COSMETIC AND PHARMACEUTICAL FOAM

Abstract

The invention relates to uses of an alcohol-free cosmetic or pharmaceutical foam carrier comprising water, a hydrophobic solvent, a foam adjuvant agent, a surface-active agent and a water gelling agent as a flame retardant or flame resistant foam. The hydrophobic solvent is preferably mineral oil; medium chain triglycerides; isopropyl myristearate or octyl dodecanol, silicone oil or vegetable oil or mixtures thereof. The cosmetic or pharmaceutical foam carrier does not contain aliphatic alcohols, also making it non-irritating and non-drying. The alcohol-free foam carrier is suitable for inclusion of both water-soluble and oil-soluble pharmaceutical and cosmetic agents.

Claims

1. A foamable carrier composition for use in the manufacture of a non-flammable, a flame retardant or a flame resistant foam, said carrier comprising: about 2% to about 75% by weight hydrophobic solvent, said hydrophobic solvent comprising at least one of mineral oil, MCT oil, isopropyl oil, octyl dodecanol, silicone oil and vegetable oil; about 25% to about 98% by weight water; about 0.1% to about 5% by weight foam adjuvant agent; about 0.1% to about 5% by weight surface-active agent; and about 0.1% to about 5% by weight water gelling agent, and a liquefied or compressed gas propellant, which is contained in a container, and which upon release provides a breakable foam suitable for topical or mucosal administration that is non-flammable, flame retardant or flame resistant.

2-61. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0125] A more complete appreciation of the present invention and many of its advantages will be understood by reference to the following detailed description when considered in connection with the following drawings, which are presented for the purpose of illustration only are not intended to limit the scope of the appended claims, and in which:

[0126] FIG. 1 illustrates the improvement in the treatment of psoriasis using Bethasone valerate 0.12% foam; and

[0127] FIG. 2 illustrates the improvement in the treatment of atopic dermatitis using Bethasone valerate 0.12% foam.

DETAILED DESCRIPTION OF THE INVENTION

Foam Flammability

[0128] Foamable compositions comprise of one or more flammable components. Upon being released from a pressurized canister usually by depression of an actuator valve the flowable composition expands rapidly to form a foam. Most or essentially all of the propellant immediately becomes a gas and dissipates into the atmosphere. A good to excellent foam, can be rich to very rich and creamy in appearance with a very fine to small bubble size. Propellant gas can to some extent be entrapped in such bubbles. Relatively small amounts of propellant may initially remain dissolved in the foam. The amount may vary according to the foam composition. For example, if the foam comprises a hydrophobic solvent and the propellant is hydrophobic a higher amount of propellant may remain in the foam immediately after release when compared to a hydrophillic foam. So it can be appreciated that the amount of propellant available to ignite in or about the surface of the foam shortly after expansion is variable and can depend extensively on the components of the foam.

[0129] Ideally, non-flammable propellants should be used so that the propellant does not contribute to the flammability of the foam. However, non-flammable CFC's are no longer being used due to the overriding concern of damage to the ozone layer and global warming consequent on uncontrolled use of such environmentally unfriendly substances. Other non-flammable gases like carbon dioxide do not deliver sufficient pressure and are more suitable for preparation of mouse cream. Other non-flammable gases like Dymel are currently not approved for use in the United States. Thus, many foamable compositions utilize hydrocarbon propellants especially one or more of propane, isobutene, and or butane on their own or more preferably in various mixtures thereof. Such propellants are clearly flammable and to the extent that a significant amount remains in or about the foam, it can readily ignite when exposed to a naked flame. Some of the other ingredients readily used in foam compositions are themselves flammable, alcohol being a classic example.

[0130] The flammability of the compositions originally disclosed in parent application U.S. patent application Ser. No. 10/532,618 was evaluated. Many were surprisingly found to be non-flammable or flame retardant, despite the fact that the foamable compositions contained significant amounts of liquid propellant and combustible hydrophobic solvents.

[0131] Surprisingly, it has been discovered that mineral oils reduce flammability of a foam, as demonstrated in a simplified standard inflammability test based on the European Standard prEN 14851, titled Aerosol containersAerosol foam flammability test, which was performed on mineral oil foam compositions. According to this simplified standard, a product is considered flammable if a stable flame appears following ignition, which is at least 4 cm high and which is maintained for at least 2 seconds. In additional embodiments, the concentration of the mineral oil is sufficient to reduce the degree of inflammability, when compared with the same composition where the oil component comprises a different oil, or other oil like substance, such as petrolatum or an ester of a fatty acid. In a further embodiment the mineral oil is combined in substantial or significant amounts with a different oil, or other oil like substance, and acts to reduce the degree of inflammability of the resultant foam, when compared with the same composition with the different oil, or other oil like substance.

[0132] Mineral oil and MCT oil were discovered to be consistently flame retardant in the test ranges measured with different hydrocarbon propellant mixtures. The initial results showed that neither appeared to be significantly influenced by the propellant mixture used nor the amount of oil or oil like substance in the emollient foam.

[0133] Mineral oil appeared to be preferred and foam compositions comprising mineral oil at 15%, 25%, 35%, 50%, and 60% by weight were all flammable retardant. Moreover, none of the 15% and none of the 35% by weight mineral oil foam compositions with three different propellant mixtures ignited.

[0134] Surprisingly, it has been discovered that MCT's also reduce the flammability of a foam, as demonstrated in a simplified standard inflammability test based on European Standard prEN 14851, titled Aerosol containersAerosol foam flammability test, which was performed on MCT foam compositions. In additional embodiments, the concentration of the MCT is sufficient to reduce the degree of inflammability, when compared with the same composition where the oil component comprises a different oil, or other oil like substance, such as petrolatum or an ester of a fatty acid. In a further embodiment the MCT is combined in substantial or significant amounts with a different oil, or other oil like substance, and acts to reduce the degree of inflammability of the resultant foam, when compared with the same composition with the different oil, or other oil like substance.

[0135] Similarly foam compositions comprising MCT oil at 15%, 35% and 50% by weight were all flammable retardant. Higher MCT oil concentrations (e.g., 60 wt %) did not pass the flammability test used. Without being bound to any particular theory this may have been a consequence of and due to the formation of a water in oil emulsion. Moreover, none of the 15% and only one of the 35 wt % MCT foam compositions with three different propellant mixtures ignited.

[0136] Surprisingly, it has been discovered that vegetable oils also reduce the flammability of a foam, as demonstrated in a simplified standard inflammability test based on European Standard prEN 14851, titled Aerosol containersAerosol foam flammability test, which was performed on soybean oil foam compositions. In additional embodiments, the concentration of the soybean oil is sufficient to reduce the degree of inflammability, when compared with the same composition where the oil component comprises a different oil, or other oil like substance, such as petrolatum or an ester of a fatty acid. In a further embodiment the soybean oil is combined in substantial or significant amounts with a different oil, or other oil like substance, and acts to reduce the degree of inflammability of the resultant foam, when compared with the same composition with the different oil, or other oil like substance.

[0137] Notably, foam compositions comprising soybean oil at 20%, 30.5% and 40% by weight were all flammable retardant and did not ignite at 30.5% or 20%.

[0138] Surprisingly, it has also been discovered that silicone oils also reduce the flammability of a foam, as demonstrated in a simplified standard inflammability test based on European Standard prEN 14851, titled Aerosol containersAerosol foam flammability test, which was performed on dimethicone foam compositions. In additional embodiments, the concentration of the dimethicone is sufficient to reduce the degree of inflammability, when compared with the same composition where the oil component comprises a different oil, or other oil like substance, such as petrolatum or an ester of a fatty acid. In a further embodiment the dimethicone oil is combined in substantial or significant amounts with a different oil, or other oil like substance, and acts to reduce the degree of inflammability of the resultant foam, when compared with the same composition with the different oil, or other oil like substance.

[0139] Notably, foam compositions comprising dimethicone at 10% and 25% by weight were all flammable retardant and did not ignite at 10%.

[0140] Foam compositions comprising other oil like substances namely, either octyl dodecanol or isopropyl myristate as hydrophobic solvent were found to be variable in behavior. In certain circumstances compositions containing significant amounts of octyl dodecanol or isopropyl myristate in addition to water were not flammable according to the simplified AFNOR like test, whereas in other certain circumstances they burnt with a flame too large and or for too long. Octyl dodecanol or isopropyl myristate appear to demonstrate similar flammability properties.

[0141] Turning to non-aqueous solvent components it was observed that petrolatum compositions were flammable. Possibly, and without being tied to any particular theory, apart from any flammability properties of the petrolatum itself, it may be that more of the propellant can remain either dissolved in the solvent or be entrapped in the bubble structure and therefore be available for ignition.

[0142] In contrast, flammability tests of compositions with 15% and 35% PPG 15 stearyl ester with different hydrocarbon propellant mixtures were found to ignite on most occasions with a flame higher than that permitted under the simplified AFNOR like test.

Hydrophobic Solvent

[0143] A hydrophobic solvent according to the present invention is a liquid material having solubility in distilled water at ambient temperature of less than about 1 gm per 100 mL, more preferable less than about 0.5 gm per 100 mL, and most preferably less than about 0.1 gm per 100 mL. It is liquid at ambient temperature.

[0144] The total content of hydrophobic solvent may vary from 2% to 75% (w/w) of the foamable composition. However, different ranges (herein composition classes A-D) have been designated, in order to facilitate a choice of an appropriate class, according to the anticipated cosmetic or pharmaceutical need. As a rule of thumb, higher hydrophobic solvent concentrations are more appropriate for the treatment of dry skin, and/or for the treatment of a disease, which is more responsive to drugs delivered in an oily vehicle. Likewise, the higher oil-content composition classes provide an enhanced occlusive effect, which in turn induces the skin penetration of an active agent. Another consideration relates to user acceptance of a product containing a high concentration of the hydrophobic solvent (from about 25% of the composition), which would leave some oily feeling post-application. Thus, a particular composition of the present invention is selected having a hydrophobic solvent concentration in view of the target population and its specific needs.

[0145] In one or more embodiments of the present invention, the hydrophobic solvent is mineral oil. Mineral oil (Chemical Abstracts Service Registry number 8012-95-1) is a mixture of aliphatic, naphthalenic, and aromatic liquid hydrocarbons that are derived from petroleum. It is typically liquid; its viscosity is in the range of about 35 CST to about 100 CST (at 40 C.), and its pour point (the lowest temperature at which an oil can be handled without excessive amounts of wax crystals forming) is below 0 C. By contrast, white petrolatum, also termed Vaseline, is disadvantageous, due to its waxy nature. It is known to leave waxy and sticky feeling after application and occasionally stain cloths. Thus, white petrolatum and other semi-solid oils are not a preferred hydrophobic solvent according to the present invention.

[0146] Yet another preferred hydrophobic solvents are liquid oils from vegetable, marine or animal sources. By way of example, the unsaturated oil may be selected from the group consisting of olive, corn, soybean, canola, cottonseed, coconut, sesame, sunflower, borage seed, syzigium aromaticum, hempseed, herring, cod-liver, salmon, flaxseed, wheat germ and evening primrose oils and mixtures thereof, at any proportion.

[0147] A particularly preferred class of oils includes polyunsaturated oils, e.g., esters, and in particular glyceryl esters, of omega-3 and omega-6 fatty acids. Examples of such polyunsaturated fatty acids are linoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Thus, in one or more embodiments of the present invention the hydrophobic solvent includes at least 6% by weight foamable composition of an oil selected from omega-3 oil, omega-6 oil, and mixtures thereof.

[0148] Another class of oils suitable for use as a phydrophobic solvent is liquid hydrophobic plant-derived oils, or essential oils, e.g. therapeutic oils containing active biologically occurring molecules that have a therapeutic effect when applied topically. Examples of such oils include rosehip oil, which contain retinoids and is known to reduce acne and post-acne scars, and tea tree oil, which possess antibacterial, antifungal and antiviral properties. Other examples of essential oils are oils of basil, camphor, cardamom, carrot, citronella, clary sage, clove, cypress, frankincense, ginger, grapefruit, hyssop, jasmine, lavender, lemon, mandarin, marjoram, myrrh, neroli, nutmeg, petitgrain, sage, tangerine, vanilla, verbena, as well as any other therapeutically beneficial oil, know in the art of herbal medication.

[0149] Medium-chain triglycerides (MCT's) have an average molecular weight of about 500. They are sometimes referred to as MCT oil or thin vegetable oil. They take the form of a colorless to slightly yellowish oily liquid that is practically odorless and tasteless and which solidifies at about 0 C. They are miscible with long-chain hydrocarbons and triglycerides but are practically insoluble in water. They consist of a mixture of triglycerides of saturated fatty acids, mainly of caprylic acid and of capric acid and contain not less than 95% of saturated fatty acids.

[0150] In one or more embodiments of the present invention, the hydrophobic solvent is an emollient. An emollient is a hydrophobic agent that softens, smoothens and improves lipid content of the skin or other mucous membranes. In one or more embodiments of the present invention, the emollient is a liquid. Without derogating the generality of this definition, examples of suitable emollients for use include isostearic acid derivatives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, diisopropyl adipate, dimethyl isosorbide, maleated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated coco-glycerides, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, octyl hydroxystearate and mixtures thereof. Other examples of other suitable emollients can also be found in the Cosmetic Bench Reference, pp. 1.19-1.22 (1996). In one or more embodiments, the hydrophobic solvent is a mixture of a mineral oil or silicone oil and an emollient.

[0151] In one or more embodiments of the present invention, silicone oil is a component of the hydrophobic solvent. Silicone oils are used in the foamable compositions due to their known skin protective and occlusive properties. Suitable silicone oils for use in the invention include non-volatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers, polydimethylsiloxanes (dimethicones) and poly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. These are preferably chosen from cyclic or linear polydimethylsiloxanes containing from about 3 to about 9, preferably from about 4 to about 5, silicon atoms. Volatile silicones such as cyclomethicones can also be used. Water-soluble silicones, such as dimethicone copolyol are not included in the definition of silicone oils (as hydrophobic solvents) according to the present invention.

[0152] In one or more embodiments of the present invention, the composition comprises at least 2% (w/w foamable composition) silicone oil, alone or as part of the hydrophobic solvent. Yet, in other embodiments, the composition comprises at least 5% (w/w) silicone oil alone or as part of the hydrophobic solvent.

[0153] The hydrophobic solvent of the present invention may comprise a mixture of two or more of the above hydrophobic solvents in any proportion.

Foam Adjuvant Agents

[0154] Foam adjuvants are included in the foamable compositions of the present invention to increase the foaming capacity of surfactants and/or to stabilize the foam. In one or more embodiments of the present invention, the foam adjuvant agents includes fatty alcohols having 15 or more carbons in their carbon chain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof). Other examples of fatty alcohols are arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well as alcohols with longer carbon chains (up to C50). Fatty alcohols, derived from beeswax, including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain, are especially well suited as foam adjuvant agents according to the present invention. The concentration of the fatty alcohol, required to support the foam system is inversely related to the length of its carbon chains.

[0155] In one or more embodiments of the present invention, the foam adjuvant agent includes fatty acids having 16 or more carbons in their carbon chain, such as hexadecanoic acid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22), octacosanoic acid (C28), as well as fatty acids with longer carbon chains (up to C50), or mixtures thereof.

[0156] Optionally, the carbon atom chain of the fatty alcohol or the fatty acid may have at least one double bond. A further class of foam adjuvant agent according to the present invention comprises a long chain fatty alcohol or fatty acid, wherein the carbon atom chain is branched. The carbon chain of the fatty acid or fatty alcohol can be substituted with a hydroxyl group, such as 12-hydroxy stearic acid.

[0157] The foam adjuvant agent according to one or more embodiments of the present invention includes a mixture of fatty alcohols, fatty acids and hydroxy fatty acids and derivatives thereof in any proportion, providing that the total amount is 0.1% to 5% (w/w) of the carrier mass. More preferably, the total amount is 0.4%-2.5% (w/w) of the carrier mass.

[0158] While fatty alcohols and fatty acids serve to stabilize the resultant foam composition, they often provide additional therapeutic properties. Long chain saturated and mono unsaturated fatty alcohols, e.g., stearyl alcohol, erycyl alcohol, arachidyl alcohol and docosanol have been reported to possess antiviral, anti infective, anti-proliferative and anti-inflammatory properties (U.S. Pat. No. 4,874,794). Longer chain fatty alcohols, e.g., tetracosanol, hexacosanol, heptacosanol, octacosanol, triacontanol, etc. are also known for their metabolism modifying properties and tissue energizing properties. Long chain fatty acids have also been reported to possess anti-infective characteristics. Thus, the pharmaceutical or cosmetic carrier, containing the foam adjuvant agent of the present invention provides an extra therapeutic benefit in comparison with currently used vehicles, which are inert and non-active.

Surface-Active Agents

[0159] Surface-active agents, according to the present invention include any agent linking oil and water in the composition.

[0160] The surface-active agent is suitably selected from anionic, cationic, nonionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants. Such surfactants are well known to those skilled in the pharmaceutical and cosmetic formulation art. Non-limiting examples of possible surfactants include polysorbates, such as polyoxyethylene (20) sorbitan monostearate (Tween 60) and poly(oxyethylene) (20) sorbitan monooleate (Tween 80); poly(oxyethylene) (POE) fatty acid esters, such as Myrj 45, Myrj 49 and Myrj 59; poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1; sucrose esters, partial esters of sorbitol and its anhydrides, such as sorbitan monolaurate and sorbitan monolaurate; mono or diglycerides, isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl sulfate and betaines.

[0161] A combination of surface active agents is possible. Any surface-active agent or combinations thereof may be used as surface-active agent. According to one or more embodiments of the present invention, the surface-active agent (or agents) has an HLB of higher than 9.

[0162] In one or more embodiments of the present invention, the surface-active agent is selected from the groups of non-ionic surfactants, cationic surfactants, amphoteric and zwitterionic surfactants, and, in particular, the surface-active agent is a non-ionic surfactant. Ionic surfactants (including cationic, anionic, amphotheric and zwitterionic surfactants) are known to be skin irritants. Therefore, non-ionic surfactants are preferred in applications including sensitive skin such as found in most dermological disorders. We have surprisingly found that non-ionic surfactants alone provide foams of excellent quality, i.e. a score of E according to the grading scale discussed below.

[0163] In one or more embodiments of the present invention, the surface active agent is solely non-ionic, comprising one or more non-ionic surfactants.

[0164] In one or more embodiments of the present invention, the surface active agent include a ratio of non-ionic surfactants to ionic surfactants in the range of 100:1 to 6:1; in some embodiments the non-ionic to ionic surfactant ratio is greater than 6:1, or greater than 8:1; or greater than 14:1, or greater than 16:1, or greater than 20:1.

[0165] Exemplary non-ionic surfactants include polyethoxylated fatty acids, fatty acid diesters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters and lower alcohol fatty acid esters.

[0166] Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have useful surfactant properties. Exemplary monoesters include esters of lauric acid, oleic acid, and stearic acid, e.g., PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. Polyethylene glycol fatty acid diesters suitable for use as non-ionic surfactants in the compositions of the present invention include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. Suitable polyethylene glycol glycerol fatty acid esters include PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.

[0167] A large number of surfactants of different degrees of hydrophobicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils. Most commonly, the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil. Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol. Among these alcohol-oil transesterified surfactants, preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen 767). Preferred hydrophobic surfactants in this class include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil M 2125 CS), PEG-6 almond oil (Labrafil M 1966 CS), PEG-6 apricot kernel oil (Labrafil M 1944 CS), PEG-6 olive oil (Labrafil M 1980 CS), PEG-6 peanut oil (Labrafil M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil M 2130 BS), PEG-6 palm kernel oil (Labrafil M 2130 CS), PEG-6 triolein (Labrafil b M 2735 CS), PEG-8 corn oil (Labrafil WL 2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40). The latter two surfactants are reported to have HLB values of 10, which are generally considered to be the approximate border line between hydrophilic and hydrophobic surfactants.

[0168] Alcohol-oil transesterification derivatives of oil soluble vitamins (e.g., vitamins A, D, E, K, etc.), such as tocopheryl PEG-100 succinate (TPGS, available from Eastman), are also suitable surfactants.

[0169] Polyglycerol esters of fatty acids are also suitable non-ionic surfactants for the present invention. Among the polyglyceryl fatty acid esters, exemplary use hydrophobic surfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), and polyglyceryl-10 trioleate. Preferred hydrophilic surfactants include polyglyceryl-10 laurate (Nikko) Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), and polyglyceryl-10 mono, dioleate (Caprol PEG 860), Polyglyceryl polyricinoleates (Polymuls) are hydrophilic and hydrophobic surfactants of this class.

[0170] Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or hydrophobic. Preferred derivatives include the polyethylene glycol derivatives. An exemplary hydrophobic surfactant in this class is cholesterol. An exemplary hydrophilic surfactant in this class is PEG-24 cholesterol ether (Solulan C-24).

[0171] A variety of PEG-sorbitan fatty acid esters are suitable for use as non-ionic surfactants in the present invention. In general, these surfactants are hydrophilic, although several hydrophobic surfactants of this class can be used. Among the PEG-sorbitan fatty acid esters, exemplary hydrophilic surfactants include PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80).

[0172] Ethers of polyethylene glycol and alkyl alcohols are suitable non-ionic surfactants for use in the present invention. Exemplary hydrophobic ethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30).

[0173] The polyoxyethylene-polyoxypropylene (POE-POP) block copolymers are a unique class of polymeric surfactants. The unique structure of the surfactants, with hydrophilic POE and hydrophobic POP moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention. These surfactants are available under various trade names, including Synperonic PE series (ICI), Pluronic series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these polymers is poloxamer (CAS 9003-11-6). Exemplary hydrophilic surfactants of this class include Poloxamers 108, 188, 217, 238, 288, 338, and 407. Exemplary hydrophobic surfactants in this class include Poloxamers 124, 182, 183, 212, 331, and 335.

[0174] Sorbitan esters of fatty acids are suitable non-ionic surfactants for use in the present invention. Among these esters, preferred hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitan monostearate, and sorbitan tristearate.

[0175] Esters of lower alcohols (C.sub.2 to C.sub.4) and fatty acids (C.sub.8 to C.sub.18) are suitable non-ionic surfactants for use in the present invention. Among these esters, preferred hydrophobic surfactants include ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), and isopropyl palmitate (Crodamol IPP).

[0176] In one or more embodiments of the present invention, the surface-active agent comprise mono-, di- and tri-esters of sucrose with food fatty acids (sucrose esters), prepared from sucrose and methyl and ethyl esters of food fatty acids or by extraction from sucroglycerides. Exemplary sucrose esters include sucrose monopalmitate and sucrose monolaurate. Suitable sucrose esters include those having a high monoester content, which have higher HLB values.

[0177] In one or more embodiments of the present invention, a combination of a non-ionic surfactant and an anionic surfactant (such as sodium lauryl sulphate) is employed, at a ratio of between 1:1 and 20:1, or at a ratio of 4:1 to 10:1. The resultant foam has a low specific gravity, e.g., less than 0.1 g/ml, which upon rubbing (shear stress) onto the skin collapses easily, to allow facile absorption.

[0178] Unlike prior art foamable compositions, the total surfactant employed to obtain a foam that is stable, of low specific gravity and has a fine bubble structure is low. Lower surfactant levels, particularly of ionic surfactants, are preferred to reduce skin irritations. Total surfactant is in the range of 0.1 to 5.0 wt % of the foamable composition, and is typically less than 2 wt %, or even less than 1 wt %.

Water Gelling Agents

[0179] The water gelling agent according to one or more embodiments of the present invention stablizes the aqueous phase by, for example, increasing viscosity and linking capability. Exemplary water gelling agents that can be used in accordance with one or more embodiments of the present invention include for example, but are not limited to, naturally-occurring polymeric materials such as, locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum sodium alginate, xanthan gum, quince seed extract, tragacanth gum, starch, chemically modified starches and the like, semi-synthetic polymeric materials such as cellulose ethers (e.g. hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose), polyvinylpyrrolidone, polyvinylalcohol, guar gum, hydroxypropyl guar gum, soluble starch, cationic celluloses, cationic guars and the like and synthetic polymeric materials such as carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like. Mixtures of the above compounds are contemplated.

[0180] Further exemplary water gelling agents include the acrylic acid/ethyl acrylate copolymers and the carboxyvinyl polymers sold, for example, by the B.F. Goodrich Company under the trademark of Carbopol Registered resins. These resins consist essentially of a colloidal water-soluble polyalkenyl polyether crosslinked polymer of acrylic acid crosslinked with from 0.75% to 2% of a crosslinking agent such as polyallyl sucrose or polyallyl pentaerythritol. Examples include Carbopol 934, Carbopol 940, Carbopol 950, Carbopol 980, Carbopol 951 and Carbopol 981. Carbopol 934 is a water-soluble polymer of acrylic acid crosslinked with about 1% of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each sucrose molecule.

[0181] The gelling agent is present in an amount in the range of about 0.1% to about 5.0 wt % of the foamable composition. In one or more embodiments, it is typically less than 1 wt % of the foamable composition.

Alcohol Free

[0182] Unlike the composition disclosed in U.S. Pat. No. 6,126,920, which contains a 40-90 wt % aliphatic alcohol, the composition of the present invention does not contain such amount alcohols. For the purpose of the present application, the term alcohol free shall mean that the composition contains no more than an incidental amount of an aliphatic alcohol, e.g. less than about 7.5% of any aliphatic alcohol, having one to six carbon atoms in their carbon backbone, or no more than 7.5% of any mixture of such aliphatic alcohols. Alcohols at these low levels are not considered to have a negative effect on skin or mucous membranes. In one or more embodiments, the foamable compositions do not contain any alcohol.

Optional Ingredients

[0183] The pharmaceutical or cosmetic foam carrier of the present invention may further optionally comprise a variety of pharmaceutical or cosmetic ingredients, which are added in order to fine-tune the consistency of the formulation, protect the formulation components from degradation and oxidation and bestow their cosmetic acceptability. Such excipients, may be selected, for example, from the group consisting of diglycerides, triglycerides, stabilizing agents, antioxidants, humectants, flavoring, colorant and odorant agents and other formulation components, used in the art of pharmaceutical and cosmetic formulary. A pharmaceutical or cosmetic composition manufactured using the foam carrier according to the present invention is very easy to use. When applied onto the afflicted body surface of humans or animals, it is in a foam state, allowing free application without spillage. Upon further application of a mechanical force; e.g., by rubbing the composition onto the body surface, it freely spreads on the surface and is rapidly absorbed.

Propellant Aerosol

[0184] Aerosol propellants are used to generate and administer the foamable composition as a foam. The total composition including propellant, foamable compositions and optional ingredients is referred to as the foamable carrier. The propellant makes up about 5-25 wt % of the foamable carrier. Examples of suitable propellants include volatile hydrocarbons such as butane, propane, isobutane or mixtures thereof, and fluorocarbon gases.

[0185] Compositions of commercially available highly flammable hydrocarbon propellants are listed in the table below.

TABLE-US-00001 TABLE B Propellant Propane % Iso-Butane % n-Butane % Propellant mol mass mol mass mol mass 5515 ~55 ~47 ~15 ~18 ~30 ~35 1681 ~16 ~13 ~81 ~84 ~3 ~3 Pinto* NL ~8 NL ~30 NL ~60 *Plus very small amounts of other gasses including ~2% isopentane; NL = Not listed in the certificate of analysis. ~ = approximately.

Composition and Foam Physical Characteristics

1. Composition Flow Properties:

[0186] It is important to have a composition, including water, hydrophobic solvents, formulation excipients and propellant, in a stable emulsion, which ascertain acceptable shelf-life of the product.

[0187] Yet, another crucial property is that said composition has to be free flowing, since otherwise, it cannot flow through the dip-tube of the aerosol container and create acceptable foam. It has been noted that in the context of the composition of the present invention, compositions comprising semi-solid hydrophobic solvents, e.g., white petrolatum, are excessively viscous and demonstrate poor flowability.

[0188] The combination of a surface active agent, foaming adjuvant and water gelling agent according to one or more embodiments of the invention provides a low specific gravity foam having superior flow properties and sheer breakability (among other attributes). According to one or more embodiments of the present invention, the total amount of surface active agent, foaming adjuvant and water gelling agent, in combination does not exceed 8% (w/w) of foamable composition. In other embodiments, the combined amounts of surface active agent, foaming adjuvant and water gelling agent is less than 5% (w/w) of foamable composition. The low solids content improves the flow properties of the foam, reduces unpleasant skin residue and reduces the cost of manufacture. As is demonstrated herein, the foam quality and foam breakability is excellent, despite the low levels of these components in the foam.

2. Foam Properties:

[0189] The following scale for foam quality is used to evaluate foams:

[0190] E (excellent): very rich and creamy in appearance, does not show any bubble structure or shows a very fine (small) bubble structure;

[0191] G (good): rich and creamy in appearance, very small bubble size, dulls more rapidly than an excellent foam;

[0192] FG (fairly good): a moderate amount of creaminess noticeable, bubble structure is noticeable;

[0193] F (fair): very little creaminess noticeable, larger bubble structure than a fairly good foam;

[0194] P (poor): no creaminess noticeable, large bubble structure; and

[0195] VP (very poor): dry foam, large very dull bubbles, difficult to spread on the skin.

[0196] Foams, adequate for topical administration according to the present invention have to be of quality grade E or G upon release from the aerosol container. Smaller bubbles mean more stable foam, which does not collapse spontaneously immediately upon discharge from the container. The finer foam structure looks and feels smoother, thus increasing its usability and appeal.

[0197] A crucial aspect of foam properties, according to the present invention is breakability. Sheer-force breakability of the foam, as attained by the composition of the present invention is clearly advantageous to thermally-induced breakability, present, for example in U.S. Pat. No. 6,126,920, and the respective Olux and Luxiq products, as demonstrated by the fact that according to the use instructions of Olux and Luxiq, the foam cannot be applied on the hand and afterwards delivered to the afflicted area, since it immediately collapses upon exposure to skin temperature.

[0198] Yet, another important property is specific gravity of the foam, as measured upon release from the aerosol can. Typically, foams according to the present invention have specific gravity of less than 0.1 g/mL and more preferably, less than 0.05 g/mL.

Fields of Pharmaceutical Applications

[0199] By including an appropriate therapeutic agent in the foamable carrier, the foam composition of the present invention is useful in the therapy of a variety of dermatological disorders (also termed dermatoses) including, in a non-limiting exemplary manner:

[0200] Dermatitis [0201] Contact Dermatitis [0202] Atopic Dermatitis [0203] Seborrheic Dermatitis [0204] Nummular Dermatitis [0205] Chronic Dermatitis Of The Hands And Feet [0206] Generalized Exfoliative Dermatitis [0207] Stasis Dermatitis [0208] Lichen Simplex Chronicus

[0209] Bacterial Infections [0210] Cellulitis [0211] Acute Lymphangitis [0212] Lymphadenitis [0213] Erysipelas [0214] Cutaneous Abscesses [0215] Necrotizing Subcutaneous Infections [0216] Staphylococcal Scalded Skin Syndrome [0217] Folliculitis [0218] Furuncles [0219] Hidradenitis Suppurativa [0220] Carbuncles [0221] Paronychial Infections [0222] Erythrasma

[0223] Fungal Infections [0224] Dermatophyte Infections [0225] Yeast Infections

[0226] Parasitic Infections [0227] Scabies [0228] Pediculosis [0229] Creeping Eruption

[0230] Viral Infections

[0231] Disorders of Hair Follicles and Sebaceous Glands [0232] Acne [0233] Rosacea [0234] Perioral Dermatitis [0235] Hypertrichosis (Hirsutism) [0236] Alopecia, including male pattern baldness, alopecia areata, alopecia universalis and alopecia totalis [0237] Pseudofolliculitis Barbae [0238] Keratinous Cyst

[0239] Scaling Papular Diseases [0240] Psoriasis [0241] Pityriasis Rosea [0242] Lichen Planus [0243] Pityriasis Rubra Pilaris

[0244] Benign Tumors [0245] Moles [0246] Dysplastic Nevi [0247] Skin Tags [0248] Lipomas [0249] Angiomas [0250] Pyogenic Granuloma [0251] Seborrheic Keratoses [0252] Dermatofibroma [0253] Keratoacanthoma [0254] Keloid

[0255] Malignant Tumors [0256] Basal Cell Carcinoma [0257] Squamous Cell Carcinoma [0258] Malignant Melanoma [0259] Paget's Disease Of The Nipples [0260] Kaposi's Sarcoma

[0261] Reactions To Sunlight [0262] Sunburn [0263] Chronic Effects of Sunlight [0264] Photosensitivity

[0265] Bullous Diseases

[0266] Pemphigus [0267] Bullous Pemphigoid [0268] Dermatitis Herpetiformis [0269] Linear Immunoglobulin A Disease

[0270] Pigmentation Disorders [0271] Hypopigmentation [0272] Vitiligo [0273] Albinism [0274] Post-inflammatory hypopigmentation [0275] Hyperpigmentation [0276] Melasma (chloasma) [0277] Drug-induced hyperpigmentation [0278] Post-inflammatory hyperpigmentation

[0279] Disorders of Cornification [0280] Ichthyosis [0281] Keratosis Pilaris [0282] Calluses And Corns [0283] Actinic keratosis

[0284] Pressure Sores

[0285] Disorders of Sweating

[0286] Inflammatory reactions [0287] Drug Eruptions [0288] Toxic Epidermal Necrolysis [0289] Erythema Multiforme [0290] Erythema Nodosum [0291] Granuloma Annulare

[0292] In one or more embodiments of the present invention, the foam composition of the present invention is useful in the therapy of non-dermatological disorders, which respond to transdermal delivery of an active agent. By way of example, such disorders include localized pain in general, as well as joint pain, muscle pain, back pain, rheumatic pain, arthritis, ostheoarthritis and acute soft tissue injuries and sports injuries. Other disorders of this class include conditions, which respond to hormone therapy, such as hormone replacement therapy, transdermal nicotine administration, and other respective disorders, known in the art of drug delivery. The foam composition of the present invention is also useful in the delivery of local anesthetic agents.

Active Pharmaceutical Agents (Drugs)

[0293] The active pharmaceutical agents, also referred to as drug(s), may consist of a single drug or a combination of drugs that can be dissolved in the water phase or the hydrophobic phase of the carrier composition. Examples of such drugs are antibiotic, antibacterial, antifungal, antiviral, antiinflammatory, anesthetic, analgesic, antiallergic, corticosteroid, retinoid and antiproliferative medications and mixtures thereof at any proportion. The concentration of drugs may be adopted to exert a therapeutic effect on a disease when applied to an afflicted area.

Antibacterial Agents

[0294] One important class of drugs comprises antibacterial agents. It is well known that bacterial infections are involved in a variety of superficial disorders of the skin, eye, mucosal membrane, oral cavity, vagina and rectum.

[0295] The antibacterial drug can be active against gram positive and gram-negative bacteria, protozoa, aerobic bacteria and unaerobic ones.

[0296] By way of example, the antibacterial drugs can be selected from the group of chloramphenicol, tetracyclines, synthetic and semi-synthesic penicillins, beta-lactames, quinolones, fluoroquinolnes, macrolide antibiotics, metronidazlole and its derivatives and analogs, dicarboxylic acids, such as azelaic acid, slicylates, peptide antibiotics, cyclosporines and any combination thereof at a therapeutically effective concentration. Another group of antibacterial agents which is non-specific, comprises strong oxidants and free radical liberating compounds, such as hydrogen peroxide, bleaching agents (e.g., sodium, calcium or magnesium hypochloride and the like) iodine, chlorohexidine and benzoyl peroxide.

[0297] Antibacterial compositions according to the present invention may be used to treat infections of the skin. An example of a very common skin infection is acne, which involve infestation of the sebaceous gland with P. acnes, as well Staphylococus aureus and Pseudomonas. Various antibacterial agents have been utilized to treat acne, however, their efficacy is limited due to their low penetration into the hydrophobic environment of the skin layers and sebaceous glands. The composition of the present invention, comprising a hydrophobic component, would facilitate an enhanced rate of penetration. Furthermore, the intrinsic antibacterial and antiinflammatory effects of the foam adjuvant agents, i.e., fatty alcohols and acids, provides a combined effect that should result in a better therapeutic response to treatment.

[0298] The composition of the present invention is particularly useful and beneficial in the prevention and treatment of secondary infections, accompanying skin-structure damage, such as in cuts, wounds, burns and ulcers. In all such cases, the present formulation is easy to use, being in foam state when applied and becoming liquid instantly upon rubbing onto the skin.

[0299] While being useful in the prevention and treatment of infections, the antibacterial foam of the present invention is also applicable for decontaminating areas, afflicted with bacterial warfare organisms, such as anthrax and smallpox.

[0300] The same advantage is expected when the composition of the present invention is topically applied to mucosal membranes, the oral cavity, the vagina and the rectum.

Anti-Fungal Agents

[0301] Fungal infections are another object of treatment using the composition of the present invention. Superficial fungal infection of the skin is one of the commonest skin diseases seen in general practice. Dermatophytosis is probably the most common superficial fungal infection of the skin. It is caused by a group of fungi, which are capable of metabolizing the keratin of human epidermis, nails or hair. There are 3 genera of dermatophytes causing dermatophytosis, i.e, microsporum, trichophyton and epidermophyton.

[0302] Candidiasis is an infection caused by the yeast like fungus Candida albicans or occasionally other species of candida. Clinical syndromes of candidiasis include: (a) oral candidiasis (oral thrush); (b) candidiasis of the skin and genital mucous membrane; and (c) candida paronychia, which inflicts the nail.

[0303] The pharmaceutical composition may comprise an antifungal drug, which is active against dermatophytes and candida, selected from the group of, but not limited to azoles, diazoles, triazoles, miconazole, fluconazole, ketoconazole, clotrimazole, itraconazole griseofulvin, ciclopirox, amorolfine, terbinafine, Amphotericin B, potassium iodide, flucytosine (5FC) and any combination thereof at a therapeutically effective concentration.

[0304] It is useful, for example for the treatment of tinea corporis, tinea pedis, tinea rubrum, tinea unguium, tinea cruris, tinea barbae and tinea versicolor, as well as yeast Infections, such as candidiasis, and candidal vaginitis.

Anti-Viral Agents

[0305] The composition of the present invention is particularly beneficial in the case of viral infections. Cold sores are caused by the herpes simplex Type 1 virus and are sometimes referred to as facial herpes. Mollusca are small viral growths that appear singly or in groups on the face, trunk, lower abdomen, pelvis, inner thighs, or penis. Shingles (herpes zoster), which usually only occurs once in a lifetime, appears as a rash (clusters of blisters with a red base). It is caused by the same virus responsible for chickenpox. Warts are a common, benign skin tumor caused by viral infection.

[0306] Viral infections are currently treated with various antiviral agents, as summarized in the following table:

TABLE-US-00002 Chemical Drug Viruses Type Vidarabine Herpesviruses Nucleoside analogue Acyclovir Herpes simplex Nucleoside (HSV) analogue Gancyclovir Cytomegalovirus Nucleoside (CMV) analogue Nucleoside-analog reverse transcriptase Retroviruses Nucleoside inhibitors (NRTI): AZT (Zidovudine), (HIV) analogue ddl (Didanosine), ddC (Zalcitabine), d4T (Stavudine), 3TC (Lamivudine) Non-nucleoside reverse transcriptase Retroviruses Nucleoside inhibitors (NNRTI): Nevirapine, (HIV) analogue Delavirdine Protease Inhibitors: Saquinavir, HIV Peptide Ritonavir, Indinavir, Nelfinavir analogue Ribavirin Broad spectrum: Triazole HCV, HSV, carboxamide measles, mumps, Lassa fever Amantadine/Rimantadine Influenza A Tricyclic strains amine Interferons Hepatitis B Protein and C

[0307] Any of the above antiviral drugs, in a therapeutically effective concentration, can be incorporated in the foam composition of the present invention. The composition of the present invention, which comprises a hydrophobic solvent, would facilitate an enhanced rate of penetration and better topical distribution of any of the above listed antiviral drugs. Furthermore, the intrinsic antiviral effects of the foam adjuvant agents, i.e., fatty alcohols and acids, provides a combined effect that should result in a better therapeutic response to treatment.

Antiinflammatory or Antiallergic Agents

[0308] Yet, according to another embodiment according to the present invention the drug is an antiinflammatory or antiallergic agent. Antiinflammatory or antiallergic agent can be selected from the group of corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), anti-histamines, immunosuppressants and any combination thereof at a therapeutically effective concentration.

[0309] The following table provides a summary of currently available corticosteroid agent and their typical therapeutically effective concentration.

TABLE-US-00003 Potency Compound Formulation Very high Clobetasol proprionate Cream or ointment 0.05% Halobetasol proprionate Cream or ointment 0.05% High Betamethasone diproprionate Cream or ointment 0.05% Betamethasone valerate Ointment 0.1% Fluocinolone acetonide Cream 0.02% Halcinonide Cream or ointment 0.1% Medium Betamethasone valerate Cream 0.1% Fluocinolone acetonide Cream or ointment 0.020% Hydrocortisone valerate Cream or ointment 0.2% Triamcinolone acetonide Cream, ointment, or lotion 0.1% or 0.020% Low Hydrocortisone Cream, ointment, or lotion 1.0% or 2.5%

[0310] The concentrations of corticosteroid drugs, as presented in the above table are provided herein only as example, and any therapeutically effective concentration of such corticosteroids can be incorporated in the composition of the present invention.

[0311] Since all corticosteroid drugs are typically hydrophobic, the carrier of the present invention, comprising a hydrophobic solvent, is most suitable as a vehicle to facilitate better topical distribution and an enhanced rate of penetration of any of the above listed drugs. Furthermore, the intrinsic antiviral, antibacterial and antiinflammatory effects of the foam adjuvant agents; i.e., fatty alcohols and acids, provides a combined effect that should result in a better therapeutic response to treatment.

[0312] Psoriasis is a very common chronic skin disease, which may be the target of treatment using the composition of the present invention. It is marked by periodic flare-ups of sharply defined red patches covered by a silvery, flaky surface.

[0313] Corticosteroid ointments, greasy preparations containing little or no water, are commonly used for treating psoriasis. Their main disadvantage is in their sticky feeling, which remains so long after treatment is over. By contrast, the foam of the present invention, while comprising considerable concentration of an oil (hydrophobic solvent), spreads very easily throughout the afflicted area and absorbs into the skin without leaving any untoward sensation or look. Examples of other inflammatory disorders, which can be treated by the composition of the present invention, wherein the drug is a steroid are atopic dermatitis, seborrhea, seborrheic dermatitis of the face and trunk, seborrheic blepharitis, contact dermatitis, stasis dermatitis (gravitational eczema; varicose eczema), exfoliative dermatitis (erythroderma), lichen simplex chronicus, pityriasis rosea and pemphigus.

[0314] Topical antihistaminic preparations currently available include 1% and 2% diphenhydramine (Benadryl and Caladryl), 5% doxepin (Zonalon) cream, phrilamine maleate, chlorpheniramine and tripelennamine, phenothiazines, promethazine hydrochloride (Phenergan) and dimethindene maleate. These drugs, as well as additional antihistamines can also be incorporated in the composition of the present invention.

[0315] It is pointed out that polyunsaturated fatty acids, containing omega-3 and omega-6 fatty acids (e.g., linoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are beneficial in the treatment of psoriasis and other skin inflammation conditions.

[0316] A second class of anti-inflammatory agents, which is useful in the foam of the present invention, includes the nonsteroidal anti-inflammatory agents (NSAIDs). The variety of compounds encompassed by this group is well-known to those skilled in the art. Specific non-steroidal anti-inflammatory agents useful in the composition invention include, but are not limited to:

[0317] 1) Oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam;

[0318] 2) Salicylates, such as salicylic acid, ethyl salicylate, methyl salycilate, aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;

[0319] 3) Acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac;

[0320] 4) Fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids;

[0321] 5) Propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and

[0322] 6) Pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone.

[0323] Any further steroidal and nonsteroidal compounds, having the capacity to prevent, alleviate the symptoms of, treat or cure inflammation processes, are generally included, as possible anti-inflammatory agents, according to the present invention.

[0324] The pharmaceutical composition of the present invention may also comprise an antiinflammatory or antiallergic agent, wherein said agent reduces the occurrence of pro-inflammatory cytokines or inhibits the effect of pro-inflammatory cytokines.

[0325] Mixtures of such anti-inflammatory agents may also be employed, as well as the dermatologically acceptable salts, esters, amides, prodrugs and derivatives of these agents.

[0326] Topical application of a foam, comprising a safe and effective dose of an NSAID can be useful in the prevention and/or alleviation of the symptoms of rheumatoid arthritis, osteoarthritis and pain. Topical NSAIDs, incorporated in the foam of the present invention can be also used in the treatment of dermatological disorders, such as acne, rosacea, hair growth disorders, actinic keratosis and certain skin cancer conditions.

Topical Anesthetics

[0327] The compositions of the present invention may contain a safe and effective amount of a topical anesthetic. Examples of topical anesthetic drugs include benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceutically acceptable salts thereof. Mixtures of such anesthetic agents may be synergistically beneficial.

Keratolytically Active Agents

[0328] The term keratolytically active agent is used herein to mean a compound which loosens and removes the stratum corneum of the skin, or alters the structure of the keratin layers of skin.

[0329] Keratolytically active agents are used in the treatment of many dermatological disorders, which involve dry skin, hyperkeratinization (such as psoriasis), skin itching (such as xerosis), acne and rosacea.

[0330] Suitable keratolytically active agent include phenol and substituted phenolic compounds. Such compounds are known to dissolve and loosen the intracellular matrix of the hyperkeratinized tissue. As such, they are used in the treatment of dermatological disorders. Dihydroxy benzene and derivatives thereof have been recognized as potent keratolytic agents. Resorcinol (m-dihydroxybenzene) and derivatives thereof are used in anti-acne preparations. Hydroquinone (p-dihydroxybenzene), besides its anti-pigmentation properties, is also keratolytic. These compounds also exhibit antiseptic properties. Cresols also possess bactericidal and keratolytic properties.

[0331] Vitamin A and its derivatives, such as retinoic acid, isoretinoic acid, retinol and retinal are another preferred class of keratolytically active agents.

[0332] Another group of keratolytically active agents include alpha-hydroxy acids, such as lactic acid and glycolic acid and their respective salts and derivatives; and beta-hydroxy acids, such as Salicylic acid (o-hydroxybenzoic acid) and its salts and pharmaceutically acceptable derivatives, which typically possess anti-inflammatory, as well as keratolytic, activity.

[0333] Yet, another class of preferred keratolytically active agents includes urea and its derivatives.

Retinoids

[0334] Another preferred group of active agents comprise retinol, retinal, all trans retinoic acid and derivatives, isomers and analogs thereof, collectively termed retinoids. Etretinate, actiretin, isotretinoin, adapalene and tazarotene are further examples of said retinoid isomers and analogs. Compositions according to the present invention, which contain retinoids as the active drug, can be used for the treatment of acne, seborrhea, various dermatoses, inflammation of the skin, mucosal membranes, vagina and the rectum, psoriasis, actinic keratosis and skin cancers, by application onto the affected area.

Insecticide and Insect Repellents Agents

[0335] Insects, such as mosquitoes, biting flies, mites, gnats, fleas, chiggers, punkies, sand flies, lice and ticks can be annoying and sometimes pose a serious risk to human and animal health. In certain areas of the United States, mosquitoes can transmit diseases like equine and St. Louis encephalitis. Biting flies can inflict a painful bite that can persist for days, swell, and become infected. Ticks can transmit serious diseases like Lyme disease and Rocky Mountain Spotted Fever.

[0336] There are several types of insect repellents to use when protecting people and animals from flying or biting insects, spiders, ticks and mites. By way of example, these may include DEET (N, N-diethyl-m-toluamide), dimethyl phthalate, piperonyl butoxide and permethrin. Insect repelling terpenoids, have been reported by Hwang, et al., J. Chem. Ecol., 11, 1297 (1985); and Ruledge, J. Am. Mosquito Control Assoc. 4, 414 (1988).

[0337] A particularly preferred group of insect repellents includes the terpenoid compounds, described in U.S. Pat. No. 5,411,992, including:

[0338] (1) Terpenoid-alcohol or terpene-ols are terpenoids which have at least one hydroxyl group. Examples of terpene-ols include: C.sub.10H.sub.16O compounds, perillyl alcohol, carveol, myrtenol, and cis-verbenol; C.sub.10H.sub.18O compounds, myrtanol, iso-pinocampheol, dihydrocarveol, isopulegol, terpineol, terpinen-4-ol, nerol, geraniol, and linalool, and C.sub.10H.sub.20O compounds, menthol, beta-citronellol, and dihydro-myrcenol;

[0339] (2) Terpenoid-esters are terpenoids, which have at least one ester group which is the product of the bonding of the hydroxyl group of a terpene-ol with an aliphatic carboxylic acid that can contain functional groups such as the hydroxyl or amine on the aliphatic chain. Examples of suitable aliphatic carboxylic acids include acetic acid, propionic acid, lactic acid, and various amino acids. Examples of terpenoid-esters include: carvyl acetate, carvyl propionate, and menthyl lactate; and

[0340] (3) Essential oils which contain terpenoids and perfumes which contain terpenoids. Non-limiting examples of essential oils which have high content of terpene-ols and esters include bergamot (62% terpenoids); sage (>50% terpenoids); styrax (>50% terpenoids); peppermint (>50% terpenoids); and pine Siberian (75% terpenoids %). Terpenes, aldehydes and ketones vary in their usefulness but as a general group have potential as insect-repellent.

[0341] The foam of the present invention is particularly suitable for the effective uniform spreading of an insect repellent agent onto large areas of the skin of humans and animals. The hydrophobic solvent present in the foam composition helps retain the insect repellent on the skin surface for an extended period of time.

[0342] Yet, in a further embodiment, the foam is suitable for delivery of insect-killing agents (insecticides) to an afflicted external surface area of humans and animals. Thus, the pharmaceutical or cosmetic composition may comprise an insecticide, known in the art of parasitology. By way of example, such insecticide can be selected from the group of permethrin, hexachlorobenzene, carbamate, naturally occurring pyrethroids, permethrin, allethrin, malathion, piperonyl butoxide and any combination thereof at a therapeutically effective concentration. Its application is very convenient and it spreads easily, even over hairy areas. The hydrophobic solvent present in the foam composition helps retain the insecticide on the treated area for an extended period of time. Furthermore, the presence of a hydrophobic solvent in the foam eases mechanical removal of lice and nits with a comb.

Anti-Cancer Drugs

[0343] Anti-cancer drugs can also be used according to the present invention as the drug of choice from skin malignant tumors, such as basal cell carcinoma, squamous sell carcinoma, melanoma and Kaposi's sarcoma, as well as the pre-cancerous condition actinic keratosis. In certain cases, topical cytotoxic and antiproliferative drugs are used to treat or prevent such cancers, including 5-fluorouracil, also called 5-FU. 5-FU, as well as any other anti-cancer agents, know in the art of cancer medicine, can be incorporated in the foam at therapeutically effective levels.

[0344] A preferred family of anticancer drugs, suitable for usage in the foam of the present formulation comprises antiestrogens, such as tamoxifen. Tamoxifen blocks the effects of the hormone estrogen in the body. It is used to prevent or delay the return of breast cancer or to control its spread.

Photodynamic Therapy Agents

[0345] The foam composition of the present invention is also useful to deliver photo-sensitizing agents, known in the art of photodynamic therapy. By way of example, such photosensitizers can be selected from the group comprising modified porphyrins, chlorins, bacteriochlorins, phthalocyanines, naphthalocyanines, pheophorbides, purpurins, m-THPC, mono-L-aspartyl chlorin e6, bacteriochlorins, phthalocyanines, benzoporphyrin derivatives, as well as photosensitiser precursors, such as aminolevulinic acid (ALA).

Active Agents for Burns, Wounds, Cuts and Ulcers

[0346] The treatment of burns, wounds, cuts and ulcers, using the composition of the present invention is particularly advantageous. The foam can include both anti-infective agents (against bacteria, fungi and/or viruses), antiinflammatory agents (steroidal and/or NSAIDs) and pain relieving components. Upon application, the foam spreads easily, covering the surface of the affected area, and without causing pain.

Skin Care Active Agents

[0347] The foam of the present invention is useful and advantageous for skin care and cosmetic care. The combination of oil and water, having moisture-retaining properties, in a spreadable foam form, can be used to substitute currently used cosmetic skin care creams, lotions, gels, etc. The cosmetic foam compositions of the present invention are suitable for the further application as cosmeceutical preparation (cosmetic products with therapeutic benefit), to treat cosmetic skin disorders, such as aging skin, wrinkles, hyperpigmentation (melasma, chloasma, freckles, etc.), scaly skin and other skin undesirable properties.

[0348] The CTFA Cosmetic Ingredient Handbook describes a wide variety of nonlimiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples of these ingredient classes include: abrasives, absorbents, aesthetic components such as fragrances, pigments, colorings/colorants, essential oils, astringents, etc. (e.g., clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate), anti-acne agents, antimicrobial agents (e.g., iodopropyl butylcarbamate), antioxidants, binders, biological additives, buffering agents, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers or materials, e.g., polymers, for aiding the film-forming properties and substantivity of the composition (e.g., copolymer of eicosene and vinyl pyrrolidone), opacifying agents, pH adjusters, propellants, reducing agents, sequestrants, skin bleaching and lightening agents (e.g., hydroquinone, kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl glucosamine), skin-conditioning agents (e.g., humectants, including miscellaneous and occlusive), skin soothing and/or healing agents (e.g., panthenol and derivatives (e.g., ethyl panthenol), aloe vera, pantothenic acid and its derivatives, allantoin, bisabolol, and dipotassium glycyrrhizinate), skin treating agents, thickeners, and vitamins and derivatives thereof.

[0349] In any embodiment of the present invention, however, the active agents useful herein can be categorized by the benefit they provide or by their postulated mode of action. It is to be understood that the active agents useful herein can in some instances provide more than one benefit or operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit the active to that particular application or applications listed.

Anti-Acne Active Agents

[0350] The compositions of the present invention may contain a safe and effective amount of one or more pharmaceutically or cosmetically acceptable anti-acne active agents. Examples of useful anti-acne actives include resorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids, nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid, isoretinoic acid and other retinoid compounds, adapalene, tazarotene, azelaic acid and azelaic acid derivatives, antibiotic agents, such as erythromycin and clyndamycin, zinc salts and complexes, and combinations thereof, in a therapeutically effective concentration.

Anti-Wrinkle Active Agents/Anti-Atrophy Active Agents and Agents to Treat Dry and Scaly Skin (Xerosis and Ichthyosis)

[0351] The compositions of the present invention may further contain a safe and effective amount of one or more anti-wrinkle actives or anti-atrophy actives, which can be easily delivered by spreading a foam onto the skin. Exemplary anti-wrinkle/anti-atrophy active agents suitable for use in the compositions of the present invention include sulfur-containing D and L amino acids and their derivatives and salts, particularly the N-acetyl derivatives; thiols; hydroxy acids (e.g., alpha-hydroxy acids such as lactic acid and glycolic acid and their derivatives and salts; or beta-hydroxy acids such as salicylic acid and salicylic acid salts and derivatives), urea, hyaluronic acid, phytic acid, lipoic acid; lysophosphatidic acid, skin peel agents (e.g., phenol, resorcinol and the like), vitamin B3 compounds (e.g., niacinamide, nicotinic acid and nicotinic acid salts and esters, including non-vasodilating esters of nicotinic acid (such as tocopheryl nicotinate), nicotinyl amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide), vitamin B5 and retinoids (e.g., retinol, retinal, retinoic acid, retinyl acetate, retinyl palmitate, retinyl ascorbate). In the case of dry, scaly skin (xerosis) and ichthyosis such agents can alleviate the symptoms by temporary relief of itching associated with these conditions.

Anti-Oxidants/Radical Scavengers

[0352] A safe and effective amount of an anti-oxidant/radical scavenger may be added to the compositions of the subject invention, preferably from about 0.1% to about 10% (w/w), more preferably from about 1% to about 5% (w/w), of the composition.

[0353] Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the tradename Trolox.sup.R), gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid and its salts, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine, methionine, proline, superoxide dismutase, silymarin, tea extracts, grape skin/seed extracts, melanin, and rosemary extracts may be used.

[0354] The foam of the present invention is suitable for delivering skin protecting and revitalizing anti-oxidants/radical scavengers. It is further pointed out that polyunsaturated fatty acids, containing omega-3 and omega-6 fatty acids (e.g., linoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are beneficial in the treatment of psoriasis and other skin inflammation conditions. Likewise, emollients and silicone oils exert moisture-retaining and skin protective effects on the skin. Thus in a preferred embodiment, a skin protective foam is provided, wherein the hydrophobic solvent comprises in full or in part, a solvent, selected from the group of emollients, silicone oil and oils, rich in unsaturated fatty acids, thus, affording a synergistic therapeutic effect of the anti-oxidants/radical scavenger agent and the vehicle components.

Self-Tanning Active Agents

[0355] The foam of the present invention is particularly suitable for the uniform delivery of a tanning active agent onto large areas of the skin. It is preferable that the compositions contain from about 0.1% to about 20%, more preferably from about 2% to about 7%, and still more preferably from about 3% to about 6%, of the composition, of dihydroxyacetone, or any other compound, know in the art as an artificial tanning active agent.

Skin Lightening and Whitening Agents

[0356] The foam of the present invention is particularly suitable for the uniform delivery of a skin lightening agent. When used, the compositions preferably contain from about 0.1% to about 10%, more preferably from about 0.2% to about 5%, of the composition, of a skin-lightening agent. Suitable skin lightening or whitening agents include those known in the art, including hydroquinone, azelaic acid and other related dicarboxylic acids, and salts and derivatives thereof, retinoids, kojic acid, arbutin, nicotinic acid and its precursors, salts and derivatives, arbutin, ascorbic acid and salts and derivatives thereof (e.g., magnesium ascorbyl phosphate or sodium ascorbyl phosphate), and herbal extracts (e.g., licorice extract, mulberry extract, placental extract).

[0357] In one or more embodiments of the present invention, the foam composition comprises a combination of a skin whitening agent and a sunscreen agent.

[0358] In one or more embodiments of the present invention, the foam composition comprises a combination of a skin whitening agent and an inorganic sunscreen agent. When inorganic sunscreen agents, e.g. TiO.sub.2, are rubbed onto the skin, they leave a white coating, which provides an immediate (although transient) whitening effect, which is highly desirable by the consumer, who wishes to see instant change in his/her appearance. The whitening agent, in combination with the inorganic sunscreen agent in the foam carrier can be easily and uniformly distributed on the skin surface, thereby affording an even instant whitening effect, unlike creams that are difficult to spread evenly on skin areas.

Sunscreens

[0359] Exposure to ultraviolet light can result in excessive scaling and texture changes of the stratum corneum. The foam of the present invention is advantageous for the delivery of sunscreen agents. Its application is very convenient and it spreads easily over large skin areas. The presence of a hydrophobic solvent in the foam ensures long lasting effect, even while bathing.

[0360] As used herein, sunscreen active or sunscreen agent includes both sunscreen agents and physical sunblocks. Suitable sunscreen actives may be organic or inorganic.

[0361] Inorganic sunscreens useful herein include the following metallic oxides; titanium dioxide having an average primary particle size of from about 15 nm to about 100 nm, zinc oxide having an average primary particle size of from about 15 nm to about 150 nm, zirconium oxide having an average primary particle size of from about 15 nm to about 150 nm, iron oxide having an average primary particle size of from about 15 nm to about 500 nm, and mixtures thereof. When used herein, the inorganic sunscreens are present in the amount of from about 0.1% to about 20%, preferably from about 0.5% to about 10%, more preferably from about 1% to about 5%, of the composition.

[0362] A wide variety of conventional organic sunscreen actives are suitable for use herein. Specific suitable sunscreen actives include, for example: p-aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); anthranilates (i.e., o-amino-benzoates; methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); salicylates (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters); cinnamic acid derivatives (menthyl and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); dihydroxycinnamic acid derivatives (umbelliferone, methylumbelliferone, methylaceto-umbelliferone); trihydroxy-cinnamic acid derivatives (esculetin, methylesculetin, daphnetin, and the glucosides, esculin and daphnin); hydrocarbons (diphenylbutadiene, stilbene); dibenzalacetone and benzalacetophenone; naphtholsulfonates (sodium salts of 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids); di-hydroxynaphthoic acid and its salts; o- and p-hydroxybiphenyldisulfonates; coumarin derivatives (7-hydroxy, 7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole, phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles); quinine salts (bisulfate, sulfate, chloride, oleate, and tannate); quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline); hydroxy- or methoxy-substituted benzophenones; uric and violuric acids; tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol) (6-propyl piperonyl) ether; hydroquinone; benzophenones (oxybenzene, sulisobenzone, dioxybenzone, benzoresorcinol, 2,2,4,4-tetrahydroxybenzophenone, 2,2-dihydroxy-4,4-dimethoxybenzophenone, octabenzone; 4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene; octocrylene; [3-(4-methylbenzylidene bornan-2-one), terephthalylidene dicamphor sulfonic acid and 4-isopropyl-di-benzoylmethane.

[0363] A safe and effective amount of the organic sunscreen active is used, typically from about 1% to about 20%, more typically from about 2% to about 10% of the composition. Exact amounts will vary depending upon the sunscreen or sunscreens chosen and the desired Sun Protection Factor (SPF).

Agents for Hair Growth Disorders

[0364] Agents, which affect the pattern of hair growth, can be suitably incorporated in the foam of the present invention. Male pattern baldness (MPB), the commonest cause of balding, is induced by the activity of the male hormone dihydrotestosterone (DHT), which converted from the hormone testosterone by the enzymes 5 alpha reductase. Current treatments of MPB include minoxidil and agents, which inhibit 5 alpha reductase, such as finasteride, spironolactone, azelaic acid and azelaic acid derivatives and salts. Such agents, as well as other agents known in the art, can be incorporated in the foam of the present invention.

[0365] It is further pointed out that polyunsaturated fatty acids, i.e., such which include any of the essential fatty acids (EFA's): linoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are also known to contribute to hair growth. Thus in a preferred embodiment, a hair growth foam is provided, wherein the hydrophobic solvent comprises in full or in part, an oil, rich in such unsaturated fatty acids.

[0366] Figure-Forming Agents; Agents to Treat Cellulite/Slimming

[0367] Figure forming agents such as used in the treatment of cellulite and in slimming products, can be suitably incorporated in the foam of the present invention. A non-limiting exemplary list of active agents, known in the treatment of cellulite and in the induction of a slimming effect include herbal extracts, such as baldderwack extract, butcher's, broom, cayenne, dandelion, red clover, Ginkgo biloba, horse chestnut, witch hazel and borage oil, omega 3 and omega 6 oils, caffeic acid and salts and derivatives thereof, xanthine agents, such as caffeine, theophiline and pentoxyphilline, and nicotinic acid and salts and derivatives thereof.

Agents to Treat Sunburn, Heat Burn, Radiation Burn, Rash and Itch

[0368] Cosmetic and pharmaceutical ingredients which are known in the art of pharmacology and cosmetology to treat dermatitis, minor skin irritations, sunburn, heat burn, radiation burn, and inhibit inflammation can be beneficially incorporated in the foam of the present invention.

[0369] Examples of such active agents include chamomile extract (Matricaria recutitia), cucumber distillate (Cucumis Sativus), lavender water (Lavendula angustifolia), rose water (Rosa damascena), witch hazel (Hamamelis virginiana), allantoin, bisabolol, rosehip oil, calendula oil, azulaene, menthol and camphor.

Use of the Foam as a Lubricating and Protective Foam

[0370] There are several potential uses of the foam, particularly the silicone-oil based foam, as a lubricating foam. Typical examples are shaving foam, moisture protection foam and antifriction foam. For such purposes, the foam can be used in its basic composition (without additional formulation aids and active ingredients), or with the addition of such additives.

Foam for Neutralization and/or Decontamination of Hazardous Chemicals and Treatment of Heat Burns

[0371] It has been reported that povidone iodine antiseptic, a popular iodine product, can ameliorate damage to guinea pig skin exposed to mustard gas and other chemical irritants and further reduces, and many times prevents, damage to human skin after accidental heat burns caused by hot water, oil or hot steam.

[0372] Other active compound, having decontamination abilities, comprise strong oxidants and free radical liberating compounds, such as hydrogen oxide, bleaching agents (e.g., sodium, calcium or magnesium hypochloride and the like) iodine, chlorohexidine and benzoyl peroxide.

[0373] The alcohol-free foam of the present invention, comprising one or more of the above decontaminating and neutralizing agents can be applied onto the contaminated skin to form a preventive layer, prior to contamination measure or as a decontamination/neutralization means, right after contamination has occurred.

Penetration Enhancers

[0374] A penetration enhancer or permeation enhancer is an agent used to increase the permeability of the skin to a pharmacologically active agent to increase the rate at which the drug diffuses through the skin and enters the tissues and bloodstream. A chemical skin penetration enhancer increases skin permeability by reversibly altering the physiochemical nature of the stratum corneum to reduce its diffusional resistance. In a review of the technical and patent literature up to 1996, numerous chemical compounds were cited as skin penetration enhancers. Most of the compounds are generally recognized as safe (GRAS) ingredients that would often be considered inert by a formulator (Osborne, D. W., Henke, J. J., Pharmaceutical Technology, November 1997, pp 58-86).

[0375] Examples of penetration enhancers, according to the present invention include: polyols, such as propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, other glycols, and glycerol; sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide; monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide units); Azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, esters, such as isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate, capric/caprylic triglycerides, octylmyristate, dodecyl-myristate; myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketones; amides, such as acetamide oleates such as triolein; various surfactants, such as sodium lauryl sulfate; various alkanoic acids such as caprylic acid; lactam compounds, such as azone; alkanols, such as oleyl alcohol; dialkylamino acetates, and admixtures thereof.

[0376] Lower alcohols, such as ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol and pentanol are not considered appropriate penentartion enhancers according to the present invention, due to their skin drying and irritation properties.

[0377] Yet, another preferred class of penetration enhancers is the cyclodextrins and related compounds. Cyclodextrins are structurally related cyclic oligomaltoses which form a new group of pharmaceutical excipients. These are torus-shaped molecules with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrins are capable of forming water-soluble inclusion complexes with a wide variety of lipophilic water-insoluble drugs by taking up a whole drug molecule, or some part of it, into the cavity. The cyclodextrin molecules are relatively large (molecular weight ranging from almost 1000 to over 1500), with a hydrated outer surface, and under normal conditions, cyclodextrin molecules will only permeate the skin barrier with considerable difficulty. It is generally believed that the cyclodextrin molecules act as true carriers by keeping lipophilic drug molecules in solution and deliver them to the skin surface where they partition from the cyclodextrin cavity into the skin.

Further Technical Parameters

[0378] The composition of the present invention may be contained in and dispensed from a container capable of withstanding the pressure of the propellant gas and having an appropriate valve/nozzle for dispensing the composition as foam under pressure. A customary liquefied or compressed gas propellant can be added, in the amount of about 5-25% of the total composition. Liquefied propellants are gases that exist as liquids under pressure, including high purity hydrocarbons such as propane, isobutane and n-butane, dimethyl ether and chlorofluorocarbons (CFCs). Compressed gasses are exemplified by air, nitrogen and carbon dioxide.

[0379] A specific embodiment according to the present invention comprises placing the composition of the present invention on a patch, occlusive tape or the skin-contact compartment of a transdermal delivery apparatus and applying such object onto the skin, in order to attain effective superficial treatment or enhanced penetration of the drug into the skin or through the skin.

[0380] Utilizing such strategy, one can apply drugs, which are currently administered systemically or that require transdermal delivery, in the preferred therapeutic system of the present invention. Examples for such drugs are nicotine, testosterone and other male hormones and male hormone precursors, estrogen and other female hormones and hormone precursors, growth hormone, insulin, caffeine, steroidal and non-steroidal antiinflammatory agents and thyroid hormone substitutes.

[0381] Other foamable compositions are described in: U.S. Patent Publication No. 2005/0232869, published on Oct. 20, 2005, entitled NONSTEROIDAL IMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. Patent Publication No. 2005/0205086, published on Sep. 22, 2005, entitled RETINOID IMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. Patent Publication No. 2006/0018937, published on Jan. 26, 2006, entitled STEROID KIT AND FOAMABLE COMPOSITION AND USES THEREOF; U.S. Patent Publication No. 2005/0271596, published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION AND USES THEREOF; U.S. Patent Publication No. 2006/0269485, published on Nov. 30, 2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S. Patent Publication No. 2007/0020304, published on Jan. 25, 2007, entitled NON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S. Patent Publication No. 2006/0193789, published on Aug. 31, 2006, entitled FILM FORMING FOAMABLE COMPOSITION; U.S. patent application Ser. No. 11/732,547, filed on Apr. 4, 2007, entitled ANTI-INFECTION AUGMENTATION OF FOAMABLE COMPOSITIONS AND KIT AND USES THEREOF; U.S. Provisional Patent Application No. 60/789,186, filed on Apr. 4, 2006, KERATOLYTIC ANTIFUNGAL FOAM; U.S. Provisional Patent Application No. 0/815,948, filed on Jun. 23, 2006, entitled FOAMABLE COMPOSITIONS COMPRISING A CALCIUM CHANNEL BLOCKER, A CHOLINERGIC AGENT AND A NITRIC OXIDE DONOR; U.S. Provisional Patent Application No. 60/818,634, filed on Jul. 5, 2006, entitled DICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. Provisional Patent Application No. 60/843,140, filed on Sep. 8, 2006, entitled FOAMABLE VEHICLE AND VITAMIN PHARMACEUTICAL COMPOSITIONS THEREOF, all of which are incorporated herein by reference in their entirety.

Stock Compositions

[0382] Non-limiting examples of how stock solutions are made up with and without active agent. Other stock solutions may be made using the same methodology by simply varying adding or omitting ingredients as would be appreciated by one of the ordinary skills in the art.

EXAMPLES

[0383] The invention is described with reference to the following examples. This invention is not limited to these examples and experiments. Many variations will suggest themselves and are within the full intended scope of the appended claims.

[0384] The general process, as typically exemplified in Example 1 may be applied in order to produce the composition of the present invention. The pharmaceutical carrier according to the present invention can also be used to prepare cosmetics for beauty purpose by adding into skin care agents and perfume.

Example 1General Procedure for Preparing Foamable Composition

[0385] Aqueous Phase:

[0386] Water gelling agent and surface-active agent are dissolved in water, with agitation. The solution is warmed to 50-70 C. Water soluble cosmetic or pharmaceutical active ingredients and optional water soluble ingredients are added with agitation to the Aqueous Phase mixture.

[0387] Hydrophobic Phase:

[0388] The hydrophobic solvent is heated to same temperature. Foam adjuvant agent is added to preheated hydrophobic solvent. Oil soluble cosmetic or pharmaceutical active ingredients* and optional oil soluble formulation ingredients are added with agitation to the Hydrophobic Phase mixture.

[0389] The warm Hydrophobic Phase is gradually poured into the warm Aqueous Phase, with agitation, followed by Ultraturax homogenization. The mixture is allowed to cool down to ambient temperature. In case of heat sensitive active ingredients, the active ingredient is added with agitation to the mixture after cooling to ambient temperature. The mixture, at ambient temperature, is added to an aerosol container, the container is sealed and appropriate amount of propellant (5-25 w % of the composition mass) is added under pressure into the container.

Example 2Vegetable Oil-Based Foam Carrier Composition

[0390]

TABLE-US-00004 Version Version Version No. 1 No. 2 No. 3 Ingredient % (W/W) Hydrophobic solvent Soybean oil 40 30.5 20 Water Water 48.5 32.5 61 Foam adjuvant agent Stearyl Alcohol 0.8 1.05 0.73 Surface-active agent Sucrose ester SP70 0.64 0.45 0.8 Water gelling agent Xanthan Gum 0.16 0.11 0.1 Methocel ELV15 0.32 0.22 0.28 Other Ingredients Antioxidant 0.02 0.02 0.02 Preservatives 0.3 0.3 0.3 Fragrance 0.2 0.2 0.2 Foam Specific gravity 0.10 0.15 0.065 (gr/mL)

[0391] The compositions use a non-ionic surfactant and contain a combined amount of surface-active agent, foam adjuvant and water gelling agent ranging from 1.83% to 1.92% (w/w). The foam of this example is useful as a carrier of active pharmaceutical and/or cosmetic active ingredients, as exemplified below. It also can be used as a protective product. Additionally, it is also useful as lubricating foam, for various purposes.

Example 3Silicone Oil-Based Foam Carrier Composition

[0392]

TABLE-US-00005 Version Version No. 1 No. 2 Specific Ingredient % (W/W) Hydrophobic solvent Dimeticone 350* 25 10 Water Water 72 87 Foam adjuvant agent Stearyl Alcohol 0.2 0.2 Surface-active agent Sucrose ester SP70 0.8 Myrj 49P 0.8 Water gelling agent Xanthan Gum 0.2 0.2 Methocel ELV15 0.4 0.4 Other Ingredients Antioxidant 0.02 0.02 Preservatives 1 1 Fragrance 0.2 0.2 Foam Specific gravity 0.10 ND (gr/mL) *Dimethylpolysiloxane of 350 cps viscosity.

[0393] The compositions use only non-ionic surfactant and contain a combined amount of surface-active agent, foam adjuvant and water gelling agent of 1.6% (w/w). The foam of this example is useful as a carrier of active pharmaceutical and/or cosmetic active ingredients, as exemplified below. It also can be used as a protective product. Additionally, it is also useful as lubricating foam, for various purposes.

Example 4Mineral Oil-Based Foam Carrier Composition

[0394]

TABLE-US-00006 Version Version Version Version Version No. 1 No. 2 No. 3 No. 4 No. 5 Ingredient % (W/W) Hydrophobic Mineral oil 69 50 50 25 25 solvent Water Water 28.4 46.7 46.7 71.88 71.9 Foam adjuvant Stearyl Alcohol 0.7 1 1 0.5 0.5 agent Surface-active Sucrose ester SP70 0.4 0.64 0 0.8 0 agent PEG S-40 0 0 0.64 0 0 Polysorbate-60 0 0 0 0 0.8 Water gelling Xanthan Gum 0.1 0 0.14 0.2 0.2 agent Methocel ELV15 0.2 0.4 0.32 0.4 0.4 Other Antioxidant 0.02 0.02 0.02 0.02 0.02 Ingredients Preservatives 1 1 1 1 1 Fragrance 0.2 0.2 0.2 0.2 0.2 Foam Specific ND ND ND ND 0.1 gravity (gr/mL)

[0395] The compositions use only non-ionic solvents, and the total amount of surface active agent, foam adjuvants and water gelling agents ranges from 1.4 to 2.1% (w/w). The foam of this example is useful as a carrier of active pharmaceutical and/or cosmetic active ingredients, as exemplified in examples below. It is also useful as lubricating foam, for various purposes.

Example 5Mixed Oils Foam Carrier Composition

[0396]

TABLE-US-00007 Version Version No. 1 No. 2 Ingredient 25% Oil 12.5% Oil Hydrophobic solvent Mineral oil 11.2% 5.6% Isopropyl myristate 5.0% 2.5% MCT oil 7.5% 3.8% Foam adjuvant agent Stearyl Alcohol 0.5% 0.25% Water Water 73.0% 85.2% Surface-active agent Sucrose ester SP70 0.8% 0.8% Distilled monoglyceride 1.2% 0.6% Sodium lauryl sulphate 0.1% 0.1% Water gelling agent Xanthan Gum 0.3% 0.3% Methocel ELV15 0.6% 0.6%

[0397] The foams of this example have a non-ionic surfactant to ionic surfactant ratio (w/w) of 20:1 and 14:1 for versions 1 and 2, respectively. Total amounts of surface active agent foam adjuvant and water gelling agent is in the range of 1.75-3.5 (w/w). It is useful as a carrier of active pharmaceutical and/or cosmetic active ingredients, as exemplified in examples below. It is also useful as lubricating foam, for various purposes.

[0398] The following examples, representing optional drug-containing foams, are prototype formulations, which have not been optimized for stability and inter-component compatibility. Such optimization is a customary need, which can be done, using means, known to those skilled in the art of pharmaceutical formulation.

Example 6Antibacterial Foam Composition

[0399]

TABLE-US-00008 Version 2 Version 3 Version 5 Version 1 Triple Fucidic Version 4 Triple Ingredient Mupirocin Antibiotic Acid Metronidazole Antibiotic Carrier Ingredients Mineral oil 48.8% 11.2% 48.8% 5.6% 5.6% Isopropyl myristate 5.0% 2.5% 2.5% MCT oil 7.5% 3.8% 3.8% Stearyl Alcohol 0.8% 0.5% 0.8% 0.25% 0.25% Water 50% 73.0% 50% 85.2% 85.2% Sucrose ester SP70 0.8% 0.8% 0.8% Myrj 40 0.8% Distilled monoglyceride 1.2% 0.6% 0.6% Tween 60 0.8% 0.8% Sodium lauryl sulphate 0.05% 0.1% 0.1% Xanthan Gum 0.2% 0.3% 0.2% 0.3% 0.3% Methocel ELV15 0.2% 0.6% 0.2% 0.6% 0.6% Active Ingredients Mupirocin .sup.2% Polymyxin B Sulfate 10,000 Units/gr 10,000 Units/gr Bacitracin Zinc 500 Units/gr 500 Units/gr Neomycin Sulfate* 0.05% 0.05% Pramoxoine HCl .sup.1% .sup.1% Fucidic acid .sup.2% Metronidazole .sup.1%

[0400] The foams of this example contain 100% non-ionic surfactant or have a non-ionic surfactant to ionic surfactant ratio ranging from 20:1 to 8:1. Total amounts of surface active agent, foam adjuvant and water gelling agent ranges from 2.05-3.5% (w/w). It is useful for the treatment of bacterial skin infection (general), cellulites, open wounds, cutaneous abscesses, furuncles, insect bite, impetigo, acne, acne-rosacea, and trichomonas vaginitis.

[0401] In certain embodiments, the foam of this example is useful for the prevention, decontamination and/or neutralization hazardous bacterial infestation (such as warfare organisms).

Example 7Antifungal Foam Composition

[0402]

TABLE-US-00009 Version 1 Version 2 Version 3 Version 4 Ingredient Terbinafine Clotrimazole Nystatin Nystatin Carrier Ingredients Mineral oil 48.8% 11.2% 48.8% 5.6% Isopropyl myristate 5.0% 2.5% MCT oil 7.5% 3.8% Stearyl Alcohol 0.8% 0.5% 0.8% 0.25% Water 50% 73.0% 50% 85.2% Sucrose ester SP70 0.8% 0.8% 0.8% Myrj 40 0.8% Tween 80 0.8% Distilled monoglyceride 1.2% 0.6% Sodium lauryl sulphate 0.05% 0.1% 0.1% Xanthan Gum 0.2% 0.3% 0.2% 0.3% Methocel ELV15 0.2% 0.6% 0.2% 0.6% Active Ingredients Terbinafine .sup.1% clotrimazole .sup.2% Nystatin 100,000 Units/gr 100,000 Units/gr

[0403] The foams of this example have 100% non-ionic surfactant or have a non-ionic surfactant to ionic surfactant ratio ranging from 20:1 to 8:1. Total surface active agent, foaming adjuvant and water gelling agent ranges from 2.05 to 3.5% (w/w). It is useful in the treatment of dermatophyte infections, Tinea corporis, Tinea pedis, Tinea rubrum, Tinea unguium, Tinea cruris, Tinea barbae, and yeast infections, such as Candidiasis, Tinea versicolor and Candidal vaginitis.

Example 8Corticosteroid Foam Composition

[0404]

TABLE-US-00010 Version 1 Version 2 Version 3 Hydro- Beta- Dexa- Ingredient cortisone methasone methasone Carrier Ingredients Mineral oil 48.8% 11.2% 5.6% Isopropyl myristate 5.0% 2.5% MCT oil 7.5% 3.8% Stearyl Alcohol 0.8% 0.5% 0.25% Water 50% 73.0% 85.2% Sucrose ester SP70 0.8% 0.4% 0.8% Tween 80 0.4% Distilled 1.2% 0.6% monoglyceride Sodium lauryl 0.05% 0.1% sulphate Xanthan Gum 0.2% 0.3% 0.3% Methocel ELV15 0.2% 0.6% 0.6% Active Ingredients Hydrocortisone .sup.1% Betamethasone 0.05% dipropionate Dexamethasone 0.1% acetate Version 4 Version 5 Ingredient Triamcinolone Flumetasone Carrier Ingredients Mineral oil 48.8% 48.8% Stearyl Alcohol 0.8% 0.8% Water 50% 50% Sucrose ester SP70 0.8% 0.8% Sodium lauryl 0.05% 0.05% sulphate Xanthan Gum 0.2% 0.2% Methocel ELV15 0.2% 0.2% Active Ingredients Triamcinolone 0.1% acetonide Flumetasone 0.02% pivalate

[0405] The foams of this example have either 100% non-ionic surfactant or have a non-ionic surfactant to ionic surfactant ratio ranging from 20:1 to 16:1. Total surface active agent, foaming adjuvant and water gelling agent ranges from 2.05 to 3.5% (w/w), Indications include psoriasis, contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, inflammatory acne, chronic dermatitis of the hands and feet, generalized exfoliative dermatitis, stasis dermatitis, lichen simplex chronicus, herpes gestationis and pruritic urticarial papules and plaques of pregnancy.

Example 9Antiviral Foam Composition

[0406]

TABLE-US-00011 Version 1 Version 2 Version 3 Ingredient Acyclovir Acyclovir -Interferon Carrier Ingredients Mineral oil 48.8% 11.2% 5.6% Isopropyl myristate 5.0% 2.5% MCT oil 7.5% 3.8% Stearyl Alcohol 0.8% 0.5% 0.25% Water 50% 73.0% 85.2% Sucrose ester SP70 0.8% 0.8% Tween 80 0.8% Distilled monoglyceride 1.2% 0.6% Sodium lauryl sulphate 0.1% Xanthan Gum 0.2% 0.3% 0.3% Methocel ELV15 0.2% 0.6% 0.6% Active Ingredients Acyclovir .sup.5% .sup.5% -Interferon 105 IU/g

[0407] The foams of this example have either 100% non-ionic surfactant or have a non-ionic surfactant to ionic surfactant ratio of 14:1. Total surface active agent, foaming adjuvant and water gelling agent ranges from 2.05 to 3.5% (w/w). Indications include Herpes simplex, Herpes zoster, Herpes gestationis and Herpes simplex genital ulcers.

Example 10Insect Repellent Foam Composition

[0408]

TABLE-US-00012 Ingredient % Isopropyl myristate 2.0% MCT oil 2.0% Stearyl Alcohol 1.2% Water 64.0% Sucrose ester SP70 0.8% Sodium lauryl sulphate 0.1% Xanthan Gum 0.3% Methocel ELV15 0.6% Propylene glycol 15% DEET 15%

Example 11Comparative Tolerability and Acceptability Study of a Corticosteroid Foam Composition Vs. A Conventional Ointment

[0409] A panel of eight testers was requested to apply about 0.5 gr. of the foam preparation of example 10, Version 2 on one arm and 0.5 gr. of commercial Betamethasone valerate ointment, in a double blind fashion. They were asked to describe their feeling about the ease of application, ease of spreading, spreadability and penetrability of each of the products and to give their general rating for each of the products on a scale of 0-3 (0=poor; 1=barely acceptable; 2=acceptable and 3=excellent).

[0410] As demonstrated in the following table, the foam preparation of example 10, Version 2 obtained higher rates in all aspects of the test.

TABLE-US-00013 Commercial Betamethasone Foam Preparation Valerate Ointment Property Mean Rating Mean Rating Ease of application 2.3 1.6 Ease of spreading 2.5 1.9 Spreadability 2.9 1.2 Penetrability 2.0 1.5 Lack of sticky feeling 2.4 1.0 Lack of greasy feeling 2.2 1.0 Lack of shiny look 1.9 1.4 Overall rating 2.5 1.4

Example 12: Human Safety and Efficacy Study of a Corticosteroid Composition in Psoriasis Patients

[0411] Two patients with mild to moderate psoriasis were administered topically a Betamethasone 0.12% foam (example 10, Version 2) twice daily for two weeks. Both patients improved significantly, as manifested by clearance of the psoriatic plaques flattening of the thickened lesions. FIG. 1 provides an exemplary response to treatment in the elbows of one of these patients. While betamethasone is know for its effect in psoriasis, such a beneficial effect after 14 days treatment is exceptional. The accelerated effect was attributed to the improved convenience and therefore, improved compliance.

Example 13: Human Safety and Efficacy Study of a Corticosteroid Composition in Psoriasis Patients

[0412] Four patients with moderate to severe, disseminated atopic dermatitis were administered topically a Betamethasone 0.12% foam (example 10, Version 2) twice daily for two weeks. All patients improved significantly, as manifested by complete clearance of all treated lesions. FIG. 2 provides exemplary responses to treatment in different body areas, after 10 days of treatment. While betamethasone is know for its effect in atopic dermatitis, such a beneficial effect after 10 days treatment is exceptional. The patients claimed that the use of the foam of the present invention was significantly more convenient than the corresponding cream and ointment. Thus, the accelerated effect was attributed to the improved convenience and therefore, improved compliance.

Example 14Foam Compositions with Urea

[0413]

TABLE-US-00014 Component % w/w Mineral oil 6.00 6.00 6.00 6.00 Isopropylmeristat 6.00 6.00 6.00 6.00 Glyceryl monostearate 0.50 0.50 0.50 0.50 Stearyl alcohol 0.20 0.20 0.20 1.00 Urea 10.00 10.00 10.00 10.00 Xantan gum 0.30 0.30 0.30 0.30 Methocel K100M 0.30 0.30 0.30 0.30 Myrj 52 3.00 TWEEN 80 1.00 Myrj 49p 3.00 TWEEN 60 1.00 1.00 1.00 Cocamidopropylbetain 0.50 0.50 Phenonip 0.30 0.30 0.30 0.30 Water to 100.0 to 100.0 to 100.0 to 100.0 Butane/propane 8.00 8.00 18.00 18.00 Foam Quality E E E E Density n/a 0.023 n/a 0.024

Example 15Compositions with Various Penetration Enhancers

[0414]

TABLE-US-00015 Part A Component % w/w Mineral oil 6.00 6.00 6.00 6.00 6.00 Isopropyl myristate 6.00 6.00 6.00 6.00 6.00 Glyceryl monostearate 0.50 0.50 0.50 0.50 0.50 Stearyl alcohol 1.00 1.00 1.00 1.00 1.00 Xantan gum 0.30 0.30 0.30 0.30 0.30 Methocel K100M 0.30 0.30 0.30 0.30 0.30 TWEEN 60 1.00 TWEEN 80 1.00 1.00 1.00 1.00 MYRJ 49p 3.00 3.00 3.00 3.00 3.00 Propylene glycol 5.00 Glycofurol 1.00 10.00 Urea 10.00 Cocoamidopro- 0.50 0.50 0.50 0.50 0.50 pylbethaine Lidocain base 4.00 4.00 4.00 4.00 4.00 Phenonip 0.30 0.30 0.30 0.30 0.30 Water to 100 to 100 to 100 to 100 to 100 Butane/propane 8 8 8 16 10 Foam Quality E E E E E Density 0.020 0.018 0.019 0.019 0.018

TABLE-US-00016 Part B Component % w/w % w/w Isopropyl myristate 30.00 30.00 Glyceryl monostearate 0.50 0.50 Stearic acid 0.45 0.45 Xantan gum 0.30 0.30 Methocel K100M 0.30 0.30 TWEEN 80 1.00 1.00 MYRJ 49p 3.00 3.00 Cocoamidopropylbethaine 0.50 0.50 Transcutol p 20.00 20.00 Hydrophilic drug Effective concentration Hydrophobic drug Effective concentration Phenonip 0.30 0.30 Water to 100.0 to 100.0 Butane/propane 8.00 8.00 Foam Quality E E Density 0.020 0.020

Example 16Inflammability Test

[0415] According to European Standard prEN 14851 (sometimes referred to as the AFNOR testAFNOR is Association Francaise de Normalisation) a product is considered inflammable if a stable flame appears following ignition, which is at least 4 cm high and which is maintained for at least 2 seconds. For the purpose of testing non-flammability a simplified test based on the European Standard test (titled Aerosol containersAerosol foam flammability test) was used. Formulations that ignited for less than 2 seconds and which showed a flame of up to 4 cm above the height of the foam or less were passed as were formulations that simply did not ignite. However, formulations where the flame was clearly greater than 4 cms were failed even if the flame burnt for less than 2 seconds. Formulations that burnt for longer than 2 seconds likewise failed.

[0416] Approximately 5 g of foam, mousse gel or paste is sprayed from the aerosol container on to a watchglass. An ignition source (a lighter) was placed at the base of the watchglass and any ignition and sustained combustion of the foam, mousse, gel or paste was observed. The test was carried out in a draught-free environment capable of ventilation, with the temperature controlled at 205 C. and relative humidity in the range of 30% to 80%.

[0417] Interestingly, it appears that the formulations, which burnt for longer than this period also burnt with a larger flame than 4 cms. Another initial trend observed was that apparently formulations that were not stabilized at 20 C may be more likely to ignite.

[0418] In setting up a system to measure flammability along the lines of the AFNOR test, a number of initial and minor but possibly potentially significant trends were observed. The first was that variability in results was noted when tests were undertaken without allowing the formulation to reach a settled equilibrium. In passing, it should be mentioned that from observations of foamable formulations in pressurized glass bottles such formulations take time to reach equilibrium and for example may thicken up considerably in texture overnight. Thus, results were more reproducible after formulations were allowed to reach equilibrium overnight in an incubator. Reproducibility was likewise improved by using larger canisters. Also, the incidence of ignition and flammability appeared to increase when the temperature was higher.

Example 17

[0419]

TABLE-US-00017 Part A -Formulations with different oil or oil like substance at 35% w/w Ingredients PFT002 PFT003 PFT004 PFT005 MCT (CAPRYLIC/CAPRIC 35.00 TRIGLYCERIDE) light mineral oil 35.00 Octyl dodecanol 35.00 IPM (ISOPROPYL 35.00 MYRISTATE) Glyceryl Monostearate 0.49 0.49 0.49 0.49 Sorbitane Stearate 0.65 0.65 0.65 0.65 Stearyl Alcohol 0.92 0.92 0.92 0.92 Steareth-21 2.17 2.17 2.17 2.17 PEG-40 Stearate 2.83 2.83 2.83 2.83 Methocel A4M 0.33 0.33 0.33 0.33 Xanthan gum 0.28 0.28 0.28 0.28 Polysorbate 80 0.98 0.98 0.98 0.98 Water purified 56.35 56.35 56.35 56.35 Total 100.00 100.00 100.00 100.00 Propellant: [propane: 8.00 8.00 8.00 8.00 iso-butane: n-butane] mixture * Results Appearance Quality G-E G-E G-E G-E Color white white white white Odor no odor no odor no odor no odor Shakability good good good good *Three different propellant mixtures were used and tested and all the formulations provided good to excellent qualilty foam.

TABLE-US-00018 Part B - Flammability Test Results PFT002 PFT003 PFT004 PFT005 35% IPM 35% 35% 35% MCT (ISOPROPYL Octyl light (CAPRYLIC/CAPRIC MYRISTATE) dodecanol mineral oil TRIGLYCERIDE) 8% 5515 8% 5515 8% 5515 8% 5515 sample weight (g) 6.00 7.40 7.60 5.80 Ignite Y Y N Y Pass Y N Y Y Fail* N Y N N 8% 1681 8% 1681 8% 1681 8% 1681 sample weight (g) 10.00 6.60 7.40 8.90 Ignite Y Y N N Pass Y N Y Y Fail* N Y N N 8% pinto 8% pinto 8% pinto 8% pinto sample weight (g) 5.90 5.80 6.20 5.60 6.30 Ignite N N N N Pass Y Y Y Y Fail* N N N N *Flame is for longer and or higher than the test limit; N = no; Y = yes

[0420] All the compositions were identical other than for the oil or emollient, which was 35% of the formulation. The foam compositions comprising light mineral oil, isopropyl myristate or MCT at 35% were all found to be non-inflammable according to the test parameters used irrespective of which propellant mixture was used. The octyl dodecanol formulation was apparently surprisingly sensitive to changes in the proportion of propane butane iso-butane mixture. Also surprising is that the octyl dodecanol formulation is sensitive to propellant at 35% w/w but not at 15% w/w and further unexpectedly it is noted that when octyl dodecanol is sensitive IPM is not sensitive. The same formula with 35% PPG 15 stearyl ether ignited with a flame that was higher than the test limit. Replacing the solid surfactants and foam adjuvants with liquid surfactants Laureth 4 (2%) and Span 80 (2%) and increasing the Polysorbate 80 to 2% did not reduce flammability of the 35% PPG formulation.

[0421] The foams produced with 1681 propellant mixture were viewed under the microscope and without being bound by any particular theory birefringence was observed and further in general terms non ignition coincided with some sort of structured order in the foam. By structured order, relatively repeatable cells of various sizes separated by a relatively similar interconnecting network is loosely intended.

Example 18

[0422]

TABLE-US-00019 Part A - Formulations -with different oil or oil like substance at 15% w/w Ingredients PFT007 PFT008 PFT009 PFT010 MCT (CAPRYLIC/CAPRIC 15.00 TRIGLYCERIDE) light mineral oil 15.00 Octyl dodecanol 15.00 IPM (ISOPROPYL MYRISTATE) 15.00 Glyceryl Monostearate 0.49 0.49 0.49 0.49 Sorbitane Stearate 0.65 0.65 0.65 0.65 Stearyl Alcohol 0.92 0.92 0.92 0.92 Steareth-21 2.17 2.17 2.17 2.17 PEG-40 Stearate 2.83 2.83 2.83 2.83 Methocel A4M 0.33 0.33 0.33 0.33 Xanthan gum 0.28 0.28 0.28 0.28 Polysorbate 80 0.98 0.98 0.98 0.98 Water purified 76.35 76.35 76.35 76.35 Total 100.00 100.00 100.00 100.00 Propellant: [propane: 8.00 8.00 8.00 8.00 iso-butane: n-butane] mixture* Appearance Quality G-E G-E G-E G-E Color white white white white Odor No odor no odor no odor no odor Shakability good good good good *Three different propellant mixtures were used and tested and all the formulations provided good to excellent quality foam.

TABLE-US-00020 Part B - Flammabilty Test Results PFT007 PFT008 PFT009 PFT010 15% IPM 15% 15% 15% MCT (ISOPROPYL Octyl light (CAPRYLIC/CAPRIC MYRISTATE) dodecanol mineral oil TRIGLYCERIDE) 8% 5515 8% 5515 8% 5515 8% 5515 sample weight (g) 7.20 5.10 7.50 7.30 Ignite Y Y N N Pass Y Y Y Y Fail* N N N N 8% 1681 8% 1681 8% 1681 8% 1681 sample weight (g) 8.40 5.00 8.90 8.40 Ignite Y Y N N Pass N Y Y Y Fail* Y N N N 8% pinto 8% pinto 8% pinto 8% pinto sample weight (g) 9.60 8.00 7.20 6.70 Ignite Y Y N N Pass N Y Y Y Fail* Y N N N *Flame is for longer and or higher than the test limit; N = no; Y = yes

[0423] All the compositions were identical other than for the oil or emollient phase, which was 15% of the formulation. The foam compositions comprising light mineral oil, octyl dodecanol or MCT were all found to be non-flammable according to the test parameters used irrespective of which propellant mixture was used. The isopropyl myristate formulation apparently may be surprisingly sensitive to changes in the proportion of propane butane iso-butane mixture.

[0424] Also surprising is that IPM is sensitive to propellant at 15% w/w but not at 35% w/w and further unexpectedly it is noted that when IPM is sensitive octyl dodecanol is not sensitive. The same formula with 15% PPG 15 stearyl ether ignited and the flame was higher than the test limit.

[0425] The foams produced with 1681 propellant mixture were viewed under the microscope and without being bound by any particular theory birefringence was observed and further in general terms non ignition coincided with some structured order in the foam. In contrast the flammable formulation appeared more random. By structured order, relatively repeatable cells of various sizes separated by a relatively similar interconnecting network is loosely intended.

Example 19Aqueous Formulation with and without 5% IPM

[0426]

TABLE-US-00021 PPG001 PPG003 IPM (ISOPROPYL MYRISTATE) 5.00 Glyceryl Monostearate 0.49 0.49 Sorbitane Stearate 0.65 0.65 Stearyl Alcohol 0.92 0.92 Steareth-21 2.17 2.17 PEG-40 Stearate 2.83 2.83 Methocel A4M 0.33 0.33 Xanthan gum 0.28 0.28 Polysorbate 80 0.98 0.98 Water purified 91.35 86.35 Total 100.00 100.00 Propellant: [propane: 8.00 8.00 iso-butane: n-butane] mixture (1681) Results Foam quality E E Color White White Odor No No Shakability Good Good Flammability test: Ignite N Y Pass Y Y Fail* N N *Flame is for longer and or higher than the test limit; N = no; Y = yes

[0427] Comments: The compositions were identical other than for the presence or absence of the emollient isopropyl myristate. When present, isopropyl myristate was at a concentration of 5% w/w of the formulation prior to addition of propellant. When absent, IPM was replaced by water. Both foam compositions were found to be non-flammable according to the test parameters used. The formulation without IPM did not ignite. So the underlying carrier formulation without oil or with only 5% is non-flammable. However, the same formulation with 15% PPG 15 stearyl ether and 76.35% water ignited with a flame higher than the test limit.

Example 20Aqueous Emulsions with 15% to 50% Oil

[0428]

TABLE-US-00022 Ingredients PPG008 PPG009 PPG011 PPG012 MCT (CAPRYLIC/CAPRIC 15.00 TRIGLYCERIDE) light mineral oil 15.00 25.00 50.00 Glyceryl Monostearate 0.49 0.49 0.49 0.49 Sorbitane Stearate 0.65 0.65 0.65 0.65 Stearyl Alcohol 0.92 0.92 0.92 0.92 Steareth-21 2.17 2.17 2.17 2.17 PEG-40 Stearate 2.83 2.83 2.83 2.83 Methocel A4M 0.33 0.33 0.33 0.33 Xanthan gum 0.28 0.28 0.28 0.28 Polysorbate 80 0.98 0.98 0.98 0.98 Water purified 76.35 76.35 66.35 41.35 Total 100.00 100.00 100.00 100.00 Propellant: [propane: 8.00 8.00 8.00 9.00 iso-butane: n-butane] mixture (1681) Foam quality E E E E Color White White White White Odor No No No No Shakability Good Good Good Good Flammability test: Ignite Y Y Y Y Pass Y Y Y Y Fail* N N N N *Flame is for longer and or higher than the test limit; N = no; Y = yes

[0429] These compositions all produced excellent quality foam. They were identical other than for the presence or absence of the emollient or oil, which was 50%, 25% or 15% of the formulation. When reduced, the oil or emollient was replaced by water. All the foam compositions were found to be non-flammable according to the test parameters used. Increasing the amount of oil from 15% to 50% did not significantly affect flammability. However, the same formulation comprising 15% PPG 15 stearyl ether and 76.35% water ignited with a flame higher than the test limit.

Example 21Aqueous Emulsions with 10% to 50% Oil

[0430]

TABLE-US-00023 PPG013 PPG015 PPG017 PPG018 PPG019 MCT 50.00 35.00 (CAPRYLIC/CAPRIC TRIGLYCERIDE) light mineral oil 35.00 Octyl dodecanol 10.00 35.00 Glyceryl Monostearate 0.49 0.49 0.49 0.49 0.49 Sorbitane Stearate 0.65 0.65 0.65 0.65 0.65 Stearyl Alcohol 0.92 0.92 0.92 0.92 0.92 Steareth-21 2.17 2.17 2.17 2.17 2.17 PEG-40 Stearate 2.83 2.83 2.83 2.83 2.83 Methocel A4M 0.33 0.33 0.33 0.33 0.33 Xanthan gum 0.28 0.28 0.28 0.28 0.28 Polysorbate 80 0.98 0.98 0.98 0.98 0.98 Water purified 41.35 81.35 56.35 56.35 56.35 Total 100.00 100.00 100.00 100.00 100.00 Propellant: [propane: 10.00 8.00 9.00 10.00 11.00 iso-butane: n-butane] mixture (1681) Foam quality E E E E E Color White White White White White Odor No No No No No Shakability Good Good Good Good Good Flammability test: Ignite N N N N N Pass Y Y Y Y Y Fail* N N N N N *Flame is for longer and or higher than the test limit; N = no; Y = yes

[0431] These compositions all produced excellent quality foam. They were identical other than for the presence or absence of the emollient or oil, which was 50%, 35% or 10% of the formulation. When reduced the oil or emollient was replaced by water. All the foam compositions were found to be non-flammable according to the test parameters used. Increasing the amount of oil from 10% to 50% did not significantly affect flammability. However, the same formulations comprising 10% PPG 15 stearyl ether and 81.35% water and comprising 35% PPG 15 stearyl ether and 56.35% water each ignited with a flame higher than the test limit.

Example 22Aqueous Emulsion with 69% Oil

[0432]

TABLE-US-00024 PFT048 light mineral oil 69.00 Stearyl Alcohol 0.70 Surphope 1816 0.40 Methocel ELV15 0.20 Xanthan gum 0.10 Water purified 29.60 Total 100.00 Propellant: [propane: 8.00 iso-butane: n-butane] mixture* (1681) Appearance Quality FG Color white Odor no odor Shakability good Flammability test 8% 1681 Sample weight (g) 5.10 Ignite N Pass Y Fail** N *Three different propellant mixtures were used and tested and all the formulations provided fairly good quality foam. **Flame is for longer and or higher than the test limit; N = no; Y = yes.

[0433] This foam corresponds to the foam formulation of Example 6, No, 1., except that the anti-oxidant, preservatives and fragrance have been replaced by and the amount has been made up to 100% with water.

[0434] This foam composition with a very high mineral oil concentration was non-flammable according to the test parameters. It is expected that by raising the sucrose ester surfactant (Surphope 1816) good to excellent foam quality can be achieved.

TABLE-US-00025 Example 23 - Oil Combinations PFT050 PFT051 PFT052 MCT (CAPRYLIC/CAPRIC 7.50 3.80 TRIGLYCERIDE) Light mineral oil 11.20 25.00 5.60 IPM (ISOPROPYL MYRISTATE) 5.00 2.50 Stearyl Alcohol 0.50 0.50 0.25 Surphope 1816 0.80 0.80 Methocel ELV15 0.60 0.40 0.60 Cocoglyceride 1.20 0.60 Xanthan gum 0.30 0.20 0.30 Sodium lauryl sulphate 0.10 0.10 Polysorbate 60 0.80 Water purified 72.80 73.10 85.45 Total 100.00 100.00 100.00 Propellant: [propane: 8.00 8.00 8.00 iso-butane: n-butane] mixture* (1681) Results Appearance Quality G-E FG G-E Color white white white Odor no odor no odor no odor Shakability good good good Flammability test 8% 1681 8% 1681 8% 1681 sample weight (g) 5.70 6.00 5.80 Ignite N N N Pass Y Y Y Fail** N N N *Three different propellant mixtures were used and tested. The oil mixture formulations all produced foam of good to excellent quality and the oil alone formulation foam was fairly good. **Flame is for longer and or higher than the test limit; N = no; Y = yes.

[0435] Foam PFT051 corresponds to the foam formulation of Example 4, No. 5 except that the anti-oxidant, preservatives and fragrance have been replaced by and the amount has been made up to 100% with water.

[0436] Foam PFT050 corresponds to the foam formulation of Example 5, No. 1.

[0437] Foam PFT052 corresponds to the foam formulation of Example 5, No. 2.

[0438] These compositions all produced excellent quality foam. They were identical other than for the presence or absence of the emollient or oil, which was 50%, 35% or 10% of the formulation. When reduced the oil or emollient was replaced by water. All the foam compositions were found to be non-flammable according to the test parameters used. Increasing the amount of oil from 10% to 50% did not significantly affect flammability.

Example 24 Soybean Oil Compositions

[0439]

TABLE-US-00026 Ingredients PFT058 PFT059 PFT060 Soybean oil 40.00 30.50 20.00 Stearyl alcohol 0.80 1.05 0.73 Sucrose ester SP70 0.64 0.45 0.80 Xanthan Gum 0.16 0.11 0.10 Methocel ELV15 0.32 0.22 0.28 Water pur. 58.08 67.67 78.09 Total 100.00 100.00 100.00 Results Appearance Quality G E E Color White White White Odor No Odor No Odor No Odor Shakability Good Good Good Propellant 8% 1681 8% 1681 8% 1681 sample weight (g) 7.20 6.80 9.20 Ignite Y N N Pass Y Y Y Fail* N N N *Flame is for longer and or higher than the test limit. N = no; Y = yes; G = good; E = excellent

[0440] Foam PFT058 corresponds to the foam formulation of Example 2, No, 1 except that the anti-oxidant, preservatives and fragrance have been replaced by and the amount has been made up to 100% with water.

[0441] Foam PFT059 corresponds to the foam formulation of Example 2, No, 2., except that the anti-oxidant, preservatives and fragrance have been replaced by and the amount has been made up to 100% with water.

[0442] Foam PFT060 corresponds to the foam formulation of Example 2, No, 3., except that the anti-oxidant, preservatives and fragrance have been replaced by and the amount has been made up to 100% with water.

[0443] These compositions all produced good to excellent quality foam. They were identical other than for the presence or absence of the emollient or oil, which was 40%, 30.5% or 20% of the formulation. When reduced the oil or emollient was replaced by water. All the foam compositions were found to be non-flammable according to the test parameters used. Reducing the amount of oil from 40% to 30% and from 30% to 20% resulted in the foam not igniting.

Example 25 Silicone Oil Compositions

[0444]

TABLE-US-00027 Ingredients PFT056 PFT057 Dimethicone 350 25.00 10.00 Stearyl alcohol 0.20 0.20 Sucrose ester SP70 0.80 Myrj 49P 0.80 Xanthan Gum 0.20 0.20 Methocel ELV15 0.40 0.40 Water pur. 73.40 88.40 Total 100.00 100.00 Results Appearance Quality G G Color White White Odor No Odor No Odor Shakability Good Good Propellant 8% 1681 8% 1681 sample weight (g) 11.20 9.10 Ignite N Y Pass Y Y Fail* N N *Flame is for longer and or higher than the test limit. N = no; Y = yes; G = good; E = excellent.

[0445] Foam PFT056 corresponds to the foam formulation of Example 3, No. 1 except that the anti-oxidant, preservatives and fragrance have been replaced by and the amount has been made up to 100% with water.

[0446] Foam PFT057 corresponds to the foam formulation of Example 3, No. 2 except that the anti-oxidant, preservatives and fragrance have been replaced by and the amount has been made up to 100% with water.

[0447] These compositional produced good quality foam. They were identical other than for the presence or absence of the emollient or oil, which was 25% or 10% of the formulation. When reduced the oil or emollient was replaced by water. All the foam compositions were found to be non-flammable according to the test parameters used. Reducing the amount of oil from 25% to 10% resulted in the foam not igniting.

Comparison Example 1W/O 57% and 60% MCT Emulsion Formulations

[0448]

TABLE-US-00028 PFT053 PFT054 PFT055 MCT (CAPRYLIC/CAPRIC 57.18 60.00 60.00 TRIGLYCERIDE) PPG 15 stearyl ether 1.01 Glyceryl Monostearate 2.00 2.00 2.00 Hexilene glycol 10.03 10.00 Stearyl Alcohol 4.71 5.00 5.00 Steareth-2 3.01 PVP K-90 2.00 2.00 Span 60 2.00 Lecithin 10.03 10.00 Water purified 10.03 11.00 31.00 Total 100.00 100.00 100.00 Propellant: [propane: 8.00 8.00 8.00 iso-butane: n-butane] mixture* (1681) Appearance Quality G G-E G-E Color yellow yellow white Odor no odor no odor no odor Shakability good good moderate Flammability test 8% 1681 8% 1681 10% 1681 Sample weight (g) 6.10 5.10 5.20 Ignite Y Y Y Pass N N N Fail** Y Y Y ~15 sec. ~15 sec. ~15 sec. of fire! of fire! of fire! *Three different propellant mixtures were used and tested. The high oil formulations produced foam of good quality. **Flame is for longer and or higher than the test limit; N = no; Y = yes.

[0449] These formulations are flammable in the presence of hexylene glycol and of lecithin. When both were substituted by water the composition was still found to be flammable according to the test parameters usedsuggesting (without being bound by this theory) that whilst MCT oil in water compositions are inherently non-flammable when there is a phase inversion such that there is a water in oil emulsion the MCT foam is more combustible and may not pass the test parameters.

Comparison Example 2-25% Petrolatum and 45% PPG Stearyl Ether Foam Formulations

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TABLE-US-00029 Ingredients % w/w % w/w Water 70.00 45.00 PPG 15 Stearyl ether 45.00 Petrolatum 25.00 Steareth-2 2.00 7.00 Steareth-21 3.00 3.00 Total 100.00 100.00 Propellant: [propane: 8.00 8.00 iso-butane: n-butane] mixture (1681) Results Quality G G-E Color White White Odor Very Faint No Flammability sample weight (g) 5.3 5.5 Ignite Y Y Pass N N Fail* Y Y *Flame is for longer and or higher than the test limit. N = no G = good Y = yes E = excellent

[0451] 25% Petrolatum in a minimal formulation and 45% PPG stearyl ether in a minimal formulation were both flammable.