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US 20080206161A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0206161 A1 TAMARKIN et al. (43) Pub. Date: Aug. 28, 2008

(54) QUIESCENT FOAMABLE COMPOSITIONS, (60) Provisional application No. 60/492.385, filed on Aug. , KITS AND USES THEREOF 4, 2003, provisional application No. 60/897,638, filed on Jan. 26, 2007. (76) Inventors: Dov TAMARKIN, Maccabim (IL); Meir EINI, Ness Ziona (IL); Doron (30) Foreign Application Priority Data FRIEDMAN, Karmei Yosef (IL); David SCHUZ, Moshav Gimzu Oct. 25, 2002 (IL) ...... 1524.86 (IL); Tal BERMAN, Rishon LeZiyyon (IL) Publication Classification Correspondence Address: (51) Int. Cl. WILMERHALEABOSTON A6IR 9/12 (2006.01) 6O STATE STREET A6IP 29/00 (2006.01) BOSTON, MA 02109 (US) (52) U.S. Cl...... 424/45 (21) Appl. No.: 12/020,381 (57) ABSTRACT (22) Filed: Jan. 25, 2008 The present invention relates to an emulsion compo sition as a foamable vehicle in which the vehicle is stable or Related U.S. Application Data stabilized by the presence of at least one quiesence agent; (63) Continuation-in-part of application No. 10/911,367, therapeutical kit containing Such composition; to methods of filed on Aug. 4, 2004, Continuation-in-part of applica treatment using Such composition; to methods of enhancing tion No. 1 1/114,410, filed on Apr. 26, 2005. the stability of such composition.

AEROSOL VALVE VALVE STEM 132 1 OOS. VALVE CUP

......

120 OUTER GASKET

SPRING 130

140 DIPTUBE Patent Application Publication Aug. 28, 2008 Sheet 1 of 3 US 2008/0206161 A1

AEROSOL VALVE VALVE STEM

132 1 OOS. VALVE CUP

t 120

DIP TUBE

F.G. 1 Patent Application Publication Aug. 28, 2008 Sheet 2 of 3 US 2008/0206161 A1

Figure 2 - microscopic pictures (x400, polarization) Emulsion composition BV3- no Aqueous composition BV6, including Crystals are observed a polymeric agent and a surfactant - no crystals are observed

A

|Aqueous composition BV4, Aqueous composition BV5, including one polymeric agent including two ploymeric agent (methocel) - Crystals are observed (methocel-Xanthan gum) - Crystals are observed C

a commercial betamethasone valerate 0.12% cream - Crystals are observed

Patent Application Publication Aug. 28, 2008 Sheet 3 of 3 US 2008/0206161 A1

SSS.

S. S & S S.S ŠSS S. S S Š S. Š

S. SS. S.

SSSSSSSSSSSSSSSSSSSSSSSS US 2008/0206161 A1 Aug. 28, 2008

QUIESCENT FOAMABLE COMPOSITIONS, mulations be resistant or resilient to aging and do not separate STEROIDS, KITS AND USES THEREOF into two phases as can be determined by exposing the formu lations to temperature changes, or by centrifugation. To the CROSS REFERENCE TO RELATED extent Such formulations display creaming there is a need for APPLICATIONS them to be easily and effectively redispersible upon exposure to light shaking. “Mild agitation” or “lightly shaking refers 0001. This application claims the benefit of priority under to the normal mild force applied to a canister containing a 35 U.S.C. S 119(e) to co-pending U.S. Provisional Applica shakable foamable formulation with propellant, which is tion No. 60/897,638 filed Jan. 26, 2007, entitled “Quiescent raised to about the level of head height and mildly brought to Foamable Compositions, Steroids, Kits and Uses Thereof, about waist height and back again a few times by an average which is incorporated in its entirety by reference. adult without excessive or vigorous force. 0002 This is application is a continuation-in-part of and 0009 Steroids are agents that are difficult to formulate for claims priority under 35 U.S.C. S 120 to co-pending U.S. pharmaceutical use. Some steroids, such as betamethasone patent application Ser. No. 1 1/114,410, filed Apr. 26, 2005, Valerate, are known to be particularly unstable and tend to entitled “Steroid Kit and Foamable Composition and Uses isomerize. Thereof which is herein incorporated in its entirety by ref 0010 Foam products may, for example be pressurized CCC. preparations composed of liquid emulsion and propellant 0003. This application is a continuation-in-part of packed into a canister, Such as an aluminum canister, mounted co-pending U.S. patent application Ser. No. 10/911.367, filed with a valve and anactuator. Upon actuation of the foam onto on Aug. 4, 2004, which claims the benefit of priority under 35 the skin, the propellant immediately vaporizes and the emul U.S.C. S 119(e) to U.S. Provisional Patent Application No. sion deposits on the skin Surface. 60/492.385, filed on Aug. 4, 2003, both entitled “Foam Car 0011. There is a need for stable foams that are breakable rier Containing Amphiphilic Copolymer Gelling Agent' and undershear upon application. The foam should ideally spread both herein incorporated in their entirety by reference. easily on skin with minimal greasy or sticky feeling and 0004. This application is a continuation-in-part of should be absorbed quickly. These foam qualities are desir co-pending International Patent Application No. IB03/ able for usability and compliance. Further desirable positive 005527, entitled “Cosmetic and Pharmaceutical Foam, des attributes are acceptable odor and color. ignating the United States and filed on Oct. 24, 2003, which 0012 Topical application with a foam product is superior claims the benefit of priority under 35 U.S.C. S 119(e) to U.S. to treatments with cream or ointment dosage forms. Usage of Provisional Patent Application Ser. No. 60/492,546, filed on foam provides a better skin moisturizing and protective Nov. 29, 2002 (same title) and under 35 USC S119(a) to capacity and is less irritable than the other dosage forms. Israeli Patent Application. No. 152486, filed Oct. 25, 2002, all Foams easily spread on large skin areas can be efficiently of which are herein incorporated in their entirety by refer rubbed into the skin. CCC. 0013 Body cavity application with a foam product is also Superior to treatments with cream or ointment dosage forms. BACKGROUND Usage of foam provides a better cavity moisturizing and 0005 Development of foamable pharmaceutical carriers protective capacity and may be less irritable than the other and compositions of active agents requires a multi-disciplin dosage forms. Breakable foams easily expand to occupy the ary approach. The challenge of preparing emulsion carriers body cavity and Subsequently collapse on mechanical shear and compositions that are capable of forming stable break to spread over large internal areas to provide a localized or able foams Suitable for topical or mucosal application is beset targeted effect as well as efficient delivery of one or more with a multitude of challenges. The active agents are often active agents/ingredients. sensitive and also may interact with other components in a 0014. The usability of a pharmaceutical product is largely composition. Agents may have limited biocompatibility or influenced by its physical properties, as manifested by its ease poor . The agents may be difficult to deliver to a of application, spreadability and absorption. Stability is a target site. primary feature that has to be ensured when a pharmaceutical 0006 Additionally, the carriers may comprise emulsions formulation, and in particulara foam pharmaceutical product, which lack physical stability and may have a short, unstable is being developed. shelf life. 00.15 Emulsions are inherently non-stable products, 0007 Another issue with foamable compositions is that an which are stabilized by the aid of Surface-active agents, Sur appropriate rheology needs to be retained so that, on the one factants, and bulking agents that contribute to increased vis hand, the composition remains shakable so that it may be cosity. Surfactants reduce the free energy between oil and easily expelled through an aerosol system and valve over its aqueous phase and build a separation film between the two period of use, yet, on the other hand have sufficient form that immiscible phases. Stronger and compact separation film it will produce a stable foam of an acceptable quality. Some contributes to enhanced stability and longer shelf life. The emulsions may be stable but do no meet the criteria of shak creaming phenomenon which may cause emulsion breaking ability or flowability as is required for a foamable formulation and phase separation should be avoided since it may finally to be expelled underpressure through a canister valve using a contribute to separation and a non-usable product. propellant. Other emulsions albeit shakable may not produce 0016 Producing emulsion foamable compositions which stable breakable foams. are physically stable and resilient to creaming and produce 0008. There is thus a need in the art to provide foamable stable breakable foams is a non obvious challenge. Producing pharmaceutical carriers and compositions of active agents, Such steroid foamable compositions which are chemically which are shakable, stable and retain the activity of one or stable and retain the desired physical properties is a double more active agents. Moreover, there is a need that these for challenge. US 2008/0206161 A1 Aug. 28, 2008

0017 Steroids are currently available in topical dosage like small levels of acid residues in the raw materials can be forms. Compositions containing steroids for topical treat significant in influencing agent stability. Similarly, the pres ment of dermatologic disorders are available primarily in ence of low levels of metal can act to catalyze reactions cream, lotion, gelandointment forms. While semi-solid com or breakdown. There is therefore a need for simple and positions, such as creams, lotions, gels and ointments are elegant solutions to stabilize active steroid ingredients in an commonly used by consumers, new forms are desirable, in emulsion environment. On one level it is far from simple or order to achieve better control of the application, while main obvious to produce emulsion foamable compositions that taining or bestowing beneficial properties of such products on when released produce foams of quality Suitable for pharma the skin. Thus, the development of new compositions having ceutical or cosmetic application that are capable of satisfying breakable foam consistency when released from a container the need for both physical stability of the foam and for chemi and liquid properties when applied onto the skin are advan cal stability of the active steroid ingredient. On a further level tageous. having realized a composition that will produce an emulsion 0018 Foams and, in particular, foam emulsions are com foam of quality there is an additional difficulty to be over plicated systems which do not form under all circumstances. come, namely how to adapt the formula and achieve a formu Slight shifts in foam emulsion composition, Such as by the lation, which can accept a range of various other active phar addition of active ingredients, may destabilize the foamable maceutical and cosmetic agents such that the composition, composition during storage, and/or impair the quality of the steroid and other active agents are compatible and capable of foam that is produced upon release from the aerosol con remaining stable for a prolonged period and the foam pro tainer. duced remains of quality. Specifically, one of the challenges 0019 Foam compositions use aliphatic , which in preparing such foamable compositions is ensuring that the promote fast drying and thereby attempt to address the sticky active pharmaceutical or therapeutic agent does not react, feeling left by many topical formulations after application; isomerize or otherwise break down to any significant extent however, alcohols, are defafting agents and may cause skinto during is storage and use. Particularly, there remains an unmet become dry and cracked. Pharmaceutical foam compositions need for improved, easy to use, stable and non-irritating including (a) an active ingredient; (b) an occlusive agent; (c) foamable formulations, with unique therapeutic or beneficial an aqueous solvent; and (d) an organic cosolvent; wherein the properties containing a stable or stabilized active pharmaceu active ingredient is insoluble in water and insoluble in both tical or cosmetic agent which when stored in and Subse water and the occlusive agent; and wherein there is enough quently expelled from a canister can be delivered as a break occlusive agent to form an occlusive layer on the skin are able foam. known. 0023 There is also a particular need for foamable compo 0020 Substantially lower -free foam compositions sitions for mucosal and body cavity application especially, for topical treatment containing higher concentrations of oils vaginal and uterine application. that are robust and suitable for inclusion of a wide range of 0024. The vaginal cavity, including the vagina and cervix, active ingredients are desired. provides a unique site for delivery of therapeutic agents, both 0021. There remains an unmet need for improved, easy to for systemic and local action. use, stable and non-irritating foam formulations, intended for 0025. There are multiple anatomical structures which treatment of dermal and mucosal tissues, especially formula comprise the internal and external female genital tract includ tions which are stable for a substantial time period. Moreover, ing the clitoris, labia minora and corpus spongiosum (vesti formulations that are able to remain physically stable and bular) erectile tissue, vagina, peri-urethral glans, urethra, Hal chemically stable or substantially so, over a sufficient period ban's fascia, anterior formix erogenous Zone, pubococcygeus of time to allow for normal pharmaceutical use. Particularly, muscle and cervix. there remains an unmet need for improved, easy to use, stable 0026. The vagina consists of a tube of autonomically and non-irritating steroid foam formulations, with unique innervated Smooth muscle (longitudinal outer, inner circular therapeutic properties. There is more particularly a need to layer) lined by stratified squamous epithelium and a Sub develop steroid carriers and compositions, steroid foamable dermal layer rich in capillaries. The Vaginal wall consists of carriers and foamable compositions and steroid foams with an inner glandular mucous type stratified squamous cell epi and without other active agents, which are stable, are non thelium Supported by a thick lamina propia. This epithelium irritating, that facilitate penetration at a target, that are pre undergoes hormone-related cyclical changes including slight sentable in an easily applicable stable form, that can be keratinization of the Superficial cells during the menstrual handled with ease thereby facilitating compliance and that are cycle. Deep in the epithelium lies the smooth muscles of the adaptable for long term use where there is a need to minimize muscularis. There is a deeper Surrounding fibrous layer above the amount of the potential isomerization of the steroids or the the muscularis which provides structural Support to the potential breakdown of ingredients/agents by oxidation/hy vagina and is rich is collagen and elastin to allow for expan drolysis. sion of the cavity. Three sets of skeletal muscles surround the 0022. Some active agents such as certain steroid com vagina including the ischiocaVernosum, bulbocavernosus, pounds are known to be generally unstable or Susceptible to transverse perinei and levator ani and pubococcygeus isomerisation or to breakdown, resulting in loss of activity muscles. and the use of stabilizers, anti-oxidants antimicrobials and 0027 Women are vulnerable to diseases of the genital tract buffers and the like in aqueous compositions to protect active as the lining of the vagina is a permeable mucous membrane. or cosmetic agents is known. The problems of protecting Intercourse, lack of lubrication during intercourse, changes in active steroid pharmaceutical agents in emulsion composi the cervix during the menstrual cycle, and asymptomatic tions are multifold and can vary according to the type of infections facilitate the transmission of infection to women. emulsion environment and the nature of the agent and excipi Prepubertal girls and adolescents are particularly vulnerable ents being used. It has been Surprisingly found that factors because their vaginal and cervical tissues may be less mature US 2008/0206161 A1 Aug. 28, 2008

and are more readily penetrated by organisms (e.g., chlamy The duration of the inside the vagina or rectum is also dia and gonococcus). Postmenopausal women are more likely important for ensuring extended activity. than younger women to get Small abrasions in the vagina during sexual activity as a result of thinning of the tissue and SUMMARY dryness. Women who already have an infection (particularly 0034. The present invention relates to improved, easy to one that causes genital lesions) are more likely to acquire or use, stable and non-irritating foamable compositions and transmit another sexually transmitted disease (STD), includ foams comprising an active agent, intended for treatment of ing HIV. Other biological risks include the use of vaginal dermal and mucosal tissues. douches, which increase the risk of pelvic inflammatory dis 0035. The present invention relates to an emulsion com ease (PID), and the influence of hormonal contraceptives on position as a vehicle in which the vehicle is stable or stabi acquiring or transmitting an STD (e.g., increased risk of lized. chlamydial infection with use of oral contraceptives). 0036. The present invention relates to an emulsion com 0028. In particular, the cervix is prone to several diseases, position as a vehicle in which an active pharmaceutical or Such as cerviciitis (an inflammation of the uterine cervix, cosmetic agent, when added is stable or stabilized. usually caused by infection), , inflammation, erosion, 0037. The present invention relates to an emulsion com intraepithelial neoplasia (CIN), polyps, dysplasia, human position as a vehicle in which the vehicle is stable or stabilized papillomavirus (HPV) infections causing some tumors, by the presence of a quiesence agent. condylomas or warts and abnormal . 0038. The present invention relates to an emulsion com 0029. Several factors must be taken into consideration position as a vehicle in which an active pharmaceutical or when developing therapeutic delivery systems for the female cosmetic agent, when added is stable or stabilized in the genital system. These factors include the vaginal anatomy, the presence of a quiesence agent. mucosal Surface, the presence and composition of vaginal 0039. The present invention more particularly relates to fluids and secretions, cervical fluids (mucus), cyclic changes quiescence foamable carriers and compositions and quies and endogenous microflora. Drug stability to activ ence agents. ity, which is quite high in vaginal environment, and is again a 0040. The present invention more particularly relates to function of menstrual cycle and lifecycle, should also be quiesence agents for use in quiescence foamable carriers and taken into account. Topical drug delivery through the cervix, compositions including a quiescence agent selected from a as needed to treat disorders of the cervix and uterus also stabilizing, a polymeric, a gelling, a viscoelastic, a pseuedo presents a challenge. plastic or semi-pseudoplastic, a resilient agent and a modu 0030 Vaginal topical formulation should be compatible lating agent. A quiescence agent may have more than one of with daily activities, be easy to administer and provide accu these characteristics. In certain compositions a combination rate dosing. Several types of formulations are known for of two or more agents is used to achieve a quiescence foam delivery to the vaginal cavity. While semi-solid formulations, able composition having more than one of there characteris Such as creams, lotions, gels and ointments are commonly tics. used, they are often reported to be messy, require frequent 0041. The present invention more particularly relates to application and can be difficult to remove after use. Further quiescence compositions which are physically and chemi more, application of topical gels and creams require several cally stable or substantially so. steps of operation. Solid formulations such as tablets, Sup 0042. The present invention more particularly relates to positories and pessaries also require frequent application, quiescence compositions which are physically and chemi show a poor retention in vagina, and exhibit insufficient cally stable or Substantially so for short, medium and or long spreadability. term periods. 0031 Rectal drug administration can be directed to both 0043. The present invention more particularly relates to local and systemic drug delivery. It has been effectively used quiescence compositions which are physically and chemi to treat local diseases of the anorectal area as well as an cally stable or Substantially so for short, medium and or long alternative to oral administration in the systemic administra term periods. tion of . Solid Suppositories are the most common dos 0044) The present invention more particularly relates to age form used for rectal drug administration and represent the quiescence compositions which are physically and chemi majority of rectal dosage forms; however, creams ointments cally stable or Substantially so at room temperature during the and foams are also being used. expected shelf life of a pharmaceutical product or for a lesser 0032 Current formulations for rectal administration still reasonable period. have significant disadvantages. They are difficult to insert 0045. The present invention more particularly relates to through the anal orifice; they are difficult to spread through pseudoplastic or semi-pseudoplastic compositions which are out the target cavity; and if spreadable, they tend to leak, physically stable or Substantially so at room temperature dur causing major discomfort to the patient. Such negative ing the expected shelf life of a pharmaceutical product or for attributes lead to their very limited use. a lesser reasonable period. 0033. Thus, new forms are desirable in order to achieve 0046. The present invention more particularly relates to better control and ease of application, while maintaining the quiescence compositions which are physically and chemi beneficial properties of such products. A product for intrav cally stable or Substantially so for short, medium and or long aginal and anorectal application would ideally exhibit the term periods and is shakable or flowable; and is stored in an following properties: (1) easy insertion, thus leading to high aerosol container, which upon release expands to form a patient compliance; (2) accurate dosing, to ensure effective breakable foam. treatment; (3) expandability, for increased coverage of the 0047. The present invention more particularly relates to target cavity Surface and cervix, and (4) drip free formulation quiescence compositions which are physically and chemi with good adhesive properties, for prolonged drug residence. cally stable or Substantially so at room temperature during the US 2008/0206161 A1 Aug. 28, 2008

expected shelf life of a pharmaceutical product or for a lesser from. It has been further found that it is possible to improve reasonable period and is shakable or flowable; and is stored in the chemical stability of the steroid or other active agent in the an aerosol container, which upon release expands to form a composition. breakable foam. 0061. In some embodiments, the compositions described 0048. The present invention more particularly relates to herein are emulsions adapted to provide excellent foam upon pseudoplastic or semi-pseudoplastic compositions which are actuation from a pressurized canister. The emulsion foam physically stable or Substantially so at room temperature dur platform is made of oily phase and water phase emulsified and ing the expected shelflife of a pharmaceutical product or for stabilized with surfactants and polymers and co-stabilizers a lesser reasonable period and is shakable or flowable; and is that impart better foam properties. stored in an aerosol container, which upon release expands to 0062. Whilst the quiescence, the creaming resilience, the form a breakable foam. pseudoplastic and semi-pseudoplastic formulations and long 0049. The present invention more particularly relates to term physical and chemical stability of the carriers, formula modulating agents that are able to be effective in relatively tions, foamable compositions and foams have been primarily low concentrations and which have little or no significant demonstrated with steroids, which are known to be unstable effect on the foam compositions. or in combination with other active agents or with compounds 0050. According to one or more embodiments, the emul with particular solubility issues, the concepts, carriers, for sion foamable carrier includes: a hydrophobic solvent, a sta mulations, foamable compositions and foams disclosed are bilizing Surfactant, at least one quiesence agent, water and a likewise applicable to active agents other than Steroids. propellant. 0063. In one or more embodiments for example the carri ers, formulations, foamable compositions and foams dis 0051. According to one or more embodiments, the emul closed herein are likewise applicable to coal tar formulations. sion foamable carrier includes: a hydrophobic solvent, a sta One of the advantages, is that they can be formulated to bilizing Surfactant, water and a propellant and one or more exhibit bioadhesive properties and can be used for body cav active pharmaceutical agents. ity applications with minimal or no leakage. They are also of 0052 According to one or more embodiments, the foam pleasantappearance and skin feeling and do not sting, making able emulsion composition, includes: a hydrophobic solvent, them suitable for delivery to sensitive areas. Also by storing a stabilizing Surfactant, a quiesence agent, water and a pro them in sealed canisters with propellant, they can provide a pellant and one or more active pharmaceutical agents. safer medium for active agents that tend to break down upon 0053 According to one or more embodiments, the foam exposure to light or air. able emulsion composition, includes: a hydrophobic solvent, 0064. In some aspects, the present invention provides an a stabilizing Surfactant, a resilient agent, a modulating agent, easy to use steroid containing a vaginal delivery system that water and a propellant and one or more active pharmaceutical will be simple to operate with minimal preparation, will be agents. very tolerable without having a feeling of foreign matter, will 0054 According to one or more embodiments, the foam provide accurate dose administration, will evenly spread able emulsion composition, includes: a solvent, a stabilizing throughout the vaginal cavity surface, will effectively reach Surfactant, a pseudoplastic or semi-pseudoplastic agent, a the cervix, will not leak and will retain intravaginally an modulating agent, water a propellant and one or more active active agent for a significant period of time. In other aspects, pharmaceutical agents. the present invention provides a steroid and a lubricating 0055 According to one or more embodiments, at least one vaginal drug vehicle for moisture replenishing or moisturiz of the active pharmaceutical agents is a steroid. ing vaginal vehicles. In other aspects, the invention provides an improved delivery system for Steroids alone or in combi 0056. According to one or more embodiments, at least one nation with other active agents to other body cavities, such as of the resilient agents is a viscoelatic, which in turn is capable the rectum, penile urethra, nasal cavity and ear cavity and to of forming a pseudoplastic or semi-pseudoplastic composi mucosal Surfaces. tion. 0065. The present invention relates to foam compositions 0057 According to one or more embodiments, the vis for intra-vaginal and body cavity application of a wide range coelatic comprises an effective amount of at least one poly of steroids on their own or in combination with a very wide meric additive selected to form a foamable carrier or compo variety of ingredients. The compositions contain at least one sition which is resilient to creaming/phase separation active steroid agent in a biocompatible alcohol-free foamable 0058 According to one or more embodiments, the vis carrier, including, oil-in-water foamable emulsions and coelatic comprises an effective amount of at least one poly water-in-oil foamable emulsions, liposome-based foams and meric additive selected to form a foamable carrier or compo nanoparticle-based foams. These compositions provide long sition which is shakable and flowable to a sufficient amount to lasting, drip-free, expandable formulations for drug delivery be expelled by the propellant from a canister to form a foam into body cavities. of appropriate quality for topical or mucosal application. 0066. In one or more embodiments it has been possible to 0059. According to one or more embodiments, the vis achieve formulations suited for body cavity use by incorpo coelatic comprising at least one polymeric additive selected rating into the breakable foam formulation a bioadhesive from the group consisting of a bioadhesive agent, a gelling character where force is required to dislodge from the foam. agent, a film forming agent and a phase change agent. In an embodiment the foam has a bioadhesive value of about 0060. In the process of trying to overcome the challenge of -3 g to about -30 g, preferably between about -8 g to about formulating the steroid-like betamethasone Valerate or cal -25 g. cipitriol, it has been discovered that it is possible to improve 0067. The present invention further provides a therapeutic and increase the physical stability of emulsion foamable com kit including a foamable steroid composition. The kit positions and therefore any resultant foam produced there includes an aerosol packaging assembly having a container US 2008/0206161 A1 Aug. 28, 2008

accommodating a pressurized product and an outlet capable 0079 a steroid compound selected from the families of of releasing the pressurized product as a foam. (a) cardanolides, (b) bufanolides, (c) Spirostans, (d) 0068. The therapeutic kit includes an aerosol packaging furostans, (e) steroid alkaloids, (f) steroid lactones, (g) assembly including (a) a container accommodating a pressur OXo-steroids, (h) steroid-alcohols and (i) Steroid ized product and (b) outlet capable of releasing the pressur amines: ized product as a foam; wherein the pressurized product con 0080 a steroid compound, where one or more of the tains a foamable composition including: (i) a steroid; (ii) at cyclopentalaphenanthrenerings is contracted by loss of least one organic carrier selected from the group consisting of an unsubstituted methylene group; a hydrophobic organic carrier, an organic polar solvent, an 0081 a steroid compound, where one or more of the emollient and mixtures thereof, at a concentration of about cyclopentalaphenanthrene rings is expanded by inclu 2% to about 50% by weight; (iii) a surface-active agent; (iv) sion of a methylene group; about 0.01% to about 10% by weight of at least one quiesence 0082 a steroid compound containing a cyclopentaa agent, (v) water, and (vi) liquefied or compressed gas propel phenanthrene skeleton and a carbocyclic or heterocyclic lantata concentration of about 3% to about 25% by weight of ring component fused to it; the total composition. 0.083 a compound, wherein two or more steroid mol 0069. The therapeutic kit includes an aerosol packaging ecules are linked together covalently: assembly including (a) a container accommodating a pressur I0084 a compound selected from the group consisting of ized product and (b) outlet capable of releasing the pressur 5C-pregnane, 53-pregnane, 5C.-cholane (allocholane), ized product as a foam; wherein the pressurized product con 5B-cholane, 5-cholestane, 53-cholestane, 5C.-ergostane, tains a foamable composition including: (i) a steroid; (ii) at 5B-ergostane, 5C-campestane, 53-campestane, 5C-poriferas least one organic carrier selected from the group consisting of tane, 53-poriferastane, 5C.-Stigmastane, 5B-stigmastane, a hydrophobic organic carrier, an organic polar solvent, an 50-gorgostaneacrihellin, actodigin, alfacalcidol, , emollient and mixtures thereof, at a concentration of about , betamethasone, brassinolide, calcidiol, calciol, 2% to about 50% by weight; (iii) a surface-active agent; (iv) , , , , cholic acid, about 0.01% to about 5% by weight of at least one resilient , , cortisol , , cortisone agent, (v) a modulating agent (vi) water, and (vii) liquefied or acetate, , deoxycorticosterone, , compressed gas propellant at a concentration of about 3% to disogluside, ecdysone, ercalciol, , , , about 25% by weight of the total composition. , , fluazacort, fluocortin, fusidic acid, 0070 The steroid kit further contains an applicator of , gonane, halometasone, , lanos appropriate length and cross section adapted for body cavity terol, , , , application. For example, an applicator ideal for intravaginal meproscillarin, , , naflocort, use for example to deliver a steroid hormone Such as esradiol norenthisterone, , , , or prgestron will be of an appropriate length to facilitate , pancuronium , , pred delivery to the area of the uterine entrance. nisone, , proscillardin, pseudotigogenin, roxi 0071. In preferred embodiments, the composition further bolone, Sarsasapogenin, Smilagenin, , timobe contains a therapeutically effective foam adjuvant to increase Sone, , tigogenin triamcinolone, urSodeoxycholic the foaming capacity of Surfactants and/or to stabilize the acid; foam. In one or more embodiments, the foam adjuvant 0085 an anti-inflammatory steroid; includes fatty alcohols having 15 or more carbons in their 0086 a steroid possessing immunomodulating and/or carbon chain, fatty acids having 16 or more carbons in their anti-inflammatory properties; carbon chain, and combinations or mixtures thereof. 0.087 a steroid, selected from the group of low-potency 0072. In one or more embodiments, a combination of a anti-inflammatory steroids, medium potency anti-in fatty acid and a fatty ester is employed. flammatory steroids and high potency anti-inflamma 0073. Optionally, the carbon atom chain of the fatty alco tory steroids; hol or the fatty acid may have at least one double bond. A 0088 an anti-inflammatory steroid, selected from the further class of foam adjuvantagent includes a branched fatty group consisting of hydrocortisone, hydrocortisone alcohol or fatty acid. The carbon chain of the fatty acidor fatty acetate, desonide, betamethasone Valerate, clobetaSone alcohol also can be substituted with a hydroxyl group, such as 17-butyrate, flucinonide, fluocinolone acetonide, 12-hydroxy Stearic acid. alcometasone dipropionate, furoate, pred 0074. In one or more embodiments, at least a portion of the nicarbate, , betamethasone-17 steroid is suspended in the composition, yet, in other embodi benzoate, methylprednisolone aceponate, betametha ments, the steroid is dissolved in the composition. Sone dipropionate, halcinonide, triamcinolone 0075. In one or more embodiments, the foam composition acetonide, halobetasol, clobetasol-17-propionate; is formulated as an oil-in-water emulsion or oil-in-water I0089 a steroid that positively affects the McKenzie microemulsion. vasoconstrictor assay; 0076. In some embodiments, the steroid is selected from 0090 a steroid hormone: the group consisting of 0.091 a steroid hormone, selected from the group con 0077 a steroid compound containing a cyclopentaa sisting of an , an and a ; phenanthrene skeleton; 0092 an androgen, selected from the group consisting 0078 a steroid compound containing a cyclopentaa of testosterone, testosterone cipionate, testosterone phenanthrene skeleton carrying one or more functional decanoate, testosterone enantate, testosterone isoca groups selected from halogens, alkyl groups, aryl proate, testosterone phenylpropionate, testosterone pro groups, benzyl groups, carboxy groups and alkoxy pionate, testosterone undecylate, 5C.-dihydrotestoster groups: one, (also termed US 2008/0206161 A1 Aug. 28, 2008

and DHEA), , androstanediol, andros cinicifiiga racemosa, licorice root, red clover, Sage, sar terone, androstenolone, prasterone enantate, prasterone Saparilla, Sassafras, angelica sinensis achillea millefo Sulfate, , , fluoxymes lium, anemone pratensis, angelica sinensis, glycyrrhiza terone, , gestrinone, , glabra, , larrea, panax, piscidia , , chlormadinone erythrina, plantago psyllium, repens, Symphy acetate, and ; tum, taraxacum officinale, trifolium pratense, turnera 0093 an estrogen selected from the group consisting of spp., tussilago farfara, Valeriana officinalis, Viburnum estradiol, , estradiol cipionate, estra prunifolium, and calendula officinalis, diol dipropionate, estradiol enantate, estradiol hexahy drobenzoate, estradiol phenylpropionate, estradiol val 0.108 anyy one of the compoundsp exemplifiedp in the erate, , estriol, estriol sodium present specification; Succinate, , , 0109) and salts thereof. , ethinylestradiol, , mestra 0110. According to further embodiments, there is pro nol, estrapronicate and ; vided a method of treating, alleviating or preventing disorders 0094 a progestogen, selected from the group consisting of the skin, a body cavity or mucosal Surface, where the of progesterone, , , disorder involves inflammation as one of its etiological fac norethisterone enantate, medroxyprogesterone acetate, tors. The method includes topically administering a foamed delmadinone acetate, acetate, dydrogester composition to a subject having the disorder, the foamed one, , norgestrel, , dydrogest composition including a steroid, at least one organic carrier erone, , , , selected from a hydrophobic organic carrier, a polar solvent, , , tybolone, cyproterone an emollient and mixtures thereof, at a concentration of about acetate, acetate, acetate; 2% to about 50% by weight, about 0.1% to about 5% by 0095 an inhibitor of a steroid hormone: weight of a surface-active agent, about 0.01% to about 5% by 0096 an inhibitor of a steroid hormone selected from weight of a polymeric additive selected from a bioadhesive the group consisting of , and agent, a gelling agent, a film forming agent and a phase spironolactone; change agent and water, wherein the steroid is administered in 0097 a D; a therapeutically effective amount. 0.098 a steroid that exhibits qualitatively the biological 0111 Disorders suitable for treatment include vaginal dis activity of calciol; orders, Vulvar disorders, anal disorders, disorders of a body 0099 a selected from the group consisting of cavity, ear disorders, disorders of the nose, disorders of the , 25-hydroxycholecalciferol, 1C.25-di respiratory system, bacterial infections, fungal infections, hydroxycholecalciferol, , 1C.,25-dihy viral infections, dermatosis, dermatitis, parasitic infections, droxyergocalciferol, 22.23-dihydroergocalciferol. 1.24. disorders of hair follicles and sebaceous glands, Scaling papu 25-trihydroxycholecalciferol, previtamin D. lar diseases, benign tumors, malignant tumors, reactions to tachysterol, (also termed tacalciol): Sunlight, bullous diseases, pigmentation disorders, disorders 0100 a vitamin D3 analogue: of cornification, pressure Sores, disorders of Sweating, 0101 isovitamin D, , (1S)-hy inflammatory reactions, Xerosis, ichthyosis, allergy, burn, droxycalciol, (24R)-hydroxycalcidiol, 25-fluorocalciol, wound, cut, chlamydia infection, gonorrhea infection, hepa ercalcidiol, ertacalciol, (5E)-isocalciol, 22.23-dihydro titis B, herpes, HIV/AIDS, human papillomavirus (HPV), ercalciol, (24S)-methylcalciol, (5E)-(10S)-10,19-dihy genital warts, bacterial vaginosis, candidiasis, cancroids, droercalciol, (24S)-ethylcalciol and (22E)-(24R)-ethyl granuloma Inguinale, lymphogranloma Venereum, mucopu 22,23-didehydrocalciol; rulent cerviciitis (MPC), molluscum contagiosum, nongono 01.02 a vitamin D analogue selected from , coccal urethritis (NGU), trichomoniasis, Vulvar disorders, , maxacalcitol, and calcitriol: Vulvodynia, Vulvar pain, yeast infection, Vulvar dystrophy, 0103 a or a : vulvar intraepithelial neoplasia (VIN), contact dermatitis, 0.104 a steroid derived or extracted from one of the osteoarthritis, joint pain, hormonal disorder, infertility, pelvic families of , , phytostanols, inflammation, endometritis, Salpingitis, oophoritis, genital ecdysones, withanolids, Sterines, steroid and cancer, cancer of the cervix, cancer of the Vulva, cancer of the Soflavonoids; vagina, vaginal dryness, dyspareunia, anal and rectal disease, 0105 a steroid selected from the group consisting of anal abscess/fistula, anal cancer, anal fissure, anal warts, alpha-sitosterol, beta-sitosterol, , campes Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecal terol, alpha-sitostanol, beta-sitostanol, Stigmastanol, incontinence, constipation, polyps of the colon and rectum; campestanol, avenosterol, brassicasterol, desmoSterol, sexual dysfunction in men and women, androgen deficiency; chalinosterol, beta-ecdysone, whithaferin A, beta-sito estrogen deficiency, growth disorders, hypogonadism, can sterine, Stigmasterine, campesterine, ergosterine, dios cer, vasomotor symptoms, menopausal disorders, Vulvar and genin, , , , muristerone, vaginal atrophy, urethritis, hypoestrogenism, osteoarthritis, poriferasterol, clionasterol, campestanol, and , uterine bleeding, hirsutism, virilization, ova cycloartenol; rian tumors, hypothalamic pituitary unit diseases, testicular 0106 a oil or a plant extract, which contains a tumors, cancer, hypopituitarism, Klinefelter's Syn steroid: drome, testicular feminisation, orchitectomy, vasomotor 0107 a plant oil or a plant extract, selected from the symptoms (such as "hot flashes') associated with the meno group consisting of nuts seeds, sprouted seeds and grains pause, metabolic abnormalities and mood disturbances. (such as alfalfa), St. Mary's thistle, , saw 0112 There is thus provided according to some embodi palmetto, panax, Siberian , foeniculum Vulgare, ments, a storable foamable emulsion composition adapted for US 2008/0206161 A1 Aug. 28, 2008

delivery of an active pharmaceutical ingredient (API) to a 0.132 wherein the at least one API remains chemically delivery site in a subject, the composition including: stable for about at least about one month; and 0113 at least one organic carrier selected from the 0.133 wherein the composition is stored in an aerosol group consisting of a hydrophobic organic carrier, an container and upon release expands to form a breakable organic polar solvent, an emollient and mixtures thereof, foam having an average bubble size range of about 30 to at a concentration of about 2% to about 50% by weight; about 250 micron. 0114 at least one surface-active agent at a concentra tion of about 0.01% to about 5% by weight; I0134. In one or more embodiments the composition is 0115 at least one polymeric agent selected from the physically and chemically stable within acceptable pharma group consisting of a bioadhesive agent, a gelling agent, ceutical limits for a foamable composition for about at least a film forming agent and a phase change agent, each in a three months. In one or more embodiments the composition is concentration of about 0.01% to about 5% by weight; physically and chemically stable within acceptable pharma 0116 water; ceutical limits for a foamable composition for about six 0117 an effective amount of at least one API selected months, for about a year or for about 2 years. from the group consisting of a steroid, a steroid deriva 0.135 The carrier compositions described herein may also tive, a further active agent together with the steroid or be suitable for storing and delivering API's other than ste derivative thereof and combinations thereof, and roids. Thus, there is also provided according to specific 0118 a propellant at a concentration of about 3% to embodiments a foamable carrier composition containing an about 25% by weight of the total foamable composition, active agent without steroid. In one embodiment the active 0119 wherein, at ambient temperature, the storable agent is coal tar or a coal tar extract. foamable emulsion composition is shakable, is resistant 0.136. In some embodiments, the compositions include at to centrifugation at about 3000 rpm for about 10 min, is least one quiescence agent. In some embodiments, the API is Substantially devoid of crystals, is resistant to at least one stable or is stabilized in the presence of at least one quies freeze-thaw cycle and does not phase separate within at cence agent. In some embodiments, the API and at least one least about one month; quiescence agent function synergistically to achieve I0120 wherein the at least one API remains chemically improved chemical or physical characteristics for the compo stable for at least about one month; and sition. In some embodiments, the API demonstrates improved I0121 wherein the composition is stored in an aerosol characteristics when combined with at least one quiescence container and upon release expands to form a breakable agent. In some embodiments, the improved chemical or foam having an average bubble size range of about 30 to physical characteristics is improved stability over time, about 250 micron. whether chemical or physical stability. In some embodi 0122. In one embodiment, when the foam or foamable ments, the improved chemical or physical characteristics emulsion composition is compressed between two Surfaces, a include, without limitation, one or more of the following negative adhesive force is required to effect their separation. properties: foam quality, bioadhesivity, color, odor, and col A negative force could be about -1 g or less. By less it is lapse time. Moreover, in some embodiments, the improved meant say for example about -3 g to about -30 g, and pref chemical or physical characteristics are demonstrated under erably about -8 g to about -25 g. various storage conditions (e.g., temperature ranging from 0123. There is also provided a storable foamable emulsion about 25° C. to about 50° C. or any specific temperature composition adapted for delivery of an active pharmaceutical between and including these temperatures; and humidity ingredient (API) to a delivery site in a Subject, the composi ranging from about 0% to about 100% relative humidity or tion comprising: any specific humidity between and including these values). In Some embodiments, the compositions demonstrate improve 0.124 at least one fatty alcohol, at a concentration of ment in at least one property. In some embodiments, the about 2% to about 50% by weight; compositions demonstrate improvement at least in two prop 0.125 at least one surface-active agent at a concentra erties. In some embodiments, the compositions demonstrate tion of about 0.01% to about 5% improvement in at least three properties. In some embodi 0.126 by weight; ments, the compositions demonstrate improvement in at least I0127 at least one polymeric agent selected from the four properties. In some embodiments, the compositions group consisting of a bioadhesive agent, a gelling agent, demonstrate improvement in at least five properties. In some a film forming agent and a phase change agent, each in a embodiments, the compositions demonstrate improvement in concentration of about 0.01% to about 5% by weight; at least six properties. In some embodiments, the composi 0128 water; tions demonstrate improvement in at least seven properties. In 0.129 an effective amount of at least one API selected Some embodiments, the compositions demonstrate improve from the group consisting of a steroid, a steroid deriva ment in at least eight properties. In some embodiments, the tive, a further active agent together with the steroid or compositions demonstrate improvement in at least nine prop derivative thereof and combinations thereof, and erties. In some embodiments, the compositions demonstrate 0.130 a propellant at a concentration of about 3% to improvement in at least ten properties. In some embodiments, about 25% by weight of the total foamable composition, the compositions demonstrate improvement in at least eleven I0131 wherein, at ambient temperature, the storable properties. In some embodiments, the compositions demon foamable emulsion composition is shakable, is resistant strate improvement in at least twelve properties. to centrifugation at about 3000 rpm for about 10 min, is 0.137 In some embodiments the bioadesivity of the com Substantially devoid of crystals, is resistant to at least one position to the delivery site requires a force of about -3 g to freeze-thaw cycle and does not phase separate within at about -30 g to dislodge the foam from the delivery site. In least about one month; Some embodiments, the bioadesivity of the composition to US 2008/0206161 A1 Aug. 28, 2008

the delivery site requires a force of about -8 g to about -25g 0.150 water; to dislodge the foam from the delivery site. 0151 an effective amount of at least one API selected 0.138. In some embodiments, the color of the composition from the group consisting of a steroid, a steroid deriva or the foam resulting from the composition is white, white to tive, a further active agent together with the steroid or off-white, yellowish, or yellow. derivative thereof and combinations thereof, and 0.139. In some embodiments, the foam quality of the com 0152 a propellant at a concentration of about 3% to position or the foam resulting from the composition is 5-6 about 25% by weight of the total foamable composition, after at least one freeze-thaw cycle. In some embodiments, 0.153 wherein, at ambient temperature, the storable the foam quality of the composition or the foam resulting foamable emulsion composition is shakable, is resistant from the composition is 5-6 after two freeze-thaw cycles, to centrifugation at about 3000 rpm for about 10 min, is three freeze-thaw cycles, four freeze-thaw cycles, five freeze Substantially devoid of crystals, is resistant to at least one thaw cycles or ten freeze-thaw cycles. In some embodiments, freeze-thaw cycle and does not phase separate within at the foam quality of the composition or the foam resulting least one month; from the composition is 5-6 after about 1 week, 2 weeks, 3 0154 wherein the at least one API remains chemically weeks, 4 weeks, 1 month, 2 months or 3 months. Storage stable for about at least one month; and conditions include, without limitation, storage at room tem 0.155 wherein the composition is stored in an aerosol perature, 25°C., 30° C., 40°C., 50° C., or 60° C. or combi container and upon release expands to form a breakable nations thereof. bioadhesive foam having an average bubble size range 0140. In some embodiments, the collapse time of the com of about 30 to about 250 micron. position or the foam resulting from the composition is, with out limitation, at least 30 seconds, at least 40 seconds, at least BRIEF DESCRIPTION OF THE DRAWINGS 50 seconds, at least 60 seconds, at least 70 seconds, at least 80 seconds, at least 100 seconds, at least 120 seconds, at least 0156 The invention is described with reference to the 140 seconds, at least 160 seconds, at least 180 seconds, at figures which are presented for the purpose of illustration and least 200 seconds, at least 220 seconds, at least 240 seconds, are not intended to be limiting. at least 260 seconds, at least 280 seconds or at least 300 O157 FIG. 1 is a schematic illustration of an aerosol valve seconds. Suitable for use in the aerosol packaging assembly according to in one or more embodiments. 0141. There is thus provided according to some further 0158 FIG. 2A-2F are photomicrographs (x400, polarized embodiments, a method for forming a breakable foam light) of (A) the emulsion composition of Example 4 demon adapted for delivery of an active pharmaceutical ingredient strating that no crystals are observable; (B) the water phase of (API) to a delivery site in a subject, the method including: the composition of Example 4 following addition of a Surfac 0.142 forming an emulsion from at least one organic tant demonstrating that no crystals are observable; (C and D) carrier, at least one Surface-active agent and at least one the water phase of the composition of Example 4 prior to the polymeric additive in water, addition of surfactant in which crystals are clearly visible; (E) 0.143 wherein the emulsion includes the at least one betamethasone Valerate powder used in the preparation of the Surface active agent in a suitable concentration relative composition of Example 4 and (F) a commercial betametha to the at least one organic carrier Such that the at least one sone Valerate 0.12% cream. Surface active agent is matched with the at least one organic carrier; 0159 FIG. 3 is a photomicrograph illustrating a steroid 014.4 mixing the emulsion with an effective amount of (bmv) emulsion. at least one API to form the storable foamable emulsion composition; and DETAILED DESCRIPTION 0145 propelling the storable foamable emulsion com 0160 The present invention relates to improved, easy to position with a propellant to form a breakable bioadhe use, stable and non-irritating Steroid foamable compositions sive foam having an average bubble size range of about and foams, intended for treatment of dermal and mucosal 30 to about 250 micron. tissues. In the process of investigating steroid foamable com 0146 There is thus provided according to some additional positions and carriers it has been noted that it is not sufficient embodiments, a method of treating, alleviating or preventing to produce foams of quality but the problem is how produce a disorder of the skin, a body cavity or a mucosal Surface, formulations which are able to display characteristics of wherein the disorder involves inflammation as one of its physical and chemical stability, which are biocompatible and etiological factors, which method includes administering which are capable of remaining Sufficiently stable physically topically to a Subject having the disorder in need thereof a and chemically for a significant or even prolonged period of therapeutically effective amount of a storable foamable emul time. sion composition including: 0.161 Formulation of an oil-in-water emulsion foam is a 0147 at least one organic carrier selected from the very delicate balance between the functional inactive ingre group consisting of a hydrophobic organic carrier, an dients, excipients, which contribute to droplet size, separating organic polar solvent, an emollient and mixtures thereof, film, viscosity and Stability. In order to assure accurate and at a concentration of about 2% to about 50% by weight; continuous foam actuation, the “Pre Foam Formulation' 0.148 at least one surface-active agent at a concentra (PFF) should be liquid and shakable in the canister, otherwise tion of about 0.01% to about 5% by weight; the PFF will not flow easily and completely towards and 0149 at least one polymeric additive selected from the through the valve. group consisting of a bioadhesive agent, a gelling agent, 0162 Stability of emulsions and resilience to creaming is a film forming agent and a phase change agent, each in a desired. In the context of foamable emulsion compositions it concentration of about 0.01% to about 5% by weight; has been discovered that improved physical stability is US 2008/0206161 A1 Aug. 28, 2008

obtained by an appropriate increase in product viscosity When the formulation is like a block or excessively viscous through use of viscoelastic agents, which can provide Suitable like an ointment it will not be shakable. On the other hand the rheology whilst retaining the requirements of shakability and foamable formulations have to be capable of being extruded by controlling droplet size. Smaller droplets will migrate in a through a valve and tube in anaerosol canister under pressure slower manner and appropriate increased Viscosity mini of a propellant and therefore the compositions should be mizes droplets migration and creaming and reduces the flowable to a sufficient extent that allows the formulation to occurrences of droplets contact and fusion. However, the pass through a tube and valve to form a foam of Sufficient formulation should have sufficient viscosity to Support emul quality upon being expelled from the aerosol. It has been sion stability, inhibit droplets migration and separation phe discovered that in the context of the foamable compositions nomenon and yet remain flowable. that in a preferred embodiment the stabilizing agent should 0163. By creaming, is meant that particles of the disperse exhibit pseudoplastic rheological behavior. In other words, to phase concentrate in the upper layer, form a cream-like con exhibit physical behavior that provides a flowable or shakable centrated emulsion. The creaming value is defined as the Viscous system that at rest is capable of introducing to or relative volume of the creamed phase and the total volume the restoring in the compositiona Sufficient viscosity to retard the sample. The expression used for calculation of the creaming motion or migration of emulsion droplets but whose viscosity Volume is as follows: decreases when Subjected to shear stress, which in this case can be vigorous shaking. 0168 By selective use of appropriate stabilizing surfac % Creaming = W Pe* Prix 100 tant, co-surfactants and stabilizing polymers the composi Votal tions can be stabilized. One method to overcome the contra dicting physical requirements is to base the stabilizing agent 0164 Creaming values are between 1% and 99%, accord on viscoelastic polymers which can form pseudo-plastic or ingly. 100% means “no creaming' which is the desirable best semi pseudoplastic compositions. score.0% (Zero value) indicates phase separation and is the 0169. Thus in one or more embodiments there is provided WOrSt SCOre. a pseudoplastic viscoelasic or semi-pseudoplastic viscoelas 0.165. In the present invention it has been discovered that it tic Steroid composition. is possible to meet and balance these contradictory aspects to 0170 It has been further discovered that by creating an improve the physical properties and increase the physical appropriate rheological emulsion flow behavior it has been stability period of the foamable composition and therefore possible to develop longer lasting compositions. By appro any resultant foam produced there from by incorporating into priate selection of agents and excipients to facilitate biocom the composition an effective amount of a stabilizing agent. In patibility and to achieve the appropriate balance of physical parallel it has likewise been discovered that it is possible to properties, including rheology, emulsion droplet size, the improve the chemical stability of the steroid or other active density of each phase, and the Viscosity of the continuous agent in the composition by use of a modulating agent in the phase, it has been discovered in the context of foamable composition. The modulating agent acts to create or maintain compositions that it is possible to prepare formulations that an environment within the formulation suitable for maintain are resilient to creaming/phase separation when Subjected to ing chemical stability of the steroid in its active form. centrifugation. It has been further discovered that it is pos 0166 It has further been discovered that it is possible to sible to prepare resilient formulations that are resilient to make foamable compositions that will produce foam of a creaming/phase separation even under harsh centrifugation reasonable quality without the addition of a polymeric or a conditions such that could be extrapolated to reflect a stable gelling agent. However, in order to produce a physically shelf life of years. rugged or durable foamable composition that will produce a 0171 It has been further discovered that polymers such as foam of quality it is necessary to introduce a Suitable stabi cellulose derivatives, Xanthan gum, Sodium CMC, methyl lizing agent, which can be polymeric or gelling agent. Addi cellulose, hydroxylpropyl methyl cellulose and the like, are tionally the polymeric or gelling agent may contribute to the Suitable to provide Viscoelastic compositions that have elegance or quality of foam produced from the composition. pseudoplastic or semi-pseudoplastic viscoelastic properties By physically rugged or durable it is intended that the formu and which are able to contribute sufficiently to viscosity sta lation is capable of physically withstanding to a substantial bilizing the PFF emulsion, but are able to temporarily loose degree one, two or possibly more freeze thaw cycles; or a this property upon stress such as human hand shaking. The period of time at an elevated temperature of say 30° C. or say result is a stable emulsion and product with low or very low 40° C. for say one or two or possibly three months; or a creaming (droplets migration) on shelf and liquid and shak prolonged period of time at room temperature for say three to able and dispensing foam upon shaking and actuation. six months or possibly longer. 0172. Thus, in one or more embodiments, there is pro 0167. It has been discovered that in the context of foam vided a resilient formulation. In certain embodiments the able formulations it is possible to improve the properties of resilient formulation is a viscoelastic formulation. In certain the foamable composition and thereby the resultant foam embodiments the viscoelastic formulation is a pseudoplastic produced there from by selecting carefully a suitable stabi Viscoelastic composition. Thus in certain formulations the lizing agent, which in turn can be a suitable polymeric agent composition comprises a resilient agent, which can in turn be or gelling agent that has appropriate rheological properties a viscoelastic or a pseudoplastic or a semi-pseudoplastic suitable for a foamable composition. On the one hand the agent. composition should be shakable to a sufficient or minimal (0173 It has been further discovered that for certain for degree. By shakable it indicates that some motion or move mulations where the active agent is susceptible tone or more ment of the formulation can be sensed when the canister of isomerization, chemical breakdown, chemical reaction, containing the formulation is shaken or is strongly shaken. oxidation and the like and the compound is to be formulated US 2008/0206161 A1 Aug. 28, 2008

in a composition Suitable for being stored for a period of time, mm. The total aperture area, i.e., the Sum of areas of all which could be a short, medium or longer period of time apertures in a given stem, is between about 0.01 mm and 1 within the context of a pharmaceutical composition in order mm or the total aperture area is between about 0.04 mm and to achieve a composition that is capable of being physically 0.5 mm. and chemically stable the formulation should comprise one or 0180. In order to provide propertherapy, precise dosing is more quiescence agents. By chemically stable reference is desired. According to one or more embodiments, the valve is intended to the chemical stability of an active agent in the attached, directly or through a tube, to a metered dose device pharmaceutical compositions and foams such that the active for dispensing an accurate dose of drug in the form of a foam. agent should be capable of remaining chemically stable or The metered dose valve is selected to release a foam in a Substantially so in the composition for a sufficient reasonable Volume that provides an adequate therapeutic dose to the period of time to allow for pharmaceutical application of an target site of the skin, a body Surface, a body cavity or effective amount of active agent to a Subject. By quiescence mucosal Surface, e.g., the mucosa of the nose, mouth, eye, ear, agents is meant agents which on their own or in combination respiratory system, vagina or rectum. or within the context of the formulation have a calming or 0181. In one or more embodiments, the meter dose valve quieting or stabilizing or modulating effect or combinations provides a unit dose of between about 10 uL and about 1000 thereof on the composition and includes the ability to calm or LL of liquid. Assuming a representative foam density (spe restore viscosity and or may include the ability to protect the cific gravity) of 0.06 g/mL, a 10 uIl valve provides a foamed composition or one or more ingredients from a form of chemi volume of about 0.17 mL, and a 1000 uL metered dose valve cal change and or may include the ability to resist or be provides a foamed volume of about 17 mL. Thus, by selecting resilient to creaming/phase separation. a specific metered dosing valve, adjusting the foam density by 0.174 Thus, in one or more embodiments there is provided fine-tuning formulation parameters and adjusting the ratio a foamable composition comprising at least one quiescence between the liquid components of the composition and the agent. propellant, one can design an adequate dosage form for a 0175 Thus, in one or more embodiments there is provided specific target site. a quiescence foamable composition including a quiescence agent selected from a stabilizing, a polymeric, a gelling, a Pharmaceutical Composition Viscoelastic, a pseuedoplastic or semi-pseudoplastic, a resil 0182 All % values are provided on a weight (w/w) basis. ient or a modulating agent. In certain embodiments an agent 0183. According to one or more embodiments, the foam may have more than one of these characteristics. In certain able therapeutic composition for administration to the skin, a other compositions a combination of two or more agents is body Surface, a body cavity or mucosal Surface, e.g., the used to achieve a quiescence foamable composition having mucosa of the nose, mouth, eye, ear, respiratory system, more than one of their characteristics. vagina or rectum, e.g., the “target site' includes: 0176). In some embodiments, a therapeutic kit including a 0.184 (1) a steroid, wherein the amount of the amount of foamable steroid composition is provided. The kit includes an the steroid is effective in the treatment of a disorder of aerosol packaging assembly having a container accommodat the target site; ing a pressurized product and an outlet capable of releasing 0185 (2) at least one organic carrier selected from a the pressurized product as a foam. hydrophobic organic carrier, a polar solvent, an emol lient and mixtures thereof, at various concentrations, Aerosol Packaging Assembly e.g., about 2% to about 5%; or about 5% to about 10%: 0177. The aerosol packaging assembly typically includes or about 10% to about 20%; or about 20% to about 50% a container Suitable for accommodating a pressurized product by weight; and an outlet capable of releasing a foam. The outlet is typi 0186 (3) a surface-active agent; cally a valve. FIG. 1 illustrates a typical aerosol valve 100. 0187 (4) about 0.01% to about 5% by weight of at least The valve is made up of the valve cup 110 typically con one polymeric agent selected from a bioadhesive agent, structed from tinplated Steel, or aluminum, an outer gasket agelling agent, a film forming agent and a phase change 120, which is the seal between the valve cup and the aerosol agent; and can (not shown), a valve housing 130, which contains the 0188 (5) a liquefied or compressed gas propellant at a valve stem 132, spring 134 and inner gasket 136, and a dip concentration of about 3% to about 25% by weight of the tube 140, which allows the liquid to enter valve. The valve total composition. stem is the tap through which the product flows. The inner 0189 Water and optional ingredients are added to com gasket 136 covers the aperture 150 (hole) in the valve stem. plete the total mass to 100%. Upon release from an aerosol The valve spring 134 is usually made of stainless steel. container, the foamable composition expands to form foam (0178. The valve stem is fitted with small apertures 150 that is suitable for topical administration. (also termed "orifices” and “holes'), through which the prod 0190. According to one or more embodiments, the foam uct flows. Valves may contain one, two, three, four or more able composition is substantially alcohol-free, i.e., free of apertures, depending on the nature of the product to be dis short chain alcohols. Short chain alcohols, having up to 5 pensed. In the closed position, the aperture(s) is covered by carbonatoms in their carbon chain skeleton and one hydroxyl the inner gasket. When the actuator is depressed it pushes the group, Such as ethanol, propanol, isopropanol, butanol, iso valve stem through the inner gasket, and the aperture(s) is butanol, t-butanol and pentanol, are considered less desirable uncovered, allowing liquid to pass through the valve and into solvents or polar solvents due to their skin-irritating effect. the actuator. Thus, the composition is substantially alcohol-free and 0179 The valve can have a stem with 1 to 4 apertures, or 1 includes less than about 5% final concentration of lower to 2 apertures. Each aperture can have a diameter of about 0.2 alcohols, preferably less than about 2%, more preferably less mm to about 1 mm, or a diameter of about 0.3 mm to about 0.8 than about 1%. US 2008/0206161 A1 Aug. 28, 2008

0191 In one or more specific embodiments where the 0201 Steroids are numbered and rings are lettered as in active ingredient is coal tar, which may be formulated for formula 1. If one of the two methyl groups attached to C-25 is inclusion in one or more of the carrier compositions of the substituted it is assigned the lower number (26); if both are present invention as an alcoholic extract. In an embodiment substituted, that carrying the substituent cited first in the the alcoholic component of the coal tar extract can amount to alphabetical order is assigned the lower number. about 8% of the total composition. Thus, when the active agent is coal tar the formulation is regarded as Substantially alcohol free if it includes less than about 10% final concen (1) tration of lower alcohols. 0192 In one or more embodiments, the alcoholic content of the coal tarextract is reduced or substantially eliminated by gentle warming to distill off the lower alcohols. 0193 In one or more embodiments, at least a portion of the steroid is suspended in the composition, yet, in other embodi ments, the steroid is dissolved in the composition. 0194 In one or more embodiments, the foam composition is formulated as an oil-in-water emulsion or oil-in-water microemulsion. 0.195 The present invention provides foamable therapeu tic compositions useful for delivery of a steroid agent to a mucosal body. The composition is dispensed as a foam pro viding a stable product that is pleasant and easy to use for high 0202 The steroids can have substituents on the steroid patient compliance. side chain as exemplified in formula 4-7: 0196. The foamable therapeutic composition is suitable for facile administration into the rectum, bladder, the cavity between the uterus and the fallopian tubes, the ovaries and (4) other body areas, which may accept topically-applied prod uctS. 0.197 In one or more embodiments, a foamable composi tion includes water in one phase and at least one solvent selected from a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof in the second phase. The compositions may be water-in-oil or oil-in-water emulsions. 0198 Despite the commonly accepted understanding that hydrophobic organic carriers, polar solvents and emollients are difficult to formulate into a foam-producing product and that addition of such solvents interferes with the foam form ing ability of a Surfactant, the present invention has surpris OH ingly identified a series of foam compositions, which, upon admixing with a liquefied gas propellant in an aerosol con tainer, produce a stable foam composition that is Suitable for topical and mucosal administration to body cavities, such as the vagina, rectum, colon, penile, urethra, nasal cavity and ear cavity. Upon discharge from an aerosol container, the com position forms an expanded foam, which does not breakdown immediately upon discharge, and remains in the body cavity for an extended time. HO 0199 Such compositions have been developed so that they H are physically stable and resilient and that the steroid remains (20S)-5C-Pregnane-3?.20.21-triol

chemically stable when the composition is placed in an aero (6) Sol container and combined with a liquefied gas propellant, to provide an emulsion, which, upon release from the aerosol container, provides atherapeutically beneficial foam product. Steroids 0200 Steroids are compounds possessing the skeleton of cyclopentaalphenanthrene or a skeleton derived therefrom by one or more bond Scissions or ring expansions or contrac tions. Methyl groups are normally present at C-10 and C-13. An alkyl side chain may also be present at C-17. Sterols are steroids carrying a hydroxyl group at C-3 and most of the skeleton of cholestane. Additional carbon atoms may be present in the side chain. US 2008/0206161 A1 Aug. 28, 2008 12

-continued (7) TABLE 1-continued (12)

(22E)-(24R)-24-Methylcholesta-5,722-trien-3?-ol 5 B-Estrane or (22E)-ergosta-5,722-trien-3?-ol trivial name ergosterol 0203 The steroids can have the formalae as exemplified in (13)

formula 9-18. In one or more embodiments, the steroid or CH3 sterol has no Substitution at C-17, as exemplified by gonane, e.g., formulae 9 and 10, estrange (also termed oestrane), e.g. Formulae 11 and 12, and , e.g., formulae 13 and 14. In one or more embodiments, the steroid or sterol has methyl groups at both C-10 and C-13 and a side chain R at C-17 (formulae 15 and 16), as exemplified in Table 1. H TABLE 1. 5C-Androstane Hydrocarbons with side chain at C-17 (9)

(14)

(10) 5?-Androstane

(15)

5f-Gonane

(11) (16)

5C-Estrane US 2008/0206161 A1 Aug. 28, 2008 13

TABLE 1-continued TABLE 1-continued (17) 5C-campestane 53-campestane

H

CH 5C- 5f-poriferastane poriferastane

44,14-Trimethyl-5C-cholestane or lanostane

(18)

5C-StigmaStane 53-stigmaStane

44,14-Trimethyl-9,19-cyclo-5C.9B-cholestane H H, CH3 5C-gorgostane 5-gorgostane or cycloartane S H3C, N 24 -CH3 Side chain 5C-Series (15) 5 B-Series (16) 2 5C-pregnane 53-pregnane H3C (allopregnane) w 4. 20 s

1 17 N. 0204 Examples of unsaturated steroids and sterols are s provided in formulae 19-22:

2 H 5C-cholane 5 B-cholane 19 H3C, CH (allocholane) (19) 3.

s 7 A.

5C-cholestane 5f-cholestane (coprostane) Estra-1,3,5(10)-triene

(20) 5C-ergostane 53-ergostane C

Estra-1,3,7,9-pentaene US 2008/0206161 A1 Aug 28, 2008 14

-continued -continued (21) (24) 2 20 17 l w OH Xw ww

17-Methyl-5C-pregnane 5C.-Androst-1-en-163-ol (25) 2

w Yw 20 (22)

17-Methyl-5C, 173-pregnane

(26) Br

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

17-(2-Bromoethyl)-5C, 17c-cholestane

0205 The stereochemistry of double bonds in the side chain is indicated using the E.Z convention. The same applies (27) to the Seco compounds of the vitamin D series (example in formula 23). In certain cases, the steroid has two carbon chains attached at position 17, e.g. 17-methyl-5C-pregnane 24, 17-methyl-5C, 173-pregnane 25, and 17-ethyl-5-choles tane and 17-(2-bromoethyl)-5C, 17-cholestane 26. Other examples of a steroid that has two carbon chains attached at 17, 17-Dimethyl-5C-androstane position 17, are 17,17-dimethyl-5C.-androstane 27 and 17 B methyl-17C-propyl-5C.-androstane 28. In certain embodi ments, the carbon skeleton of a steroid a carbon atom is replaced by a hetero atom, as exemplified by 17 B-hydroxy (28) 4-oxaandrost-5-en-3-one 29. Yet, in additional embodiments, an additional ring is formed by means of a direct link between any two carbon atoms of the steroid ring system or the attached side chain, as exemplified by formulae 30, 31 and 32.

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

(23) (29) OH

O O (22E)-Cholesta-5,22,25-trien-3?-ol 17B-Hydroxy-4-oxaandrost-5-en-3-one cf. also formula 7 US 2008/0206161 A1 Aug. 28, 2008 15

-continued

(30) (33)

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

(34)

(31)

OH 6H HO H 5,7c-Cyclo-5C-cholestan-4C-ol 3f,14-Dihydroxy-5f-card-20(22)-enolide trivial name: digitoxigenin

(35)

(32)

(20R)-18.21-Cyclo-5C-cholane OH 3f,5,14-Trihydroxy-19-oxo-5f-card-20(22)-enolide trivial name: strophanthidin

(36) 0206. Many important naturally occurring steroids con tain one or more additional heterocyclic ring(s), fused or attached to ring D, formed by modifications of the side chain. These steroids can be grouped into the following families: (a) cardanolides, e.g., 5 B-cardanolide 33, 3?,14-dihydroxy-5B card-20(22)-enolide (digitoxigenin) 34 and 3 B.5,14-trihy droxy-19-oxo-5B-card-20(22)-enolide (strophanthidin) 35, as well as epoxycardanolides, containing a 14.21- or a 16.21 oxygen bridge, as shown in 36, (b) bufanolides, e.g., struc tures 37-39, (c) spirostans, e.g., structures 40-43, (d) furo A 16B,213-epoxy-203-cardanolide Stans, e.g., structures 44-45, and (e) steroid alkaloids.

US 2008/0206161 A1 Aug. 28, 2008

-continued -continued (48) (45) COOH

27

OH

H 5 B-Androstane-17B-carboxylic acid

(49) HO H (25R)-5a-Furost-20(22)-ene-3f,26-diol trivial name: pseudotigogenin

0207. Several biologically important steroids are deriva tives of the parent hydrocarbons carrying various functional groups. Some of the common functional groups include but are not limited to halogens, alkyl groups, aryl groups, benzyl 3f-Hydroxy-4-methyl-5C-cholesta-8,24-diene-4C-carboxylate groups, carboxy groups and alkoxy groups. or 3?-hydroxy-30-norlanosta-8.24-dien-28-oate 0208. In one or more embodiments, the steroid is selected from the group consisting of an acid, a salt of an acid, as exemplified in formulae 46-49, and esters, as exemplified in (50) formulae 50 and 51. In one or more embodiments, the steroid COOCH is a lactone, as exemplified in formulae 52-54.

(46)

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

(51) 2 O) ming/-coch

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

(47) COO (52) O H HO Kv O

HO HO H H 3C,11B-Dihydroxy-20-oxo-5f-pregnan-21-oate 3|B-Hydroxy-5C-cholano-24,17-lactone US 2008/0206161 A1 Aug. 28, 2008

-continued -continued (53) (56)

HO 12C-Hydroxy-5f-cholestane-3C-yl benzoate (20R)-3?-Hydroxypregn-5-ene-20, 18-carbolactone 0210. In one or more embodiments, the steroid is an oxo compound. The oxo compound can be an aldehde, as exem (54) plified by 5-androstan-19-al, 5-cholan-24-al, 3-formyl-5- O 211 cholan-24-oic acid and by formulae 57 and 58, or a ketone, as 2 exemplified by 5-androstan-3-one, pregn-5-ene-320-dione

O and 11-oxo-5-cholan-24-oic acid. 0211. In one or more embodiment, the steroid is an alcohol as exemplified by 5-cholestane-3,11-diol, 3-hydroxy-5-an drostan-17-one (trivial name: androsterone) and by formulae 59.

A. O 'SCOCH, (57) 7B-Acetylthio-3-oxo-17C-pregn-4-ene-21, 17-carbolactone international non-proprietary name: spironolactone

0209. In one or more embodiments, the steroid is an ester of a steroid alcohol, as exemplified by 5-cholestan-3-yl acetate, 5-cholestane-3,12-diyl diacetate, 3-oxoandrost-4- en-17-yl acetate (trivial name ), 17-hy droxy-20-oxopregn-5-en-3-yl Sulfate, 3-acetoxy-5-cardano 3C,7C,12C-Triydroxy-5f-cholestan-24-al lide, 3-benzoyloxy-11-hydroxy-20-oxo-5-pregnan-21-oate or cholaldehyde (from cholic acid) (58) (monobenzoate of 47), 3-acetoxy-5-cholano-24, 17-lactone O (acetate of 52), 3-O-acetylcholic acid, 17-O-benzoylestra diol-17, 3-O-linolenoylcholesterol, as well as in formulae 55 and 56.

(55) H 5C-Androstane-17B-carbaldehyde (59) COONat

5f-Cholestane-3C,12C-diyl 12-acetate 3-benzoate Sodium 3C,12C-dihydroxy-5f-cholan-24-oate common name: sodium 7-deoxycholate US 2008/0206161 A1 Aug. 28, 2008 19

0212. In additional embodiments, the steroid is an amine as exemplified by androst-5-en-3-amine and formula 60, an TABLE 2-continued ether as exemplified by 17-methoxyandrost-4-en-3-one, (20S)-3,17.20-trimethoxy-5-pregnane, (20S)-3,17 Trivial names of some important steroid derivatives dimethoxy-5-pregnan-20-ol. 21-O-methylcortisol and for Trivial name Systematic steroid name mula 61, an acetal or a ketal of an oxo steroid (also named as Calcitriol (94) (5Z,7E)-(1S,3R)-9,10-secocholesta-5,7,10(19)- dialkoxy steroids) as exemplified by 3.3-dimethoxycholest triene-1,3,25-triol Cholesterol cholest-5-en-3P-ol 4-ene, 2.3-(methylenedioxy)pregn-5-ene and formula 62. Cholic acid 3C,7c.12c-trihydroxy-5P-cholan-24-oic acid Corticosterone 11P,21-dihydroxypregn-4-ene-320-dione Cortisol 11P.17.21-trihydroxypregn-4-ene-3,20-dione (60) Cortisolacetate 21-O-acetylcortisol Cortisone 17,21-dihydroxypregn-4-ene-3,11,20-trione 21-O-acetylcortisone Deoxycorticosterone 21-hydroxypregn-4-ene-320-dione (i.e. The 11 deoxy derivative of corticosterone) Ecdysone (22R)-2P,3P,14.22,25-pentahydroxy-5P-cholest 7-en-6-one Ercalciol = (5Z,7E.22E)-(3S)-9,10-secoergosta-5,7,10(19).22 ergocalciferol tetren-3-ol Ergosterol (7) (22E)-ergosta-5,722-trien-3-ol Estradiol-17C. estra-1,3,5(10)-triene-3,17C-diol (CH3)2N Estradiol-17P estra-1,3,5(10)-triene-3,17-diol Estriol estra-1,3,5(10)-triene-3,16C, 17P-triol (20S)-3?-(Dimethylamino)-5C-pregnan-20-ol Estrone 3-hydroxyestra-1,3,5(10)-trien-17-one (61) lanosta-8.24-dien-3-ol '' COOH Lithocholic acid 3c-hydroxy-5P-cholan-24-oic acid Progesterone pregn-4-ene-320-dione Pseudotigogenin (25R)-5C-furost-20(22)-ene-3P,26-diol Sarsasapogenin (25S)-5P-spirostan-3P-ol Smilagenin (25R)-5P-spirostan-3P-ol Testosterone (63) 17P-hydroxyandrost-4-en-3-one Tigogenin (25R)-5c-spirostan-3-ol

0214. Additional non-limiting examples of steroids that are applicable according to the present invention are provided in formulae 63-79. (62) (63)

O 17B-Hydroxyandrost-4-en-3-one (testosterone) CN1 (64) 3,3-(Ethylenedioxy)-5f-cholestane OH

0213 Examples of trivial names retained for important steroid derivatives, these being mostly natural compounds of significant biological activity, are given in Table 2. O TABLE 2 ent-17B-Hydroxyandrost-4-en-3-one (ent-testosterone)

Trivial names of some important steroid derivatives (65) Trivial name Systematic steroid name Aldosterone 18,11-hemiacetal of 11P,21-dihydroxy-320 dioxopregn-4-en-18-all or 11P.18-epoxy-183.21 dihydroxypregn-4-ene-320-dione Androsterone 3C-hydroxy-5C-androstan-17-one Brassinolide (22R,23R)-2C,3C.22.23-tetrahydroxy-6,7-seco 5C-cmpestano-6,7-lactone Calcidiol (93) (5Z,7E)-(3S)-9,10-secocholesta-5,7,10(19)-triene 3.25-diol Calciol = (5Z,7E)-(3S)-9,10-secocholesta-5,7,10(19)-trien cholecalciferol (92) 3-ol 5f,9B,10C-Pregnane-320-dione

US 2008/0206161 A1 Aug. 28, 2008 21

-continued -continued (76) (81) O

Fa

7

I6 15

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

(82)

18a-Homo-5C-estrane (not 13-ethyl-5C-gonane or 13-ethyl-18-nor-5C-estrane) 8(14)a-Homo-5C-androstane (78)

(83)

(79) 8(9)a-Homo-5C-androstane

(84)

Des-A-androstane

0215. In one or more embodiments, the steroid is a com pound, in which one or more of the cyclopentalaphenan threne rings is contracted by loss of an unsubstituted methyl enegroup, as exemplified by 4-nor-5-androstane (78), where C-4 is missing. In other embodiments one or more of the cyclopentaalphenanthrene rings is expanded by inclusion of 9(10)a-Homo-19-nor-5C, 10C (H)-pregnane a methylene group, as exemplified by formulae 80-86.

(85)

(80)

4a-Homo-5C.-androstane 13(17)a-Homo-5C-pregnane US 2008/0206161 A1 Aug. 28, 2008 22

-continued -continued (86) (102)

4a-Homo-7-nor-5C.-androstane 2C,3C-(Methylenedioxy)pregn-5-ene 0216. In one or more embodiments, the steroid contains additional rings that are formed within, or on, a steroid (103) nucleus. In additional embodiments, the steroids contains a bivalent bridge Such as —O-O-, -CH2—, linking non adjacent ring positions as exemplified by formulae 99-102. 0217. In one or more embodiments, the steroid contains a cyclopentaalphenanthrene skeleton and a carbocyclic or het erocyclic ring component fused to it, as exemplified by for mulae 103-111, and in other embodiments, an additional ring is linked to the cyclopentalaphenanthrene skeleton through a spiro system, as exemplified by formula 1 12. Furo4',3'2':4,5,6 androstane (99) O

(104)

3 3C.9-Epidioxy-5C-androstan-17-one (100)

OCH

(105)

17 B-Methoxy-17C, 14-(epoxymethano)- 5C.-androstane (101)

(106)

Benzo2,3-5C-androstane US 2008/0206161 A1 Aug. 28, 2008

-continued -continued

(107) (112)

3H-Cyclopropa2,3-5C-androstane Spiro5C-androstane-3,1'-cyclopropanel (108)

(113)

2C,3C-Dihydro-3H-cyclopropa2,3-5C-androstane

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

(109)

0218. Yet, in certain embodiments, two or more steroid molecules are linked together covalently, as exemplified by formulae 3a and 3b.

(3a) 17CH-Benzo(12,13,17-5C.-androstane C8H17

(110) C)

3H-Cyclopropa2,3-5C.-androstane

3H-Cyclopropa2,3-5C-androstane 0219. Table 3 provides examples of steroids that are useful according to the present invention.

US 2008/0206161 A1 Aug. 28, 2008 25

TABLE 3-continued Exemplary steroids, which are useful according to the present invention. Molecular Trivial name Chemical name formula Timobesone S-methyl 9-fluoro-11P,17a-dihydroxy-16P- C22H2FOS methyl-3-oxoandrosta-1,4-diene-17F carbothioate Triamcinolone 9-fluoro-11P.16c.17.21-tetrahydroxypregna- C2H2FO 1,4-diene-320-dione Ursodeoxycholic 3c.,7P-dihydroxy-5P-cholan-24-oic acid C2H40O4 acid

0220 Mixtures of these steroids may also be employed and in the oil phase of the composition. In more specific according to the present invention. embodiments, the composition contains a solubilized steroid, 0221 Solubility of the steroid is an important factor in the although the composition does not contain an “organic co development of a stable foamable composition according to Solvent. An "organic co-solvent, is one of the group con the present invention. sisting of an ester of a fatty acid for example a C12-C's alkyl 0222 For definition purposes in context herein, the descriptive terminology for solubility according to the US benzoate, a medium to long chain alcohol, an aromatic and/or Pharmacopoeia (USP23, 1995, p. 10), the European Pharma alkyl pyrollidinone, an aromatic and/or alkyl, and/or cyclic copoeia (EP, 5" Edition (2004), page 7) and several other ketone, an aromatic and/or alkyl, and/or cyclic ether, Substi textbooks used in the art of pharmaceutical Sciences (see for tuted and/or unsubstituted single or multiple ring aromatic, example, Martindale, The Extra Pharmacopoeia,30" Edition straight chain and/or branched chain and/or cyclic alkane or (1993), page Xiv of the Preface; and Remington's Pharma silicone. ceutical Sciences, 18" Edition (1990), page 208) is adapted: 0227. In yet additional embodiments, the steroid is not fully dissolved in either the aqueous phase or the oil phase of the emulsion concurrently, and thus, it is suspended in the Parts of Solvent Required for 1 emulsion, i.e., at least a portion of the steroid portion remains Descriptive Term Part of Solute in Solid State in the final composition. In Such a case, the Very soluble Less than 1 polymeric agents that are listed herein serve as Suspension Freely soluble From 1 to 10 stabilizing agents to stabilize the composition. Soluble From 10 to 30 Sparingly soluble From 30 to 100 0228. In certain embodiments, the composition and prop Slightly soluble From 100 to 1,000 erties of the aqueous phase of the emulsion (e.g., pH, electro Very slightly soluble From 1,000 to 10,000 lyte concentration and chelating agents) and/or the composi Practically insoluble or Insoluble 10,000 and over tion of the oil phase of the emulsion are adjusted to attain a desirable solubility profile of the active agent. 0223 Thus, in one or more embodiments, the steroid is “soluble”, “freely soluble” or “very soluble” (as defined 0229. The steroid is included in the composition in a con above) in the aqueous phase of the emulsion. In other embodi centration that provides a desirable ratio between the efficacy ments, the agent possesses hydrophobic characteristics and and safety. Typically, steroids are included in the composition the steroid is “soluble”, “freely soluble' or “very soluble” in in a concentration between about 0.005% and about 12%. the oil phase of the emulsion. Yet, in certain cases, the steroid However, in Some embodiments, the concentration is is “very slightly soluble”, “slightly soluble' or “sparingly between about 0.005% and about 0.5%, in other embodiment soluble' in either the water phase or oil phase of the emulsion. between about 0.5% and about 2%, and in additional embodi 0224 Yet, in one or more embodiments, the steroid is ments between about 2% and about 5% or between about 5% insoluble i.e., “requires 10,000 parts or more of a solvent to be and about 12%. solubilized', in either the water phase of the composition, or 0230. In one or more embodiments, the steroid possesses the oil phase of the composition, but not in both. immunomodulating and/or anti-inflammatory properties. 0225. It has been surprisingly discovered herein, that Without being bound to a specific theory, immunomodulating while insoluble in water, a steroid can be solubilized in the aqueous phase of the emulsion (prior to combining the oil and and/or anti-inflammatory steroids act, among other aqueous phases to form an emulsion), by adding a surfactant nisms, through inhibition of the activity of phospholipase A. and optionally, a polymeric agent, without the need of an They also may have anti-proliferative effects on keratinocytes "organic co-solvent. It has been further Surprisingly discov and other cell types. They can Suppress collagen synthesis by ered that including a steroid in a foamable emulsion that is fibroblasts, but this may lead to adverse effects. Anti-inflam insoluble both in water and in the oil phase of the composition matory steroids are roughly grouped according to relative can result in a composition in which the steroid is dissolved, anti-inflammatory activity, but activity may vary consider with no relation to the addition of an “organic co-solvent. ably depending upon the vehicle, the site of application, dis 0226. Thus, in further embodiments, the steroid is solubi ease, the individual patient and whether or not an occlusive lized in the emulsion, although it is insoluble both in water dressing is used, as exemplified in Table 4. US 2008/0206161 A1 Aug. 28, 2008 26

male hormones/ include testosterone, testosterone TABLE 4 cipionate, , testosterone enantate, tes tosterone isocaproate, testosterone phenylpropionate, test Exemplary anti-inflammatory steroids that are useful according to the osterone propionate, testosterone undecylate, 5C-dihydrotes present invention. tosterone, dehydroepiandrosterone (also termed prasterone Relative Typical concentration in and DHEA), androstenedione, androstanediol, androsterone, Potency Generic Name topical products androstenolone, prasterone enantate, prasterone sodium Sul Low Hydrocortisone O.S96-19 fate, ormeloxifene, mesterolone, , methylt Potency hydrocortisone acetate O.S.-1.0% Desonide O.O2-0.2% estosterone, gestrinone, delmadinone, delmadinone acetate, Medium Betamethasone valerate O.05%-0.1% chlormadinone, chlormadinone acetate, danazoland testolac Potency O.O2-0.2% tOne. Clobetasone-17-butyrate O.05% Flucinonide O.01%-0.05% 0236. In one or more embodiments, the steroid hormone is Fluocinolone acetonide O.O1-0.01% a female hormone or an estrogen. Non-limiting examples of AlcometaSone dipropionate O.01% female hormones/ include estradiol, estradiol ben Mometasone furoate O.1% Zoate, estradiol cipionate, , estradiol Triamcinolone acetonide O.025%-0.1% enantate, estradiol hexahydrobenzoate, estradiol phenylpro High Betamethasone-17-benzoate O.025% Potency Methylprednisolone aceponate O.1% pionate, , polyestradiol phosphate, estriol, Betamethasone dipropionate 0.025%, 0.05% estriol Sodium Succinate, estriol Succinate, polyestriol phos Halcinonide O.1% phate, quinestradol, ethinylestradiol, estrapronicate, mestra Triamcinolone acetonide O.S9/o nol, estrapronicate and equilin. Highest Halobetasol O.05% Potency Clobetasol-17-propionate O.05% 0237. In one or more embodiments, the steroid hormone is a progestogen. Non-limiting examples of include progesterone, norethisterone, norethisterone acetate, 0231. In one or more embodiments, the steroid is selected norethisterone enantate, medroxyprogesterone acetate, del from the group of low-potency anti-inflammatory steroids, madinone acetate, , , medium potency anti-inflammatory steroids and high desogestrel, norgestrel, levonorgestrel, dydrogesterone, potency anti-inflammatory steroids. gestodene, chlormadinone acetate, dienogest, drospirenone, 0232. In one or more embodiments, the anti-inflammatory lynestrenol, tybolone, , , steroid is included in the composition at a concentration between about 0.005% and about 1%. . 0233. The McKenzie vasoconstrictor assay, as described, 0238 Yet, in additional embodiments, the steroid an for example, in the British Journal of Dermatology 1975; inhibitor of a steroid hormone. Non-limiting examples of 93:563-71 and versions thereof, has been the primary method Such inhibitors are finasteride, dutasteride and spironolac used for classifying the potency of a product, containing an tOne. anti-inflammatory steroids. Thus, in one or more embodi 0239. In one or more embodiments, the steroid is a vitamin ments, the anti-inflammatory steroid is a steroid that posi D. The term vitamin D is used to describe all steroids that tively affects the vasoconstrictor assay. exhibit qualitatively the biological activity of calciol (vitamin 0234. In one or more embodiments, the steroid is a hor D). Non limiting examples of vitamin D compounds are mone. Hormones are known to affect a variety of biological provided in Table 5. processes in any organism, and thus, their inclusion in the 0240 Yet, in additional embodiments, the steroid is a vita composition, which is intended for local treatment of the skin, min D analogue. Exemplary vitamin D analogs include the vagina, the rectum as well as other body Surfaces and calcipotriol, tacalcitol, maxacalcitol, and calcitriol, with cal cavities provided an advantageous treatment modality. Such cipotriol being especially preferred. compositions containing hormones can be further adminis and derivatives are known to degrade at low pH levels. There tered systemically, via the transdermal or transmucosal route, fore, in certain preferred embodiments, the steroid is a vita in order to alleviate a disorder that is affected by the specific min D. or an analogue or a derivative thereof, the pH is hormone, or in order to tune the hormonal balance of the body adjusted to the range between about 7 and about 10, or in order to attain certain effects controlled by hormones, such between about 7.5 and about 9. In one or more embodiments, as contraception and birth induction. the pH is adjusted using a buffering agent, Suitable of main 0235. In one or more embodiments, the steroid hormone is taining a pH level between about 7 and about 10, or between a male hormone or an androgen. Non-limiting examples of about 7.5 and about 9.

TABLE 5 Examples of Vitamin D compounds Vitamin D name Systematic steroid name Cholecalciferol (also termed calciol, (5Z,7E)-(3S)-9,10-seco-5,7,10(19)- cholecalciferol, vitamin D and cholestatrien-3-ol collecalciferol) 25-Hydroxycholecalciferol (also termed (5Z,7E)-(3S)-9,10-seco-5,7,10(19)- calcidiol) cholestatriene-3,25-diol 1C,25-Dihydroxycholecalciferol (also (5Z,7E)-(1S,3R)-9,10-seco-5,7,10(19)- termed calcitriol) cholestatriene-1,3,25-triol US 2008/0206161 A1 Aug. 28, 2008 27

TABLE 5-continued Examples of vitamin D compounds Vitamin D name Systematic steroid name Ergocalciferol (also termed ercalciol and ergocalciferol) C.25-Dihydroxyergocalciferol (also ermed ercalcitriol) 5,7,10(19).22-ergostatetraen-1,3,25-triol 22,23-Dihydroergocalciferol (also (5Z,7E)-(3S)-9,10-seco-5,7,10(19)- ermed (24S)-methylcalciol and 22,23 ergostatrien-3-ol dihydroercalciol) C.24R,25-Trihydroxycholecalciferol (also termed calcitetrol) cholestatriene-1,3,24,25-tetrol Previtamin D (also termed precalciferol and (6Z)-tacalciol) 3-ol Tachysterol (also termed tacalciol) (6E)-(3S)-9,10-seco-5(10),6,8-cholestatrien sovitamin D (also termed (5E)- (5E,7E)-(3S)-9,10-seco-1 (10)5,7- isocalciol) cholestatrien-3-ol Dihydrotachysterol (also termed (5E,7E)-(3S,10S)-9,10-seco-5,7- dihydroercalciol) cholestadien-3-ol

0241 Further examples of vitamin D compounds include, 0244. In one or more embodiments, the steroid is a com but are not limited to (1S)-Hydroxycalciol (also termed 1 (c- pound that is positively identified using a laboratory method, hydroxycholecalciferol and alfacaleidol), (24R)-Hydroxy Suitable of detecting a steroid. calcidiol (also termed 24(R).25-dihydroxycholecalciferol), 25-Fluorocalciol (also termed 25-fluorocholecalciferol), Additional Active Agents Ercalcidiol (also termed 25-hydroxyergocalciferol), Ertacal 0245. Whenever there is reference to an additional active ciol (also termed tachysterol, (5E)-Isocalciol (also termed agentherein it will be appreciated by a man of the art that each isovitamin D, 22.23-Dihydroercalciol), (24S)-methylcalciol of the additional active agents described herein can be an (also termed vitamin D), (5E)-(10S)-10, 19-Dihydroercal active agent in there own right on their own or in combination ciol, (also termed dihydrotachysterol, hytakerol, and dihy with other active agents in any of the carriers, foamable drotachysterol), (24S)-Ethylcalciol (also termed vitamin Ds) compositions and foams. Likewise whenever there is refer and (22E)-(24R)-Ethyl-22.23-didehydrocalciol, (also termed ence to an active or therapeutic agent herein it will be appre vitamin D). ciated by a man of the art that each of the active or therapeutic 0242. In one or more embodiments, the steroid is a phy agents described herein can be an additional therapeutic agent tosteroid or a phytosterol. As used herein, the term “phy in combination with other active agents in any of the carriers, tosteroid' or “phytosterol includes all steroids that are foamable compositions and foams obtained, derived or extracted from plant sources. Non-lim 0246 Several disorders of the skin, a body cavity or iting examples of families of phytosteroids and phytosterols mucosal Surface (e.g., the mucosa of the nose, mouth, eye, include ecdysones, withanolids, Sterines, steroid saponins ear, vagina or rectum) involve a combination of inflammation, and Soflavonoids. Non-limiting examples of phytosteroid and cell proliferation and differentiation abnormalities, and other phytosterol compounds include alpha-sitosterol, beta-sito biological abnormalities that can be effected by a steroid; and sterol, Stigmastanol, , alpha-sitostanol, beta-sito other etiological factors that require an additional therapeutic stanol, Stigmastanol, campestanol, avenosterol, brassicast modality. For example, psoriasis involves inflammation as erol, desmosterol, chalinosterol, beta-ecdysone, whithaferin well as excessive cell proliferation and inadequate cell differ A, beta-sitosterine, Stigmasterine, campesterine, ergosterine, entiation. Atopic dermatitis involves inflammation, skin dry , daidzein, glycitein, genistein, muristerone, ness and keratinocyte growth abnormality. Bacterial, fungal poriferasterol, clionasterol, campestanol, and cycloartenol, as and viral infections involve pathogen colonization at the well as all natural or synthesized forms and derivatives affected site and inflammation. Likewise, hair growth disor thereof. Such as fatty acid esters, such as esters, ders and other pilosebaceous disorders involve an impaired oleoyl esters, and esters, including isomers. hormonal balance (which can be affected by a steroid hor 0243 Plant oils and extracts which contain steroids are mone or a steroid hormone antagonist), together with other also useful. Non limiting examples of that contain etiological factors, that can be affected a non-steroidal active steroids include nuts seeds, sprouted seeds and grains (such as agent. Hence, in many cases, the inclusion of an additional alfalfa), St. Mary's thistle, ginkgo biloba, saw palmetto, therapeutic agent in the foamable pharmaceutical composi panax, Siberian ginseng, foeniculum Vulgare, Cimicifiiga tion, contributes to the clinical activity of the steroid. Thus, in racemosa, licorice root, red clover, Sage, Sarsaparilla, Sassa one or more embodiments, the foamable composition further fras, angelica sinensis achillea millefolium, anemone praten includes at least one additional therapeutic agent, in a thera sis, angelica sinensis, glycyrrhiza glabra, hypericum perfora peutically effective concentration. tum, larrea, panax, piscidia erythrina, plantago psyllium, 0247. In one or more embodiments, the at least one addi serenoa repens, symphytum, taraxacum officinale, trifolium tional non-steroidal therapeutic agent is selected from the pratense, turnera spp., tussilago farfara, Valeriana officinalis, group consisting of an anti-infective, an , an anti Viburnum prunifolium, calendula officinalis bacterial agent, an antifungal agent, an antiviral agent, an US 2008/0206161 A1 Aug. 28, 2008 28 antiparasitic agent, a anti-inflammatory drug, an stable carrier for the active agents which can be a chemically immunosuppressive agent, an immunomodulator, an immu stable or stabilizing environment for the active agent. Chemi noregulating agent, a hormonal agent, vitaminA, a cal stability is improved by appropriate use of modulating derivative, vitamin B, a vitamin B derivative, , a agents. vitamin C derivative, , a vitamin E derivative, vita min F, a vitamin F derivative, , a vitamin K deriva 0253) Suitable therapeutic agents include but are not lim tive, a wound healing agent, a disinfectant, an anesthetic, an ited to active herbal extracts, acaricides, age spot and keratose antiallergic agent, an alpha hydroxyl acid, lactic acid, gly removing agents, allergen, analgesics, local anesthetics, anti colic acid, a beta-hydroxy acid, a protein, a , a neu acne agents, antiallergic agents, antiaging agents, antibacte ropeptide, a allergen, an immunogenic Substance, a haptene, rials, , antiburn agents, anticancer agents, antidan an oxidizing agent, an , a dicarboxylic acid, aze druff agents, antidepressants, antidermatitis agents, laic acid, sebacic acid, adipic acid, fumaric acid, a retinoid, an antiedemics, antihistamines, antihelminths, antihyperkera antiproliferative agent, an anticancer agent, a photodynamic tolyte agents, antiinflammatory agents, antiirritants, antil therapy agent, an anti-wrinkle agent, a radical scavenger, a ipemics, antimicrobials, antimycotics, antiproliferative metal oxide (e.g., titanium dioxide, oxide, Zirconium agents, , anti-wrinkle agents, antipruritics, antip oxide, oxide), silicone oxide, an anti wrinkle agent, askin Soriatic agents, antirosacea agents antiseborrheic agents, anti whitening agent, a skin protective agent, a masking agent, an Septic, antiswelling agents, antiviral agents, antiyeast agents, anti-wart agent, a refatting agent, a lubricating agent and astringents, topical cardiovascular agents, chemotherapeutic mixtures thereof. agents, , dicarboxylic acids, disinfectants, fun 0248. In certain cases, the disorder to be treated involves gicides, hair growth regulators, hormones, hydroxy acids, unaesthetic lesions that need to be masked. For example, immunosuppressants, immunoregulating agents, insecti rosacea involves papules and pustules, which can be treated cides, repellents, agents, lactams, metals, with a steroid, as well as erythema, telangiectasia and red metal oxides, mitocides, , non-steroidal anti ness, which do not respond to treatment with a steroid. Thus, inflammatory agents, oxidizing agents, pediculicides, photo in one or more embodiments, the additional active agent is a dynamic therapy agents, retinoids, Sanatives, Scabicides, self masking agent, i.e., a pigment. Non limiting examples of tanning agents, skin whitening agents, asoconstrictors, suitable pigments include brown, yellow or red iron oxide or vasodilators, , vitamin D derivatives, wound healing hydroxides, oxides or hydroxides, titanium oxides agents and wart removers. AS is known to one skilled in the or hydroxides, zinc oxide, FD&C Blue No. 1 aluminum lake, art, in Some instances a specific active agent may have more FD&C Blue No. 2 aluminum lake and FD&C Yellow No. 6 than one activity, function or effect. aluminum lake. 0254. In an embodiment, the therapeutic agent is an active herbal extract. Suitable active herbal extracts include but are Coal Tar Solution (LCD) not limited to angelica, anise oil, astragali radix, azalea, ben 0249 Coal tar or crude coal tar is obtained by the destruc Zyl acetate, birch tar oil, bornyl acetate, cacumen biotae, tive distillation of bituminous coal at very high temperatures. , cantharidin, capsicum, cineole, cinnamon bark, The crude coal tar can be further refined with alcohol extrac cinnamon leaf, citronella, citroneliol, citronellyl acetate, cit tion to yield liquor carbonis detergens (LCD). It is believed ronellyl formate, eucalyptus, eugenyl acetate, flos carthami, that over 10,000 different compounds make up coal tar but fructus mori, garlic, , geranium, geranyl acetate, only 400 or so have been identified. The main groups of habanera, isobutyl angelicate, lavender, ledum latifolium, compounds making up crude coal tarare 48% hydrocarbons, ledum palustre, lemongrass, , , linallyl 42% carbon and 10% water. acetate, methyl anthranilate, methyl cinnamate, meZereum, 0250 In its natural form coal tar is a thick, nearly black, neem, nerol, neryl acetate, nettle root extract, oleum ricini, Viscous liquid with a characteristic Smell. It is most often oregano, , alpha.-..beta.-pinene, radix angeli obtained in solution form (0.1 to 20%) and mixed with other cae sinesis, radix paenoiae rubra, radix polygoni multiflori, ingredients. Crude coal tar and LCD have long been used to radix rehmanniae, rhizoma pinelliae, rhizoma Zingiberis treat psoriasis, eczema, Seborrhea and other skin diseases. recens, Sabadilla, Sage, Sandalwood oil, , Coal tar has , anti-itching and photosensitizing semen sesami nigrum, staphysagria, tree oil, alco properties. After an initial but short proliferation of epidermal hols, terpene hydrocarbons, terpene esters, , terpin cells, coal tar treatment slows epidermal cell production and eol, terpinyl acetate and derivatives, esters, salts and mixtures results in an overall reduction in epidermal thickness. Coaltar thereof. In an embodiment, the active agent is an acaricide. may not clear psoriasis as quickly as some other agents, but Suitable acaricides include but are not limited to amitraz, longer periods of remission occur with its use. In one or more flumethrin, fluvalinate and derivatives, esters, salts and mix embodiments LCD is used in combination with one or more tures thereof. steroids. 0255. In an embodiment, the therapeutic agent is an age 0251. In an embodiment, the active agent or additional spot and keratoses removing agent. Suitable age spot and active agent is coal tar. In an embodiment, active agent or the keratoses removing agent include but are not limited to additional active agentisan biologically active agent which is hydroxy acids, and other related dicarboxylic isolated, distilled, extracted or otherwise derived from coal acids, retinoids, kojic acid, arbutin, nicotinic, ascorbic acid, tar. and derivatives, esters, salts and mixtures 0252) Active agents can be used on their own or in com thereof. Certain nonsteroidal anti-inflammatory agents, such bination with other agents. The vehicles and compositions as are also useful for the treatment of keratoses. can be used to provide a physically and or chemically stable 0256 In an embodiment, the therapeutic agent is an anal or stabilizing environment for the active agent(s). The cream gesic. Suitable analgesics include but are not limited to ben ing resistant, Viscoelastic compositions provide a physically Zocaine, picrate, dibucaine, dimethisoquin, dyclo US 2008/0206161 A1 Aug. 28, 2008 29 nine, , pramoxine, , salicylates and 0265 A normalization of keratinization leading to an anti derivatives, esters, salts and mixtures thereof. comedonal effect of azelaic acid may also contribute to its 0257. In an embodiment, the therapeutic agent is a local clinical activity. Electron microscopic and immunohis anesthetic. Suitable local anesthetics include but are not lim tochemical evaluation of skin biopsies from human Subjects ited to , benzyl alcohol, , butamben treated with AZELEXR (20% azelaic acid cream) demon picrate, chlorprocaine, , dibucaine, dimethisoquin, strated a reduction in the thickness of the stratum corneum, a dyclonine, , , , lidocaine, reduction in number and size of keratohyalin granules, and a , , pramoxine, , tetracaine, Sali reduction in the amount and distribution offilaggrin (a protein cylates and derivatives, esters, salts and mixtures thereof. component of keratohyalin) in epidermal layers. This is Sug 0258. In an embodiment, the therapeutic agent is an anti gestive of the ability to decrease microcomedo formation. acne agent. Suitable antiacne agents include but are not lim ited to N-acetylcysteine, adapalene, azelaic acid, benzoyl 0266. In an additional embodiment, the dicarboxylic acid peroxide, cholate, clindamycin, deoxycholate, , contains 10 to 32 carbonatoms in their carbonatom skeleton, flavinoids, glycolic acid, meclocycline, metronidazol, mupi Such as brassylic acid (n=11), thapsic acid (n=14), 14-meth rocin, octopirox, phenoxy ethanol, phenoxy proponol, pyru ylnonacosanedioic acid (C29) and 14,15-dimethyltriacon Vic acid, resorcinol, retinoic acid, , Scymnol tanedioic acid (C30). Sulfate, Sulfacetamide-, Sulfur, tazarotene, tetracycline, 0267. The carbon atom skeleton of the dicarboxylic acid and derivatives, esters, salts and mixtures can be saturated or unsaturated. Such as in the case of maleic thereof. acid and fumaric acid. 0259. In an embodiment, the therapeutic agent is an anti 0268 An ester of a dicarboxylic acid is a chemical com aging agent. Suitable antiaging agents include but are not pound produced by the reaction between a dicarboxylic acid limited to Sulfur-containing D and L amino acids, alpha and at least one alcohol, with the elimination of a molecule of hydroxy acids S, beta-hydroxy acids (e.g. salicylic acid), urea, water. The reaction of a dicarboxylic acid with one alcohol , , ; lysophosphatidic molecule results in a mono ester of said dicarboxylic acid, and acid, skin peel agents (e.g., phenol, resorcinol and the like), the reaction of a dicarboxylic acid with two alcohol molecules Vitamin B3 compounds (e.g., niacinamide, nicotinic acid and results in a diester of the dicarboxylic acid. nicotinic acid salts and esters, including non-vasodilating 0269. The alcohol molecule, to be linked to the dicarboxy esters of nicotinic acid (Such as tocopheryl nicotinate), nic lic acid, can be selected from the group of an alkyl an aryl otinyl amino acids, nicotinyl alcohol esters of carboxylic alcohol. Exemplary alcohol, Suitable according to the present acids, nicotinic acid N-oxide and niacinamide N-oxide), Vita invention include methyl alcohol, ethyl alcohol, propyl alco min B5 and retinoids (e.g., , , retinoic acid, reti hol, , butyl alcohol, isobutyl alcohol, t-butyl nyl acetate, retinyl palmitate, retinyl ascorbate) skin barrier alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, decyl forming agents, and derivatives, esters, salts and alcohol, capryl alcohol, phenol, benzyl alcohol and the like. mixtures thereof. 0270. In one or more embodiments, the alcohol is a bio logically active alcohol. In an embodiment, biologically Dicarboxylic Acid and Esters Thereof active alcohol possesses keratolytic activities. Examples of keratolytically active alcohol Suitable according to the 0260. In an embodiment, the organic carrier comprises an present invention include ortho-, meta- and para-hydroxy ester of a dicarboxylic acid. In the context herein, a dicar alkylbenzoate, salicylic acid, ortho-, meta-, and para-dihy boxylic acid is an organic material, having two carboxylic droxybenzene, ortho-, meta-, and para-hydroxytoluene, acid moieties on its carbon atom skeleton. They have the alpha-hydroxy acid, retinol, and derivatives thereof Such as general molecular formula HOOC-(CH), COOH. provided in U.S. Pat. No. 6,180,669. In an embodiment, the 0261. In an embodiment, the dicarboxylic acid is a short biologically active alcohol is selected from the group consist chain dicarboxylic acid. The simplest Short-chaindicarboxy ing of steroidal hormones, steroidal anti-inflammatory lic acid are oxalic acid (n=0), malonic acid (n=1). Succinic agents, vitamin E and vitamin D, such as provided in U.S. Pat. acid (n=2) and glutaric acid (n-3). Appl. 20040191196. 0262. Additional members of dicarboxylic acid group are derived from natural products or from synthesis, having “n” Antibiotics value from 4 up to 21. In one or more embodiments, the dicarboxylic acid is selected from the group consisting of 0271 In an embodiment, the therapeutic agent is an anti adipic acid (hexanedioic acid; n=4), pimelic acid (hep biotic. The terms “antibiotic” as used herein shall include, but tanedioic acid; n=5), Suberic acid (octanedioic acid; n=6), is not limited to, any Substance being destructive to or inhib aZelaic acid (nonanedioic acid; n=7), sebacic acid (de iting the growth of bacteria or any Substance having the canedioic acid; n=8) and dodecanedioic acid (n=10). capacity to inhibit the growth of or to destroy bacteria. 0263. In an embodiment, the additional active agent is 0272. In one or more embodiments, the antibiotic agent is aZelaic acid. AZelaic acid is a naturally occurring Saturated selected from the group consisting of a beta-lactamantibiotic, dicarboxylic acid. (Structural Formula: HOOC-(CH),- an aminoglycoside, an ansa-type antibiotic, an COOH: Chemical Name: 1,7-heptanedicarboxylic acid; anthraquinone, an azole, an antibiotic glycopeptide, a mac Empirical Formula: CH16O4; Molecular Weight: 188.22) rolide, an antibiotic nucleoside, an antibiotic peptide, an anti 0264. The exact mechanism of action of azelaic acid is not biotic polyene, an antibiotic polyether, an antibiotic qui known. AZelaic acid has been shown to possess antimicrobial nolone, an antibiotic steroid, a Sulfonamide, an antibiotic activity against Propionibacterium acnes and Staphylococ metal, an oxidizing agent, a periodate, a hypochlorite, a per cus epidermidis. The antimicrobial action may be attributable manganate, a Substance that release free radicals and/or active to inhibition of microbial cellular protein synthesis. oxygen, a cationic antimicrobial agent, a quaternary ammo US 2008/0206161 A1 Aug. 28, 2008 30 nium compound, a biguanide, a triguanide, a bisbiguanide, a ride, cefdinir, cefditoren, cefditoren pivoxil, cefepime, cefe polymeric biguanide, and analogs, derivatives, salts, ions and tamet, cefetamet pivoxil, cefixime, cefimenoXime, complexes thereof. cefnetazole, cefiminox, cefiminox, cefimolexin, cefodizime, 0273 Suitable antibiotics include but are not limited to cefonicid, cefoperaZone, ceforanide, cefoselis, cefotaxime, amanfadine hydrochloride, amanfadine Sulfate, amikacin, cefotetan, cefotiam, cefoxitin, cefoZopran, cefpiramide, cef arnikacin Sulfate, aminoglycosides, amoxicillin, amplicillin, pirome, cefpodoxime, cefpodoxime proxetil, cefprozil, ansamycins, , beta-lactams, candicidin, capreomy cefauinome, cefradine, cefroxadine, cefsulodin, ceftazidime, cin, carbenicillin, cephalexin, cephaloridine, cephalothin, cefteram, cefteram pivoxil, ceftezole, ceftibuten, cefti cefazolin, cephapirin, cephradine, cephaloglycin, chloram Zoxime, ceftriaxone, cefuroxime, cefuroxime axetil, cepha phenicols, , chlorhexidine gluconate, chlo losporin, cephamycin, chitinovorin, ciclacillin, clavulanic rhexidine hydrochloride, chloroxine, , chlo acid, clometocillin, cloxacillin, , deoxy pluraci rtetracycline, chlortetracycline hydrochloride, ciprofloxacin, domycin, dicloxacillin, dihydro pluracidomycin, epicillin, circulin, clindamycin, clindamycin hydrochloride, clotrima epithienamycin, ertapenem, faropenem, flomoxef, fluclox Zole, cloxacillin, demeclocycline, dicloSXacillin, diiodohy acillin, hetacillin, imipenem, lenampicillin, loracarbef, droxyquin, doxycycline, ethambutol, ethambutol hydrochlo mecillinam, meropenem, metampicillin, meticillin, mezlocil ride, erythromycin, erythromycin estolate, erythromycin lin, moxalactam, nafcillin, northienamycin, oxacillin, Stearate, farnesol, floxacillin, gentamicin, gentamicin Sulfate, panipenem, penamecillin, penicillin, phenethicillin, piper , griseofulvin, haloprogin, haloquinol, hexachlo acillin, taZobactam, pivampicillin, pivoefalexin, pivmecilli rophene, iminocyldline, iodate, , iodochlorhydrox nam, pivmecillinam hydrochloride, pluracidomycin, propi ycuin, kanamycin, kanamycin Sulfate, lincomycin, lineomy cillin, Sarmoxicillin, Sulbactam, Sulbenicillin, talampicillin, cin, lineomycin hydrochloride, macrollides, meclocycline, temocillin, terconazole, thienamycin, ticarcillin and analogs, methacycline, methacycline hydrochloride, methenamine, salts and derivatives thereof. methenamine hippurate, methenamine mandelate, methicil 0276 Aminoglycosides include, but are not limited to, lin, metronidazole, miconazole, miconazole hydrochloride, 1,2'-N-DL-isoseryl-3',4'-dideoxykanamycin B, 1,2'-N-DL microcrystalline and nanocrystalline particles of silver, cop isoseryl-kanamycin B, 1.2-N-(S)-4-amino-2-hydroxybu per, Zinc, mercury, tin, lead, bismuth, and chro tyryl-3',4'-dideoxykanamycin B, 1,2'-N-(S)-4-amino-2- mium, minocycline, minocycline hydrochloride, mupirocin, hydroxybutyryl-kanamycin B, 1-N-(2- nafcillin, , neomycin Sulfate, netilmicin, netilmicin Aminobutanesulfonyl) kanamycin A, 1-N-(2- Sulfate, nitrofurazone, norfloxacin, nystatin, octopirox, ole aminoethanesulfonyl-3',4'-dideoxyribostamycin, 1-N-(2- andomycin, orcephalosporins, oxacillin, oxytetracycline, Aminoethanesulfonyl)3'-deoxyribostamycin, 1-N-(2- oxytetracycline hydrochloride, parachlorometa Xylenol, aminoethanesulfonyl)3'4'-dideoxykanamycin B, 1-N-(2- paromomycin, paromomycin Sulfate, penicillins, penicillin aminoethanesulfonyl)kanamycin A, 1-N-(2- G. penicillin V, pentamidine, pentamidine hydrochloride, aminoethanesulfonyl)kanamycin B, 1-N-(2- phenethicillin, polymyxins, quinolones, streptomycin Sul aminoethanesulfonyl)ribostamycin, 1-N-(2- fate, tetracycline, tobramycin, tolnaftate, triclosan, trifampin, aminopropanesulfonyl)3'-deoxykanamycin B, 1-N-(2- rifamycin, rollitetracycline, spectinomycin, spiramycin, aminopropanesulfonyl)3'4'-dideoxykanamycin B, 1-N-(2- streptomycin, Sulfonamide, tetracyclines, tetracycline, tobra aminopropanesulfonyl)kanamycin A 1-N-(2- mycin, tobramycin Sulfate, triclocarbon, triclosan, trimetho aminopropanesulfonyl)kanamycin B, 1-N-(L-4-amino-2- prim-sulfamethoxazole, tylosin, Vancomycin, yrothricin and hydroxy-butyryl)2,3'-dideoxy-2'-fluorokanamycin A, 1-N- derivatives, esters, salts and mixtures thereof. (L-4-amino-2-hydroxy-propionyl)2,3'-dideoxy-2'- 0274. In one or more embodiments, the antibiotic agent is fluorokanamycin A, 1-N-DL-3',4'-dideoxy selected from the classes consisting of beta-lactam antibiot isoserylkanamycin B, 1-N-DL-isoserylkanamycin, 1-N-DL ics, aminoglycosides, ansa-type antibiotics, , isoserylkanamycin B, 1-N-L-(-)-(alpha-hydroxy-gamma antibiotic azoles, antibiotic glycopeptides, macrollides, anti aminobutyryl)-XK-62-2,2',3'-dideoxy-2'-fluorokanamycin biotic nucleosides, antibiotic , antibiotic polyenes, A.2-hydroxygentamycin A3.2-hydroxygentamycin B, 2-hy antibiotic polyethers, quinolones, antibiotic steroides, Sul droxygentamycin B1, 2-hydroxygentamycin JI-20A 2-hy fonamides, tetracycline, dicarboxylic acids, antibiotic met droxygentamycin JI-20B, 3"-N-methyl-4"-C-methyl-3',4'- als, oxidizing agents, Substances that release free radicals dodeoxy kanamycin A, 3"-N-methyl-4"-C-methyl-3',4'- and/or active oxygen, cationic antimicrobial agents, quater dodeoxy kanamycin B, 3"-N-methyl-4"-C-methyl-3',4'- nary ammonium compounds, biguanides, triguanides, bis dodeoxy-6'-methyl kanamycin B, 3',4'-Dideoxy-3'-eno biguanides and analogs and polymers thereof and naturally ribostamycin.3',4'-dideoxyneamine.3',4'- occurring antibiotic compounds. dideoxyribostamycin, 3'-deoxy-6'-N-methyl-kanamycin 0275 Beta-lactam antibiotics include, but are not limited B.3'-deoxyneamine.3'-deoxyribostamycin, 3'-oxysaccharo to, 2-(3-alanyl)clavam, 2-hydroxymethylclavam, 8-epi-thie cin,3,3'-nepotrehalosadiamine, 3-demethoxy-2"-N-formim namycin, acetyl-thienamycin, amoxicillin, amoxicillin idoylistamycin B disulfate tetrahydrate, 3-demethoxyistamy Sodium, amoxicillin trihydrate, amoxicillin- clavu cin B.3-O-demethyl-2-N-formimidoylistamycin B, 3-O- lanate combination, amplicillin, amplicillin sodium, amplicillin demethylistamycin B,3-trehalosamine,4", trihydrate, amplicillin-Sulbactam, apalcillin, aspoxicillin, azi 6"-dideoxydibekacin, 4-N-glycyl-KA-6606VI, 5"-Amino-3', docillin, azlocillin, aztreonam, bacampicillin, biapenem, car 4',5'-trideoxy-butirosin A, 6'-deoxydibekacin,6'-epifortimi benicillin, carbenicillin disodium, carfecillin, carindacillin, cin A, 6-deoxy-neomycin (structure 6-deoxy-neomycin B),6- carpetimycin, cefacetril, cefaclor, cefadroxil, cefalexin, cefa deoxy-neomycin B, 6-deoxy-neomycin C, 6-deoxy loridine, cefalotin, cefamandole, cefamandole, cefapirin, paromomycin, acmimycin, AHB-3',4'-dideoxyribostamycin, cefatrizine, cefatrizine propylene glycol, cefazedone, cefazo AHB-3'-deoxykanamycin B, AHB-3'-deoxyneamine. AHB lin, cefbuperaZone, cefcapene, cefcapene pivoxilhydrochlo 3'-deoxyribostamycin, AHB-4'-6"-dideoxydibekacin, AHB US 2008/0206161 A1 Aug. 28, 2008

6'-deoxydibekacin, AHB-dideoxyneamine, AHB staphylocidin, talisomycin, teicoplanin, Vancomycin, Victo kanamycin B, AHB-methyl-3'-deoxykanamycin B, mycin, Xylocandin, Zorbamycin and analogs, salts and deriva amikacin, amikacin Sulfate, apramycin, arbekacin, astromi tives thereof. cin, astromicin Sulfate, bekanamycin, bluenSomycin, bohol 0281 Macrollides include, but are not limited to, acetylleu mycin, butirosin, butirosin B, catenulin, coumamidine gam comycin, acetylkitasamycin, angolamycin, azithromycin, mal, coumamidine gamma2, D.L-1-N-(alpha-hydroxy-beta , brefeldin, carbomycin, chalcomycin, cirramy aminopropionyl)-XK-62-2, dactimicin, de-O-methyl-4-N- cin, , concanamycin, deisovaleryl-niddamy glycyl-KA-6606VI.de-O-methyl-KA-66061, de-O-methyl cin, demycinosyl-mycinamycin, Di-O-methyltiacumicidin, KA-70381,destomycin A, destomycin B, di-N6'.O3 dirithromycin, erythromycin, erythromycinestolate, erythro demethylistamycin A, dibekacin, dibekacin Sulfate, mycin ethyl Succinate, erythromycin lactobionate, erythro dihydrostreptomycin, dihydrostreptomycin Sulfate, epi-for mycin Stearate, flurithromycin, focusin, foromacidin, hateru mamidoylglycidylfortimicin B, epihygromycin, formim malide, haterumalide, josamycin, josamycin ropionate, juvenimycin, juvenimycin, kitasamycin, ketotiacumicin, idoyl-istamycin A, formimidoyl-istamycin B, fortimicin B, lankavacidin, lankavamycin, leucomycin, machecin, marido fortimicin C, fortimicin D, fortimicin KE, fortimicin KF, mycin, megalomicin, methyleucomycin, methymycin, fortimicin KG, fortimicin KG 1 (stereoisomer KG1/KG2), midecamycin, miocamycin, mycaminosyltylactone, mycino fortimicin KG2 (stereoisomer KG1/KG2), fortimicin KG3, mycin, neutramycin, niddamycin, nonactin, oleandomycin, framycetin, framycetin Sulphate, gentamicin, gentamycin phenylacetyldeltamycin, pamamycin, picromycin, rokitamy Sulfate, globeomycin, hybrimycin A1, hybrimycin A2, hybri cin, rosaramicin, , sedecamycin, shincomycin, mycin B1, hybrimycin B2, hybrimycin C1, hybrimycin C2, spiramycin, Swalpamycin, , tellithromycin, hydroxystreptomycin, hygromycin, hygromycin B, isepami tiacumicin, tilmicosin, treponemycin, troleandomycin, cin, isepamicin Sulfate, istamycin, kanamycin, kanamycin tylosin, Venturicidin and analogs, salts and derivatives Sulphate, kasugamycin, lividomycin, marcomycin, microno thereof. micin, micronomicin Sulfate, mutamicin, myomycin, N-dem 0282 Antibiotic nucleosides include, but are not limited ethyl-7-O-demethylcelesticetin, demethylcelesticetin, meth to, amicetin, angustmycin, azathymidine, blasticidin S. anesulfonic acid derivative of istamycin, nebramycin, epiroprim, flucytosine, gougerotin, mildiomycin, nikkomy nebramycin, neomycin, netilmicin, oligostatin, paromomy cin, nucleocidin, oxanosine, oxanosine, , pyrazo cin, quintomycin, ribostamycin, saccharocin, seldomycin, mycin, showdomycin, sinefungin, sparsogenin, Spicamycin, Sisomicin, Sorbistin, spectinomycin, Streptomycin, tobramy tunicamycin, uracil polyoxin, Vengicide and analogs, salts cin, trehaloSmaine, trestatin, validamycin, Verdamycin, and derivatives thereof. Xylostasin, Zygomycin and analogs, salts and derivatives 0283 Antibiotic peptides include, but are not limited to, thereof. actinomycin, aculeacin, alaZopeptin, amfomycin, amythia 0277 Ansa-type antibiotics include, but are not limited to, mycin, antifungal from Zalerion arboricola, antrimycin, apid, 21-hydroxy-25-demethyl-25-methylthioprotostreptovaricin, apidaecin, aspartocin, auromomycin, bacileucin, bacillomy cin, bacillopeptin, bacitracin, bagacidin, berninamycin, beta 3-methylthiorifamycin, ansamitocin, atropisostreptovaricin, alanyl-L-, bottromycin, capreomycin, caspofungine, awamycin, halomicin, maytansine, naphthomycin, rifabutin, cepacidine, cerexin, cillofungin, circulin, colistin, cyclodep rifamide, rifampicin, rifamycin, rifapentine, rifaximin, rubra sipeptide, cytophagin, dactinomycin, daptomycin, decapep dirin, Streptovaricin, tolypomycin and analogs, salts and tide, desoxymulundocandin, echanomycin, echinocandin B, derivatives thereof. echinomycin, ecomycin, enniatin, etamycin, fabatin, ferri 0278 Antibiotic anthraquinones include, but are not lim mycin, ferrimycin, ficellomycin, fluoronocathiacin, fusarici ited to, auramycin, cinerubin, ditrisarubicin, ditrisarubicin C, din, gardimycin, gatavalin, globopeptin, glyphomycin, figaroic acid fragilomycin, minomycin, rabelomycin, rudol gramicidin, herbicolin, iomycin, iturin, iyomycin, iZupeptin, fomycin, Sulfurmycin and analogs, salts and derivatives janiemycin, janthinocin, jolipeptin, katanosin, killertoxin, thereof. antibiotic, lipopeptide from Zalerion sp., lyso 0279 Antibiotic azoles include, but are not limited to, bactin, lysozyme, macromomycin, magainin, meliftin, aZanidazole, bifonazole, butoconazol, chlormidazole, chlor mersacidin, mikamycin, mureidomycin, mycoplanecin, midazole hydrochloride, cloconazole, cloconazole monohy mycosubtilin, neopeptifluorin, neoviridogrisein, metropsin, drochloride, clotrimaZol, dimetridazole, econazole, econa nisin, nocathiacin, nocathiacin 6-deoxyglycoside, nosihep Zole nitrate, enilconazole, fenticonazole, fenticonazole tide, octapeptin, pacidamycin, pentadecapeptide, peptiflu nitrate, fezatione, fluconazole, flutrimazole, isoconazole, iso orin, permetin, phytoactin, phytostreptin, planothiocin, plus conazole nitrate, itraconazole, , lanoconazole, bacin, policillin, polymyxin antibiotic complex, polymyxin B, metronidazole, metronidazole benzoate, miconazole, polymyxin B1, polymyxin F. preneocarzinostatin, quinomy miconazole nitrate, neticonazole, , niridazole, cin, quinupristin-dalfopristin, Safracin, salmycin, Salmycin, omoconazol, ornidazole, oxiconazole, oxiconazole nitrate, salmycin, Sandramycin, Saramycetin, siomycin, sperabillin, propenidazole, secnidazol, Sertaconazole, Sertaconazole sporamycin, a streptomyces compound, Subtilin, teicoplanin nitrate, Sulconazole, Sulconazole nitrate, tinidazole, tiocona aglycone, telomycin, thermothiocin, thiopeptin, thiostrepton, Zole, Voriconazol and analogs, salts and derivatives thereof. tridecaptin, tsushimycin, tuberactinomycin, tuberactinomy 0280 Antibiotic glycopeptides include, but are not limited cin, , , viomycin, Virginiamycin, Zer to, acanthomycin, actaplanin, avoparcin, balhimycin, bleo Vacin and analogs, salts and derivatives thereof. mycin B ( bleomycin), chloroorienticin, chlo 0284. In one or more embodiments, the antibiotic peptide ropolysporin, demethylvancomycin, enduracidin, galacar is a naturally-occurring peptide that possesses an antibacte din, guanidylfungin, hachimycin, demethylvancomycin, rial and/or an antifungal activity. Such peptide can be N-nonanoyl-teicoplanin, phleomycin, platomycin, ristocetin, obtained from a herbal or a vertebrate source. US 2008/0206161 A1 Aug. 28, 2008 32

0285 Polyenes include, but are not limited to, amphoteri 1.11-undecanedioic acid, 1,12-dodecanedioic acid, 1,13 cin, amphotericin, aureofungin, ayfactin, azalomycin, blasti tridecanedioic acid and 1,14-tetradecanedioic acid. Thus, in cidin, candicidin, candicidin methyl ester, candimycin, can one or more embodiments, dicarboxylic acids, having dimycin methyl ester, chinopricin, filipin, flavofungin, between about 6 and about 14 carbon atoms in their carbon fradicin, hamycin, hydropricin, levorin, lucensomycin, luc atom skeleton, as well as their salts and derivatives (e.g., knomycin, mediocidin, mediocidin methyl ester, , esters, amides, mercapto-derivatives, anhydraides), are use methylamphotericin, natamycin, niphimycin, nystatin, nysta ful immunomodulators in the treatment of disorders of the tin methyl ester, oxypricin, partricin, pentamycin, perimycin, skin and mucosal membranes that involve inflammation. AZe pimaricin, primycin, proticin, rimocidin, sistomycosin, Sor laic acid and its salts and derivatives are preferred. It has angicin, trichomycin and analogs, salts and derivatives antibacterial effects on both aerobic and anaerobic organ thereof. isms, particularly propionibacterium acnes and Staphylococ 0286 Polyethers include, but are not limited to, 20-deoxy cus epidermidis, normalizes keratinization, and has a cyto epi-narasin, 20-deoxysalinomycin, carriomycin, dianemy toxic effect on malignant or hyperactive melanocytes. In a cin, dihydrolonomycin, etheromycin, ionomycin, iso-la preferred embodiment, the dicarboxylic acid is azelaic acid in salocid, lasalocid, lenoremycin, lonomycin, lysocellin, a concentration greater than 10%. Preferably, the concentra monensin, narasin, oxolonomycin, a polycyclic ether antibi tion of azelaic acid is between about 10% and about 25%. In otic, Salinomycin and analogs, salts and derivatives thereof. Such concentrates, azelaic acid is Suitable for the treatment of 0287 Quinolones include, but are not limited to, an alkyl a variety of skin disorders, such as acne, rosacea and hyper methylendioxy-4-(1H)-oxocinnoline-3-carboxylic acid, ala pigmentation. trofloxacin, cinoxacin, ciprofloxacin, ciprofloxacin hydro 0292. In one or more embodiments, the antibiotic agent is chloride, danofloxacin, dermofongin A, enoxacin, an antibiotic metal. A number of metals ions been shown to enrofloxacin, fleroxacin, flumequine, gatifloxacin, gemi possess antibiotic activity, including silver, copper, Zinc, mer floxacin, grepafloxacin, levofloxacin, lomefloxacin, lom cury, tin, lead, bismutin, cadmium, chromium and ions efloxacin, hydrochloride, miloxacin, moxifloxacin, nadi thereof. It has been theorized that these antibiotic metal ions floxacin, nalidixic acid, nifuroquine, norfloxacin, ofloxacin, exert their effects by disrupting respiration and electron trans orbifloxacin, oxolinic acid, paZufloxacine, pefloxacin, port systems upon absorption into bacterial or fungal cells. pefloxacin mesylate, pipemidic acid, piromidic acid, prema Anti-microbial metal ions of silver, copper, Zinc, and gold, in floxacin, roSoxacin, rufloxacin, sparfloxacin, temafloxacin, particular, are considered safe for in vivo use. Anti-microbial to sufloxacin, trovafloxacin and analogs, salts and derivatives silver and silverions are particularly useful due to the fact that thereof. they are not substantially absorbed into the body. 0288 Antibiotic steroids include, but are not limited to, 0293 Thus, in one or more embodiment, the antibiotic aminosterol, ascosteroside, cladosporide A, dihydrofusidic metal consists of an elemental metal, selected from the group acid, dehydro-dihydrofusidic acid, dehydrofusidic acid, consisting of silver, copper, Zinc, mercury, tin, lead, bismutin, fusidic acid, squalamine and analogs, salts and derivatives cadmium, chromium and gold, which is Suspended in the thereof. composition as particles, microparticles, nanoparticles or col 0289 Sulfonamides include, but are not limited to, loidal particles. The antibiotic metal can further be interca chloramine, dapsone, mafenide, phthalylsulfathiazole, Succi lated in a chelating Substrate. nylsulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlo 0294. In further embodiments, the antibiotic metal is rpyridazine, Sulfadiazine, Sulfadiazine silver, Sulfadicramide, ionic. The ionic antibiotic metal can be presented as an inor Sulfadimethoxine, Sulfadoxine, Sulfaguanidine, Sulfalene, ganic or organic salt (coupled with a counterion), an organo SulfamaZone, Sulfamerazine, Sulfamethazine, Sulfame metallic complex or an intercalate. Non binding examples of thizole, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfa counter inorganic and organic ions are sulfadiazine, acetate, monomethoxine, Sulfamoxol, Sulfanilamide, Sulfaperine, Sul benzoate, carbonate, iodate, iodide, lactate, laurate, nitrate, faphenazol, Sulfapyridine, Sulfaquinoxaline, oxide, palmitate, a negatively charged protein. In preferred SulfaSuccinamide, Sulfathiazole, Sulfathiourea, Sulfatola embodiments, the antibiotic metal salt is a silver salt, such as mide, Sulfatriazin, Sulfisomidine, Sulfisoxazole, Sulfisoxazole silver acetate, silver benzoate, silver carbonate, silver iodate, acetyl, Sulfacarbamide and analogs, salts and derivatives silver iodide, silver lactate, silver laurate, silver nitrate, silver thereof. oxide, silver palmitate, silver protein, and silver Sulfadiazine. 0290 Tetracyclines include, but are not limited to, dihy 0295. In one or more embodiments, the antibiotic metal or drosteffimycin, demethyltetracycline, aclacinomycin, metal is embedded into a substrate, such as a polymer, a akrobomycin, baumycin, bromotetracycline, cetocyclin, (such as Zeolite, clay and silica). chlortetracycline, clomocycline, daunorubicin, demeclocy 0296. In further embodiments, the antibiotics comprise cline, doxorubicin, doxorubicin hydrochloride, doxycycline, oxidizing agents and Substances that release free radicals lymecyclin, marcellomycin, meclocycline, meclocycline Sul and/or active oxygen. fosalicylate, methacycline, minocycline, minocycline hydro In one or more embodiments, the antibiotic agent comprises chloride, museftamycin, oxytetracycline, rhodirubin, rollitet strong oxidants and free radical liberating compounds, Such racycline, rubomycin, serirubicin, Steffimycin, tetracycline as oxygen, hydrogen peroxide, benzoyl peroxide, elemental and analogs, salts and derivatives thereof. halogen species, as well as oxygenated halogen species, 0291 Dicarboxylic acids, having between about 6 and bleaching agents (e.g., Sodium, or about 14 carbon atoms in their carbon atom skeleton are hypochloride and the like), perchlorite species, iodine, iodate, particularly useful in the treatment of disorders of the skin and and benzoyl peroxide. Organic oxidizing agents are also mucosal membranes that involve microbial. Suitable dicar included in the definition of “oxidizing agent according to boxylic acid moieties include, but are not limited to, adipic the present invention, such as quinones. Such agents possess acid, pimelic acid, Suberic acid, azelaic acid, sebacic acid, a potent broad spectrum activity. US 2008/0206161 A1 Aug. 28, 2008

0297. In one or more embodiments the antibiotic agent is herein includes any organic material comprising three or a cationic antimicrobial agent. The outermost Surface of bac more repeating units, and includes oligomers, polymers, terial cells universally carries a net negative charge, making copolymers, block copolymers, terpolymers, etc. The poly them sensitive to cationic Substances. Examples of cationic merbackbone may be, for example a polyethylene, ploypro antibiotic agents include: quaternary ammonium compounds pylene or polysilane polymer. (QAC’s)—QAC's are surfactants, generally containing one 0304. In one or more embodiments, the cationic antimi quaternary nitrogen associated with at least one major hydro crobial polymer is a polymeric biguanide compound. When phobic moiety; alkyltrimethyl ammonium are mix applied to a Substrate, such a polymer is known to form a tures of where the alkyl group is between 8 and 18 carbons barrier film that can engage and disrupt a microorganism. An long, such as cetrimide (tetradecyltrimethylammonium bro exemplary polymeric biguanide compound is polyhexameth mide); , which is a mixture of n-alky ylene biguanide (PHMB) salts. Other exemplary biguanide ldimethylbenzyl ammonium chloride where the alkyl groups polymers include, but are not limited to poly(hexamethyl (the hydrophobic moiety) can be of variable length; dialkyl enebiguanide), poly(hexamethylenebiguanide) hydrochlo methyl ammonium halides; dialkylbenzyl ammonium ride, poly(hexamethylenebiguanide) gluconate, poly(hexam halides; and QAC dimmers, which bear bi-polar positive ethylenebiguanide) stearate, or a derivative thereof. In one or charges in conjunction with interstitial hydrophobic regions. more embodiments, the antimicrobial material is Substan 0298. In one or more embodiments, the antibiotic agent is selected from the group of biguanides, triguanides, bisbigu tially water-insoluble. 0305 Yet, in one or more embodiment, the antibiotic is a anides and analogs thereof. non-classified antibiotic agent, including, without limitation, 0299 Guanides, biguanides, biguanidines and triguanides aabomycin, acetomycin, acetoxycycloheximide, acetylnan are unsaturated nitrogen containing molecules that readily aomycin, an actinoplanes sp. Compound, actinopyrone, afl obtain one or more positive charges, which make them effec astatin, albacarcin, albacarcin, albofungin, albofungin, alisa tive antimicrobial agents. The basic structures a guanide, a mycin, alpha-R.S.-methoxycarbonylbenzylmonate, biguanide, a biguanidine and a triguanide are provided below. altromycin, amicetin, amycin, amycin demanoyl compound, amycine, amycomycin, anandimycin, anisomycin, anthra 4 2 2 mycin, anti-Syphilis imune Substance, anti-tuberculosis HN NH NH imune Substance, antibiotic from Eschericia coli, antibiotics 4 6 from Streptomyces refuineus, anticapsin, antimycin, aplas 5 3 NH NH HN HN NH2 HN HN 1 momycin, aranorosin, aranorosinol, arugomycin, ascofura 3 none, ascomycin, ascosin, Aspergillus flavus antibiotic, NH asukamycin, aurantinin, an Aureolic acid antibiotic Sub 5 stance, aurodox, avilamycin, azidamfenicol, azidimycin, Biguanide Biguanidine bacillaene, a Bacillus larvae antibiotic, bactobolin, benano 6 4 2 mycin, benzanthrin, benzylmonate, bicoZamycin, bravomi NH NH NH cin, brodimoprim, butalactin, calcimycin, calvatic acid, can 7 l 5 ul 3 ls diplanecin, carumonam, carzinophilin, celesticetin, cepacin, HN HN HN NH2 cerulenin, cervinomycin, chartreusin, chloramphenicol, Triguanide chloramphenicol palmitate, chloramphenicol Succinate Sodium, chlorflavonin, chlorobiocin, chlorocarcin, chromo mycin, ciclopiroX, ciclopiroX olamine, citreamicin, cla 0300. In one or more preferred embodiments, the guanide, dosporin, claZamycin, clecarmycin, clindamycin, coliformin, biguanide, biguanidine or triguanide, provide bi-polar con collinomycin, copiamycin, corallopyronin, corynecandin, figurations of cationic and hydrophobic domains within a coumermycin, culpin, cuprimyxin, cyclamidomycin, cyclo single molecule. heximide, dactylomycin, danomycin, danubomycin, delami 0301 Examples of guanides, biguanides, biguanidines nomycin, demethoxyrapamycin, demethylscytophycin, der and triguanides that are currently been used as antibacterial madin, desdamethine, dexylosyl-benanomycin, agents include chlorhexidine and chlorohexidine salts, ana pseudoaglycone, dihydromocimycin, dihydronancimycin, logs and derivatives, such as chlorhexidine acetate, chlorhexi diumycin, dnacin, dorrigocin, dynemycin, dynemycin triac dine gluconate and chlorhexidine hydrochloride, picloxy etate, ecteinascidin, efrotomycin, endomycin, ensanchomy dine, alexidine and polihexanide. Other examples of cin, equisetin, ericamycin, esperamicin, ethylmonate, everni guanides, biguanides, biguanidines and triguanides that can nomicin, feldamycin, flambamycin, flavensomycin, conceivably be used according to the present invention are florfenicol, fluvomycin, fosfomycin, fosfonochlorin, frederi chlorproguanil hydrochloride, proguanil hydrochloride (cur camycin, frenolicin, fumagillin, fumifungin, funginon, fusa rently used as antimalarial agents), metforminhydrochloride, candin, fusafungin, gelbecidine, glidobactin, grahamimycin, phenformin and buformin hydrochloride (currently used as granaticin, griseofulvin, griseoviridin, grisonomycin, antidiabetic agents). hayumicin, hayumicin, haZymicin, hedamycin, heneicomy 0302. In one or more embodiments, the cationic antimi cin, heptelicid acid, holomycin, humidin, isohematinic acid, crobial agent is a polymer. karnatakin, kaZusamycin, kristenin, L-dihydrophenylala 0303 Cationic antimicrobial polymers include, for nine, a L-isoleucyl-L-2-amino-4-(4-amino-2, 5'-cyclohexa example, guanide polymers, biguanide polymers, or poly dienyl) derivative, lanomycin, leinamycin, leptomycin, liba mers having side chains containing biguanide moieties or nomycin, lincomycin, lomofungin, lysolipin, magnesidin, other cationic functional groups, such as benzalkonium manumycin, melanomycin, methoxycarbonyl methyl groups or quarternium groups (e.g., quaternary amine monate, methoxycarbonylethylmonate, methoxycarbon groups). It is understood that the term “polymer as used ylphenylmonate, methyl pseudomonate, methylmonate, US 2008/0206161 A1 Aug. 28, 2008 34 microcin, mitomalcin, mocimycin, moenomycin, 0309 Mixtures of these antibiotic agents may also be monoacetyl cladosporin, monomethyl cladosporin, mupiro employed according to the present invention. cin, mupirocin calcium, mycobacidin, myriocin, myxopyro 0310. In an embodiment, the therapeutic agent is an anti nin, pseudoaglycone, nanaomycin, nancimycin, nargenicin, dandruff agent. Suitable antidandruff agents include but are neocarcinostatin, neoenactin, neothramycin, nifurtoinol, nocardicin, nogalamycin, novobiocin, octylmonate, olivo not limited to aminexil, benzalkonium chloride, benzetho mycin, orthosomycin, oudemansin, oxirapentyn, oxoglau nium chloride, 3-bromo-1-chloro-5,5-dimethyl-hydantoin, cine methiodide, pactacin, pactamycin, papulacandin, paulo chloramine B, chloramine T. chlorhexidine, N-chlorosuccin mycin, phaeoramularia fungicide, phenelfamycin, phenyl, imide, climbazole-, 1,3-dibromo-5,5-dimethylhydantoin, cerulenin, phenylmonate, pholipomycin, pirlimycin, pleuro 1,3-dichloro-5,5-dimethyl-hydantoin, betulinic acid, betu mutilin, a polylactone derivative, polynitroXin, polyoxin, por lonic acid, celastrol, crataegolic acid, cromakalin, cyproter firomycin, pradimicin, prenomycin, prop-2-enylmonate, pro one acetate, dutasteride, finesteride, , ketoconozole, tomycin, pseudomonas antibiotic, pseudomonic acid, oleanolic acid, phenyloin, picrotone olamine, Salicylic acid, purpuromycin, pyrinodemin, pyrrolnitrin, pyrrolomycin, Sulphides, triclosan, triiodothyronine, ursolic acid, amino, chloro pentenedioic acid, rapamycin, rebeccamycin, , Zincomadine, and derivatives, resistomycin, reuterin, reveromycin, rhizocticin, roridin, esters, salts and mixtures thereof. rubiflavin, naphthyridinomycin, Saframycin, Saphenamycin, 0311. In an embodiment, the therapeutic agent is an anti Sarkomycin, Sarkomycin, Sclopularin, selenomycin, siccanin, histamine. Suitable antihistamines include but are not limited spartanamicin, spectinomycin, spongistatin, Stravidin, Strep to chlorcyclizine, , mepyramine, methapy tolydigin, Streptomyces arenae antibiotic complex, streptoni rilene, tripelennamine and derivatives, esters, salts and mix grin, Streptothricins, streptovitacin, Streptozotocine, a strobi tures thereof. lurin derivative, stubomycin, Sulfamethoxazol-trimethoprim, Sakamycin, tejeramycin, terpentecin, tetrocarcin, thermoru Antifungal bin, thermozymocidin, thiamphenicol, thioaurin, thiolutin, 0312. In an embodiment, the therapeutic agent is an anti thiomarinol, thiomarinol, tirandamycin, tolytoxin, trichoder mycotic, also termed antifungal agent. The terms “antimy min, trienomycin, trimethoprim, trioxacarcin, tyrissamycin, cotic' and “antifungal as used herein include, but are not umbrinomycin, unphenelfamycin, urauchimycin, usnic acid, limited to, any Substance being destructive to or inhibiting the uredolysin, variotin, Vermisporin, Verrucarin and analogs, growth of fungi and yeast or any substance having the capac salts and derivatives thereof. ity to inhibit the growth of or to destroy fungi and/or yeast. 0306 In one or more embodiments, the antibiotic agent is 0313. In one or more embodiments, the antifungal agent is a naturally occurring antibiotic compound. As used herein, an agent that is useful in the treatment of a Superficial fungal the term “naturally-occurring antibiotic agent” includes all infection of the skin, dermatophytosis, microsporum, tricho antibiotic that are obtained, derived or extracted from plant or phyton and epidermophyton infections, candidiasis, oral can vertebrate sources. Non-limiting examples of families of didiasis (thrush), candidiasis of the skin and genital mucous naturally-occurring antibiotic agents include phenol, resorci membrane, candida paronychia, which inflicts the nail and nol, antibiotic aminoglycosides, anamycin, quinines, nail bed and genital and vaginal candida, which inflict geni anthraquinones, antibiotic glycopeptides, azoles, macrollides, talia and the vagina. Thus, in one or more embodiments, the avilamycin, agropyrene, cnicin, aucubin antibioticsaponin antifungal agent is selected from the group including but not fractions, (isoquinoline alkaloid), arctiopicrin (ses limited to, azoles, diazoles, triazoles, miconazole, flucona quiterpene lactone), lupulone, humulone (bitter acids), alli Zole, ketoconazole, clotrimazole, itraconazole, Climbazole, cin, , echinacoside, coniosetin, tetramic acid, ima griseofulvin, ciclopiroX, ciclopiroX-olamine, amorolfine, ter nine and novoimanine. binafine, Amphotericin B, potassium iodide and flucytosine 0307 Ciclopirox and ciclopiroxolamine possess fungi (5FC) at a therapeutically effective concentration. cidal, fungistatic and sporicidal activity. They are active 0314 Azoles are pharmaceutically active compounds that against a broad spectrum of dermatophytes, yeasts, moulds are unsaturated five member ring heterocyclic compound, and other fungi. Such as trichophyton species, microsporum wherein one, two or three members of the ring are nitrogen species, epidermophyton species and yeasts (candida albi atoms, as exemplified in a non-limiting way and illustrated in cans, candida glabrata, other candida species and cryptococ the following schemes: cus neoformans). Some aspergillus species are sensitive to ciclopiroX as are some penicillium. Likewise, ciclopiroX is effective against many gram-positive and gram-negative bac teria (e.g., , proteus mirabilis, pseudomonas aeruginosa, Staphylococcus and Streptococcus species), as well as mycoplasma species, trichomonas vaginalis and acti nomyces. Azole Imidazole 12.4 Triazole 12.3 Triazole Thiadiazole 0308 Plant oils and extracts which contain antibiotic NN agents are also useful. Non limiting examples of plants that contain agents include thyme, perilla, lavender, tea tree, ter \ fezia clayeryi, Micromonospora, pufterlickia Verrucosa, Pyrazole putterlickia pyracantha, putterlickia retroSpinosa, Maytenus ilicifolia, maytenus evonymoides, maytenus aquifolia, faenia interjecta, cordyceps sinensis, couchgrass, holy thistle, plan 0315 Azole is a compound including an unsaturated five tain, burdock, hops, , buchu, chaparral, myrrh, red member ring heterocyclic compound, wherein one, two or clover and yellow dock, garlic and St. John's wort. three members of the ring are nitrogen atoms. US 2008/0206161 A1 Aug. 28, 2008

0316 Examples of therapeutic azoles include, but are not rosemary, sage, spearmint, star anise, St. John's wort, red limited to, azanidazole, bifonazole, butoconazol, chlormida clover, tangerine, tea tree, terfezia clayeryi, thyme Vanilla, Zole, climbazole, cloconazole, clotrimazole, dimetridazole, verbena, white clover and yellow dock. econazole, enilconazole, fenticonazole, fezatione, flucona 0329. In an embodiment, the antifungal agent is an anti Zole, flutrimazole, isoconazole, itraconazole, ketoconazole, microbial metal. A number of metals ions been shown to lanoconazole, metronidazole, metronidazole benzoate, possess antibiotic activity, including silver, copper, Zinc, mer miconazole, neticonazole, nimorazole, niridazole, omocona cury, tin, lead, bismutin, cadmium, chromium and ions Zol, ornidazole, oxiconazole, posaconazole, propenidazole, thereof. It has been theorized that these anti-microbial metal raVuconazole, secnidazol, Sertaconazole, Sulconazole, thia ions exert their effects by disrupting respiration and electron bendazole, tinidazole, tioconazole, Voriconazol and salts and transport systems upon absorption into bacterial or fungal derivatives thereof. Such azoles are mainly used as antifungal cells. Anti-microbial metal ions of silver, copper, Zinc, and agents, yet several of them also possess other therapeutic gold, in particular, are considered safe for in Vivo use. Anti benefits, such as anti-inflammatory, antibacterial and antivi microbial silver and silver ions are particularly useful due to ral effects. the fact that they are not substantially absorbed into the body. 0317. Additional non-limiting exemplary classes of azoles 0330. Thus, in one or more embodiment, the anti-micro include oxazoles, thiazoles, thiadiazoles and thiatriazoles, bial metal consists of an elemental metal, selected from the benzimidazoles, and salts and derivatives thereof. group consisting of silver, copper, Zinc, mercury, tin, lead, 0318. In an embodiment, the azole is metronidazole. bismutin, cadmium, chromium and gold, which is suspended 0319. In one or more embodiments, the antifungal agent is in the composition as particles, microparticles, nanoparticles a peptide. or colloidal particles. The anti-microbial metal can further be 0320 In certain embodiments, antifungal agent is a natu intercalated in a chelating Substrate. rally-occurring peptide that possesses an antibacterial and/or 0331. In further embodiments, the anti-microbial metal is an antifungal activity. Such peptide can be obtained from a ionic. The ionic antibiotic metal can be presented as an inor herbal or a vertebrate source. ganic or organic salt (coupled with a counterion), an organo 0321. In an embodiment, the antifungal agent is a polyene. metallic complex or an intercalate. Non binding examples of Polyene compounds are so named because of the alternating counter inorganic and organic ions are sulfadiazine, acetate, conjugated double bonds that constitute a part of their mac benzoate, carbonate, iodate, iodide, lactate, laurate, nitrate, rollide ring structure. Polyenes include, but are not limited to, oxide, palmitate, a negatively charged protein. In preferred amphotericin, aureofungin, ayfactin, azalomycin, blasticidin, embodiments, the antibiotic metal salt is a silver salt, such as candicidin, candicidin methyl ester, candimycin, candimycin silver acetate, silver benzoate, silver carbonate, silver iodate, methyl ester, chinopricin, filipin, flavofungin, fradicin, hamy silver iodide, silver lactate, silver laurate, silver nitrate, silver cin, hydropricin, levorin, lucensomycin, lucknomycin, oxide, silver palmitate, silver protein, and silver Sulfadiazine. mediocidin, mediocidin methyl ester, mepartricin, methy 0332 Yet, in another embodiment, the antifungal agent is lamphotericin, natamycin, niphimycin, nystatin, oxypricin, an oxidizing agent or a substance that releases free radicals partricin, pentamycin, perimycin, pimaricin, primycin, proti and/or active oxygen. Exemplary oxidizing agents are hydro cin, rimocidin, sistomycosin, Sorangicin, trichomycin and gen peroxide, benzoyl peroxide, elemental halogen species analogs, salts and derivatives thereof. (compounds), as well as oxygenated halogen species (com 0322. In an embodiment, the antifungal agent is a pyrimi pounds), bleaching agents (e.g., Sodium, calcium or magne dine, such as Flucytosine. sium hypochloride and the like), perchlorite species (com 0323. In an embodiment, the antifungal agent is an ally pounds), iodine and iodate compounds. Organic oxidizing lamine, Such as terbinafine and naftifine. agents are also included in the definition of “oxidizing agent' 0324. In an embodiment, the antifungal agent is a morpho according to the present invention, Such as quinones. Such line derivative, Such as amorolfine. agents possess a potent broad spectrum activity 0325 In an embodiment, the antifungal agent is selected 0333. In further embodiments, the antibiotic agent is a from the group consisting of CiclopiroX, ciclopiroXolmine, cationic antimicrobial agent. The outermost Surface of bacte griseofulvin. rial and fungal cells universally carries a net negative charge, 0326 In an embodiment, the antifungal agent is a Thio making them sensitive to cationic Substances. Examples of carbamate, Such as tolnaftate. cationic antibiotic agents include: quaternary ammonium 0327. In an embodiment, the antifungal agent is a Sulfona compounds, such as alkyltrimethyl ammonium bromides, mide, Such as Mafenide and Dapsone. benzalkonium chloride, dialkylbenzyl ammonium halides, 0328. In an embodiment, the antifungal agent consists of a and dimers thereof, which bear bi-polar positive charges in plant oil or a plant extract possessing antifungal activity; or a conjunction with interstitial hydrophobic regions. plant oil or extract which contains antifungal agents. Non 0334. In one or more embodiments, the antifungal agent is limiting examples of plants containing agents include, but are an agent that is useful in the treatment of a Superficial fungal not limited to, anise, basil, bergemont, burdock, buchu, chap infection of the skin, dermatophytosis, microsporum, tricho arral, camphor, cardamom, carrot, canola, Cassia, catnip, phyton and epidermophyton infections, candidiasis, oral can cedarwood, citronella, clove, couchgrass, cypress, echinacea, didiasis (thrush), candidiasis of the skin and genital mucous eucalyptus, faenia interjecta, garlic, ginger, , holy membrane, candida paronychia, which inflicts the nail and thistle, hops, hyssop, jasmine, jojova, lavender, lavandin, nail bed and genital and vaginal candida, which inflict geni lemon, lime, mandarin, marigold, marjoram, maytenus ilici talia and the vagina. folia, maytenus evonymoides, maytenus aquifolia, 0335 Suitable antimycotics include but are not limited to micromonospora, myrrh, neroli, nutmeg, , ordyceps allylamines, amorolfine, amphotericin B. azole compounds, sinensis, peppermint, perilla, petitgrain, plantain, putterlickia bifonazole, butoconazole, chloroxine, clotrimazole, ciclo Verrucosa, putterlickia pyracantha, putterlickia retroSpinosa, piroX olamine, clotrimazole, econazole, elubiol, fenticona US 2008/0206161 A1 Aug. 28, 2008 36

Zole, fluconazole, flucytosine (5FC), griseofulvin, itracona enzyme inhibitors, calcium antagonists, angiotensin II recep Zole, ketoconazole, mafenide acetate, miconazole, naftifine, tor antagonists, direct acting Smooth muscle vasodilators, natamycin, tolnaftate, nystatin, polyenes, oxiconazole, Sul adrenergic inhibitors, antagonists, mineralocorti bentine, Sulconazole, terbinafine, terconazole, tioconazole, coid antagonists, vasopeptidase inhibitors and renin undecylenic acid and derivatives, esters, salts and mixtures inhibitors. Active agents belonging to Such drug classes, as thereof. well as active agents belonging to other classes, which cause a vasodilator effect are also included in the scope of vasoac Vasoactive, Blocker and Cholinergic Agent tive agents according to the present invention. Vasoactive 0343 Non-nitrate vasodilators from different classes 0336 A vasoactive agent is a substance that changes the include, but are not limited to sildenafil, dipyridamole, cat diameter of a blood vessel. echolamine, isoproternol, , prostaglandin, prosta 0337. In one or more embodiments, the vasoactive agent is cyclin, enalaprilat (ACE-inhibitor), (), a vasodilator. A vasodilator is any of various agents that relax acepromazine (C.-blocker), praZosin (C.-blocker), enalapril or widen blood vessels and thereby maintain or lower blood (ACE-inhibitor), captopril (ACE-inhibitor), (Ca pressure. ), , tadalafil. Vardenafil, phenyleph 0338 Alteration in the release and action of endothelium rin, etilefein, , and salts, isomers, analogs derived vasoactive factors is responsible for changes in vas and derivatives thereof. cular reactivity early in the course of vascular disease. These 0344. In one or more embodiments, the vasoactive agent is factors include , eicosanoids, endothelium-de selected from the group of vasodilator peptides and proteins. rived hyperpolarizing factor, endothelin, and angiotensin 11. Non-limiting examples of vasodilator paprides include, but 0339 Nitric oxide (NO) has been recognized as an impor are not limited to , bradykinin-like peptide 1, tant messenger molecule having a broad spectrum of func bradykinin-like peptide III Phyllokinin (bradykinyl-isole tions in many biological systems ranging from physiological ucyl-tyrosine O-sulfate), megaScoliakinin (Thr6bradyki control to pathological cytotoxic effect1-3. Along with pros nin-Lys-Ala), lysyl-bradykinin-like waspkinin, lysyl-brady tacyclin, NO is responsible for endothelium derived tonic , maximakinin (Bombinakinin M), bombinakinin-GAP, relaxation of all types of blood vessels. NO is formed from kininogen-1 associated peptides, kininogen-2 associated pep L-arginine through the action of a family of isoenzymes, the tides, T-kinin, thiostatin, prolixin-S, Vespulakinin 2, Vespaki nitric oxide synthases (NOS). Thus, in one or more embodi nin X, , adrenomedullin, ghrelin, maxadilan, Sub ments, the vasoactive agent is selected from the group of stance P, calcitonin gene-related peptide (CGRP), Natriuretic therapeutic agents that modulate the production of nitric peptides (NPs), e.g., atrial natriuretic peptide (ANP), C-type oxide or otherwise modulate or activate the effect of nitric natriuretic peptide (CNP), and adrenomedulin (ADM), oxide. In one or more embodiments, the vasoactive agent is adrenomedullin, Ovine corticotropin-releasing factor, sau selected from the group of therapeutic agents that modulate vagine, urotensin and salts, isomers, analogs and derivatives the activity of the enzyme nitric oxide synthase. In one or thereof. more embodiments, the vasoactive agent is selected from the 0345. In one or more embodiments, the vasoactive agent is group of therapeutic agents that enhance the effect of NO by selected from the group of therapeutic agents that induce the inhibiting from the phosphodiesterase group. Such production of a vasodilator peptide or otherwise enhance or as phosphodiesterase type 5 (PDE5). activate the effect of a vasodilator peptide. 0340. In one or more embodiments, the vasoactive agent is 0346. In one or more embodiments, the vasoactive agent is selected from the group including nitrites, nitrates and their a Substance derived or extracted from herbs having a vasodi analogs, esters and salts. In one or more embodiments the lator effect. Non limiting examples of herbs that contain vasoactive agent possesses a moiety selected from the group vasoactive agents include achillea millefolium (Yarrow), consisting of ONO, and ONO2. allium sativum (garlic), amoracia rusticana (horseradish), 0341 Exemplary vasodilators include, but are not limited berberis Vulgaris (barberry), Cimicifiuga racemosa (black to, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobu cohosh), coleus forskholii (coleus), coptis (Goldenthread), tyl nitrite, glyceryl trinitrate, also known as nitroglycerin, crataegus (hawthorn), eleutherococcus senticosus (Siberian octyl nitrite, sodium nitrite, sodium nitroprusside, clonitrate, ginseng), ginkgo biloba(ginkgo), melissa officinalis (lemon erythrity1 tetranitrate, isosorbide mononitrate, isosorbide balm), Olea europaea (olive leaf), panax ginseng (Chinese dinitrate, mannitol hexanitrate, pentaerythritol tetranitrate, ginseng), petroselinum crispum (parsley), penetrinitol, triethanolamine trinitrate, trolnitrate phosphate baicalensis (baical skullcap), tilia europaea (linden flower), (triethanolamine trinitrate diphosphate), propatylnitrate, trigonella foenum-graecum (fenugreek), urtica dioica nitrite esters of Sugars, nitrite esters of polyols, nitrate esters (nettles), Valeriana officinalis (), viburnum (cramp, of Sugars, nitrate esters of polyols, , apresoline, bark, blackhaw), Veratrum viride (American hellebore), ver , , hydrochlorothiazide, minoxidil, pen bena officinalis (vervain), Xanthoxylum americanum (prickly taerythritol, tolaZoline, scoparone (6.7-dimethoxycoumarin) ash), Zingiber officinale (ginger), rauwolfia serpentina (In and salts, isomers, analogs and derivatives thereof. dian Snakeroot), viscum album, wildyam, sasparilla, licorice, 0342. In one or more embodiments, the vasoactive agent damiana, yucca, saw palmetto, gotu kola (centella asiatica), belongs to a class of drugs that are known of possess vasodi and salts, , brazil nut, walnut and analogs lator properties. Non limiting examples of drug classes that and derivatives thereof. possess vasodilator properties include, but are not limited to, 0347 According to one or more embodiments, the foam beta-adrenergic blockers, alpha-adrenoceptor blockers, pros able composition includes a vasodilator and a vasoactive taglandin and prostaglandin-like compounds, inhibitors of agent such that the vasodilator can have a synergistic effect by type 5 phosphodiesterase (PDE-5), angiotensin converting readily facilitating facile penetration of the vasoactive agent. US 2008/0206161 A1 Aug. 28, 2008 37

0348. In one or more embodiments, the vasoactive agent is arrhythmia and Subarachnoid hemorrhage. Calcium channel a vasoconstrictor. A vasoconstrictor is any of various agents blockers may further relieve or prevent reactive vasodilation that narrow blood vessels and thereby maintain or increase of migraine Sufferers by inhibiting the vasoconstriction dur blood pressure, and/or decrease blood flow. There are many ing the prodromal phase. disorders that can benefit from treatment using a vasocon 0360. There are two main classes of calcium channel strictor. For example, redness of the skin (e.g., erythema or blockers: dihydropyridines (e.g., , , cuperose), which typically involves dilated blood vessels, amlodipine, and ) and nondihydropy benefit from treatment with a vasoconstrictor, which shrinks ridines which include (a benzothiazepine) and Vera the capillaries thereby decreasing the untoward redness. pamil (a phenylalkylamine). is an antihistamine 0349 Other descriptive names of the vasoconstrictor with calcium channel blocking activity. group include vasoactive , vasopressor agents and 0361. In an embodiment, the can vasoconstrictor drugs. Certain vasoconstrictors act on spe be selected from the group consisting of an amlodipine, cific receptors, such as vasopressin receptors or adrenorecep , , , , darodipine, dilt tOrS. iazem, , felodipine, , , lercani 0350. In one or more embodiments, the vasoconstrictor is dipine, , , mepirodipine, nicardipine, a calcium channel . Calcium channel agonists are nifedipine, , , nimodipine, , agents that increase calcium influx into calcium channels of , perhexyline, tiapamil, , pharmaceuti excitable tissues, thereby causing vasoconstriction. cally acceptable salts, isomers, analogs and derivatives 0351. Non limiting examples of vasoconstrictors include thereof. ephedrine, epinephrine, phenylephrine, angiotensin, vaso pressin, and analogs and derivatives thereof. Cholinergic Drugs 0352. In one or more embodiments, the vasoactive agent is a Substance derived or extracted from herbs, having a vaso 0362 Cholinergic drugs produce the same effects as ace constrictor effect. tylcholine. Acetylcholine is the most common neurohormone 0353 Thus, in one or more embodiments, the vasoactive of the parasympathetic nervous system, the part of the periph agent is a Substance derived or extracted from a herbal source, eral nervous system responsible for the every day work of the selected from the group including ephedra sinica (mahuang), body. A cholinergic agent, also known as a parasympathomi polygonum bistorta (bistort root), hamamelis Virginiana metic agent, is a chemical which functions to enhance the (witch hazel), hydrastis canadensis (goldenseal), lycopus Vir effects mediated by acetylcholine in the central nervous sys ginicus (bugleweed), aspidosperma quebracho (quebracho tem, the peripheral nervous system, or both. These include blanco), cytisus scoparius (Scotch broom), cypress and salts, acetylcholine receptor agonists muscarine and nicotine, as isomers, analogs and derivatives thereof. well as anticholinesterases. 0354 Yet, in additional embodiments, the vasoactive 0363 Suitable cholinergic drugs in accordance with the agent is a metal oxide or a mineral. Such as Zinc oxide and present invention are selected from a cholinergic agonist of bismuth Subgallate. acetylcholine, bethanechol, , methacholine, and 0355 The McKenzie vasoconstrictor assay, as described, pilocarpine, or an anticholinesterase of ambenonium, neo for example, in the British Journal of Dermatology 1975; Stigmine, physostigmine, pyridostigmine, dyflos, and ecothi 93:563-71 and versions thereof, has been the primary method nopate, and pharmaceutically acceptable salts, isomers, ana used for classifying the strength of a vasoconstrictor clinical logs and derivatives thereof. efficacy. Thus, in one or more embodiments, the vasoactive agent is an agent that positively affects the vasoconstrictor Nitric Oxide Donors assay. 0364 Nitric oxide is an inorganic free radical, which has 0356. Mixtures of these vasoactive agents may also be the of N=O and abbreviated to NO, and is employed according to the present invention. a remarkably versatile biological messenger. The chemical 0357 Solubility of the vasoactive agent is an important properties of NO are crucial in defining its biological roles, factor in the development of a stable foamable composition both as a transcellular signal in the cardiovascular and ner according to the present invention. Vous systems and as a cytotoxicantipathogenic agent released during an inflammatory response. Endogenous NO is synthe Calcium Channel Blockers sized from the amino acid L-arginine by three isoforms of the 0358 Calcium channel blockers are a chemically and enzyme NO synthase (NOS). The endothelial (eNOS) and pharmacologically heterogeneous group of drugs, but physi neuronal (nNOS) isoforms that synthesize NO for transcel ologically they all share the ability to selectively antagonize lular signaling are constitutively expressed tightly regulated the calcium ion movements that are responsible for the exci by a number of cofactors. These NOS isoforms typically tation-contraction coupling in the cardiovascular system. synthesize small amounts of NO and require activation by Beyond their cardiovascular effects, calcium channel block Ca"-calmodulin, making them sensitive to agents and pro ers are known to possess other effects, such as inhibition of cesses that increase intracellular calcium levels. The NO gen the growth and proliferation of vascular Smooth muscle cells erated diffuses to neighboring target cells where it acts pri and fibroblasts, inhibition of the synthesis of extracellular marily through activation of soluble guanylate cyclase (sGC) matrix proteins, immunomodulation, inhibition of mast cell to generate coiMP from GTP, and bring about the cellular degranulation and platelet aggregation and Suppression of response through a reduction in intracellular calcium levels. neutrophil adhesion and Superoxide anion (O-2) production. 0365. In an embodiment, the nitric oxide donors can be Some calcium channel blockers also have analgesic effects. selected from several classes, including, but not limited to 0359 Current therapeutic uses of calcium channel block inorganic nitrites and nitrates (e.g., sodium nitrite), organic ers include (but are not limited to) hypertension, angina, nitrites and nitrates, Sodium nitroprusside, molsidomine and US 2008/0206161 A1 Aug. 28, 2008

its metabolites, diazeniumdiolates, S-nitrosothiols, 0373) In an embodiment, the therapeutic agent is a chemo mesoionic OXatriazole and derivatives thereof iron-Sulphur therapeutic agent. Suitable chemotherapeutic agents include nitrosyls. Sinitrodil, FK-409 (4-Ethyl-2-(Z)-hydroxyimi but are not limited to daunorubicin, doxorubicin, idarubicin, nol-5-nitro-3(E)-hexeneamide) and derivatives thereof and amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, hybrid NO donor drugs. teniposide, vinblastine, Vincristine, mitomycin C, 5-FU, 0366. In an embodiment, the organic nitric oxide donor , docetaxel, actinomycin D, , topotecan, includes at least one organic nitrate, which includes esters of irinotecan, gemcitabine cyclosporin, Verapamil, Valspodor, nitric acid and may be an acyclic or cyclic compound. For probenecid, MK571, GF120918, LY335979, biricodar, ter instance, the organic nitrate may be ethylene glycol dinitrate; fenadine, , pervilleine A, XR9576 and derivatives, isopropyl nitrate; amyl nitrite, amyl nitrate, ethyl nitrite, butyl esters, salts and mixtures thereof. nitrite, isobutyl nitrite, octyl nitrite, glyceryl-1-mononitrate, 0374. Several disorders of the skin, a body cavity or glyceryl-1,2-dinitrate, glyceryl-1,3-dinitrate, nitroglycerin, mucosal Surface (e.g., the mucosa of the nose, mouth, eye, -1,2,4-triol-trinitrate; erythrityl tetranitrate; pen ear, vagina or rectum) involve a combination of inflammation, taerythrity1 tetranitrate; sodium nitroprusside, clonitrate, cell proliferation and differentiation abnormalities, and other erythrity1 tetranitrate, isosorbide mononitrate, isosorbide biological abnormalities that can be effected by a steroid; and dinitrate, mannitol hexanitrate, pentaerythritol tetranitrate, other etiological factors that require an additional therapeutic penetrinitol, triethanolamine trinitrate, trolnitrate phosphate modality. For example, psoriasis involves inflammation as (triethanolamine trinitrate diphosphate), propatylnitrate, well as excessive cell proliferation and inadequate cell differ nitrite esters of sugars, nitrate esters of Sugars, nitrite esters of entiation. Atopic dermatitis involves inflammation, skin dry polyols, nitrate esters of polyols, nicorandil, apresoline, dia ness and keratinocyte growth abnormality. Bacterial, fungal Zoxide, hydralazine, hydrochlorothiazide, minoxidil, pen and viral infections involve pathogen colonization at the taerythritol, tolaZoline, scoparone (6.7-dimethoxycoumarin) affected site and inflammation. Likewise, hair growth disor and pharmaceutically acceptable salts, isomers, analogs and ders and other pilosebaceous disorders involve an impaired derivatives thereof. hormonal balance (which can be affected by a steroid hor 0367. In one embodiment, vasoactive drugs that act via mone or a steroid hormone antagonist), together with other eNOS activity enhancement, such as sildenafil. Vardenafiland etiological factors, that can be affected a non-steroidal active tadalafil are also regarded “nitric oxide donors.” agent. Hence, in many cases, the inclusion of an additional 0368. In an embodiment, the active agent is an antipruritic. therapeutic agent in the foamable pharmaceutical composi Suitable antipruritics include but are not limited to , tion, contributes to the clinical activity of the steroid. Thus, in methdilazine, trimeprazine, urea and derivatives, esters, salts one or more embodiments, the foamable composition further and mixtures thereof. includes at least one additional therapeutic agent, in a thera 0369. In an embodiment, the therapeutic agent is an addi peutically effective concentration. tional antipsoriatic agent. Suitable additional antipsoriatic 0375. In one or more embodiments, the at least one addi agents include but are not limited to 6-aminonicotinamide, tional non-steroidal therapeutic agent is selected from the 6-aminonicotinic acid, 2-aminopyrazinamide, anthralin, group consisting of an anti-infective, an antibiotic, an anti 6-carbamoylnicotinamide, 6-chloronicotinamide, 2-carbam bacterial agent, an antifungal agent, an antiviral agent, an oylpyrazinamide, corticosteroids, 6-dimethylaminonicotina antiparasitic agent, a nonsteroidal anti-inflammatory drug, an mide, dithranol, 6-formylaminonicotinamide, 6-hydroxy immunosuppressive agent, an immunomodulator, an immu nicotinic acid, 6-substituted , 6-substituted noregulating agent, a hormonal agent, vitaminA, a vitamin A nicotinic acid, 2-substituted pyrazinamide, tazarotene, derivative, vitamin B, a vitamin B derivative, vitamin C, a thionicotinamide, trichothecene mycotoxins and derivatives, vitamin C derivative, vitamin E, a vitamin E derivative, vita esters, salts and mixtures thereof. min F, a vitamin F derivative, vitamin K, a vitamin K deriva 0370. In an embodiment, the active agent is an antirosacea tive, a wound healing agent, a disinfectant, an anesthetic, an agent. Suitable antirosacea agents include but are not limited antiallergic agent, an alpha hydroxyl acid, lactic acid, gly to azelaic acid, metronidazole, Sulfacetamide and derivatives, colic acid, a beta-hydroxy acid, a protein, a peptide, a neu esters, salts and mixtures thereof. Certain nonsteroidal anti ropeptide, a allergen, an immunogenic Substance, a haptene, inflammatory agents, such as Salicylic acid, Salycilates, an oxidizing agent, an antioxidant, a dicarboxylic acid, aze and diclofenac are also useful for the treatment of laic acid, sebacic acid, adipic acid, fumaric acid, a retinoid, an Rosacea. antiproliferative agent, an anticancer agent, a photodynamic 0371. In an embodiment, the therapeutic agent is an anti therapy agent, an anti-wrinkle agent, a radical scavenger, a seborrheic agent. Suitable antiseborrheic agents include but metal oxide (e.g., titanium dioxide, Zinc oxide, Zirconium are not limited to glycolic acid, Salicylic acid, selenium Sul oxide, iron oxide), silicone oxide, an anti wrinkle agent, askin fide, Zinc pyrithione, a dicarboxylic acid, such as azelaic acid whitening agent, a skin protective agent, a masking agent, an and derivatives, esters, salts and mixtures thereof. anti-wart agent, a refatting agent, a lubricating agent and 0372. In an embodiment, the therapeutic agent is an anti mixtures thereof. viral agent. Suitable antiviral agents include but are not lim 0376. In certain cases, the disorder to be treated involves ited to acyclovir, gancyclovir, ribavirin, amantadine, riman unaesthetic lesions that need to be masked. For example, tadine nucleoside-analog reverse transcriptase inhibitors, rosacea involves papules and pustules, which can be treated Such as , , , tavudine, lami with a steroid, as well as erythema, telangiectasia and red Vudine and Vidarabine, non-nucleoside reverse transcriptase ness, which do not respond to treatment with a steroid. Thus, inhibitors, such as and , protease in one or more embodiments, the additional active agent is a inhibitors, such as , , and nelfi masking agent, i.e., a pigment. Non limiting examples of navir, and interferons and derivatives, esters, salts and mix suitable pigments include brown, yellow or red iron oxide or tures thereof. hydroxides, chromium oxides or hydroxides, titanium oxides US 2008/0206161 A1 Aug. 28, 2008 39 or hydroxides, zinc oxide, FD&C Blue No. 1 aluminum lake, acid, galactaric acid, galacturonic acid, glucaric acid, glucu FD&C Blue No. 2 aluminum lake and FD&C Yellow No. 6 ronic acid, glyceric acid, glycolic acid, gularic acid, gulonic aluminum lake. acid, hydroxypyruvic acid, idaric acid, isocitric acid, lactic 0377. In an embodiment, the active agent is a hair growth acid, lyxaric acid, malic acid, mandelic acid, mannaric acid, regulator. Suitable hair growth regulators include but are not methyllacetic acid, mucic acid, phenylacetic acid, pyruvic limited to N-acetylgalactosamine, N-acetylglucosamine, acid, , ribaric acid, ribonic acid, saccharic acid, N-acetylmannosamine, acitretin, aminexil, ascomycin, asi talaric acid, tartaric acid, tartronic acid, threaric acid, tropic atic acid, azelaic acid, benzalkonium chloride, benzethonium acid, uronic acids, Xylaric acid and derivatives, esters, salts chloride, , benzyl nicotinate, benzoyl peroxide, and mixtures thereof. benzyl peroxide, betulinic acid, betulonic acid, calcium pan tothenate, celastrol, cepharanthine, chiorpheniramine male Keratolytic Agents ate, clinacycin hydrochloride, crataegolic acid, cromakalin, 0380. In an embodiment, the active agent is a keratolytic cyproterone acetate, diaZoxide, diphenhydramine hydrochlo agent. The term "keratolytic agent' is used herein to mean a ride, dutasteride, estradiol, ethyl-2-hydroxypropanoate, fin compound which loosens and removes the stratum corneum asteride, D-fucono-1,5-lactone, furoate, L-galactono-1,4- of the skin, or alters the structure of the keratin layers of skin. lactone, D-galactosamine, D-glucaro-1,4-lactone, Keratolytic agents are used in the treatment of many derma D--3-sulphate, , hydrocortisone, 2-hy tological disorders, which involve dry skin, hyperkeratiniza droxypropionic acid, isotretinoin, itraconazole, ketocona tion (Such as psoriasis), skin itching (such as Xerosis), acne Zole, latanoprost, 2-methylpropan-2-ol, minocyclin, minoxi and rosacea. Suitable keratolytic agents include but are not dil, mipirocin, mometaSone, oleanolic acid, , 1.10 limited to N-acetylcysteine, azelaic acid, cresols, dihydroxy , phenyloin, prednisolone, progesterone, compounds, such as resorcinol and hydroquinone, propan-2-ol, pseudoterins, resorcinol, selenium sulfide, taZ alpha-hydroxy acids, such as lactic acid and glycolic acid, arotene, triclocarbon, triclosan, triiodothyronine, ursolic phenol, pyruvic acid, resorcinol, Sulfur, salicylic acid, ret acid, Zinc pyrithione and derivatives, esters, salts and mix inoic acid, isoretinoic acid, retinol, retinal, urea and deriva tures thereof. tives, esters, salts and mixtures thereof. 0378. In an embodiment, the therapeutic agent is a hor 0381. The term “keratolytic agent” refers herein to a com mone. Suitable hormones include but are not limited to meth pound which loosens and removes the stratum corneum of the yltestosterone, androsterone, androsterone acetate, andros skin, or alters the structure of the keratin layers of skin. terone propionate, androsterone benzoate, androsteronediol, 0382 Suitable keratolytic agents also include alpha-hy androsteronediol-3-acetate, androsteronediol-17-acetate, droxy acids. Alfa hydroxy acids are keratolytic, and they are androsteronediol 3-17-diacetate, androsteronediol-17-ben also capable of trapping moisture in the skin and initiating the Zoate, androsteronedione, androstenedione, . formation of collagen. Suitable hydroxy acids include but are dehydroepiandrosterone, Sodium dehydroepiandrosterone not limited to agaricic acid, aleuritic acid, allaric acid, altraric Sulfate, dromostanolone, dromostanolone propionate, ethyl acid, arabiraric acid, ascorbic acid, atrolactic acid, benzilic estrenol, fluoxymesterone, phenpropionate, nan acid, citramalic acid, citric acid, dihydroxytartaric acid, drolone decanoate, nandrolone furylpropionate, nandrolone erythraric acid, galactaric acid, galacturonic acid, glucaric cyclohexane-propionate, nandrolone benzoate, nandrolone acid, glucuronic acid, glyceric acid, glycolic acid, gularic cyclohexanecarboxylate, androsteronediol-3-acetate-1-7- acid, gulonic acid, hydroxypyruvic acid, idaric acid, isocitric benzoate, Oxandrolone, oxymetholone, , testoster acid, lactic acid, lyxaric acid, malic acid, mandelic acid, one, testosterone decanoate, 4-, 5a-dihy mannaric acid, methylacetic acid, mucic acid, phenyllacetic drotestosterone, testolactone, 17a-methyl-19 acid, pyruvic acid, quinic acid, ribaric acid, ribonic acid, nortestosterone, desogestrel, dydrogesterone, ethynodiol saccharic acid, talaric acid, tartaric acid, tartronic acid, diacetate, medroxyprogesterone, levonorgestrel, medroX threaric acid, tropic acid, uronic acids, Xylaric acid and yprogesterone acetate, hydroxyprogesterone caproate, nore derivatives, esters, salts and mixtures thereof. thindrone, norethindrone acetate, norethynodrel, allylestre 0383 Yet, another preferred keratolytic agent is urea, as nol. 19-nortestosterone, lynoestrenol, acetate, well as derivatives thereof. Urea possesses both keratolytic , , , , and skin-hydration properties which are beneficial to the cyproterone acetate, chlormadinone acetate, megestrol damaged tissue of the skin. acetate, , norgestrel, desogrestrel, , 0384 Another preferred group of keratolytic agents, suit gestodene, nomegestrol acetate, progesterone, 5a-pregnan able for inclusion in the therapeutic composition according to 3b.20a-diol sulfate, 5a-pregnan-3b.20b-diol sulfate, 5a-preg the present invention is beta-hydroxy acids, such as salicylic nan-3b-ol-20-one, 16.5a-pregnen-3b-ol-20-one, 4-pregnen acid (o-hydroxybenzoic acid). Beta hydroxyl acids are kera 20b-ol-3-one-20-Sulfate, acetoxypregnenolone, tolytic, and they are also have anti-inflammatory and antibac acetate, cyproterone, dihydrogesterone, fluorogestone terial properties. acetate, gestadene, hydroxyprogesterone acetate, hydroxym 0385 Short chain carboxylic acids (carboxylic acids hav ethylprogesterone, hydroxymethyl progesterone acetate, ing up to 6 carbonatoms in their skeleton) are also suitable for 3-ketodesogestrel, megestrol, acetate, norethis inclusion in the therapeutic composition as keratolytic terone, progestins and derivatives, esters, salts and mixtures agents. Examples of short chain carboxylic acid include, but thereof. are not limited to formic acid, , , 0379. In an embodiment, the therapeutic agent is a butyric acid (Butanoic acid), Valeric acid (pentanoic acid) and hydroxyacid. Suitable hydroxy acids include but are not lim caproic acid (hexanoic acid). In the context of the present ited to agaricic acid, aleuritic acid, allaric acid, altraric acid, invention, di-carboxylic acids having up to 6 carbon atoms in arabiraric acid, ascorbic acid, atrolactic acid, benzilic acid, their skeleton are also suitable under the definition of short citramalic acid, citric acid, dihydroxytartaric acid, erythraric chain carboxylic acids having up to 6 carbon atoms in their US 2008/0206161 A1 Aug. 28, 2008 40 skeleton. Non-limiting examples of suitable dicarboxylic D-glucaro-1,4-lactam, D-glucurono-6.3-lactam, 2.5-tri-O- acids are malonic acid (propanedioic acid). Succinic acid acetyl-D-glucurono-6.3-lactam, 2-acetamido-2-deoxyglu (butanedioic acid), glutaric acid (Pentanedioic acid) and adi cono-1,5-I-actam, 2-acetamido-2-deoxygalactono-1,5-lac pic acid (Hexanedioic acid). Also suitable under the definition tam, D-glucaro-1,4:6.3-dilactam-, L-idaro-1,5-lactam, 2.3.5. of short chain carboxylic acid are unsaturated short chain tri-O-acetyl-D-glucaro-1,4-lactam, 2,5-di-O-acetyl-D- carboxylic acids, i.e., short chain carboxylic acids, having glucaro-1,4:6.3-dilactam, D-glucaro-1,5-lactam methyl one or more double bonds in their carbon skeleton; and halo ester, 2-propionoamide-2-deoxyglucaro-1,5-lactam and genated short chain carboxylic acids, such as fluoroethanoic derivatives, esters, salts and mixtures thereof. acid (CH2FCO2H), chloroethanoic acid (CH2CICO2H) and dichloroethanoic acid (CHCl2CO2H). Dicarboxylic acids, Nonsteroidal Anti-Inflammatory Agent having between about 6 and about 14 carbon atoms in their carbonatom skeleton also possessleratolytic properties. Suit 0391. In an embodiment, the therapeutic agent is a non able dicarboxylic acid moieties include, but are not limited to, steroidal anti-inflammatory agent. adipic acid, pimelic acid, Suberic acid, azelaic acid, sebacic 0392 Inflammation is defined as "redness, swelling, and acid, 1,11-undecanedioic acid, 1,12-dodecanedioic acid, fever in a local area of the body, often with pain and disturbed 1,13-tridecanedioic acid and 1,14-tetradecanedioic acid. function, in reaction to an infection or to a physical or chemi 0386. Another group of keratolytic agents include phenol cal injury' (Random House Webster's Dictionary). Typical and Substituted phenolic compounds. Such compounds are symptoms of disorders of the skin, body Surfaces, body cavi known to dissolve and loosen the intracellular matrix of the ties and mucosal Surfaces (e.g., the mucosa of the nose, hyperkeratinized tissue. Dihydroxybenzene and derivatives mouth, eye, ear, respiratory system, vagina or rectum) that thereof have been recognized as potent keratolytic agents. involve inflammation, as at least one of their etiological fac Resorcinol (m-dihydroxybenzene) and derivatives thereof tors, include redness (rash, erythema), tissue thickening and/ are used in anti-acne preparations. Hydroquinone (p-dihy or Swelling (oedema), itch (pruritus), blistering and exudate. droxybenzene), besides its anti-pigmentation properties, is Inflammatory disorders can by short term or long term also keratolytic. (chronic). Inflammation typically involves overproduction of 0387 Vitamin A and its derivatives, such as retinol, reti pro-inflammatory cytokines, such as TNF-alpha, TNF-beta, nal, retinoic acid, retinyl acetate, retinyl palmitate, retinyl interleukin-1, interleukin-4, interleukin-6, interleukin-10, ascorbate, isotretinoin, tazarotene, adapalene, 13-cis-retinoic interleukin-12, IFN-gamma from T cells, or increased release acid, acitretin all-trans beta , alpha carotene, lyco of cytokines and pro-inflammatory mediators from mast pene, 9-cis-beta-carotene, and are another cells. class of keratolytic agents, which alter the structure of the 0393. In the context herein, a nonsteroidal immunomodu skin and promote peeling. lating agent (also termed herein “nonsteroidal anti-inflamma 0388. In certain embodiments, the keratolytic agent tory agent” and “NSAID) is a pharmaceutically active com includes at least two keratolytic agents. At least two or more pound, other than a , which affects the immune keratolytic agents in the therapeutic composition, a safe and system in a fashion that results in a reduction, inhibition, effective peeling agent is attained, which breaks down the prevention, amelioration or prevention of an inflammatory keratin layer of the skin, where the microorganisms reside. As process and/or the symptoms of inflammation and or the a result of such breaking down of the keratin layer, the micro production pro-inflammatory cytokines and other pro-in organisms cannot further Survive in the infected area. The flammatory mediators, thereby treating or preventing a dis combination of at least two keratolytic agents enables a selec ease that involves inflammation. tive breaking down of keratin in infected skin areas, while 0394. In one or more embodiments, the NSAID is an non-infected skin areas are not affected. This phenomenon is inhibitor of the cyclooxygenase (COX) enzyme. Two forms explained by the fact that the keratin layer in infected skin of cyclooxygenase are known today: the constitutive areas is deformed and thus it is more vulnerable to keratolytic cyclooxygenase (COX-1); and the inducible cyclooxygenase disintegration. Furthermore, combining at least two kera (COX-2), which is proinflammatory. Thus, in one or more tolytic agents facilitates use of each agent in a Substantially embodiments, the NSAID is selected from the group consist minimally-irritating concentration, thus decreasing the over ing of a COX-1 inhibitor, a COX-2 inhibitor or a non-selective all irritation of the therapeutic composition. NSAID, which simultaneously inhibits both COX-1 and 0389. In one or more embodiments, the keratolytic agent COX-2. includes at least two keratolytic agents, from different fami 0395. The term “selective COX-2 inhibitor relates o a lies of chemicals. Thus, in preferred embodiments, the kera compound able to inhibit cyclooxygenase-2 without signifi tolytic agent includes at east two agents, from different cant inhibition of COXe-1. Typically, it includes compounds chemical families, selected from the group consisting of: (1) that have a COX-2ICs of less than about 0.2 micro molar, and an alpha-hydroxy acid; (2) a beta-hydroxy acid; (3) a short also have a selectivity ratio of COX-2 inhibition over COX-1 chain carboxylic acid; (4) a hydroxylbenzene; (5) a vitamin A inhibition of at least 50, and more typically, of at least 100. derivative; and (6) urea. As detailed above, each of these Inhibitors of the cyclooxygenase pathway in the keratolytic agent families possess, in addition to their kera of used in the present invention may inhibit tolytic property, additional therapeutically-beneficial feature, enzyme activity through a variety of mechanisms. By the way Such as anti-inflammatory, skin hydration and antibacterial of example, and without limitation, the inhibitors used in the properties for readily contributing to the overall therapeutic methods described herein may block the enzyme activity benefit of the therapeutic composition. directly by acting as a Substrate for the enzyme. 0390. In an embodiment, the active agent is a lactam. 0396. Selective COX-2 Inhibitors include, in an exem Suitable lactams include but are not limited to L-galactono plary manner diaryl-substituted furanones (e.g., ); 1.4-lactam, L-arabino-1,5-lactam, D-fucono-1,5-lactam, diaryl-substituted pyrazoles (e.g., ); indole acetic US 2008/0206161 A1 Aug. 28, 2008

acids (e.g., ); and Sulfonanilides (e.g., ) 0405. In one or more embodiments, the NSAID is selected and salts and derivatives thereof. from the group of enolic acids, enolic acid salts, enolic acid 0397. In one or more embodiments, the selective COX-2 esters, amides, anhydrides and salts and derivatives thereof. inhibitor is selected from the group consisting of celecoxib, Non-limiting examples of enolic acid derivatives include oxi , , rofecoxib, , , cams (piroXicam, ) and pyrazolidinediones (phe , , 4-(4-cyclohexyl-2-methyloxazol-5- nylbutaZone, oxyphenthratraZone) yl)-2-fluorobenzenesulfonamide, 2-(3,5-difluorophenyl)-3- 0406 Yet, in additional embodiments, the NSAID is an (4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one, N-2-(cy alkanone (e.g., ). clohexyloxy)-4-nitrophenylmethanesulfonamide, 2-(3,4- 0407 Certain imidazole drugs (e.g., ketoconazole) also difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-4- possess anti-inflammatory properties, (See: JAm Acad. Der (methylsulfonyl)-phenyl-3(2H)-pyridazinone, 2-(2,4- matol. 1991 August; 25(2 Pt 1):257-61). dichloro-6-methylphenyl)amino-5-ethyl-1-benzeneacetic 0408. Another group of nonsteroidal immunomodulating acid, (3Z)-3-(4-chlorophenyl)-4-(methylsulfonyl)phenyl agents includes agents, which inhibit pro-inflammatory met-hylenedihydro-2(3H)-furanone, and (S)-6,8-dichloro cytokines, such as TNF-alpha, TNF-beta, interleukin-1, inter 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid. leukin-4, interleukin-6, interleukin-10, interleukin-12 and 0398. In additional embodiments, the selective COX-2 IFN-gamma from T cells, which are especially important in inhibitor is selected from the group consisting of ibuprofen, the induction of inflammation or inhibit the release of cytok , , , , , ines and pro-inflammatory mediators from mast cells. , , , , , 04.09 Agents that are used to affect the untoward influence prapoprofen, , tioxaprofen, , alminopro of pro-inflammatory cytokines are chemically or biologi fen, , fluprofen, bucloxic acid, indomethacin, cally-originated materials that Suppress the pro-inflammatory , , , diclofenac, fenclofenec, effect of a pro-inflammatory cytokine via various mecha , ibufenac, isoxepac, furofenac, tiopinac, nisms, including, but not limited to (a) inhibiting the forma Zidometacin, acetyl salicylic acid, , piroxicam, tion of a pro-inflammatory cytokine; (b) Suppressing the tenoxicam, nabumetone, , , mefe interaction of a pro-inflammatory cytokine with its receptors; namic acid, , , podophyllotoxin or (c) neutralization the proinflammatory cytokine by direct derivatives, , , , oxyphenb or indirect interaction. utaZone, , , acemetacin, fen 0410 Examples of chemical anti TNF-C. agents are known tiazac, clidanac, oxipinac, , meclofenamic pharmaceutical materials, such as pentoxifylline, pro acid, , , flufenisal, Sudoxicam, pentofylline, torbafylline (and other related Xanthines), etodolac, piprofen, salicylic acid, magnesium trisali , , and structural analogs cylate, salicylate, benorylate, , clopinac, , thereof. Examples for biological anti-TNF-C. agents are anti , and 2-fluoro-a-methyl 1, 1'-biphenyl-4-ace-tic TNF-C. antibodies and soluble TNF-B receptors. Additional acid, 4-(nitrooxy)butyl ester. compounds are those that impair the signal transduction cas 0399. In one or more embodiments, the NSAID is salicylic cade from the receptor to other functional organs of the living acid a salicylic acid derivatives. Exemplary Salicylic acid cell. Such active agents, as well additional compounds, which derivative include, in a non limiting fashion, , sodium are capable of inhibiting the production or otherwise Sup salicylate, choline magnesium trislicylate, , pressing the pro-inflammatory effects of TNF-C. can be used diflunisal, Salicylsalicylic acid, SulfaSalazine, olsalazine, in the composition. esters of Salicylic acid with a carboxylic acid, esters of Sali 0411 Immunosuppressant agents, immunoregulating cylic acid with a dicarboxylic acid, esters of Salicylic acid agents and immunomodulators constitute an additional class with a fatty acid, esters of salicylic acid with a hydroxyl fatty of nonsteroidal anti-inflammatory agents, which are used acid, esters of salicylic acid with an , esters according to the present invention. Such agents are chemi of salicylic acid with a polycarboxylic acid, and any com cally or biologically-derived agents that modify the immune pound wherein Salicylic acid is linked to an organic moiety response or the functioning of the (as by the through a covalent bond. stimulation of antibody formation or the inhibition of white 0400. In one or more embodiments, the NSAID is para blood cell activity). Immunosuppressant agents and immu aminophenol (e.g., acetaminophen) and salts and derivatives nomodulators include, among other options, cyclic peptides, thereof. Such as cyclosporine, tacrolimus, tresperimus, , 04.01. In one or more embodiments, the NSAID is an Sirolimus (rapamycin), Verolimus, laflunimus, lacquinimod indole or an indole-acetic acid derivative (e.g., indometha and imiquimod. In one or more embodiments, the non steroi cin, Sulindac, etodolac) and salts and derivatives thereof. dal immunomodulating agent is a calcineurin Inhibitor. 0402. In one or more embodiments, the NSAID is an aryl 0412. In one or more embodiments, the NSAID is a nitric acetic acids (e.g., tolmetin, diclofenac, ketorolac) and salts oxide inhibitor. Nitric oxide (NO) is a potent secondary mes and derivatives thereof. senger that is both highly reactive and highly diffusible. It is 0403. In one or more embodiments, the NSAID is an aryl generated physiologically by a family of enzymes, referred to propionic acid and salts and derivatives thereof. Exemplary as NO synthases (NOS). Overproduction of NO plays a key arylpropionic acid derivative include, in a non limiting fash role in the pathology of a wide range of disorders including ion, are ibuprofen, naproxen, flubiprofen, ketoprofen, feno disorders that involve inflammation, and NOS inhibitors have profen, oxaprozin. been suggested as anti-inflammatory agents. Agents that neu 0404 In one or more embodiments, the NSAID is anthra tralize NO (also called “NO scavengers') are considered as nilic acids or an anthranilic acid derivative, also termed potential anti-inflammatory agents as well. “fenamates' (e.g., mefenamic acid, ) and 0413 Also useful are compounds that inhibit or slow salts and derivatives thereof. down the migration of leucocytes (white blood cell), e.g., US 2008/0206161 A1 Aug. 28, 2008 42 macrophages, neutrophils, and monocytes towards an sipatrigine, , , spheroidine, maculotoxin, afflicted skin Surface or mucosal membrane, which is known Vinpocetine, anthopleurin-c, , crobenetine, to accelerate the inflammatory process. lifarizine, lanodipine, , encamide, and flunarizine 0414. Among other inhibitors of leucocyte chemoaxis, or is an isomer, a pharmaceutically acceptable salt, ester, or dicarboxylic acids, having between about 6 and about 14 prodrug thereof. carbon atoms in their carbon atom skeleton are particularly 0421. In an embodiment, the potassium useful in the treatment of disorders of the skin and mucosal modulator is selected from the list of potassium ion channel membranes that involve inflammation. Suitable dicarboxylic modulators, provided in U.S. Pat. Appl. 20040224940 and acid moieties include, but are not limited to, adipic acid, 2004O22O187. pimelic acid, Suberic acid, azelaic acid, Sebacic acid, 1.11 0422. In one or more embodiments, the NSAID is a modu undecanedioic acid, 1,12-dodecanedioic acid, 1,13-tride lator of serotonin (5-hydroxytryptamine, 5-HT) activity. canedioic acid and 1,14-tetradecanedioic acid. Thus, in one or 5-HT is known to affect inflammation through its modulation more embodiments, dicarboxylic acids, having between effect on cytokine production (Cloéz-Tayarani et al. Int. about 6 and about 14 carbon atoms in their carbon atom Immunol. 2003, 15233). In certain embodiments, the sero skeleton, as well as their salts and derivatives (e.g., esters, tonin activity modulator is a serotonin . It amides, mercapto-derivatives, anhydraides), are useful has been shown that serotonin reduces inflammation and immunomodulators in the treatment of disorders of the skin assists healing of experimental skin wounds, and thus, sero and mucosal membranes that involve inflammation. AZelaic tonin reuptake inhibitor can be used to control inflammation acid and its salts and derivatives are preferred. and associated disorders. 0415 Certain preferred dicarboxylic acid derivatives 0423. In one or more embodiments, the serotonin reuptake include a dicarboxylic acid wherein at least one ester moiety inhibitor is selected from the group consisting of citalopram, of the compound comprises a keratolytic agent, selected from , fluvoxamine, paroxetine, escitalopram oxalate, the group consisting of alpha-hydroxy acids and derivatives sertraline, norfluoxetine and N-demethylsertraline. thereof, beta-hydroxy acids and derivatives thereof, hydroxy 0424. In an embodiment, the serotonin reuptake inhibitor benzoic acid and their ester, anhydride and amine derivatives, is selected from the list of potassium ion channel modulators, alkylhydroxybenzoate, dihydroxy benzene and their ester, provided in US Pat Appl. 2004.0171664. anhydride and amide derivatives, cresols and their ester, 0425. In one or more embodiments, the NSAID is an anti anhydride and amide derivatives. Keratolytic agents also oxidant. Reactive oxygen species play an important role in include alcohol derivatives of Vitamin A (retinoic acid), e.g., mediating skin inflammation, and antioxidants may provide retinol and derivatives thereof, as provided in U.S. Pat. No. protection. 6,180,669. Additional preferred dicarboxylic acid derivatives 0426 Non-limiting examples of antioxidant agents comprise at least one esterofa active alcohol moiety, selected include 21-4-2-amino-6-(diethylamino)-4-pyrimidinyl)-1- from the groups of steroid hormones, corticosteroids, vitamin piperazinyl-17C.-hydroxypregna-4.9(11)-diene-320-dione, E and vitamin D, as provided in US Patent Application 17O-hydroxy-21-4-2,6-bis(dimethylamino)-4-pyrimidi 2004O191196. nyl-1-piperazinylpregna-4.9(11)-diene-320-dione, 21-4- 0416. In one or more embodiments, the NSAID is an ion 2-(diethylamino)-6-(1-pyrrolidinyl)-4-pyrimidinyl-1-pip . Ion channels are protein macromolecules erazinyl-17C.-hydroxypregna-4.9(11)-diene-3,20-dione, located in the cell membranes that enable the selective move 17O-hydroxy-21-4-2-(diethylamino)-6-(4-methyl-1-piper ment of sodium, potassium, and calcium from outside the cell azinyl (4-pyrimidinyl)-1-piperazinylpregna-4.9(11)-diene to inside the cell and Vice-versa. 3.20-dione, 17O-hydroxy-21-4-2,6-bis(diethylamino)-4- 0417. In one or more embodiments, the NSAID is a potas pyrimidinyll-piperazinylpregna-4.9(1)-diene-3,20-dione, sium ion channel modulator. It has been shown that the potas 1O-hydroxy-21-4-2-(diethylamino-)-6-(1-piperidinyl)-4- sium ion channel modulator play important roles in control pyrimidinyl-1-piperazinylpregna-4.9(11)-diene-320-di ling T-cell activation and thus, they can be used to control one, 21-4-2,6-bis(diethylamino)-4-pyrimidinyl)-4-pyrim inflammation. idinyl-1-piperazinyl-1-piperazinyl-17C-hydroxy-16C.- 0418. In one or more embodiments, the potassium ion methylpregna-1,4,9(11)-triene-3,20-dione, 17O-hydroxy channel modulator is selected from the group consisting of 21-4-2,6-bis(4-methyl-1-piperazinylpregna-4.9(11)- , dendrotoxin I, dendrotoxin K, alpha-dendro diene-320-dione, 17O-hydroxy-6C.-methyl-21 4-2,6-bis-(1- toxin, beta-dendrotoxin, gamma-dendrotoxin, margatoxin, pyrrolidinyl-4-pyrimidinyl-1-piperazinylpregna-1,4,9(11)- Stichodactyla toxin, tityustoxin K, apamin, charylotoxin, clo triene-3,20-dione, 21-4-2,6-bis(diethylamino)-4- trimazole, chloride, iberiotoxin, kaliotoxin, pyrimidinyl-1-piperazinyl-1-1C.17C-dihydroxypregn-4- Y, noxiustoxin, , , ene-320-dione, 21-4-2,6-bis(diethylamino)-4- , , nategliniide, repagliniide, gly pyrimidinyl-1 piperazinyl-17C.-hydroxypregn-4-ene-320 buride, , nicorandil, fampiridine and penitrem A, or dione, 21-4-2,6-bis(diethylamino)-4-pyrimidinyl)-1- is a pharmaceutically acceptable salt or prodrug thereof. piperazinyl-17C.-hydroxy-6C.-methylpregna-1,4,9(11)- 0419. In an embodiment, the potassium ion channel triene-3,20-dione, 17O-hydroxy-21-4-2,6-bis(- modulator is selected from the list of potassium ion channel pyrrolidinyl)-4-ppyrimidinyl-1-piperazinylpregna-4.9 modulators, provided in WO 2004 1093895. (11)-diene-320-dione, 21-4-2,6-bis(diethylamino)-4- 0420. In one or more embodiments, the NSAID is a pyrimidinyl-1-piperazinyl-11C.-hydroxypregn-4-ene-320 Sodium ion channel modulator. In one or more embodiments, dione, 21-4-2,6-bis(diethylamino)-4-pyrimidinyl)-1- the Sodium ion channel blocker is selected from the group piperazinyl-11C.17C.-dihydroxypregn-4-ene-320-dione, consisting of , procainimide, quinidine, tocam 17O-hydroxy-16C.-methyl-21-4-2,6-bis-(1-pyrrolidinyl)- ide, mexiletene, lidocane, phenyloin, fosphenyloin, flecam 4-pyrimidinyl-1-piperazinylpregna-1,4,9(-11)-triene-3, ide, , morcizine, lubeluzole, , 20-dione, 17O-hydroxy-21-4-2,6-bis(1-pyrrolidinyl)-4-py

US 2008/0206161 A1 Aug. 28, 2008 44 indole-2-carboxylic acid; 4,6-dichloro-3-(E)-(2-oxo-1- 0433 Mixtures of these non-steroidal immunomodulators phenyl-3-pyrrolidinylidene)methyl)-1H-indole-2-carboxylic may also be employed according to the present invention. acid: 6-chloro-2.3.4.9-tetrahydro-9-methyl-2,3-dioxo-1H 0434 Suitable non-steroidal anti-inflammatory agent indeno1.2-bipyrazine-9-acetic acid; 7-chlorothiokynurenic include but are not limited to azelaic acid, , piroxi acid; 8-chloro-2,3-dihydropyridazino 4.5-bquinoline-1,4- cam, isoxicam, tenoxicam, Sudoxicam, CP-14.304, Salicy dione 5-oxide salt with 2-hydroxy-N,N,N-trimethyl-etha lates, aspirin, disalcid, benorylate, trilisate, Safapryn, Solprin, naminium; aptiganel; besonprodil; budipine; conantokin G: diflunisal, fendosal, acetic acid derivatives, diclofenac, fen delucemine; ; ; fluorofelbamate; gacy clofenac, indomethacin, Sulindac, tolmetin, isoxepac, furo clidine; ; ipenoxazone; kaitocephalin; lanicemine; fenac, tiopinac, Zidometacin, acematacin, fentiazac, Zomepi licostinel; midafotel; milnacipran; N'-(2-chloro-5-(meth rac, clindanac, oxepinac, , ketorolac, fenamates, ylthio)phenyl-N-methyl-N-3-(methylthio)phenyl-guan mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic idine; N'-(2-chloro-5-(methylthio)phenyl-N-methyl-N-3- acids, propionic acid derivatives, ibuprofen, naproxen, (R)-methylsulfiny-Iphenyl-guanidine; neramexane: benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fen ; ; ; alpha.-amino-2-(2- bufen, indopropfen, pirprofen, carprofen, Oxaprozin, prano phosphonoethyl)-cyclohexanepropanoic acid; alpha.- profen, miroprofen, tioxaprofen, Suprofen, , amino-4-(phosphonomethyl)-benzeneacetic acid; 8-4-(1,1- tiaprofen, pyrazoles, phenylbutaZone, , dimethylheptyl)-2-hydroxyphenyldecahydro-2- feprazone, azapropaZone, trimethaZone and derivatives, naphthalene ; 5.6,6a,7,8,9,10,10a-octahydro-6- esters, salts and mixtures thereof. methyl-3-(1R)-1-methyl-4-pheny-I butoxy-19 0435. In an embodiment, the therapeutic agent is insecti phenanthridinediol; Desacetyl-L-nantradol; R-(+)- cide. The term “', is used herein to mean a com : 11-hydroxy-9.15-dioxoprosta-8,12,13 pound which kills, inhibits the growth of impeded the pro dienoic acid; 2-3-methyl-6-(1-methylethenyl)-2- liferation of or repels . include, for cyclohexen-1-yl-5-pentyl-(1R-trans)-1.-3-benzenediol example, agents that can kill lice, flees, ticks, mites, Scabies (); 3-amyl-1-hydroxy-6.6.9-trimethyl-6H and mousquitos, as well as agents that repel Such insects. dibenzob.dpyran (): 3-(1,1-dimethylheptyl)-6a, Suitable insecticides include but are not limited to DDT, 7,8,9,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-(-6aR.9R, , malathion, permethrin, allethrin, biopermethrin, 10aR)-6H-dibenzob.dpyran-9-methanol; 7-(1,1-dimethyl transpermethrin, , diethyl-m-toluamide, dimethyl heptyl)-1,2,3,4,4a,9b-hexahydro-2,2-dimethyl-4-methyl , piperonyl butoxide, pyrethroids and derivatives, ene-1,3-methanodibenzofuran-9-ol; 7-(1,1-dimethylheptyl)- esters, salts and mixtures thereof. 1,2,3,4,4a,9b-hexahydro-2,2-dimethyl-4-methylene-1-(s).3- 0436. In an embodiment, the therapeutic agent is a vasodi methanodibenzofuran-9-ol; 2-4-(acetyloxy)methyl-6,6- lator. Suitable vasodilators include but are not limited to dimethylbicyclo[3.1.1 hept-3-en-2-yl)-5-(1,1'-1- agents that modulate the activity of the enzyme nitric oxide dimethylheptyl)-diacetate 1R-(1a,2a,5a)-1,3-benzenediol; synthase, nicotinic acid, ethyl nicotinate, amyl nitrite, amyl 2-4-(acetyloxy)methyl-6,6-dimethylbicyclo[3.1.1 hept-3- nitrate, ethyl nitrite, butyl nitrite, isobutyl nitrite, glyceryl en-2-yl)-5-(1,1-dimethylheptyl)-diacetate 1S-(1a,2a,5a)-1, trinitrate, octyl nitrite, sodium nitrite, Sodium nitroprusside, 3-benzenediol; 5-(1,1-dimethylheptyl)-2-[4-(hydroxym clonitrate, erythrity1 tetranitrate, isosorbide mononitrate, ethyl)-6,6-dimethylbicyclo[3.1.1]hep-t-3-en-2-yl)-1S-(1a, isosorbide dinitrate, mannitol hexanitrate, pentaerythritoltet 2a.5a)-1,3-benzenediol; and 5-(1,1-dimethylheptyl)-2-4- ranitrate, penetrinitol, triethanolamine trinitrate, trolnitrate (hydroxymethyl)-6,6-dimethylbicyclo[3.1.1 hep-t-3-en-2- phosphate (triethanolamine trinitrate diphosphate), pro yl)-1R-(1a,2a,5a)-1,3-benzenediol; or is an isomer, a patylnitrate, nitrite esters of Sugars, nitrite esters of polyols, pharmaceutically acceptable salt, ester, or prodrug thereof. nitrate esters of Sugars, nitrate esters of polyols, nicorandil, 0429. In one or more embodiments, the NSAID is an apresoline, diaZoxide, hydralazine, hydrochlorothiazide, angiotensin 11 . Angiotensin II receptor minoxidil, pentaerythritol, tolaZoline, scoparone, a beta-adr energic blocker, an alpha-adrenoceptor blocker, a prostaglan antagonists are known to affect inflammation and pain, as din, sildenafil, dipyridamole, catecholamine, isoproternol, shown, for example in J Pharmacol Exp. Ther: 2003 October; furosemide, prostaglandin, prostacyclin, enalaprilat, mor 307(1):17-23. Epub 2003 Aug. 27. phine, acepromazine, prazosin (C.-blocker), enalapril, Capto 0430. In certain embodiments, the angiotensin II receptor pril, amlodipine, minoxidil, tadalafil. Vardenafil, phenyleph antagonist is selected from the group consisting of cande rin, etilefein, caffeine, capsaicin, an extract capsicum, Sartan, eprosartan, irbesartan, losartan, olmesartan, tasosar achillea millefolium (Yarrow), allium sativum (garlic), amo tan, , Valsartan, Saralasin, and 1-4-(dimethy racia rusticana (horseradish), berberis Vulgaris (barberry), lamino)-3-methylphenyl)methyl-5-(diphenylac-etyl)-4,5,6, cinicifuga racemosa (black cohosh), coleus forskholii (co 7-tetrahydro-1H-imidazo[4,5-cpyridine-6-carboxylic acid leus), coptis (goldenthread), Crataegus (hawthorn), eleuth ditrifluoroacetate, or an isomer, a pharmaceutically accept erococcus senticosus (Siberian ginseng), ginkgo biloba able salt, ester, or prodrug thereof. (ginkgo), melissa officinalis (lemon balm), Olea europaea 0431. In one or more embodiments, the NSAID is an (olive leaf), panax ginseng (Chinese ginseng), petroselinum UDP-glucuronosyltransferase inhibitor (UGT inhibitor). crispum (parsley), (baical skullcap), 0432. In certain embodiments, the UGT inhibitor is tilia europaea (linden flower), trigonella foenum-graecum selected from the group consisting of , (fenugreek), urtica dioica (nettles), Valeriana officinalis , octyl gallate, , querce (Valerian), Viburnum (cramp, bark, black haw), Veratrum tin, , benzoin gum, capsaicin, dihydrocapsaicin, viride (American hellebore), verbena officinalis (vervain), eugenol, , geraniol, menthol, menthyl Xanthoxylum americanum (prickly ash), Zingiber officinale acetate, , allspiceberry oil, N-Vanillylnonanamide, (ginger), rauwolfia serpentina (Indian Snakeroot), viscum clovebud oil, peppermint oil, and silymarin. album, wild yam, sasparilla, licorice, damiana, yucca, saw US 2008/0206161 A1 Aug. 28, 2008 45 palmetto, gotu kola (centella asiatica), yohimbine and salts, 0442 Compound (I) (2E,4E,6E.8E)-3,7-dimethyl-9-(2,6, hazelnut, brazil nut and walnut, and derivatives, esters, salts 6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol is and mixtures thereof. also known as vitamin A, vitamin A alcohol, retinal, vitamin 0437. In an embodiment, the therapeutic agent is a vaso A. vitaminA, alcohol, axerophtholoraxerol. Compound (II) constrictor. Suitable vasodilators include but are not limited also known as vitamin A aldehyde, vitamin A aldehyde, to ephedrine, epinephrine, phenylephrine, angiotensin, vaso retinene or retinene and retinal or, if liable to be confused pressin; an extract ephedra sinica (ma huang), polygonum with the adjective retinal (pertaining to the retina), retinalde bistorta (bistort root), hamamelis Virginiana (witch hazel), hyde. Compound (III) also known as tretinoin (see note), hydrastis canadensis (goldenseal), lycopus virginicus (bu Vitamin A acid or vitamin A acid should be designated ret gleweed), aspidosperma quebracho (quebracho blanco), inoic acid. Compound (IV), is known as axerophthene. Func cytisus scoparius (Scotch broom) and cypressand and deriva tional substitution at the 15 position of the basic hydrocarbon tives, esters, salts and mixtures thereof. is denoted by the use of the group names retinyl (R is CH ) or retinylidene (R is CH=), with retention of the original Retinoid Agents numbering of the basic hydrocarbon. For example (V) is 0438. In an embodiment, the active agent is a retinoid. retinyl acetate and (VI) is retinylamine. Derivatives of retinal 0439. In the context of the present invention, a retinoid is include for example Compound (VII)— retinal oxime and a compound a class of compounds consisting of four iso Compound (VII) N-retinylidene-L-lysine. Other deriva prenoid units joined in a head-to-tail manner, and derivatives, tives of retinoic acid, named as carboxylic acid derivatives salts, structural analogs and functional analogs thereof, as Compound (IX)— ethyl retinoate and Compound (X)-1-O- reviewed hereinina non-limiting fashion. Typically, retinoids retinoyl-b-D-glucopyranuronic acid. may be formally derived from a monocyclic parent com 0443 Retinoids that differ in hydrogenation level from the pound containing five carbon-carbon double bonds and a parent structure (displayed above) are named by use of the functional group at the terminus of the acyclic portion. prefixes hydro and dehydro together with locants specify 0440 Suitable, but non-limiting, retinoids for use in the ing the carbon atoms at which hydrogen atoms have been present invention are listed below. added or removed. Examples of Such retinoid compounds are 0441. It is convenient to omit the explicit representation of Compound (XI)-3,4-Didehydroretinol (also known as dehy C and H atoms in the parent skeletal structure of retinoids as droretinol or vitamin A) and Compound (XII)-4,5-Didehy follows: dro-5,6-dihydroretinol (also known as alpha-Vitamin A).

(I) R = CH-OH (VI) R = CH-NH2, (II) R = CHO (VII) R = CH=NOH (III) R = COH (VIII) R = CH=NCHCHNHCO2H (IV) R = CH (IX) R = CO-C2H5

(V) R = CHOCOCH, COOH (X) R- = HO O-CO OH

Compound (XI) Compound (XII)

N1 N1 N1 N. OH 1N1-S-1N1S OH US 2008/0206161 A1 Aug. 28, 2008 46

-continued Compound (XIII) Compound (XIV) OCH5 1N1-S-1N1S OH S1s-1s-1s O O 5 F

Compound (XV) Compound (XVI)

------>n n N N N N OH 2 N N N N R O

CHO1

Compound (XVII) Compound (XVIII) R OH

2 N1 N1N1 N. O 2 1N1s-1s-1s O cHo-1 Y 3 5 R = OCHs O

Compound (XIX) Compound (XX)

21Ne. Nea Yea ar 2n-4N4N4N OCOCH

4

Compound (XXI) Compound (XXII)

R = COCH

Compound (XXIII) Compound (XXIV)

N1N1 N1 N. enan-1\4N4. N-s R y US 2008/0206161 A1 Aug. 28, 2008

-continued Compound (XXV) Compound (XXVI) COOH COOH N O

Compound (XXVII) O

21 OCH2CH N 2 N

S Compound (XXVIII)

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

Compound (XXIX) OH s1s1s1s1s1s1s1s1s

HO

0444 Substituted derivatives of retinoids are exemplified 0445 Arotinoids or retinoidal benzoic acid derivatives by Compound (Xiii)-5,6-Epoxy-5,6-dihydroretinol (also contain, aromatic rings replacing either the basic B-ionone known as hepaxanthin) and Compound (XIV)—Ethyl type ring structure or unsaturated bonds of the tetraene side 12-fluororetinoate. Seco Retinoids are exemplified by Com chain of the parent retinoid skeleton, as exemplified by Com pound (XV)—1.6-Seco-1,2-didehydroretinol, also known as pound (XXV) and Compound (XXVI)—6-3-(1-adamantyl)- g-vitaminA, and Nor Retinoids, which result from the elimi 4-methoxyphenyl-2-naphthoic acid, also known as ada nation of a CH, CH, CH or C group from a retinoid are exemplified by Compound (XVI)-N-Ethyl-3-methoxy-2-me palene. Several artinoids, possessing potent retinoid thyl-17-nor-1,2,3,4-tetradehydroretinamide (also known as properties, including but not limited to short retinoids, short motretinide), Compound (XVII)— Ethyl 3-methoxy-2-me heterocyclic retinoids, isoxazole-containing retinoids, het thyl-17-nor-1,2,3,4-tetradehydroretinoate (also known as erocyclic isoxazole-containing retinoids, isoxazoline-con etretinate), acitretin (Compound (XVII), wherein R—H) and taining retinoids, stilbene retinoid analogs, are disclosed in Compound (XVIII)-5-Acetyl-4,18-dinor-retinoic acid. Retro Pure Appl. Chem. Vol. 73, No. 9, pp. 1437-1444, 2001. Retinoids are exemplified by Compound (XIX)-4,5-Didehy 0446 Tazarotene (Ethyl 6-2-(4,4-dimethylthiochroman dro-15.5-retro-deoxyretinol (also known as anhydro Vitamin 6-yl)ethynylnicotinate) is exemplary to a retinoid precur A and Compound (XX)-4, 14-retro-Retinyl acetate. Stereoi sor Compound (XXVII), suitable as retinoid for use in the somers of retinoids are exemplified by Compound (XXI)- present invention. (3R)-3-Hydroxyretinol and Compound (XXII)-(3R)-3-Ac 0447 Yet, other non-limiting exemplary retinoid precur etoxyretinol. Other stereochemical isomers can are sors are , such as all-trans beta carotene Com exemplified by Compound (XXIII)-13-cis-Retinoic acid or pound (XXVIII), alpha carotene, and 9-cis-beta (7E9E, 11E,13Z)-retinoic acid (also known as isotretinoin) carotene, as well as Xanthophils (also termed and Compound (XXIV)-(6E.8E, 10E, 12E. 15Z)-4,14-retro "oxicarotenoids’), such as lutein and Zeaxanthin Com Retinaloxime. pound (XXIX). US 2008/0206161 A1 Aug. 28, 2008 48

0448 Salts and derivatives of retinoid compounds are also two main components in foods are retinol and the caro suitable as “retinoid for use in the present invention. tenoids. Retinoid refers to the chemical entity retinol or 0449 Retinoid compounds can be ascertained recognized other closely related naturally occurring derivatives. These and identified by methods known in the art. One method include: retinal (retinaldehyde); retinoic acid; and retinyl involves the use of competitive nuclear retinoic acid (RA and esters (e.g. retinyl acetate, retinyl palmitate, retinyl propi RX) receptor binding assays for identifying compounds onate). Retinoids also include structurally related synthetic which bind directly to the receptors. For instance, J. J. Repa et analogues which may or may not have retinol-like activity. al., “All-trans-retinol is a ligand for the retinoic acid recep Vitamin A (in the form of retinal) is essential for normal tors', Proc. Natl. Acad. Sci. USA, Vol. 90, pp. 7293-7297, function of the retina and particularly for visual adaptation to 1993, discloses a competitive RA receptor binding assay darkness. Other forms (retinol, retinoic acid) are necessary based on human neuroblastoma cell nuclear extracts. H. for maintenance of the structural and functional integrity of Torma et al. (1994) “Biologic activities of retinoic acid and epithelial tissue and the immune system, cellular differentia 3,4-dehydroretinoic acid in human keratinoacytes are similar tion and proliferation, bone growth, testicular and ovarian and correlate with receptor affinities and transactivation prop function and embryonic development. It may act also as a erties.J. Invest. Dermatology, Vol. 102, pp. 49-54) discloses co-factor in biochemical reactions. Deficiency can amongst assays for measuring binding affinities for the nuclear retinoic other things result in skin dryness and papular eruptions. acid receptors and for measuring transcriptional activation Vitamin A and its derivatives have the ability to normalize induction. M. F. Boehm et al. (1994) “Synthesis of high keratinization. Note that vitamin C may ameliorate the toxic specific activity. Sup.3H-9-cis-retinoic acid and its applica effects of vitamin A; that large doses increase the need for tion for identifying retinoids with unusual binding proper Vitamin E; and that Vitamin E protects against the oxidative ties.J. Med. Chem. Vol. 37, pp. 408-414) discloses a ligand destruction of vitamin A. Retinol is susceptible to breakdown binding assay and a receptor/reporter cotransfection assay for from oxygen and light. Synthetic retinoids may be used for monitor regulation of gene expression. EP 0552 612 A2, skin problems (e.g. Acne). published Jul. 28, 1993, describes ligand-binding trapping assays based on incubation of radiolabeled compounds with 0457 According to certain embodiments the retinoid is transfected COS-1 cells which express RA and RX receptors. selected from the group consisting of: (1) a compound con 0450 Mixtures of these retinoids may also be employed sisting of four isoprenoid units joined in a head-to-tail man according to the present invention. ner, a compound having the formula: 0451 Suitable retinoids include but are not limited to ret inol, retinal, retinoic acid, all-trans retinoic acid, isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein and Zeaxanthin. 0452. In an embodiment, the therapeutic agent is selected from the group consisting of an immunosuppressants and immunoregulating agents. Suitable immunosuppressants and immunoregulating agents include but are not limited to cyclic peptides, such as cyclosporine, tacrolimus, tresperimus, pimecrolimus, Sirolimus (rapamycin), Verolimus, laflunimus, 0458 where R is selected from the group consisting of H, laquinimod, imiquimod derivatives, esters, salts and mixtures alkyl, aryl, alkenyl, benzyl, CHOH, CHNH, CHO, thereof. In one or more embodiments, the immunomodulator CH=NOH, COH, CH=NCHCHNHCOH, CH, is a calcineurin Inhibitor. COCH, CHOCOCH, a heteroatom, a saccharide and a 0453. In an embodiment, the therapeutic agent is a wart ; (2) a compound selected from the group con remover. Suitable wart removers includebut are not limited to sisting of a hydro retinoid, a dehydro retinoid, 3,4-Didehy imiquimod, podophyllotoxin and derivatives, esters, salts and droretinol, 4.5-Didehydro-5,6-dihydroretinol, a substituted mixtures thereof. derivative of a retinoid, 5,6-epoxy-5,6-dihydroretinol, ethyl 12-fluororetinoate, a seco retinoid, 1.6-Seco-1,2-didehy Vitamin droretinol, a nor retinoid, (3) a compound which results from the elimination of a CH, CH, CH or C group from a retinoid, 0454. The term vitamin includes those vitamins and N-ethyl-3-methoxy-2-methyl-17-nor-1,2,3,4-tetradehy derivatives thereof (including salts) which are officially rec droretinamide, ethyl 3-methoxy-2-methyl-17-nor-1,2,3,4- ognized as vitamins, and those vitamins which were once tetradehydroretinoate, 5-acetyl-4,18-dinor-retinoic acid, a recognized or designated as vitamins but are now classified in retro retinoid, 4,5-didehydro-15.5-retro-deoxyretinol, 4,14 another way (e.g. vitamin F) and pseudo Vitamins including retro-retinyl acetate, a stereoisomer of a retinoid, (3R)-3- those Substances which are a member of a group or complex hydroxyretinol, (3R)-3-Acetoxyretinol, (7E9E, 11E. 13Z)- but are not formally recognized (e.g. para-aminobenzoic acid retinoic acid, (6E.8E, 10E, 12E. 15Z)-4,14-retro (PABA), which is claimed to prevent greying hair and to be retinaloxime, an arotinoids, a retinoidal benzoic acid useful as an anti aging Supplement) and also vitamin mimet derivative, 6-3-(1-adamantyl)-4-methoxyphenyl-2-naph ics, which have vitamin like properties or effects. thoic acid, a short retinoid, a short heterocyclic retinoid, an 0455 Suitable vitamins include vitaminA, vitamins of the isoxazole-containing retinoids, a heterocyclic isoxazole-con B complex B1, B2, B3, B5, B6, B7, B9, B12, vitamin C, taining retinoid, an isoxazoline-containing retinoid, a stil vitamins D1-D4, vitamin E, vitamin Kand so called vitamin bene retinoid analog, a retinoid precursor, (ethyl 6-2-(4.4- F and a derivative thereof and combinations thereof. dimethylthiochroman-6-yl)ethynylnicotinate, a carotene, a 0456 Vitamin A is a fat-soluble vitamin and describes Xanthophil and an oxicarotenoid; (4) a compound selected compounds that exhibit the biological activity of retinol. The from the group consisting of retinol, retinal, retinoic acid, US 2008/0206161 A1 Aug. 28, 2008 49 all-trans retinoic acid, isotretinoin, tazarotene, adapalene, 0464 Vitamin B is water soluble vitamin. Vitamin B a 13-cis-retinoic acid, acitretin, all-trans beta carotene, alpha generic term used to describe the compounds that exhibit the carotene, lycopene, 9-cis-beta-carotene, lutein and Zeaxan biological activity of . It occurs in food as pyridox thin; (5) a compound that is positively identified using a ine, pyridoxal and . Vitamin B is converted in laboratory method, Suitable of detecting a retinoid, and salts erythrocytes to and, to a lesser extent, and derivatives thereof. pyridoxamine phosphate. It acts as a co-factor for enzymes 0459 Vitamin B is known as the vitamin B complex and which are involved in more than 100 reactions that affect comprises B (), B (), B (), Bs protein, lipid and metabolism. Pyridoxal phos (), B (pyridoxine), B., (), Bo (folic phate is also involved in: the synthesis of several neurotrans acid) and B (). Adequate amounts of all B mitters; the metabolism of several vitamins (e.g. The conver Vitamins are required for optimal functioning; deficiency or sion of to niacin); haemoglobin and sphingosine excess of one B may lead to abnormalities in the metabolism formation. Lack of Vitamin B may affect vitamin C. of another. Examples are pyridoxine hydrochloride and pyridoxine dio 0460. Thiamine is a water soluble vitamin and is also Ctanate. known as aneurine and functions as a co-enzyme in the oxi 0465 Biotin is a water soluble vitamin which was for dative decarboxylation of alpha ketoacids (involved in energy merly known as vitamin H or co-enzyme R. Biotin functions production) and in the transketolase reaction of the as an integral part of the enzymes that transport carboxyl units phosphate pathway (involved in carbohydrate metabolism). and fix carbon dioxide. Biotin enzymes are important in car Thiamine is also important in nerve transmission (indepen bohydrate and lipid metabolism, and are involved in gluco dently of co-enzyme function). It may also act as an insect neogenesis, fatty acid synthesis, propionate metabolism and repellant. the catabolism of amino acids. Biotin has been claimed to be 0461 Riboflavin is a water soluble vitamin and functions of value in the treatment of brittle finger nails, acne, sebor as a component of two flavin co-enzymes—flavin mono rhoeic dermatitis, hair fragility and alopecia. nucleotide (FMN) and flavin dinucleotide (FAD). It 0466 Folic acid (pteroylglutamic acid) is a water soluble participates in oxidation-reduction reactions in numerous Vitamin and is the parent compound for a large number of metabolic pathways and in energy production. Examples derivatives collectively known as . is the generic include: the oxidation of glucose, certain amino acids and term used to describe the compounds that exhibit the biologi fatty acids; reactions with several intermediaries of the Krebs cal activity of folic acid; it is the preferred term for the vitamin cycle; conversion of pyridoxine to its active co-enzyme; and present in foods which represents a mixture of related com conversion of tryptophantoniacin. Riboflavin has a role as an pounds (folates). Folates are involved in a number of single antioxidant. It may be involved in maintaining the integrity of carbon transfer reactions, especially in the synthesis of erythrocytes. Common forms are riboflavin, riboflavin purines and pyrimidines (and hence the synthesis of DNA), butyrate and flavin adenine dinucleotide. glycine and . They are also involved in some 0462 Niacin is a water-soluble vitamin and describes the amino acid conversions and the formation and utilization of compounds that exhibit the biological properties of nicotina formate. Deficiency leads to impaired cell division (effects mide. It occurs as and nicotinic acid. It is some most noticeable in rapidly regenerating tissues). times known as niacinamide. An example of a derivative is 0467 Vitamin B is a water-soluble vitamin and it is the benzyl nicotinate. Niacin functions as a component of two generic term used to describe the compounds that exhibit the co-enzymes, nicotinamide adenine dinucleotide (NAD) and biological activity of cyanocobalamin. It includes a range of nicotinamide adenine dinucleotide diphosphate (NADP). -containing compounds, known as cobalamins. Cyano These co-enzymes participate in many metabolic processes cobalamin and hydroxocobalaminare the two principal forms including glycolysis, tissue respiration, lipid, amino acid and in clinical use. Vitamin B is involved in the recycling of purine metabolism. It has been shown to have ant-inflamma folate co-enzymes and the degradation of valine. It is also tory properties that result in the improvement of acne. Topi required for nerve myelination, cell replication, haemato cally it has showed benefit for various skin conditions includ poiesis and nucleoprotein synthesis. ing psoriasis and rosacea. It has also been said to have a photo 0468 Vitamin C is a water-soluble vitamin and describes protection role, perhaps through anti-oxidant activity and the compounds that exhibit the biological activity of ascorbic reduces or prevents UV damage to cells and UV induced acid. These include L-ascorbic acid (ascorbic acid) and L-de disorders. hydroascorbic acid (). The functions of 0463 Pantothenic acid is also a water soluble vitamin and Vitamin C are based mainly on its properties as a reducing functions mainly as a component of co-enzyme A and acyl agent. It is required for: the formation of collagen and other carrier protein. Co-enzyme A has a central role as a co-factor organic constituents of the intercellular matrix in bone, teeth for enzymes involved in the metabolism of lipids, carbohy and capillaries; and the optimal activity of several enzymes— drates and proteins; it is also required for the synthesis of it activates certain liver-detoxifying enzyme systems (includ cholesterol, Steroid hormones, acetylcholine and porphyrins. ing drug-metabolizing enzymes) and is involved in the Syn As a component of acyl carrier protein, pantothenic acid is thesis of and norepinephrine (noradrenaline) and in involved in various transfer reactions and in the assembly of the metabolism of folic acid, histamine, , tryp acetate units into longer-chain fatty acids. Pantothenic acid tophan and tyrosine. Vitamin C also acts: as an antioxidant has been used for a wide range for disorders such as acne, (reacting directly with aqueous free radicals)—which is alopecia, allergies, burning feet, asthma, grey hair, dandruff, important in the protection of cellular function; and to and cholesterol lowering. Panthenol the alcoholic form func enhance the absorption of non-haem iron. It can function as a tions as a humetic. Examples of pantothenic acid derivatives whitening agent. Vitamin C may assist with wound healing. are calcium pantothenate, D-pantothenyl alcohol, pantoth Vitamin C can spare vitamin E and vice versa and it may enyl ethyl ether, and acetylpentothenyl ethyl ether. reduce toxic effects of vitamin A. Vitamin C is unstable in US 2008/0206161 A1 Aug. 28, 2008 50

Solution especially alkaline Solution and readily undergoes qualitatively the biological activity of . The oxidation on exposure to air. Oxidation is accelorated by light form of vitamin K present in foods is phytomenadione (vita and heat. Cosmetic forms include calcium ascorbate, magne min K). The Substances synthesized by bacteria are known as sium ascorbate, Sodium ascorbate, Sodium ascorbyl phos menaquinones (vitamin K). The parent compound of the phate, ascorbyl palmitate, magnesium ascorbyl phosphate, vitamin K series is known as (vitamin Ks); it is not L-ascorbic acid and magnesium-L-ascorbyl-2-phosphate, natural Substance and is not used in humans. L-ascorbic acid palmitate, L-ascorbic acid 2-sulfate, L-ascor sodium phosphate is water-soluble derivative of menadione. bic acid phosphate, and DL-.alpha--L-ascorbic Vitamin K is an essential co-factor for the hepatic synthesis of acid phosphate diester dipotassium. L-ascorbic acid is the proteins involved in the regulation of blood clotting. These most bioactive form and has been found to have many skin benefits but it is unstable in the presence of water and oxygen. are: prothrombin (factor II), factors VII, IX, X and proteins C, Inclusion of ascorbic acid in the vitamin carrier, wherein the S and Z. Vitamin K is responsible for the carboxylation of the composition does not contain or is essentially free of water or bone protein, , to its active form. Osteocalcin wherein water is not freely available due to the hygroscopic regulates the function of calcium in bone turnover and min properties of the composition r and or is not exposed to air eralisation. Vitamin K is also required for the of during storage makes it possible to derive stable products Some other proteins found in plasma and the . It is with the most bioactive form of vitamin C. reported to speed up resolution of bruising to decrease future 0469 Vitamin D is a fat-soluble vitamin and describes all bruising and correct aspects of photoaging. sterols that exhibit the biological activity of cholecalciferol. 0472. Pseudo vitamins: Vitamin F was the designation These include: vitamin D (calciferol), vitamin D (ergocal originally given to essential fatty acids that the body cannot ciferol) vitamin D (cholecalciferol), 1 (OH)D (1 Hydroxy manufacture. They were “de-vitaminized' because they are cholecalciferol; alfacalcidol), 25(OH)D (25 Hydroxychole fatty acids. Fatty acids are a major component of fats which, calciferol; ), 1.25(OH),D, (1.25, like water, are needed by the body in large quantities and thus Dihydroxycholecalciferol; calcitriol), 24.25(OH)D (24.25. do not fit the definition of vitamins which are needed only in Dihydroxycholecalciferol) and dihydrotachysterol, calcipot trace amounts. Herbalists and naturopaths have named vari riene, 25-hydroxycholecalciferol, 1C.,25-dihydroxycholecal ous therapedic chemicals “vitamins’, even though they are ciferol, 11,25-dihydroxyergocalciferol, 22.23-dihydroergo not, including vitamin T. S.-Methylmethionine (vitamin U) calciferol, 1,24,25-trihydroxycholecalciferol, previtamin D, and vitamin X. Some authorities say that ubiquinone, also tachysterols (also termed tacalciol), isovitamin D, dihydro called , is a vitamin. Ubiquinone is manufac tachysterol, (1S)-hydroxycalciol, (24R)-hydroxycalcidiol, tured in small amounts by the body, like vitamin D. Pangamic 25-fluorocalciol, ercalcidiol, ertacalciol, (5E)-isocalciol, acid, vitamin Bis; the related Substance dimethylglycine is 22.23-dihydroercalciol, (24S)-methylcalciol, (5E)-(10S)-10, quite wrongly referred to as vitamin Bls but also labeled B. 19-dihydroercalciol, (24S)-ethylcalciol and (22E)-(24R)- The toxins laetrile and amygdaline are sometimes referred to ethyl-22.23-didehydrocalciol. Vitamin D is essential for pro as vitamin B7. Both pangamic acid and laetrile were first moting the absorption and utilisation of calcium and proposed as vitamins by Ernst T. Krebs; neither are recog , and normal calcification of the skeleton. Along nized by the medical community. are sometimes with and calcitonin, it regulates serum called vitamin P. Animal, bird, and bacterial growth factors calcium concentration by altering serum calcium and phos have been designated vitamins such as para-aminobenzoic phate blood levels, as needed, and mobilizing calcium from acid (PABA) vitamin Bo, the folacin (see folic acid) pteryl bone. It maintains neuromuscular function and various other heptaglutamic acid vitamin B or vitamin Bc-conjugate and cellular processes, including the immune system. Calcipot orotic acid as vitamin B. A few substances were once riene, as well as other vitamin C forms is useful in the treat thought to be B-complex vitamins and are referred to as ment of psoriasis. B-vitamins in older literature, including B (adenine) and Bs 0470 Vitamin E is a fat-soluble vitamin and describes all (adenylic acid), but are no longer recognized as Such. An tocopherol and derivatives that exhibit the bio antitumor pterin phosphate named Vitamin Ba and later logical activity of alpha tocopherol. Those used commer abandoned. cially are d-alpha tocopherol (natural vitamin E), d-alpha 0473 Vitamins as antioxidants. The antioxidant vitamins tocopherol acetate, d-alpha tocopherol Succinate, d.l-alpha can be divided into those that are water-soluble and exist in tocopherol (synthetic vitamin E), d.l-alpha tocopherol acetate aqueous Solution primarily vitamin C and those that are and d.l-alpha tocopherol Succinate. Vitamin E is an antioxi fat-soluble and exist in membranes or lipoproteins—Vitamin dant, protecting polyunsaturated fatty acids in membranes E and betacarotene. Lipid membranes are particularly Vulner and other critical cellular structures from free radicals and able to oxidative breakdown by free radicals. Vitamin E pro products of oxidation. It works in conjunction with dietary tects cell membranes from destruction by undergoing prefer Selenium (a co-factor for peroxidase), and also ential oxidation and destruction. Some quinones, such as with vitamin C and other enzymes, including Superoxide ubiquinone (co-enzyme Q) also appear to have antioxidant dismutase and catalase. Vitamin E is not very stable. It may properties. All these Substances can act as free radical scav have an anti-inflammatory effect and some studies state that it engers and can react directly with free radicals. Riboflavin improves immune function in the elderly. It is also said to also has a role as an antioxident. reduce oxidative damage and to improve lung function. Vita 0474 They are believed to protect against certain diseases min E can spare vitamin Cand Vice versa. It is said to be photo by preventing the deleterious effects of free-radical-mediated protective and to have an anti aging effect on skin showing processes in cell membranes and by reducing the Susceptibil reduced wrinkles and tumors ity of tissues to oxidative stress. An article by MP Ludo 0471 Vitamin K is a fat soluble vitamin and describes entitled "Antioxidants and Vitamins in Cosmetics' Clinics in 2-methyl-1,4-naphthaquinone and all derivatives that exhibit Dermatology (2001): 19:467-473 discusses the benefits of US 2008/0206161 A1 Aug. 28, 2008

Vitamins and derivatives in cosmetics. Note that as well as photosensitiser precursors, such as aminolevulinic and flavonoids also act as antioxidants acid and derivatives, esters, salts and mixtures thereof. 0475 Synergism between vitamins is known, for example, 0494. In an embodiment, the therapeutic agent is an anti synergism between vitamin A and vitamin E is described by oxidant or a radical scavenger. Suitable antioxidants and radi Gallarate, Carlofti, Trotta, and Bovo in the International Jour cal scavengers agents include but are not limited to ascorbic nal of Pharmacuetics 188 (1999) 233-241 discussing a study acid, ascorbylesters offatty acids, magnesiumascorbyl phos on the stability of ascorbic acid. Any synergism known in the phate, sodium ascorbyl phosphate, ascorbyl Sorbate, toco literature between vitamins to potentiate or facilitate their pherol, tocopheryl Sorbate, tocopheryl acetate, butylated action can be used in the present invention. Details of the hydroxy benzoic acid, 6-hydroxy-2,5,7,8-tetramethylchro solubility of vitamins can be found for example in the Merck man-2-carboxylic acid, , propyl gallate, , Index and other similar reference works and databases. Sorbic acid, lipoic acid, diethylhydroxylamine, amino-guani 0476. In one or more embodiment, the surface active agent dine, glutathione, dihydroxy fumaric acid, lycine pidolate, can range from about less than 0.1% up to about 15% or up to arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, about 20% by weight of composition depending on the sur , lysine, methionine, , , factant selected or preferably is about 0.2% to about 0.5% by silymarin, tea extracts, grape skin/seed extracts, melanin, and weight of composition. polyunsaturated oils, containing omega-3 and omega-6 fatty 0477. In one or more embodiments, the vitamin is selected acids (e.g., linoleic and linolenic acid, gamma-linoleic acid, from the group consisting of vitaminA, B, B2, Bs, Bs, B, B7, eicosapentaenoic acid and docosahexaenoic acid and deriva B. B. PABA, C, D-D, E, Kand F and a derivative thereof. tives, esters, salts and mixtures thereof. 0478. In another embodiment, the vitamin or a derivative 0495. In an embodiment, the therapeutic agent is a self thereof is susceptible to oxidation. tanning agent, such as dihydroxyacetone. 0479. In a further embodiment, the vitaminor a derivative 0496. In an embodiment, the therapeutic agent is an agent, thereof is soluble in water. capable of treating hyperhidrosis. Suitable hyperhidrosis 0480. In another embodiment, the vitamin is selected from agents include but are not limited to anticholinergic drugs, the group consisting of vitamin B, B2, Bs, Bs, B, B7, Bo, boric acid, tannic acid, resorcinol, potassium permanganate, B. PABA and C and a derivative thereof. formaldehyde, glutaraldehyde, methenamine, a Lewis acid, 0481. In an embodiment, the vitamin is vitamin B3 or a aluminum chloride, aluminum chlorohydrates, Zirconium derivative thereof or combinations thereof. chlorohydrates, aluminum-zirconium-Glycine (AZG) com 0482 In an embodiment, the vitamin is vitamin C or a plex, aluminum hydroxybromide, a glycopyrrolate com derivative thereof or combinations thereof. pound, a 5-alpha-reductase inhibitor, finasteride, , 0483. In an embodiment, the vitamin is the vitamin is , Spironolactone, saw palmetto extract, cholestan-3- vitamin K or a derivative thereof or combinations thereof. one, a mono- and dicarboxylic acid having 4 to 18 carbon 0484. In an embodiment, the vitamin is vitamin A or a atoms, botulinum toxin, a 5-HT2C receptor antagonist, a derivative thereof or combinations thereof. 5-HT2C receptor antagonist, ketanserin, ritanserin, 0485. In an embodiment, the vitamin is vitamin E or a , meSulergine, , fluoxetine, mirtaza derivative thereof or combinations thereof. pine, olanzapine and Ziprasidone. 0486 In an embodiment, the vitamin is the vitamin is 0497. In an embodiment, the additional therapeutic agent vitamin F or a derivative thereof or combinations thereof. is a Sunscreen agent. Suitable Sunscreen agents include but 0487. In one or more embodiments, the vitamin is a com are not limited to titanium dioxide, Zinc oxide, Zirconium bination of two or more vitamins selected from the group oxide, iron oxide, p-aminobenzoic acid and its derivatives comprising vitamin A, B, C, K, E, and F and a derivative (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); anthranilic acid derivatives (i.e., o-amino-benzoates, thereof. methyl, menthyl, phenyl, benzyl, phenylethyl, linallyl, terpi 0488. In an embodiment, the vitamin or a derivative nyl, and cyclohexenyl esters); Salicylates (amyl, phenyl, thereof or combinations thereof comprises an antioxident. octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol 0489. In another embodiment, the vitamin or a derivative esters); cinnamic acid derivatives (menthyl and benzyl esters, thereof or combinations thereof improves stimulates or pro a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); dihy motes target site metabolism. droxycinnamic acid derivatives (umbelliferone, methylum 0490. In a still further embodiment, the vitamin or a belliferone, methylaceto-umbelliferone); trihydroxy-cin derivative thereof or combinations thereof alleviates, amelio namic acid derivatives (esculetin, methylesculetin, rates, treats, prevents, retards or otherwise has a beneficial daphnetin, and the glucosides, esculin and daphnin); hydro effect on a skin or boy cavity condition. carbons (diphenylbutadiene, stilbene): dibenzalacetone and 0491. In an embodiment, the skin condition is selected benzalacetophenone; naphtholsulfonates (sodium salts of from the group consisting of skin pigmentation, dry skin, a 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic Wound, acne, psoriasis and skin aging. acids); di-hydroxynaphthoic acid, o- and p-hydroxybiphe 0492. In one or more embodiments, the vitamin is a com nyldisulfonates, derivatives (7-hydroxy, 7-methyl, bination of two or more vitamins selected from the group 3-phenyl), diazoles (2-acetyl-3-bromoindazole, phenylben comprising vitamin B, E and C and a derivative thereof. ZOxazole, methylnaphthoxazole, quinine salts (bisulfate, Sul 0493. In an embodiment, the therapeutic agent is a photo fate, chloride, oleate, and tannate); derivatives dynamic therapy (PDT) agent. Suitable PDT agents include (8-hydroxyquinoline salts, 2-phenylduinoline); hydroxy- or but are not limited to modified porphyrins, chlorins, bacterio methoxy-Substituted benzophenones; uric and violuric acids; chlorins, phthalocyanines, naphthalocyanines, pheophor tannic acid and its derivatives (e.g., hexaethylether); (butyl bides, purpurins, m-THPC, mono-L-aspartyl chlorine6, bac carbotol) (6-propyl piperonyl)ether; hydroquinone; ben teriochlorins, phthalocyanines, benzoporphyrin derivatives, Zophenones (oxybenzene, Sulisobenzone, dioxybenzone, US 2008/0206161 A1 Aug. 28, 2008 52 benzolesorcinol, 2,2,4,4-tetrahydroxybenzophenone, 2,2'- viscosity is in the range of between about 35 CST and about dihydroxy-4,4'-dimethoxybenzophenone, octabenzone; 100 CST (at 40°C.), and its pour point (the lowest tempera 4-isopropyldibenzoylmethane; butylmethoxydibenzoyl ture at which an oil can be handled without excessive amounts methane: etocrylene; octocrylene; 3-(4-methylbenzylidene of wax crystals forming so preventing flow) is below 0°C. bornan-2-one), terephthalylidene dicamphor Sulfonic acid The term “hydrophobic organic carrier does not include and 4-isopropyl-di-benzoylmethane. thick or semi-solid materials, such as white petrolatum, also 0498. In an embodiment, the additional therapeutic agent termed “Vaseline', which, in certain compositions is disad is a figure-forming agent and an agent, capable of treating Vantageous due to its waxy nature and semi-solid texture. cellulite. Suitable such agents include but are not limited to 0505 According to one or more embodiments, hydropho baldderwack extract, butcher's broom, cayenne, dandelion, bic solvents are liquid oils originating from vegetable, marine red clover, ginkgo biloba, horse chestnut, witch hazel and or animal sources. Suitable liquid oil includes Saturated, borage oil, , nicotinic acid, theophiline and pen unsaturated or polyunsaturated oils. By way of example, the toxyphilline and salts and derivatives thereof. unsaturated oil may be olive oil, corn oil, oil, canola 0499. Several disorders of the skin, body cavity or oil, cottonseed oil, coconut oil, sesame oil, Sunflower oil, mucosal Surface (e.g., the mucosa or the cavity of the nose, borage seed oil, SyZigium aromaticum oil, hempseed oil, mouth, eye, ear, vagina or rectum) involve a combination of herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ etiological factors. For example, fungal and bacterial infec oil, evening primrose oils or mixtures thereof, in any propor tions and that are inflamed and have symptoms of redness tion. and/or itching warrant therapy that combines an anti-infective 0506 Suitable hydrophobic solvents also include polyun agent and an anti-inflammatory agent. Thus, in several cases, saturated oils containing poly-unsaturated fatty acids. In one combining at least two active agents that treat different etio or more embodiments, the unsaturated fatty acids are selected logical factors results in a synergistic effect and consequently from the group of omega-3 and omega-6 fatty acids. higher Success rate of the treatment. Examples of such polyunsaturated fatty acids are linoleic and 0500. In certain cases, the composition contains two active linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic agents, where each of the active agents require a different pH acid (EPA) and docosahexaenoic acid (DHA). Such unsatur environment in order to remain stable. For example, corticos ated fatty acids are known for their skin-conditioning effect, teroids are typically stable at acidic pH values (they have a which contribute to the therapeutic benefit of the present maximum stability at a pH of about 4-6) and of vitamin D foamable composition. Thus, the hydrophobic solvent can analogues are typically stable at basic pH values (they have a include at least 6% of an oil selected from omega-3 oil, maximum stability at pH values above about 8). In order to omega-6 oil, and mixtures thereof. In this context, oils that circumvent the problem of instability in Such cases a dual possess therapeutically-beneficial properties are termed applicator can be used, one canister with bnV at acidic pH and “therapeutically active oils.” the other canister at alkali pH. Alternatively, one of the active 0507 Another class of hydrophobic solvents is the essen ingredients could be provided as a precurser, which is more tial oils, which are also considered therapeutically active oil, stable. which contain active biologically occurring molecules and, 0501. Wheneverthere is reference to an active agent and or upon topical application, exert a therapeutic effect, which is derivatives the reference includes, derivatives, conjugates, conceivably synergistic to the beneficial effect of the steroid analogues, prodrugs, chelates, complexes, ions, isomers, in the composition. enantimers, and salts thereof. 0508 Another class of therapeutically active oils includes liquid hydrophobic plant-derived oils, which are known to Hydrophobic Solvent possess therapeutic benefits when applied topically. 0502. The foamable composition can be an emulsion, or 0509 Silicone oils also may be used and are desirable due microemulsion, including an aqueous phase and an organic to their known skin protective and occlusive properties. Suit carrier phase. The organic carrier is selected from a hydro able silicone oils include non-volatile silicones, such as poly phobic organic carrier (also termed herein “hydrophobic sol alkyl siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes Vent'), an emollient, a polar solvent, and a mixture thereof. and polyether siloxane copolymers, polydimethylsiloxanes 0503 A “hydrophobic organic carrier as used herein, (dimethicones) and poly(dimethylsiloxane)-(diphenyl-silox refers to a material having solubility in distilled water at ane) copolymers. These are chosen from cyclic or linear ambient temperature of less than about 1 gm per 100 mL. polydimethylsiloxanes containing from about 3 to about 9, more preferable less than about 0.5gm per 100 mL, and most preferably from about 4 to about 5, silicon atoms. Volatile preferably less than about 0.1 gm per 100 mL. It is liquid at silicones such as cyclomethicones can also be used. Silicone ambient temperature. The identification of a hydrophobic oils are also considered therapeutically active oil, due to their organic carrier or “hydrophobic solvent, as used herein, is barrier retaining and protective properties. not intended to characterize the solubilization capabilities of 0510. In one or more embodiments, the hydrophobic car the solvent for any specific active agent or any other compo rier includes at least 2% by weight silicone oil or at least 5% nent of the foamable composition. Rather, Such information is by weight. provided to aid in the identification of materials suitable for 0511. The solvent may be a mixture of two or more of the use as a hydrophobic carrier in the foamable compositions above hydrophobic solvents in any proportion. described herein. 0512. A further class of solvents includes “emollients’ 0504. In one or more embodiments, the hydrophobic that have a softening or soothing effect, especially when organic carrier is an oil. Such as mineral oil. Mineral oil applied to body areas, such as the skin and mucosal Surfaces. (Chemical Abstracts Service Registry number 8012-95-1) is a Emollients are not necessarily hydrophobic. Examples of mixture of aliphatic, naphthalenic, and aromatic liquid hydro Suitable emollients include hexyleneglycol, propylene gly carbons that derive from petroleum. It is typically liquid; its col, isostearic acid derivatives, isopropyl palmitate, isopropyl US 2008/0206161 A1 Aug. 28, 2008 isostearate, diisopropyl adipate, diisopropyl dimerate, male ring polymeric materials, such as locust gum, sodium ated , octyl palmitate, cetyl lactate, cetyl ricino alginate, Sodium caseinate, egg albumin, gelatin agar, carra leate, tocopheryl acetate, acetylated lanolin alcohol, cetyl geenin gum, Sodium alginate, Xanthan gum, quince seed acetate, phenyl trimethicone, glyceryl oleate, tocopheryl extract, tragacanth gum, guar gum, starch, chemically modi linoleate, wheat germ glycerides, arachidyl propionate, myri fied Starches and the like, semi-synthetic polymeric materials styllactate, decyl oleate, propylene glycol ricinoleate, isopro Such as cellulose ethers (e.g. hydroxyethyl cellulose, methyl pyl lanolate, pentaerythrityl tetrastearate, neopentylglycol cellulose, carboxymethyl cellulose, hydroxy propylmethyl dicaprylate/dicaprate, isononyl isononanoate, isotridecyl cellulose), guar gum, hydroxypropyl guar gum, Soluble isononanoate, myristyl myristate, triisocetyl citrate, octyl starch, cationic celluloses, cationic guars, and the like, and dodecanol, Sucrose esters of fatty acids, octyl hydroxy Stear synthetic polymeric materials, such as carboxyvinyl poly ate and mixtures thereof. mers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic 0513. According to one or more embodiments, the hydro acid polymers, polymethacrylic acid polymers, polyvinyl phobic organic carrier includes a mixture of a hydrophobic acetate polymers, polyvinyl chloride polymers, polyvi Solvent and an emollient. According to one or more embodi nylidene chloride polymers and the like. Mixtures of the ments, the foamable composition is a mixture of mineral oil above compounds are contemplated. and an emollient in a ratio between 2:8 and 8:2 on a weight 0519 Further exemplary gelling agents include the acrylic basis. acid/ethyl acrylate copolymers and the carboxyvinyl poly mers sold, for example, by the B.F. Goodrich Company under Polar Solvent the trademark of Carbopol R, R resins. These resins consist 0514. A “polar solvent' is an organic solvent, typically essentially of a colloidal water-soluble polyalkenyl polyether soluble in both water and oil. Examples of polar solvents crosslinked polymer of acrylic acid crosslinked with from include polyols. Such as glycerol (glycerin), propylene gly 0.75% to 2% of a crosslinking agent such as polyallyl sucrose col, hexylene glycol, diethylene glycol, propylene glycol or polyallyl pentaerythritol. Examples include CarbopolR) n-alkanols, , di-terpenes, tri-terpenes, terpen-ols, 934, Carbopol R 940, Carbopol R 950, Carbopol.R. 980, Car limonene, terpene-ol. 1-menthol, dioxolane, ethylene glycol, bopolR 951 and Carbopol R 981. Carbopol R. 934 is a water other glycols, Sulfoxides, such as dimethylsulfoxide soluble polymer of acrylic acid crosslinked with about 1% of (DMSO), dimethylformanide, methyl dodecyl sulfoxide, a polyallyl ether of Sucrose having an average of about 5.8 dimethylacetamide, monooleate of ethoxylated glycerides alkyl groups for each Sucrose molecule. (with 8 to 10 ethylene oxide units), azone (1-dodecylazacy 0520. In one or more embodiment, the composition cloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, esters, such as includes at least one polymeric agent, which is a water isopropyl myristate/palmitate, ethyl acetate, butyl acetate, soluble cellulose ether. Preferably, the water-soluble cellu methyl proprionate, capric/caprylic triglycerides, lose ether is selected from the group consisting of methylcel octylmyristate, dodecyl-myristate; myristyl alcohol, lauryl lulose, hydroxypropyl cellulose, hydroxypropyl alcohol, lauric acid, lauryl lactate ketones; amides, such as methylcellulose (Methocel), hydroxyethyl cellulose, methyl acetamide oleates Such as triolein; various alkanoic acids hydroxyethylcellulose, methylhydroxypropylcellulose, Such as caprylic acid; lactam compounds, such as aZone; hydroxyethylcarboxymethylcellulose, carboxymethylcellu alkanols, such as dialkylamino , and admixtures lose and carboxymethylhydroxyethylcellulose. More prefer ably, the water-soluble cellulose ether is selected from the thereof. group consisting of methylcellulose, hydroxypropyl cellu 0515 According to one or more embodiments, the polar lose and hydroxypropyl methylcellulose (Methocel). In one solvent is a polyethylene glycol (PEG) or PEG derivative that or more embodiments, the composition includes a combina is liquid at ambient temperature, including PEG200 (MW tion of a water-soluble cellulose ether; and a naturally-occur (molecular weight) about 190-210 kD), PEG300 (MW about ring polymeric materials, selected from the group including 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 Xanthan gum, guar gum, carrageenan gum, locust bean gum (MW about 570-630 kD) and higher MW PEGs such as PEG and tragacanth gum. 4000, PEG 6000 and PEG 10000 and mixtures thereof. 0521. Yet, in other embodiments, the gelling agent Polymeric Agent/Additive includes inorganic gelling agents, such as silicone dioxide (fumed silica). 0516. The polymeric agent serves to stabilize the foam 0522 Mucoadhesive/bioadhesion has been defined as the composition and to control drug residence in the target organ. attachment of synthetic or biological macromolecules to a Exemplary polymeric agents are classified below in a non biological tissue. Mucoadhesive agents are a class of poly limiting manner. In certain cases, a given polymer can belong meric biomaterials that exhibit the basic characteristic of a to more than one of the classes provided below. hydrogel, i.e. Swell by absorbing water and interacting by 0517. In one or more embodiments, the composition means of adhesion with the mucous that covers epithelia. includes at least one gelling agent. A gelling agent controls Compositions may contain a mucoadhesive macromolecule the residence of a therapeutic composition in the target site of or polymer in an amount Sufficient to confer bioadhesive treatment by increasing the viscosity of the composition, properties. The bioadhesive macromolecule enhances the thereby limiting the rate of its clearance from the site. Many delivery of biologically active agents on or through the target gelling agents are known in the art to possess mucoadhesive Surface. The mucoadhesive macromolecule may be selected properties. from acidic synthetic polymers, preferably having at least one 0518. The gelling agent can be a natural gelling agent, a acidic group per four repeating or monomeric Subunit moi Synthetic gelling agent and an inorganic gelling agent. Exem eties, such as poly(acrylic)- and/or poly(methacrylic) acid plary gelling agents that can be used in accordance with one (e.g., Carbopol R, CarbomerR), polycarpophil, poly(meth or more embodiments include, for example, naturally-occur ylvinyl ether/maleic anhydride) copolymer, and their mix US 2008/0206161 A1 Aug. 28, 2008 54 tures and copolymers; acidic synthetically modified natural different size particles Some bigger and some Smaller, which polymers, such as carboxymethylcellulose (CMC); neutral when moving at high speed become orientated in the direction synthetically modified natural polymers. Such as (hydrox offlow particles and their interaction decreases. The viscosity ypropyl)methylcellulose; basic amine-bearing polymers profile can be an important factor in determining what is an Such as chitosan; acidic polymers obtainable from natural appropriate pseudoplastic or semi-pseudoplastic composi Sources, such as alginic acid, hyaluronic acid, , gum tion. For example, compositions displaying Newtonian flow tragacanth, and karayagum; and neutral synthetic polymers, profiles are unsuitable. Compositions displaying non-Newto Such as polyvinyl alcohol or their mixtures. An additional nian flow or showing plastic flow are not ideal although in group of mucoadhesive polymers includes natural and chemi certain circumstances it may be possible to achieve usable cally modified cyclodextrin, especially hydroxypropyl-3-cy foamable compositions. The preferable profile is that of a clodextrin. Such polymers may be present as free acids, pseudoplastic or semi-pseudoplastic flow. bases, or salts, usually in a final concentration of about 0.01% to about 0.5% by weight. Stoke's Equation 0523) A suitable bioadhesive macromolecule is the family of acrylic acid polymers and copolymers, (e.g., CarbopolR). 0532. The velocity at which a sphere will rise or fall in a These polymers contain the general structure—CH2—CH liquid varies as the square of its diameter: (COOH)-.. Hyaluronic acid and other biologically-derived polymers may be used. 0524 Exemplary bioadhesive or mucoadhesive macro dipa -pe)reo molecules have a molecular weight of at least 50 kDa, or at V 18n least 300 kDa, or at least 1,000 kDa. Favored polymeric ionizable macromolecules have not less than 2 mole percent 0533 where V particle velocity acidic groups (e.g., COOH, SOH) or basic groups (NH2, 0534 d-particle diameter NRH, NR), relative to the number of monomeric units. The 0535 p-discrete phase density acidic or basic groups can constitute at least 5 mole percent, 0536 p-continuous phase density or at least 10 mole percent, or at least 25, at least 50 more 0537 r radius of axis of rotation percent, or even up to 100 mole percent relative to the number 0538 co-angular velocity of monomeric units of the macromolecule. 0525 Yet, another group of mucoadhesive agent includes 0539 m-continuous phase viscosity inorganic gelling agents such as silicon dioxide (fumed (0540. Note: (rico) is replaced by g, the force of gravity silica), including but not limited to, AEROSIL 200 (DE when not in a centrifugal field GUSSA). 0541. The physical stability of an emulsion can be 0526 Many mucoadhesive agents are known in the art to improved according to Stokes' law by adding appropriate also possess gelling properties. emulsifers/stabilizers to increase the viscosity of the continu 0527 The foam composition may contain a film forming ous phase and or to reduce and or maintain the droplet size. component. The film forming component may include at least 0542 Emulsifier molecules (surfactants) have hydrophilic one water-insoluble alkyl cellulose or hydroxyalkyl cellu and hydrophobic parts. They adsorb at the interface between lose. Exemplary alkyl cellulose or hydroxyalkyl cellulose the disperse phase and the continuous phase thus forming a polymers include ethyl cellulose, propyl cellulose, butyl cel dense film around the droplets of the disperse phase. This film lulose, cellulose acetate, hydroxypropyl cellulose, hydroxy prevents the coalescence of the droplets. Thus they act to butyl cellulose, and ethylhydroxyethyl cellulose, alone or in maintain droplet size. They can also encourage the formation combination. In addition, a plasticizer or a cross linking agent of smaller droplets may be used to modify the polymer’s characteristics. For example, esters such as dibutyl or diethyl phthalate, amides Such as diethyldiphenyl urea, vegetable oils, fatty acids and Dr.g . alcohols such as oleic and myristyl acid may be used in Vs = - 1st combination with the cellulose derivative. 0528. In one or more embodiments, the composition 0543 Vs Stokes sinking (or creaming) velocity includes a phase change polymer, which alters the composi 0544 Dr density differences between the phases of the tion behavior from fluid-like prior to administration to solid emulsion like upon contact with the target mucosal Surface. Such phase 0545 G-acceleration, due to gravity change results from external stimuli, such as changes in tem (0546) X-droplet diameter perature or pH and exposure to specific ions (e.g., Ca"). (0547 he dynamic viscosity of the continuous phase 0529 Non-limiting examples of phase change polymers 0548. As can be seen from above, the droplet motion can include poly(N-isopropylamide) and Poloxamer 407(R). be reduced by one or more of decreasing the droplet diameter, 0530. The polymeric agent is present in an amount in the by decreasing the density difference and by increasing the range of about 0.01% to about 5.0% by weight of the foam Viscosity of the continuous phase. composition. In one or more embodiments, it is typically less 0549. In some cases emulsions as they becomesticky also than about 1 wt % of the foamable composition. have a certain yield point caused by a hydrocolloidal stabi Pseudoplastic or Semi-pseudoplasic Agents lizer preventing floating of the oil droplet. 0550 Stabilizers are therefore selected for the purposes of 0531. Pseudoplastics or viscoelasic fluids are capable of improving resistance to creaming and are effectively care displaying a decreased Viscosity when shear stress is fully selected thickening agents and or emulsifiers. In one or increased. This behavior is typical of Suspensions made of more embodiments, appropriate effective amounts of thick US 2008/0206161 A1 Aug. 28, 2008

ening agents are dissolved in the continuous phase to increase plex emulgator, combination of surfactant and foam adjuvant its viscosity or create a yield point. This restricts the move and the like is selected Such that the range of particle size or ability of the droplets such that less collisions between the range of average particle size in the emulsion prior to filling of droplets occur thereby reducing also the risk of coalescence. the emulsion into aerosol canisters, is about 1 micron to about In certain other embodiments appropriate effective amounts less than 30 microns, preferably is about 1 micron to about ofemulsifiers are added to maintain or reduce droplet size. In less than 10 microns, more preferably is about 1 micron to other embodiments both thickening and emulsifying agents about less than 5 microns. In certain embodiments, the par are added to provide a multi approach to improving resilience to creaming whilst maintaining or achieving the desired rhe ticle size or average particle size can be reduced to below 1 ology, flowability and shakability as described in the specifi micron to about 0.3 microns and can be a nanoemulsion. cation. 0554 Foams are very complex and sensitive systems and 0551. It should be kept in mind that the stabilizing emul are not formed at will. Mere addition of basic ingredients like sifier or Surfactant may be multifunctional in nature. It Sup oil, water, Surfactant and propellant is far from Sufficient to ports the separating film between the phases; it increases produce homogenous emulsions that can be used to provide a Viscosity; it acts as a foam booster or adjuvant and it acts to shelf stable, shakable pharmaceutical or cosmetic composi stabilize, maintain or reduce droplet size. It may act on its tions from which foams of quality that are homogenous, own or in combination with one or more surfactants and it stable, breakable upon mechanical force can be generated. may be a complex emulgator. Combinations of emulsifiers/ Small deviations may lead to emulsion separation or foam surfactants may be preferable to achieve a reduced or stabi collapse. Much consideration needs to be given to facilitate lized droplet size. the introduction of an active agent, Such as examining com 0552. In one or more embodiments, the composition con patibility and non reactivity with the various excipients and tains one or more polymeric or gelling agents in a concentra container and determining shelf life chemical stability tion to provide viscosity of less than 12,000 CP's. Polymeric 0555 Conventional emulsions are not thermodynamically agents having molecular weight of more that about 500 pos stable. API's can be unstable in an aqueous environment. One sess gelling properties; i.e., they can increase the Viscosity of approach to is to form micro emulsions and nano emulsions, a composition. Therefore, by combining polymeric agents which can be thermodynamically stable, making them a with different molecular weights/melting points, one can favorable vehicle for pharmaceutical compositions, which attain varying levels of flowability and pseudoplasicity/semi have to maintain stability for long periods of time. However, pseudoplasticity as desirable for stabilizing the composition the resultant emulsions are different, the properties such as to be resilient to creaming. According to Some embodiments, Viscosity and particle size are different, considerations for the concentration of the polymeric or gelling agent should be selection of ingredients and amounts to be used for micro and in a level that results in viscosity, prior to filling of the com nano emulsions are different, the method of preparation is position into aerosol canisters, of less than 12,000 CP's, and different and can be time consuming and expensive. Also more preferably, less than 10,000 CP's. In one or more other making micro and nano emulsions with a polymeric agent embodiments, the concentration of the polymeric agent is present is quite different to achieving emulsion formulations selected Such that the range of Viscosity of the composition, without one incorporated and Vice versa. prior to filling of the composition into aerosol canisters, is 0556. To achieve regular emulsions that are suitable and about 500 CP's to about less than 20,000 CPs, and preferably, adapted for pharmaceutical use and are physically stable for is about 1000 CP’s to about less than 12,000 CP's. And more long periods of time without phase separation, and chemi preferably about 3000 CP's to about less than 9000 CP's, and cally stable such that the ingredients and API are compatible more preferably about 4000 CP’s to about 7000 CP's. In still and do not break down or react with each other or packaging other embodiments a more viscous pre foam formulation is materials in which they are stored careful selection of ingre desirable. For example where the application is body cavity dients and materials and the proportions is required. For an use and the Viscosity is a desirable consequence of the nature aqueous foam emulsion system the Surfactants and any foam and amount of at least one bioadhesive agent being present. adjuvants and the oil phase and the hydrophobic propellant The bioadhesive agent may itself generate a high, medium or should be selected to achieve good compatibility so that the lower viscosity. In an embodiment it comprises a high vis ingredients complement each others function in achieving the cosity methyl cellulose. In another embodiment it can be a multiple objectives of a storage stable emulsion; a chemically lower viscosity methyl cellulose. In either case the methyl stable system and a resultant reproducible foam which itself cellulose can be alone or in combination with one or more is stable with an appropriate bubble size, satisfactory collapse other polymeric agents such as carbopol or polycarbophil. time, non stinging and with a pleasant texture and sensation The low viscosity methyl cellulose may nevertheless be used upon contact or spreading and delivery of an effective amount to generate foamable pre foam formulations with a higher of the active agent to the target site. viscosity For bioadhesive formulations a wide range of vis 0557 Bubble size can be from a few microns to several cosity may be allowable from about 1000 CPs to about to hundreds of microns. In some situations two bubble size about 100,000 CPs, preferably from about 2000 CPs to about ranges can be seen a main range and a secondary range of to about 30,000 CPs. larger bubbles. Preferably substantially all the bubbles are 0553 Particle or droplet size of the emulsions can be a within a main range. In an embodiment the bubble size ranges significant factor. The emulsions should primarily comprise from an average of about 30 to about 250 micron. In a pre of droplets with a size oran average size of about less than 30 ferred embodiment it ranges from about 50 to about 220 microns, preferably less than about 20 microns, more prefer micron, in another preferred embodiment it ranges from ably less than about 10 microns and more preferably still less about 70 t about 200 micron. In a more preferred embodiment than about 5 microns in size. In one or more embodiments the average bubble size ranges from about 80 to about 150 amount of Surfactant, combination of Surfactants, the com micron. US 2008/0206161 A1 Aug. 28, 2008 56

0558 Stabilizers for the purpose of anticreaming, in prod preferably a HLB value or average in or towards the lipophilic ucts of the present invention, are polymeric or gelling agents side of the scale are not always binding for oil in water like and emulsifiers, which act as Surfactants emulsions and that good quality foams can be produced with amongst other things to stabilize or reduce droplet size. a surfactant or surfactant combination both where the HLB 0559. In principle, any polymeric or gelling agent may be values are in or towards the lipophilic side of the scale and suitable. See for example the comprehensive list of polymeric more surprisingly where the HLB values are in or towards the or gelling agents. Preferably, Suitable polymeric or gelling hydrophilic side of the scale. agents such are cellulose derivatives, Xanthan gum, Sodium 0563. According to one or more embodiments of the CMC, methylcellulose, hydroxylpropyl methyl cellulose and present invention, the one or more surfactants (Surface active the like, Some polymeric or geling agents may be suitable agents) of the present invention are compatible with one or from the point of view of rheology but are less desirable from more organic carriers, such as oils. By "compatible' is meant a secondary aspect of say leaving a film on the skin, which that the Surfactant(s) is matched with the carrier, as is appre may flake. So in one or more embodiments the polymeric ciated by a person skilled in the art. agent selected does not form an undesirable film on the skin. 0564. According to one or more embodiments the compo 0560 Polysaccharides are preferred stabilizing polymers sition contains a single Surface active agent having an HLB for foams. Suitable polysaccharides can be natural polysac value between about 2 and 9, or more than one surface active charides, derivatives thereof and modified poysacharides or agent and the weighted average of their HLB values is derivatives. Polysaccharides are complex , between about 2 and about 9. Lower HLB values may in made up of multiple Sugar molecules. This term is commonly certain embodiments be more applicable to water in oil emul used only for those containing more than ten sions. residues. Examples of polysaccharides include starch, dex 0565 According to one or more embodiments the compo trin, glycogen, cellulose and . Glycosaminoglycan sition contains a single Surface active agent having an HLB (GAG) is the polysaccharide unit that makes up proteogly value between about 7 and 14, or more than one surface active cans, a molecule made of saccharides and proteins. GAGS are agent and the weighted average of their HLB values is extracellular matrix molecules that help give tissues like car between about 7 and about 14. Midrange HLB values may, in tilage their rigid structure and may also be useful stabilizing certain embodiments, be more suitable for oil in water emul molecules. GAGS include chondroitinSulphate, dermatan Sul sions. phate, keratan Sulphate, heparan Sulphate, heparin, and hyalu 0566. According to one or more other embodiments the roman. Starches are polymers of glucose in which glucopyra composition contains a single surface active agent having an nose units are bonded by alpha-linkages. Starches can also be HLB value between about 9 and about 19, or more than one useful stabilizers. For example, amylose consists of a linear surface active agent and the weighted average of their HLB chain of several hundred glucose molecules and amylopec values is between about 9 and about 19. tine is a branched molecule made of several thousand of 0567 Preferably, the composition contains a non-ionic glucose units. Surfactant. Nonlimiting examples of possible non-ionic Sur 0561 Examples of polymeric agents and surfactants are factants include a polysorbate, polyoxyethylene (20) sorbitan described else where in detail in the specification. Foam adju monostearate, polyoxyethylene (20) Sorbitan monooleate, a vants, described elsewhere, can also be suitable for stabilizing polyoxyethylene fatty acid ester, Myri 45, Myr 49, Myr 52 the formulations. and Myr 59; a polyoxyethylene alkyl ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene Surface-Active Agent oxide hexadecyl ether, polyethylene glycol cetyl ether, brij 0562. The composition further contains a surface-active 38, brij 52, brij 56 and brij W1, a sucrose ester, a partial ester agent. Surface-active agents (also termed 'Surfactants”) of Sorbitol and its anhydrides, Sorbitan monolaurate, Sorbitan include any agent linking oil and water in the composition, in monolaurate, a monoglyceride, a diglyceride, isoceteth-20 the form of emulsion. A surfactant's hydrophilic/lipophilic and mono-, di- and tri-esters of Sucrose with fatty acids. In balance (HLB) describes the emulsifier's affinity toward certain embodiments, Suitable Sucrose esters include those water or oil. HLB is defined for non-ionic surfactants. The having high monoester content, which have higher HLB val HLB scale ranges from 1 (totally lipophilic) to 20 (totally CS. hydrophilic), with 10 representing an equal balance of both 0568. Non-limiting examples of non-ionic surfactants that characteristics. Lipophilic emulsifiers form water-in-oil have HLB of about 7 to about 12 include steareth 2 (HLB-4. (w/o) emulsions; hydrophilic Surfactants form oil-in-water 9); glyceryl monostearate/PEG 100 stearate (AV HLB-11.2): (ofw) emulsions. The HLB of a blend of two emulsifiers stearate Laureth 4 (HLB-9.7) and cetomacrogol ether (e.g., equals the weightfraction of emulsifier A times its HLB value polyethylene glycol 1000 monocetyl ether). More exemplary plus the weight fraction of emulsifier B times its HLB value stabilizing surfactants which may be suitable for use in the (weighted average). In many cases a single Surfactant may present invention are found below. Suffice. In other cases a combination of two or more Surfac tants is desired. As will be appreciated by a person skilled in the art which Surfactant or Surfactant system is more appro priate is related to the vehicle and intended purpose. In gen PEG-Fatty Acid Monoester Surfactants eral terms a combination of Surfactants is usually preferable Chemical name Product example name HLB where the vehicle is an emulsion. In an emulsion environment PEG-30 Stearate Myri 51 >10 a combination of Surfactants can be significant in producing PEG-40 laurate Crodet LAO (Croda) 17.9 breakable forms of good quality. It has been further discov PEG-40 oleate Crodet O40 (Croda) 17.4 ered that the generally thought considerations for oil in water PEG-45 Stearate Nikkol MYS-45 (Nikko) 18 emulsions of using a surfactant or Sufactant combination with US 2008/0206161 A1 Aug. 28, 2008 57

-continued Polyethylene Glycol Alkyl Ethers PEG-Fatty Acid Monoester Surfactants Chemical name Product example name HLB Chemical name Product example name HLB PEG-2 oleyl ether oleth-2 Brij92/93 (Atlas/ICI) 4.9 PEG-3 oleyl ether oleth-3 Volpo 3 (Croda) &10 PEG-5 oleyl ether oleth-5 Volpo 5 (Croda) &10 PEG-50 Stearate Myri 53 >10 PEG-10 oleyl ether oleth-10 Volpo 10 (Croda), Brij 12 96/97 (Atlas/ICI) PEG-100 Stearate Myri 59, Arlacel 165 (ICI) 19 PEG-20 oleyl ether oleth-20 Volpo 20 (Croda), Brij 15 98/99 (Atlas/ICI) PEG-4 lauryl ether laureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23 lauryl ether laureth-23Brij 35 (Atlas/ICI) 17 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-2 cetyl ether Brij 52 (ICI) 5.3 PEG-Fatty Acid Diester Surfactants: Chemical name Product example name HLB PEG-4 dilaurate Mapeg.RTM. 200 DL (PPG), 7 KeSSco RTMPEG 200 DL Sugar Ester Surfactants (Stepan), LIPOPEG 2-DL (Lipo Chem.) Chemical name Product example name HLB PEG-4 distearate Kessco RTM. 200 5 DS (Stepan.Sub) Sucrose distearate Sisterna SP50, Surfope 1811 11 PEG-32 dioleate KeSSco RTMPEG 1540 DO 15 (Stepan) PEG-400 dioleate) Cithrol 4DO series (Croda >10 PEG-400 disterate Cithrol 4DS series (Croda) >10 PEG-20 glyceryl oleate Tagat. RTM. O (Goldschmidt) >10 Sorbitan Fatty Acid Ester Surfactants Chemical name Product example name HLB Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 8.6 (Croda), Arlacel 20 (ICI) Transesterification Products of Oils and Alcohols Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 6.7 (Croda), Nikkol SP-10 (Nikko) Chemical name Product example name HLB Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 4.3 (Croda), Crill 50 (Croda) PEG-30 castor oil Emalex C-30 (Nihon Emulsion) 11 Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 4.7 PEG-40 hydrogenated Cremophor RH 40 (BASF), 13 (Croda), Nikkol SS-10 (Nikko) castor oil) Croduret (Croda), Emulgin HRE 40 (Henkel) 0569. In one or more embodiments the surface active agent is a complex emulgator in which the combination of two or more Surface active agents can be more effective than a single surfactant and provides a more stable emulsion or Polyglycerized Fatty Acids. Such as: improved foam quality than a single Surfactant. For example and by way of non-limiting explanation it has been found that Chemical name Product example name LB by choosing say two surfactants, one hydrophobic and the Polyglyceryl-6 dioleate Caprol.RTM. 6G20 (ABITEC): 8.5 other hydrophilic the combination can produce a more stable PGO-62 (Calgene), PLUROL emulsion than a single surfactant. Preferably, the complex OLEIQUE CC 497 emulgator comprises a combination of Surfactants wherein (Gattefosse)Hodag there is a difference of about 4 or more units between the HLB values of the two surfactants or there is a significant differ ence in the chemical nature or structure of the two or more Surfactants. 0570 Specific non limiting examples of surfactant sys PEG-Sorbitan Fatty Acid Esters tems are, combinations of polyoxyethylene alkyl ethers. Such Chemical name Product example name HLB as Brij 59/Brij 10; Brij 52/Brij 10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/Brij 721); combinations of PEG-20 sorbitan Tween 40 (Atlas/ICI), Crillet 2 16 monopalmitate (Croda) polyoxyethylene stearates such as Myri 52/Myri 59; combi PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 15 nations of sucrose esters, such as Surphope 1816/Surphope monoStearate (Croda) 1807; combinations of sorbitan esters, such as Span 20 Span PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 80; Span 20 Span 60; combinations of sucrose esters and (Croda) PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 15 sorbitan esters, such as Surphope 1811 and Span 60; combi (Croda) nations of liquid polysorbate detergents and PEG com pounds, such as Tween 80 PEG-40 stearate; methyl glucaso sequistearate; polymeric emulsifiers, such as Permulen (TR1 US 2008/0206161 A1 Aug. 28, 2008

or TR2); liquid crystal systems, such as Arlatone (2121), and at least one ionic Surfactant in a ratio in the range of about Stepan (Mild RM1), Nikomulese (41) and Montanov (68) and 100:1 to 6:1. In one or more embodiments, the non-ionic to the like. ionic Surfactant ratio is greater than about 6:1, or greater than 0571. In certain embodiments, the surfactant is preferably about 8:1; or greater than about 14:1, or greater than about a combination of Steareth-2 and Steareth-21; in certain other 16:1, or greater than about 20:1. In further embodiments, embodiments the Surfactant is a combination of polysorbate Surface active agent comprises a combination of a non-ionic 80 and PEG-40 stearate. In certain other embodiments the Surfactant and an ionic Surfactant, at a ratio of between 1:1 surfactant is a combination of glyceryl monostearate/PEG and 20:1. 100 Stearate. 0580. In one or more embodiments, a combination of a 0572. In one or more embodiments the stability of the non-ionic Surfactant and an ionic Surfactant (Such as sodium composition can be improved when a combination of at least lauryl Sulphate and cocamidopropylbetaine) is employed, at a one non-ionic surfactant having HLB of less than 9 and at ratio of between 1:1 and 20:1, or at a ratio of 4:1 to 10:1. The least one non-ionic Surfactant having HLB of equal or more resultant foam has a low specific gravity, e.g., less than 0.1 than 9 is employed. The ratio between the at least one non g/ml. ionic surfactant having HLB of less than 9 and the at least one 0581. In selecting a suitable surfactant or combination non-ionic Surfactant having HLB of equal or more than 9, is thereof it should be borne in mind that the upper amount of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4. The resultant surfactant that may be used may be limited by the shakability HLB of such a blend of at least two emulsifiers is preferably of the composition. In general terms, as the amount of non between about 9 and about 14. liquid surfactant is increased the shakability of the formula 0573 Thus, in an exemplary embodiment, a combination tion reduces until a limitation point is reached where the of at least one non-ionic surfactant having HLB of less than 9 formulation becomes non shakable and unsuitable. Thus in an and at least one non-ionic Surfactant having HLB of equal or embodiment any effective amount of Surfactant may be used more than 9 is employed, at a ratio of between 1:8 and 8:1, or provided the formulation remains shakable. at a ratio of 4:1 to 1:4, wherein the HLB of the combination of 0582. In certain embodiments, the amount of surfactant or emulsifiers is preferably between about 9 and about 14. combination of surfactants is between about 0.05% to about 0574. In certain cases, the surface active agent is selected 20%; between about 0.05% to about 15%. or between about from the group of cationic, Zwitterionic, amphoteric and 0.05% to about 10%. In a preferred embodiment the concen ampholytic Surfactants, such as sodium methyl cocoyl tau tration of surface active agent is between about 0.2% and rate, sodium methyl oleoyl taurate, sodium lauryl Sulfate, about 5%. In a more preferred embodiment the concentration triethanolamine lauryl sulfate and betaines. of surface active agent is between about 1% and about 4%. 0575. Many amphiphilic molecules can show lyotropic 0583. If the composition is formulated as a substantially liquid-crystalline phase sequences depending on the Volume non flowing composition for use as a gel, ointment or cream, balances between the hydrophilic part and hydrophobic part. then the above limitation of shakability does not apply. Suit These structures are formed through the micro-phase segre able formulations include polyethylene glycol or derivatives gation of two incompatible components on a nanometer scale. or mixtures thereof. For example, comprising higher molecu Soap is an everyday example of a lyotropic liquid crystal. lar weight polymers or polymer combinations which are usu Certain types of Surfactants tend to form lyotropic liquid ally waxy or solid at room temperature such as PEG 4000 crystals in emulsions interface (oil-in-water) and exert a sta alone or a Peg 4000/400 combination with significant bilizing effect. Non limiting examples of surfactants with amounts of say PEG 4000 of 5% of 10% of 15% of 20% of postulated tendency to form interfacial liquid crystals are: 25% of 30% of as a basis for gels, ointments or creams. Other phospholipids, alkyl glucosides. Sucrose esters, Sorbitan similar combinations may be envisaged of say PEG6000/ esters. In certain embodiments surfactants which tend to form PEG200; PEG4000/PEG200; PEG4000/PEG400/PEG200; liquid crystals may improve the quality of foams produced and the like. from compositions. 0584 As will be appreciated by someone skilled in the art, 0576. In one or more embodiments, the surfactant is a as the levels of PEG are increased the composition will Surfactant or Surfactant combination is capable of or which become more Suitable foragel or ointment pharmaceutical or tends to form liquid crystals. cosmetic composition. 0577. In one or more embodiments, the at least one surface active agent is solid, semi Solid or waxy. Modulating Agent 0578. In one or more embodiments, the surface-active agent includes at least one non-ionic Surfactant. Ionic Surfac 0585. The term modulating agent is used to describe an tants are known to be irritants. Therefore, non-ionic Surfac agent which can improve the stability of or stabilize a foam tants are preferred in applications including sensitive tissue able carrier or composition and or an active agent by modu Such as found in most mucosal tissues, especially when they lating the effect of a substance or residue present in the carrier are infected or inflamed. We have surprisingly found that or composition. The Substance or residue may for example be non-ionic Surfactants alone can provide formulations and acidic or basic and potentially alter pH in an emulsion envi foams of good or excellent quality in the carriers and compo ronment or it may be one or more metalions which may act as sitions. a potential catalyst in an emulsion environment. 0579. Thus, in a preferred embodiment, the surface active 0586. In one or more embodiments the modulating agent agent, the composition contains a non-ionic Surfactant. In is used to describe an agent which can affect pH in an aqueous another preferred embodiment the composition includes a Solution. The agent can be any of the known buffering sys mixture of non-ionic Surfactants as the sole Surface active tems used in pharmaceutical or cosmetic formulations as agent. Yet, in additional embodiments, the foamable compo would be appreciated by a man of the art. It can also be an sition includes a mixture of at least one non-ionic Surfactant organic acid, a carboxylic acid, a fatty acid an amino acid, an US 2008/0206161 A1 Aug. 28, 2008 59 , an alpha or beta hydroxyl acid an organic base (HEDTA), nitrilotriacetic acid (NTA), O.O'-bis(2-aminoet or a nitrogen containing compound. hyl)ethyleneglycol-N.N.N',N'-tetraacetic acid (EGTA), 0587. In one or more further embodiments the modulating trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid agent is used to describe an agent, which is a chelating or (CyDTA) or a pharmaceutically acceptable salt thereof (nor sequestering or complexing agent that is Sufficiently soluble mally as a sodium salt), more preferably EDTA, HEDTA and or functional in the solvent to enable it to “mop up' or “lock” their salts; most preferably EDTA and its salts. metal ions. 0596. In one or more embodiments, a preferred non lim 0588. In the embodiment modulating agent is used to iting example of the chelating agent is EDTA. Typically, the describe an agent which can effect pH in an aqueous solution chelating and sequestering agent is present in the composition the term modulating agent more particularly means an acid or at a level of up to about 5.0%, preferably 1.0 percent, by base or buffer system or combinations thereof, which is intro weight, of the composition. duced into or is present in and acts to modulate the ionic or 0597. In one or more embodiments, the modulating agent polar characteristics and any acidity or basesity balance of an may also be a preservative or an antioxidant or an ionization emulsion carrier, composition, foamable carrier or foamable agent. Any preservative, antioxidant or ionization agents Suit composition or resultant foam. able for pharmaceutical or cosmetic application may be used. 0589. The substance or residue can be introduced into the Non limiting examples of antioxidants are tocopherol Succi formulation from any one or more of the ingredients, some of nate, propyl galate, butylated hydroxy and butyl which themselves may have acidic or basic properties. For hydroxyanisol. In one or more embodiments the modulating example the polymer or solvent may contain basic residues in agent is a . Ionization agents may be positive or may which case it may be desirable or beneficial to add an acid. be negative depending on the environment and the active Alternatively the Surfactant may contain some acid residues agent or composition that is to be protected. Ionization agents in which case the addition of a base may be desirable and may for example act to protect or reduce sensitivity of active beneficial. In some cases more than one ingredient may con agents. Non limiting examples of positive ionization agents tain residues which may ameliorate or compound their sig are benzyl conium chloride, and cetyl pyridium chloride. Non nificance. For example if one ingredient provided weak acid limiting examples of negative ionization agents are sodium residues and another, stronger acid residues, then the pH in an lauryl Sulphate, sodium lauryl lactylate and phospholipids. emulsion environment should be lower. In contrast, if one 0598. In one or more embodiments the formulations residue was acid and the other basic, the net effect in the described herein may further contain a modulating agent. formulation maybe significantly reduced. In some circum stances the active ingredient may favor an acidic pH or more Humectant significantly may need to be maintained at a certain acidic pH 0599. A humectant, is a substance that helps retain mois otherwise it may readily isomerize, chemically reactor break ture and also prevents rapid evaporation. Non limiting down, in which case introducing acidic components such as examples are propylene glycol, propylene glycol derivatives, an acidic polymer might be of help. In an embodiment suffi glycerin, hydrogenated Starch hydrosylate, hydrogenated cient modulating agent is added to achieve an artificial pH in lanolin, lanolin wax, D manitol, Sorbitol, Sodium 2-pyrroli which the active agent is preferably stable. done-5-carboxylate, sodium lactate, sodium PCA, soluble 0590. A buffer, as defined by Van Slyke Van Slyke, J. collagen, dibutyl phthalate, and gelatin. Other examples may Biol. Chem. 52, 525 (1922), is “a substance which by its be found in the Handbook of Pharmaceutical Additives pub presence in Solution increases the amount of acid oralkali that lished by Gower. must be added to cause unit change in pH. 0591. A buffer solution is a solution of a definite pH made Moisturizers up in Such a way that this pH alters only gradually with the addition of alkali or acid. Such a solution consists of a solu 0600. A moisturizer, is a substance that helps retain mois tion of a salt of the week acid in the presence of the three acid ture or add back moisture to the skin. Examples are allantoin, itself. The pH of the solution is determined by the dissociation petrolatum, urea, lactic acid, sodium PCV, glycerin, shea equilibrium of the free acid. buffer, caprylic/capric/stearic triglyceride, candelilla wax, 0592. An acid can be a strong acid or a weak acid. A strong propylene glycol, lanolin, hydrogenated oils, , acid is an acid, which is a virtually 100% ionized in solution. sodium hyaluronate and lysine PCA. Other examples may be In contrast, a weak acid is one which does not ionize fully, found in the Handbook of Pharmaceutical Additives pub when it is dissolved in water. The lower the value for pKa, the lished by Gower. stronger is the acid and likewise, the higher the value for pKa, 0601 Pharmaceutical compositions may in one or more the weaker is the acid. embodiments usefully comprise in addition a heumectant or a 0593. A base can be a strong base or a weak base. A strong moisturizer or combinations thereof. base is a base, which is fully ionic with 100% hydroxide ions. In contrast, a weak base is one which does not convert fully Foam Adjuvant into hydroxide ions in solution. The lower the value for pKb. 0602 Preferably, a therapeutically effective foam adju the stronger is the base and likewise, the higher the value for vant is included in the foamable compositions, to increase the pKb the weaker is the base. foaming capacity of Surfactants and/or to stabilize the foam. 0594. In one or more embodiments, the modulating agent In one or more embodiments, the foam adjuvant agent comprises an organic compound. includes fatty alcohols having 15 or more carbons in their 0595. In one or more preferred embodiments, the chelat carbon chain, Such as cetyl alcohol and Stearyl alcohol (or ing agent is selected from the group consisting of ethylene mixtures thereof). Other examples of fatty alcohols are diaminetetraacetic acid (EDTA), diethylenetriaminepen arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacon taacetic acid (DTPA), hydroxyethylenediaminetriacetic acid tanol (C30), as well as alcohols with longer carbon chains (up US 2008/0206161 A1 Aug. 28, 2008 60 to C50). Fatty alcohols, derived from beeswax and including 0610 Optionally, the composition further contains a pen a mixture of alcohols, a majority of which has at least 20 etration enhancer. This is particularly important when the carbonatoms in their carbon chain, are especially well Suited steroid is Supposed to reach deeper layers of the target tissue as foam adjuvant agents. The amount of the fatty alcohol or when the active agent is intended for systemic administra required to Support the foam system is inversely related to the tion, via the transdermal or transmucosal route. Non limiting length of its carbon chains. Foam adjuvants, as defined herein examples of penetration enhancers include propylene glycol, are also useful in facilitating improved spreadability and butylene glycols, glycerol, pentaerythritol, Sorbitol, manni absorption of the composition. In some embodiments, the tol, oligosaccharides, dimethyl isosorbide, monooleate of fatty alcohol includes at least one unsaturated fatty alcohol. ethoxylated glycerides having about 8 to 10 ethylene oxide 0603. In one or more embodiments, the foam adjuvant units, polyethylene glycol 200-600, transcutol, glycofurol agent includes fatty acids having 16 or more carbons in their and cyclodextrins. carbon chain, Such as hexadecanoic acid (C16) Stearic acid (C18), arachidic acid (C20), behenic acid (C22), octa Propellants cosanoic acid (C28), as well as fatty acids with longer carbon 0611 Examples of suitable propellants include volatile chains (up to C50), or mixtures thereof. As for fatty alcohols, hydrocarbons such as butane, , isobutane and fluoro the amount offatty acids required to support the foam system carbon gases, or mixtures thereof. is inversely related to the length of its carbon chain. 0612. In an embodiment the propellant is 1681, which is a 0604. In one or more embodiments, a combination of a mixture of propane, isobutene and butane. In another embodi fatty acid and a fatty ester is employed. ment it is AP70, which is a mixture of propane, isobutene and 0605 Optionally, the carbon atom chain of the fatty alco butane with a higher pressure. hol or the fatty acid may have at least one double bond. A 0613. The propellant makes up about 5-25 wt % of the further class of foam adjuvantagent includes a branched fatty foamable composition. In some circumstances the propellant alcohol or fatty acid. The carbon chain of the fatty acidor fatty may be up to 35%. The propellants are used to generate and alcohol also can be substituted with a hydroxyl group, such as administer the foamable composition as a foam. The total 12-hydroxy Stearic acid. composition including propellant, foamable compositions 0606 An important property of the fatty alcohols and fatty and optional ingredients is referred to as the foamable com acids used in context of the composition is related to their position. therapeutic properties, perse. Long chain Saturated and mono 0614 Alcohol and organic solvents render foams inflam unsaturated fatty alcohols, e.g., Stearyl alcohol, erucyl alco mable. It has been surprisingly discovered that fluorohydro hol, arachidyl alcohol and behenyl alcohol (docosanol) have carbon propellants, other than chloro-fluoro carbons been reported to possess antiviral, antiinfective, antiprolifera (CMCs), which are non-oZone-depleting propellants, are par tive and antiinflammatory properties (see, U.S. Pat. No. ticularly useful in the production of a non-flammable foam 4,874,794). Longer chain fatty alcohols, e.g., tetracosanol, able composition. Such propellants include, but are not lim hexacosanol, heptacosanol, octacosanol, triacontanol, etc., ited to, hydrofluorocarbon (HFC) propellants. are also known for their metabolism modifying properties and 0615. In one or more embodiments, the non inflammable tissue energizing properties. Long chain fatty acids have also propellants are used in combination with the more traditional been reported to possess anti-infective characteristics. hydrocarbon propellants. 0607 Thus, in preferred embodiments, a combined and 0616) In one or more embodiments foamable composi enhanced therapeutic effect is attained by including both a tions comprise a combination of a HFC such as dimethyl ether steroid and a therapeutically effective foam adjuvant in the and a hydrocarbon propellant Such as n-butane or mixtures of same composition, thus providing a simultaneous anti-in hydrocarbon propellants such as propane, isobutane and flammatory and antiinfective effect from both components. butane. Furthermore, in a further preferred embodiment, the compo sition concurrently comprises a steroid, a therapeutically 0.617 Aerosol propellants are used to generate and admin effective foam adjuvant and a therapeutically active oil, as ister the foamable composition as a foam. The total compo detailed above. Such combination provides an even more sition including propellant, foamable compositions and enhanced therapeutic benefit. Thus, the foamable carrier, optional ingredients is referred to as the foamable carrier. The containing the foam adjuvant provides an extra therapeutic propellant makes up about 3% to about 25 wt % of the foam benefit in comparison with currently used vehicles, which are able carrier. Examples of suitable propellants include volatile inert and non-active. hydrocarbons such as butane, propane, isobutane or mixtures 0608. The foam adjuvant according to one or more pre thereof, and fluorocarbon gases. ferred embodiments includes a mixture offatty alcohols, fatty Composition and Foam Physical Characteristics acids and hydroxy fatty acids and derivatives thereof in any proportion, providing that the total amount is 0.1% to 5% 0618. A pharmaceutical or cosmetic composition manu (w/w) of the carrier mass. More preferably, the total amount factured using the foam carrier according to one or more is 0.4%-2.5% (w/w) of the carrier mass. embodiments is very easy to use. When applied onto the 0609. The therapeutic foam may further optionally afflicted body Surface of mammals, i.e., humans or animals, it include a variety of formulation excipients, which are added is in a foam state, allowing free application without spillage. in order to fine-tune the consistency of the formulation, pro Upon further application of a mechanical force, e.g., by rub tect the formulation components from degradation and oxi bing the composition onto the body Surface, it freely spreads dation and modify their consistency. Such excipients may be on the surface and is rapidly absorbed. selected, for example, from stabilizing agents, antioxidants, 0619. The foam composition creates a stable emulsion humectants, preservatives, colorant and odorant agents and having an acceptable shelf-life of at least one year, or at least otherformulation components, used in the art of formulation. two years at ambient temperature. A feature of a product for US 2008/0206161 A1 Aug. 28, 2008

cosmetic or medical use is long term stability. Propellants, 06-0018937, published on Jan. 26, 2006, entitled STEROID which are a mixture of low molecular weight hydrocarbons, KIT AND FOAMABLE COMPOSITION AND USES tend to impair the stability of emulsions. It has been observed, THEREOF; U.S. Publication No. 05-0271596, published on however, that emulsion foam compositions according to the Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSI present invention are surprisingly stable. Following acceler TION AND USES THEREOF; U.S. Publication No. ated stability studies, they demonstrate desirable texture; they 06-0269485, published on Nov.30, 2006, entitled ANTIBI form fine bubble structures that do not break immediately OTIC KIT AND COMPOSITION AND USES THEREOF: upon contact with a surface, spread easily on the treated area and absorb quickly. U.S. Publication No. 07-0020304, published on Jan. 25, 0620. The composition should also be free flowing, to 2007, entitled NON-FLAMMABLE INSECTICIDE COM allow it to flow through the aperture of the container, e.g., and POSITION AND USES THEREOF; U.S. Publication No. aerosol container, and create an acceptable foam. Composi 06-0193789, published on Aug. 31, 2006, entitled FILM tions containing semi-solid hydrophobic solvents, e.g., white FORMING FOAMABLE COMPOSITION: U.S. patent petrolatum, as the main ingredients of the oil phase of the application Ser. No. 1 1/732,547, filed on Apr. 4, 2007, emulsion, exhibit high viscosity and poor flowability and are entitled ANTI-INFECTION AUGMENTATION OF FOAM ABLE COMPOSITIONS AND KITANDUSESTHEREOF: inappropriate candidates for a foamable composition. U.S. patent application Ser. No. 1 1/732,547, filed on Apr. 4, 0621 Foam quality can be graded as follows: 2007, KERATOLYTIC ANTIFUNGAL FOAM: U.S. patent 0622 Grade E (excellent): very rich and creamy inappear application Ser. No. 1 1/767,442, filed on Jun. 22, 2007, ance, does not show any bubble structure or shows a very fine entitled FOAMABLE COMPOSITIONS AND KITS COM (small) bubble structure: does not rapidly become dull; upon PRISING ONE OR MORE OF A CHANNEL AGENT, A spreading on the skin, the foam retains the creaminess prop CHOLINERGIC AGENT, A NITRIC OXIDE DONOR, erty and does not appear watery. AND RELATED AGENTS AND THEIR USES: U.S. patent 0623 Grade G (good): rich and creamy in appearance, application Ser. No. 1 1/825,406, filed on Jul. 5, 2007, entitled very small bubble size, “dulls' more rapidly than an excellent DICARBOXYLIC ACID FOAMABLE VEHICLE AND foam, retains creaminess upon spreading on the skin, and PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. does not become watery. patent application Ser. No. 1 1/900,072, filed on Sep. 10, 0624 Grade FG (fairly good): a moderate amount of 2006, entitled FOAMABLE VEHICLE AND VITAMIN creaminess noticeable, bubble structure is noticeable; upon AND FLAVONOID PHARMACEUTICAL COMPOSI spreading on the skin the product dulls rapidly and becomes TIONS THEREOF; and U.S. patent application Ser. No. Somewhat lower in apparent viscosity. 11/947,751, filed Nov. 29, 2007, entitled COMPOSITIONS 0625 Grade F (fair): very little creaminess noticeable, WITH MODULATINGAGENTS, all of which are incorpo larger bubble structure than a “fairly good' foam, upon rated herein by reference in their entirety. More particularly spreading on the skin it becomes thin in appearance and any of the active ingredients; the solvents; the Surfactants; watery. foam adjuvants; polymeric agents, penetration enhancers; 0626 Grade P (poor): no creaminess noticeable, large preservatives, humectants; moisturizers; and other excipients bubble structure, and when spread on the skin it becomes very as well as the propellants and methods listed therein can be thin and watery in appearance. applied herein and are incorporated by reference. 0627 Grade VP (very poor): dry foam, large very dull 0632. The invention is described with reference to the bubbles, difficult to spread on the skin. following examples. This invention is not limited to these 0628 Topically administrable foams are typically of qual examples and experiments. Many variations will Suggest ity grade E or G, when released from the aerosol container. themselves and are within the full intended scope of the Smaller bubbles are indicative of more stable foam, which does not collapse spontaneously immediately upon discharge appended claims. from the container. The finer foam structure looks and feels 0633. A “stable foam is defined herein as a composition, Smoother, thus increasing its usability and appeal. which upon release from an aerosol can, creates a foam mass, 0629. A further aspect of the foam is breakability. The which is Sustained on a Surface for at least one minute, more breakable foam is thermally stable, yet breaks under sheer preferably at least two minutes, and yet more preferably for at force. Sheer-force breakability of the foam is clearly advan least 5 minutes. A period of minutes is regarded as a short tageous over thermally-induced breakability. Thermally sen term, but nevertheless it allows a good and more than Suffi sitive foams immediately collapse upon exposure to skin cient period of time for a Subject to receive foam dispensed on temperature and, therefore, cannot be applied on the hand and a body surface and to spread it or to transfer it to another afterwards delivered to the afflicted area. region and to spread it. 0630. Another property of the foam is specific gravity, as 0634. In terms of spreadability and absorption an accept measured upon release from the aerosol can. Typically, foams able foam is one, that does not readily collapse upon dispens have specific gravity of less than 0.12 g/mL, or less than 0.10 ing on the skin; spreads easily on a skin Surface; at least g/mL, or less than 0.08 g/mL, depending on their composition partially absorbed following rubbing onto the skin, and more and on the propellant concentration. preferably, substantially absorbed following rubbing on the 0631 Other foamable compositions are described in: U.S. skin. Publication No. 05-0232869, published on Oct. 20, 2005, 0635. In terms of tactile properties, an acceptable foam is entitled NONSTEROIDAL IMMUNOMODULATING KIT one, that: creates a pleasant feeling after application; leaves AND COMPOSITION AND USES THEREOF; U.S. Publi minimal oily residue; and leaves minimal shiny residual look. cation No. 05-0205086, published on Sep. 22, 2005, entitled 0636 Skin drying and skin barrier function. Short chain RETINOIDIMMUNOMODULATINGKITAND COMPO alcohols are known to dry the skin and impair the integrity of SITION AND USES THEREOF; U.S. Publication No. the skin barrier. By contrast, including a film forming agent in US 2008/0206161 A1 Aug. 28, 2008 62 the composition of the present invention foes not cause or mucosal Surfaces, including, but not limited to the cranial unwanted skin barrier damage. cavity, the thoratic cavity, the abdominal cavity, the venteral 0637 Irritability. Due to the lack of lower alcohols (C- cavity, the vagina, the rectum and penile cavities, the urinary Cs) and improvement in skin barrier function, skin irritability tract, the nasal cavity, the mouth, the eye, the ear the perito is eliminated. neum, the large and Small bowel, the caecum, bladder, and stomach, the cavity between the uterus and the fallopian Fields of Pharmaceutical Applications tubes, the ovaries and other body areas, which may accept 0638. By including an appropriate steroid and optional topically-applied products. The composition is suitable to active agents in the compositions, the composition are useful treat conditions of a body cavity and a mucosal membrane, in treating a patient having any one of a variety of dermato Such as post-Surgical adhesions, chlamydia infection, gonor logical disorders, which include inflammation as one or their rhea infection, hepatitis B, herpes, HIV/AIDS, human papil etiological factors (also termed "dermatoses'). Such as clas lomavirus (HPV), genital warts, bacterial vaginosis, candidi sified in a non-limiting exemplary manner according to the asis, chancroid, granuloma Inguinale, lymphogranloma following groups: venereum, mucopurulent cervicitis (MPC), molluscum con 0639 (i) Dermatitis including contact dermatitis, atopic tagiosum, nongonococcal urethritis (NGU), trichomoniasis, dermatitis, Seborrheic dermatitis, nummular dermatitis, Vulvar disorders, Vulvodynia, Vulvar pain, yeast infection, chronic dermatitis of the hands and feet, generalized vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), con exfoliative dermatitis, stasis dermatitis; lichen simplex tact dermatitis, pelvic inflammation, endometritis, salpingi chronicus; diaper rash; tis, oophoritis, genital cancer, cancer of the cervix, cancer of 0640 (ii) Bacterial infections including cellulitis, acute the Vulva, cancer of the vagina, vaginal dryness, dyspareunia, lymphangitis, lymphadenitis, erysipelas, cutaneous anal and rectal disease, anal abscess/fistula, anal cancer, anal abscesses, necrotizing Subcutaneous infections, staphy fissure, anal warts, Crohn's disease, hemorrhoids, anal itch, lococcal scalded skin syndrome, folliculitis, furuncles, pruritus ani, fecal incontinence, constipation, polyps of the hidradenitis Suppurativa, carbuncles, paronychial infec colon and rectum. tions, erythrasma; 0655 According to one or more embodiments, the com 0641 (iii) Fungal Infections including dermatophyte positions are also useful in the therapy of non-dermatological infections, yeast Infections; parasitic Infections includ disorders by providing transdermal delivery of a steroid that ing scabies, pediculosis, creeping eruption; is effective against non-dermatological disorders. The com (0642 (iv) Viral Infections; position is further useful for the treatmentofear inflammation 0643 (v) Disorders of hair follicles and sebaceous and/or infection, such as otitis externa and otitis media. Otitis glands including acne, rosacea, perioral dermatitis, is commonly treated by a combination of an antimicrobial hypertrichosis (hirsutism), alopecia, including male pat agent and a steroid (e.g., Neomycin, polymyxin B, and hydro tern baldness, alopecia greata, alopecia universalis and cortisone). The composition is additionally useful in the treat alopecia totalis; pseudofolliculitis barbae, keratinous ment of disores of the nasal cavity, such as rhinitis and sinusi cyst; tis. Corticosteroids and estrogens, in combination with 0644 (vi) Scaling papular diseases including psoriasis, Vitamin A and/or vitamin Dare occasionally sprayed into the pityriasis rosea, lichen planus, pityriasis rubra pilaris; nose to treat the inflammation or to reduce crusting by pro 0645 (vii) Benign tumors including moles, dysplastic moting mucosal Secretions in nasal cavity disorders. nevi, skin tags, lipomas, angiomas, pyogenic granu 0656. In one or more embodiments, the disorder is a health loma, seborrheic keratoses, dermatofibroma, keratoa abnormality that responds to treatment with a steroid hor canthoma, keloid; mone. A typical example of Such abnormality is sexual dys 0646 (viii) Malignant tumors including basal cell car function in men and women whereby androgen therapy is cinoma, squamous cell carcinoma, malignant mela Successfully used to restore sexual function. Other non-lim noma, paget's disease of the nipples, kaposi's sarcoma; iting examples of disorders/medical indications that are in the 0647 (ix) Reactions to sunlight, including sunburn, Scope of treatment with a steroid hormone according to the chronic effects of Sunlight, photosensitivity; present invention are androgen deficiency, estrogen defi 0648 (X) Bullous diseases including pemphigus, ciency, growth disorders, hypogonadism, cancer, vasomotor bullous pemphigoid, dermatitis herpetiformis, linear symptoms, menopausal disorders, Vulvar and vaginal atro immunoglobulin A disease; phy, urethritis, hypoestrogenism, osteoarthritis, osteoporosis, 0649 (xi) Pigmentation disorders including hypopig uterine bleeding, Hirsutism, Virilization, ovarian tumors, mentation Such as vitiligo, albinism and postinflamma hypothalamic pituitary unit diseases, testicular tumors, pros tory hypopigmentation and hyperpigmentation Such as tate cancer, hypopituitarism, Klinefelter's syndrome, testicu melasma (chloasma), drug-induced hyperpigmentation, lar feminisation, orchitectomy, vasomotor symptoms (such as postinflammatory hyperpigmentation; “hot flashes') associated with the , metabolic 0650 (xii) Disorders of cornification including ich abnormalities and mood disturbances. thyosis, keratosis pilaris, calluses and corns, actinic 0657 More specific examples of body cavity applications keratosis: of steroids on their own or in combination with one or more 0651 (xiii) Pressure sores: other active agents are presented below without derogating 0652 (xiv) Disorders of sweating; and from the above fields of application. By including an appro 0653 (XV) Inflammatory reactions including drug erup priate active agent in the foamable composition, it is useful in tions, toxic epidermal necrolysis; erythema multiforme, the therapy and prevention of a variety of disorders of a body erythema nodosum, granuloma annulare. cavity or mucosal Surfaces, including, but not limited to the 0654 The same advantage is expected when the compo cranial cavity, the thoracic cavity, the abdominal cavity, the sition, including a steroid, is topically applied to a body cavity Ventral cavity, the vagina, the rectum and penile cavities, the US 2008/0206161 A1 Aug. 28, 2008

urinary tract, bladder, the cavity between the uterus and the 0671 Cellulose acetate phthalate, which inactivates HIV fallopian tubes, the ovaries, the nasal cavity, the mouth, the 1, herpesvirus types I (HSV-1) and 2 (HSV-2) and the major eye, the ear the peritoneum, the large and Small bowel, the nonviral STD pathogens; and found effective in animal mod caecum, bladder, and stomach, and other body cavities or els for vaginal infection by HSV-2 and simian immunodefi spaces, which may accept topically-applied products. ciency virus. 0658 Exemplary treatable disorders are listed below. 0672. Several polymers, such as hydroxypropyl methyl 0659 Bacterial, Fungal and Viral Infections cellulose phthalate, carrageenans, naphthalene Sulfonate 0660 Bacterial, fungal and viral infections: a variety of polymer, Sodium alginate, and cationic polymer, such as chi anti-infective, anti-bacterial, anti-fungal and anti-viral agents tosan, are insoluble in water and can be solubilized in water can be included in the foam, to be used for the treatment and/or prevention of diseases, such as chlamydia, gonorrhea, by adjusting the pH of the environment to about 6 or above, or hepatitis B, herpes, HIV/AIDS, human papallomavirus by the use of appropriate organic solvents. Vaginal Secretions (HPV) & genital warts; Syphilis; bacterial vaginosis, candidi from healthy, reproductive-age women are characteristically asis, chancroid, granuloma inguinale, lymphogranloma acidic (pH values of 3.4 to 6.0). Consequently, the topical venereum, mucopurulent cervicitis (MPC), molluscum con application of a formulation in which Such polymers would be tagiosum, nongonococcal urethritis (NGU), trichomoniasis, soluble (i.e., pH>6) would be expected to contribute to a and Vulvar disorders. vaginal environment which is physiologically undesirable. 0661. A variety of active agents, known in the art, can be 0673 Thus, in one embodiment of present invention, there included in the foam to be used for the treatment and/or is an advantage to an oily foamable carrier, comprising Sol prevention of diseases such as Vulvodynia (Vulvarpain), yeast vents that solubilize water-insoluble polymers such as men infections, genital warts (condyloma) Vulvar dystrophy, Vul tioned above. By way of non-limiting example, such solvents var intraepithelial neoplasia (VIN), invasive cancer of the include polyethylene glycol, propylene glycol, hexylene gly Vulva, contact dermatitis, pelvic inflammation, pelvic inflam col, benzyl alcohol, DMSO, isosorbide derivatives, such as matory disease (PID), genital cancer and cancer of the cervix, dimethyl isosorbide, glycofurol and ethoxydiglycol (transcu Vulva or vagina. tol). 0662 Vaginal Dryness 0674. In one or more embodiments, the foam composition 0663 Vaginal dryness is caused by a number of conditions is useful in the therapy of disorders that respond to transmu and can be either an occasional hassle or a chronic problem. cosal delivery of an active agent. By way of example, Such A variety of anti-inflammatory active agents, hormones, disorders include, which respond to hormonetherapy, such as moisturizing, refatting and lubricating agents and local anes hormone replacement therapy, and other systemic disorders, thetic agents can be included in the foam, to be used for the known to be affected by drugs that are delivered transmucos treatment and/or prevention of vaginal dryness. ally. 0664) Dyspareunia 0675. The goal of a mucosal vaccine is to induce antigen 0665 Dysareunia is pain in the vagina or pelvis experi specific immune responses (cellular and humoral) that are enced during sexual intercourse. A variety of anti-inflamma detectable at the mucosal Surfaces of the host. Because many tory active agents, hormones, moisturizing, refatting and pathogens initiate infection at the mucosal Surfaces, patho lubricating agents and agents can be included gen-specific mucosal immune responses may provide Supe in the foam, to be used for the treatment and/or prevention of rior protection against infectious diseases than immune vaginal pain. Anal and rectal disease, such as anal abscess/ responses induced by parenteral vaccines because parenteral fistula, anal cancer, anal fissure, anal warts, Crohn's disease, vaccines do not induce mucosal immunity. hemorrhoids, anal itch, also called pruritus ani, fecal incon 0676 In the context of the present invention, the term tinence, and polyps of the colon and rectum all may be treated immunization or vaccination refers to administering a prepa using the foamable composition according to one or more ration that contains an infectious agent or its components, embodiments. which is able to stimulate an immune response that will 0.666 The foam composition, comprising an active agent protect a person from illness due to that agent. Such vaccines that is known to treat one of said anorectal disorders and are expected be capable of preventing the transmission or administered rectally, expands effectively in the rectal cavity limiting the severity of sexually-transmitted infections. Such and provides optimal coverage of the cavity Surface, for as HIV and other infectious disease. Vaccines are usually improved therapeutic results. administered in conjunction with an adjuvant—a Substance 0667 HIV and STD Treatment and Prevention that is used in a vaccine to improve the immune response so 0668. When comprising appropriate protective agents, the that less vaccine is needed to produce a non-specific stimu foam is active against HIV infection and other infections lator of the immune response. There are several types of (bacterial and fungal), including sexually transmitted disease adjuvants, including, for example, minerals such as alumi (STD) by creating a protective layer and/or decreasing the num hydroxide, aluminum phosphate and calcium phosphate, frequency of transmission. Non-binding examples of protec oil emulsions, products from bacteria (their synthetic deriva tive agents include: tives as well as liposomes) or gram-negative bacteria, endot 0669 Negatively charged sulfated polymers, which have oxins, cholesterol, fatty acids, aliphatic amines, paraffinic and been reported to have anti-HIV-1 activity and are being con Vegetable oils. sidered for development as topical microbicides. 0677. The foam composition, comprising an immunizing 0670 Dextrin sulphate, a microbicide, which in various agent, and optionally an adjuvant and administered onto the laboratory and pre-clinical studies, has been shown to block mucosal tissue of a body cavity, expands effectively in said the transfer of HIV virus into mammalian cells while at the cavity and provides optimal coverage of the cavity Surface, same time not causing injury to normal cell tissue. for improved therapeutic results. US 2008/0206161 A1 Aug. 28, 2008 64

0678 Post-Surgical Adhesions Treatment and Prevention Zyl peroxide (an anti-acne agent), retinoids, such as retinoic 0679. Adhesions are scars that form abnormal connections acid and retinol, fluconazole (an antifungal agent) (Y between tissue surfaces. Post-Surgical adhesion formation is a Kawashima et al. 1992.D’Souza et al. 2005,Wster R C et al. natural consequence of Surgery, resulting when tissue repairs 1991.Tansel et al. 2003). itself following incision, cauterization, Suturing, or other 0686 Microsponges are used as a topical carrier system. means of trauma. When comprising appropriate protective When applied to the skin, the microSponges release the active agents, the foam is Suitable for the treatment or prevention of ingredient on a time mode and also in response to other post Surgical adhesions. The use of foam is particularly stimuli (rubbing, temperature, pH, etc). By delivering the advantageous because foam can expand in the body cavity active gradually to the skin, MicroSponge-benzoyl peroxide and penetrate into hidden areas that cannot be reached by any formulations, for example, have excellent efficacy with mini other alternative means of administration. mal irritation. These are typical benefits from their use. 0680 Hormonal Therapy 0687 In addition to their drug entrapping properties, 0681. The foamable composition is suitable for adminis microSponges are capable of absorbing skin secretions, there tering a hormone to a mucosal membrane or a body cavity, in fore reducing oiliness and shine from the skin. Clinical stud order to deliver the hormone into the tissue of the target organ, ies demonstrated that the use of microSponges in a lotion in any disorder that responds to treatment with a hormone. reduced perceived oiliness on the skin by 50%; shine was Topically applied hormones can also be useful in contracep reduced by 20% microspheres. tion, when administered in foam, using a metered dose unit. 0688 Other embodiments of the present invention are 0682. The following examples exemplify the therapeutic directed to trapsomes other than microSponges. A person kits and pharmacological compositions and methods and uses skilled in the art, will understand that one trapsome may be described herein. Both exemplary postulated examples and replaced by one or more other trapsomes in the compositions examples of actual formulations are provided. Formulations of the present invention. without physical or chemical data are to be considered as 0689 "Silicon' containing solid matter includes silicon exemplary postulatd examples. The examples are for the pur oxide, also termed “silica”, “fumed silica” and “silica gel', a poses of illustration only and are not intended to be limiting. white or colorless insoluble solid (SiO); and talc, which is Many of the examples are formulations comprising a steroid fine grained mineral consisting of hydrated magnesium sili and or an LCD extract. As would be appreciated by a man of cate. Silicon may provide two different effects in emulsion the art they may be formulated with LCD on its own or with compositions: a) a trapsome effect; and b) a sensation effect at least one steroid, or with other active agents described to the skin. herein or with combinations thereof. 0690. Other trapsomes include according to some 0683. In one or more embodiments, the active agent may embodiment, carbon, for example in the form of amorphous be consigned to a body which is suspended or contained carbon or graphite; and/or oxidizing agents, such as benzoyl within the formulation. In some embodiments, the active peroxide, calcium and magnesium hypochlorite. agent is carried by the body. In other embodiments, the active 0691. According to some embodiments, the emulsion agent is captured by the body. In further embodiments, the compositions may include metallic silver, in Small particles, active agent is contained in the body. In some embodiments, including nanocrystalline silver, which is used for antibacte the body is a trapsome. rial and wound healing purposes; other metal particles and 0684. A “Trapsome' is an insoluble body that is insoluble mineral particles. Metallic particles may also provide a trap in water and in the final formulations described herein that is some effect. capable of entrapping, incorporating or otherwise Suspending 0692. According to some embodiments, the emulsion an active agent within its structure or confines and releasing it compositions may further include cosmetic scrub materials, upon a certain signal or stimulus, which can be a physical or including, for example meals of Strawberry seeds, raspberry a chemical or other signal. Non limiting examples of Sub seeds, apricot seeds, Sweet almond, cranberry seeds; and pig stances that can act as trapsomes are a) microSponges, b) ments, which are insoluble in the bubbled-gel composition. silica, c) mineral bodies like (i) Zeolite, (ii) bentonite, (iii) 0693 Silica Silicone, as used in the application is “sili graphite, inclusive (iv) polymers, (v) dendrimers and (V) lipo cone oil, like dimethicone, and silicone copolymers and Sur Somes, etc. Trapsomes may be used to incorporate one or factants containing Solid matter includes silicon oxide, also more active agents in a emulsion. For example, the trapsome termed “silica”, “fumed silica” and “silica gel, a white or may retain the at least one active agent during storage, yet colorless insoluble solid (SiO); and talc, which is fine release the at least one active agent at the delivery site respon grained mineral consisting of hydrated magnesium silicate. sive to a local temperature effect, a local pH effect, a local An example of entrapping silica is silica microcapsules, made conductivity effect or any other local parameter of the deliv by Sol-Gel Technologies, that can be fine-tuned to provide ery site, which is different from that of the storage conditions. optimal release properties for numerous actives including 0685. In one or more embodiments the trapsome is a liquids, hydrophobic materials, and Solids with poor water micropsponge. MicroSponges are macroporous beads, typi solubility, as described, for example, in U.S. Pat. No. 6,436, cally 10-25 microns in diameter, loaded with active agent. 3759, 6,303,149, 6,238,650: They consist of a copolymer, such as methyl methacrylate/ 0694 “Graphite intercalation compounds' are intercala glycol dimethacrylate crosspolymer. Depending on their tion compounds with a graphite host. In this type of com chemical composition, microSponges may be biodegradable. pound the graphite layers remain largely intact and the guest MicroSponges have the capacity to entrap a wide range of molecules or atoms are located in between. When the hostand active ingredients such as emollients, fragrances, essential the guest interact by charge transfer, the in-plane electrical oils, Sunscreens and anti-infective, etc. Examples of drugs conductivity generally increases. When the guest forms cova that have been incorporated in microSponges include ibupro lent bonds with the graphite layers as in fluorides or oxides the fen ketoprofen (non-steroidal anti-inflammatory agent), ben conductivity decreases as the conjugated sp° system col US 2008/0206161 A1 Aug. 28, 2008 lapses. In a graphite intercalation compound not every layer is bubbled-gel compositions of the present invention as inert necessarily occupied by guests. In so-called Stage 1 com carriers for one or more active agents. pounds graphite layers and intercalated layers alternate and in 0699. A "liposome' is a spherical vesicle composed of a stage 2 compounds two graphite layers with no guest material bilayer membrane. In biology, this specifically refers to a in between alternate with an intercalated layer. The actual membrane composed of a phospholipid and cholesterol composition may vary and therefore these compounds are an bilayer (see on the right). Liposomes can be composed of example of non-stoichiometric compounds. It is customary to naturally-derived phospholipids with mixed lipid chains (like specify the composition together with the stage. egg phosphatidylethanolamine), or of pure Surfactant com 0695) A zeolite' is a mineral having a micro-porous ponents like DOPE (dioleoylphosphatidylethanolamine). structure. More than 150 Zeolite types have been synthesized Liposomes, usually but not by definition, contain a core of and 48 naturally occurring Zeolites are known. They are basi aqueous solution; lipid spheres that contain no aqueous cally hydrated alumino-silicate minerals with an “open’ rial are called micelles, however, reverse micelles can be structure that can accommodate a wide variety of cations, made to encompass an aqueous environment. such as Na', K", Ca" Mg" and others. These positive ions 0700 Liposomes are used for drug delivery due to their are rather loosely held and can readily be exchanged for unique properties. Aliposome encapsulates a region on aque others in a contact solution. Some of the more common min ous solution inside a hydrophobic membrane; dissolved eral Zeolites are: analcime, chabazite, heulandite, natrolite, hydrophilic Solutes can not readily pass through the lipids. phillipsite, and stilbite. An example mineral formula is: Hydrophobic chemicals can be dissolved into the membrane, NaAlSiOo-2H2O, the formula for natrolite. Zeolite prod and in this way liposome can carry both hydrophobic mol ucts may be used in the bubbled-gel compositions of the ecules and hydrophilic molecules. To deliver the molecules to present invention as inert carriers for one or more active sites of action, the lipid bilayer can fuse with other bilayers agents. Such as the cell membrane, thus delivering the liposome con 0696 Natural zeolites form where volcanic rocks and ash tentS. layers react with alkaline groundwater. Zeolites also crystal 0701 Liposomes products may be used in the bubbled-gel lized in post-depositional environments over periods ranging compositions of the present invention as carriers for one or from thousands to millions of years in shallow marine basins. more active agents, for targeted delivery of one or more active Naturally occurring Zeolites are rarely pure and are contami agents to a delivery site. nated to varying degrees by other minerals, metals, quartz or 0702 “Microsponges” are rigid, porous and spongelike other Zeolites. For this reason, naturally occurring zeolites are round microscopic particles of cross-linked polymer beads excluded from many important commercial applications (e.g., polystyrene or copolymers thereof), each defining a where uniformity and purity are essential. substantially noncollapsible pore network. The Micro 0697 Zeolites are the aluminosilicate members of the sponges can be loaded with an active ingredient and can family of microporous solids known as "molecular sieves'. provide a controlled time release of the active ingredient to The term molecular sieve refers to a particular property of skin or to a mucosal membrane upon application of the for these materials, i.e. the ability to selectively sort molecules mulation. The slow release is intended to reduce irritation by based primarily on a size exclusion process. This is due to a the active. Microsponge R. delivery technology was devel very regular pore structure of molecular dimensions. The oped by Advanced Polymer Systems. maximum size of the molecular or ionic species that can enter 0703 Microsponges have a size range in between 5 to 300 the pores of a zeolite is controlled by the diameters of the um depending upon the degree of Smoothness or after feel tunnels. These are conventionally defined by the ring size of required for the end formulations and can reduce perceived the aperture, where, for example, the term “8 ring refers to a oiliness. closed loop that is built from 8 tetrahedrally coordinated 0704. Wide ranges of uses for microsponges incorporated silicon (or ) atoms and 8 oxygen atoms. These in foamable compositions are suggested aiming to provide rings are not always perfectly flat and symmetrical due to a increased efficacy for delivery of active agents topically and variety of effects, including strain induced by the bonding in a body cavity with enhanced control, spreadability, safety, between units that are needed to produce the overall structure, stability and improved aesthetic properties. Microspheres can or coordination of Some of the oxygen atoms of the rings to store an active agent until its release is triggered by applica cations within the structure. Therefore, the pore openings for tion to the skin Surface Such as through rubbing and or higher all rings of one size are not identical. Thus, Zeolites may serve than-ambient skin temperature. MicroSponge do not pass to preferentially release one active agent, according to a small through the skin but collect on the skin surface and slowly pore size opening and release another agent via larger pore release the entrapped agent. The empty spheres are washed size openings. away with cleansing. 0698 “Bentonite” is an absorbent aluminium phyllosili cate generally impure clay consisting mostly of montmoril 0705 Microsponges may be incorporated in wide ranges lonite. There are a few types of bentonites and their names of foam formulations. In one or more embodiments micro depend on the dominant elements, such as K, Na, Ca, and Al. sponges may be incorporated into the formulations exempli As noted in several places in the geologic literature, there are fied and described herein. some nomenclatorial problems with the classification of ben 0706. In an embodiment, the amount of microsponges tonite clays. Bentonite usually forms from weathering of may be varied from about 1% to about 25% of the formula Volcanic ash, most often in the presence of water. However, tion, preferably about 5% to 15%. the term bentonite, as well as a similar clay called tonstein, 0707. In an embodiment, any active agent suitable for have been used for clay beds of uncertain origin. For indus loading in microSponges may be used, such as benzyl peroX trial purposes, two main classes of bentonite exist: sodium ide (BPO), tretinoin, hydroquinone, kotoprofen, retinol, flu and calcium bentonite. Bentonite products may be used in the conazole, ibuprofen, trolamine and the like. US 2008/0206161 A1 Aug. 28, 2008 66

0708. In an embodiment, the microsponges are loaded to the microSponges including the trapped drug and any other with one or more steroids. ingredients incorporated when loading the microSponges. 0709. In an embodiment, the microsponges are loaded with coal tar. General Methodology 0710. In an embodiment, the microsponges are loaded 0719 Emulsion Pre-Foamable Foam Formulation with one or more vitamins or with one or more flavonoids or 0720) 1. Mix oily phase ingredients and heat to 75°C. to combinations thereof. In another embodiment the vitamins melt all ingredients and obtain homogeneous mixture. and or flavonoids are fat soluble. In another embodiment they 0721 2. Mix polymers in water with heating or cooling are water soluble. as appropriate for specific polymer. 0711. In an embodiment, the vitamin is a retinoid, prefer 0722. 3. Add all other water soluble ingredients to ably a vitaminA, more preferably, retinoic acid or isoretinoic water-polymer solution and heat to 75° C. acid. 0723 4. Add slowly internal phase to external phase at 0712. In an embodiment, the vitamin is preferably a vita 75°C. under vigorous mixing and homogenize to obtain min D, a derivative or analogue thereof, more preferably fine emulsion. calcipotriol or calcitriol or tacalcitol with or without a corti 0724 5. Cool to below 40° C. and add sensitive ingre costeroid such as betmethasone or its esters (eg brmv), fluci dients with mild mixing. nonide, hydrocortisone or clobetasol proprionate. 0725 6. Cool to room temperature. 0726 Note: The formulation can the be stored and as 0713. In an embodiment, since retinoids and BPO can dry required introduced into anaerosol canister with propel the skin, water Soluble humectants, e.g., urea, Sodium PCA, lant. alpha-hydroxy acids, glycerin and other polyols may be added. Production Under Vacuum 0714 As can be noted from above and herein different types of active agents may be loaded into the microSponges. 0727 Optionally, the foamable formulation may be pro duced under nitrogen and under vacuum. Whilst the whole Accordingly the foam formulation selected in which to dis process can be carried out under an oxygen free environment, perse the microSponges should be adapted so that the active it can be sufficient to apply a vacuum after heating and mixing agent remains Substantially entrapped in the microSponges. all the ingredients to obtain an emulsion or homogenous In another embodiment the active agent is present both in the liquid. Preferably the production chamber is equipped to foam formulation and in the microSponges so that some of the apply a vacuum but if not the formulation can be for example active agent is available for immediate penetration on appli placed in a dessicator to remove oxygen prior to filing and cation of the foam and that other amounts of active agent are crimping. provided by slow or controlled release from the microsponges now sitting on the topical Surface. Canisters Filling and Crimping 0715. Where the active agent is oil soluble but not water 0728. Each aerosol canister is filled with PFF and crimped soluble then formulations with minimal or no oil are preferred with valve using vacuum crimping machine. The process of where the active agent is primarily to be located in the micro applying a vacuum will cause most of the oxygen present to sponges. So in an embodiment there is no oil in the formula be eliminated. Addition of hydrocarbon propellant may with tions, only gels. In another embodiment, there are no signifi out being bound by any theory further help to reduce the cant amounts of true oils that solubilize the active ingredients likelihood of any remaining oxygen reacting with the active and extract them from the microSponges. ingredient. It may do so, without being bound by any theory, 0716. In an embodiment, where the active ingredient is by one or more of dissolving in the oil or hydrophobic phase insoluble in water and is entrapped in the microSponges, there of the formulation, by dissolving to a very limited extent in is provided true oil in water emulsion, where the active ingre the aqueous phase, by competing with Some oxygen from the dient is only exposed to the external water phase and does not formulation, by diluting out any oxygen, by a tendency of access the internal oil phase. This may be achieved in an oxygen to occupy the dead space, and by oxygen occupying embodiment by formulating an aqueous oil gel foam with part of the space created by the vacuum being the unfilled Substantial water content. Volume of the canister or that remaining oxygen is rendered 0717. In an embodiment, the foam formulation comprises substantially ineffective in the formulation. a large amount of hydrophobic surfactant or hydrophobic Pressurizing complex emulgators which can form a tight close surfactant layer Surrounding the oil droplets sitting in the water phase to Propellant Filling separate but still holding the water and oil phases together as an emulsion, thereby preventing or at least Substantially 0729 Pressurizing is carried out using a hydrocarbon gas reducing any leakage of active agent into the oil phase. In a orgas mixture. Canisters are filled and then warmed for 30sec further embodiment there is provided a foam, where the gel in a warm bath at 50° C. and well shaken immediately there ling agent is not fat soluble so as to prevent or at least Sub after. stantially reduce leakage. 0718 The methodology of loading microsponges with Closure Integrity Test active agent and amounts that can be loaded are described in 0730 Each pressurized canister is subjected to bubble and WO 01/85102, which is incorporated herein by way of refer crimping integrity testing by immersing the canister in a 60° ence. Where Drug MicrospongeX% w/w is provided it refers C. water bath for 2 minutes. Canisters are observed for leak US 2008/0206161 A1 Aug. 28, 2008 67 age as determined by the generation of bubbles. Canisters C. (24 hours) followed by +400°C. (24 hours) measuring the releasing bubbles are rejected. appearance and again repeating the cycle for up to three times. Analytical Methodology Chemical Stability Foam Tests 0737. The amount of active agent present is analyzed in foam expelled from various pressurized canisters containing 0731. By way of non limiting example the objectives of foam formulations using HPLC. Analysis is carried out at hardness, collapse time and FTC stability and other tests are Zero time and at appropriate time intervals thereafter. The briefly set out below as would be appreciated by a person of canisters are stored in controlled temperature incubators at 5° the art. C., at 25°C., at, 40° C. and at 50° C. At appropriate time intervals canisters are removed and the amount of active agent Hardness in the foam sample is measured. 0732. LFRA100 instrument is used to characterize hard Bubble Size ness. A probe is inserted into the test material. The resistance of the material to compression is measured by a calibrated 0738. Foams are made of gas bubbles entrapped in liquid. load cell and reported in units of grams on the texture analyzer The bubble size and distribution reflects in the visual texture instrument display. Preferably at least three repeat tests are and smoothness of the foam. Foam bubbles size is determined made. The textural characteristics of a dispensed foam can by dispensing a foam sample on a glass slide, taking a picture affect the degree of dermal penetration, efficacy, spreadability of the foam Surface with a digital camera equipped with a and acceptability to the user. The results can also be looked at macro lens. The diameter of about 30 bubbles is measured as an indicator of softness. Note: the foam sample is dis manually relatively to calibration standard template. Statisti pensed into an aluminum sample holder and filled to the top of cal parameters such as mean bubble diameter, standard devia the holder. tion and quartiles are then determined. Measuring diameter may also be undertaken with image analysis Software. The Collapse Time camera used was a Nikon D40X Camera (resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 0733 Collapse time (CT) is examined by dispensing a mm F2.8 EX DG HSM). Pictures obtained are cropped to given quantity of foam and photographing sequentially its keep a squared region of 400 pixelsx400 pixels. appearance with time during incubation at 36°C. It is useful for evaluating foam products, which maintain structural sta Bioadhesion bility at skin temperature for at least 1 min. Thus foams which are structurally stable on the skin for at least one minute are 0739 Bioadhesion (adhesive force) is an important prop termed “short term stable' compositions or foams. erty which needs to be examined for the selection of the foam formulation prototype. Adhesiveness is defined as the force Drainage: (g) needed to overcome attraction between two vaginal tis Sue-surfaces after being in contact. An animal model system 0734. A simple indication of the rate of drainage or for measuring adhesiveness using pig vaginal tissues was whether there is any significant drainage can be obtained from developed for this purpose. Measurements make use of the the collapse time method and results. In the collapse time LFRA Brookfield Texture Analyzer. Two sections of pig vagi method the foam is observed and filmed for 300 secs. The nal tissue (2x2 cm) are used; one is positioned in the center of height of the foam is measured against a marked ruler and any a Petri dish and the other is attached to the base of texture changes recorded and plotted as a graph. Also the foam qual analyzer probe. A PFF sample is spread uniformly on the ity is observed. If during the measurement there is a change in tissue section on the Petridish. The probe is moved down and quality it is noted. So simply if there is a reduction in quality up, first bringing the two sections into contact, followed by say from Good to Fairly Good or from Excellent to Good then separation. The Texture Analyzer enables the measurement of significant drainage is considered to have occurred. And the the force for separating the tissue sections. The adhesive force approximate time point when this change has been noted is is expressed as a negative force with the force to bring the two said to be the drainage time. A slow drainage is a drainage of sections in contact as a positive force. more than 300 seconds. 0740 Measurement of bioadhesion was performed on for mulations which are considered appropriate for vaginal use, Viscosity which showed Suitable physical and chemical properties at (0735. Viscosity is measured with Brookfield LVDV-11+ T-0 and after storage. Adhesiveness of Replens Gel an exist PRO with spindle SCs at ambient temperature and 10, 5 ing product was measured to serve as a reference. and 1 RPM. Viscosity is usually measured at 10 RPM. How ever, at about the apparent upper limit for the spindle of TABLE 6 ->50,000 CP, the viscosity at 1 RPM may be measured, although the figures are of a higher magnitude. Adhesiveness Test Results for Reference Product. Replens Gel. Formulation Adhesive force (g)* FTC (Freeze Thaw Cycles) Replens Gel For vaginal -12.13 0736. To check the foam appearance under extreme con lubrication) ditions of repeated cycles of cooling, heating, (first cycle) *results, average of three determinations cooling, heating (second cycle) etc., commencing with -100° US 2008/0206161 A1 Aug. 28, 2008

Creaming by Centrifugation: againstaverage peak area ratio of BMV standard (0.2 mg/mL) to the IS present in the standard solution at the same concen 1. Principle of Test tration as in samples. 0741. The centrifugation used in this procedure serves as a stress condition simulating the aging of the liquid dispersion EXAMPLES under investigation. Under these conditions, the centrifugal force applied facilitates the coalescence of dispersed globules Example 1 or sedimentation of dispersed solids, resulting in loss of the Oil in Water Anti-Inflammatory Steroid Foamable desired properties of the formulated dispersion. Emulsion Compositions with/without Additional Active Agents 2. Procedure 0751) 0742 2.1. Following preparation of the experimental formulation/s, allow to stand at room temperature for >24 h. 0743. 2.2. Handle pentane in the chemical hood. Add to Composition Code: each experimental formulation in a 20-mL glass vial a HB1 BV1 BV2 HB2 HB3 quantity of pentane equivalent to the specified quantity Ingredient % of propellant for that formulation, mix and allow formu lation to stand for at least 1 h and not more than 24 h. Hydrocortisone butyrate O.10 (steroid) 0744 2.3. Transfer each mixture to 1.5 mL microtubes. Betamethasone valerate O.12 O.12 Tap each microtube on the table surface to remove (steroid) entrapped air bubbles. Haolbetasol (steroid) O.O2 O.O1 Alpha-Bisabolol O.2O O.2O 0745 2.4. Place visually balanced microtubes in the (additional active agent) centrifuge rotor and operate the centrifuge at 3,000 rpm D-Pantheno SOP 1O.OO 1O.OO for 10 minor at 10,000 rpm for 10 min. The centrifuge (additional active agent) can be a BHG HEMLE Z 231 M. Mineral oil 12.00 12.OO 12.00 12.OO 12.00 Isopropyl myristate 12.00 12.00 12.00 12.00 12.00 07:46 2.5. Visually inspect samples following centrifu Dimeticone V100 3.00 3.00 3.00 3.00 3.00 gation for creaming and for emulsion breakdown. Glyceryl monostearate OSO OSO O.SO OSO O.SO MYR 52 3.00 3.00 3.00 3.00 3.00 Microcrystalline 2.00 1.OO 2.00 2.OO 2.00 Hardness cellulose + carboxymethyl cellulose 1. Scope TWEEN 8O 1.00 1.OO 1.00 1.OO 1.00 Cocoamidopropyl betaine OSO OSO O.SO OSO O.SO 0747. The LFRA100 instrument is used to characterize Preservative O.30 O.30 O.30 O.30 O.30 hardness. Purified water To 100 TO 100 TO 100 TO 100 TO 100 2. Principle of Test 0748. This principle of operation of the LFRA texture Example 2 analyzer is to drive a probe into the test material. The resis tance of the material to compression is measured by a cali Oil in Water Steroid Hormone Foamable Emulsion brated load cell and reported in units of grams on the instru Compositions ment display. At least 3 repeat test measurements are made for each sample. Operation and calibration is according instru 0752 ment instructions and program. Note: the foam sample is dispensed into an aluminum sample holder and filled to the top of the holder. Composition Code: 0749 Chemical stability at 25° C. and at 40° C.; API HB1 BV1 BV 2 HB2 concentration; and assay of degradation product are all mea Ingredient % sured by an HPLC tests specific for each one of the API's as will be appreciated by a an of the art. For example, the HPLC (steroid hormone) O.25 0.25 O.25 O.25 Propylene glycol (penetration enhancer) 2.OO 4.OO method for quantitative analysis of Betamethasone 17 Valer Diethylene glycol monoethyl ether 6.OO ate and Betamethasone 21 valerate (BMV 17 and 21) is (penetration enhancer) briefly set out below: Mineral oil 12.OO 12.OO 12.OO 12.00 Isopropyl myristate 12.OO 12.OO 12.OO 12.00 Dimeticone V100 3.00 3.00 3.00 3.00 Principle of Test Glyceryl monostearate OSO O.SO O.SO OSO MYR 52 3.00 3.00 3.00 3.00 0750 About 1 g of foam or pre-foam formulation is dis Microcrystalline cellulose + carboxymethyl 2.OO 1.OO 2.OO 2.OO solved in 0.1% acetic acid in methanol (diluent), to which an cellulose internal standard (IS) solution is added. BMV, BMV-21 and TWEEN 8O 1.OO 1.OO 100 1.OO IS are extracted by heating, cooling and centrifugation of the Cocoamidopropyl betaine OSO O.SO O.SO OSO Preservative O.30 O.30 O.30 O.30 sample solution. The clear layer is analyzed by HPLC using a Purified water To To To To C-18 column; elution is performed with a mobile phase con 1OO 100 100 100 taining acetonitrile:water 60:40. The content of BMV and BMV-21 is calculated using the respective peak area ratio US 2008/0206161 A1 Aug. 28, 2008 69

Example 3 prepared, with and without a surface active agent. See, FIGS. 2B and 2C. In this particular case, the Surface active agent Oil in Water Foamable Emulsion Compositions system consisted of a combination of one non-ionic Surfac Comprising Steroids from Natural Sources tants PEG-40 stearate and Polysorbate 60, as shown in the 0753 Avocado (Persea gratissima) oil and extracts are following compositions: used as an example of plants that contain phytosteroids. The oil and extracts contain two important phytosteroids—Stig masterol and beta-sitosterol, which are known to provide a Composition No: variety of beneficial effects, such as tissue regeneration, improvement of skin elasticity, moisturization, stimulation of Water Phase, Water Phase, Water Phase, collagen synthesis, inhibition of leukotriene and prostaglan Ingredient No Surfactant With Surfactant With Surfactant din formation (anti-inflammatory effect), anti-bacterial Betamethasone 0.12 gr. 0.12 gr. 0.12 gr. effects, skin barrier repair, film-forming properties, improve valerate (steroid) ment of trans-epidermal water loss. Lanolin oil contains high PEG-40 Stearate 2.50 gr. levels of cholesterol, iso-cholesterol and derivatives thereof. (Surface active agent) The following compositions include avocado oil and lanolin Polysorbate 60 1.00 gr. oil as part of the oil phase of the composition. (Surface active agent) Xanthan gum 0.26 gr. 0.26 gr. (polymeric agent) Methocel K100 0.26 gr. 0.26 gr. 0.26 gr. (polymeric agent) Composition No: Citric acid 1.30 gr. 1.30 gr. 1.30 gr. Sodium citrate 1.10 gr. 1.10 gr. 1.10 gr. LN1 LN2 AV1 Water 61.46 gr. 61.46 gr. 61.46 gr. Ingredient % Lanolin oil 2.50 2.50 Avocado concentrate - Avocadin, 5.60 (0757. As shown in FIG. 2B-2D, composition BV4 and produced by Crodarom (steroid) BV5, prior to the addition of a surface active agent exhibited Mineral oil 5.60 5.60 high crystal content (Plate 3 and 4), while in composition Isopropyl myristate 5.60 5.60 5.60 BV6 including a surface active agent system, no crystals were Glyceryl monostearate O45 O45 O45 observed (Plate 2). For reference purposes in FIGS. 2E and Stearyl alcohol O.85 O.85 O.85 Xanthan gum O.2O O.20 O.2O 2F, Plates 5 and 6 illustrate the microscopic pictures of Methocel K10OM O.2O O.20 O.2O Betamethasone Valerate powder and a commercial Polysorbate 80 O.90 O.90 O.90 betamethasone Valerate 0.12% cream (Betnovate, Glaxo PEG-40 Stearate 2.60 2.60 2.60 Smithkline). EDTA disodium O.2O O.20 O.2O 0758 Thus, in one or ore embodiments there is provided a Preservative O.25 O.25 O.25 composition containing a steroid solubilized or Substantially Propellant 8.OO 8.00 8.OO solubilized in the composition, but insoluble both in water Water To 100 To 100 To 100 and in the oil phase of the composition.

Example 4 Example 5 An Emulsion Composition Containing a Steroid 0759. This monocenter, single Investigator study was con ducted to determine the skin irritation, and sensitivity of a Solubilize in the Composition, but Insoluble Both in series of foamable compositions in Subjects with normal and Water and in the Oil Phase of the Composition sensitive skin. The objectives of the study were: 0754) 0760. To assess the skin irritation potential of Foamix Products and two controls: purified water as the negative control and SLS as the positive control, by means of a single Composition No: 48-hour patch application to the skin of healthy volunteers, BV3 having either “normal skin' or “sensitive skin'. Ingredient % 0761. A total of forty subjects were screened. Thirty sub Betamethasone valerate (steroid) O.12 jects with “normal skin' and ten subjects with “sensitive Mineral oil 3O.OO skin', who satisfied the inclusion and exclusion criteria, were Glyceryl Stearate 1.OO Stearyl alcohol 1.OO able to accept the prohibitions and restrictions and provided PEG-40 Stearate 2.50 written informed consent were enrolled onto the study and Xanthan gum O.26 participated in the Irritation and sensitivity tests study. Methocel K100 O.26 Polysorbate 60 1.OO Results Citric acid 1.30 Sodium citrate 1.10 0762. Irritation Potential in Subjects with Normal Skin: Water 61.46 0763 Thirty subjects with normal skin successfully com pleted the skin Irritation study. 0755. The emulsion composition of Example 4 was micro 0764. 30 subjects received Foamix Product No. 7 and 2 scopically observed at X400 magnification with polarization. controls one positive and one negative. The patches remained As demonstrated in FIG. 2A (Plate 1), no crystals were in place for 48 hours. observed in the emulsion composition. 0765. Foamix tested article No. 7 did not reveal any sign of 0756. In an effort to identify the components that contrib irritation following application, in any of the study subjects. ute to solubilization, the aqueous phase of the emulsion was Thus, under the current study protocol and conditions, Foa US 2008/0206161 A1 Aug. 28, 2008 70 mix tested article, Betamethasone Valerate 0.12% can be regarded as non-irritating to normal skin. -continued Irritation Potential in Subjects with Sensitive Skin: 0766 Ten subjects with sensitive skin successfully com 6(a) Matrix with Carboxymethylcellulose sodium pleted the Irritation Test. 0767. Each received Foamix Products No. 7 at a dose of USAN name WW 9% WW 9% WW 9% about 0.1 mL under occlusive patches. The patches remained Lanolin O.OO O.OO O.OO in place for 48 hours. Octyl dodecanol 3.00 6.OO O.OO 0768 Foamix tested article No. 7 did not reveal any sign of Cetearyl octanoate 0.75 1...SO O.OO irritation following application, in any of the study subjects. Glyceryl monostearate O.OO 1.OO O.OO Thus, under the current study protocol and conditions, Foa Cetearyl alcohol 1.00 1.OO 1.OO mix tested article Betamethasone Valerate 0.12% can be Ceteareth-20 O.OO 3.00 3.00 regarded as non-irritating to sensitive skin. Polyoxyl 40 stearate 2.50 O.OO O.OO Dimethicone 350 O.OO O.OO 1.OO Safety Benzyl alcohol O60 O.60 O.60 Carboxymethylcellulose OSO O.SO O.SO 0769 No adverse events was recorded. Sodium Polysorbate 80 1.00 O.OO O.OO Dimethicone copolyol 1.00 O.OO O.OO List of tested Products ID numbers Cyclomethicone O.OO 1.OO O.OO Purified water 72.30 63.80 69.8O Product ProductID Number Glycerin S.OO S.OO S.OO Betamethasone Valerate 0.12% 7 LCD 1O.OO 1O.OO 1O.OO Purified water 12 Peppermint oil 1.00 1.OO 1.OO detergent solution 2% Sodium lauryl Sulphate 13 Hydrocortisone O.10 O.10 O.10

Total 1OOOO 100.00 100.00 NaOH (18% Solution) to pH 6.0 Tested Article Formulation Results of testing (0770 Appearance:

Quality E E E Test Article No 7: Betamethasone valerate 0.12% Color Yellow Yellow Yellow Odor Faint Faint Faint Ingredients % Wiw Collapse time, sec >12O >120 >12O Betamethasone valerate O.12 Density, g/mL. O.O37 O.O39 O.O36 Isopropyl myristate 1O.OO Centrifugation 3K rpm x 10 min Stable Stable Stable Octyldodecanol 12.00 Centrifugation 10K rpm x 10 min 90 95 95 Stearyl alcohol 1.OO Glyceryl Stearate 1.OO *Stable = no phase separation or creaming wereobserved. PEG-40 Stearate 2.60 Methylcellulose K10OM O.28 Xanthan gum O.28 Polysorbate 60 1.OO Purified water 68.32 in phenoxyethanol 1.OO 6(b). Matrix with Hypronellose and Xanthan gun Citric acid 1.30 Sodium citrate 1.10 USAN name WW 9% WW 9% WW 9% Total product: 100.00 Mineral oil, heavy 1O.OO 10.00 O.OO PPG-15 Stearyl ether 3.00 O.OO O.OO Caprylic Capric triglyceride O.OO O.OO S.OO Sopropyl myristate O.OO O.OO S.OO Lanolin O.OO 2.00 O.OO Example 6 Cetearyl alcohol O.OO 1.00 O.OO Ceteareth-20 O.OO O.OO 3.00 Hydrocortisone and LCD Matrix of Compositions Stearic acid 1.OO O.OO 1.00 Showing Resilience to Creaming a) with Carboxym Polyoxyl 40 stearate 2.50 2.50 O.OO ethylcellulose Sodium and b) with Hypromellose and Dimethicone 350 1.OO O.OO O.OO Xanthan Gum Benzyl alcohol O.6O O.60 O.60 Hypromellose K100M O.25 O.25 O.25 Xanthan gum O.25 O.25 O.25 0771) Polysorbate 80 1.OO 1.00 O.OO Dimethicone copolyol 1.OO O.OO 1.00 Cyclomethicone O.OO 1.00 O.OO Purified water 63.30 65.30 67.8O 6(a) Matrix with Carboxymethylcellulose Sodium Glycerin S.OO S.OO S.OO LCD 1O.OO 10.00 10.00 USAN name WW9% WW 9% WW 9% Peppermint oil 1.OO 1.00 1.00 Hydrocortisone O.10 O.10 - 10 Mineral oil, heavy O.OO O.OO S.OO PPG-15 Stearyl ether O.OO 3.00 3.00 Total 1OOOO 100.00 100.00 Petrolatum, white 1.25 2.50 O.OO NaOH (18% Solution) to pH 6.0 US 2008/0206161 A1 Aug. 28, 2008 71

-continued -continued 6(b). Matrix with Hypronellose and Xanthan gun 7(a) Matrix with Carboxymethylcellulose sodium USAN name WW 9% WW 9% WW 9% USAN name WW 9% WW 9% WW 9% Results of testing Cetearyl octanoate 0.75 1...SO O.OO Appearrance: Glyceryl monostearate O.OO 1.OO O.OO Cetearyl alcohol 1.00 1.OO 1.OO Quality E E E Ceteareth-20 O.OO 3.00 3.00 Color Yellow Yellow Yellow Polyoxyl 40 stearate 2.50 O.OO O.OO Odor Faint Faint Faint Dimethicone 350 O.OO O.OO 1.OO Collapse time, sec >12O >12O >12O Density, g/mL O.O38 O.044 O.036 Benzyl alcohol O60 O.60 O.60 Centrifugation 3K RPM 10 min Stable Stable Stable Carboxymethylcellulose OSO O.SO O.SO 10K rpm x 10 min, % of creaming 30 2O 2O Sodium Polysorbate 80 1.00 O.OO O.OO *Stable = no phase separation or creaming were observed. Dimethicone copolyol 1.00 O.OO O.OO Cyclomethicone O.OO 1.OO O.OO 0772 Comments: Foams comprising LCD in combination Purified water 72.30 63.80 69.8O with Hydrocortisone were prepared with exemplary ingredi Glycerin S.OO S.OO S.OO ents, mineral oil, PPG-15 stearyl ether, capric/caprylic trig LCD 1O.OO 1O.OO 1O.OO lyceride, octyl dodecanol and isopropyl myristate, stabilized Peppermint oil 1.00 1.OO 1.OO with ceteareth 20, or PEG-40 stearate, and polysorbate 80 and Fluocinonide O.10 O.10 O.10 co-stabilized with glyceryl monostearate, Stearic acid, and stabilizing resilient polymers, methylcellulose, Xanthan gum Total 1OOOO 100.00 100.00 or sodium carboxymethyl cellulose, Vaseline and lanoline, NaOH (18% Solution) to pH 6.0 glycerin and silicone as skin feeling modifiers, and benzyl Results of testing alcohol as microbial preservative. Appearance: 0773 All the foamable compositions produced excellent foams with a reasonable collapse time during which the Quality E E E expanded foam remains substantially intact. Both of the resil Color Yellow Yellow Yellow ientagents a) methylcellulose and Xanthan gum orb) Sodium Odor Faint Faint Faint Carboxymethyl cellulose were successfully applied to pro Collapse time, sec >12O >120 >12O duce a pseudoplastic or semi-pseudoplastic formulation Density, g/Ml O.O37 O.O39 O.O36 which was resistant to creaming/phase separation when Sub Centrifugation 3K rpm x 10 min Stable Stable Stable jected to both significant centrifugal force. No separation of Centrifugation 10K rpm x 10 min 90 95 95 oily phase ingredients and no creaming were observed fol lowing centrifugation at 3000 rpm. It can be extrapolated that E = excellent: compositions, which can withstand Such a g-force are prob *Stable = no phase separation or creaming was observed. ably capable of remaining physically stable at room tempera ture during the expected two years shelflife of a pharmaceu tical product or for a lesser reasonable period. The three compositions comprising sodium carboxymethyl cellulose 7(2) Matrix with Hypronellose and Xanthan gun were also substantially resilient to harsh centrifugation at 10,000 rpm. It may be possible to further increase the resil USAN name WW 9% WW 9% WW 9% ience of the compositions for example by raising the level of Mineral oil, heavy 1O.OO 10.00 O.OO the resilient agents. PPG-15 Stearyl ether 3.00 O.OO O.OO Caprylic Capric triglyceride O.OO O.OO S.OO Sopropyl myristate O.OO O.OO S.OO Example 7 Lanolin O.OO 2.00 O.OO Cetearyl alcohol O.OO 1.00 O.OO A matrix of Compositions Comprising Fluocinonide Ceteareth-20 O.OO O.OO 3.00 and LCD as Active Agents, which are Resilient to Stearic acid 1.OO O.OO 1.00 Creaming Polyoxyl 40 stearate 2.50 2.50 O.OO Dimethicone 350 1.OO O.OO O.OO Benzyl alcohol O.6O O.60 O.60 0774 Hypromellose K100M O.25 O.25 O.25 Xanthan gum O.25 O.25 O.25 Polysorbate 80 1.OO 1.00 O.OO Dimethicone copolyol 1.OO O.OO 1.00 T(a) Matrix with Carboxymethylcellulose sodium Cyclomethicone O.OO 1.00 O.OO Purified water 63.30 65.30 67.8O USAN name WW9% WW 9% WW 9% Glycerin S.OO S.OO S.OO LCD 1O.OO 10.00 10.00 Mineral oil, heavy O.OO O.OO S.OO Peppermint oil 1.OO 1.00 1.00 PPG-15 Stearyl ether O.OO 3.00 3.00 Fluocinonide O.10 O.10 O.10 Petrolatum, white 1.25 2.50 O.OO Lanolin O.OO O.OO O.OO Total 1OOOO 100.00 100.00 Octyl dodecanol 3.00 6.OO O.OO NaOH (18% Solution) to pH 6.0 US 2008/0206161 A1 Aug. 28, 2008 72

room temperature during the expected two years shelf life of -continued a pharmaceutical product or for a lesser reasonable period. The three compositions comprising sodium carboxymethyl T(2) Matrix with Hypronellose and Xanthan gun cellulose were also resilient to harsh centrifugation at 10,000 USAN name WW 9% WW 9% WW 9% rpm. Results of testing Example 8 Appearance: Formulation of Betamethasone Valerate which is Physically Stable and in which the Active Pharma ColorQuality YellowE YellowE YellowE ceutical Ingredient is also Stable Chemically for a) Odor Faint Faint Faint Two Years at Room Temperature and b) Six Months Collapse time, sec >12O >12O >12O at 40° C. Density, g/mL O.O38 O.044 O.036 Centrifugation 3K RPM 10 min Stable Stable Stable 0777 10K rpm x 10 min, % of creaming 30 2O 2O E = excellent: ngredient % ww *Stable = no phase separation or creaming were observed. Sopropyl myristate 1O.OO 0775 Comments: Foams comprising LCD in combination Octyl dodecanol 12.00 with flucocinide were prepared with exemplatory ingredients, Stearyl alcohol 1.OO mineral oil, PPG-15 stearyl ether, capric/caprylic triglycer- E. 1.OO ide, octyl dodecanol and isopropyl myristate, stabilized with Hypromellose O.28 ceteareth 20, or PEG-40 stearate, and polysorbate 80 and Xanthan gum O.28 co-stabilized with glyceryl monostearate, Stearic acid, and Polysorba n 1.OO stabilizing- resilient- polymers, methylcellulose, Xanthan gum Water,Mixture purifie of Propyl, Ethyl and Methyl 68.3141.OO or sodium carboxymethyl cellulose, Vaseline and lanoline, in glycerin and silicone as skin feeling modifiers, and benzyl 2-phenoxyethanol alcohol as microbial preservative. Citric aci 1.30 Sodium citrate 1.10 0776 All the foamable compositions produced excellent Betamethasone Valerate O.126 foams with a reasonable collapse time of over two minutes Total: 100.00 during which the expanded foam remains Substantially intact. Citric acid or/and sodium citrate to pH = 4.0–4.4 Both of the resilient agents a) methylcellulose and Xanthan Propellant (butane, isobutane, propane) 8.OO gum or b) sodium carboxymethyl cellulose were successfully ColorFoam quality Excellentwhite applied to produce a pseudoplastic or semi-pseudoplastic Odor no odor formulation which was resistant to creaming/phase separa- Density O.O34 tion when Subjected to a significant centrifugal force. No R time > 3 separation of oily phase ingredients and no creaming were Centrifugation8Cl(SS 3,000 RPM Stable observed following centrifugation at 3OOO rpm. It can be Centrifugation: 10,000 RPM 30% extrapolated that compositions, which can withstand Such a g-force are probably capable of remaining physically stable at

Stability of BMV-formulation at 40 C. Specification Test parameter for Release TO T1 T2 T-3 T-6 API assay:

concentration(% O. 120-0.132 O.128 0.125 0.123 O.124 O.120 wfw) % of label claim: 100.0-110.0 106.7 1040 102.5 103.3 1OOO Assay of NMT 2.5 ND O653 1.4 2.1 5.30 degradation product (BM21V as % of BM17V peak) Appearance: NA NA Quality Good (G)- E E E excellent (E) Color White to off White White White white Odor Very faint to no No Odor Very faint Very faint odor odor Density (g/mL) O.O3O to O.O70 O.O34 NA NA O.O37 O.041 Expansion time &3OO 48 NA NA 50 45 (Sec) US 2008/0206161 A1 Aug. 28, 2008

-continued Stability of BMV-formulation at 40 C. Specification Test parameter for Release TO T1 T2 T-3 T-6 Collapse time (sec) 2120 >3OO NA NA >3OO >300 pH (diluted 1:5 in 3.90-440 3.94 NA NA 3.99 4.02 water) Texture, hardness For Information 15.3 NA NA 16.1 16.5 (g) only T = time in months, NA = not applicable; ND: not determined.

-continued Stability of BMV-formulation at 25 C. Chemical name WW 9% WW9% Specification Stearyl alcohol 1.OO Test parameter for Release TO T-6 T-12 PEG-40 Stearate 2.50 2.50 Xanthan gum O.26 API assay: Hydroxypropyl methyl cellulose K100 O.26 Carboxymethyl cellulose OSO concentration(% O.120-0.132 O.128 O.126 O.12S Polysorbate 60 1.OO wfw) Polysorbate 80 1.00 % of label claim: 100.0-11.O.O 106.7 105.8 104.2 Citric acid 1.30 O.70 Assay of Sodium citrate 1.10 O60 degradation Water 87.53 81.65 product Betamethasone dipropionate O.OS O.OS

(BM21V as % of NMT 2.5 ND O46 O.74 Total 89.98 100.00 BM17V peak) Propellant 8.OO 8.00 Content uniformity, NMT 5.0 1.6 NA 3.8 Results intra-canister (%): Appearance: Appearance: Quality Excellent Excellent Quality Good (G)- E E E Color White White excellent (E) Odor No odor No odor Color White to off White White White Collapse time >12O >12O white Hardness 14.28 18.59 Odor Very faint to No odor Very faint Very faint Density O.O24 O.O3S no odor odor Density (g/mL) O.O3O to 0.070 O.O34 O.O34 O.O39 Expansion time &300 48 60 48 0780 Betamethasone diropionate was formulated in two (Sec) exemplary composition, the first low oil concentration and the Collapse time (sec) 2120 >300 >3OO >300 pH (diluted 1:5 in 3.90-440 3.94 3.98 4.01 second medium oils concentration. In these examples, the water) major emollient oil is isopropyl myristate and the stabilizers Texture, hardness For 15.3 14.4 1S.O are common Surfactants and polymers. The foams are of (g) Information excellent quality and withstand at least one cycle of stress only freeze and thaw. 0778 Comments: The results show that betamethsone 17 Example 10 Valerate was stabile in the formulation with negligible degra dation to betamethasone 21 Valerate at room temperature and PPG ofw Emulsion: with Fluocinonide in Combina an also under accelerated conditions of 40C. tion with Clindamycin Phosphate 0781 Example 9 Betamethasone Diproprionate Foamable Emulsion Compositions Betamethasone Dipropionate Matrix Chemical name WW9% WW 9% 0779) PPG-15 stearyl ether 6.OO 1S.OO Octyldodecanol 6.OO Brij721 1.60 1.60 Laureth-4 2.20 2.20 Chemical name WW 9% WW9% Ceteth-20 1...SO 1...SO Methyl cellulose O.25 O.25 Isopropyl myristate 2.OO 12.00 K10OM Glyceryl Stearate 1.OO 1.OO Xanthan gum O.25 O.25 US 2008/0206161 A1 Aug. 28, 2008 74

-continued -continued

Chemical name WW 9% WW9% Chemical name WW9% WW 9% Water, purified 76.90 73.90 Odor No odor No odor Benzyl alcohol 1.OO 1.00 Collapse time >12O >12O Propylene Glycol 3.00 3.00 Hardness 12.S1 1246 Clindamycin Phosphate 1.2 1.2 Density O.O38 O.O37 Fluocinonide O.10 O.10 Centrifugation 3K 10 min Stable Stable Sodium Hydroxide To pH 4.7 To pH 4.7 Centrifugation 1 OK 10 min 35% 359 Solution 18% creaming creaming Results Appearance: *Stable = no phase separation or creaming were observed. Quality Excellent Excellent 0784 Comments: Hydrocortisone in combination with Color White White Odor No odor No odor clindamycin phosphate were formulated in two emollient Collapse time >12O >12O oil-in-water emulsions, one based on octyl dodecanol in com Hardness 12.S1 1246 bination with PPG-15 stearyl ether and the other solely on Density O.O38 O.O37 PPG-15 sterayl ether. Both formulations produced foams of Centrifugation 3K 10 min Stable Stable Centrifugation 1 OK 10 min 35% 35% excellent quality with beneficial physical properties Such as creaming creaming desired hardness, a reasonable collapse time of over two minutes during which the expanded foam remains Substan *Stable = no phase separation or creaming were observed. tially intact, and resistance to creaming/phase separation when subjected to centrifugation at 3000 rpm. It can be 0782 Comments: Fluocinonide in combination with clin extrapolated that compositions, which can withstand Such a damycin phosphate were formulated in two emollient oil-in g-force are probably capable of remaining physically stable at water emulsions, one based on octyl dodecanol in combina room temperature during the expected two years shelf life of tion with PPG-15 stearylether and the other solely on PPG-15 a pharmaceutical product or for a lesser reasonable period. sterayl ether. Both formulations produced foams of excellent quality with beneficial physical properties such as desired Example 12 hardness, a reasonable collapse time of over two minutes during which the expanded foam remains Substantially intact, A matrix of Compositions Comprising Hydrocorti and resistance to creaming/phase separation when subjected Sone and AZelaic Acid (AZL) as Active Agents, to centrifugation at 3000 rpm. It can be extrapolated that which are Resilient to Creaming compositions, which can withstand Such a g-force are prob ably capable of remaining physically stable at room tempera 0785 ture during the expected two years shelflife of a pharmaceu tical product or for a lesser reasonable period. Example 11 Chemical name WW9% WW9% WW 9% WW 9% Caprylic Capric S.OO 1O.OO 10.00 1O.OO Two Compositions Comprising Hydrocortisone and Triglyceride Clindamycin Phosphate (CDM) as Active Agents, Cetearyl alcohol O.90 1.OO 1.00 1.OO Glyceryl Stearate O45 OSO O.SO OSO which are Resilient to Creaming Cholesterol 1.OO 1.OO Benzyl alcohol 1.OO 1.OO 0783 Benzoic acid O.2O O.20 Butylated O.10 O.10 O.10 O.10 hydroxytoluene PEG-40 Stearate 2.60 2.60 2.60 2.60 Chemical name WW 9% WW9% Methylcellulose O.10 O.10 O.10 K10OM PPG-15 stearyl ether 6.OO 1S.OO Methylcellulose A4M O.10 Octyldodecanol 6.OO O Xanthan gum O.25 O.25 O.25 O.25 Brif21 1.60 1.60 Polysorbate 80 O.90 O.90 O.90 O.90 Laureth-4 2.2O 2.20 EDTA disodium O.10 Ceteth-20 1...SO 1...SO Sodium Hydroxide OSO Methyl cellulose O.25 O.25 Water purified 55.60 57.35 53.35 67.05 K1OOM Dimethyl isosorbode 1O.OO S.OO Xanthan gum O.25 O.25 Propylene glycol 6.OO S.OO 10.00 Water, purified 76.OO 73.00 PEG-4OO S.OO Benzyl alcohol 1.OO 1.00 AZelaic Acid 1S.OO 1S.OO 1S.OO 1S.OO Propylene Glycol 3.00 3.00 Hydrocortisone 1.OO 1.OO 1.00 1.OO Clindamycin Phosphate 1.2 1.2 Hydrocortisone 1.OO 1.00 Total 100 100 1OO 100 Sodium Hydroxide To pH 4.7 To pH 4.7 Results Solution 18% Appearance: Results Appearance: Quality E E E E Color O.W O.W O.W O.W Quality Excellent Excellent Odor V.F.O V.F.O V.F.O V.F.O Color White White Collapse time >12O >12O >12O >12O US 2008/0206161 A1 Aug. 28, 2008

-continued -continued

Chemical name WW9% WW 9% WW 9% WW 9% WW 9% WW 9% WW 9% WW 9%

Hardness 22.3 21.3 39.0 14.5 Odor V.F.O:s V.F.O:s V.F.O:s V.F.O:s Density O.O38 O.O3O O.O32 O.044 Collapse time >12O >12O >12O >12O Centrifugation 3K Stable Stable Stable Stable Hardness 22.3 21.3 39.0 14.5 10 min Density O.O38 O.O3O O.O32 O.044 Centrifugation 10K 10% 40% 30% 20% Centrifugation 3K Stable:* Stable: * Stable:* Stable:* 10 min Creaming Creaming Creaming Creaming 10 min Centrifugation 10K 10% 40% 30% 20% *Stable = no phase separation or creaming were observed; E = excellent; 10 min Creaming Creaming Creaming Creaming OW = off white; and V.F.O = very faint odor. *Stable = no phase separation or creaming: E = excellent; V.F.O = very faint 0786 Comments: It is very difficult to stabilize such com odor. positions since azaleic acid is a Solid and significant quanti ties are required. Hydrocortisone, in combination with aza 0788 Comments: fluocinonide in combination with aze leic acid, were successfully formulated in oil-in-water laic acid were formulated in oil-in-water emulsions based on emulsions. The formulations produced foams of excellent caprylic/capric triglyceride. The 15% azelaic acid Suspension quality with beneficial physical properties such as desired with fluocinonide shows minimal settling and azelaic acid hardness, a reasonable collapse time of over two minutes particles in the emollient emulsion are readily re-suspendable during which the expanded foam remains Substantially intact, upon slight hand shaking. The formulations produced foams and resistance to creaming/phase separation when subjected of excellent quality with beneficial physical properties such to centrifugation at 3000 rpm. It can be extrapolated that as desired hardness, a reasonable collapse time of over two compositions, which can withstand Such a g-force are prob minutes during which the expanded foam remains Substan ably capable of remaining physically stable at room tempera tially intact, and resistance to creaming/phase separation ture during the expected two years shelflife of a pharmaceu when subjected to centrifugation at 3000 rpm. It can be tical product or for a lesser reasonable period. These extrapolated that compositions, which can withstand Such a compositions were rugged and resilient to harsh centrifuga g-force are probably capable of remaining physically stable at tion of 10,000 rpm. room temperature during the expected two years shelf life of Example 13 a pharmaceutical product or for a lesser reasonable period. A matrix of Compositions Comprising Fluocinonide Example 14 and AZelaic Acid (AZL) as Active Agents, which are Resilient to Creaming A Composition Comprising Hydrocortisone Butyrate, which is Resilient to Creaming 0787 0789

WW 9% WW 9% WW 9, WW 9% WW 9% Chemical name Chemical name

Caprylic Capric S.OO 1O.OO 1O.OO 1O.OO Mineral oil 12.00 Triglyceride Isopropyl myristate 12.00 Cetearyl alcohol O.90 1.OO 1.00 1.OO Dimeticone V100 3.00 Gleceryl Stearate O45 O.SO OSO O.SO Glyceryl monostearate O.SO Cholesterol 1.00 1.OO MYR 52 3.00 Benzyl alcohol 1.00 1.OO Microcrystalline cellulose + 2.OO Benzoic acid O.20 O.20 carboxymethyl cellulose) Butylated O.10 O.10 O.10 O.10 TWEEN 8O 1.OO hydroxytoluene Cocoamidopropyl betaine O.SO PEG-40 Stearate 2.60 2.60 2.60 2.60 Citric acid buffer 1.O Methylcellulose K10OM O.10 O.10 O.10 Preservative O.30 Methylcellulose A4M O.10 Purified water 64.60 Xanthan gum O.25 O.25 O.25 O.25 Hydrocortisone butyrate O.10 Polysorbate 80 O.90 O.90 O.90 O.90 EDTA disodium O.10 Total 100.00 Sodium Hydroxide O.SO Propellant 8.OO Water purified 56.50 58.25 54.25 67.95 results Dimethyl isosorbode 1O.OO S.OO Propylene glycol 6.OO S.OO 1O.OO Appearance: PEG-4OO S.OO AZelaic Acid 1S.OO 1S.OO 1S.OO 1S.OO Quality Excellent Fluocinonide O.10 O.10 O.10 O.10 Color White Odor No odor Total 100 100 100 100 Collapse time >12O Results A. B C D Hardness 16.87 Appearance: Density O.O38 Centrifugation 3K 10 min Stable Quality E E E E Color Off white Off white Off white Off white *Stable = no phase separation or creaming were observed. US 2008/0206161 A1 Aug. 28, 2008 76

0790 Hydrocortisone butyrate was formulated in an Example 16 emollient oil-in-water emulsion with silicone to provide an Two Compositions Comprising Clobetasol-17-Propi enhanced silky skin feeling. The formulation produced a onate as Active Agents, which is Resilient to Cream foam of excellent quality with beneficial physical properties 1ng Such as desired hardness, a reasonable collapse time of over 0793 two minutes during which the expanded foam remains Sub stantially intact, and resistance to creaming/phase separation when subjected to centrifugation at 3000 rpm. It can be WW9% WW 9% extrapolated that compositions, which can withstand Such a Chemical name g-force are probably capable of remaining physically stable at Mineral oil 2.00 12.00 room temperature during the expected two years shelf life of Sopropyl myristate 2.00 a pharmaceutical product or for a lesser reasonable period. Glyceryl Stearate 1.00 1.00 Stearyl alcohol 1.00 PEG-40 Stearate 2.50 2.50 Xanthan gum O.26 Example 15 Methocel K100 O.26 Carboxymethyl cellulose O.SO A Composition Comprising Fluocinolone Acetonide, Polysorbate 60 1.00 Polysorbate 80 1.00 which is Resilient to Creaming Citric acid 1.30 0.7 Sodium citrate 1.10 O.6 0791) Purified Water 87.53 81.65 Clobetasol-17-propionate O.OS O.OS

WW 9% Total 1OOOO 100.00 Propellant 8.00 8.00 Chemical name Results

Mineral oil 12.00 Appearance: Glyceryl Stearate 1.00 PEG-40 Stearate 2.50 Quality Excellent Excellent Carboxymethyl cellulose O.SO Color White White Polysorbate 80 1.00 Odor No odor No odor Citric acid buffer 1.O Collapse time >12O >12O Water 81.99 Hardness 22.2 18.44 Fluocinolone acetonide O.O1 Density O.O38 O.042 Centrifugation 3k10 min stable stable Total 100.00 Propellant 8.00 *Stable = no phase separation or creaming: NIM = not measured. Results 0794. Clobetasole proprionate was formulated with low Appearance: and medium oil content and stabilized to a desired pH with the Quality Excellent aid of a citric buffer. Both formulations produced a foam of Color White excellent quality and resistance to creaming/phase separation Odor No odor when subjected to centrifugation at 3000 rpm. It can be Collapse time >12O extrapolated that compositions, which can withstand Such a Hardness 14.99 Density O.O3S g-force are probably capable of remaining physically stable at Centrifugation 3K 10 min Stable room temperature during the expected two years shelf life of pH 4.2–4.4 a pharmaceutical product or for a lesser reasonable period. It is observed that the variations in the types of polysorbate, *Stable = no phase separation or creaming polymers and oils and in the citric acid concentration, do not appear to affect the physical stability. 0792 Comments: Fluocinolone acetonide was stabilized at pH 4.5 by the aid of a citrate buffer in a mineral oil in water Example 17 foamable emollient emulsion stabilized with a complex emulgator PEG-40 stearate and between 80 and with co Hydrocortisone and C. Clopiroxolamine (CPO) with and without Various Oils including Silicone and Dif Surfactant glyceryl Stearate and with carboxymethyl cellu ferent Excipient Options lose. The formulation produced a foam of excellent quality with beneficial physical properties such as desired hardness, 0795 a reasonable collapse time of over two minutes during which the expanded foam remains Substantially intact, and resis 17(a) Matrix with three different oils. tance to creaming/phase separation when Subjected to cen trifugation at 3000 rpm. It can be extrapolated that composi WW 9% WW 9% WW 9% tions, which can withstand Such a g-force are probably USAN name capable of remaining physically stable at room temperature Mineral oil, light S.OO O.OO O.OO during the expected two years shelf life of a pharmaceutical Caprylic Capric triglyceride O.OO 1O.OO O.OO product or for a lesser reasonable period. US 2008/0206161 A1 Aug. 28, 2008 77

-continued -continued 17(a) Matrix with three different oils. 18(b) Matrix without oils WW 9% WW 9% WW 9% WW9% WW 9% WW9% Isopropyl myristate S.OO O.OO O.OO Octyldodecanol O.OO O.OO 1O.OO Results Cyclomethicone 2.OO O.OO O.OO Glyceryl Stearate O45 O45 O45 Appearance: Stearyl alcohol O.85 O.85 O.85 Sorbitan stearate O.6O O60 O60 Ouality Excellent Excellent Excellent Steareth-21 O.OO O.OO 2.00 Color White White White Laureth-4 2.OO 2.00 O.OO Odor None None None PEG-40 Stearate 2.60 2.60 2.60 Creaming (centrifugation) 3,000 rpm 70 30 NM Benzyl Alcohol 2.OO 2.00 O.OO (%) Methocel A15C O.30 O.30 O.30 Creaming (centrifugation) 10,000 70 50 NM Xanthan gum O.26 O.26 O.26 rpm (%) Polysorbate 80 O.90 O.90 O.90 Hardness (g) NM 11 NM Glycerin O.OO O.OO O.OO Collapse time at 36°C. (s) 120 >300 NM Water, purified 76.04 78.04 80.04 Ciclopiroxolamine 1.OO 1.00 1.00 0796 Hydrocortisone was formulated with ciclopiroxola Hydrocortisone 1.OO 1.00 1.00 mine (CPO) with and without various oils including silicone Total 1OOOO 1OOOO 1OOOO and different excipient options. All foams were of excellent Lactic acid to pH 7.0 to pH 7.0 To pH 7.0 quality. Propellant (Propane/Butane? 8.0 8.0 1.O 0797. A different propellant type, perfluorocarbon Sobutane) (Dymel 134(R) was tested and also found to be appropriate for Dymel 134 (R) 7.0 Results propelling the steroid foamable formulation. 0798 Resilience to creaming was significantly reduced at Appearance: 3000 rpm in the absence of oils. Increasing the centrifugal force in the absence of oils did not substantially change the Quality Excellent Excellent Good resilence. Color White White White Odor None None None Example 19 Centrifugation 3,000 RPM 10 min 100 1OO NM Centrifugation 10,000 RPM 10 min 25 40 NM Example 19(a) Hardness (g) 12 13 NM Foamable Pharmaceutical Emulsion Compositions Collapse time at 36°C. (s) 120 >3OO >3OO with 25% Petrolatum as Unctuous Emollient, Ste areth-2/Steareth-21/ASOS, and Betamethasone 17 Valerate Micronized, as API 0799 18(b) Matrix without oils

WW 9% WW 9% WW 9% Betamethasone USAN name 17 valerate PPG-15 Stearyl ether O.OO 1S.OO O.OO micronized Glyceryl Stearate O.SO O.OO O.SO Stearyl alcohol O.92 O.OO O.92 Water 63.43 Behenyl alcohol O.OO 1.00 O.OO Carbomer 941 O.12 Sorbitan stearate O.65 O.OO O.65 sodium Lauryl Sulfate O.10 Ceteth-2 O.OO 2.00 O.OO Disodium EDTA O.OS Ceteareth-20 O.OO 1.60 O.OO Methylparaben O.20 Steareth-21 2.20 O.OO 2.20 Petrolatum 25.00 PEG-40 Stearate 2.85 O.OO 2.85 Stearath-2 1.73 Methocel A4M O.OO O16 O.OO Steareth-20 O.S8 Methocel A15C O.35 O.OO O.35 Propylparaben O.15 Xanthan gum O.30 O.OO O.30 Cetyl alcohol O.10 Pemulen TR2 O.OO O.OS O.OO Cyclomethicone S.OO Polysorbate 80 1.OO O.OO 1.OO Aluminum starch 3.00 Glycerin O.OO 3.00 O.OO octenylsuccinate Dimethyl isosorbide O.OO O.OO 1O.OO Imidazolidinyl urea O.30 Propylene glycol O.OO S.40 O.OO Triethanolamine O.12 Water, purified 89.23 69.79 79.23 API O.12 Ciclopiroxolamine 1.OO 1.00 1.OO Hydrocortisone 1.OO 1.00 1.OO Total 100.00 Propellant 8.00 Total 100.00 100.00 100.00 (Propane/Butane/Isobutane) Lactic acid to pH to pH to pH FOAM QUALITY Excellent 7.5 + 0.2 7.5 - 0.2 7.5 + 0.2 ODOR White Propellant (Propane/Butane? 8.0 8.0 8.0 COLOR V.F.O Sobutane) SHAKABILITY GOOD US 2008/0206161 A1 Aug. 28, 2008

-continued -continued AWW9/o BWW 9. CWW 9, Betamethasone 17 Glyceryl monostearate 2.0 valerate Polysorbate 60 O.6 O6 micronized Sorbitan Monostearate 0.4 0.4 Hydroxypropyl O.3 HARDNESS 9.77 methyl cellulose COLLAPSE TIMEAT 180 SEC. Methyl cellulose O.3 36 C. Carbomer 934P O.2 O.3 Triethanolamine O.2 O.3 Hydroxyethyl cellulose O.3 Cetearyl alcohol 1.O 1.O Example 19(b) Propylene Glycol 3.0 3.0 3 Propyl 4-hydroxybenzoate O.1 O.1 O.1 Foamable Pharmaceutical Emulsion Compositions Methyl 4-hydroxybenzoate O.2 O.2 O.2 water purified 81.9 819 81.5 with 12.5% Petrolatum as Unctuous Emollient, Ste Sodium citrate O.2 areth-2/Steareth-21/ASOS and Betamethasone 17 Citric Acid 0.4 Valerate Micronized, as API Estradiol hemihydrate O.OOS1 O.OOS1 O.OOS1 Propellan 8.O 8.0 8 0800 Results Centrifugation 3,000 rpm 10 min Stable Stable 90% Betamethasone 17 creaming valerate Centrifugation 10,000 rpm 70% creaming 90% 30% micronized 10 min creaming creaming Appearance Good Good Good Water 75.93 Color White White White Carbomer 941 O.12 Odor Very faint odor no odor no odor sodium Lauryl O.1 Density (g) O.OS6 O.O86 0.057 sulfate Hardness (g) 1423 23.782 5.86 Disodium EDTA O.OS Collapse time (Sec) >3OO >300 >3OO Methylparaben O.2 Ph S.92 5.45 3.55 Petrolatum 12.5 Stearath-2 1.73 *Stable = no phase separation or creaming Steareth-20 O.S8 Propylparaben O.15 0803 Comments: Estradiol foam designed to deliver a Cetyl alcohol O.1 Cyclomethicone 5 dose of 25 micrograms of Estradiol in each dose of 0.5 ml of Aluminum starch 3 PFF. The foamable composition was packaged in pressurized octenylsuccinate aluminum canisters fitted with metered dose valves of various Imidazolidinyl urea O.3 dosage volumes: 100, 200, 500 and 1,000 microlitters. The Triethanolamine O.12 Estradiol PFF was filled and pressurized using metered dose API O.12 valves of the “dose retention chamber type and “rapid fill/ drain' type. The metered dose valves or metering valve are Total 100 Propellant 8 available commercially from Valois pharmaceutical division, (Propane/Butane/Isobutane) France, Lablabo, France and Seaquist-perfect, France or FOAM QUALITY Excellent USA. ODOR White 0804. The formulations produced foams of good quality COLOR V.F.O with beneficial physical properties such as desired hardness, SHAKABILITY GOOD a stable collapse time of over five minutes during which the HARDNESS 10.47 expanded foam remains Substantially intact, and in the pres COLLAPSETIME >300 SEC ence of liquid paraffin a resistance to creaming/phase sepa AT 36° C. ration when subjected to centrifugation at 3000 rpm. It can be extrapolated that compositions, which can withstand Such a 0801 Comments: Excellent steroid foams with good g-force are probably capable of remaining physically stable at physical properties and an elegant skin feeling were produced room temperature during the expected two years shelf life of using petrolatum as unctuous emollient. a pharmaceutical product or for a lesser reasonable period. Example 20 Example 21 Estradiol Emulsion Foamable Compositions for Progesterone Metered Dose 0805 0802 Progesterone formulation AWW 9 BWW 96 CWW 9% WW 9% Ingredient Chemical name Liquid Paraffin 10.1 10.2 Octyldodecanol 1O.O Mineral Oil 8.O Peg-100 stearate 2.0 2.0 2.O Carbomer 934P O.3 US 2008/0206161 A1 Aug. 28, 2008 79

-continued -continued Progesterone formulation % Wiw % wiw % wiw % wiw % wiw WW 9% Cocoamidopropyl betaine O41 O41 O41 O41 O41 Cetearyl Alcohol 1.O Betametasone valerate O.12 O.12 O.12 Sorbitan Monostearate 0.4 Hydrocortisone butyrate O.10 O.10 Hypromellose O.3 Propylene glycol 3.00 3.00 3.00 3.00 3.00 Polysorbate 60 O6 Parabens (phenoxy O.8 O.8 O.8 O.8 O.8 Tri ethanolamine O.2 ethanol and methyl, ethyl Water purified 79.4 and propyl hydroxy Propyl 4-hydroxybenzoate O.1 benzoate mixture) Methyl 4-hydroxybenzoate O.2 Propellant 12.00 12.00 12.00 12.00 12.00 Propylene Glycol 3.0 Propane?butane PEG-100 Stearate 2.0 Water To 100 TO 100 TO 100 TO 100 TO 100 Progesterone 4.0 Control 100 Propellant 8.0 0808. The liquefied or gas propellant can be added at a Results concentration of about 3% to about 25%. The foams of this Centrifugation 3,000 rpm, 10 min Stable proposed example have a non-ionic Surfactant to ionic Sur Centrifugation 10,000 rpm, 10 min 70% creaming factant ratio ranging from about 20:1 to about 14:1. Total Appearance Good Surface active agent, foam adjuvant and polymeric agent Color White ranges from about 2% to about 3.5% (w/w). Odor Very faint Examp le 23 odor Prophetic Example of Composition Comprising a Stable = no phase separation or creaming Corticosteroid for Mucosal or Body Cavity Applica tion 0806 Comments: Note the composition can be delivered for example as a metered dose of say a 4.0% vaginal appli 0809 cation with each dose being of (1) one ml comprising 40 mg progesterone. Ingredient Example 22 Betamethasone valerate Prophetic Example of Corticosteroid Foam Compo Caprylic Capric Triglycerides Propylene glycol sitions For Mucosal Or Body Cavity Application Potent solvent 0807 Stearyl alcohol Glyceryl monostearate PVP K90 Preservative % Wiw % wiw % Wiw % Wiw % wiw Propellant Propane?butane Mineral oil 5.60 5.60 5.60 5.60 5.60 Purified water* TO 100 Isopropyl myristate 5.60 5.60 5.60 5.60 5.60 Glyceryl monostearate O45 O45 1.00 1.OO 1.OO Stearyl alcohol O.85 O.85 O.85 O.85 O.85 0810 The liquefied or gas propellant can be added at a Myri 52 2.60 2.60 2.60 2.60 2.60 concentration of about 3% to about 25%. Water content is Xanthan gum O.26 about 10% Methocel K10OM O.26 Chitosan 1.00 Examp le 24 Hyaluronic acid OSO O.SO Avice CL611 2.OO 2.00 2.OO 2.OO Calcipitriol Foamable Compositions, Physical and TWEEN 8O O.90 O.90 O.90 O.90 O.90 Chemical Stability 0811

a) Formulations

Formulation: 1 2 3 4 5 6 Phase Ingredient % Wiw % Wiw % Wiw % Wiw % ww % Wiw

API Solution Calcipotriol O.OOS O.OOS O.OOS O.OOS O.OOS O.OOS hydrate Propylene glycol S.OO S.OO PEG-400 S.OO S.OO S.OO S.OO Oil Phase PPG-15 stearyl 15 15 3 10 3 3 ether Octyldodecanol 12 12 12 Isopropyl 5 5 myristate US 2008/0206161 A1 Aug. 28, 2008 80

-continued

a) Formulations

Formulation: 1 2 3 4 5 6 Phase Ingredient % Wiw % Wiw % Wiw % ww % Wiw % Wiw

Lanolin 2 2 2 2 Behenyl alcohol 1 1 1 1 1 1 Steareth-21 1.5 1.5 Ceteareth-20 1.5 1.5 1.S. 1.5 Ceteth-20 1.5 1.5 Laureth-4 2 2 2 2 2 2 Dichlorobenzyl O.1 O.1 O.1 O.1 O.1 O.1 alcoho Water Phase Carboxymethyl O.S O.S O.S O.S cellulose sodium Methyl cellulose O.15 O.15 Xanthan gum O.15 O.15 Buffering Tromethamine O.S O.S Agents Phase Disodium O.25 O.25 O.25 O.25 phosphate dehydrate Disodium O.OS O.OS O.OS O.OS O.OS O.OS edentate dehydrate Preservative Diazolidinyl urea O.3 O.3 O.3 O3 O.3 O.3 Phase Glycerin 3 3 3 3 3 3 pH Adjustment NaOH, 18% to pH to pH to pH to pH To pH To pH Solution 8.5 OS 8.5 OS 8.5 OS 8.5 OS 8.5 OS 8.5 - O.S Propellant 8.00 8.OO 8.00 8.OO 8.00 8.OO Purified water To 100 To 100 To 100 To 100 To 100 To 100

b) Creaming resilience Pre-Foam Formulation Serum Bottles Foam Formulations in Canister Creaming Creaming pH Assay Appearance Collapse Formulation (centrifugation) (centrifugation) pH 1:5 diluted of API Scoring Density pH 1:5 diluted time Name 3,000 rpm (%) 10,000 rpm (%) undiluted with water (% w/w) Quality Color Odor g/mL) with water at 36° C. s. 1 1OO 40 8.67 8. SO OOO45 6 1 1 O.O32 8.60 >300 2 1OO 100 8.11 7.86 OOOSO 6 1 1 O.O38 7.77 >300 3 1OO 70 8.37 8.15 OOO48 6 1 1 O.O38 7.92 >300 4 1OO 75 8.50 8.32 OOO49 6 1 1 O.O37 8.OO >300 5 1OO 85 8.54 8.2O OOOSO 6 1 1 O.O37 8.07 >300 6 1OO 50 8.79 8.60 OOO44 6 1 1 O.043 8.50 >300 6 = Excellent: 1 = white or off white: 1 = no odor or faint odor.

c) Density and Foam Ouality Test on subjection to freeze thaw cycles. Foam Quality Density Density Scoring Density Density g/mL) % ADensity g/mL) % ADensity Formulation FTC 3 wk 3 wk g/mL g/mL) % ADensity 3 wk 3 wk 3 wk 3 wk Name T-0 4 cycles 30° C. 40° C. TO FTC FTC 30° C. 30° C. 40° C. 40° C. 1 6 6 6 6 O.O32 O.O31 -3 O.O32 O O.O3O -6 2 6 6 6 6 O.O38 O.O34 -11 O.O38 O O.O3S -8 3 6 6 6 6 O.O38 O.O32 -16 O.O41 8 O.043 13 4 6 6 6 6 O.O37 O.O39 5 O.O37 O O.O37 O 5 6 6 6 6 O.O37 O.O38 3 O.O39 5 O.O47 27 6 6 6 6 6 O.043 O.O38 -12 O.O37 -14 O.O38 -12

6 = Excellent US 2008/0206161 A1 Aug. 28, 2008 81

d) pH & Stability on subjection to freeze thaw cycles

Shakability pH diluted 1:5 pH diluted 1:5 Scoring pH diluted 1:5 pH diluted 1:5 with water A pH with water A pH 1 = Shakable

Formulation with water with water A pH 3 wk 3 wk 3 wk 3 wk 3 wk 3 wk Name TO FTC FTC 30° C. 30° C. 40° C. 40° C. TO 30° C. 40° C.

1 8.60 8.41 -0.19 8.66 O.O6 8.52 -O.O8 ND 1 1 2 7.77 7.66 -0.11 7.77 O 7.75 -O.O2 ND 1 1 3 7.92 7.74 -0.18 7.90 -0.02 7.85 -O.07 ND: 1 1 4 8.00 7.78 -0.22 7.99 -0.01 7.87 -0.13 ND 1 1 5 8.07 7.71 -0.36 8.13 O.O6 7.92 -0.15 ND: 1 1 6 8. SO 8.54 O.04 8.6S O.15 8.63 0.13 ND* 1 1

ND: not determined

Chemical Stability Results for Pre-Foam Formulations suitable for storing, together with at least one API without 0812. Each pre-foam formulation was tested for chemical losing any significant API activity. These compositions are stability at baseline (T-0), following the FTC procedure and deemed “storable compositions', wherein less than 100 ppm after 3 weeks of storage at various temperatures. Stability of the API activity is lost during the storage period of at least data results were compared to T-0. Stability test results are one week. summarized in Tables a-b. Example 25 0814 O/W Emulsion Carrier Formulations with Light a: Chemical Stability Results of Pre-Foam Formulations Mineral Oil with and without Petrolatum 0815 A) with Xanthan Gum and Methocel as Polymeric Assay of API (% w/w Agent Pre-Foam Formulations Pre-Foam Formulations in Canisters in Serum Bottles without gas HLB RHLB OO1 OO2 OO6 Formulation 3 wk 3 wk Name TO 30° C. 3 w SO C. 3 w AOC. 50° C. light mineral oil 1O.S 11.00 11.00 6.OO cetostearyl alcohol 15.5 2.00 2.OO 2.00 white petrolatum 7 14.00 2 O.OOSO O.OOS2 O.OO47 O.OOS9 O.OO47 Ceteth 10 12.9 2.50 Sorbitane laurate 8.6 3.00 4 O.0049 OOO49 O.OO45 O.OOSO O.OO48 steareth-2 4.9 4.30 5 O.OOSO O.OOS1 O.OO45 O.OOS3 O.OO43 steareth-2 15.5 2.90 6 O.OO44 OOO44 O.0043 O.OO46 O.OO43 glyceryl Stearate 3.8 2.90 2.00 polysorbate 80 15 1...SO peg 40 stearate 16.9 2.8O Xanthan gum O.30 O.30 O.30 methocelk100M O.30 O.30 O.30 purified water 79.20 79.20 69.90 b: Chemical Stability Results of Foam Formulation Total: 100.00 1OOOO 100.00 Assay of API (% w/w Propellant (AP-70) 8.00 8.OO 8.00 Cent. 3K Stable Stable Stable Pre-Foam Cent. 1 OK Stable Stable Stable Formulation Foam Viscosity. 17676.23 11181.61, 19531.83 Formulation (Serum Bottles) Formulation in Canisters oam quality G-E G-E G-E color White White White Name TO 3 wk 30° C. 3 wk 40°C. odor No odor No odor No odor Shakability moderate moderate poor 1 O.OO45 O.OO46 O.0049 Density O.O31 O.O3S O.043 2 O.OOSO O.OOSO O.OOS2 Collapse time >300, G 3OOFG >300.G 3 O.OO48 O.OO46 O.OO47 BUBBLE SIZE 119 110 116 4 O.0049 O.0049 O.0049 (Lm) 5 O.OOSO O.0049 O.OOS1 BUBBLE SIZE O O O 6 O.OO44 O.OO45 O.OO47 (above 500 m)

0813. The two tables hereinabove demonstrate that the 0816 Comments: The above carriers all generated foams foamable emulsion compositions of the present invention are of good to excellent quality in the presence and absence of US 2008/0206161 A1 Aug. 28, 2008

petrolatum. The foamable formulations all showed good resistance to accelerated aging and were found to be stable -continued even when subjected to centrifugation at 10,000 rpm for 10 mins. They all had good bubble size averages and a collapse HLB RHLB O11 time in excess of 300 secs. These formulations are suitable as methocelk100M O.25 foamable vehicles for active agents including coal tar and or purified water 72.10 steroids. The stability of the emulsions is at least to an extent Total: 100.00 Propellent (AP-70) 8.OO a reflection of careful selection of compatible surfactants, and Cent. 3K Stable matching with the oily phase. Cent. 1 OK Stable viscosity. 1 rpm-348.885.53 0817 B) Without Polymeric Agent foam quality G color White odor no odor Shakability O QFC008- QFCO12 Density O.O45 HLB RHLB O71220 O8O106 Collapse time >300G BUBBLE SIZE (im) 79 ight mineral oil 1O.S 11.00 1S.OO BUBBLE SIZE (above 500 m) O Sopropyl myristate 11.5 1S.OO cetostearyl alcohol 15.5 3.00 3.00 glyceryl Stearate 3.8 3.20 4...SO polysorbate 80 15 2.20 3.70 0820 Comments: These unique fatty alcohol carrier for peg 40 stearate 16.9 3.30 3.80 mulations are stable to centrifugation and generate good qual purified water 77.30 55.00 ity foam and good bubble size with a collapse time in excess Total: 100.00 1OOOO of 300 secs. These formulations are suitable as foamable Propellant (AP-70) 8.00 8.00 vehicles for active agents including coal tar and or Steroids Cent. 3K Stable Stable Cent. 10K 90% Cream. Stable Viscosity. 13725.07 43O3.08 Example 27 oam quality G-E G color White White odor No odor v.fodor PPG 15 Stearyl Ether or Isoprpyl Myristate/Avo Shakability poor 1 cardo Oil Emulsion Carrier Formulations Density O.063 O.O39 Collapse time >300G >300G BUBBLE SIZE (im) 123 69 0821 BUBBLE SIZE (above O O 500 m) HLB RHLB OO)4 005 0818 Comments: The above carriers all generated foams PPG 15-stearyl ether 7 18.00 of good to excellent quality. The foamable formulations all Isopropyl myristate 11.5 6.OO showed good resistance to accelerated aging. When subjected cetostearyl alcohol 15.5 2.OO Stearyl alcohol 15.5 1.00 to centrifugation at 10,000 rpm for 10 mins both showed Avocado oil 7 6.OO resistance to creaming one being stable. They all had good steareth-2 4.9 6.50 bubble size averages and a collapse time in excess of 300 secs. steareth-2 15.5 2.50 These formulations are suitable as foamable vehicles for glyceryl Stearate 3.8 3.30 polysorbate 80 15 1.00 active agents including coal tar and or steroids. The stability peg 40 stearate 16.9 2.00 of the emulsions is at least to an extent a reflection of careful Xanthan gum O.30 O.30 selection of compatible Surfactants, and matching with the methocelk100M O.30 O.30 oily phase. purified water 70.40 80.10 Total: 1OOOO 100.00 Propellent (AP-70) 8.OO 8.00 Example 26 Cent. 3K Stable Stable Cent. 1 OK Stable Stable viscosity. 27962.03 15196.76 Fatty Alcohol Carrier Formulation oam quality G-E G-E color White White 08.19 odor No odor No odor Shakability moderate moderate Density OO67 O.042 Collapse time >3OOG >300 FG HLB RHLB O11 BUBBLE SIZE (im) 194 158 BUBBLE SIZE (above 500 m) O O Stearyl alcohol 15.5 6.OO Oleyl alcohol 14 6.OO cetyl alcohol 15.5 6.OO 0822 Comments: These carrier formulations are also polysorbate 65 1O.S 2.70 polysorbate 20 16.7 3.60 stable to centrifugation and generate good quality foam and peg 40 Stearate 16.9 3.10 good bubble size with a collapse time in excess of 300 secs. Xanthan gum O.25 These formulations are suitable as foamable vehicles for active agents including coal tar and or steroids US 2008/0206161 A1 Aug. 28, 2008

Example 28 -continued LCD Carrier Formulations

0823. Part A-O/w Emulsion Formulations with Heavy cf HLB RHLB Ex.O09 6b Ex.O10 6b Mineral Oil and Hydrocortisone Viscosity. 13213.18 foam quality FG G color Yellow odor charact.odor O09 O10 Shakability 1 cf HLB RHLB Ex. 6b Ex. 6b Density O.042 Mineral oil, heavy 1O.S 1 O.OO 10.00 Collapse time >300G BUBBLE SIZE (im) 197 Lanolin 10 2.OO 2.00 BUBBLE SIZE (above 500 m) 6.3 cetostearyl alcohol 15.5 2.OO 2.00 aOWe lm Cyclomethicone 7.75 1.OO 1.00 E.se s 3. . 0824 Comments: By increasing the surfactant mix the peg 40 stearate 16.9 1.60 2.00 foam quality of the carrier formulation was improved. The Xanthan gum O.25 O.25 formulations are stable to centrifugation at 3000K and do not methocelk100M O.25 O.25 phase separate at 10,000 rpm for 10 mins. These formulations purifiedBenzyl alcohol water 63.30O.60 61.90O60 are suitableitabl as ffoamable b1 vehicleshicles ffor active agents includiincluding Glycerin S.OO S.OO coal tar and or steroids LCD 1O.OO 1O.OO Peppermint oil 1.OO 1.00 Example 29 Hydrocortisone - - - - Bioadhesive Estradiol Formulations with Carbopol Total: 100.00 1OOOO or Polycarbophil and High or Low Viscosity Propellent (AP-70) 8.OO 8.00 Hypromellose Cent. 3K10K Stable60% 85%Stable Cream. Part A High9. Viscosity Hypromelloseyp Formulations and Car Cream. bopol 0825

Part A High Viscosity Hypronellose Formulations and Carbopol

1 2 3 4 5 6 % ww % Wiw % Wiw % ww % Wiw % Wiw

HV

Octyldodecanol 13.5 5 13.5 5 5 13.5 Sopropyl 5 5 5 5 5 5 myristate Sorbitan 1 1 Stearate Polysorbate 60 1 O.S 1 Polysorbate 80 O.S Stearic acid 3 2 Stearyl alcohol 3 3 Cetearyl alcohol 3 3 Polyoxyl 100 2.5 2.5 2.5 2.5 2.5 2.5 Stearate Carbopol 934P 1 0.4 0.4 0.4 0.4 0.4 Polycarbophil Hypromellose O.2 O.2 O.2 O.2 O.2 O.2 (Methocel K10OM) Triethanolamine O.2 O.2 O.2 O.2 O.2 O.2 Lactic Acid to pH to pH to pH to pH to pH to pH 4.0-4.5 4.0-4.5 4.0-4.5 4.0-4.5 4.0-4.5 4.0-4.5 Propylene 2 3.33 3.33 3.34 3.34 3.34 glycol Propyl paraben O.1 O.1 O.1 O.1 O.1 O.1 Methyl paraben O.15 O.15 O.15 O.15 O.15 O.15 Estradiol O.OOS O.OOS O.OOS O.OOS O.OOS O.OOS hemihydrate Purified water to 100.00 to 1 OOOO to 1 OOOO to 100.00 to 1 OOOO to 1 OOOO Propellant 8% 8% 8% 8% 8% 8% (propane, butane, isobutenemix) US 2008/0206161 A1 Aug. 28, 2008 84

-continued Part A High Viscosity Hypronellose Formulations and Carbopol

1 2 3 4 5 6 % ww % Wiw % Wiw % Wiw % Wiw % Wiw Results pH (undiluted) 4.OS 4.41 4.57 canisters 4.56 4.38 Were blocked pH (dil. 1:5 with 4.2 4.69 4.97 4.85 4.63 water) Centrifugation at:

1) 3,000 rpm: stable 90% stable stable stable (% creaming) creaming 2) 10,000 rpm stable 10% 90% 90% 90% (% creaming): creaming creaming creaming creaming Viscosity (cPs) 1061.64 7673 23570 37417 181OS Microscopy no crystals no crystals no crystals no crystals no crystals (x200) observed observed observed observed observed Homogeneity of homogeneous homogeneous homogeneous homogeneous homogeneous contents Foam quality at G G FG FG G TO Foam quality G FG FG FG G after 3 weeks storage at 25°C.

0826 Comments: These high viscous formulations were the formulation did not expel from the canister. Formulations found to be physically stable, homogenous and resistant to 1 and 6 produced good quality foam which remained aging as seen from the centrifugation tests. The high viscosity unchanged after 3 weeks storage. hypermellose formulations proved to be more resistant to creaming at 10,000 rpm for about 10 mins than there low Part B Low Viscosity Hypromellose Formulations and Car viscosity counterparts seen below. The difficulties in achiev bopol ing good formulations at high Viscosity can be seen when 0.5% polysorbate was replaced by 1% sorbitam stearate and 0827

Part B LOW Viscosity Hypronellose Formulations and Carbopol

1 2 3 4 5 6 % Wiw % Wiw % Wiw % Wiw % Wiw % Wiw

Octyldodecanol 13.5 5 13.5 5 5 13.5 sopropyl 5 5 5 5 5 5 myristate Sorbitan stearate 1 1 Polysorbate 60 1 Polysorbate 80 O.S O.S 1 Stearic Acid 3 2 Stearyl alcohol 3 3 Cetearyl alcohol 3 3 Polyoxyl 100 2.5 2.5 2.5 2.5 2.5 2.5 Stearate Carbopol 934 1 0.4 0.4 0.4 0.4 0.4 Polycarbophil Hypromellose O.2 O.2 O.2 O.2 O.2 O.2 (Methocel K10OLV) Triethanolamine O.2 O.2 O.2 O.2 O.2 O.2 Lactic Acid for pH C.S C.S C.S C.S C.S C.S or pH adjustment o 4.0-4.5 Propylene glycol 2 2 2 2 2 2 Propyl paraben O.1 O.1 O.1 O.1 O.1 O.1 Methyl paraben O.15 O.15 O.15 O.15 O.15 O.15 US 2008/0206161 A1 Aug. 28, 2008 85

-continued Part B Low Viscosity Hypronellose Formulations and Carbopol

1 2 3 4 5 6 % Wiw % Wiw % Wiw % Wiw % ww % Wiw

Estradiol O.OOS O.OOS O.OOS O.OOS O.OOS O.OOS hemihydrate Purified water to 100.00 to 10O.OO to 1 OOOO to 100.00 to 100.00 to 1 OOOO Propellant 8% 8% 8% 8% 8% 8% (propane, butane, isobutenemix) Results pH (undiluted) 4.16 4.28 4.03 4.14 4.37 4.46 pH (dil. 1:5 with Not 4.63 4.43 4.42 4.72 4.9 water) Recorded Centrifugation at: 1) 3,000 rpm: stable 20% stable stable 90% stable (% creaming) creaming creaming 2) 10,000 rpm 80% 10% 30% 10% 20% 20% (% creaming): creaming creaming creaming creaming creaming creaming Viscosity (cPs) 30664 2242 23661 15808 19712 15739 Microscopy no crystals no crystals no crystals no crystals no crystals no crystals (x200) observed observed observed observed observed observed Homogeneity of homogeneous homogeneous homogeneous homogeneous homogeneous homogeneous contents Bioadhesiveness -17.66 -8.5 -8.75 -14.41 -14.05 -5.32 (g): Foam quality at E E E E E E TO Foam quality Not tested FG E E E E after 3 weeks at 25o C.

0828 Comments: These formulations made with lower Viscous hypromellose were found to be stable, homogenous -continued and resistant to aging as seen from the centrifugation tests. When blocked formulation 4 was repeated with low viscosity 9.6 wiw7 0.% ww8 0.% ww9 hypromellose the formulation was shakable and homoge neous. All these formulations displayed bioadhesive proper- Stearate O Carbopol 934 0.4 t1es. When the level of carbopol was increased form 0.4% to Polycarbophil 2 O.2 O.2 1% the bioadhesive strength of the formulation increased Hypromellose O.2 O.2 substantially. Some of the bioadhesion may be due to the (Methocel K10OLV) presence of waxy fatty acids such as Sorbitan Stearate. The Triethanolamine O.2 O.2 O.2 foams made with lower viscosity hypromellose were all of Lacticor pH Acidadjustment for pH C.S C.S C.S excellent quality. Thus, in a preferred embodiment the o 4.0-4.5 hypromellose is low viscosity. In an embodiment the level of Propylene glycol 2 2 2 bioadhesiveness is about -3 g to about -30.g Propyl paraben O.1 O.1 O.1 Methyl paraben O.15 O.15 O.15 Part C Low Viscosity Hypromellose Formulations and Poly- Estradiol O.OOS O.OOS O.OOS carbophil with and without Carbopol hemihydrate Purified water to 100.00 to 1 OOOO to 1 OOOO Propellant 8% 8% 8% (propane, butane, isobutenemix) 7 8 9 Results % Wiw % ww % Wiw pH (undiluted) canisters were 3.93 4.26 Y- pH (dil. 1:5 with blocked 4.36 4.62 water) stano Centrifugation at: myristate Sorbitan stearate 1 1) 3,000 rpm: 25% creaming. 25% creaming. Polysorbate 60 (% creaming) Polysorbate 80 O.S O.S 2) 10,000 rpm 20% creaming 20% creaming Stearic Acid 3 (% creaming): Stearyl alcohol 1.5 1.5 Viscosity (cPs) 35.8 76.6 Cetearyl alcohol Microscopy (x200) crystals no crystals Polyoxyl 100 2.5 2.5 2.5 observed observed US 2008/0206161 A1 Aug. 28, 2008

g) a propellantata concentration of about 3% to about 25% -continued by weight of the total foamable composition, wherein, at ambient temperature, the storable foamable emul 7 8 9 sion composition is shakable, is resistant to centrifugation at % Wiw % ww % Wiw about 3000 rpm for about 10 min, is substantially devoid of Homogeneity of creaming re- creaming re crystals, is resistant to at least one freeze-thaw cycle and does contents dispersible on dispersible on light shaking light shaking not phase separate within at least about one month; Foam quality at T-0 E E wherein the at least one API remains chemically stable for at Foam quality after E E least about one month; and 3 weeks at 25°C. wherein the composition is stored in anaerosol container and upon release expands to form a breakable foam having an 0829 Comments: The formulations with polycarbophil average bubble size range of about 30 to about 250 micron. showed creaming but not phase separation on standing but 2. The storable foamable emulsion composition of claim 1, were easily re-dispersed on light shaking. The canister wherein when compressed between two Surfaces a negative became blocked when higher levels of polycarbophil are used adhesion force is required to effect their separation. with Stearic acid. Upon reducing the amount of polycarbophil 3. The storable foamable emulsion composition of claim 1, from 2% to about 0.2% and eliminating stearic acid excellent wherein the at least one API is contained in a Trapsome. foam was observed, which remained unchanged after 3 weeks 4. The storable foamable emulsion composition of claims Storage. 1, 2 and 3, wherein the API is selected from the group con sisting of: Note i. a steroid compound containing a cyclopentaaphenan 0830) 1. Viscosity of Methocel 100LV is-110 cFs (low threne skeleton; viscosity); whereas for “Methocel 100M viscosity is 103, ii. a steroid compound containing a cyclopentaaphenan 510 cps (high viscosity) being almost 1000 times greater. threne skeleton carrying one or more functional groups 2. Stearyl alcohol, sorbitan stearate, cetostearyl alcohol are Selected from halogens, alkyl groups, aryl groups, ben powders (solid). Zyl groups, carboxy groups and alkoxy groups; 3. Polysorbate is a viscous liquid. iii. a steroid compound selected from the families of (a) 0831. The references cited herein teach many principles of cardanolides, (b) bufanolides, (c) spirostans, (d) furo treatment of disorders that are applicable to the present inven stans, (e) steroid alkaloids, (f) steroid lactones, (g) oxo tion. Therefore the full contents of these publications are steroids, (h) steroid-alcohols and (i) steroid-amines; incorporated by reference herein where appropriate for teach iv. a steroid compound, where one or more of the cyclo ings of additional or alternative details, features and/or tech pentaalphenanthrene rings is contracted by loss of an nical background. unsubstituted methylene group; 0832. It is appreciated that certain features of the inven V. asteroid compound, where one or more of the cyclopenta tion, which are, for clarity, described in the context of separate aphenanthrene rings is expanded by inclusion of a embodiments, may also be provided in combination in a methylene group; single embodiment. Conversely, various features of the vi. a steroid compound containing a cyclopentalaphenan invention, which are, for brevity, described in the context of a threne skeleton and a carbocyclic or heterocyclic ring single embodiment, may also be provided separately or in any component fused to it; suitable subcombination. vii. a compound, wherein two or more steroid molecules 0833 Although the invention has been described in con are linked together covalently: junction with specific embodiments thereof, it is evident that viii. a compound selected from the group consisting of many alternatives, modifications and variations will be appar 5-pregnane, 53-pregnane, 5C.-cholane (allocholane), ent to those skilled in the art. 5B-cholane, 53-cholestane, 53-cholestane, 5C.-ergos tane, 5-ergostane, 5C-campestane, 5-campestane, What is claimed is: 5C-poriferastane, 53-poriferastane, 5C.-StigmaStane, 1. A storable foamable emulsion composition adapted for 5-stigmaStane, 5C-gorgostaneacrihellin, actodigin, alfa delivery of an active pharmaceutical ingredient (API) to a calcidol, aldosterone, androsterone, betamethasone, delivery site in a subject, the composition comprising: brassinolide, calcidiol, calciol, calcitriol, canrenone, a) at least one organic carrier selected from the group clomegestone, cholesterol, cholic acid, corticosterone, consisting of a hydrophobic organic carrier, an organic cortisol, cortisol acetate, cortisone, cortisone acetate, polar solvent, an emollient and mixtures thereof, at a cyproterone, deoxycorticosterone, dexamethasone, concentration of about 2% to about 50% by weight; disogluside, ecdysone, ercalciol, ergosterol, estradiol, b) at least one surface-active agent at a concentration of estriol, estrone, ethinylestradiol, fluazacort, fluocortin, about 0.01% to about 5% by weight; fusidic acid, gestrinone, gonane, halometasone, hydro c) at least one polymeric agent selected from the group cortisone, lanosterol, lithocholic acid, mebolazine, consisting of a bioadhesive agent, a gelling agent, a film medroxyprogesterone, meproscillarin, mespirenone, forming agent and a phase change agent, each in a con mestranol, naflocort, norenthisterone, norgesterone, centration of about 0.01% to about 5% by weight; norgestrel, Oxandrolone, oxymetholone, pancuronium d) water; bromide, prednisolone, , progesterone, e) an effective amount of at least one API selected from the proscillardin, pseudotigogenin, roXibolone, Sarsasapo group consisting of a steroid, a steroid derivative, and genin, Smilagenin, Spironolactone, timobesone, test combinations thereof; osterone, tigogenin triamcinolone, urSodeoxycholic f) optionally, a further active agent; and acid; US 2008/0206161 A1 Aug. 28, 2008 87

ix. an anti-inflammatory Steroid; XXV. isovitamin D3, dihydrotachysterol3, (1S)-hydroxy X. a steroid possessing immunomodulating and/or anti calciol, (24R)-hydroxycalcidiol, 25-fluorocalciol, ercal inflammatory properties; cidiol, ertacalciol, (5E)-isocalciol, 22.23-dihydroercal Xi. a steroid, selected from the group of low-potency anti ciol, (24S)-methylcalciol, (5E)-(10S)-10, 19 inflammatory Steroids, medium potency anti-inflamma dihydroercalciol, (24S)-ethylcalciol and (22E)-(24R)- tory Steroids and high potency anti-inflammatory ste ethyl-22.23-didehydrocalciol; roids; XXVi. a vitamin D3 analogue selected from the group con xii. an anti-inflammatory Steroid, selected from the group sisting of calcipotriol, tacalcitol, maxacalcitol, and cal consisting of hydrocortisone, hydrocortisone acetate, citriol; desonide, betamethasone Valerate, clobetasone-17-bu XXVii. a phytosteroid or a phytosterol; tyrate, flucinonide, fluocinolone acetonide, alcometa XXviii. asteroid derived or extracted from one of the fami Sone dipropionate, mometasone furoate, prednicarbate, lies of phytosteroids, phytosterols, phytostanols, ecdys triamcinolone acetonide, betamethasone-17-benzoate, ones, withanolids, sterines, steroid saponins and Sofla methylprednisolone aceponate, betamethasone dipropi vonoids; onate, halcinonide, triamcinolone acetonide, halobeta XXix. a steroid selected from the group consisting of alpha Sol, clobetasol-17-propionate; sitosterol, beta-sitosterol, Stigmastanol, campesterol, xiii. a steroid that positively affects the McKenzie vaso alpha-sitostanol, beta-sitostanol, StigmaStanol, constrictor assay; campestanol, avenosterol, brassicasterol, desmoSterol, Xiv. a steroid hormone; chalinosterol, beta-ecdysone, whithaferin A, beta-sito XV. a steroid hormone, selected from the group consisting sterine, Stigmasterine, campesterine, ergosterine, dios of an androgen, an estrogen and a progestogen; genin, daidzein, glycitein, genistein, muristerone, Xvi. an androgen, selected from the group consisting of poriferasterol, clionasterol, campestanol, and testosterone, testosterone cipionate, testosterone cycloartenol; decanoate, testosterone enantate, testosterone isoca XXX. a plant oil or a plant extract, which contains a steroid; proate, testosterone phenylpropionate, testosterone pro and pionate, testosterone undecylate, 5C-dihydrotestoster XXXi. a plant oil or a plant extract, selected from the group one, dehydroepiandrosterone (also termed prasterone consisting of nuts seeds, sprouted seeds and grains (such and DHEA), androstenedione, androstanediol, andros as alfalfa), St. Mary's thistle, ginkgo biloba, saw pal terone, androstenolone, prasterone enantate, prasterone metto, panax, Siberian ginseng, foeniculum Vulgare, Sodium Sulfate, ormeloxifene, mesterolone, fluoxymes cinicifiiga racemosa, licorice root, red clover, Sage, sar terone, methyltestosterone, gestrinone, delmadinone, Saparilla, Sassafras, angelica sinensis achillea millefo delmadinone acetate, chlormadinone, chlormadinone lium, anemone pratensis, angelica sinensis, glycyrrhiza acetate, danazol and testolactone; glabra, hypericum perforatum, larrea, panax, piscidia Xvii. an estrogen selected from the group consisting of erythrina, plantago psyllium, Serenoa repens, Symphy estradiol, estradiol benzoate, estradiol cipionate, estra tum, taraxacum officinale, trifolium pratense, turnera diol dipropionate, estradiol enantate, estradiol hexahy spp., tussilago farfara, Valeriana officinalis, Viburnum drobenzoate, estradiol phenylpropionate, estradiol val prunifolium, and calendula officinalis. erate, polyestradiol phosphate, estriol, estriol sodium 5. The storable foamable emulsion composition of claim 4, Succinate, estriol Succinate, polyestriol phosphate, further comprising at least one quiescence agent selected quinestradol, ethinylestradiol, estrapronicate, mestra from the group consisting of a stabilizing agent, a polymeric nol, estrapronicate and equilin; agent, a gelling agent, a Viscoelastic agent, a pseuedoplastic Xviii. a progestogen, selected from the group consisting of or semi-pseudoplastic agent, a resilient agent and a modulat progesterone, norethisterone, norethisterone acetate, ing agent and mixtures thereof. norethisterone enantate, medroxyprogesterone acetate, 6. The storable foamable emulsion composition of claim 1, delmadinone acetate, flugestone acetate, dydrogester wherein the foam demonstrates at least seven of the following one, desogestrel, norgestrel, levonorgestrel, dydrogest properties: erone, gestodene, chlormadinone acetate, dienogest, drospirenone, lynestrenol, tybolone, cyproterone (a) a foam quality of 5-6, acetate, megestrol acetate, nomegestrol acetate; (b) a bioadhesivity to said delivery site, requiring a force of about -3 g to -30 g to dislodge said foam from said xix. an inhibitor of a steroid hormone: delivery site: XX. an inhibitor of a steroid hormone selected from the (c) a bioadhesivity to said delivery site, requiring a force of group consisting of finasteride, dutasteride and Spirono about -8 g to about -25 g to dislodge said foam from lactone; said delivery site: XXi. a vitamin D; xxii. a steroid that exhibits qualitatively the biological (d) a color of white to off-white; or a yellowish color: activity of calciol; (e) no odor or faint odor; or Substantially masked odor, XXiii. a vitamin D selected from the group consisting of (f) a foam quality of 5-6 after at least one freeze-thaw cycle: cholecalciferol, 25-hydroxycholecalciferol, 1C.25-di (g) a foam quality of 5-6 after about 3 weeks storage at 30° hydroxycholecalciferol, ergocalciferol, 1C.,25-dihy C.; droxyergocalciferol, 22.23-dihydroergocalciferol. 1.24. (h) a foam quality of 5-6 after about 3 weeks storage at 40° 25-trihydroxycholecalciferol, , C.; and tachysterol3 (also termed tacalciol); (i) a foam quality of 5-6 after about 3 weeks storage at 50° XXiv. a vitamin D3 analogue; C.; US 2008/0206161 A1 Aug. 28, 2008

() a collapse time of more than 50 seconds; an oxidizing agent, an antioxidant, a dicarboxylic acid, aze (k) a collapse time of more than 120 seconds; and laic acid, sebacic acid, adipic acid, fumaric acid, a retinoid, an (1) a collapse time of more than 180 seconds. antiproliferative agent, an anticancer agent, a photodynamic 7. The storable foamable emulsion composition of claim 6, therapy agent, benzoyl chloride, calcium hypochlorite, mag wherein the foam demonstrates all of said properties. nesium hypochlorite, an anti-wrinkle agent, a radical scaven 8. The storable foamable emulsion composition of claim 5, ger, a metal, silver, a metal oxide, titanium dioxide, Zinc wherein the resilient agent is a viscoelastic material capable oxide, Zirconium oxide, iron oxide, silicone oxide, talc, car of forming a pseudoplastic or semi-pseudoplastic composi bon, an anti wrinkle agent, a skin whitening agent, a skin tion. protective agent, a masking agent, an anti-Wartagent, a refat 9. The storable foamable emulsion composition of claim8, ting agent, a lubricating agent and mixtures thereof. wherein the viscoelastic material comprises an effective 18. The storable foamable emulsion composition of claim amount of at least one polymeric additive selected to form a 1, wherein the at least one polymeric agent is selected from foamable carrier or composition which is resilient to cream the group consisting of a water-soluble cellulose ether and ing and or phase separation. naturally-occurring polymeric material. 10. The storable foamable emulsion composition of claim 19. The storable foamable emulsion composition of claim 8, wherein the viscoelastic material comprises an effective 18, wherein the water-soluble cellulose ether is selected from amount of at least one polymeric additive selected to form a the group consisting of methylcellulose, hydroxypropyl cel foamable carrier or composition which is shakable and flow lulose, hydroxypropyl methylcellulose (Methocel), hydroxy able to a sufficient amount to be expelled by a propellant from ethyl cellulose, methylhydroxyethylcellulose, methylhy a canister to form a foam of appropriate quality for topical or droxypropylcellulose, mucosal application. hydroxyethylcarboxymethylcellulose, carboxymethylcellu 11. The storable foamable emulsion composition of claim lose, carboxymethylhydroxyethylcellulose, Xanthan gum, 8, wherein the viscoelastic material is at least one polymeric guar gum, carrageenin gum, locust bean gum and tragacanth additive selected from the group consisting of polysaccha gun. rides, natural polysaccharides, derivatives thereof modified 20. The storable foamable emulsion composition of claim poysacharides, derivatives thereof, starch, dextrin, glycogen, 1, comprising: cellulose and chitin, glycosaminoglycans (GAG's), chon i.a steroid; droitin Sulphate, dermatan Sulphate, keratan Sulphate, hepa ii. at least one organic carrier selected from a hydrophobic ran Sulphate, heparin, and hyaluronan, amylose and amy organic carrier, an emollient and mixtures thereof, at a lopectine, cellulose derivatives, Xanthan gum, sodium CMC, concentration of about 2% to about 50% by weight; methylcellulose, hydroxyl propyl methyl cellulose, car iii. a surface-active agent; bomer, carbopol, and polycarbophil. iv. about 0.01% to about 5% by weight of at least one 12. The storable foamable emulsion composition of claim polymeric agent selected from the group consisting of a 1, wherein the delivery site is a body cavity. bioadhesive agent, a gelling agent, a film forming agent 13. The storable foamable emulsion composition of claim and a phase change agent; 12, wherein said composition is suitable for spreading Sub V. water, and stantially throughout the body cavity surface, effectively such vi. liquefied or compressed gas propellant at a concentra that the active agent reaches a target area. tion of about 3% to about 25% by weight of the total 14. The storable foamable emulsion composition of claim composition, 13, wherein the body cavity is selected from the group con sisting of vagina, rectum, colon, penile urethra, nasal cavity wherein the composition is an emulsion, which is flowable to and ear cavity. a sufficient extent to be expelled by the propellant from a 15. The storable foamable emulsion composition of claim canister to form a bioadhesive foam of appropriate quality for 14, wherein the body cavity is a vagina, and wherein the foam topical, body cavity or mucosal application having a bioad is adapted to spread substantially throughout the vaginal cav hesivity to said delivery site, requiring a force of about-3g to ity surface, effectively such that the API reaches the cervix. about -30 g to dislodge said foam from said delivery site. 16. The storable foamable emulsion composition of claim 21. A composition according to claim 1 wherein: 15, wherein the foam has a bioadhesivity of at least to said (a) the at least one organic carrier comprises at least one delivery site, requiring a force of about -3 g to about -30 g to carrier selected from the group consisting of ocytyl dislodge said foam from said delivery site. dodecanol, isopropyl myristate, mineral oil, capric/ca 17. The storable foamable emulsion composition of claim prylic triglyceride, silicone, lanolin and glycerin; 1, further comprising at least one additional non-steroidal (b) the at least one a surface-active agent comprises at least therapeutic agent selected from the group consisting of an one of, Polysorbate 60, Polysorbate 80, Polyoxyl 100 anti-infective, an antibiotic, an antibacterial agent, an anti stearate, PEG 40 stearate, PPG 15 Stearyl Ether, and fungal agent, an antiviral agent, an antiparasitic agent, an Ceteareth 20, immunosuppressive agent, an immunomodulator, an immu (c) the at least one polymeric additive comprises at least noregulating agent, a hormonal agent, vitaminA, a vitamin A one of hypromellose, polycarbophil, carbopol and addi derivative, vitamin B, a vitamin B derivative, vitamin C, a tionally optionally propylene glycol; and vitamin C derivative, vitamin E, a vitamin E derivative, vita (d) optionally further comprising a foam adjuvant compris min F, a vitamin F derivative, vitamin K, a vitamin K deriva ing at least one of cetearyl alcohol, oleyl alcohol, Stearyl tive, a wound healing agent, a disinfectant, an anesthetic, an alcohol and Stearic acid. antiallergic agent, an alpha hydroxyl acid, lactic acid, gly 22. A storable foamable emulsion composition adapted for colic acid, a beta-hydroxy acid, a protein, a peptide, a neu delivery of an active pharmaceutical ingredient (API) to a ropeptide, a allergen, an immunogenic Substance, a haptene, delivery site in a subject, the composition comprising: US 2008/0206161 A1 Aug. 28, 2008

a) at least one fatty alcohol, at a concentration of about 2% subject having the disorder in need thereofatherapeutically to about 50% by weight; effective amount of a storable foamable emulsion composi b) at least one surface-active agent at a concentration of tion comprising: about 0.01% to about 5% by weight; a. at least one organic carrier selected from the group c) at least one polymeric agent selected from the group consisting of a hydrophobic organic carrier, an organic consisting of a bioadhesive agent, a gelling agent, a film polar solvent, an emollient and mixtures thereof, at a forming agent and a phase change agent, each in a con concentration of about 2% to about 50% by weight; b. at least one Surface-active agent at a concentration of centration of about 0.01% to about 5% by weight; about 0.01% to about 5% by weight; d) water; c. at least one polymeric additive selected from the group e) an effective amount of at least one API selected from the consisting of a bioadhesive agent, a gelling agent, a film group consisting of a steroid, a steroid derivative, a forming agent and a phase change agent, each in a con further active agent together with the steroid or deriva centration of about 0.01% to about 5% by weight; tive thereof and combinations thereof, and d. water; f) a propellantata concentration of about 3% to about 25% e. an effective amount of at least one API selected from the by weight of the total foamable composition, group consisting of a steroid, a steroid derivative, a wherein, at ambient temperature, the storable foamable emul further active agent together with the steroid or deriva sion composition is shakable, is resistant to centrifugation at tive thereof and combinations thereof, and about 3000 rpm for about 10 min, is substantially devoid of f. a propellant at a concentration of about 3% to about 25% crystals, is resistant to at least one freeze-thaw cycle and does by weight of the total foamable composition, not phase separate within at least about one month; wherein, at ambient temperature, the storable foamable emul wherein the at least one API remains chemically stable for sion composition is shakable, is resistant to centrifugation at about at least about one month; and about 3000 rpm for about 10 min, is substantially devoid of wherein the composition is stored in an aerosol container and crystals, is resistant to at least one freeze-thaw cycle and does upon release expands to form a breakable foam having an not phase separate within at least about one month; average bubble size range of about 30 to about 250 micron. wherein the at least one API remains chemically stable for at 23. The storable foamable emulsion composition of claim least about one month; and 22, wherein the fatty alcohol includes at least one unsaturated wherein the composition is stored in anaerosol container and fatty alcohol. upon release expands to form a breakable bioadhesive foam 24. A method of treating, alleviating or preventing a disor having an average bubble size range of about 30 to about 250 der of the skin, a body cavity or a mucosal Surface, wherein micron. the disorder involves inflammation as one of its etiological factors, which method comprise administering topically to a