Topical aerosol foam

Abstract

The present invention is directed to an aerosol foam composition comprising an emulsifier blend containing a poorly water-soluble active pharmaceutical ingredient (API), cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate, and a hydrocarbon propellant. The aerosol foam composition is preferably an oil-in-water emulsion. The propellant is a mixture of liquefied hydrocarbon gases, preferably a propane / isobutane / butane blend. The hydrocarbon propellant produces an aerosol foam that is stable, has consistent physical properties, excellent aesthetic appearance, and no discernible API degradation after extended periods or accelerated storage conditions.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 294,178, filed December 28, 2021, and U.S. Provisional Application No. 63 / 371,967, filed August 19, 2022, the contents of which are incorporated by reference in their entireties herein.

[0002] The present invention is directed to an oil-in-water emulsion aerosol foam composition having an alkyl phosphate ester anionic surfactant or a blend of alkyl phosphate ester surfactants as an emulsifier. More specifically, the present invention relates to a pharma-ceutically acceptable emulsion aerosol foam composition comprising a poorly water-soluble pharma-ceutically active agent and an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate (also known as ceteth-10 phosphate). The aerosol foam is delivered using a propellant blend. [Background technology]

[0003] Foam formulations have been used for decades as delivery systems for cosmetic and pharmaceutical applications. Foams are preferred for some applications because they spread better and minimize rubbing. This is particularly advantageous when treating inflamed skin or areas of the skin covered with hair. Foam vehicles are preferred over ointments, gels, and creams because they are easier to apply and less sticky and oily. Patient preference for foam vehicles can lead to improved patient compliance and therefore better treatment outcomes.

[0004] There are various types of foam formulations that can be used to deliver active ingredients, including aqueous, hydroalcoholic, emollient, solvent, petrolatum and oil-based foams. Different formulations have different characteristics, for example, emollient foams have soothing and moisturizing effects, while hydroalcoholic foams promote skin penetration and dissolution of active agents. Foams can be made using propellant-free production methods such as the AIRSPRAY® foam dispenser (a foam dispenser having a pump assembly that includes a liquid pump, an air pump and a common actuator for simultaneously operating the liquid pump and the air pump) or by using a pressurized container and a propellant.

[0005] Topical foams differ from ointments and creams in that the characteristics of the foam medium change. Prior to application, foam formulations are usually in the form of a suspension or emulsion. When an aerosol foam formulation is expelled from a container, the liquid propellant volatilizes to produce a semi-solid foam product that is expanded with the gas phase propellant. When propellant-free production methods are used, air is pumped into the suspension or emulsion as the foam is expelled. The method used to produce the foam affects the appearance and stability of the foam.

[0006] Foams can be designed with specific properties depending on factors such as the condition being treated, the area of ​​the body being treated, and the active pharmaceutical ingredients in the formulation. The foam medium must have adequate stability so that it does not collapse after being discharged from the container; low shear sensitivity so that only minimal rubbing is required; be non-irritating, non-allergenic, non-toxic, and must keep the active pharmaceutical agent solubilized. Additionally, aerosol foam media must contain propellants that have minimal or no effect on the atmospheric ozone layer. Foams applied to the face or anterior torso must have minimal odor, since the addition of fragrances to cover malodors is undesirable for pharmaceuticals. The structure of the foam is affected by various parameters, including the type and concentration of foaming agent, the viscosity of the liquid phase, salt concentration, temperature and pH of the formulation.

[0007] Commercially viable three-phase medicated aerosols rely on surfactants that have limited solubility in both the internal oil phase and the external aqueous phase. Upon shaking, the liquid hydrocarbon propellant mixes with the dispersed globules of the oil phase. The surfactants concentrate at the interface between the propellant / oil phase and the aqueous phase to form a thin film called a "lamella". It is the specific composition of this lamella that determines the structural strength and general characteristics of the foam that forms as the internal phase liquid propellant transitions to gas as soon as the medicated emulsion leaves the pressurized environment of the aerosol canister. This transition from liquid to gas phase results in the formation of the foam bubbles. Dense, tightly layered lamellae produce highly structured foams that can support their weight. Stable foams are not always formed. The formation of stable foams with the desired structure depends on many factors, including but not limited to the specific ingredients, concentrations of ingredients, viscosity of the liquid phase, and propellant. These factors can be adjusted to produce stable foams with various structures such as expandable foams, fast-breaking foams, rigid foams, and robust foams.

[0008] Foam collapse occurs when the pressure generated by the expanding internal gas phase exceeds the cohesive strength of the foam lamellae. Three sources of the expanding internal gas phase are: 1) additional degassing of liquid hydrocarbon propellants with low vapor pressure, 2) mechanical pressure on the foam during rubbing (squeezing), and 3) adiabatic cooling of the foam concentrate (70 psig) as it passes through that value and becomes a foam at ambient pressure, followed by general warming of the foam to ambient (20-25°C) or skin (32°C) temperatures. In the case of triple emulsion medicated foams stabilized with alkyl phosphate ester surfactants, when the lamellae are reduced to single surfactant bilayers, further expansion of the internal gas phase causes foam cell rupture and product flow to the skin surface.

[0009] Expanding and quick-disintegrating foams are characterized by an expanding internal gas phase that rapidly ruptures lamellae to form visibly larger foam cells. Expanding foams initially appear "expanded" as the internal foam cells join together, but as the surface foam cells collapse, the product flows out and the active is delivered to the skin application site.

[0010] In the case of hard and tough foams, a fully degassed internal phase warmed to skin temperature does not generate enough pressure to overcome the cohesive strength of the lamellae. The gas cells do not burst until the additional pressure of rubbing occurs. These more stable foams are ideal for application to the scalp, as the foam can be placed against the scalp lesion on a "part of hair" and then rubbed in, breaking the foam and applying actives to the diseased skin with minimal product loss to the hair.

[0011] For a three-phase medicated emulsion foam to be commercially acceptable, the liquid hydrocarbon propellant must be properly mixed with the inner oil phase of the emulsion to form a foam as the product exits the canister. If the propellant is not properly mixed, only a few foam cells will form as the liquid propellant transitions to gas, and most of the propellant will transition to gas outside of the emulsion upon actuation. Shaking and then immediately actuating through the valve will result in the delivery of an inhomogeneous, very dense, and unacceptable "sputtering" foam. Even if the canister is properly shaken and inverted, the propellant will be discharged separately from the emulsion concentrate, and the propellant will empty from the canister before the entire amount of product is dispensed. This foam product is commercially unacceptable because the canister will be incompletely emptied. For example, if a formulation is labeled to dispense 60 grams of foam (one month's supply), but the propellant is completely depleted after dispensing 48 grams of foam, the patient will not receive the full prescribed treatment. Such foam canisters fail the requirements for minimum delivery mass and will be withdrawn from the market.

[0012] Stable foams are not always formed. The formation of a stable foam with the desired structure depends on many factors, including but not limited to the specific ingredients, the concentrations of the ingredients, the viscosity of the liquid phase, and the propellant. Any excipient that increases the solubility of the surfactant in the outer aqueous phase when added to the formulation will destabilize the emulsion, reducing the stiffness of the lamellae, resulting in the foam bubbles bursting as soon as the liquid propellant transitions to gas. In other words, the fluid emulsion is expelled from the canister and flows rapidly away from the application site on the skin, rather than forming a topical foam that remains at the application site until it is rubbed in to break the lamellae and release the pharmaceutical agent to the desired treatment site.

[0013] Diethylene glycol monoethyl ether (DEGEE), a cosmetic and pharmaceutical solvent, present in the aqueous continuous phase of emulsions has been shown to increase the solubility of surfactants and waxy components of lamellae in the continuous aqueous phase during the emulsification process (Hernandez, et al., Journal of Dispersion Science and Technology, Investigating the effect of transcutol on the physical properties of an O / W cream, Vol 41, No. 4, pp 600-606, 2020). The dramatic destabilization of polyoxyethylene-20-stearyl ether and polyoxyethylene-2-stearyl ether emulsions when the DEGEE concentration is increased above 25% suggests that it is surprising to maintain sufficiently thick and tight lamellar structures to produce stable foams in the presence of 25% or more DEGEE. Summary of the Invention [Means for solving the problem]

[0014] Foam stability can be evaluated by measuring foam half-life. Foam half-life is the time required for half of the liquid continuous phase of foam product to flow out. Shorter half-life means less foam stability. Desirable foam half-life is based on the intended use of foam. For certain foam applications, such as self-tanning foams and sunscreen foams, where foam is applied to a large area of ​​the body surface, foam half-life is preferably less than 30 seconds to minimize application time. For topical medicated foams of the present invention, foam half-life of more than 30 seconds is desirable, and in some embodiments foam half-life of more than 1 minute is preferred.

[0015] Aerosol foams have been found to produce stable foams suitable for topical application of active pharmaceutical ingredients (APIs). Aerosol foam formulations consist of two components: a product concentrate and a propellant. The product concentrate is the active drug combined with additional ingredients or co-solvents necessary to produce a stable and effective product. The concentrate in a medicinal aerosol formulation can be a solution, suspension, emulsion, semi-solid, or powder. Topical foam products usually have an emulsion product concentrate. The propellant provides the force to expel the product concentrate from the container and is further responsible for the delivery of the formulation as a foam. The propellant can also function as a solvent for the pharmaceutical active or functional excipients that make up the product concentrate.

[0016] Unfortunately, formulating a stable aerosol foam containing poorly water-soluble APIs can be difficult. Poorly water-soluble APIs may not be consistently delivered at high enough concentrations to produce the desired therapeutic effect after extended periods or accelerated storage conditions, and / or bioavailability may decrease. Additionally, undissolved APIs can clog valves. This is likely when poorly water-soluble APIs are used in formulations that contain significant amounts of water, such as oil-in-water emulsions. Stable foam products containing fully dissolved poorly water-soluble APIs improve efficacy and patient compliance.

[0017] Propellant Propellants are used to exert pressure within the container and expel the product concentrate from the container. Propellants are chemicals that have a vapor pressure greater than atmospheric pressure at 40°C (105°F). Medicinal aerosols are generally made up of chlorofluorocarbons, fluorocarbons (trichloromonofluoromethane, dichlorodifluoromethane), hydrocarbons (propane, butane, isobutane), hydrochlorofluorocarbons and hydrofluorocarbons, as well as compressed gases (nitrogen, NO 2 , CO 2 ) and other propellants.

[0018] Chlorofluorocarbon (CFC) propellants have been used for many years, but because of their role in depleting the ozone layer, the use of CFCs has been significantly reduced. Hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs), whether or not they contain chlorine, differ from CFCs in that they have one or more hydrogen atoms. They decompose in the atmosphere at a faster rate than CFCs, so HCFCs and HFCs have less impact on the ozone layer. HCFCs and HFCs are used in topical pharmaceuticals. HCFCs and HFCs are highly miscible with water, making them more useful as solvents compared to other propellants. In the case of foam concentrates consisting of oil-in-water emulsions, HCFCs and HFCs mix easily with the continuous phase of the emulsion, providing an excellent topical drug delivery vehicle for highly water-soluble actives such as urea and salicylic acid. KERAFOAM® 42 emollient foam is a keratolytic emollient foam that is a tissue softener for skin and / or nails, containing urea, preservatives, buffers, water, ceteareth-10 phosphate, cetearyl alcohol and dicetyl phosphate. SALKERA® emollient foam is keratolytic and contains 6% salicylic acid USP incorporated in an aqueous emollient foam vehicle containing humectants, preservatives, buffering agents, water, ceteareth-10 phosphate, ceteth-20 phosphate, cetostearyl alcohol, dicetyl phosphate and propylene glycol.

[0019] Hydrocarbon (HC) propellants are used in topical medicated aerosols because of their low environmental impact, low toxicity, and non-reactivity. HCs are also useful for producing three-phase (two-layer) aerosols because their density is less than 1 and they are immiscible with water. The hydrocarbons remain on top of the water layer, providing the force to push the contents out of the container. Hydrocarbon propellants do not contain halogens, so hydrolysis does not occur, making these good propellants for water-based aerosols. Unfortunately, hydrocarbon propellants are flammable and can explode. Flammability can be reduced by mixing the hydrocarbons with other liquefied gases. The liquid hydrocarbon propellant inside the canister does not mix well with the oil phase inside the oil-in-water emulsion and can destabilize the foam concentrate. This results in a lack of uniformity in the contents of the dose released from the canister. For this reason, no oil-in-water emulsion aerosol foam products that cannot deplete the ozone layer have been developed that contain water-insoluble APIs.

[0020] [Table 1]

[0021] Propane, butane, and isobutane are the most commonly used hydrocarbons. They are used alone or in mixtures to obtain the desired vapor pressure, density, and degree of flammability. Blends of propane, isobutane, and n-butane are usually designated "AP" or "NIP", followed by a dash and a number which is the pounds per square inch of pressure (measured with a pressure gauge) of the particular propellant blend at 70°F. For example, AP-48 propellant is a 31:23:46 blend of propane:isobutane:butane that delivers 48 psig in the can at 70°F, while AP-70 propellant is a 55:15:30 blend of propane:isobutane:butane that delivers 70 psig in the can at 70°F.

[0022] Inert compressed gas propellants expel the product concentrate in essentially the same form as it was placed in the container. The pressure of the compressed gas is in the head space of the aerosol container. Compressed gas propellants are readily available, inexpensive and non-flammable, but as the product is used up, the pressure in the can drops. For pharmaceutical products, this steady drop in pressure with each actuation can result in the first dose of active material delivered being significantly different from the last dose of active material delivered from the canister. Also, once the compressed gas is used up, any product remaining in the canister cannot be administered to the patient. For these reasons, compressed gas propellants are not typically used in medicinal aerosols.

[0023] product concentrate Aerosol foams are produced when an oil-in-water emulsion product concentrate is mixed with a propellant and the propellant is in the inner oil phase of the emulsion. If the propellant is in the external phase (i.e., as in a water-in-oil emulsion), no foam is produced but a spray or wet stream. Rapidly degrading foams produce a foam when released from the container, but the foam disintegrates in a relatively short time. This type of foam is used to apply product concentrates to large areas without the need to manually rub or spread the product. Because the foam disintegrates quickly, the active drug is more rapidly available. Stable foams are produced when surfactants that have limited solubility in both the organic and aqueous phases are used. The surfactants concentrate at the interface between the propellant / oil phase and the aqueous phase to form a thin film called a "lamella". It is the specific composition of this lamella that determines the structural strength and general characteristics of the foam. Dense, tightly layered lamellae produce highly structured foams that can support their weight.

[0024] The emulsifiers or surfactants used to formulate the product concentrate and the use of alcohol in the formulation are two of the most important ingredients in topical medicated foams. Surfactants in emulsion aerosols can include fatty acids saponified with triethanolamine, anionic surfactants, and more recently, non-ionic surfactants such as polyoxyethylene fatty esters, polyoxyethylene sorbitan esters, alkylphenoxyethanols, and alkanolamides. The first dermatological foams contain high concentrations of alcohol (about 60% ethanol) and use the non-ionic surfactant polysorbate 60 and hydrocarbon propellants to create a fast-dissolving foam. The topical foams Olux® (clobetasol), Luxiq® (betamethacone), Lexette® (halobetasol), and Evoclin® (clindamycin) are high alcohol foams. Unfortunately, the high alcohol foam proved irritating and burning for some psoriasis patients, so the alcohol was removed from clobetasol foam and the polysorbate 60 was replaced with polyoxyl 20 cetostearyl ether to market the first emollient topical medicated foam, Olux-E®. Finacea® topical foam has a very similar composition to Olux-E®, as it contains propylene glycol but no alcohol and uses a surfactant blend of polysorbate 80 and polyoxyl 40 stearate to form the foam lamellae. The latest advancement in topical medicated foam technology is Amzeeq® topical minocycline foam for the treatment of acne and rosacea. This product does not contain solvents, but uses a blend of multiple natural oils to dissolve the minocycline, in combination with hydrogenated castor oil as a surfactant to form the foam lamellae.

[0025] The present invention is directed to an aerosol foam composition comprising an API with a water solubility of less than 60 mg / l. The aerosol foam composition is preferably an oil-in-water emulsion containing an emulsifier blend of cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate in combination with a propellant. The propellant is a mixture of liquefied hydrocarbon gases, preferably a propane / isobutane / butane blend. The hydrocarbon propellant results in an aerosol foam containing a poorly water soluble API that is stable, has consistent physical properties, excellent aesthetic appearance, and no discernible API degradation after extended periods (storage at ambient temperature for greater than 24 months) or accelerated storage conditions (storage at 40° C. and 75% relative humidity for 6 months). [Brief description of the drawings]

[0026] [Figure 1A] Figures 1A-1E show acceptable and unacceptable foams. Figures 1A-1D show acceptable foam structures including expandable, quick-degrading, hard and robust foams immediately after and 5 minutes after extrusion. Figure 1E shows an unacceptable foam where the propellant and concentrate are poorly mixed, resulting in sputtering during extrusion. [Figure 1B] Figures 1A-1E show acceptable and unacceptable foams. Figures 1A-1D show acceptable foam structures including expandable, quick-degrading, hard and robust foams immediately after and 5 minutes after extrusion. Figure 1E shows an unacceptable foam where the propellant and concentrate are poorly mixed, resulting in sputtering during extrusion. [Figure 1C] Figures 1A-1E show acceptable and unacceptable foams. Figures 1A-1D show acceptable foam structures including expandable, quick-degrading, hard and robust foams immediately after and 5 minutes after extrusion. Figure 1E shows an unacceptable foam where the propellant and concentrate are poorly mixed, resulting in sputtering during extrusion. [Figure 1D]Figures 1A-1E show acceptable and unacceptable foams. Figures 1A-1D show acceptable foam structures including expandable, quick-degrading, hard and robust foams immediately after and 5 minutes after extrusion. Figure 1E shows an unacceptable foam where the propellant and concentrate are poorly mixed, resulting in sputtering during extrusion. [Figure 1E] Figures 1A-1E show acceptable and unacceptable foams. Figures 1A-1D show acceptable foam structures including expandable, quick-degrading, hard and robust foams immediately after and 5 minutes after extrusion. Figure 1E shows an unacceptable foam where the propellant and concentrate are poorly mixed, resulting in sputtering during extrusion. [Diagram 2] Figure 2 shows acceptable foams containing ketoconazole from Formulations 5-8 after 5 minutes of exhalation. Formulations 5 and 7 produced acceptable expandable foams. Formulation 6 produced an acceptable firm foam. Formulation 8 produced an acceptable hard foam. [Diagram 3] Figure 3 shows acceptable and unacceptable foams containing econazole nitrate from formulations 9-12 after 5 minutes of exhalation. Formulation 9 produced unacceptable sputtering foam. Formulations 10 and 12 produced acceptable, robust foams. Formulation 11 produced unacceptable sputtering foam. [Figure 4] Figure 4 shows acceptable foams containing ivermectin from formulations 13 to 16 after 5 minutes of expulsion. Formulations 13 to 15 produced acceptable expandable foams and formulation 16 produced acceptable quick-disintegrating foams. [Diagram 5] FIG. 5 shows acceptable, rapidly disintegrating foams containing clobetasol propionate from Formulations 17-20 5 minutes after expulsion. [Figure 6]Figure 6 shows acceptable and unacceptable foams containing oxymetazoline from Formulations 21-24 after 5 minutes of dispensing. Formulation 21 produced an acceptable, sturdy foam. Formulation 22 produced an unacceptable sputtering foam. Formulations 23 and 24 produced acceptable, hard foams. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] It has been found that topical application of potent pharmacological agents to treat skin diseases provides better delivery, less systemic exposure and greater ease of use for patients. The molecular structure of the compound ultimately determines the ability of the drug to cross the epithelium of the tissue to which the product is applied. For dermal applications, the choice of ingredients of the formulation determines the maximum skin penetration that the preparation can achieve. The present invention is suitable for use with many APIs, particularly APIs with low water solubility. Examples of APIs with low water solubility suitable for use in the present invention include, but are not limited to, ketoconazole, econazole nitrate, ivermectin, clobetasol propionate, calcipotriene, halobetasol propionate, tazarotene, oxymetazoline free base and desonide. A low water solubility API is defined herein as an API with a water solubility of 60 mg / l or less. Creams, lotions, gels, ointments, aerosol foams and solutions are just some of the more familiar forms of topical formulations, often containing a fully dissolved API for application to the skin, as disclosed for roflumilast in U.S. Pat. No. 5,712,298 ("the '298 patent") (column 12, lines 37-64), which is incorporated herein by reference. For the treatment of such skin conditions, emulsions, suspensions, gels or solutions for topical application have been described, but these are of limited use due to the poor solubility of the compounds.

[0028] The cream formulation containing the poorly water-soluble API was combined with a propellant. The foam concentrate was formulated to produce a foam that does not collapse after being discharged from the container, has low shear sensitivity such that only minimal rubbing is required, is non-irritating, non-allergenic and non-toxic, and maintains the API dissolved. Additionally, the aerosol foam medium contains a propellant that has minimal or no impact on the atmospheric ozone layer. The foam concentrate and propellant components can be adjusted to produce foams with various properties such as expandable foams, fast-degrading foams, hard foams and robust foams. Preferably, the product discharged from the canister is a smooth white or off-white foam with uniform cells that can support its own weight until rubbing begins. Once rubbing begins, the foam breaks down quickly and spreads evenly across the application site. The product preferably has a foam half-life of greater than 60 seconds. The amount of foam dispensed by the canister may be metered or unmetered to dispense a consistent amount of foam and a consistent dose of API.

[0029] The aerosol foam contains 1-10%, preferably 2-5%, of an emulsifier containing an alkyl phosphate ester anionic surfactant or a blend of alkyl phosphate ester surfactants to ensure mixing with the propellant. An emollient or oil is included in an amount to produce a visually pleasing foam. Preferably, the emollient includes 2-6%, preferably 5%, petrolatum; and 2-3%, preferably 2.5%, isopropyl palmitate. Preferably, the oil includes 8-12% diisopropyl adipate and 8-12% oleyl alcohol.

[0030] The propellant provides the force to expel the product concentrate from the container and is further responsible for the delivery of the formulation as a foam. Aerosol foam propellants are mixtures of liquefied hydrocarbon gases and therefore can act as a solvent for the API or can be mixed with the internal oil phase of the product concentrate emulsion. The use of hydrocarbon propellants may reduce or eliminate the need for additional solvents such as hexylene glycol and DEGEE (diethylene glycol monoethyl ether). Hexylene glycol is preferably in an amount of 0-20% w / w and DEGEE is preferably in an amount of 10-35% w / w. The hydrocarbon propellant partially mixes with the API concentrate but mainly forms a separate liquid layer (less dense than the concentrate) in the can. This is also commonly referred to as a three-phase medicinal aerosol. Therefore, the can needs to be shaken to distribute the propellant evenly throughout the finished product before applying the released foam to the patient's skin.

[0031] product concentrate The product concentrate in foam consists of an oil-in-water emulsion of a poorly water-soluble active ingredient, 10-35% diethylene glycol monoethyl ether NF (TRANSCUTOL® P), 30-80% water, 7.5-20% oil phase, and 1-10%, and in some embodiments 2-5%, Clodaphos CES™, an anionic surfactant-based emulsifying wax. These ingredients produce a foam for the treatment of the scalp and face. This foam concentrate is capable of forming a rapidly degrading and expandable foam that disintegrates after application to the skin (without rubbing) in a relatively short time. This type of foam is used to apply the product concentrate to large areas without the need to manually rub or spread the product. The active drug is available more rapidly as the foam disintegrates quickly, and the foam is more easily applied to areas of the skin with a high density of terminal hair, i.e., the scalp. Depending on the amount of poorly water-soluble active and the oil phase and / or emulsifying wax selected, this foam concentrate can also form a stable foam that does not break down until the product released from the canister is rubbed in. Viscosity values ​​for a range of Clodafos CES™ concentrations are given in Table 3. 10% Clodafos CES™, containing 0.3% roflumilast as the poorly water-soluble active, produced unacceptable foam that "sputtered" when released from the can. Sputtering (shown in Figure 1E) indicates insufficient mixing between the liquid propellant and the emulsion foam concentrate inside the canister. However, the 2% Clodafos CES™ formulation with 0.3% roflumilast produced an acceptable, hard foam (shown in Figure 1C).

[0032] The final composition of 0.3% roflumilast foam is given in Table 2. Roflumilast release foam products with this composition have consistent physical properties, excellent aesthetic appearance, no discernible roflumilast degradation after extended periods (storage for 24 months or more under ambient conditions) or accelerated storage conditions (storage for 6 months at 40°C and 75% relative humidity), and demonstrate acceptable but variable roflumilast assay results during development. A series of quality-by-design experiments focused on characterization of analytical methodology for sample preparation, optimization of product concentrates, and packaging compatibility were completed. It was determined that inclusion of hexane extraction during sample preparation would minimize variability in assay results.

[0033] [Table 2]

[0034] The preferred viscosity is 4000-11,000 centipoise (cP). Viscosity was tested using a Brookfield viscometer, which determines viscosity by measuring the force to rotate a spindle through a sample at a given speed. A regular viscosity spring (RV) was used, with a #14 spindle at 30 rpm, sample chamber 6R. However, any digital viscometer (DVE, DV1, DV2, or DV3) is suitable to measure viscosity. The read time was 2 minutes, and the temperature was controlled room temperature (CRT, 20-25°C).

[0035] [Table 3]

[0036] The released foam products containing poorly water-soluble actives have consistent physical properties, excellent aesthetics, acceptable assay results after extended periods (storage under ambient conditions for 3 months or more) or accelerated storage conditions (storage at 40°C and 75% relative humidity for 3-6 months), and no deleterious amounts of degradation products. Typical data generated for poorly water-soluble actives are given in Table 4 (long-term stability storage) and Table 5 (accelerated stability storage) for the 2% Clodafos CES™ formulation of the 0.3% roflumilast formulation described in Table 2. The preferred aesthetics of the foam concentrates were optimized by reducing the emollients in half (5% instead of 10% for petrolatum and 2.5% instead of 5.0% for isopropyl palmitate). To optimize the aesthetics of the foam formulations, only two of the 2% Clodafos CES™ foam concentrate formulations were compared. The foam concentrate with 15% complex moisturizer felt "oilier" during rubbing compared to the foam concentrate containing 7.5% complex moisturizer. Because the foam product is formulated to treat seborrheic dermatitis skin on the scalp and face (both anatomical sites known to have oily skin prior to foam application), it was considered an aesthetic advantage to lower the moisturizer content of the foam compared to the cream. To compensate for the removal of the 15.5% emulsifier / emollient, the amount of water in the foam is increased to just over 65% in the foam concentrate compared to approximately 50% water in the roflumilast cream. Unofficial 3-month stability data for 64 grams of the product concentrate formulation (Table 2) supplied with 8 grams of AP-70 propellant is shown in Tables 4 and 5.

[0037] [Table 4]

[0038] [Table 5]

[0039] Propellant Hydrocarbon propellants have been found to provide topical foams with desirable properties: they do not contain halogens and therefore do not undergo hydrolysis, making them good propellants for water-based aerosols such as oil-in-water emulsions containing poorly water-soluble APIs.

[0040] Six different hydrocarbon propellants, one N-butane / dimethyl ether blend and one hydrofluorocarbon propellant were screened in the 2% Clodafos CES™ formulation of the 0.3% roflumilast formulation listed in Table 2. The six hydrocarbon propellants were isobutane (A-31), N-butane (A-17), propane / isobutane (A-46), propane / isobutane (A-70), propane / isobutane / N-butane (AP-70), Aeropin 35 (Aeropin 35 is a blend of propane / isobutane / N-butane with a vapor pressure of 35 psig at 70° F. such that the ratio of isobutane to N-butane is fixed at 2 / 3), and Butane 48 (Butane 48 is a ratio of propane / isobutane / N-butane / isopentane of 30.8 / 22.9 / 45.8 / 0.5). The hydrocarbon blend with dimethyl ether (DME) was 53% DME and 47% N-butane. The hydrofluorocarbon propellant was 1,1,1,2-tetrafluoroethane (HFA134a). AP-70 propellant produced the highest quality foam in the initial foam propellant screening study. HFA-134a (1,1,1,2-tetrafluoroethane), a propellant used in highly water-soluble urea (KERAFOAM® 42) and salicylic acid (SALKERA®) emollient foams, was combined with Formulation 1. The emitted product was a clumpy, gelatinous looking material with no gas bubbles distributed in the liquid. Table 1 gives the properties of the three hydrocarbon propellants blended to make the aerosol propellants designated "AP" or "NIP" and Table 6 lists the appearance of the aerosolized topical foam products.

[0041] [Table 6]

[0042] The aesthetic appearance of the foam formulations shown in Table 2 (64 grams of concentrate containing 2% Clodafos CES™ formulation with 0.3% roflumilast) when delivered with 8 grams of either AP-48 or AP-70 propellant was compared. The AP-48 propellant is a 31:23:46 blend of propane:isobutane:butane, while the AP-70 propellant is a 55:15:30 blend of the same hydrocarbons. While both foams were found to be perfectly acceptable, the stiffer appearance and slightly slower breakage of the AP-48 propellant foam was preferred by approximately two-thirds of the individuals who tested the product. The other third of the testers had no preference or only a slight preference for the more rapidly degrading AP-70 foam. It was concluded that both the AP-48 and AP-70 hydrocarbon blends exhibited good topical foam characteristics and excellent aesthetic appearance. By adjusting the propane to butane ratio, any pressure between 48 and 70 psig can be achieved. From an aesthetic standpoint, any ratio of hydrocarbon propellant blend of propane / isobutane / n-butane that provides a pressure of about 48-70 psig at 70°F has been shown to be acceptable.

[0043] Foam Products Aerosol foams are produced when an oil-in-water emulsion product concentrate is mixed with a liquid hydrocarbon propellant, with the propellant in the internal oil phase. If the propellant is in the external phase (i.e., as in a water-in-oil emulsion), no foam is produced, but droplets or wet streams. Stable foams are produced when surfactants with limited solubility in both the internal oil phase and the external water phase are used. The surfactants concentrate at the interface between the propellant / oil phase and the water phase to form thin films called "lamellae." It is the specific composition of these lamellae that determines the structural strength and general characteristics of the foam. Dense, tightly layered lamellae produce highly structured foams that can support their own weight. In a preferred embodiment, two alkyl phosphate ester surfactants are used that are not commonly used in topical foam products. These alkyl phosphate ester surfactants are found in the emulsifier Crodaphos CES™.

[0044] For all topical medicated foams, it is assumed that when the last lamella ruptures (the foam bubbles are destroyed), all of the propellant is released from the formulation. The specific composition of the foam lamellae determines the structural strength and general characteristics of the foam. The liquid crystal stabilized oil-in-water emulsion low water solubility API concentrate has numerous clodaphos CES lamellae surrounding each oil droplet. The solvent DEGEE (diethylene glycol monoethyl ether) is miscible in both water and oil and therefore may partition between the oil and water phases and is distributed in numerous lamellae at the emulsion interface. The concentrate is added to the can, the valve is crimped on the top of the can, and the propellant is added under pressure through the valve of the first container closure system. Inside the can, some of the liquid propellant partitions into the oil phase. When the can is shaken, the propellant readily mixes with the oil droplets of the concentrate to form a milky emulsion inside the can. When released from the can, as the propellant transitions from liquid to gas under pressure, the volume of liquid propellant remaining in the oil globule rapidly expands into hydrocarbon gas bubbles trapped within the foam lamella. As the propellant expands, the multiple lamellae of the liquid droplet rapidly collapse into a single lamella of foam. When the pressure associated with the volume of gaseous propellant exceeds the strength of the surfactant lamellae, the foam cells collapse and the API concentrate flows to the surface of the skin.

[0045] Various hydrocarbon blends can be used in the propellants to change the foam properties. For example, AP-70 propellant contains more propane to create a high pressure propellant bubble, thus making the foam bubbles slightly larger. AP-70 propellant also expands the foam bubbles somewhat after the foam is formed on the outside of the can, which should make them "break down" slightly faster than foams with AP-48, which has a lower pressure as the propellant. In a side-by-side comparison of foams in media delivered with either AP-48 or AP-70 propellants, the firmer appearance and slightly slower break down of the AP-48 propellant foam was preferred. Both the AP-48 and AP-70 hydrocarbon blends exhibit good topical foam characteristics and excellent aesthetic appearance.

[0046] The compositions according to the invention may be formulated with additional ingredients such as fillers, carriers and excipients conventionally used in topical cosmetic and pharmaceutical products. Additional ingredients may be added to the compositions to improve stability or aesthetic appearance, including, but not limited to, preservatives (e.g., p-hydroxybenzoic acid esters, benzyl alcohol, phenylmercuric salts, chlorocresol), antioxidants, sequestering agents, stabilizers, buffers, pH adjusters, skin penetration enhancers, film formers, dyes, pigments, diluents, bulking agents, fragrances and other excipients.

[0047] The poorly water-soluble active pharmaceutical ingredient may be selected from the group of active substances having a water solubility of less than 60 mg / liter, including, but not limited to, ketoconazole, econazole nitrate, ivermectin, clobetasol propionate, calcipotriene, halobetasol propionate, tazarotene, oxymetazoline free base, and desonide.

[0048] [Table 7]

[0049] The compositions according to the invention may be formulated with active agents in addition to the poorly water soluble active pharmaceutical ingredient depending on the condition being treated. Additional active agents include anthralin (dithranol), azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumaric acid esters, corticosteroids (e.g., aclometasone, amcinonide, betamethasone, clobetasol, clocotolone, mometasone, triamcinolone, fluocinolone, fluocinonide, flurandrenolide, diflorasone, dexamethasone, cyclosporine ... These include, but are not limited to, sonide, desoximetasone, dexamethasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, prednicarbate, prednisone), corticotropin, vitamin D analogs (e.g., calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, bronchodialators (e.g., beta agonists, anticholinergics, theophylline), and antibiotics (e.g., erythromycin, ciprofloxacin, metronidazole).

[0050] The pharmacoactive agent with low water solubility can be encapsulated to control the release rate from the composition and protect the active agent from degradation.Encapsulation can also be used to modify skin penetration.Methods for encapsulating active pharmaceutical ingredients are known in the art, including but not limited to encapsulation in liposomes, microparticles, nanoparticles, nanocarriers, nanospheres, microspheres, microcapsules, nanocapsules, nanosponges, and microsponges.

[0051] The foam composition may be administered on a schedule suitable for the condition being treated; preferably, the foam composition is administered one or more times per day, and more preferably, the composition is administered one to two times per day.

[0052] The compositions can be used in veterinary and human medicine for the treatment and prevention of all diseases that are deemed treatable or preventable by the use of poorly water-soluble active substances, including, but not limited to, proliferative, inflammatory and allergic skin diseases such as psoriasis (vulgaris), eczema atopic dermatitis; parasitic infestations; fungal skin infections; bacterial or fungal overgrowth; acne; rosacea and erythematotelangiectatic rosacea; and lichen sclerosus.

[0053] The following examples are provided to enable one of ordinary skill in the art to make and use the methods and compositions of the present invention. These examples are not intended to limit the scope of what the inventors regard as the invention. Additional advantages and modifications will be readily apparent to those skilled in the art. EXAMPLES

[0054] Example 1 Eight different hydrocarbon propellants, a 47 / 53 wt / wt blend of N-butane / dimethyl ether and the hydrofluorocarbon HFA134a, were added to the foam concentrates listed in Table 8 [either Formulation 1 or Formulation 2] and the appearance of the emitted foam was described after gentle shaking of the canister. The target ratio was 5 grams of propellant added to 62 grams of foam concentrate. As confirmed in Table 6, the use of either N-butane or isobutane alone as the propellant, as well as a blend of propane and isobutane, produced a runny product that did not meet the appearance requirements for the foam. However, the propane / isobutane / N-butane blend propellant produced a smooth, white, uniform emitted foam. The foam using the tri-hydrocarbon propellant blend initially supported its own weight but was easily destroyed during rubbing. The addition of isopentane to the propane / isobutane / N-butane propellant blend destabilized the emitted foam and produced a runny product.

[0055] [Table 8]

[0056] Dimethyl ether is commonly added to hydrocarbon propellants to increase the solubility of water-insoluble actives in the canister, especially when the foam concentrate contains alcohol (ethanol or isopropyl alcohol). As seen in Table 6, the addition of dimethyl ether to n-butane resulted in a runny product upon dispensing that did not meet the appearance requirements for foam.

[0057] HFA-134a (1,1,1,2-tetrafluoroethane), a propellant used in highly water soluble urea (KERAFOAM® 42) and salicylic acid (SALKERA®) emollient foams, was combined with Formulation 1. The emitted product was a clumpy, gelatinous looking material with no gas bubbles distributed throughout the liquid.

[0058] Example 2 Determination of Dispersed Content Uniformity Over the Life of a Canister The appearance of 64 grams of foam concentrate (Formulation 1 containing 0.15% roflumilast) was compared when delivered with 5 grams, 6 grams, 8 grams, or 10 grams of AP-70 propellant. The emitted foam appearance for these four foam concentrate to propellant ratios was an indistinguishable smooth, white foam product with small, uniformly sized gas bubbles.

[0059] Additional analytical testing was completed on Formulation 1 (containing 0.3% roflumilast) to determine the dispersed roflumilast content uniformity over the life of the canister. Two clinically relevant doses (approximately 1 gram) were dispensed from the beginning of the can (first actuation after shaking the can by hand approximately 5 times). A differential weighing of the can was completed to quantify the amount of foam dispensed and the assay results of the two separate foam extractions were averaged to represent the "start average" value. 15 grams of foam was dispensed and the canister was allowed to return to room temperature. The canister was shaken by hand an additional 5-6 times and two clinically relevant doses (approximately 1 gram) were dispensed from the middle of the canister. The assay results of the two separate foam extractions were averaged to represent the "middle average" value. An additional 15 grams of foam was dispensed and the canister was allowed to return to room temperature. This series of sampling was repeated to obtain the "end average" data. Data comparing the "Starting Average," "Middle Average," and "Ending Average" for lot PGX-C containing 10 grams of AP-70 propellant compared to a lot containing 8 grams of AP-70 propellant are shown in Table 9.

[0060] USP <607> According to the Medicinal Foam-Product Quality Test, the dispersed content uniformity over the life of the canister should not exceed 10%. The official method instructs dispensing the amount according to the labeled instructions and separately collecting the appropriate amount of individually measured foam formulation. The sample size should not exceed the maximum dose recommended by the product label for a single application. The labeled instructions for use will dictate whether the can should be shaken before dispensing the foam and the orientation (upright or inverted) in which it should be dispensed. The foam portions should be retained corresponding to 1) the initial portion from the filled canister, 2) the portion from the middle of the canister (within the range of 40%-60% of the labeled canister content), and 3) the portion in which 85% of the labeled content corresponds to the delivered canister content. The canister should be dispensed at room temperature. If the canister cools as a result of dispensing, it should be warmed to room temperature before subsequent delivery. Using appropriate sample preparation methods (e.g., degassing) and analytical techniques, determine the API concentration in each of the three portions. None of the three results are outside the assay range of the product. The maximum difference in the amount of active ingredient measured inside the canister is NMT 10.0% at the beginning, middle, and end.

[0061] As seen in Table 9, the addition of 10 grams of HC propellant destabilizes the O / W emulsion in the canister. When the canister is shaken, the liquid propellant (specific gravity = 0.54) mixes with the internal oil phase (petrolatum / isopropyl palmitate / cetostearyl alcohol - specific gravity = 0.83) where it causes the swollen emulsion globules to float away from the inverted valve / actuator (creaming of the emulsion). Since the water insoluble actives are disproportionately located around the oil phase of the emulsion, repeating this process of shaking the canister and releasing the foam concentrates the actives in the canister. The O / W emulsion is formulated to be 100% pure and 100% pure, based on the USP <607> If the content uniformity is destabilized to the point of exceeding the maximum difference limit (10% or less) that specifies content uniformity over the life of the canister according to , the aerosol foam formulation is no longer commercially viable. At the target 64 gram fill of 0.3% roflumilast Formulation 1, increasing the amount of AP-70 hydrocarbon propellant suddenly and unexpectedly destabilized the foam concentrate emulsion such that the foam formulation was no longer acceptable as a commercial drug product.

[0062] [Table 9]

[0063] Example 3: Effect of increasing concentrations of diethylene glycol monoethyl ether The same USP method detailed in Example 2 for determining dispersed content uniformity over the life of the canister <607> Medicated Foam-Product Quality Testing was used to determine the effect of increasing concentrations of diethylene glycol monoethyl ether (Table 10).

[0064] [Table 10]

[0065] O / W emulsion is USP <607> If the emulsion is destabilized to the point where it exceeds the maximum difference limit (10% or less) that specifies content uniformity over the life of the canister, the aerosol foam formulation is no longer commercially viable. At a target charge of 64 grams of 0.3% roflumilast foam concentrate and 8 grams of AP-70 hydrocarbon propellant, the emulsion in the canister suddenly and unexpectedly destabilized as the DEGEE concentration increased from 35% to 40% (Table 10). The emulsion of this foam formulation containing 40% DEGEE is not acceptable for commercialization of the drug product.

[0066] [Table 11]

[0067] Example 4 Two clinically relevant doses (approximately 1 gram) were dispensed from the beginning, middle and end of the canister as detailed in Example 2. The amount of foam dispensed was quantified by completing differential weighing of the canister, and the assay results of the two separate foam extractions were averaged to yield the Beginning Average (B), Middle Average (M) or End Average (E) values ​​shown in Table 11. After each pair of clinically relevant actuations, approximately 15 grams of foam was dispensed into a glass container, tightly closed and stored for optional assay. These samples were labeled Beginning Retention (BR), Middle Retention (MR) and End Retention (ER). The six assay values ​​for Formulation 4 from Table 10 (representing the assay of the entire contents of the canister) are shown in Table 12.

[0068] [Table 12]

[0069] The data presented in Table 12 provides a dramatic example of how creaming of the foam concentrate emulsion inside the canister can cause a dramatic change in the dosage level of the active to the patient. From the development of roflumilast emulsion formulations, it is known that increasing the amount of DEGEE from 25% to 40% improves roflumilast solubility in the foam concentrate, but even increasing DEGEE above 35% destabilizes the emulsion. The assay pattern after assaying the canister in full (Table 12) shows that during actuation, the active is transferred to the portion of the emulsion containing roflumilast that is held within the canister. The data from Table 12 can be understood by following the assay steps. The product was shaken whole and a starting 1 gram sample was dispensed with an assay of 96.4%. The can was again shaken, expelling approximately 15 grams of foam into the jar in one actuation - causing globules of the roflumilast-rich, propellant-swollen, destabilized emulsion phase to separate (cream) and displace from the valve of the inverted canister. Creaming of the emulsion drives an extreme amount of roflumilast toward the interface between the emulsion and the liquid propellant, ensuring that the "start hold" has a very low assay value of 69.4%. The can was returned to room temperature, shaken and actuated briefly, and a 1 gram intermediate sample was removed and assayed at 99.0% of label. Again, due to the destabilized emulsion, roflumilast was prevented from being expelled from the canister during the "intermediate hold" expulsion (72.2% of label) and during the long actuations. With approximately two-thirds of the triphasic medicinal aerosol expelled at a low potency, the end actuation of 1 gram had the highest assay value of 131.3% of label. A final long actuation to produce an "end hold" assay value maintains the trend towards lower roflumilast assay values ​​(111.0% labeled) compared to the end sample (131.3% labeled). Depending on the time the canister is held in an inverted position after shaking, the physically unstable emulsion foam product can deliver 69% of the labeled dose or 131% of the labeled dose. Formulation 4 is not a commercially viable medicinal aerosol foam product.

[0070] Example 5 Hydrocarbon Blend Ratios The aesthetic appearance of the ARQ-154 foam formulations shown in Table 2 (64 gram concentrate) when delivered with 8 grams of either AP-48 or AP-70 propellant was compared. The AP-48 propellant is a 31:23:46 propane:isobutane:N-butane blend, while the AP-70 propellant is a 55:15:30 blend of propane:isobutane:N-butane. While both foams were found to be perfectly acceptable, the stiffer appearance and slightly slower breakage of the AP-48 propellant foam was preferred by approximately two-thirds of the individuals who tested the product. The other third of testers had no preference or only a slight preference for the more rapidly degrading AP-70 foam. It was concluded that both the AP-48 and AP-70 hydrocarbon blends exhibited good topical foam characteristics and excellent aesthetic appearance. By adjusting the ratio of the propane to isobutane:N-butane mixture, any pressure between 48 and 70 psig could be achieved. From an aesthetic standpoint, any ratio of hydrocarbon propellant blend of propane / isobutane / n-butane that provided pressures of about 48-70 psig at 70°F was shown to be acceptable.

[0071] Example 6. Formulations with various low water solubility APIs

[0072] [Table 13]

[0073] [Table 14]

[0074] [Table 15]

[0075] [Table 16]

[0076] [Table 17]

[0077] Example 7 Can Liner Compatibility Test Since the introduction of a hexane extraction step greatly reduced the variability in the assay results, samples of commercial can liners were filled with 0.3% foam concentrate and supplied with AP-70 propellant. Three different can sizes were compared to glass compatible bottles. Current Roflumilast Foam 60 gram cans were compared to larger Trivium cans (PPG-2845 and PPG-8900) filled with 275.2 grams of concentrate (equivalent to 64 grams of concentrate in the 60 gram can) and 34.4 grams of AP-70 propellant (equivalent to 8 grams of propellant in the 60 gram can) in a 53 mm x 235 mm can. The smaller Roflumilast Foam 10 gram sample cans were filled with 12.0 grams of concentrate and 2.3 grams of AP-70 propellant. The bulk concentrate was packaged and propellant was added. Cans were stored inverted and upright at ambient conditions. Bottles were gassed and shipped on the same day but stored upright and horizontal. The assay results for roflumilast, methylparaben and propylparaben are shown in Table 18.

[0078] [Table 18]

[0079] The variability of results and the lower than expected values ​​for the glass bottle samples make it difficult to determine the exact loss to the can liner. However, the trends in the data indicate that the epoxy phenolic liner is the best in terms of retaining close to the target roflumilast values, with MPE and BPA similar but slightly inferior to the epoxy phenolic liner, and the current PAM liner being the least compatible liner with the roflumilast foam product. From the data in Table 18, it appears that the epoxy phenolic liner is not compatible with the parabens, especially propylparaben. If this incompatibility between the preservatives and the epoxy phenolic can liner is confirmed, an excess of roflumilast may be required to compensate for the slight roflumilast loss from using the PAM can liner in the primary container for roflumilast foam.

[0080] Example 8 Roflumilast Foam Final Formulation Experiment To select the final roflumilast formulation for the production of the three primary stability batches, a matrix of four packaging / propellant combinations are stabilized and placed. The four configurations are: 1) cans with the current PAM liner fed with AP-70 propellant (Phase 2 IP), 2) cans with the current PAM liner fed with AP-48 propellant, 3) cans with an epoxy phenolic liner fed with AP-70 propellant, and 4) an epoxy phenolic can fed with AP-48 propellant. The product concentrate has the composition shown in Table 2 with IPP added to the active phase during processing. The target fill weight is 64.0 grams for the product concentrate and 8.0 grams for the propellant. Forty cans of each of the four configurations are filled, gassed, and stabilized. Three cans from each configuration are drawn each time and tested for assay, impurities, and preservatives.

[0081] Example 9 Storage Stability The following formulations were prepared and mixed with propellants AP-48 or AP-70 to determine whether stable foams were formed after storage under ambient conditions for 30 days or more.

[0082] [Table 19]

[0083] Example 10: Evaluation of Foam Quality Foams were prepared and evaluated using foam quality and foam expansion techniques. Five foam formulations containing poorly water soluble active pharmaceutical ingredients were prepared to determine if a suitable foam product was produced. The APIs included ivermectin, clobetasol proprionate, oxymetazoline free base, ketoconazole, and econazole nitrate. The product concentrate containing the API was mixed with NIP-70 propellant in a ratio of 88.9% product concentrate to 11.1% propellant. All five formulations resulted in foam products as shown in Figures 2-6. Foam quality was evaluated visually and by using foam density and foam expansion techniques.

[0084] Aerosol can components were prepared according to the table below.

[0085] [Table 20]

[0086] The sample variation tolerances were as follows:

[0087] [Table 21]

[0088] Example 11 Four formulations were tested for each of five different poorly water-soluble active agents, including ivermectin, clobetasol propionate, oxymetazoline, ketoconazole, and econazole nitrate.

[0089] Samples were prepared for each variable. Each can was filled with 64 g of product concentrate containing the API and then crimped. The cans were then pressurized with 8 g of NIP-70 propellant. The propellant was filled manually using a burette system followed by gravimetric analysis of the individual samples. A range of + / - 5% from the target weight was considered acceptable. No samples deviated from the target by more than 3%. The finished aerosol products used 75% of the specified can brim fill capacity. The finished cans were tested for leaks by immersion in a water bath at 55°C for 10 minutes. No leaks were detected during visual inspection of the submerged cans. The finished cans were shaken by hand for only 10 seconds and allowed to rest for at least 2 days to ensure complete mixing of the propellant with the product concentrate.

[0090] Visual analysis was used to study the samples to determine the presence or absence of foam after extrusion. Foam was defined as the visual presence of numerous air bubbles sharing a minimum of one liquid film wall that could be disrupted if agitated by an external force. Foam was visually analyzed immediately after extrusion and again 5 minutes after extrusion. Formulations 5-8, 10, 12-21, 23, and 24 were found to produce acceptable foams immediately after extrusion and 5 minutes after extrusion. Acceptable foams were smooth white or off-white foams with uniform air bubbles and were able to support their own weight. The foam half-life was greater than 60 seconds. The resulting foams are shown in Figures 2-6. All five APIs produced foams with all formulations tested. A wide range of foam structures was observed for the various formulations, indicating the range of foams that can be produced using the APIs tested. Foam structures can be optimized for specific indications.

[0091] [Table 22-1]

[0092] [Table 22-2]

Claims

1. 1. An aerosol foam comprising: an active pharmaceutical ingredient having a water solubility of less than 60 mg / L in an oil-in-water emulsion, cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate; and a propane / isobutane / butane propellant blend, wherein the active pharmaceutical ingredient having a water solubility of less than 60 mg / L is not roflumilast.

2. 10. The aerosol foam of claim 1, wherein the oil-in-water emulsion has a viscosity of 4,000 to 11,000 cP.

3. 10. The aerosol foam of claim 1, wherein the propellant and oil-in-water emulsion are in a ratio of about 1:8 to 1:

6.

4. 10. The aerosol foam of claim 1, which is released from the container but disintegrates after application to the skin of a subject.

5. 10. The aerosol foam of claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of ketoconazole, econazole nitrate, ivermectin, clobetasol propionate, calcipotriene, halobetasol propionate, tazarotene, oxymetazoline free base, and desonide.

6. 10. The aerosol foam of claim 1, further comprising at least one component selected from the group consisting of hexylene glycol and diethylene glycol monoethyl ether.

7. 7. The aerosol foam of claim 6, wherein the diethylene glycol monoethyl ether is in an amount of from 25% w / w to 35% w / w.

8. 7. The aerosol foam of claim 6, further comprising at least one additional ingredient selected from the group consisting of solvents, humectants, surfactants or emulsifiers, polymers or thickeners, preservatives, antioxidants, sequestering agents, stabilizers, buffers, pH adjusters, skin penetration enhancers, film formers, dyes, pigments, and fragrances.

9. 7. The aerosol foam of claim 6, further comprising an additional active agent selected from the group consisting of anthralin, azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarate esters, corticosteroids, corticotropin, vitamin D analogs, acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, bronchodialators, and antibiotics.

10. 10. The aerosol foam of claim 1, wherein the cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate are in the emulsifier blend in an amount of 2-4% by weight of the total composition.

11. 11. The aerosol foam of claim 10, wherein the emulsifier blend is in an amount of 2% by weight of the total composition.

12. 10. The aerosol foam of claim 1, further comprising water in an amount of 55 to 70% by weight of the total composition.

13. 10. The method of claim 1, wherein the active pharmaceutical ingredient is in an amount of 0.05 to 2% by weight of the total composition.

14. 10. The aerosol foam of claim 1, comprising the active pharmaceutical ingredient, white petrolatum, isopropyl palmitate, cetearyl alcohol, dicetyl phosphate, ceteareth-10 phosphate, hexylene glycol, diethylene glycol monoethyl ether, methylparaben, propylparaben, purified water, and a propane / isobutane / butane propellant blend.

15. 1. A pharmaceutical composition for use in a method for treating a patient having an inflammatory skin condition, the composition comprising: an active pharmaceutical ingredient having a water solubility of less than 60 mg / L in an oil-in-water emulsion, cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate; and an aerosol foam comprising a propane / isobutane / butane propellant blend, the composition being topically administered to a patient in need of treatment, wherein the active pharmaceutical ingredient having a water solubility of less than 60 mg / L is not roflumilast.

16. 16. The pharmaceutical composition of claim 15, wherein the aerosol foam further comprises hexylene glycol and / or diethylene glycol monoethyl ether.

17. 17. The pharmaceutical composition of claim 16, wherein the diethylene glycol monoethyl ether is in an amount of 25% w / w to 35% w / w.

18. 15. The pharmaceutical composition of claim 14, wherein the composition is administered once or twice per day.

19. 16. The pharmaceutical composition of claim 15, wherein the patient is suffering from a proliferative, inflammatory and / or allergic skin disease.

20. 20. The pharmaceutical composition of claim 19, wherein the proliferative, inflammatory and allergic skin disease is selected from the group consisting of psoriasis (vulgaris), eczema, acne, lichen simplex, lichen sclerosus, prurigo nodularis, actinic dermatitis, pruritus, alopecia areata, hypertrophic scar, discoid lupus erythematosus, and pyoderma.

21. 20. The pharmaceutical composition of claim 19, wherein the patient is suffering from an inflammatory skin disease.

22. 22. The pharmaceutical composition of claim 21, wherein the patient is suffering from atopic dermatitis.

23. 16. The pharmaceutical composition of claim 15, wherein the aerosol foam is free of hexylene glycol.

24. 1. A method for solubilizing an active pharmaceutical ingredient having a water solubility of less than 60 mg / l into an aerosol foam, comprising: combining an active pharmaceutical ingredient having a water solubility of less than 60 mg / l, cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate in an oil-in-water emulsion; combining the oil-in-water emulsion with a propane / isobutane / butane propellant blend to produce an aerosol foam; Including, The method, wherein the active pharmaceutical ingredient having a water solubility of less than 60 mg / l is not roflumilast.

25. 1. An aerosol foam comprising an active pharmaceutical ingredient having a water solubility of less than 60 mg / L in an oil-in-water emulsion, cetearyl alcohol, dicetyl phosphate, ceteareth-10 phosphate and diethylene glycol monoethyl ether, and a propane / isobutane / butane propellant blend, wherein the oil-in-water emulsion has a viscosity of 4,000 to 11,000 cP, the foam is free of hexylene glycol, the diethylene glycol monoethyl ether is in an amount of 25% w / w to 35% w / w, the aerosol foam is released from a container but disintegrates after application to the skin of a subject, and the aerosol foam has a foam half-life of greater than 60 seconds.

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