Topical Roflumilast Aerosol Foam

Abstract

The present invention is directed to an aerosol foam composition comprising roflumilast, an emulsifier blend containing 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 results in an aerosol foam that is stable, has consistent physical properties, has excellent aesthetics, and has no discernible degradation after extended periods or accelerated storage conditions.

Description

[Technical field]

[0001] The present invention is directed to an oil-in-water emulsion aerosol foam composition having an alkyl phosphate anionic surfactant or a blend of alkyl phosphate surfactants as an emulsifier.More specifically, the present invention relates to a medicamentously acceptable emulsion aerosol foam composition comprising roflumilast, water and oil, emulsified by a blend of cetearyl alcohol, dicetyl phosphate and ceteareth-10 phosphate (also known as ceteth-10 phosphate).The aerosol foam is dispensed using a propellant blend. [Background technology]

[0002] Foam formulations have been used as delivery systems for cosmetic and pharmaceutical applications for decades. Foams are preferred in some applications because they spread more easily and minimize friction. This is particularly advantageous when treating inflamed skin or skin areas that are covered with hair. Foam vehicles are preferred over ointments, gels, and creams because they are easier to apply, less sticky, and have a less greasy feel. Patient preference for foam vehicles may lead to improved patient compliance and therefore better treatment outcomes.

[0003] There are various types of foam formulations that can be used to deliver active ingredients, including aqueous, hydroalcoholic, emollient, solvent-based, petrolatum-based and oil-based foams.Different formulations have different properties, for example, emollient foams have soothing, moisturizing effects, and hydroalcoholic foams promote skin penetration and solubility of active agents.Foams can be made using propellant-free generation methods, such as AIRSPRAY® foam dispenser (a foam dispenser with 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.

[0004] Topical foams differ from ointments and creams in that the properties of the foam vehicle change. Prior to application, foam formulations are usually in the form of a suspension or emulsion. When an aerosol foam formulation is released from a container, the liquid propellant evaporates to produce a semi-solid foam formulation that is expanded with gas phase propellant. When a propellant-free generation method is used, air is pumped into the suspension or emulsion as the foam is expelled. The method used to generate the foam affects the appearance and stability of the foam.

[0005] Foams can be designed to have specific properties depending on factors such as the condition being treated, the body area being treated, and the active pharmaceutical components in the formulation. The foam vehicle should have suitable stability so as not to disintegrate after being released from the container; should have low shear sensitivity so that only minimal scrubbing is required; should be non-irritating, non-allergenic, and non-toxic; and should keep the active agent solubilized. Additionally, aerosol foam vehicles should contain propellants that have minimal or no impact on the atmospheric ozone layer. Foams applied to the face or upper front torso should have minimal odor, since the addition of fragrances to mask malodors is undesirable for pharmaceutical products. Foam structure is influenced by a variety of parameters, including the type and concentration of ingredients, the viscosity of the liquid phase, salt concentration, temperature and pH of the formulation.

[0006] Commercially viable three-phase pharmaceutical aerosols rely on surfactants that have limited solubility in both the internal oil phase and the external water phase. Upon shaking, the liquid hydrocarbon propellant mixes with the dispersed oil phase globules. The surfactants concentrate at the interface between the propellant / oil phase and the water phase to form a thin film called a "lamella". The specific composition of this lamella dictates the structural strength and general characteristics of the foam that is formed when the liquid propellant in the internal phase transitions to a gas immediately after the pharmaceutical emulsion leaves the pressurized environment of the aerosol canister. This liquid to gas phase transition results in the formation of a foam bubble. Thick, dense lamellar layers result in a highly structured foam that can support its own weight. This does not necessarily result in the formation of a stable foam. 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. These factors can be adjusted to produce stable foams with a variety of structures, including expandable, quick breaking, stiff, and stout foams.

[0007] 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) further degassing of the lower vapor pressure liquid hydrocarbon propellant, 2) mechanical pressure (squeezing) on ​​the foam during rubbing, and 3) general temperature increase of the foam to ambient (20-25°C) or skin temperature (32°C) following adiabatic cooling as the foam concentrate (70 psig) passes through the valve and becomes foam at ambient pressure. In the case of triple emulsion pharmaceutical foams stabilized by alkyl phosphate surfactants, when the lamellae are reduced to a single surfactant bilayer film, further expansion of the internal gas phase causes the foam cells to burst and release the formulation onto the skin surface.

[0008] Expandable and quick-disintegrating foams are characterized by a rapid expansion of the internal gas phase, rupturing lamellae and creating apparently larger foam cells. Expandable foams initially appear to "puff up" as the internal foam cells join, but as the foam cells on the surface collapse, the outflow of the formulation delivers the active to the skin application site.

[0009] In the case of hard and tough foams, a fully degassed internal phase brought to skin temperature does not create enough pressure to overcome the cohesive strength of the lamellae. The gas cells do not burst until additional rubbing pressure is applied. These more stable foams are ideal for application to the scalp, since the foam can be placed against a scalp lesion in a "part of hair" and then rubbed to break the foam and apply the active agent to the affected skin area with minimal loss of formulation to the hair.

[0010] For a three-phase pharmaceutical emulsion foam to be commercially acceptable, the liquid hydrocarbon propellant must be properly mixed with the internal oil phase of the emulsion so that a foam forms when the formulation is discharged from the canister. If the propellant does not mix properly, only a few foam cells will form as the liquid propellant transitions to gas, and most of the propellant will transition to gas outside the emulsion when actuated. Shaking and immediate actuation through the valve will result in the delivery of a non-uniform, very dense, unacceptable "sputtering" foam. Proper shaking and inverting the canister will result in the delivery of propellant that separates from the emulsion concentrate, so that the propellant is depleted from the canister before the entire amount of the formulation is expelled. This foam formulation is commercially unacceptable because the canister is never completely emptied. For example, if a formulation is labeled to deliver 60 grams of foam (a one-month supply), but the propellant is completely depleted after delivering 48 grams of foam, the patient will not receive the full prescribed treatment. Such foam canisters do not meet the minimum delivery mass requirements and are withdrawn from the market.

[0011] It is not always possible to form a stable foam. 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 added to the formulation that improves the solubility of the surfactant in the external aqueous phase will destabilize the emulsion, reduce the rigidity of the lamellae, and cause the foam bubbles to burst as soon as the liquid propellant transitions to gas. In other words, the fluid emulsion expelled from the canister does not form a topical foam that remains at the application site until rubbing breaks the lamellae and releases the drug formulation to the desired treatment site, but rather flows away quickly from the skin application site.

[0012] Diethylene glycol monoethyl ether (DEGEE), a cosmetic and pharmaceutical solvent, has been shown to be present in the aqueous continuous phase of emulsions during the emulsification process and to improve the solubility of surfactants and waxy components of the lamellae in the continuous aqueous phase (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 as the DEGEE concentration increases above 25% suggests that it is surprising to maintain lamellar lamellae thick and dense enough to produce stable foams in the presence of 25% or more DEGEE. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Hernandez,et al.,Journal of Dispersion Science and Technology,Investigating the effect of transcutol on the physical properties of an O / W cream,Vol41,No.4,pp600-606,2020 Summary of the Invention

[0014] Foam stability can be evaluated by determining foam half-life. Foam half-life is the time required for half the volume of the liquid continuous phase of a foam formulation to flow out. The shorter the half-life, the lower the foam stability. The desired foam half-life is based on the intended use of the foam. In certain foam applications where the foam is applied to a large area of ​​the body surface (e.g., self-tanning foams and sunscreen foams), the foam half-life is preferably less than 30 seconds to minimize application time. For the topical pharmaceutical foams of the present invention, a foam half-life of more than 30 seconds is desirable, and a foam half-life of more than 1 minute is preferred.

[0015] Aerosol foams have been found to provide stable foams suitable for topical application of active pharmaceutical ingredients (APIs). Aerosol foam formulations consist of two components: a formulation concentrate and a propellant. The formulation concentrate combines the active drug with additional components or co-solvents required to create a stable and effective formulation. The concentrate of a pharmaceutical aerosol formulation can be a solution, suspension, emulsion, semi-solid, or powder. Topical foam formulations usually have an emulsion formulation concentrate. The propellant provides the force to eject the formulation concentrate from the container and is also responsible for the delivery of the formulation as a foam. The propellant can also act as a solvent for the pharmaceutical actives or functional excipients that make up the formulation concentrate, reducing the need for additional solvents.

[0016] Propellant Propellants are used to create pressure within the container and expel the formulation concentrate from the container. Propellants are chemicals that have a vapor pressure greater than atmospheric pressure at 40°C (105°F). Pharmaceutical aerosols are generally made using propellants such as chlorofluorocarbons, fluorocarbons (trichloromonofluoromethane, dichlorodifluoromethane), hydrocarbons (propane, butane, isobutane), hydrochlorofluorocarbons and hydrofluorocarbons, and compressed gases (nitrogen, NO2, CO2).

[0017] Chlorofluorocarbon (CFC) propellants have been used for many years, but use of CFCs has been significantly reduced due to their depletion of the ozone layer. Hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs) may or may not contain chlorine and differ from CFCs in that they have one or more hydrogen atoms. HCFCs and HFCs decompose in the atmosphere at a faster rate than CFCs, so they have less impact on the ozone layer. HCFCs and HFCs are used in topical pharmaceuticals. HCFCs and HFCs are more miscible with water and therefore 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 and provide 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 the skin and / or nails and contains preservatives, buffers, water, ceteareth-10 phosphate, cetearyl alcohol and dicetyl phosphate. SALKERA® Emollient Foam is a keratolytic agent containing 6% salicylic acid USP incorporated into an aqueous-based emollient foam vehicle containing humectants, preservatives, buffering agents, water, ceteareth-10 phosphate, ceteareth-20 phosphate, cetostearyl alcohol, dicetyl phosphate and propylene glycol.

[0018] Hydrocarbon (HC) propellants are used in topical pharmaceutical aerosols because they have less environmental impact, are less toxic, and are non-reactive. HCs are also useful for making three-phase (two-layer) aerosols because their density is less than 1 and they are not miscible with water. The hydrocarbons remain on top of the aqueous layer, providing the force to push the contents out of the container. They do not contain halogens, and therefore no hydrolysis occurs, making them good propellants for aqueous aerosols. Unfortunately, hydrocarbon propellants are flammable and can explode. Flammability can be reduced by mixing the hydrocarbons with other liquefied gases. The liquid hydrocarbon propellants in the canister may not mix well with the internal oil phase of the oil-in-water emulsion, destabilizing the foam concentrate. This results in a lack of content uniformity for the dose emitted from the canister.

[0019] [Table 1]

[0020] 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, iso-butane, and n-butane are usually designated "AP" or "NIP" followed by a dash and a number which is the pressure in pounds per square inch for the particular propellant blend at 70° F. (as determined by a pressure gauge). For example, AP-48 propellant is a 31:23:46 propane:isobutane:butane blend that provides 48 psig in the can at 70° F., while AP-70 propellant is a 55:15:30 propane:isobutane:butane blend that provides 70 psig in the can at 70° F.

[0021] Inert compressed gas propellants expel the formulation concentrate in substantially 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 the pressure in the can drops as the formulation is used up. For pharmaceutical formulations, this constant pressure drop with each actuation can cause the first dose of active agent delivered from the canister to be significantly different from the last dose of active agent delivered. Also, when the compressed gas is depleted, any formulation remaining in the canister cannot be administered to the patient. For these reasons, compressed gas propellants are not typically used in pharmaceutical aerosols.

[0022] Formulation concentrate Aerosol foams are produced when an oil-in-water emulsion formulation concentrate is mixed with a propellant and the propellant is in the internal oil phase of the emulsion. When the propellant is in the external phase (i.e., as in a water-in-oil emulsion), no foam is produced, but splashes or wet flow occurs. Rapidly degrading foams create a foam when released from the container, but the foam disintegrates in a relatively short time. This type of foam is used to apply the formulation concentrate to a large area without rubbing or spreading the formulation by hand. Because the foam disintegrates quickly, the active drug is available more quickly. Stable foams are produced when using surfactants that have limited solubility in both the organic and aqueous phases. The surfactants concentrate at the interface between the propellant / oil phase and the aqueous phase to form a thin film called a "lamella". The specific composition of this lamella dictates the structural strength and general properties of the foam. Thick, dense, layered lamellae result in a highly structured foam that can support its own weight.

[0023] The emulsifiers or surfactants used to formulate the formulation concentrate and the use of alcohol in the formulation are two of the most important factors in topical pharmaceutical foams. Surfactants in emulsion aerosols can include fatty acids saponified with triethanolamine, anionic surfactants, and more recent examples include nonionic surfactants such as polyoxyethylene fatty esters, polyoxyethylene sorbitan esters, alkylphenoxyethanols, and alkanolamides. The first dermatological foams contained high levels of alcohol (about 60% ethanol) and used the nonionic surfactant polysorbate 60 and hydrocarbon propellants to create a fast-dissolving foam. Topical foams Olux® (clobetasol), Luxiq® (betamethacone), Lexette® (halobetasol), and Evoclin® (clindamycin) are high alcohol foams. Unfortunately, high alcohol foams have been found to sting and burn in some psoriasis patients, so the alcohol was removed from clobetasol foam and the polysorbate 60 was replaced with polyoxyl 20 cetostearyl ether to launch the first emollient topical pharmaceutical 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 foam lamellae. A recent advancement in topical pharmaceutical foam technology is Amzeeq® topical minocycline foam for the treatment of acne and rosacea. This formulation does not contain a solvent, but uses a blend of multiple natural oils to dissolve the minocycline, in combination with hydrogenated castor oil as a surfactant to form foam lamellae.

[0024] The present invention is directed to an aerosol foam composition comprising roflumilast. The aerosol foam composition is preferably an oil-in-water emulsion combined with a propellant. The propellant is a mixture of liquefied hydrocarbon gases, preferably a propane / isobutane / butane blend. The hydrocarbon propellant results in a roflumilast aerosol foam that is stable, has consistent physical properties, has excellent aesthetics, and has no discernible roflumilast degradation after long periods (storage at ambient temperature for more than 24 months) or accelerated storage conditions (storage at 40°C and 75% relative humidity for 6 months). Preferably, the roflumilast aerosol foam does not contain alcohol or propylene glycol. [Brief description of the drawings]

[0025] 1A-1E show acceptable and unacceptable forms. [Figure 1A] FIG. 1A shows acceptable foam structure for expanded foam immediately after dispensing and 5 minutes after dispensing. [Figure 1B] FIG. 1B shows acceptable foam structure for a fast collapsing foam immediately after dispense and 5 minutes after dispense. [Figure 1C] FIG. 1C shows acceptable foam structure for a rigid foam immediately after dispense and 5 minutes after dispense. [Figure 1D] FIG. 1D shows acceptable foam structure for a robust foam immediately after dispensing and 5 minutes after dispensing. [Figure 1E] FIG. 1E shows unacceptable foam where the propellant and concentrate did not mix properly, resulting in ejection during extrusion. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Topical application of potent pharmacologically active agents such as roflumilast for treating skin diseases has been found to provide superior delivery, lower systemic exposure, and better ease of use for patients. The molecular structure of the compound ultimately dictates the ability of the drug to cross the epithelium of the tissue to which the formulation is applied. In skin applications, the choice of the formulation's components dictates the maximum skin penetration the formulator can achieve. Creams, lotions, gels, ointments, aerosol foams, and solutions are just a few of the more familiar forms of topical roflumilast formulations, which often contain the active pharmaceutical ingredient (API) for skin application completely dissolved, as disclosed in U.S. Pat. No. 5,712,298 ("the '298 patent"), incorporated herein by reference (column 12, lines 37-64). For the treatment of such skin diseases, emulsions, suspensions, gels, or solutions of roflumilast for topical application have been described, but their application is limited due to the compound's low solubility.

[0027] The composition contains roflumilast, a salt of roflumilast, an N-oxide of roflumilast or a salt thereof, preferably in an amount of 0.005-2% w / w, more preferably 0.05-1% w / w, and most preferably 0.1-0.5% w / w per dosage unit. A 0.3% roflumilast cream (ARQ-151) formulation, an oil-in-water emulsion previously shown to be effective and well tolerated in the treatment of plaque psoriasis, was combined with a propellant. A roflumilast foam concentrate was formulated to produce a foam that does not disintegrate after release from the container, has low shear sensitivity so that only minimal scrubbing is required, is non-irritating, non-allergenic and non-toxic, and keeps roflumilast solubilized. Additionally, the roflumilast aerosol foam vehicle contains a propellant that has minimal or no impact on the atmospheric ozone layer. The ingredients in the roflumilast foam concentrate and propellant can be adjusted to produce foams with different properties, such as expandable foams, quick-degrading foams, hard foams and sturdy foams.Preferably, the formulation expressed from the canister is a smooth white or off-white foam with a uniform foam that can support its own weight until rubbing begins.As soon as rubbing begins, the foam breaks down quickly and spreads evenly throughout the application site.The formulation preferably has a foam half-life of more than 60 seconds.The amount of foam dispensed by the canister may or may not be metered to dispense a consistent amount of foam and a consistent dose of roflumilast.

[0028] Roflumilast aerosol foam includes 1-5%, preferably 2%, of an emulsifier containing an alkyl phosphate anionic surfactant or a blend of alkyl phosphate surfactants to ensure mixing with the propellant. Emollients are included in amounts that result in an aesthetically pleasing foam. Preferably, the emollients include 2-6%, preferably 5%, petrolatum; and 2-3%, preferably 2.5%, isopropyl palmitate.

[0029] The propellant provides the force to eject the formulation concentrate from the container and is also responsible for the delivery of the formulation as a foam. Roflumilast aerosol foam propellants are a mixture of liquefied hydrocarbon gases and therefore can also act as a solvent for roflumilast or can mix with the internal oil phase of the emulsion of the formulation concentrate. The use of a hydrocarbon propellant can reduce or eliminate the need for additional solvents such as hexylene glycol and DEGEE (diethylene glycol monoethyl ether). Hexylene glycol is preferably present in an amount of 0-20% w / w and DEGEE is preferably present in an amount of 10-35% w / w. The hydrocarbon propellant partially mixes with the roflumilast concentrate but primarily forms a separate liquid layer (less dense than the concentrate) inside the can. This is commonly referred to as a three-phase pharmaceutical aerosol. It is therefore necessary to shake the can to distribute the propellant evenly throughout the final formulation before the released foam is applied to the patient's skin.

[0030] The final composition of the 0.3% roflumilast foam is shown in Table 2. Roflumilast release foam formulations with this composition have consistent physical properties, have excellent aesthetics, no discernible roflumilast degradation after extended (over 24 months storage under ambient conditions) or accelerated storage (six months storage at 40°C and 75% relative humidity) conditions, and demonstrated acceptable but variable roflumilast assay results during development. A series of quality by design experiments focused on characterizing analytical methods for sample preparation, optimization of formulation concentrates, and packaging compatibility were completed. It was determined that variability in assay results could be minimized by inclusion of hexane extraction during sample preparation.

[0031] [Table 2]

[0032] Formulation concentrate The formulation concentrate in roflumilast foam consists of an oil-in-water emulsion of the active component roflumilast, i.e., about 90% water-miscible continuous phase, 7.5% oil phase (a blend of the moisturizers petrolatum and isopropyl palmitate), and 1-5%, preferably 2-4%, more preferably 2% of anionic surfactant-based emulsifying wax Crodafos CES or Crodafos CES-PA (PA indicates that the palm kernel oil starting material is from a sustainable source). These ingredients result in a rapidly degrading foam of roflumilast for the treatment of the scalp and face. Rapidly degrading foams are formulations that form a foam when released from the container, but the foam disintegrates in a relatively short time after application (rubbing) to the skin. This type of foam is used to apply the formulation concentrate to large areas without rubbing or spreading the formulation by hand. The active drug is available more quickly because the foam disintegrates rapidly, and the foam is more easily applied to skin areas with a high density of terminal hair, i.e., the scalp. A pH adjuster is added before emulsification to adjust the pH. The pH should not exceed the upper specification limit of pH=6 for the final formulation. Preferred pH adjusters include NaOH and HCl. Viscosity values ​​at various concentrations of Crodafos CES with 10% petrolatum and 5% IPP as the oil phase are shown in Table 3. Note that 10% Crodafos CES is in a roflumilast cream formulation and is not suitable for use in an aerosol foam as the foam was "squeezed" when released from the can. Squeezing (as shown in Figure 1E) indicates insufficient mixing of the liquid propellant and emulsion foam concentrate inside the canister. The preferred viscosity is 4000-11000 centipoise (cP). Viscosity was tested using a Brookfield viscometer, which determines viscosity by measuring the force to rotate a spindle in the sample at a given speed. A regular viscosity spring (RV) was used with a #14 spindle at 30 rpm and sample chamber 6R. However, any digital viscometer (DVE, DV1, DV2, or DV3) is suitable for determining the viscosity.The reading time was 2 min and the temperature was controlled at room temperature (CRT, 20-25°C).

[0033] [Table 3]

[0034] The favorable aesthetics of the roflumilast foam concentrate were obtained by halving the emollients (5% petrolatum instead of 10% and 2.5% isopropyl palmitate instead of 5.0%). Only two 2% Crodafos CES foam concentrate formulations were compared for the aesthetics of the roflumilast foam formulations. The foam concentrate with 15% of the combined moisturizers felt more "oily" during rubbing compared to the foam concentrate containing 7.5% of the combined moisturizers. Because the roflumilast foam formulations were formulated to treat seborrheic dermatitis skin on the scalp and face (both anatomical sites known to have oily skin prior to foam application), reducing the moisturizer content of the foam compared to the cream was considered to be an aesthetic advantage. To compensate for the removal of 15.5% of the emulsifiers / emollients, the amount of water in the foam was increased to just over 65% in the foam concentrate compared to approximately 50% water in the roflumilast cream. Three-month informal stability data for the 64 gram formulation concentrate blend (Table 2) gasified with 8 grams of AP-70 propellant are shown in Tables 4 and 5.

[0035] [Table 4]

[0036] [Table 5]

[0037] Propellant Hydrocarbon propellants have been found to produce roflumilast foams with desirable properties. They do not contain halogens and therefore do not undergo hydrolysis, making them good propellants for aqueous aerosols such as oil-in-water emulsions containing roflumilast. In addition to functioning as a propellant, hydrocarbon propellants can also function as solvents, potentially reducing the amount of additional solvent required to produce an effective and aesthetically acceptable foam. The particular hydrocarbon used and the ratio of propellant to emulsion affect the density and stability of the aerosol foam.

[0038] As a first development step in formulating an aesthetically acceptable roflumilast foam, seven different hydrocarbon propellants and one N-butane / dimethyl ether blend were screened along with the Crodafos CES emulsion concentrate. The seven 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, e.g., the ratio of isobutane to N-butane is fixed at 2 / 3), and Butane 48 (Butane 48 is a propane / isobutane / N-butane / isopentane in the ratio of 30.8 / 22.9 / 45.8 / 0.5). The hydrocarbon blend with dimethyl ether (DME) was 53% DME and 47% n-butane. The AP-70 propellant produced the best quality foam in the initial roflumilast foam propellant screening test. Table 1 (above) provides the properties of the three hydrocarbon propellants that are blended to create the aerosol propellant designated "AP."

[0039] The aesthetics of the ARQ-154 foam formulation (64 grams of concentrate) shown in Table 2 when gasified with 8 grams of either AP-48 or AP-70 propellants were compared. The AP-48 propellant is a 31:23:46 propane:isobutane:butane blend, while the AP-70 propellant is a 55:15:30 blend of the same hydrocarbons. Both foams were found to be fully acceptable, but approximately two-thirds of the formulation subjects preferred the more stable appearance and slightly slower breakdown of the AP-48 propellant foam. The remaining third of the subjects had no preference or 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 local foam properties and excellent aesthetics. By adjusting the propane to butane ratio, any pressure between 48 and 70 psig could be achieved. In terms of aesthetics, hydrocarbon propellant blends of any ratio of propane / isobutane / n-butane that provide pressures of about 48-70 psig at 70°F have been shown to be acceptable.

[0040] Roflumilast foam preparation Aerosol foams are produced when an oil-in-water emulsion formulation concentrate is mixed with a liquid hydrocarbon propellant, and the propellant is 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, and splashing or wet flow occurs. Stable foams are produced when surfactants with limited solubility in both the internal oil phase and the external aqueous phase 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". The specific composition of this lamella determines the structural strength and general properties of the foam. Thick, dense, layered lamellae result in a highly structured foam that can support its own weight. In a preferred embodiment, two alkyl phosphate surfactants are used that are not commonly used in topical foam formulations. These alkyl phosphate surfactants are present in the emulsifier Crodafos CES.

[0041] For all topical pharmaceutical foams, it is assumed that all the propellant is released from the formulation when the last lamella ruptures (the foam bubble breaks). The specific composition of the foam lamellae dictates the structural strength and general properties of the foam. The liquid crystal stabilized oil-in-water emulsion roflumilast concentrate has multiple Crodafos CES lamellae surrounding each oil droplet. The solvent DEGEE (diethylene glycol monoethyl ether) is miscible in both water and oil, and therefore likely separates between the oil and water phases and distributes in multiple lamellae at the emulsion interface. The concentrate is added to the can, the valve is crimped in place at the top of the can, and the propellant is added under pressure through the valve of the primary container closure system. In the can, a portion of the liquid propellant separates into the oil phase. When the can is shaken, the propellant immediately mixes with the oil droplets of the concentrate to form a milky emulsion in the can. As the propellant transitions from a pressurized liquid to a gas when released from the can, the volume of the liquid propellant present within the oil globules expands rapidly into hydrocarbon gas bubbles trapped within the foam lamellae. As the propellant expands, the multiple lamellae of the liquid droplets 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 roflumilast concentrate is released to the surface of the skin.

[0042] Different hydrocarbon blends can be used in the propellants to change the foam properties. For example, AP-70 propellant contains more propane to produce a higher pressure propellant foam, so the foam bubbles should be slightly larger. AP-70 propellant also expands the foam bubbles somewhat after the foam leaves the can, and should "break down" a little faster than the roflumilast foam with the lower pressure AP-48 propellant. The more stable appearance and slightly slower break down of the AP-48 propellant foam was preferred in a side-by-side comparison of vehicle foams gassed with either AP-48 or AP-70 propellants. Both AP-48 and AP-70 hydrocarbon blends show good local foam properties and good aesthetics.

[0043] The compositions according to the invention can be formulated with additional ingredients such as fillers, carriers and excipients typically found in topical cosmetic and pharmaceutical preparations. Additional ingredients such as, 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 to improve stability or aesthetics may be added to the compositions.

[0044] The compositions according to the invention can be formulated with additional active agents depending on the condition being treated. For example, when treating proliferative, inflammatory and allergic skin diseases, the additional active agents can include, but are not limited to, Anthralin (Dithranol), Azathioprine, Tacrolimus, Coal Tar, Methotrexate, Methoxsalen, Salicylic Acid, Ammonium Lactate, Urea, Hydroxyurea, 5-Fluorouracil, Propylthouracil, 6-Thioguanine, Sulfasalazine, Mycophenolate Mofetil, Fumarate Esters, Corticosteroids (e.g., Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone, Mometasone, Triamcinolone, etc.). , Fluocinolone, Fluocinonide, Flurandrenolide, Diflorasone, Desonide, Desoximetasone, Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate, Prednisone), corticotropin, Vitamin D analogs (e.g., Calcipotriene, Calcitriol), Acitretin, Tazarotene, Cyclosporine, Resorcinol, Colchicine, Adalimumab, Ustekinumab, Infliximab, Bronchodilators (e.g., Beta agonists, Anticholinergics, Theophylline), and Antibiotics (e.g., Erythromycin, Ciprofloxacin, Metronidazole).

[0045] Roflumilast can be encapsulated to control the release rate from the composition and protect it from degradation.Encapsulation can also be used to modify skin permeation.Methods for encapsulating active pharmaceutical ingredients are known in the art, and include, but are not limited to, encapsulation in liposomes, microparticles, nanoparticles, nanocarriers, nanospheres, microspheres, microcapsules, nanocapsules, nanosponges, and microsponges.

[0046] 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, more preferably, the composition is administered one to two times per day.

[0047] The composition can be used in veterinary and human medicine to treat and prevent all diseases that are considered treatable or preventable by using roflumilast, including but not limited to proliferative, inflammatory and allergic skin diseases; disorders based on excessive release of TNF and leukotrienes; eye disorders; arthritis disorders; and disorders that can be treated by the tissue relaxing effect of PDE inhibitors.Preferably, the composition is used to treat proliferative, inflammatory and allergic skin diseases such as psoriasis (vulgaris), eczema, acne, lichen simplex, lichen sclerosus, prurigo nodularis, sunburn, pruritus, alopecia areata, hypertrophic scar, discoid lupus erythematosus, and pyodermias.

[0048] 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 their invention. Additional advantages and modifications will be readily apparent to those skilled in the art. EXAMPLES

[0049] Example 1

[0050] [Table 6]

[0051] 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 6 [either Formulation 1 or Formulation 2] and the appearance of the released foam was recorded after gentle shaking of the canister. The target ratio was 62 grams of foam concentrate plus 5 grams of propellant. As seen in Table 7, the use of either N-butane or isobutane alone as the propellant, as well as a blend of propane and isobutane, resulted in aesthetically unacceptable drooling formulations. However, the propane / isobutane / N-butane blended propellant resulted in a smooth, white, uniformly released foam. The foam using the three hydrocarbon propellant blend initially supported its own weight but quickly collapsed during rubbing. The addition of isopentane to the propane / isobutane / N-butane propellant blend destabilized the released foam resulting in a formulation that appeared drooling.

[0052] 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 can be seen in Table 7, the addition of dimethyl ether to n-butane resulted in a formulation that appeared droopy upon dispensing, which did not meet appearance requirements.

[0053] 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 released formulation was a lumpy, gelatinous appearing material without air bubbles distributed in the liquid.

[0054] [Table 7]

[0055] Example 2 Determining the uniformity of dispersed content over the life of a canister The appearance of 64 grams of foam concentrate (Formulation 1 containing 0.15% roflumilast) was compared when gasified with 5, 6, 8, or 10 grams of AP-70 propellant. The appearance of the emitted foam for these four foam concentrate to propellant ratios was an indistinguishable smooth white foam formulation with small, uniformly sized bubbles.

[0056] Additional analytical testing was completed on Formulation 1 (containing 0.3% roflumilast) to determine the uniformity of dispersed roflumilast content throughout the canister's life. 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). The amount of foam dispensed was quantified by completing a can weight difference measurement, and the assay results of the two separate foam extracts were averaged to obtain the "beginning average" value. 15 grams of foam were dispensed and the canister was allowed to return to room temperature. The canister was shaken by hand an additional 5-6 times, after which two clinically relevant doses (approximately 1 gram) were dispensed from the middle of the canister. The assay results of the two separate foam extracts were averaged to obtain 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," "Mid-Average," and "Ending Average" for lot PGX-C containing 10 grams of AP-70 propellant to the lot containing 8 grams of AP-70 propellant are shown in Table 8.

[0057] USP <607> According to Pharmaceutical Foams-Product Quality Tests, uniformity of dispersed content throughout the canister life should not exceed 10%. This compendial method instructs dispensing the amount according to the labelled instructions and collecting separately the appropriate individually weighed amount of foam drug formulation. Sample size should not exceed the maximum dose recommended in the formulation's labelling for a single application. Labelled instructions for use will determine whether the can should be shaken before expelling the foam and the orientation (upright or inverted) when expelled. Portions of foam should be retained corresponding to: 1) the first portion from the filled canister, 2) a portion from the middle of the canister (in the range of 40%-60% of the labelled canister content), and 3) a portion corresponding to a canister content where 85% of the labelled content has been delivered. Canisters should be dispensed at room temperature. If the canister has become cold as a result of dispensing, it should be allowed to warm to room temperature before the next delivery. Using appropriate sample preparation (e.g., degassing) and analytical methods, the drug substance concentration in each of the three portions can be determined. None of the three results were outside the formulation assay range. The maximum difference in the amount of active component determined within the canister is 10.0% or less at the beginning, middle, and end.

[0058] As seen in Table 8, 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) which causes the swollen emulsion globules to rise (cream the emulsion) away from the inverted valve / actuator. Since the water insoluble actives are disproportionately present around the oil phase of the emulsion, repeating this process of shaking the canister and releasing the foam helps to concentrate the actives in the canister. O / W emulsions are formulated to be soluble in water at 100% water per ... <607> to the point where it exceeds the maximum difference limit (10% or less) specified for content uniformity over the life of the canister pursuant to, the aerosol foam drug formulation is no longer commercially viable. For a targeted 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 drug formulation was no longer acceptable for commercial drug use.

[0059] [Table 8]

[0060] Example 3 Effects of increasing concentrations of diethylene glycol monoethyl ether To determine the uniformity of the dispersed content over the life of the canister, the same USP <607> The Pharmaceutical Foams-Product Quality Tests were used to determine the effect of increasing concentrations of diethylene glycol monoethyl ether (Table 9).

[0061] [Table 9]

[0062] O / W emulsion is USP <607> If the emulsion is destabilized to the point where it exceeds the specified maximum difference limit (10% or less) for content uniformity over the life of the canister at 0.3%, the aerosol foam drug formulation is no longer commercially viable. For a targeted 64 gram charge of 0.3% roflumilast foam concentrate and 8 gram charge of AP-70 hydrocarbon propellant, the emulsion in the canister suddenly and unexpectedly destabilizes as the DEGEE concentration increases from 35% to 40% (Table 10). The emulsion of this foam drug formulation containing 40% DEGEE is not acceptable for commercialization of the drug product.

[0063] [Table 10]

[0064] Example 4 As detailed in Example 2, two clinically relevant doses (approximately 1 gram) were dispensed from the beginning, middle and end of the canister. The amount of foam dispensed was quantified by completing a weight difference measurement of the canister, and the assay results of the two separate foam extractions were averaged to obtain the Beginning Average (B), Middle Average (M) or End Average (E) values ​​shown in Table 10. After each clinically relevant pair of actuations, approximately 15 grams of foam was dispensed into a glass container, sealed and stored for assay as desired. These samples were labeled Beginning Retention (BR), Middle Retention (MR) and End Retention (ER). The six assay values ​​for Formulation 4 from Table 9 (representing the assay of the entire contents of the canister) are shown in Table 11.

[0065] [Table 11]

[0066] The data shown in Table 11 provides a dramatic example of how creaming of a foam concentrate emulsion in a canister can cause a dramatic change in the dosing level of the active to the patient. From the development of roflumilast emulsion formulations, it has been found that increasing the amount of DEGEE from 25% to 40% increases the solubility of roflumilast in the foam concentrate, but increasing DEGEE above 35% also causes emulsion destabilization. The assay pattern after assaying the entire canister (Table 11) shows that the active is migrating during actuation to the roflumilast-containing portion of the emulsion held in the canister. The data from Table 11 can be understood by explaining the assay step by step. After shaking the entire can of formulation and expelling the starting 1 gram sample, the assay value is 96.4%. The can is shaken again and approximately 15 grams of foam is dispensed into the jar in one actuation - the roflumilast-rich, propellant-swollen globules of the destabilized emulsion phase separate (cream) and migrate out of the valve of the inverted canister. Creaming of the emulsion drives a disproportionate amount of roflumilast toward the interface between the emulsion and the liquid propellant, confirming the "initial retention" having a very low assay value of 69.4%. The can is allowed to return to room temperature, shaken, and a 1 gram intermediate sample is taken from a short actuation which assays at 99.0% of label. Again, due to the destabilized emulsion, no roflumilast is dispensed from the canister during the long actuation during the "intermediate retention" dispense (72.2% of label). The terminal 1 gram actuation has the highest assay value of 131.3% of label, as approximately two-thirds of the three-phase medicinal aerosol is dispensed with low efficacy. A final long actuation to yield an "end hold" assay value maintains the trend of having a lower roflumilast assay value (111.0% label) compared to the terminal sample (131.3% label). Depending on the time the canister is held inverted after shaking, the physically unstable emulsion foam formulation was able to deliver either 69% of the labeled dose or 131% of the labeled dose. Formulation 4 is not suitable as a commercially viable medicinal aerosol foam formulation.

[0067] Example 5 Hydrocarbon Blend Ratios The aesthetics of the ARQ-154 foam formulation (64 grams of concentrate) shown in Table 2 when gasified with 8 grams of either AP-48 or AP-70 propellant were 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 propane:isobutane:N-butane blend. Both foams were found to be fully acceptable, but approximately two-thirds of the formulation subjects preferred the more stable appearance and slightly slower breakdown of the AP-48 propellant foam. The remaining third of the subjects had no preference or 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 local foam properties and excellent aesthetics. By adjusting the ratio of the propane and isobutane:N-butane mixtures, any pressure between 48 and 70 psig could be achieved. In terms of aesthetics, hydrocarbon propellant blends of any ratio of propane / isobutane / n-butane that provide pressures of about 48-70 psig at 70°F have been shown to be acceptable.

[0068] Example 6 Phase 2 Clinical Resupply of Roflumilast Foam - 4% Roflumilast Overdose Batch An analytical method used to quantify roflumilast in the foam drug formulation was developed and validated using unused roflumilast foam. When stability testing of the roflumilast foam drug formulation was completed, the roflumilast assay value was observed to decrease over time without a corresponding increase in known roflumilast degradation products or unknown chromatographic peaks. Further investigation confirmed that roflumilast does not degrade in the foam drug formulation, but rather that the original extraction conditions found to be suitable for unused foam drug formulation samples do not fully extract roflumilast from the aged foam drug formulation. A novel sample preparation method involving a hexane:acetonitrile extraction step was validated and used to characterize the 3-month stability for lots PGW-C and PGX-C (dual GMP batches of 0.3% roflumilast foam manufactured by DPT Laboratories, San Antonio, Texas).

[0069] The 200 kg bulk concentrates of lots PGW-C and PGX-C had 6 point sampling (top center, top edge 0°, top edge 180°, middle center, middle edge 0° and bottom). The assay data for the bulk concentrates is shown below in Table 12. The bulk concentrate is added to an aerosol can, the valve is crimped onto the can, propellant is added through the valve to the can, and finally the actuator / cap assembly is snapped into place.

[0070] In the first step of preparing the packaged foam drug formulation samples, all propellant is removed from the foam samples, a hexane:acetonitrile extraction is completed, and the roflumilast concentration is calculated in the foam formulation minus the propellant (same matrix as the bulk concentrate). As shown in Table 12 below, there is an average loss of 4% potency (% label) between the concentrate being added to the can (before the addition of propellant) and its removal from the can (for stability testing).

[0071] [Table 12]

[0072] A 525 kg GMP batch of roflumilast foam bulk concentrate containing a 4% roflumilast overage was manufactured. The lot number for this overage batch was RDS-C. Using a validated method (sample preparation included a hexane:acetonitrile extraction step), release results were 101.9% of label (0.3% roflumilast) for cans from the beginning of the packaging process, 100.1% of label for cans from the middle of the packaging process, and 100.1% of label for cans from the end of the packaging process. The apparent loss of assay value of roflumilast foam was corrected by adding a 4% roflumilast overage during compounding of the bulk concentrate. Example 7 Content Uniformity of Release Foam Dose Two clinically relevant doses (approximately 1 gram) were dispensed from the start of the can (first actuation after shaking the can by hand approximately 5 times). The amount of foam dispensed was quantified by completing a weight difference measurement of the can, and the assay results of the two separate foam extractions were averaged to obtain a "start average" value. Approximately 15 grams of foam was dispensed into a glass container, sealed, and stored as a "start hold" sample for assay at a later date if desired. This series of sampling was repeated to obtain "middle average" and "end average" data. After the two clinically relevant doses had been dispensed from the end of the can, all remaining foam was dispensed from the can to obtain an "end hold" sample. The assay results of these six dispensed doses are shown in Table 13. All dispensed foam doses were within specification, and the low assay results (3.5% to 4.9% assay loss) using the "whole can" assay for Lot PGX-C (Table 12) were only seen in this content uniformity study for foam doses dispensed from actuations from the start of the can. The high RSD values ​​for the content uniformity results, combined with the smaller percent assay losses, facilitated the experimental design to test modifications of the addition order, composition, and propellant of the roflumilast foam used in the Phase 2 clinical trial.

[0073] [Table 13]

[0074] The process modification batches were 1720-0204R01 ('204 batch) and 1720-0206R01 ('206 batch). In the '204 batch, the active phase (DEGEE, parabens and roflumilast) was blended into the oil phase prior to emulsification. In the '206 batch, the emollient isopropyl palmitate was not added to the Crodafos CES and petrolatum oil phase, but rather was retained and dissolved in the DEGEE in the active phase, which was added to the batch after emulsification. Both of these "order of addition" process modifications for the formulation concentrate were gassed with AP-70 propellant. As shown in Table 14, combining the oil and active phases prior to emulsification resulted in dramatically lower out-of-specification assay values, with an RSD of 6.2%. This is in contrast to batch '206 (IPP added to the active phase) which gave assay values ​​in the range of 96-100% with an RSD of 2.1%. The addition of IPP to the active substance phase was a process change made to the Roflumilast Foam Phase 3 test substance.

[0075] Four formulation changes were made, increasing hexylene glycol to 4% (DPT Lot 1720-0205R01), increasing IPP to 5% (DPT Lot 1720-0213R01), increasing DEGEE to 35% (DPT Lot 1720-0123R01), and increasing DEGEE to 40% (DPT Lot 1720-0211R01). Increasing DEGEE to 35% had higher mean assay values ​​and lower %RSD when gassed with AP-70, but increasing DEGEE to 40% resulted in a very inhomogeneous release foam. Results from the '123 and '211 batches showed that the addition of excess DEGEE (35%-40%) caused abrupt formulation failure.

[0076] Samples of the formulation concentrate having the composition in Table 2 were gasified with AP-48 and AP-31 (isobutane only) propellants. Both low pressure propellants had low assay values ​​consistent with the PGX-C whole can assay results, but AP-31 had an RSD of 1.4% and AP-48 had an RSD of 0.6%. Due to the appearance of the '123 batches using only DME as the propellant, and known incompatibility of DME with aerosol filling equipment, DME is no longer being considered as a propellant for roflumilast foam formulations.

[0077] As described above, the aesthetics of roflumilast foams gassed with 8 grams of either AP-48 or AP-70 propellant were compared. Both foams were found to be completely acceptable, with approximately two-thirds of subjects in each formulation preferring the more stable appearance and slightly slower breakdown of the AP-48 propellant foam. The remaining one-third of subjects had no preference or a slight preference for the more rapidly degrading AP-70 foam.

[0078] [Table 14]

[0079] Two clinically relevant doses (approximately 1 gram) were dispensed from the beginning, middle and end of the can. The amount of foam dispensed was quantified by completing a weight difference measurement of the can and the assay results of the two separate foam extractions were averaged to obtain the beginning average (B), middle average (M) or end average (E) values ​​shown in Table 14. After each clinically relevant pair of actuations, approximately 15 grams of foam was dispensed into a glass container, sealed and stored for optional assay. These samples were labeled as beginning retention (BR), middle retention (MR) and end retention (ER). Can 1 (clinical lot PGX-C) from Table 13 and batches '205, '206, '528 with AP-48, and '211 from Table 14 were selected for assay of these optional retention samples. Note that by assaying the retention samples the entire can of roflumilast foam is assayed. The results of these five lots of roflumilast foam are shown in Table 15.

[0080] [Table 15]

[0081] Example 8 Can Liner Compatibility Test Since the introduction of a hexane extraction step significantly reduced the variability of the assay results, a sampling of commercial can liners were filled with 0.3% foam concentrate and gasified with AP-70 propellant. Three different can sizes were compared to glass compatible bottles. A current 60 g can of Roflumilast Foam was compared to the larger Trivium cans (PPG-2845 and PPG-8900), which are 53 mm x 235 mm cans filled with 275.2 g of concentrate (equivalent to 64 g of concentrate for the 60 g can) and 34.4 g of AP-70 propellant (equivalent to 8 g of propellant for the 60 g can). The smaller 10 g sample cans of Roflumilast Foam were filled with 12.0 g of concentrate and 2.3 g of AP-70 propellant. The bulk concentrate was packaged and propellant was added. The cans were stored inverted and upright at ambient conditions. The 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 16.

[0082] [Table 16]

[0083] [Table 17]

[0084] It is difficult to determine the exact loss to the can liner due to the variability in results and the lower than expected values ​​for the glass bottle samples. However, the trends in the data indicate that the epoxy phenolic liner is the best in terms of retaining roflumilast values ​​close to the target, with MPE and BPA being similar but slightly inferior to the epoxy phenolic liner, and the current PAM liner being the least compatible liner for the roflumilast foam formulation. From the data in Table 16, it appears that the epoxy phenolic liner may not be compatible with parabens, especially propylparaben. If this incompatibility between the preservative and the epoxy phenolic can liner is confirmed, an excess of roflumilast may be required to compensate for the slight roflumilast loss due to the use of the PAM can liner in the primary container for roflumilast foam. Example 9 Roflumilast foam final blending experiment A matrix of four packaging / propellant combinations are placed on stable conditions to select the final roflumilast formulation for manufacturing of three major stability batches. The four configurations are: 1) current PAM lined cans gassed with AP-70 propellant (Phase 2 IP), 2) current PAM lined cans gassed with AP-48 propellant, 3) epoxy phenolic lined cans gassed with AP-70 propellant, and 4) epoxy phenolic cans gassed with AP-48 propellant. The formulation concentrate has the composition shown in Table 2, with IPP added to the active phase during processing. The target fill weights are 64.0 grams for the formulation concentrate and 8.0 grams for the propellant. Forty (40) cans of each of the four configurations are filled, gassed, and placed on stable conditions. Three (3) cans from each configuration are pulled each time and tested for assay, impurities, and preservatives. Example 10 Storage stability The following formulations were prepared and mixed with propellants AP-48 or AP-70 to determine whether stable foams would form after greater than 30 days of storage under ambient conditions.

[0085] [Table 18]

[0086] Example 11 Evaluation of Foam Quality Foams were prepared and evaluated using foam quality and foam expansion techniques. Foam concentrate roflumilast formulations included formulations with and without hexylene glycol as shown below.

[0087] [Table 19]

[0088] The aerosol can components were prepared according to the table below.

[0089] [Table 20]

[0090] The variable tolerances for the samples were as follows:

[0091] [Table 21]

[0092] N=3 samples were prepared for each variable. Each can was filled with 64 g of intermediate containing roflumilast and subsequently crimped. The cans were then pressurized with 8 g of NIP-70 propellant. The propellant was manually filled 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 formulation utilized 75% of the specified can brim fill capacity. The finished cans were tested for leaks by immersion in a 55°C water bath for 10 minutes. No leaks were detected during visual inspection of the immersed cans. The finished cans were shaken by hand for no more than 10 seconds and allowed to stand for at least 2 days to ensure complete mixing of the propellant and foam concentrate.

[0093] The samples were tested using visual analysis to determine the presence or absence of foam after dispensing. Foam was defined as the visual presence of multiple bubbles sharing a minimum of one liquid film wall that could be disrupted when agitated by an external force. Visual analysis of foam was performed immediately after dispensing and also 5 minutes after dispensing. Both Formulation 5 and Formulation 8 were found to produce acceptable foams immediately after dispensing and 5 minutes after dispensing. The foams were smooth white or off-white with uniform bubbles and were capable of supporting their own weight. The foam half-life was greater than 60 seconds. The absence of hexylene glycol did not affect the acceptability of the foam.

Claims

1. 1. An aerosol foam comprising roflumilast, cetearyl alcohol, dicetyl phosphate, ceteareth-10 phosphate in an oil-in-water emulsion and a propane / isobutane / butane propellant blend, wherein the oil-in-water emulsion has a viscosity of 4000 to 11000 cP, the propellant and oil-in-water emulsion are in a ratio of about 1:8 to 1:6, and the aerosol foam is released from a container but disintegrates after application to the skin of a subject.

2. 1. An aerosol foam comprising an oil-in-water emulsion and a propane / isobutane / butane propellant blend, the oil-in-water emulsion consisting of: Roflumilast 0.3% w / w White petrolatum 5.0% w / w Isopropyl palmitate 2.5% w / w Emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate 2.0% w / w Hexylene glycol 2.0% w / w Diethylene glycol monoethyl ether 25.0% w / w Methylparaben 0.2% w / w Propylparaben 0.05% w / w pH adjuster (appropriate amount to pH 5.5) Purified water, add enough to bring the volume up to 100ml.

3. 1. An aerosol foam comprising an oil-in-water emulsion and a propane / isobutane / butane propellant blend, the oil-in-water emulsion consisting of: Roflumilast 0.3% w / w White petrolatum 5.0% w / w Isopropyl palmitate 2.5% w / w Emulsifier blend comprising cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate 2.0% w / w Diethylene glycol monoethyl ether 25.0% w / w Methylparaben 0.2% w / w Propylparaben 0.05% w / w pH adjuster (appropriate amount to pH 5.5) Purified water, add enough to bring the volume up to 100ml.

4. 10. The aerosol foam of claim 1, further comprising hexylene glycol in an amount from 0% w / w to 4.00% w / w and / or diethylene glycol monoethyl ether in an amount from 25% w / w to 35% w / w.

5. 5. The aerosol foam of claim 4, wherein the hexylene glycol is in an amount of from 2.00% w / w to 4.00% w / w and / or the diethylene glycol monoethyl ether is in an amount of from 25% w / w to 35% w / w.

6. 10. The aerosol foam of claim 1, 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 adjuster solutions, skin penetration enhancers, film formers, dyes, pigments, and fragrances.

7. 10. The aerosol foam of claim 1, 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, bronchodilators, and antibiotics.

8. 10. The aerosol foam of claim 1, wherein the roflumilast is present in an amount of 0.05 to 2% by weight of the total composition.

9. 2. The aerosol foam of claim 1, wherein said propane / isobutane / butane propellant blend is AP-70.

10. 1. A pharmaceutical composition for use in a method of inhibiting phosphodiesterase 4 in a patient, the method comprising topically administering the pharmaceutical composition to a patient in need thereof, the pharmaceutical composition comprising an aerosol foam comprising roflumilast, cetearyl alcohol, dicetyl phosphate, ceteareth-10 phosphate in an oil-in-water emulsion and a propane / isobutane / butane propellant blend, the oil-in-water emulsion having a viscosity of 4000-11000 cP, the propellant and oil-in-water emulsion being in a ratio of about 1:8 to 1:6, and the aerosol foam being released from a container but disintegrating after application to the patient's skin.

11. The pharmaceutical composition of claim 10, wherein the patient is suffering from a proliferative, inflammatory and / or allergic skin disease.

12. 12. The pharmaceutical composition of claim 11, 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, sunburn, pruritus, alopecia areata, hypertrophic scar, discoid lupus erythematosus, and pyoderma.

13. The pharmaceutical composition of claim 11, wherein the patient is suffering from inflammatory dermatitis.

14. The pharmaceutical composition of claim 13, wherein the patient is suffering from atopic dermatitis.

15. 11. The pharmaceutical composition of claim 10, wherein the aerosol foam further comprises at least one component selected from the group consisting of hexylene glycol and diethylene glycol monoethyl ether.

16. 14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is administered one or more times daily.

17. 17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is administered once or twice daily.

18. 11. The pharmaceutical composition of claim 10, wherein the aerosol foam is free of hexylene glycol.

19. 11. The pharmaceutical composition of claim 10, wherein the aerosol foam further comprises diethylene glycol monoethyl ether in an amount of 25% to 35% w / w.

20. 1. An aerosol foam comprising roflumilast, cetearyl alcohol, dicetyl phosphate, ceteareth-10 phosphate and diethylene glycol monoethyl ether in an oil-in-water emulsion and a propane / isobutane / butane propellant blend, wherein the oil-in-water emulsion has a viscosity of 4000 to 11000 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, and the aerosol foam has a foam half-life of 30 seconds or greater.

21. 21. The aerosol foam of claim 20, wherein the aerosol foam has a half-life of 5 minutes or greater.

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