trans retinoic acid, isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans 0504. In an embodiment, the additional therapeutic agent beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene, is insecticide. The term “insecticide, is used herein to mean lutein and Zeaxanthin. a compound which kills, inhibits the growth of impeded the proliferation of or repels insects. Insecticides include, for 0508. In an embodiment, the additional therapeutic agent example, agents that can kill lice, flees, ticks, mites, Scabies is selected from the group consisting of an immunosuppres and mousquitos, as well as agents that repel Such insects. sants and immunoregulating agents. Suitable immunosup Suitable insecticides include but are not limited to DDT, pressants and immunoregulating agents include but are not US 2008/0069779 A1 Mar. 20, 2008 32 limited to cyclic peptides, such as cyclosporine, tacrolimus, octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol tresperimus, pimecrolimus, sirolimus (rapamycin), Veroli esters); cinnamic acid derivatives (menthyl and benzyl mus, laflunimus, laquinimod, imiquimod derivatives, esters, esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); salts and mixtures thereof. In one or more embodiments, the dihydroxycinnamic acid derivatives (umbelliferone, methy immunomodulator is a calcineurin Inhibitor. lumbelliferone, methylaceto-umbelliferone); trihydroxy cinnamic acid derivatives (esculetin, methylesculetin, daph 0509. In an embodiment, the additional therapeutic agent netin, and the glucosides, esculin and daphnin); is a wart remover. Suitable wart removers include but are not hydrocarbons (diphenylbutadiene, stilbene): dibenzalac limited to imiquimod, podophyllotoxin and derivatives, etone and benzalacetophenone; naphtholsulfonates (sodium esters, salts and mixtures thereof. salts of 2-naphthol-3,6-disulfonic and of 2-naphthol-6.8- 0510. In an embodiment, the additional therapeutic agent disulfonic acids); di-hydroxynaphthoic acid, o- and p-hy is a photodynamic therapy (PDT) agent. Suitable PDT droxybiphenyldisulfonates, coumarin derivatives (7-hy agents include but are not limited to modified porphyrins, droxy, 7-methyl 3-phenyl), diazoles (2-acetyl-3- chlorins, bacteriochlorins, phthalocyanines, naphthalocya bromoindazole, phenylbenzoxazole, methyl naphthoxazole, nines, pheophorbides, purpurins, m-THPC, mono-L-aspar quinine salts (bisulfate, Sulfate, chloride, oleate, and tan tyl chlorine6, bacteriochlorins, phthalocyanines, benzopor nate); quinoline derivatives (8-hydroxyquinoline salts, phyrin derivatives, as well as photosensitiser precursors, 2-phenylduinoline); hydroxy- or methoxy-Substituted ben Such as aminolevulinic acid and derivatives, esters, salts and Zophenones; uric and violuric acids; tannic acid and its mixtures thereof. derivatives (e.g., hexaethylether); (butyl carbotol) (6-propyl piperonyl)ether; hydroquinone; benzophenones (oxyben 0511. In an embodiment, the additional therapeutic agent Zene, Sulisobenzone, dioxybenzone, benzoresorcinol, 2.2.4. is an antioxidant or a radical scavenger. Suitable antioxi 4-tetrahydroxybenzophenone, 2,2'-dihydroxy-4,4'- dants and radical scavengers agents include but are not dimethoxybenzophenone, octabenZone; limited to ascorbic acid, ascorbyl esters of fatty acids, 4-isopropyldibenzoylmethane; butylmethoxydibenzoyl magnesium ascorbyl phosphate, sodium ascorbyl phosphate, methane: etocrylene; octocrylene; 3-(4-methylbenzylidene ascorbyl Sorbate, tocopherol, tocopheryl Sorbate, tocopheryl bornan-2-one), terephthalylidene dicamphor Sulfonic acid acetate, butylated hydroxybenzoic acid, 6-hydroxy-2,5,7,8- and 4-isopropyl-di-benzoylmethane. tetramethylchroman-2-carboxylic acid, gallic acid, propyl gallate, uric acid, Sorbic acid, lipoic acid, diethylhydroxy 0515. In an embodiment, the additional therapeutic agent lamine, amino-guanidine, glutathione, dihydroxy fumaric is a figure-forming agent and an agent, capable of treating acid, lycine pidolate, arginine pilolate, nordihydroguaiaretic cellulite. Suitable such agents include but are not limited to acid, bioflavonoids, curcumin, lysine, methionine, proline, baldderwack extract, butchers, broom, cayenne, dandelion, Superoxide dismutase, silymarin, tea extracts, grape skin/ red clover, ginkgo biloba, horse chestnut, witch hazel and seed extracts, melanin, and polyunsaturated oils, containing borage oil, caffeic acid, nicotinic acid, theophiline and omega-3 and omega-6 fatty acids (e.g., linoleic and linolenic pentoxyphilline and salts and derivatives thereof. acid, gamma-linoleic acid, eicosapentaenoic acid and 0516 Several disorders of the skin, body cavity or docosahexaenoic acid and derivatives, esters, salts and mix mucosal Surface (e.g., the mucosa or the cavity of the nose, tures thereof. mouth, eye, ear, vagina or rectum) involve a combination of 0512. In an embodiment, the additional therapeutic agent etiological factors. For example, fungal and bacterial infec is a self-tanning agent. Such as dihydroxyacetone. tions and that are inflamed and have symptoms of redness and/or itching warrant therapy that combines an anti-infec 0513. In an embodiment, the additional therapeutic agent tive agent and an anti-inflammatory agent. Thus, in several is an agent, capable of treating hyperhidrosis. Suitable cases, combining at least two active agents that treat differ hyperhidrosis agents include but are not limited to anticho ent etiological factors results in a synergistic effect and linergic drugs, boric acid, tannic acid, resorcinol, potassium consequently higher Success rate of the treatment. permanganate, formaldehyde, glutaraldehyde, meth 0517. In certain cases, the composition contains two enamine, a Lewis acid, aluminum chloride, aluminum chlo active agents, where each of the active agents require a rohydrates, Zirconium chlorohydrates, aluminum-zirco different pH environment in order to remain stable. For nium-Glycine (AZG) complex, aluminum hydroxybromide, example, corticosteroids are typically stable at acidic pH a glycopyrrolate compound, a 5-alpha-reductase inhibitor, values (they have a maximum stability at a pH of about 4-6) finasteride, epristeride, flutamide, spironolactone, saw pal and of vitamin D analogues are typically stable at basic pH metto extract, cholestan-3-one, a mono- and dicarboxylic values (they have a maximum stability at pH values above acid having 4 to 18 carbon atoms, botulinum toxin, a about 8). In order to circumvent the problem of instability it 5-HT2C receptor antagonist, a 5-HT2C receptor antagonist, is preferred that the composition is Substantially non-aque ketanserin, ritanserin, mianserin, meSulergine, cyprohepta ous. The term “substantially non-aqueous” is intended to dine, fluoxetine, mirtazapine, olanzapine and Ziprasidone. indicate that the composition has a water content below 0514. In an embodiment, the additional therapeutic agent about 5%, preferably below about 2%, such as below about is a Sunscreen agent. Suitable Sunscreen agents include but 1.5%. are not limited to titanium dioxide, Zinc oxide, Zirconium oxide, iron oxide, p-aminobenzoic acid and its derivatives Fields of Applications (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic 0518. The foamable carrier is suitable for treating any acid); anthranilic acid derivatives (i.e., o-amino-benzoates, infected surface. In one or more embodiments, foamable methyl, menthyl, phenyl, benzyl, phenylethyl, linallyl, terpi carrier is suitable for administration to the skin, a body nyl, and cyclohexenyl esters); salicylates (amyl, phenyl, Surface, a body cavity or mucosal Surface, e.g., the cavity US 2008/0069779 A1 Mar. 20, 2008

and/or the mucosa of the nose, mouth, eye, ear, respiratory important since the composition creates a thin, semi-occlu system, vagina or rectum (severally and interchangeably sive layer, which coats the damaged tissue, while allowing termed herein “target site'). exudates to be released from the tissue. 0519. By selecting a suitable active agent, or a combina tion of at least two active agents, the foamable composition 0523 The composition is also suitable for administering is useful in treating an animal or a human patient having any a hormone to the skin or to a mucosal membrane or to a body one of a variety of dermatological disorders, including cavity, in order to deliver the hormone into the tissue of the dermatological pain, dermatological inflammation, acne, target organ, in any disorder that responds to treatment with acne Vulgaris, inflammatory acne, non-inflammatory acne, a hormone. acne fulminans, nodular papulopustular acne, acne conglo 0524. In light of the hygroscopic nature of the composi bata, dermatitis, bacterial skin infections, fungal skin infec tions, viral skin infections, parasitic skin infections, skin tion, it is further suitable for the treatment and prevention of neoplasia, skin neoplasms, pruritis, cellulitis, acute lym post-Surgical adhesions. Adhesions are scars that form phangitis, lymphadenitis, erysipelas, cutaneous abscesses, abnormal connections between tissue surfaces. Post-Surgical necrotizing Subcutaneous infections, Scalded skin syndrome, adhesion formation is a natural consequence of Surgery, folliculitis, furuncles, hidradenitis Suppurativa, carbuncles, resulting when tissue. repairs itself following incision, cau paronychial infections, rashes, erythrasma, impetigo, terization, Suturing, or other means of trauma. When com ecthyma, yeast skin infections, warts, molluscum contagio prising appropriate protective agents, the foam is suitable for Sum, trauma or injury to the skin, post-operative or post the treatment or prevention of post Surgical adhesions. The Surgical skin conditions, scabies, pediculosis, creeping erup use of foam is particularly advantageous because foam can tion, eczemas, psoriasis, pityriasis rosea, lichen planus, expand in the body cavity and penetrate into hidden areas pityriasis rubra pilaris, edematous, erythema multiforme, that cannot be reached by any other alternative means of erythema nodosum, grannuloma annulare, epidermal administration. necrolysis, Sunburn, photosensitivity, pemphigus, bullous 0525) Other foamable compositions are described in: pemphigoid, dermatitis herpetiformis, keratosis pilaris, cal U.S. Publication No. 05-0232869, published on Oct. 20, louses, corns, ichthyosis, skin ulcers, ischemic necrosis, 2005, entitled NONSTEROIDAL IMMUNOMODULAT miliaria, hyperhidrosis, moles, Kaposi's sarcoma, mela ING KIT AND COMPOSITION AND USES THEREOF: noma, malignant melanoma, basal cell carcinoma, squamous U.S. Publication No. 05-0205086, published on Sep. 22, cell carcinoma, poison ivy, poison oak, contact dermatitis, 2005, entitled RETINOID IMMUNOMODULATING KIT atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, AND COMPOSITION AND USES THEREOF; U.S. Pub baldness, alopecia, Behcet’s syndrome, cholesteatoma, Der lication No. 06-0018937, published on Jan. 26, 2006, cum disease, ectodermal dysplasia, gustatory Sweating, nail entitled STEROID KIT AND FOAMABLE COMPOSI patella syndrome, lupus, hives, hair loss, Hailey-Hailey TION AND USES THEREOF; U.S. Publication No. disease, chemical or thermal skin burns, Scleroderma, aging 05-0271596, published on Dec. 8, 2005, entitled VASOAC skin, wrinkles, Sun spots, necrotizing fasciitis, necrotizing TIVE KIT AND COMPOSITION AND USES THEREOF: myositis, gangrene, Scarring, and Vitiligo. U.S. Publication No. 06-0269485, published on Nov. 30, 0520 Likewise, the foamable composition is suitable for 2006, entitled ANTIBIOTIC KIT AND COMPOSITION treating a disorder of a body cavity or mucosal Surface, e.g., AND USES THEREOF; U.S. Publication No. 07-0020304, the mucosa of the nose, mouth, eye, ear, respiratory system, published on Jan. 25, 2007, entitled NON-FLAMMABLE vagina or rectum. Non limiting examples of Such conditions INSECTICIDE COMPOSITION AND USES THEREOF: include chlamydia infection, gonorrhea infection, hepatitis U.S. Publication No. 06-0193789, published on Aug. 31, B, herpes, HIV/AIDS, human papillomavirus (HPV), genital 2006, entitled FILM FORMING FOAMABLE COMPOSI warts, bacterial vaginosis, candidiasis, chancroid, granu TION: U.S. patent application Ser. No. 11/732,547, filed on loma Inguinale, lymphogranloma Venereum, mucopurulent Apr. 4, 2007, entitled ANTI-INFECTION AUGMENTA cervicitis (MPC), molluscum contagiosum, nongonococcal TION OF FOAMABLE COMPOSITIONS AND KIT AND urethritis (NGU), trichomoniasis, Vulvar disorders, vulvo USES THEREOF; U.S. Provisional Patent Application No. dynia, Vulvar pain, yeast infection, Vulvar dystrophy, Vulvar 60/789,186, filed on Apr. 4, 2006, KERATOLYTIC ANTI intraepithelial neoplasia (VIN), contact dermatitis, pelvic FUNGAL FOAM: U.S. Provisional Patent Application No. inflammation, endometritis, Salpingitis, oophoritis, genital 0/815948, filed on Jun. 23, 2006, entitled FOAMABLE cancer, cancer of the cervix, cancer of the Vulva, cancer of COMPOSITIONS COMPRISING A CALCIUM CHAN the vagina, vaginal dryness, dyspareunia, anal and rectal NEL BLOCKER, A CHOLINERGIC AGENT AND A disease, anal abscess/fistula, anal cancer, anal fissure, anal NITRICOXIDE DONOR; U.S. Provisional Patent Appli warts, Crohn's disease, hemorrhoids, anal itch, pruritus ani, cation No. 60/818,634, filed on Jul. 5, 2006, entitled fecal incontinence, constipation, polyps of the colon and DICARBOXYLIC ACID FOAMABLE VEHICLE AND rectum. PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. Provisional Patent Application No. 60/843,140, filed on Sep. 0521. In an embodiment, the composition is useful for the 8, 2006, entitled FOAMABLE VEHICLE AND VITAMIN treatment of an infection. In one or more embodiments, the PHARMACEUTICAL COMPOSITIONS THEREOF, all of composition is suitable for the treatment of an infection, which are incorporated herein by reference in their entirety. selected from the group of a bacterial infection, a fungal More particularly any of the active ingredients; the solvents: infection, a yeast infection, a viral infection and a parasitic the Surfactants; foam adjuvants; polymeric agents, penetra infection. tion enhancers; preservatives, humectants; moisturizers; and 0522. In an embodiment, the composition is useful for the other excipients as well as the propellants listed therein can treatment of wound, ulcer and burn. This use is particularly be applied herein and are incorporated by reference. US 2008/0069779 A1 Mar. 20, 2008 34

0526. The following examples further exemplify the ben 0544 5. In case of polymers dissolved in water or efit agent foamable pharmaceutical carriers, pharmaceutical organic solvent, dissolve the polymers in the solvent compositions thereof, methods for preparing the same, and with heating or cooling as appropriate for specific therapeutic uses of the compositions. The examples are for polymer and add to the oily mixture under vigorous the purposes of illustration only and are not intended to be mixing at ~40° C. limiting of the invention. Many variations may be carried Production Under Vacuum out by one of ordinary skill in the art and are contemplated. 0545 Optionally, the foamable formulation may be pro Methodology duced under nitrogen and under vacuum. Whilst the whole process can be carried out under an oxygen free environ 0527. A general procedure for preparing foamable com ment, it can be sufficient to apply a vacuum after heating and positions is set out in WO 2004/037225, which is incorpo mixing all the ingredients to obtain an emulsion or homog rated herein by reference. enous liquid. Preferrably the production chamber is Emulsion Foam equipped to apply a vacuum but if not the formulation can 0528 1. Mix oily phase ingredients and heat to 75° C. be for example placed in a dessicator to remove oxygen prior to melt all ingredients and obtain homogeneous mix to filing and crimping. ture. Canisters Filling and Crimping 0529 2. Mix polymers in water with heating or cooling 0546) Each aerosol canister is filled with PFF and as appropriate for specific polymer. crimped with valve using vacuum crimping machine. The process of applying a vacuum will cause most of the oxygen 0530 3. Add all other water soluble ingredients to present to be eliminated. Addition of hydrocarbon propellant water-polymer solution and heat to 75° C. may without being bound by any theory further help to 0531. 4. Add slowly internal phase to external phase at reduce the likelihood of any remaining oxygen reacting with 75° C. under vigorous mixing and homogenize to the active ingredient. It may do so, without being bound by obtain fine emulsion. Alternatively the external phase is any theory, by one or more of dissolving in the oil or added slowly to the internal phase. hydrophobic phase of the formulation, by dissolving to a very limited extent in the aqueous phase, by competing with 0532 5. Cool to below 40° C. and add sensitive Some oxygen from the formulation, by diluting out any ingredients with mild mixing. oxygen, by a tendency of oxygen to occupy the dead space, 0533 6. Cool to room temperature. and by oxygen occupying part of the space created by the vacuum being the unfilled volume of the canister or that Waterless Foam remaining oxygen is rendered Substantially ineffective in the 0534 1. Dissolve the polymers in the main solvent formulation. with heating or cooling as appropriate for specific 0547 Pressurizing polymer. Add the all other ingredients and heat to 75° C. to melt and dissolve the various ingredients. 0548 Propellant Filling 0549 Pressurizing is carried out using a hydrocarbon gas 0535 2. Cool to below 40° C. and add sensitive or gas mixture. Canisters are filled and then warmed for 30 ingredients with mild mixing. sec in a warm bath at 50° C. and well shaken immediately 0536 3. Cool to room temperature. thereafter. Oily Waterless Foam 0550 Closure Integrity Test. 0551 Each pressurized canister is subjected to bubble 0537) 1. Mix all ingredients excluding polymers and and crimping integrity testing by immersing the canister in heat to 75° C. to melt and dissolve and obtain homo a 60°C. water bath for 2 minutes. Canisters are observed for geneous mixture. leakage as determined by the generation of bubbles. Canis 0538 2. Mix well and cool to below 40° C. and add the ters releasing bubbles are rejected. polymers and sensitive ingredients with moderate mix Tests ing. 0552. By way of non limiting example the objectives of 0539) 3. Cool to room temperature. hardness, collapse time and FTC stability tests are briefly set Oily Foam with Phospholipids and/or Water out below as would be appreciated by a person of the art. Hardness 0540 1. Swell the phospholipids in the main oily Solvent under mixing for at least 20 minutes until 0553 LFRA100 instrument is used to characterize hard uniform Suspension is obtained. ness. A probe is inserted into the test material. The resistance of the material to compression is measured by a calibrated 0541) 2. Add all other ingredients excluding polymers load cell and reported in units of grams on the texture and heat to 75° C. to melt and dissolve and obtain analyzer instrument display. Preferably at least three repeat homogeneous mixture. tests are made. The textural characteristics of a dispensed 0542. 3. Mix well and cool to below 40° C. and add the foam can affect the degree of dermal penetration, efficacy, polymers and sensitive ingredients with moderate mix spreadability and acceptability to the user. The results can ing. also be looked at as an indicator of softness. Note: the foam sample is dispensed into an aluminum sample holder and 0543. 4. Cool to room temperature. filled to the top of the holder. US 2008/0069779 A1 Mar. 20, 2008

Collapse Time Experimental Procedure 0554 Collapse time (CT) is examined by dispensing a Diffusion Cells given quantity of foam and photographing sequentially its appearance with time during incubation at 36°C. It is useful 0564) The permeability of porcine skin to ascorbic acid for evaluating foam products, which maintain structural was measured in-vitro with a Franz diffusion cell system. stability at skin temperature for at least 1 min. The solutions on the receiverside were stirred by externally driven, Teflon coated magnetic bars. Viscosity 0565. One experiment was performed using a diffusion 0555 Viscosity is measured with Brookfield LVDV-II+ cell system containing 12 cells. Cells 1-3 contained MPO16 PRO with spindle SC4-25 at ambient temperature and 10, 5 (5%), cells 4-6 contained AAP023 (30%), cells 7-9 con and 1 RPM. Viscosity is usually measured at 10 RPM. tained AAP029 (5%), cells 10-11 contained Vitamin C However, at about the apparent upper limit for the spindle of serum and cell 12 as reference cell ->50,000CP, the viscosity at 1 RPM may be measured, although the figures are of a higher magnitude. Skin Preparation 0566 Excised pig ear skin, approximately 4x4 cm, is FTC (Freeze Thaw Cycles) supplied after dermatome sectioning at a thickness of ~500 0556. To check the foam appearance under extreme con pm and stored at -18°C. until use. ditions of repeated cycles of cooling, heating, (first cycle) cooling, heating (second cycle) etc., commencing with 0567 Transepidermal water loss measurements (TEWL, -100° C. (24 hours) followed by +400° C. (24 hours) Tewameter TM300) were performed and only those pieces measuring the appearance and again repeating the cycle for that the TEWL levels were within specification (<15 g/m·h) were mounted in the diffusion cells and then the donor up to three times. chambers were clamped in place. The receiver chamber, 0557 Creaming by centrifugation: defined as the side facing the dermis, was filled with phosphate buffer (0.1M, pH 7.4)+0.2% sodium met 1. Principle of test abisulfite. 0558. The centrifugation used in this procedure serves Permeation Study as a stress condition simulating the aging of the liquid dispersion under investigation. Under these conditions, 0568 Product specimens (200 mg) were applied on the the centrifugal force applied facilitates the coalescence skin. of dispersed globules or sedimentation of dispersed 0569 0.5 mL were withdrawn from receiving chamber at solids, resulting in loss of the desired properties of the T-0, 3, 6, 9, 12, 22 and 24 hours an inserted into 2-ml vials formulated dispersion. for rate study. 2. Procedure Tape-Stripping Procedure for the Removal of Material 05:59 2.1. Following preparation of the experimental Adhered to Skin formulation/s, allow to stand at room temperature for 0570 Adhere a piece of cello tape on each skin slice 224 h. within the mold and overlay with 2 Kg weight for about 10 0560 2.2. Handle pentane in the chemical hood. Add seconds. Remove the weight and transfer the tape into a 50 to each experimental formulation in a 20-mL glass vial mL tube containing 10 mL receptor fluid a quantity of pentane equivalent to the specified quan 0571 Repeat cello-tape adherence procedure for addi tity of propellant for that formulation, mix and allow tional nine times (9 individual cell-tapes) and transfer all formulation to stand for at least 1 h and not more than nine collected tapes to a 50 mL tube containing 3 mL 24 h. receptor fluid. Repeat cello-tape adherence for additional ten 0561) 2.3. Transfer each mixture to 1.5 mL microtubes. times (10 individual cell-tapes) and transfer all ten tapes to Tap each microtube on the table surface to remove a 50 mL tube containing 3 mL receptor fluid. entrapped air bubbles. Skin extraction: Cut out the skin diffusion area (1.77 cm) 0562 2.4. Place visually balanced microtubes in the from the skin section, and transfer to a 5-mL tube containing centrifuge rotor and operate the centrifuge at 3,000 rpm 3 mL of the extracting solution. for 10 min or at 1,000 rpm for 10 min. 0572 The receiver and the skin extract solutions were transferred quantitatively into vials and analyzed by HPLC. Penetration Protocol The analyses were usually performed within two days from Objective the sampling time. 0563 The study was designed to evaluate the skin per Calculation meability of a) non alcoholic emollient and b) waterless 0573 The permeating drug quantity per unit of the skin foam preparations comprising 5% and c)30% ascorbic acid, Surface area was calculated by using the following formula: and d) topical commercial/vitamin C serum with milicap sules (Holy Land Cosmetics—C The Success), which is also 0574 According to requirements specified in the percu annon alcoholic formulation comprising up to 12% ascorbic taneous absorption protocol, study results may be presented acid (and 5% ascorbyl palmitate). as shown below: US 2008/0069779 A1 Mar. 20, 2008 36

0575 % API detected: for unabsorbed dose, % pen Part A etration (retention) of API and % permeation of API (accumulation in receptor Solution) Non Aqueous Formulations API detected (ug) x 100 Example 1 API(%)=(%) applied dose (pig) Foamable Carriers Containing Polyols and a 0576) Intra-Canister Uniformity Polymeric Agent 0577 1. Representative product containers are col 0583) lected, sample test solutions are prepared and the content of the analyte is determined according to stan dard methods in the art. Variability of content is char acterized as percent difference or relative standard TECH PG- TECH PG- TECH PG deviation, as appropriate, according to the number of O14 O15 O16 samples evaluated. Ingredient 9% WW 9% WW 9% WW Propylene glycol (PG) 82.OO 92.00 6O.OO 0578 2. The results ascertain variability or uniformity Laureth-4 2.00 2.OO 2.OO within a given container in content of analytes (prima Glyceryl stearate and 4.OO 4.OO 3.00 rily active pharmaceutical ingredients, but also preser PEG-1OO Stearate vatives) taken from different parts of a pressurized (Simulsol 165) canister drug products PEG 4OOO 1O.OO Glycerin anhydrous 33.00 0579. 3. Two full canisters were shaken according to Hydroxypropylcellulose 2.00 2.OO 2.OO product instructions. About 1-3 g of Foam was dis (Klucel EF) pensed from each canister and discarded. Foam Sufi cient for two replicate sample solution preparations was Total 1OOOO 1OOOO 1OOOO then dispensed into a glass beaker. This represents the initial sample. A middle portion is then dispensed from each canister being about half the canister contents. 0584) Notes: This middle dispensed portion may be discarded or 0585. The compositions are substantially non-aqueous collected for testing purposes, as necessary. Foam Sufficient for two replicate sample solution preparations 0586. In order to create a foam, a propellant can be was then dispensed into a glass beaker. This represents added at a concentration of about 3% to about 25%. the final sample. A Small amount of formulation remains in the canister. The foam samples were stirred 0587. The compositions were shakable and produced to remove gas/air bubbles. From both the initial and foam of good quality. final foam portions from each canister 4 separate 0588 Composition TECH PG-015 contains the mini sample solutions are prepared and analyzed, 2 from the mum number of components that constitute a foamable initial portion and 2 from the final portion. The percent composition, which upon release from an aerosol pres difference is calculated as follows: surized container affords foam of Good or Excellent quality. It contains a diol (PG), a polymeric agent Difference between content determined in initial & (Klucel EF), and a non-ionic Surface active agent final portions x 100 (PEG-100 stearate and Laureth 4) Mean of content of initial & final portions 0589 Composition TECH PG-014 demonstrates that the addition of 10% PEG (secondary polar solvent) 0580 and the intra canister uniformity evaluated from maintains Good foam quality. the results. 0590 Composition TECH PG-016 demonstrates that a Stock Compositions mixture of two polyols (PG and glycerin maintains 0581. Non-limiting examples of how stock solutions are Good foam quality. This composition possesses high made up with and without API. Other stock solutions may be skin hydration effect. made using the same methodology by simply varying adding or omitting ingredients as would be appreciated by one of Example 2 the ordinary skills in the art. Foamable Carriers Containing Polyols EXAMPLES 0591) 0582 The invention is described with reference to the following examples. For the purpose of the Examples below it was sufficient to apply a vacuum only at the crimping stage TECH PG- TECH PG- TECH PG although for long term stability preferably any vacuum O21 O24 O25 should be applied during manufacture as well at a Sufficient Ingredient 9% WW 9% WW 9% WW pressure so that any oxygen remaining in the formulation is Propylene glycol (PG) 91.OO S8.00 43.OO virtually negligible. This invention is not limited to these Stearyl alcohol 2.OO 1.OO 1.OO examples and experiments. Many variations will suggest Laureth-4 2.OO 2.OO 2.OO themselves and are within the full intended scope of the Glyceryl stearate and 3.00 3.00 3.00 appended claims. US 2008/0069779 A1 Mar. 20, 2008

0603 Composition TECH PG-025 demonstrates that -continued the addition of 15% DMI (foam adjuvant) facilitates the formation of foam with Excellent quality. This com TECH PG- TECH PG- TECH PG position possesses high skin penetration enhancing O21 O24 O25 Ingredient 9% WW 9% WW 9% WW properties. 0604. In order to create a foam, a propellant can be PEG-1OO Stearate added at a concentration of about 3% to about 25%. (Simulsol 165) Glycerin 33.00 33.00 Hydroxypropylcellulose 2.00 3.00 3.00 Example 3 (Klucel EF) Dimethyl isosorbide (DMI) 1S.OO Foamable Carriers Containing Polyols

Total 100.00 100.00 1OOOO 0605)

0592. The following procedure was employed when the TECH PG- TECHPG- TECHPG compositions of Example 2 were produced. O26 O27 O28 Step 1: Preparation of Phase A Ingredient 9% WW 9% WW 9% WW Stearyl alcohol 2.OO 1.OO 1.00 0593 1. Heat Propylene glycol and stearyl alcohol to Propylene glycol (PG) 76.OO 46.OO 78.00 80-850 C. Laureth-4 2.OO 2.OO 2.00 Glyceryl stearate (and) 1...SO 0594 2. Add Klucel while mixing. PEG-1OO Stearate (Simulsol 165) Glycerin anhydrous 33.00 0595 3. Cool to 70-75° C. Add all other ingredients Hydroxypropylcellulose 2.OO 1...SO 1...SO while mixing. Agitation continues until solution uni (Klucel EF) formity is reached Dimethyl isosorbide (DMI) 1S.OO 1S.OO 1S.OO Glyceryl stearate 1.OO 1.00 0596 4. Cool solution to 30°C. with moderate mixing. Ceteareth-6 (and) 2.OO 1...SO Stearyl alcohol Step 2: Canisters Filling and Crimping (Macrogol cetostearyl ether) 0597 1. Each aerosol canister 35x70mm is filled with Total 100.00 1OOOO 100.00 30+5% g of the composition Foam quality Excellent Excellent Excellent 0598 2. Each canister was closed with an aerosol valve, using a vacuum crimping machine. 0606) Notes: Step 3: Pressurizing 0607 Composition TECH PG-027 demonstrates that a mixture of two polyols (PG and glycerin, plus DMI 0599 Propellant (mix of propane, butane and isobutane) (secondary polar solvent) maintains Excellent foam was added to each of the canisters. quality. This composition possesses high skin hydration effect. It further possesses high skin penetration 0600) Notes: enhancing properties. 0601 The compositions were shakable and produced 0608. In order to create a foam, a propellant can be foam of excellent quality. added at a concentration of about 3% to about 25%. 0602 Composition TECH PG-021, 24 and 25 demon Example 4 strates that the addition of 1-2% stearyl alcohol (foam adjuvant) facilitates the formation of foam with Excel Additional Foamable Carriers Containing Polyols, lent quality. Substituting Stearyl alcohol with stearic Having Excellent Foam Structure acid results in an excellent foam too. 0609)

TECH-PG TECH-PG TECH-PG TECH-PG TECH-PG O29 O3O O31 O32 O33 Ingredient % Wiw % Wiw % Wiw % Wiw % Wiw Propylene Glycol 91.0 58.0 43.O 46.0 78.0 Stearyl Alcohol 2.0 1.O 1.O 1.O 1.O Glycerin 33.0 33.0 33.0 Klucel EF 2.0 3.0 3.0 1.5 1.5 Laureth-4 2.0 2.0 2.0 2.0 2.0 Simulsol 165 3.0 3.0 3.0 1.5 Dimethyl Isosorbide 1S.O 1S.O 1S.O Macrogol Cetostearyl Ether 1.5 Glyceryl Stearate 1.O US 2008/0069779 A1 Mar. 20, 2008

Example 5 Additional Foamable Carriers which can be Used for Vitamins with and without an Active Agent WAN OO1. WAN OO2 WAN OO3 WAN OO4 0610) Gel Phase Stock 001 93.00% Gel Phase Stock 002 93.00% Gel Phase Stock 003 93.00% Gel Phase Stock 004 93.00% Gel Phase Gel Phase Gel Phase Gel Phase Ascorbic Acid S.00% S.00% S.00% S.00% Ingredient OO1 OO2 OO3 OO4 Niacinamide 2.00% 2.00% 2.00% 2.00% Propylene glycol 88.00 78.00 46.00 78.00 Total: 1OOOO 1OOOO 1OOOO 1OOOO Glycerin anhydrous 33.00 1O.OO Stearyl Alcohol 2.00 1.OO 1.00 2.OO Hydroxypropyl Cellulose 2.00 1...SO 1...SO 2.OO Laureth-4 2.00 2.OO 2.00 2.OO 0619) Notes: Glyceryl Monostearate? 1...SO PEG 1 OO Stearate GMS NE 2.00 1.OO 2.OO 0620. In order to create a foam, a propellant can be Macrogol Cetostearyl 1.00 1...SO 1.OO added at a concentration of about 3% to about 25%. ether PPG-15 stearyl ether 3.00 3.00 0621 Following addition of a propellant to the com Dimethyl isosorbide 1S.OO 1S.OO position, foamable composition, which upon release from an aerosol pressurized container affords foam of Total: 100.00 100.00 100.00 100.00 Good or Excellent quality. 0611. The polar solvents of the composition, including 0622 Following application of each of the foams on propylene glycol, glycerin and dimethyl isosorbide act as facial skin is favorable. The foam is easily spread and penetration enhancers for the vitamins and optional addi immediately absorbed into the skin with no extensive tional therapeutic agents. rubbing. 0612 Stock compositions were made from the above Example 8 formulations, which were used as described below. Example 6 Foamable Ascorbic Acid and Tocopheryl Acetate Compositions Foamable Ascorbic Acid Compositions 0613 Ascorbic acid was added to the carrier composi 0623 Ascorbic acid and tocopheryl acetate were concur tions of example 5, as follows. rently added to the carrier compositions of example 5, as follows.

WAS OO1 WAS OO2 WAS OO3 WAS 004 WAT OO1 WAT OO2 WAT OO3 WAT OO4 Gel Phase Stock 001 95.00% Gel Phase Stock 002 95.00% Gel Phase Stock 001 94.00% Gel Phase Stock 003 95.00% Gel Phase Stock 002 94.00% Gel Phase Stock 004 95.00% Gel Phase Stock 003 94.00% Ascorbic Acid S.00% S.00% S.00% S.00% Gel Phase Stock 004 94.00% Ascorbic Acid S.00% S.00% S.00% S.00% Total: 1OOOO 1OOOO 1OOOO 1OOOO Tocopheryl Acetate 1.00% 1.00% 1.00% 1.00%

Total: 1OOOO 1OOOO 1OOOO 1OOOO 0614) Notes: 0615. In order to create a foam, a propellant can be added at a concentration of about 3% to about 25%. 0624) Notes: 0616) Following addition of a propellant to the com 0625. In order to create a foam, a propellant can be position, foamable composition, which upon release added at a concentration of about 3% to about 25%. from an aerosol pressurized container affords foam of Good or Excellent quality. 0626. Following addition of a propellant to the com 0.617 Following application of each of the foams on position, foamable composition, which upon release facial skin is favorable. The foam is easily spread and from an aerosol pressurized container affords foam of immediately absorbed into the skin with no extensive Good or Excellent quality. rubbing. Example 7 Example 9 Foamable Ascorbic Acid and Nicinamide Compositions Foamable Niacinamide Compositions 0618) Ascorbic acid and niacinamide were concurrently 0627 Niacinamide was added to the carrier compositions added to the carrier compositions of example 5, as follows. of example 5, as follows. US 2008/0069779 A1 Mar. 20, 2008 39

provides the results of this short-term stability study, which indicated high compatibility between the polyol composi tion and the steroid drugs, which are known to be tempera WNIOO1 WNIOO2 ture-sensitive. Gel Phase Stock 001 96.00% Gel Phase Stock 002 96.00% Niacinamide 4.00% 4.00% % Degradation after Control: 1OOOO 1OOOO 4 weeks at 50° C.

TECH-PG 032 TECH-PG. O33 0628 Notes: Bethamethasone Valerate 0.12% 1.8% 1.7% Clobetasol Propionate 0.05% 4.2% S.0% 0629. In order to create a foam, a propellant can be Bethamethasone Dipropionate 0.05% O O added at a concentration of about 3% to about 25%. Fluocinolone Acetonide 0.025% 1.3% 1.7% Hydrocortisone Acetate 0.5% 1.6% 2.1% 0630. Following addition of a propellant to the com Hydrocortisone Butyrate 0.1% 2.6% 2.8 position, foamable composition, which upon release from an aerosol pressurized container affords foam of See Example 4 Good or Excellent quality. b) Prophetic Foamable Polyols Compositions, Example 10 Containing a Vitamin and a Steroid Drug Foamable Ascorbic Acid and Alpha Tocopherol 0636 Additionally, one or more of the following vita Compositions mins can be included in formulations TECH-PG 30, 31 and 33 (see Example 4): vitamin C (ascorbic acid) between 0.1 0631 Ascorbic acid and alpha tocopherol were concur and 5% say, 0.1% 1%, 2%. 3%, 4%, or 5%; vitamin C rently added to the carrier compositions of example 5, as (magnesium ascorbyl phosphate) 3%, retinol 1%, retinoic follows. acid 0.1%, niacinamide 2% and tocopherol 1% and Vitamin K. between 0.1 and 2% say, 0.1% or 1% or 2%, and are made up as indicted in Example 18. WAT OO1 WAT OO2 WAT OO3 WAT OO4 Example 12 Gel Phase Stock 001 94.00% Gel Phase Stock 002 94.00% Foamable Polyol Pharmaceutical Composition Gel Phase Stock 003 94.00% Gel Phase Stock 004 94.00% Comprising a Combination of Betamethasone Ascorbic Acid S.00% S.00% S.00% S.00% Dipropionate and Calcipotriol Alpha Tocopherol 1.00% 1.00% 1.00% 1.00% 0637) Total: 1OOOO 1OOOO 1OOOO 1OOOO

FXCLB1 FXCLB2 0632) Notes: Ingredient 9% WW 9% WW 0633. In order to create a foam, a propellant can be Propylene glycol 90.945 77.945 added at a concentration of about 3% to about 25%. Stearyl alcohol 2.00 1.00 Klucel EF 2.00 1...SO Laureth-4 2.00 2.00 0634) Following addition of a propellant to the com Simulsol 165 3.00 position, foamable composition, which upon release Macrogol Cetostearyl Ether 1...SO Glyceryl Stearate 1.00 from an aerosol pressurized container affords foam of Dimethyl isosorbide 1S.OO Good or Excellent quality. Calcipotriol O.OOS O.OOS Betamethasone Dipropionate O.OS O.OS Example 11 a) Foamable Polyols Compositions, Containing a 0638) Notes: Steroid Drug 0639 Composition FXCLB1 and FXCLB2 contain 0635 The following steroids were included in formula two active agents (a corticosteroid and a vitamin D tions TECH-PG 30, 31 and 33 (see Example 4): betametha derivative, which are known to exert a synergistic sone Valerate 0.12%, clobetasol propionate 0.05%, therapeutic effect in psoriasis. These compositions con betamethasone dipropionate 0.05%, fluocinolone acetonide tribute to enhanced skin penetration of the active 0.025%, hydrocortisone acetate 0.5% and hydrocortisone agents. butyrate 0.1%. All samples were stored at 50° C. for 4 0.640. The liquefied or gas propellant can be added at weeks, in order to assess their stability. The following table a concentration of about 3% to about 25%. US 2008/0069779 A1 Mar. 20, 2008

Example 13 Foamable Compositions Containing Polyethylene Glycol 0641)

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

PEG400 87.50 91SO 87.50 89.50 87.50 87.50 87.50 Klucel MX (hydroxypropyl cellulose) 0.50 O OSO O OSO O O.SO Klucel LF (hydroxypropyl cellulose) O O.SO O O.SO O O.SO O Lipocol C2 (POE (2) cetyl ether) 2.OO 2.00 O O O O O Myri 52 O O 2.OO 2.00 O O O Steareth-2 O O O O 2.00 2.OO O Dermofeel G1OL (Polyglyceryl-10 O O O O O O 2.00 Laurate) Propellant 10 6 10 8 10 10 10 Density O.O60 O.063 O.O63 0.055 O.OS2 O.OSO 0.075

0642) Notes: 0.643. The liquefied or gas propellant can be added at -continued a concentration of about 3% to about 25%. % Wiw % wiw % wiw % wiw 0644. The foams of this example have a non-ionic Cetostearyl alcohol 8.OO Surface active agent at a concentration of 2%. Total Klucel MF OSO PVP K-90 OSO amounts of Surface active agent foam adjuvant and Sisterna SPSO S.OO 8.OO 8.OO polymeric agent is in the range of 2.5%. Propylene glycol 2.50 DMI 55.50 59.00 59.50 2O.OO 0.645. The compositions are useful as carriers of vari Water pure 1O.OO ous active therapeutic active agents. Phenonip OSO OSO OSO OSO Propellant 8.OO 8.OO 8.OO 8.OO Example 14 Foamable Hygroscopic Composition Containing Dimethyl Isosorbide Example 15 0646) Comparison Between Polyethylene-Based Foamable Compositions with and without Gelling Agent 0647. The compositions of the test articles are provided % Wiw % wiw % Wiw % wiw in the following table. All foams were dispensed on a warm Oleyl alcohol 2.50 surface (38° C.), and the time to full collapse of the foam IPM S.OO S.OO S.OO was measured. As shown in the table, it has been strikingly Caprylic Capric Triglyceride S.OO S.OO S.OO 46.OO demonstrated that foam compositions without a gelling (MCT oil) agent exhibit a 100% breakdown within 30 seconds, while Epikuron P100 1O.OO foams containing gelling agent remained, with and without PPG-15 stearyl ether 2.OO Sorbitane stearate 8.OO 8.OO 8.00 2.OO surfactant, were stable for several minutes. This is relevant Glyceryl monostearate 1.OO 1.00 1.OO from the usability point of view, since a foam that is unstable Stearyl alcohol S.OO S.OO at skin temperature cannot be applied to large areas affec tively.

Formulation Formulations with gelling without gelling agent agent

PG33 PG34 PG35 PG36 TEC49 PG29 % Wiw % wiw % wiw % Wiw % wiw % Wiw

PEG 400 87.25 93.00 91.OO 92.00 90SO 93.50 Klucel GE (gelling agent) OSO OSO Ceteareth-16 2.OO 1.OO Emulsiying Wax NF 18O Steareth-10 O.40 O.SO US 2008/0069779 A1 Mar. 20, 2008

-continued

Formulation Formulations with gelling without gelling agent agent

PG33 PG34 PG35 PG36 TEC49 PG29 % Wiw % wiw % wiw % Wiw % wiw % wiw

PEG-40 Stearate 1.35 Steareth-2 O.60 1.OO O.SO 1.OO Span 60 2.70 Polysorbate 60 O.90 Propellant 6.OO 6.OO 6.OO 6.OO 8.OO 6.OO Collapse time (Seconds; &30 &30 &30 &30 240 >300 38° C.)

Example 16 TABLE 1-continued Foamable Hygroscopic Composition Containing Polyethylene Glycol with No Surfactant Exemplary Concentrations of Examples of Active Agents EXPAND Additional Exemplary 0648) therapeutic agent Concentration Exemplary Use Ciclopirox 190 Fungal infection, Seborrhea, dandruff, % Wiw Clindamycin 2% Bacterial infection, acne, rOSacea, PEG 400 93.50 AZelaic acid 15% Acne, rosacea, Klucel GF OSO pigmentation disorder and Propellant (Butane/propane) 6.OO various dermatoses Foam quality E Metronidazole O.25%-2% Rosacea, bacterial infections Density O.09 and parasite infestations Diclofenac 190 Osteoarthritis, joint pain Tacrolimus O.2% Atopic dermatitis, eczema and inflammation Benzoyl peroxide 1%-10% Acne Example 17 Alpha-hydroxy acids 1%-20% Aging, wrinkles Salicylic acid 1%-10% Acne Hydroquinone 190-10% Pigmentation disorders Prophetic Foamable Vitamin Compositions with an Caffeine 190-10% Cellulite Additional Therapeutic Agent Coenzyme Q 10 0.1%-10% Aging, pigmentation 0649. Foamable vitamin compositions are made up with. an active agent at either say 1%, 2%. 3%, 4%. 5%, 10%, 15%, 20%, 25%, 30% or more by weight of composition and 0651. The above examples represent different drug added to any of the compositions illustrated in Examples classes and it is to be understood that other drugs belonging 5-10 wherein the percentage amount of one or both polar to each of the classes represented above may be included and Solvents is reduced by an approximately equivalent amount used in the compositions in a safe and effective amount. by weight in the composition. Example 18 0650 More particularly exemplary concentrations of additional therapeutic agents in foamable compositions are Prophetic Foamable Carriers which can be Used for set out in Table 1. Each active agent is added into, for Vitamins with and without an Active Agent example, any of the carriers listed in any of Examples 5-10 0652) a) Foamable vitamin carriers are made up with above in a therapeutically effective concentration and PEG or hexylene glycol or butylene glycol instead of amount. The methodology of addition is well known to those glycerin anhydrous by weight of composition and of the art. The composition is adjusted in each case so that added to any of the compositions illustrated in it is made up to 100% w/w as appropriate by polar solvent. Examples 5-10 0653 b) Foamable vitamin carriers are made up with TABLE 1. PEG or hexylene glycol or butylene glycol instead of propylene glycol by weight of composition and added Exemplary Concentrations of Examples of Active Agents EXPAND to any of the compositions illustrated in Examples 5-10 Additional Exemplary Example 19 therapeutic agent Concentration Exemplary Use Hydrocortisone acetate 190 Steroid responsive Prophetic Foamable Vitamin Compositions with an Betamethasone valerate O.1% inflammation and psoriasis or Additional Active Agent Clobetasol propionate O.05% atopic dermatitis Acyclovir 59% Viral infection, herpes 0654 Foamable vitamin compositions are made up with. an active agent at either say 1%, 2%. 3%, 4%. 5%, 10%, US 2008/0069779 A1 Mar. 20, 2008 42

15%, 20%, 25%, 30% or more by weight of composition and added to any of the compositions illustrated in Example 19 -continued wherein the percentage amount of one or both polar solvents is reduced by an approximately equivalent amount by AAPO11 weight in the composition. More particularly examples of Appearance additional active agents are as described in Example 19 above. Quality Good Color White Example 20 Odor No Odor Shakability Good ph (1:5) 5% Ascorbic Acid, PEG or PG, and Surfactant or Microscope No Polymeric Agent crystals Centrifugation 1 K Creaming 0655) 35% Density (griml) O.138 Hardness (g) 9.54 AAPOO6 AAPOO7 AAPOO8 AAPOO9 Collapse time (sec.) >3OO Ingredient

PEG 200 93.00 93.00 Propylene Glycol 93.00 93.00 0660) Note: (PG) Steareth-2 2.OO 2.OO 0661 Replacing PEG with PG resulted in poor foam Klucel EF 2.OO 2.OO Ascorbic acid S.OO S.OO S.OO S.OO Example 22 Total: 100.00 100.00 1OOOO 1OOOO Propellant (1681) 8.OO 8.OO 8.OO 8.OO propane:iso 5% Ascorbic Acid, PEG or PG or DMI, and butane:n- Surfactant with and without Polymeric Agent butane mixture Appearance 0.662 Quality Good Good Good Good Color White White White White Odor No Odor No Odor No Odor No Odor Shakability Good Good Good Good AAPO12 AAPO13 AAPO14 AAPO15 Microscope No No crystals No crystals No crystals crystals Ingredient Centrifugation 3K Homogenous Homogenous PEG 200 93.00 Density (griml) O. 102 0.055 0.770 O.078 Propylene Glycol 93.00 Hardness (g) 10.01 38.74 4922 11.23 DMI 89.00 91.OO Collapse time (sec.) 70 >3OO >300 30 Glyceryl 2.OO 3.00 nonOStearate Stearyl alcohol 3.00 0656) Note: Steareth-21 2.OO 2.OO Klucel EF 1.OO 1.OO 0657 All the formulations produced good quality Ascorbic acid S.OO S.OO S.OO S.OO foam without crystals Total: 1OOOO 1OOOO 100.00 100.00 Propellant (1681) 8.OO 8.OO 8.OO 8.OO 0658) 5% Ascorbic acid is solubilized in high levels of propane:iso PEG or PG butane:n- butane mixture Example 21 Appearance Quality Good Good Good Good 5% Ascorbic Acid, PEG and Surfactant Color White White White White Odor Faint Odor No Odor Faint Odor No Odor 0659 Shakability Good Good Good Good ph (1:5) Microscope Crystals No crystals Crystals No crystals Density (griml) 0.077 O.09S 0.157 O.098 AAPO11 Hardness (g) 14.58 11.82 FG 37.55 Collapse time (sec.) 40 >3OO Ingredient

PEG 200 93.00 Propylene Glycol 0663) Note: PEG-40 Stearate 2.OO Ascorbic acid S.OO 0664 All the formulations produced good quality Total: 1OOOO foam. Propellant (1681) propane:iso-butane:n- 8.OO butane mixture 0665 5% Ascorbic acid is solubilized in high levels of PEG or PG but not in DMI US 2008/0069779 A1 Mar. 20, 2008 43

Example 23 -continued 5%-7% Ascorbic Acid, PEG and Surfactant with a Ingredient CCPO11 CCPO12 Fatty Alcohol but without Polymeric Agent 9. Foam Color Yellow Yellow 0666) PFF Color Off white Off white Microscope No No Crystals Crystals

AAPO19 AAPO20 AAPO21 AAPO29 0671) Note: Ingredient 0672 All the formulations produced excellent quality PEG 200 91.OO foam. Propylene Glycol 87.OO 91.OO 92.50 Oleyl alcohol O.SO 0673 Potentially synergistic combination of quercitin Cetostearyl alcohol 8.OO Steareth-2 2.00 2.OO 2.OO and roSmarinic acid. Ascorbic acid 30 - - - - S.OO 0674) A significant excess of two types of reactive Total: 100.00 100.00 100.00 100.00 antioxidant flavonoids is provided to be available to Propellant (1681) 8.OO 8.00 8.OO 8.OO react in place of vitamin C. propane:iso butane:n- butane mixture Part B Appearance Aqueous Formulations Quality Good Good Good Good Color White White White White E le 24 Odor No Odor No Odor No Odor No Odor Xample Shakability Good Good Good Good Microscope No Crystals- Crystals- No 5% Ascorbic Acid Plus a-Tocopherol crystals PFF& Foam PFF& Foam crystals Density (griml) O.12O 0675) Hardness (g) 35.98 Collapse time (sec.) >300

AAPOO1 AAPOO3 AAPOO4 0667) Note: Ingredient 0668 All the formulations produced good quality PPG-15 Stearyl Ether 1S.OO 14.00 12.00 foam Octyldodecanol 12.00 11.OO 10.00 Oleyl alcohol 1O.OO 1O.OO 9.00 - 0 - Cyclomethicone 3.00 3.00 4.OO 0669 5% Ascorbic acid is solubilized but increasing Glyceryl monostearate 6.OO 6.OO S.OO the amount to 7% results in crystals appearing in the pre Stearyl alcohol 6.OO 6.OO 6.OO foam and foam compositions Cocoglycerides 6.OO 6.OO 6.OO Myristyl alcohol 2.50 2.50 2.50 Hydrogenated Castor Oil 3.SO 3.SO 3.SO Example 23A Diisopropyl adipate 1O.OO 1O.OO 9.00 Aluminum starch 1O.OO 7.OO 7.00 Octylensuccinate Quercitin and Rosmarinic Acid, PG and Surfactant Ascorbic acid S.OO S.OO S.OO with and without Ascorbic Acid a-Tocopherol 1.OO 1.OO 1.00 Water 1O.OO 1S.OO 2O.OO 0670) Total: 1OOOO 1OOOO 100.00 Propellant (1681) propane:iso- 8.OO 8.OO 8.00 butane:n-butane mixture Appearance ngredient CCPO11 CCPO12 Quality Good Good Good propylene glycol 96.80 91.8O Color White White White (PG) Odor No Odor No Odor No Odor steareth 2 2.OO 2.OO Shakability Good Good Good Rosmarinic acid O.2O O.2O Microscope Crystals Crystals No Quercetin 1.OO 1.OO crystals Ascorbic acid S.OO

Total: 1OOOO 1OOOO Propellant (5515) 8.OO 8.OO 0676 Note: E.td 0677 All the formulations produced good quality Foam Quality Excellent Excellent foam Foam Odor No Odor No Odor Foam Shakability Good Good 0678) By increasing the amount of water to about 20% eliminates crystals in the foam compositions. US 2008/0069779 A1 Mar. 20, 2008 44

Example 25 -continued 5% Ascorbic Acid Plus Preservative AAPO16 AAPO17 AAPO18 0679) Appearance

Quality Excellent Good- Excellent AAPOOS Color White White White Odor No Odor No Odor No Odor Ingredient Shakability Good Good Good Mineral oil light 5.60 ph (1:5) 2.91 Isopropyl myristate 5.60 Microscope No crystals No crystals No crystals Glyceryl monostearate O.45 Centrifugation 1 K Creaming 60% Homogenous Separation 30% Stearyl alcohol O.85 Centrifugation 3K Creaming 20% Creaming 40% Sedimentation Polysorbate 80 O.90 40% PEG-40 Stearate 2.60 Xanthan gum O.30 Density (griml) O.O34 O.064 Avice RC 581 2.00 Hardness (g) 14.46 10.08 Sodium Citrate 1.00 Collapse time (sec.) >3OO 190 Ascorbic acid S.OO Disodium metabisulfite O.10 EDTA disodium O.10 Sharomix 824 1.00 Water 74SO 0681) Notes:

Total: 100.00 0682 All the formulations produced good quality Propellant (1681) propane:iso- 8.00 foam without crystals butane:n-butane mixture Appearance 0683 Formulation 17 breaks quickly without mechani Quality Excellent cal stimulation Color White Odor No Odor Shakability Good Example-27 ph (1:5) 3.69 Microscope No 5%-35% Ascorbic Acid Plus Preservative and crystals Density (griml) O.O39 Polymer with and without Mineral Oil Hardness (g) 9.16 Collapse time (sec.) >3OO 0684)

Example-26 AAPO22 AAPO23 AAPO24 AAPO2S Ingredient 5%-20% Ascorbic Acid Plus Preservative, Different Polymeric Agents and with and without Mineral Mineral oil light 12.00 Polysorbate 80 2.00 2.OO 3.00 2.OO Oil Avice RC 581 2.00 2.OO 2.OO Pemulen TR2 O.40 0680) Ascorbic acid 25.00 3O.OO S.OO 3S.OO Disodium metabisulfite O.SO O.6O O.10 O.70 Water 70.50 65.40 79.50 60.30

Total: 100.00 1OOOO 100.00 1OOOO AAPO16 AAPO17 AAPO18 Propellant (1681) 8.00 8.OO 8.00 8.OO Ingredient propane:iso butane:n-butane mixture Mineral oil light 11.00 11.00 Appearance Polysorbate 80 O.90 2.OO PEG-40 Stearate 2.60 Quality Excellent Excellent Excellent Excellent Sucrose ester 1811 2.00 Color White White White White Xanthan gum O.30 Odor No Odor No Odor No Odor No Odor Avice RC 581 2.00 2.OO Shakability Good Good Good Good CMC O.SO Microscope No No No Crystals Ascorbic acid S.OO S.OO crystals crystals crystals PFF& Disodium O.10 O.10 Foam metabisulfite Hardness (g) 10.39 13.59 11.34 Water 78.10 81.40 75.90

Total: 100.00 100.00 1OOOO Propellant (1681) 8.00 8.00 8.OO 0685. Notes: propane:iso-butane:n- butane mixture 0686 All the formulations upto about 30% ascorbic acid produced good quality foam without crystals. US 2008/0069779 A1 Mar. 20, 2008 45

Example-28 -continued Octyl Dodecanol and Isopropyl Myristate Silicone Compositions, with Preservative AAPO31 Quercetin 3.00 1.OO 0687) Water 80.2O 77.20

Total: 1OOOO 1OOOO Propellant (1681) 8.OO 8.OO AAPO26 AAPO27 AAPO28 propane:iso-butane:n- butane mixture Ingredient Appearance

Octyl dodecanol 6.OO 6.OO Quality Excellent Excellent Cyclomethicone 1.OO 1.00 1.OO Color yellow yellow Isopropyl myristate 6.OO Odor No Odor No Odor Glyceryl monostearate O.SO O.SO OSO Shakability Good Good Stearyl alcohol 1.OO 1.00 1.OO Polysorbate 80 1.OO 1.00 PEG-40 Stearate 2.50 2.50 Steareth-2 3.00 Steareth-21 2.OO 0692) Notes: Avice RC 581 2.OO 2.00 2.OO Ascorbic acid S.OO S.OO S.OO 0693 All the formulations produced excellent quality Disodium metabisulfite O.20 O.20 O.2O foam EDTA disodium O.10 O.10 O.10 Sharomix 824 1.OO 1.00 1.OO incorporate Substantial Water 79.70 79.70 78.20 0694 It was possible to amounts of flavonoid in the above formulations Total: 100.00 100.00 1 OOOO Propellant (1681) 8.OO 8.00 8.OO propane:iso-butane:n- Example-30 butane mixture Appearance Rosmarinic Acid Composition with and without Quality Excellent Excellent Excellent Ascorbic Acid and in Combination with Quercitin Color White White White Odor No Odor No Odor No Odor 0695) Shakability Good Good Good ph (1:5) Microscope No crystals No crystals No crystals Density (griml) AAPO32 AAPO33 AAPO34 AAPO3S Hardness (g) 10.03 9.64 Ingredient Mineral oil light 11.OO 11.OO 11.00 0688) Notes: Propylene Glycol 92.8O Polysorbate 80 O.90 O.90 O.90 PEG-40 Stearate 2.60 2.60 2.60 0689 All the formulations produced good quality Steareth-2 2.OO foam without crystals Xanthan gum O.30 O.30 O.30 Avice RC 581 2.OO 2.OO 2.00 0690 Formulation 28 breaks quickly without mechani Ascorbic acid S.OO S.OO cal stimulation Rosmarinic acid O.2O O.2O O.2O O.20 Quercetin 1.00 Water 78.00 83.OO 82.OO Example-29 Total: 1OOOO 1OOOO 1OOOO 100.00 Propellant (1681) 8.OO 8.OO 8.OO 8.00 Mineral Oil and Flavonoid Composition with and Appearance without Ascorbic Acid Quality Excellent Good Excellent Excellent Color yellow White White yellow 0691) Odor No Odor No Odor No Odor No Odor Shakability Good Good Good Good Microscope No No No No crystals crystals crystals crystals AAPO31 Ingredient 0696) Notes: Mineral oil light 11.OO 11.OO Polysorbate 80 O.90 O.90 0697 All the formulations produced excellent quality PEG-40 Stearate 2.60 2.60 Xanthan gum O.30 O.30 foam without crystals Avice RC 581 2.OO 2.OO Ascorbic acid S.OO 0.698) It was possible to incorporate Substantial amounts of flavonoids in the above formulations US 2008/0069779 A1 Mar. 20, 2008 46

Part C -continued Microsponge(R) Prophetic Formulations Stock Formulation Example-31 Ingredient Oil in Water Foam Formulation Comprising Citric acid O.18 MicroSponges Loaded with Active Agent Sodium citrate O.14 Water, purified 27.48 0699) Sharomix 824 O.20 Total 100.00

% Wiw % Wiw Ingredient 0707) Drug MicroSponge (R) 10 10 Mineral oil 5 15 Isopropyl myristate 5 15 Ingredient 8. b C d Glyceryl monostearate 1 1 Brij 72 3.00 3.00 Stock 90-00 95-00 75-OO 85-OO Brij 721 2.OO 2.00 MicroSponges 1O-OO 1S-OO 2S-OO 1S-OO Methocel E15 O.26 O.26 Phenonip O.6O O.60 Total 1OO-OO 1OO-OO 1OO-OO 1OO-OO Propellant 8.OO 8.00 Propellant 1O-OO 1O-OO 1O-OO 1O-OO Water to 1OOOO 100.00 0708) Notes: 0700) Notes: 0709) To the stock formulation 100-X microsponges 0701. This prophetic formulation can be adapted for a of X w/w % may be added say from about 1% to about range of low to Medium oil content oil-in-water emul 25% w/w of the formulation sion foam. 0710. This prophetic formulation can be adapted for a 0702. The amount of microsponges may be varied range of high oil content oil-in-water emulsion foam of from about 1% to about 25% of the formulation by upto about 90 oil phase. increasing or decreasing the amount of the aqueous 0711) Any active agent suitable for loading in micro phase. sponges may be used, such as benzyl peroxide, tretin 0703. Any active agent suitable for loading in micro oin, hydroquinone and the like sponges may be used, such as benzyl peroxide, tretin 0712. In a preferred formulation the microsponges are oin, hydroquinone and the like loaded with one or more vitamins or with one or more 0704. In a preferred formulation the microsponges are flavonoids or combinations thereof loaded with one or more fat soluble vitamins or with one or more fat soluble flavonoids or combinations 0713 The liquefied or gas propellant can be added at thereof a concentration of about 3% to about 35%. 0705 The liquefied or gas propellant can be added at Example-32 a concentration of about 3% to about 25%. Water in Oil Foam Formulation Comprising Example-32 MicroSponges Loaded with Active Agent High Oil/Petrolatum in Water Foam Formulation 0714) Comprising MicroSponges Loaded with Active Agent 0706) Ingredient % ww Drug Micosponge (R) 1O.OO Isopropyl Myristate 400 Lanolin 4...SO Stock Formulation Beeswax 18O Glyceryl monostearate and PEG100 0.75 Ingredient stearate (Simulsol 165 Seppic) Glyceryl oleate O.70 White Petrolatum (sofmetic) 42.OO Arlatone 2121 (Uniquema) O.45 Mineral oil, light 18.00 Arlacel P135 (Uniquema) O.35 Cetearyl alcohol 2.OO Ceteth-2 (Lipocol C2) 4.6O Ceteth-20 (Lipocol C-20) 2.16 Sucrose ester SP3O 0.75 Span 80 3.84 Sucrose ester SP10 0.75 Behenyl alcohol 1.OO Xanthan gum O.35 Aluminum starch octenyl Succinate 3.00 Water purified 30.00 US 2008/0069779 A1 Mar. 20, 2008 47

0724. In a preferred formulation the microsponges are -continued loaded with one or more vitamins or with one or more flavonoids or combinations thereof Ingredient % Wiw 0725. The liquefied or gas propellant can be added at Disodium EDTA O.30 a concentration of about 3% to about 25%. Magnesium Sulphate O.SO Mineral oil light to 100.00 Propellant 8.00 Example-34 Petrolatum Non Aqueous Foam Formulations 0715. This prophetic formulation can be adapted for a Comprising MicroSponges Loaded with Active range of high oil content water in oil emulsion foam of Agent upto about 80% oil phase by reducing the water con 0726) tent. 0716. The amount of microsponges may be varied from about 1% to about 25% of the formulation by Ingredient a % ww b% Wiw c 96 ww increasing or decreasing the amount of the aqueous phase. Drug Micosponge (R) 1O.OO S.OO 1S.OO Petrolatum, (sofmetic) 75.00 83.00 73.00 Mineral oil, light 3.00 7-OO 7-OO 0717. Any active agent suitable for loading in micro PPG-15 stearyl ether S.OO sponges may be used, such as benzyl peroxide, tretin Lecithin S.OO S.OO S.OO oin, hydroquinone and the like Sorbitan stearate 2.00 Control: 100.00 100.00 1OOOO 0718. In a preferred formulation the microsponges are Propellant 1O.OO 10.00 1O.OO loaded with one or more fat soluble vitamins or with one or more fat soluble flavonoids or combinations thereof 0727. This prophetic formulation can be adapted for a high range of petrolatum content of upto about 90%. 0719. The liquefied or gas propellant can be added at a concentration of about 3% to about 25%. 0728. The amount of microsponges may be varied from about 1% to about 25% of the formulation by Example-33 increasing or decreasing the amount of the petrolatum 0729) Any active agent suitable for loading in micro Oily Foam Formulation Comprising MicroSponges sponges may be used, such as benzyl peroxide, tretin Loaded with Active Agent oin, hydroquinone and the like 0720) 0730. In a preferred formulation the microsponges are loaded with one or more vitamins or with one or more flavonoids or combinations thereof Ingredient % Wiw 0731. The liquefied or gas propellant can be added at a concentration of about 3% to about 35%. Drug Micosponge (R) 10.00 Caprylic? Capric Triglyceride (MCT oil) 47.50 PPG-15 stearyl ether 1.00 Example-35 Glyceryl monostearate 2.00 Stearyl alcohol 4.70 Hydrophilic Solvent Foam Formulation Comprising Sorbitan stearate 2.00 MicroSponges Loaded with Active Agent Epikuron P100 8.00 PVP K-90 O.SO 0732) Foam Propylene glycol (PG) 8.00 Purified water 8.00 Sharomix 824 O.30 Propellant 8.00 Control: 100.00 % Wiw % Wiw Drug MicroSponge (R) 10 10 Propylene glycol To 100 PEG 400 To 100 0721 This prophetic substantially non aqueous formu Ceteth 2 1 1 lation can be adapted for a medium range of MCT oil HPMC O.S O.S3.OO content say plus or minus 10% oil by varying the Propellant 8.00 8.OO water/PG content. 0722. The amount of microsponges may be varied 0733. This prophetic formulation can be adapted for a from about 1% to about 25% of the formulation by high range of hydrophilic solvent content of upto about increasing or decreasing the amount of the oil, PG and aqueous phases. 95%. 0734 The amount of microsponges may be varied 0723) Any active agent suitable for loading in micro from about 1% to about 25% of the formulation by sponges may be used, such as benzyl peroxide, tretin increasing or decreasing the amount of the hydrophilic oin, hydroquinone and the like solvent US 2008/0069779 A1 Mar. 20, 2008 48

0735. Any active agent suitable for loading in micro 0744. In a preferred formulation the microsponges are sponges may be used, such as benzyl peroxide, tretin loaded with one or more vitamins or with one or more oin, hydroquinone and the like flavonoids or combinations thereof. 0736. In a preferred formulation the microsponges are 0745. In the example active agent is present in the loaded with one or more vitamins or with one or more foam formulation and in the microSponges. Moreover, flavonoids or combinations thereof it is possible for the microSponges to have loaded the 0737. The liquefied or gas propellant can be added at same and or other or different active agents. a concentration of about 3% to about 35%. 0746. The liquefied or gas propellant can be added at Example-36 a concentration of about 3% to about 25%. Liquid Wax Foam Formulation Comprising Section D MicroSponges Loaded with Active Agent Pharmaceutical and Cosmetic Prophetic 0738 Stock A Formulations Example 37 Ingredients A1 Exemplary Prophetic Foams Containing Active Jojoba Oil 2O Pharmaceutical Ingredients (API) Pemulen TR-2 O.62 Polysorbate 80 3 0747 Exemplary concentrations of active ingredients in Purified water 76.38 foamable compositions are set out in Table 2 and in the Control: 100 following additional prophetic examples. Each active ingre dient is added into, for example, any of the carriers listed in any of the above Examples in a therapeutically effective 0739 Stock B concentration and amount. The methodology of addition is well known to those of the art. The composition is adjusted in each case so that it is made up to 100% w/w by addition or reduction of one or more solvents as is appropriate to the Ingredients B1 active agents concerned. Isostearic acid 30 Caprilicicapric triglycerides 2.5 0748. A Exemplary Concentration Ranges of Some Oleyl alcohol 7.5 APIs which are Addable to Foams Sorbitan Stearate O.65 Imiquimod 5 TABLE 2 Benzyl alcohol 2 Xanthan gum O.35 Hydroxypropyl methylcellulose O.35 Class Concentration Exemplary Use Glycerin 2 Hydrocortisone 196 Steroid responsive inflammation and Polysorbate 60 2.5 acetate Methyl hydroxybenzoate O.2 Betamethasone O.12% psoriasis or atopic dermatitis Propyl hydroxybenzoate O.O2 valerate Purified water 46.93 Clobetasol O.05% proprionate Total: 1OO Acyclovir 59 Viral infection, herpes Ciclopirox 196 Fungal infection, seborrhea, dandruff, Clindamycin 1-2% Bacterial infection, acne, rosacea, AZelaic acid 15% Acne, rosacea, 0740 pigmentation disorder and various dermatoses Metronidazole O.25%-296 Rosacea, bacterial infections and parasite infestations Ingredient 8. b Diclofenac 196 Osteoarthritus, joint pain Tacrolimus O.2% Atopic dermatitis, eczema and Stock A or B 90-00 95-00 inflammation Microsponges 1O-OO 1S-OO Caffeine 59 anti-cellulite Total 1OO-OO 1OO-OO Clotrimazole 196 Fungal infection Propellant 1O-OO 1O-OO Lidocaine base 296 Local anesthetic Terbinafine HCL 196 Fungal infection Gentamycin O.1% Bacterial skin infections, burns or ulcers 0741. This prophetic formulations can be adapted for a Dexpanthenol 59 Wounds, ulcers, minor skin infections high range of liquid wax content of upto about 70%. Urea 5-10% Emollient and keratolytic Atopic dermatitis, eczema, ichthyosis 0742 The amount of microsponges may be varied and hyperkeratotic skin disorders from about 1% to about 25% of the formulation by Ammonium 12%-17.5% Dry scaly conditions of the skin increasing or decreasing the amount of water and liquid lactate including ichthyosis WaxS Povidone-iodine 10% Antimicrobial —antiseptic Benzoyl peroxide 190-10% Acne 0743 Any active agent suitable for loading in micro Alpha-hydroxy 1%-20% Aging, wrinkles sponges may be used, such as benzyl peroxide, tretin acids oin, hydroquinone and the like US 2008/0069779 A1 Mar. 20, 2008 49

TABLE 2-continued -continued

Class Concentration Exemplary Use AAP-O16 AAPO23 Salicylic acid 190-10% Acne Hydroquinone 190-10% Pigmentation disorders Avice RC 581 2.OO 2.OO calcipotriol O.OOS Psoriasis Polysorbate 80 O.90 2.OO calcitriol O.OO3 Psoriasis Water pure 78.00 65.40 Ascorbic acid S.OO 3O.OO Disodium metabisulfite O.2O O.6O B Prophetic Steroid Compositions 0749. The following steroids can be included in carriers, Total 1OOOO 1OOOO compositions and foams: betamethasone Valerate 0.12%, Propellant 8.OO 8.OO clobetasol propionate 0.05%, betamethasone dipropionate 0.05%, fluocinolone acetonide 0.025%, hydrocortisone acetate 0.5% and hydrocortisone butyrate 0.1%. 0754) C Prophetic Vitamin and Steroid Compositions 0750 Additionally, one or more of the following vita mins can be included in the carriers, compositions and Sample name Time point Sample conc. (% w/w) foams: vitamin C (ascorbic acid) between 0.1 and 5% say, AAPO16- TO S.O1 T-2w, 25° C. S.OO 0.1% 1%, 2%. 3%, 4%, or 5%; vitamin C (magnesium T-2w, 40° C. S.18 ascorbyl phosphate) 3%, retinol 1%, retinoic acid 0.1%, T-2w, Sun 4.79 niacinamide 2% and tocopherol 1% and Vitamin K. between 0.1 and 2% say, 0.1% or 1% or 2%; vitamin D, a derivative or analogue thereof such as calcipotriol between 0.001% to about 0.02% preferably 0.005%; calcitriol between about 0755) 0.001% to about 0.02% preferably about 0.003%; such as tacalcitol between about 0.001% to about 0.02% w/w pref erably 0.004%. Sample name Time point Sample conc. (% w/w) D Prophetic Vitamin Compositions with or without an AAPO23 TO 29.75 Additional Therapeutic Agent T-2w, 25° C. 30.79 T-2w, 40° C. 30.51 0751. Foamable vitamin compositions at either say 0.1% T-2w, Sun 29.07 1%, 2%. 3%, 4%, or 5%, by weight of composition are made *glass vial with pre foam formulation (PFF) + 8% pentane located in the up with or without an active agent and added to any of the Sll. vehicles or compositions illustrated in the above Examples. E. Different Drug Classes Note: 0752 All the above examples represent different drug 0756. No significant breakdown was seen in any of the classes and it is to be understood that other drugs belonging samples save possibly in the Sun exposed samples. to each of the classes represented above or described else where in the specification may be included and may be used 0757. See Examples 26 and 27 above for physical in the compositions in a safe and effective amount. parameters. Section E Example 40 Chemical Stability Test Stability of Ascorbic Acid in Non-Aqueous Foam Formulations Example 39 0758) Stability of Ascorbic Acid in Aqueous Foam Formulations 0753) AAPO29 AAPOO7 Propylene Glycol 92.50 93.00 Oleyl alcohol OSO 2.00 Steareth-2 2.OO AAP-O16 AAPO23 Ascorbic acid S.OO S.OO Mineral oil light 11.OO Total 1OOOO S.OO PEG-40 Stearate 2.60 Propellant (1681) 8.OO 8.00 Xanthan gum O.30 US 2008/0069779 A1 Mar. 20, 2008 50

0759) -continued Average in 90 of applied dose Sample conc. Sample name Time point (% w/w) Vitamin C AAPO16- AAPO23- AAPO29- Serum AAPOO7- TO S.OO (n = 3) (n = 3) (n = 3) (n = 2) T-2w, 250 C S.10 T-2w, 400 C S.O.9 Total skin S.69 4.13 1.08 2.33 T-2w, Sun 5.50 (Tape 2, 3 and SE) Total Mass 89.37 77.56 87.90 78.58 balance 0760) *Commercial cosmetic product *Tape 1 = Surface; Tape 2 = Upper Stratum Corneum; Tape 3 = Lower Stratum Corneum; SE = is the extract of the skin remaining after removal of Tapes 1, 2, and 3, and includes the hair follicle root. Sample conc. (% 0765 Comment: Sample name Time point ww The penetration study results (presented as a mean of “n” AAPO29- TO 5.14 repeat experiments) may indicate that T-2w, 25° C. 4.8O T-2w, 40° C. 4.83 0766 a) The aqueous formulations prepared as T-2w, Sun 4.88 described in Examples 26 and 27 have about double the penetration in whole skin compared to that seen in the *glass vial with PFF + 8% pentane located in the Sun. comparative aqueous commercial preparation. 0761) Note: 0767 b) Increased loading of vitamin C in the aqueous formulations did not appear to affect the amount found 0762. No breakdown of substance was seen in any of within the whole skin, however increased loading did the samples. result in higher levels passing through the skin indi cating that Some transport mechanism being operative. 0763) See Examples 20 and 23 above for physical parameters 0768 c) All the formulations prepared as described in Examples 26, 27 and 23 resulted in higher penetration Section F into the stratum corneum. 0769 d) The non aqueous formulation as described in Permeation Test Example 23 disclosed the lowest levels in the remain ing skin and of penetration through the skin. Without Example 41 being bound by any theory, water and or minerals may play a role in transport and the absence thereof retards Penetration of Ascorbic Acid from Aqueous and penetration except to an extent in the stratum corneum. Non Aqueous Formulations In and Through Skin The waterless formulation may be useful where deliv ery of the Vitamin, flavonoid or other agent is not 0764 See Methodology for the protocol. Formulations desirable systemically and is only required in the 16, 23, and 29 below appear in Examples 26, 27 and 23 Stratum COrneum. respectively as well as in Examples 39 and 40 above. What is claimed is: 1. A foamable hygroscopic Vitamin and or flavonoid Average in 90 of applied dose containing composition comprising: Vitamin C a. at least one agent selected from the group consisting of AAPO16- AAPO23- AAPO29- Serum vitamins and flavonoids; and (n = 3) (n = 3) (n = 3) (n = 2) b. at least one hygroscopic Solvent at a Sufficient concen Vit C 59 30% 59 12% (plus 5% tration to provide an AW value of the hygroscopic ascorbyl palmitate) vitamin and or flavonoid containing composition of Aqueous Yes Yes No Yes less than 0.9; Tape 1 70.45 39.48 82.18 53.24 Tape 2 3.45 1.38 148 1.06 c. a foam stabilizer selected from the group consisting of Tape 3 O.34 O.S4 O.20 O.08 at least one Surface-active agent; and at least one SE 1.90 2.21 O40 1.19 polymeric agent selected from the group consisting of RC (as is) 13.23 33.96 3.64 23.01 a bioadhesive agent, a gelling agent, a film forming Total Stratum 3.79 1.92 1.68 1.14 Corneum (Tapes agent and a phase change agent and mixtures thereof; 2, 3) and Total without tape 1 18.92 38.09 5.72 25.34 (Tape 2, 3, SE and d. a hydrocarbon propellant at a concentration of about RC) 3% to about 25% by weight of the total composition; and US 2008/0069779 A1 Mar. 20, 2008 51

wherein the composition is contained in a pressurized 16. The foamable composition of claim 15, wherein the container to which a vacuum was applied prior to filling polyol is selected from the group consisting of a diol, a triol with a hydrocarbon propellant, is substantially flowable and a saccharide, and provides a foam upon release; wherein applying a vacuum to and filling a canister wherein the diol is selected from the group consisting of containing the composition with hydrocarbon propel propylene glycol, butanediol, butenediol, butynediol, lant contributes to stabilize the agent against degrada pentanediol, hexanediol, octanediol, neopentylglycol, tion. 2-methyl-1,3-propanediol, diethylene glycol, triethyl 2. The composition of claim 1, wherein the vitamin is ene glycol, tetraethylene glycol, dipropylene glycol and selected from the group consisting of vitamin A, B1, B2, B3, dibutylene glycol and, wherein the triol is selected from B5, B6, B7, B9, B12, PABA, C, D1, D2, D3, D4, D5, E, K the group consisting of glycerin, butane-1,2,3-triol, and F combinations thereof. butane-1,2,4-triol and hexane-1,2,6-triol. 3. The composition of claim 1, wherein the vitamin or 17. The foamable composition of claim 15, wherein the flavonoid is soluble in water. PEG is selected from the group consisting of PEG 200, PEG 4. The composition of claim 1, wherein the vitamin or 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000 flavonoid is soluble in a hydrophobic solvent. and PEG 8000. 5. The composition of claim 1, wherein the vitamin is a 18. The foamable composition of claim 15, wherein the combination of two or more vitamins selected from the hygroscopic solvent comprises a hygroscopic solvent mix group consisting of vitamin A, B3, C. K. E. and F. 6. The composition of claim 1, wherein the vitamin is a ture of at least one polyol and at least one PEG. combination of two or more vitamins selected from the 19. The foamable composition of claim 15, which is non group consisting of vitamin A, C, D1, D2, D3, D4, and D5. aqueous or Substantially non aqueous, also comprising 7. The composition of claim 1, wherein the flavonoid is wherein the hygroscopic solvent comprises (1) at least one selected from the group consisting of flavonols; flavones hygroscopic solvent selected from a diol, a triol and PEG, flavonones flavan-3-ols anthocyanins and proanthocyani and (2) at least a secondary hygroscopic Solvent, which is dins. selected from the group consisting of dimethyl isosorbide, 8. The composition of claim 1, wherein the flavonoid is a tetrahydrofurfuryl alcohol polyethyleneglycol, ether, single flavonoid, a combination of two or more flavonoids or DMSO, a pyrrolidone, N-Methyl-2-pyrrolidone, 1-Methyl a synergistic combination of two or more flavonoids and is 2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG selected from the group consisting of benzquercin, dioSmin, type surfactant, an alpha hydroxy acid, lactic acid and ethoxazorutoside, flavodate, sodium hesperidin, leuco glycolic acid. cianido, monoxerutin, oxerutin, quercetin, rutoside, ros 20. The composition of claim 1, wherein the Aw value of marinic acid, kaempferol, myricetin apigenin, luteolin, hes the composition is selected from the ranges of (1) about 0.8 peretin, naringenin, eriodictyol, cyanidin, delphinidin, and about 0.9; (2) about 0.7 and about 0.8; and (3) less than malvidin, pelargonidin, peonidin, petunidin, catechin, gal about 0.7. locatechin, epicatechin, and epigallocatechin 21. The composition of claim 1, further comprising up to 9. The composition of claim 1, wherein the flavonoid is 10% of water. quercetin and or roSmarinic acid and the Vitamin is vitamin 22. The composition of claim 1, wherein the composition A, and or C and or D (D1, D2, D3, D4, or D5) and or E. is Substantially non-aqueous and/or Substantially alcohol 10. The composition of claim 1, wherein the vitamin is a free. combination of two or more vitamins selected from the 23. The composition of claim 1, comprising a vitamin, a group comprising vitamin B3, E and C and a derivative flavonoid and or a conservational agent, a stabilizer, and thereof. Solvent comprising water, wherein the flavonoid and or 11. The composition of claim 1 wherein the vitamin, conservational agent can Substantially conserve or stabilize flavonoid or a derivative thereof or combinations thereof the vitamin or ameliorate, reduce or inhibit its breakdown improves, stimulates or promotes target site metabolism. and wherein the vitamin, flavonoid, stabilizer, conserva 12. The composition of claim 1, further comprising a tional agent, and solvent provide a composition that is preservative and/or modulating agent and/or an antioxidant. Substantially resistant to aging. 13. The composition of claim 12, wherein the preservative is selected from the group consisting of disodium metabisul 24. The composition of claim 1, wherein the vitamin and fate and sharomix 824 and the modulating agent is EDTA or flavonoid or derivative thereof or combinations thereof and or optionally a buffering agent. are loaded into microSponges. 14. The composition of claim 1, further comprising an 25. A foamable composition comprising a stabilized additional therapeutic agent. Vitamin, comprising: 15. The composition of claim 1, wherein the hygroscopic Solvent is selected from the group consisting of a water-unstable vitamin; a. polyethylene glycols (PEGS); an antioxidative flavonoid; and b. Surfactants comprising PEG, a foamable carrier comprising: c. polyols; d. monosaccharides, disaccharides, oligosaccharides and i. water: Sugar alcohols in an amount to provide hygroscopic ii. a foam stabilizer selected from the group consisting properties; and of at least one Surface-active agent; and at least one e. honey. polymeric agent selected from the group consisting US 2008/0069779 A1 Mar. 20, 2008 52

of a bioadhesive agent, a gelling agent, a film form 38. The foamable composition of claim 37 wherein the ing agent and a phase change agent and mixtures preservative is selected from the group consisting of diso thereof dium metabisulfate and sharomix 824 and the modulating agent is EDTA and or optionally a buffering agent. iii. about 0.005% to about 5% conservational agent; 39. The foamable composition of claim 26, wherein the and polar solvent is a polyol is selected from the group consist iv. a propellant at a concentration of about 3% to about ing of a diol, a triol and a saccharide. 25% by weight of the total composition, wherein the diol is selected from the group consisting of where said foamable carrier reduces the destabilizing propylene glycol, butanediol, butenediol, butynediol, effect of water on the vitamin, pentanediol, hexanediol, octanediol, neopentylglycol, 2-methyl-1,3-propanediol, diethylene glycol, triethyl wherein the composition is contained in a pressurized ene glycol, tetraethylene glycol, dipropylene glycol and container, is substantially flowable and provides a foam dibutylene glycol and, wherein the triol is selected from upon release. the group consisting of glycerin, butane-1,2,3-triol, 26. The foamable composition of claim 25, wherein the butane-1,2,4-triol and hexane-1,2,6-triol. foamable carrier further comprises a solvent selected from 40. The foamable composition of claim 26, wherein the the group consisting of a hydrophilic Solvent, a hydrophobic polar solvent is a PEG is selected from the group consisting Solvent, a polar solvent, a silicone, an emollient and mix of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG tures thereof. 4000, PEG 6000 and PEG 8000. 27. The foamable composition of claim 25, wherein the 41. The foamable composition of claim 26, wherein the Vitamin is selected from the group consisting of vitamin A, carrier composition comprises a polar solvent mixture of at B1, B2, B3, B5, B6, B7, B9, B12, PABA, C, D1, D2, D3, least one polyol and at least one PEG. D4, D5, E, K and F and a derivative thereof or combinations 42. The foamable composition of claim 26, which is non thereof. aqueous or Substantially non aqueous, also comprising 28. The foamable composition of claim 25, wherein the wherein the hygroscopic solvent comprises (1) at least one vitamin or flavonoid is soluble in water. hygroscopic solvent selected from a diol, a triol and PEG, 29. The foamable composition of claim 25, wherein the and (2) at least a secondary hygroscopic Solvent, which is vitamin or flavonoid is soluble in a hydrophobic solvent. selected from the group consisting of dimethyl isosorbide, 30. The foamable composition of claim 25, wherein the tetrahydrofurfuryl alcohol polyethyleneglycol, ether, Vitamin is a combination of two or more vitamins selected DMSO, a pyrrolidone, N-Methyl-2-pyrrolidone, 1-Methyl from the group consisting of vitamin A, B3, C. K. E. and F 2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG and a derivative thereof. type surfactant, an alpha hydroxy acid, lactic acid and 31. The foamable composition of claim 25, wherein the glycolic acid. Vitamin is a combination of two or more vitamins selected 43. The foamable composition of claim 26, wherein the from the group consisting of vitamin A, C, D1, D2, D3, D4, polymeric agent is selected from the group consisting of and D5 and a derivative thereof. locust bean gum, Sodium alginate, sodium caseinate, egg 32. The foamable composition of claim 25, wherein the albumin, gelatin agar, carrageenin gum, Sodium alginate, flavonoid is selected from the group consisting of flavonols; Xanthan gum, quince seed extract, tragacanth gum, guar flavones flavonones flavan-3-ols anthocyanins and proan gum, cationic guars, hydroxypropyl guar gum, starch, an thocyanidins. amine-bearing polymer, chitosan, alginic acid, hyaluronic 33. The foamable composition of claim 25, wherein the acid, a chemically modified Starch, a carboxyvinyl polymer, flavonoid is a single flavonoid, a combination of two or more polyvinylpyrrolidone, polyvinyl alcohol, a polyacrylic acid flavonoids or a synergistic combination of two or more polymer, a polymethacrylic acid polymer, polyvinyl acetate, flavonoids and is selected from the group consisting of a polyvinyl chloride polymer, a polyvinylidene chloride benzquercin, dioSmin, ethoxazorutoside, flavodate, sodium polymer, methylcellulose, hydroxypropyl cellulose, hydrox hesperidin, leucocianido, monoxerutin, oxerutin, quercetin, ypropyl methylcellulose, hydroxyethyl cellulose, hydroxy rutoside, roSmarinic acid, kaempferol, myricetin apigenin, propylmethyl cellulose, methylhydroxyethylcellulose, luteolin, hesperetin, maringenin, eriodictyol, cyanidin, del methylhydroxypropylcellulose, hydroxyethylcarboxymeth phinidin, malvidin, pelargonidin, peonidin, petunidin, cat ylcellulose, carboxymethyl cellulose, carboxymethylcellu echin, gallocatechin, epicatechin, and epigallocatechin. lose carboxymethylhydroxyethylcellulose, a cationic cellu 34. The foamable composition of claim 25, wherein the lose PEG 1000, PEG 4000, PEG 6000 and PEG 8000 of flavonoid is quercetin and or roSmarinic acid and the vitamin Carbopol.R. 934, Carbopol R 940, Carbopol.R. 941, Car is vitamin A, and or C and or D (D1, D2, D3, D4, or D5) and bopol R 980, Carbopol R 981. hydroxypropylcellulose and or E or a derivative thereof. carbomer. 35. The foamable composition of claim 25, wherein the 44. The foamable composition of claim 25, wherein the Vitamin is a combination of two or more vitamins selected Surface active agent is selected from the group consisting of from the group comprising vitamin B3, E and C and a a polysorbate, polyoxyethylene (20) Sorbitan monostearate, derivative thereof. polyoxyethylene (20) Sorbitan monooleate, a polyoxyethyl 36. The composition of claim 25 wherein the vitamin, ene fatty acid ester, Myr 45, Myr 49, Myri 52 and Myr 59. flavonoid or a derivative thereof or combinations thereof a polyoxyethylene alkylyl ether, polyoxyethylene cetyl improves, stimulates or promotes target site metabolism. ether, polyoxyethylene palmityl ether, polyethylene oxide 37. The foamable composition of claim 25, further com hexadecyl ether, polyethylene glycol cetyl ether, brij 38, brij prising a preservative and or modulating agent and or an anti 52, brij 56 brij 72, brij 721 and brij W1, a sucrose ester, a oxidant. partial ester of sorbitol, sorbitan monolaurate, sorbitan US 2008/0069779 A1 Mar. 20, 2008

monolaurate a monoglyceride, a diglyceride, isoceteth-20, a wherein the vitamin, flavonoid, stabilizer, conservational Sucrose ester, or selected from the group consisting of agent, and solvent provide a composition that is Sub steareth 2, glyceryl monostearate/PEG 100 stearate, Glyc stantially resistant to aging. eryl Stearate, Steareth-21, peg 40 stearate, polysorbate 60, 51. A method of treating a disorder or condition of polysorbate 80, sorbitan stearate, laureth 4, Sorbitan mammalian Subject, comprising: monooleate, ceteareth 16 ceteareth 20, steareth 10, steareth administering a foam produced from a foamable vitamin 20, ceteth 20, Macrogol Cetostearyl Ether, ceteth 2, PEG-30 and or flavonoid composition to a target site, the DipolyhydroxyStearate. Sucrose distearate, polyoxyethylene composition comprising: (100) stearate, PEG 40 stearate, PEG 100 stearate, laureth 4, cetomacrogol ether, Cetearyl alcohol, Cetearyl glucoside, a foamable composition comprising a stabilized-vita Oleyl alcohol, Steareth-2, Diisopropyl adipate, Capric/ca min, comprising: prilic triglicerides, Polysorbate 20; Polysorbate 80, Mon a therapeutically effective amount of a water-un tanov 68 (CETEARYL ALCOHOL (and) CETEARYL stable vitamin; GLUCOSIDE), Simusol 165 (Glyceryl stearate and PEG an optional flavonoid; and 100 stearate). Methylglucose sequistearate, Peg 30 dipoly hydroxy Stearate. Sucrose Stearic acid esters, Sorbitan laureth, a foamable carrier comprising: Sorbitan Stearate, polyglyceryl-10 laurate, epikuuron 80, i. water: span 80 and mixtures thereof. 45. The foamable composition of claim 26, further com ii. a foam stabilizer selected from the group con prising a foam adjuvant selected from the group consisting sisting of at least one surface-active agent; at least one polymeric agent selected from the of a fatty alcohol, a fatty acid and a hydroxyl fatty acid or group consisting of a bioadhesive agent, a gel liquid wax. ling agent, a film forming agent and a phase 46. The foamable composition of claim 25, further com prising at least one additional therapeutic agent in addition change agent and mixtures thereof; to the vitamin and flavonoid or combinations thereof in a iii. about 0.005% to about 5% conservational therapeutically effective concentration. agent; and 47. The foamable composition of claim 25, wherein the iv. a propellant at a concentration of about 3% to vitamin and flavonoid or combinations thereof are provided about 25% by weight of the total composition, in a microSponge. 48. The foamable composition of claim 25, further com where said foamable carrier reduces the destabilizing prising at least one additional therapeutic agent selected effect of water on the vitamin, from the group consisting of active herbal extracts, acari wherein the composition is contained in a pressurized cides, age spot and keratose removing agents, allergen, container, is substantially flowable and provides a foam analgesics, local anesthetics, antiacne agents, antiallergic upon release. agents, antiaging agents, antibacterials, antibiotics, antiburn 52. The method of claim 51, wherein the vitamin and or agents, anticancer agents, antidandruff agents, antidepres flavonoid or derivative thereof or combinations thereof are sants, antidermatitis agents, antiedemics, antihistamines, loaded into microSponges. antihelminths, antihyperkeratolyte agents, antiinflammatory 53. The method of claim 51 further comprising an addi agents, antiirritants, antilipemics, antimicrobials, antimy tional therapeutic agent in addition to the Vitamin, flavonoid cotics, antiproliferative agents, antioxidants, anti-wrinkle or combinations thereof. agents, antipruritics, antipsoriatic agents, antirosacea agents 54. The method of claim 51, wherein the target site is antiseborrheic agents, antiseptic, antiswelling agents, anti selected from the group consisting of the skin, a body cavity, viral agents, anti-yeast agents, astringents, topical cardio a mucosal Surface, the nose, the mouth, the eye, the ear vascular agents, chemotherapeutic agents, corticosteroids, canal, the respiratory system, the vagina and the rectum. dicarboxylic acids, disinfectants, fungicides, hair growth 55. The method of claim 51, wherein the disorder is regulators, hormones, hydroxy acids, immunosuppressants, selected from the group consisting of dermatological pain, immunoregulating agents, insecticides, insect repellents, dermatological inflammation, acne, acne Vulgaris, inflam keratolytic agents, lactams, metals, metal oxides, mitocides, matory acne, non-inflammatory acne, acne fulminans, nodu neuropeptides, non-steroidal anti-inflammatory agents, oxi lar papulopustular acne, acne conglobata, dermatitis, bacte dizing agents, pediculicides, photodynamic therapy agents, rial skin infections, fungal skin infections, viral skin retinoids, Sanatives, scabicides, self tanning agents, skin infections, parasitic skin infections, skin neoplasia, skin whitening agents, asoconstrictors, vasodilators, wound heal neoplasms, pruritis, cellulitis, acute lymphangitis, lymphad ing agents and wart removers. enitis, erysipelas, cutaneous abscesses, necrotizing Subcuta 49. The foamable composition of claim 46, wherein the at neous infections, Scalded skin Syndrome, folliculitis, least one additional therapeutic agent is an anti-infective furuncles, hidradenitis Suppurativa, carbuncles, paronychial agent. infections, rashes, erythrasma, impetigo, ecthyma, yeast skin 50. The composition of claim 25, comprising a vitamin, a infections, warts, molluscum contagiosum, trauma or injury flavonoid and or a conservational agent, a stabilizer, and to the skin, post-operative or post-Surgical skin conditions, Solvent comprising water, Scabies, pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, wherein the flavonoid and or conservational agent can edematous, erythema multiforme, erythema nodosum, gran substantially conserve or stabilize the vitamin or ame nuloma annulare, epidermal necrolysis, Sunburn, photosen liorate, reduce or inhibit its breakdown and sitivity, pemphigus, bullous pemphigoid, dermatitis herpe US 2008/0069779 A1 Mar. 20, 2008 54 tiformis, keratosis pilaris, callouses, corns, ichthyosis, skin nolone, flucetonide, flucloronide, fluclorolone acetonide, ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, flucortine butylesters, fludroxycortide, fludrocortisone, flu Kaposi's sarcoma, melanoma, malignant melanoma, basal methasone, flumethasone pivalate, flumethasone pivalate, cell carcinoma, squamous cell carcinoma, poison ivy, poison flunisolide, fluocinolone, fluocinolone acetonide, fluocino oak, contact dermatitis, atopic dermatitis, rosacea, purpura, nide, fluocortin butyl, fluocortolone, fluorometholone, flu moniliasis, candidiasis, baldness, alopecia, Behcet’s Syn osinolone acetonide, fluperolone, fluprednidene acetate, flu drome, cholesteatoma, Dercum disease, ectodermal dyspla prednisolone hydrocortamate, fluradrenolone, sia, gustatory Sweating, nail patella syndrome, lupus, hives, fluradrenolone acetonide, flurandrenolone, fluticaSone, hal hair loss, Hailey-Hailey disease, chemical or thermal skin cinonide, halobetasol, hydrocortisone, hydrocortisone burns, Scleroderma, aging skin, wrinkles, Sun spots, necro acetate, hydrocortisone butyrate, hydrocortisone cyclopen tizing fasciitis, necrotizing myositis, gangrene, Scarring, and tylpropionate, hydrocortisone Valerate, hydroxyltriamcino vitiligo, chlamydia infection, gonorrhea infection, hepatitis lone, medrysone, meprednisone, alpha.-methyl dexametha B, herpes, HIV/AIDS, human papillomavirus (HPV), genital Sone, methylprednisolone, methylprednisolone acetate, warts, bacterial vaginosis, candidiasis, chancroid, granu mometasone furoate, paramethasone, prednisolone, pred loma Inguinale, lymphogranloma Venereum, mucopurulent nisone, pregnenolone, progesterone, Spironolactone, triam cervicitis (MPC), molluscum contagiosum, nongonococcal cinolone, triamcinolone acetonide and derivatives, esters urethritis (NGU), trichomoniasis, Vulvar disorders, vulvo and salts thereof. dynia, Vulvar pain, yeast infection, Vulvar dystrophy, Vulvar 58. The method of claim 53, wherein the at least one intraepithelial neoplasia (VIN), contact dermatitis, pelvic additional therapeutic agent is an anti-infective agent. inflammation, endometritis, Salpingitis, oophoritis, genital 59. The method of claim 53, wherein the at least one cancer, cancer of the cervix, cancer of the Vulva, cancer of anti-infective agent is selected from the group consisting of the vagina, vaginal dryness, dyspareunia, anal and rectal an antibiotic agent, an antibacterial agent, an antifungal disease, anal abscess/fistula, anal cancer, anal fissure, anal agent, an agent that controls yeast, an antiviral agent and an warts, Crohn's disease, hemorrhoids, anal itch, pruritus ani, antiparasitic agent. fecal incontinence, constipation, polyps of the colon and 60. The method of claim 53, comprising (1) at least one rectum; and wherein the active agent is suitable for treating Vitamin; and (2) at least one additional therapeutic agent said disorder. selected from the group of an antifungal agent, an antimi 56. The method of claim 53, wherein the at least one crobial agent, an antiviral agent, an anti-acne agent, an additional therapeutic agent is selected from the group antipsoriasis agent, a keratolytic agent and an antiacne consisting of active herbal extracts, acaricides, age spot and agent. keratose removing agents, allergen, analgesics, local anes 61. The method of claim 53, wherein the additional thetics, antiacne agents, antiallergic agents, antiaging therapeutic agent comprises a combination of (1) a corti agents, antibacterials, antibiotics, antiburn agents, antican costeroid; and (2) and active agent selected from the group cer agents, antidandruff agents, antidepressants, antiderma of an anti-infective agent, an antifungal agent, an antimi titis agents, antiedemics, antihistamines, antihelminths, anti crobial agent, an antiviral agent, an anti-acne agent, a hyperkeratolyte agents, antiinflammatory agents, retinoid, a vitamin D, a vitamin D3 derivative, calcipotriol, antiirritants, antilipemics, antimicrobials, antimycotics, anti calcitriol and antipsoriasis agent, a keratolytic agent, an proliferative agents, antioxidants, anti-wrinkle agents, anti anti-proliferative agent, an anti-cancer agent, a non-steroidal pruritics, antipsoriatic agents, antirosacea agents antisebor anti-inflammatory agent, an immunomodulator, an immu rheic agents, antiseptic, antiswelling agents, antiviral agents, nosuppressant and an anti-rosacea agent. anti-yeast agents, astringents, topical cardiovascular agents, 62. The method of claim 53, wherein the additional chemotherapeutic agents, corticosteroids, dicarboxylic therapeutic agent comprises a combination of (1) a kera acids, disinfectants, fungicides, hair growth regulators, hor tolytic agent, and (2) and active agent selected from the mones, hydroxy acids, immunosuppressants, immunoregu group of a corticosteroid, an anti-infective agent, an anti lating agents, insecticides, insect repellents, keratolytic fungal agent, an antimicrobial agent, an antiviral agent, an agents, lactams, metals, metal oxides, mitocides, neuropep anti-acne agent, a retinoid, a vitamin D, a vitamin D3 tides, non-steroidal anti-inflammatory agents, oxidizing derivative, calcipotriol, calcitriol and antipsoriasis agent, an agents, pediculicides, photodynamic therapy agents, retin anti-proliferative agent, an anti-cancer agent, a non-steroidal oids, Sanatives, scabicides, self tanning agents, skin whit anti-inflammatory agent, an immunomodulator, an immu ening agents, asoconstrictors, vasodilators, wound healing nosuppressant and an anti-rosacea agent. 63. A method of treating a disorder or condition of agents and wart removers. mammalian Subject, comprising: 57. The method of claim 53, wherein the at least one active agent is selected from the group consisting of alclom administering to a target site a foam produced by release etaSone dipropionate, amcinafel, amcinafide, amcinonide, of a foamable vitamin and flavonoid composition from beclomethasone, beclomethasone dipropionate, betameth a pressurized canister containing a composition to Sone, betamethasone benzoate, betamethasone dexametha which a vacuum was applied prior to filling with a Sone-phosphate, dipropionate, betamethasone Valerate, hydrocarbon propellant, the composition comprising: budesonide, chloroprednisone, chlorprednisone acetate, a. a vitamin and/or flavonoid; and clescinolone, clobetasol, clobetasol propionate, clobetasol Valerate, clobetaSone, clobetaSone butyrate, clocortelone, b. a substantially non-aqueous carrier, the carrier com cortisone, cortodoxone, craposone butyrate, desonide, des prising oxymethasone, dexamethasone, desoxycorticosterone i. about 50% to about 98% of a polar solvent selected acetate, dichlorisone, diflorasone diacetate, diflucortolone from the group consisting of polyols and polyethyl Valerate, difluorosone diacetate, diflurprednate, fluadre ene glycols (PEGs); US 2008/0069779 A1 Mar. 20, 2008 55

ii. 0% to about 48% of a secondary polar solvent; disease, anal abscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids, anal itch, pruritus ani, iii. a surface-active agent or foam adjuvant; fecal incontinence, constipation, polyps of the colon and iv. 0% to about 5% by weight of at least one polymeric rectum; and wherein the active agent is suitable for treating agent, said disorder. V. 0% to about 5% of a conservation agent; and 68. The method of claim 63, wherein the at least one additional therapeutic agent is selected from the group vi. a propellant at a concentration of about 3% to about consisting of active herbal extracts, acaricides, age spot and 25% by weight of the total composition; keratose removing agents, allergen, analgesics, local anes wherein applying a vacuum and filling the canister thetics, antiacne agents, antiallergic agents, antiaging containing the composition with hydrocarbon pro agents, antibacterials, antibiotics, antiburn agents, antican pellant contributes to stabilize the vitamin against cer agents, antidandruff agents, antidepressants, antiderma degradation. titis agents, antiedemics, antihistamines, antihelminths, anti 64. The method of claim 63, wherein the vitamin and or hyperkeratolyte agents, antiinflammatory agents, flavonoid or derivative thereof or combinations thereof are loaded into microSponges. antiirritants, antilipemics, antimicrobials, antimycotics, anti 65. The method of claim 63, further comprising an proliferative agents, antioxidants, anti-wrinkle agents, anti additional therapeutic agent in addition to the vitamin, and pruritics, antipsoriatic agents, antirosacea agents antisebor or flavanoid a derivative thereof or combinations thereof. rheic agents, antiseptic, antiswelling agents, antiviral agents, 66. The method of claim 63, wherein the target site is anti-yeast agents, astringents, topical cardiovascular agents, selected from the group consisting of the skin, a body cavity, chemotherapeutic agents, corticosteroids, dicarboxylic a mucosal Surface, the nose, the mouth, the eye, the ear acids, disinfectants, fungicides, hair growth regulators, hor canal, the respiratory system, the vagina and the rectum. mones, hydroxy acids, immunosuppressants, immunoregu 67. The method of claim 63, wherein the disorder is lating agents, insecticides, insect repellents, keratolytic selected from the group consisting of dermatological pain, agents, lactams, metals, metal oxides, mitocides, neuropep dermatological inflammation, acne, acne Vulgaris, inflam tides, non-steroidal anti-inflammatory agents, oxidizing matory acne, non-inflammatory acne, acne fulminans, nodu agents, pediculicides, photodynamic therapy agents, retin lar papulopustular acne, acne conglobata, dermatitis, bacte oids, Sanatives, scabicides, self tanning agents, skin whit rial skin infections, fungal skin infections, viral skin ening agents, asoconstrictors, Vasodilators, wound healing infections, parasitic skin infections, skin neoplasia, skin agents and wart removers. neoplasms, pruritis, cellulitis, acute lymphangitis, lymphad 69. The method of claim 63, wherein the at least one enitis, erysipelas, cutaneous abscesses, necrotizing Subcuta active agent is selected from the group consisting of alclom neous infections, scalded skin Syndrome, folliculitis, etaSone dipropionate, amcinafel, amcinafide, amcinonide, furuncles, hidradenitis Suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeast skin beclomethasone, beclomethasone dipropionate, betameth infections, warts, molluscum contagiosum, trauma or injury Sone, betamethasone benzoate, betamethasone dexametha to the skin, post-operative or post-Surgical skin conditions, Sone-phosphate, dipropionate, betamethasone Valerate, Scabies, pediculosis, creeping eruption, eczemas, psoriasis, budesonide, chloroprednisone, chlorprednisone acetate, pityriasis rosea, lichen planus, pityriasis rubra pilaris, clescinolone, clobetasol, clobetasol propionate, clobetasol edematous, erythema multiforme, erythema nodosum, gran Valerate, clobetaSone, clobetaSone butyrate, clocortelone, nuloma annulare, epidermal necrolysis, Sunburn, photosen cortisone, cortodoxone, craposone butyrate, desonide, des sitivity, pemphigus, bullous pemphigoid, dermatitis herpe oxymethasone, dexamethasone, desoxycorticosterone tiformis, keratosis pilaris, callouses, corns, ichthyosis, skin acetate, dichlorisone, diflorasone diacetate, diflucortolone ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Valerate, difluorosone diacetate, diflurprednate, fluadre Kaposi's sarcoma, melanoma, malignant melanoma, basal nolone, flucetonide, flucloronide, fluclorolone acetonide, cell carcinoma, squamous cell carcinoma, poison ivy, poison flucortine butylesters, fludroxycortide, fludrocortisone, flu oak, contact dermatitis, atopic dermatitis, rosacea, purpura, methasone, flumethasone pivalate, flumethasone pivalate, moniliasis, candidiasis, baldness, alopecia, Behcet’s Syn flunisolide, fluocinolone, fluocinolone acetonide, fluocino drome, cholesteatoma, Dercum disease, ectodermal dyspla nide, fluocortin butyl, fluocortolone, fluorometholone, flu sia, gustatory Sweating, nail patella syndrome, lupus, hives, osinolone acetonide, fluperolone, fluprednidene acetate, flu hair loss, Hailey-Hailey disease, chemical or thermal skin prednisolone hydrocortamate, fluradrenolone, burns, Scleroderma, aging skin, wrinkles, Sun spots, necro fluradrenolone acetonide, flurandrenolone, fluticaSone, hal tizing fasciitis, necrotizing myositis, gangrene, Scarring, and cinonide, halobetasol, hydrocortisone, hydrocortisone vitiligo, chlamydia infection, gonorrhea infection, hepatitis acetate, hydrocortisone butyrate, hydrocortisone cyclopen B, herpes, HIV/AIDS, human papillomavirus (HPV), genital tylpropionate, hydrocortisone Valerate, hydroxyltriamcino warts, bacterial vaginosis, candidiasis, chancroid, granu loma Inguinale, lymphogranloma Venereum, mucopurulent lone, medrysone, meprednisone, alpha.-methyl dexametha cervicitis (MPC), molluscum contagiosum, nongonococcal Sone, methylprednisolone, methylprednisolone acetate, urethritis (NGU), trichomoniasis, Vulvar disorders, vulvo mometasone furoate, paramethasone, prednisolone, pred dynia, Vulvar pain, yeast infection, Vulvar dystrophy, Vulvar nisone, pregnenolone, progesterone, Spironolactone, triam intraepithelial neoplasia (VIN), contact dermatitis, pelvic cinolone, triamcinolone acetonide and derivatives, esters inflammation, endometritis, Salpingitis, oophoritis, genital and salts thereof. cancer, cancer of the cervix, cancer of the Vulva, cancer of 70. The method of claim 63, wherein the at least one the vagina, vaginal dryness, dyspareunia, anal and rectal additional therapeutic agent is an anti-infective agent. US 2008/0069779 A1 Mar. 20, 2008 56

71. The method of claim 63, wherein the at least one anti-acne agent, a retinoid, a vitamin D, a vitamin D3 anti-infective agent is selected from the group consisting of derivative, calcipotriol, calcitriol and antipsoriasis agent, an an antibiotic agent, an antibacterial agent, an antifungal anti-proliferative agent, an anti-cancer agent, a non-steroidal agent, an agent that controls yeast, an antiviral agent and an anti-inflammatory agent, an immunomodulator, an immu antiparasitic agent. nosuppressant and an anti-rosacea agent. 72. The method of claim 63, comprising (1) at least one 75. A non-aqueous or Substantially non aqueous foamable Vitamin; and (2) at least one additional therapeutic agent composition, comprising: selected from the group of an antifungal agent, an antimi crobial agent, an antiviral agent, an anti-acne agent, an ascorbic acid in an amount of up to about 7 wt %; antipsoriasis agent, a keratolytic agent and an antiacne agent. about 50% to about 98% of a hygroscopic solvent com 73. The method of claim 63, wherein the additional prising a mixture of at least one polyol and PEG, therapeutic agent comprises a combination of (1) a corti at least one of a surfactant and a foam adjuvant selected costeroid; and (2) and active agent selected from the group from the group consisting of fatty alcohol, a fatty acid of an anti-infective agent, an antifungal agent, an antimi and a hydroxyl fatty acid or liquid wax; and a hydro crobial agent, an antiviral agent, an anti-acne agent, a retinoid, a vitamin D, a vitamin D3 derivative, calcipotriol, carbon propellant at a concentration of about 3% to calcitriol and antipsoriasis agent, a keratolytic agent, an about 25% by weight of the total composition, anti-proliferative agent, an anti-cancer agent, a non-steroidal wherein said foamable carrier reduces the destabilizing anti-inflammatory agent, an immunomodulator, an immu effect of water on the vitamin, and nosuppressant and an anti-rosacea agent. 74. The method of claim 63, wherein the additional wherein the composition is contained in a pressurized therapeutic agent comprises a combination of (1) a kera container, is substantially flowable and provides a foam tolytic agent, and (2) and active agent selected from the upon release. group of a corticosteroid, an anti-infective agent, an anti fungal agent, an antimicrobial agent, an antiviral agent, an