US20200155524A1 | 2020-05-21 | |||
EP1409022A1 | 2004-04-21 | |||
US20210161870A1 | 2021-06-03 | |||
US5712298A | 1998-01-27 |
Claims 1. An aerosol foam comprising an active pharmaceutical ingredient with water solubility below 60 mg/l, cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate in an oil in water emulsion; and a propane/isobutane/butane propellant blend, wherein said active pharmaceutical ingredient with water solubility below 60 mg/l is not roflumilast. 2. The aerosol foam according to claim 1, wherein said oil in water emulsion has a viscosity of 4,000-11,000 cP. 3. The aerosol foam according to claim 1, wherein said propellant and oil in water emulsion are in a ratio of about 1:8 to 1:6. 4. The aerosol foam according to claim 1, wherein said aerosol foam is emitted from a container but collapses after application to a subject’s skin. 5. The aerosol foam according to claim 1, wherein said 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. The aerosol foam according to claim 1, further comprising at least one component selected from the group consisting of hexylene glycol and diethylene glycol monoethyl ether. 7. The aerosol foam according to claim 6, wherein said diethylene glycol monoethyl ether is in an amount of 25% w/w to 35% w/w. 8. The aerosol foam according to claim 6, further comprising at least one additional component selected from the group consisting of a solvent, moisturizer, surfactant or emulsifier, polymer or thickener, preservative, antioxidant, sequestering agent, stabilizer, buffer, pH adjusting solution, skin penetration enhancer, film former, dye, pigment, and fragrance. 9. The aerosol foam according to 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, fumaric acid esters, corticosteroids, corticotropin, vitamin D analogues, acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, bronchodialators, and antibiotics. 10. The aerosol foam according to claim 1, wherein said cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate are in an emulsifier blend in an amount of 2 to 4% by weight of the total composition. 11. The aerosol foam according to claim 10, wherein said emulsifier blend is in an amount of 2% by weight of the total composition. 12. The aerosol foam according to claim 1, further comprising water in an amount of 55 to 70% by weight of the total composition. 13. The method according to claim 1, wherein said active pharmaceutical ingredient is in an amount of 0.05 to 2% by weight of the total composition. 14. The aerosol foam according to claim 1, wherein said aerosol foam comprises said 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. A method for treating a patient with an inflammatory skin condition, comprising topically administering an aerosol foam comprising an active pharmaceutical ingredient with water solubility below 60 mg/l, cetearyl alcohol, dicetyl phosphate, and ceteareth- 10 phosphate in an oil in water emulsion; and a propane/isobutane/butane propellant blend to a patient in need thereof, wherein said active pharmaceutical ingredient with water solubility below 60 mg/l is not roflumilast. 16. The method according to claim 14, wherein said aerosol foam further comprises hexylene glycol and/or diethylene glycol monoethyl ether. 17. The method according to claim 16, wherein said diethylene glycol monoethyl ether is in an amount of 25% w/w to 35% w/w. 18. The method according to claim 14, wherein said composition is administered 1-2 times per day. 19. The method according to claim 15, wherein said patient is suffering from a proliferative, inflammatory and/or allergic dermatoses. 20. The method according to claim 19, wherein said proliferative, inflammatory and allergic dermatoses is selected from the group consisting of psoriasis (vulgaris), eczema, acne, Lichen simplex, Lichen sclerosus, Prurigo nodularis, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, and pyodermias. 21. The method according to claim 19, wherein said patient is suffering from an inflammatory dermatoses. 22. The method according to claim 21, wherein said patient is suffering from atopic dermatitis. 23. The method according to claim 15, wherein said aerosol foam does not include hexylene glycol. 24. A method for solubilizing an active pharmaceutical ingredient with a water solubility below 60 mg/l in an aerosol foam, comprising combining an active pharmaceutical ingredient with a water solubility below 60 mg/l, cetearyl alcohol, dicetyl phosphate, and ceteareth-10 phosphate in an oil in water emulsion, and combining the oil in water emulsion with a propane/isobutane/butane propellant blend to produce an aerosol foam, wherein said active pharmaceutical ingredient with water solubility below 60 mg/l is not roflumilast. 25. An aerosol foam comprising an active pharmaceutical ingredient with water solubility below 60 mg/l, 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 said oil in water emulsion has a viscosity of 4,000-11,000 cP, wherein said foam does not include hexylene glycol, wherein said diethylene glycol monoethyl ether is in an amount of 25% w/w to 35% w/w, wherein said aerosol foam is emitted from a container but collapses after application to a subject’s skin, and wherein said aerosol foam has a foam half-life of more than 60 seconds. |
* 8-10 grams of propellant is added to 64 grams (target) of the emulsion concentrate to deliver a minimum 60 grams of foam product Preferred viscosities are between 4000-11,000 centipoise (cP). The viscosity was tested using a Brookfield Viscometer which determines the viscosity by measuring the force to turn the spindle in the sample at a given rate. 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 for determining viscosity. The time to read was 2 minutes and the temperature was controlled room temperature (CRT, 20- 25°C). Table 3. Viscosity values for varying levels of Crodafos CES in the 2% Crodafos CES TM formulation of 0.3% roflumilast formulation shown in Table 2 The emitted foam product containing a low water soluble active has consistent physical properties, excellent aesthetics, acceptable assay results and no harmful quantities of degradation products after long term (storage under ambient conditions for 3 or more months) or accelerated storage conditions (storage at 40°C and 75% relative humidity for 3 to 6 months). Typical data generated for a low water soluble active is given in Table 4 (long-term stability storage) and Table 5 (accelerated stability storage) for the 2% Crodafos CES TM formulation of 0.3% roflumilast formulation described in Table 2. The preferred aesthetics of the foam concentrate was optimized by reducing the emollients by half (5% rather than 10% for petrolatum and 2.5% rather than 5.0% for isopropyl palmitate). Only two 2% Crodafos CES™ foam concentrate formulations were compared to optimize the aesthetics of the foam formulation. The foam concentrate having 15% combined moisturizers felt “oily” during rub-in compared to the foamed concentrate containing 7.5% combined moisturizers. Since the foam product was formulated to treat the scalp and facial seborrheic dermatitis skin (both anatomical sites known to have oily skin prior to foam application), it was considered an aesthetic advantage to reduce the moisturizer content of the foam compared to the cream. To compensate for the removal of 15.5% of the emulsifier/emollients, the amount of water in the foam is increased to just over 65% in the foam concentrate compared to ~50% water in the roflumilast cream. Three months of informal stability data for 64 grams product concentrate formulation (Table 2) gassed with 8 grams of AP-70 propellant is shown in Tables 4 and 5. Table 4. Stability Data for the 2% Crodafos CES TM formulation of 0.3% roflumilast formulation stored at 25°C Inverted ^ Assay % label claim results are the average value of n = 9 replicates for each test and timepoint, normalized against the bulk formulation concentrate. * Description: White, opaque, foam with small, compact bubbles. Foam is not runny. **(Average Delivery Rate grams/second): Method: USP 603 Table 5. Stability Data for the 2% Crodafos CES TM formulation of 0.3% roflumilast formulation stored at 40°C Inverted NT = Not Tested ^ Assay % label claim results are the average value of n = 9 replicates for each test and timepoint, normalized against the bulk formulation concentrate. * Description: White, opaque, foam with small, compact bubbles. Foam is not runny. **(Average Delivery Rate grams/second): Method: USP 603 Propellants A hydrocarbon propellant has been found to result in a topical foam with the desired properties. They contain no halogens and therefore hydrolysis does not occur making these good propellants for water-based aerosols such as an oil in water emulsion comprising low water soluble APIs. Six different hydrocarbon propellants, one N-Butane/dimethyl ether blend and one hydrofluorocarbon propellant were screened with the 2% Crodafos CES TM formulation of 0.3% roflumilast formulation described 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 having 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 30.8/22.9/45.8/0.5 ratio of Propane/Isobutane/N-Butane/Isopentane). The hydrocarbon blend with dimethyl ether (DME) was 53% DME and 47% N-Butane. The hydrofluorocarbon propellant was 1,1,1,2-tetrafluoroethane (HFA 134a). The AP-70 propellant produced the best quality foam in the initial foam propellant screening study. HFA-134a (1,1,1,2- tetrafluoroethane), the 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 that did not comprise gas bubbles distributed in a liquid. Table 1 provides the properties of the three hydrocarbon propellants that are blended to create the “AP” or “NIP” designated aerosol propellants and Table 6 lists the appearance of aerosolize topical foam products. Table 6. Foam appearance for the 2% Crodafos CES TM formulation containing 0.3% roflumilast combined with different commercially available propellants
The aesthetics of the foam formulation shown in Table 2 (64 grams concentrate that contained 2% Crodafos CESTM formulation of 0.3% roflumilast) when gassed with 8 grams of either AP-48 or AP-70 propellant were compared. The AP-48 propellant is a 31:23:46 Propane:Isobutane:Butane blend while AP-70 propellant is a 55:15:30 blend of the same hydrocarbons. While both foams were found completely acceptable, the firmer appearance and slightly slower breaking of the AP-48 propellant foam was preferred by about two-thirds of the individuals testing the products. The other third of the testers had either no preference or a slight preference for the quicker breaking AP-70 foam. It was concluded that both the AP-48 and AP-70 hydrocarbon blends show good topical foam characteristics and excellent aesthetics. By adjusting the ratio of propane to the butanes, any pressure between 48 and 70 psig can be achieved. In terms of aesthetics, any ratio of the hydrocarbon propellant blend of Propane/Isobutane/N-Butane that gives a pressure around 48-70 psig at 70°F has been shown acceptable. The Foam Product An aerosol foam is produced when the oil in water emulsion product concentrate is mixed with the liquid hydrocarbon propellant and the propellant is in the internal oil phase. If the propellant is in the external phase (i.e., like a water-in-oil emulsion), foams are not created but sprays or wet streams result. Stable foams are produced when surfactants are used that have limited solubility in both the internal oil and external aqueous phases. Surfactants concentrate at the interface between the propellant/oil phase and the aqueous phase to form a thin film referred to as the "lamella." It is the specific composition of this lamella that dictates the structural strength and general characteristics of the foam. Thick and tightly layered lamellae produce very structured foams which can support their own weight. In a preferred embodiment, two alkyl phosphate surfactants are used which are not commonly used in a topical foam product. These alkyl phosphate surfactants are in the emulsifier Crodafos CES™. For all topical pharmaceutical foams, it is assumed that all propellant is released from the formulation when the last lamella ruptures (foam bubble breaks). The specific composition of the foam lamella dictates the structural strength and general characteristics of the foam. The liquid crystal stabilized oil-in-water emulsion low water soluble API concentrate has multiple Crodafos CES lamella surrounding each oil droplet. The solvent DEGEE (diethylene glycol monoethyl ether) is both water and oil miscible, thus it is likely partitioned between the oil and water phases and distributed within the multiple lamella at the interface of the emulsion. The concentrate is added to the can, the valve crimped into place on the top of the can and the propellant added under pressure through the valve of the primary container closure system. Within 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 white, emulsion in the can. As the propellant transitions from a liquid under pressure to a gas when emitted from the can, the volume of liquid propellant resident within the oil globule rapidly expands to become the hydrocarbon gas bubble trapped within the lamella of the foam. As the propellant expands, the multiple lamella of the droplet quickly becomes the single lamella of the foam. Once the pressure associated with the volume of gaseous propellant exceeds the strength of the surfactant lamella, the foam cell breaks and API concentrate drains to the surface of the skin. Different hydrocarbon blends can be used in the propellant to change the properties of the foam. For example, the AP-70 propellant contains more propane to produce a higher-pressure propellant bubble, and thus should make slightly larger foam bubbles. The AP-70 propellant should also cause the foam bubbles to expand somewhat after the foam comes out of the can and be a little “faster breaking” than a foam having the lower pressure AP-48 as the propellant. The firmer appearance and slightly slower breaking of the AP-48 propellant foam was preferred in a side-by-side comparison of vehicle foams gassed with either the AP-48 or AP-70 propellants. Both the AP-48 and AP-70 hydrocarbon blends show good topical foam characteristics and excellent aesthetics. Compositions according to the present invention may be formulated with additional components such as fillers, carriers and excipients conventionally found in cosmetic and pharmaceutical topical products. Additional components including but not limited to preservatives (e.g. p-hydroxybenzoic esters, benzyl alcohol, phenylmercury salts, chlorocresol), antioxidants, sequestering agents, stabilizers, buffers, pH adjusting solutions, skin penetration enhancers, film formers, dyes, pigments, diluents, bulking agents, fragrances and other excipients to improve the stability or aesthetics, may be added to the composition. The low water soluble active pharmaceutical ingredient can be selected from the group of actives with water solubility below 60 mg/liter. This group of actives includes but is not limited to ketoconazole, econazole nitrate, ivermectin, clobetasol propionate, calcipotriene, halobetasol propionate, tazarotene, oxymetazoline free base and desonide. Table 7 Water Solubility Data: *ALOGPS calculated value Compositions according to the present invention may be formulated with active agents in addition to the low water soluble active pharmaceutical ingredient depending on the condition being treated. The additional active agents include but are not limited to 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, Desonide, Desoximetasone, Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate, Prednisone), Corticotropin, Vitamin D analogues (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). The pharmaceutically active agent which has low solubility in water can be encapsulated to control the release rate from the composition and to 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 and include but are not limited to encapsulation in liposomes, microparticles, nanoparticles, nanocarriers, nanospheres, microspheres, microcapsules, nanocapsules, nanosponges, and microsponges. The foam composition can be administered on a schedule appropriate for the condition being treated, preferably the foam composition is administered one or more times per day, more preferably the composition is administered 1-2 times per day. The composition can be used in veterinary and in human medicine for the treatment and prevention of all diseases regarded as treatable or preventable by using a low water soluble active, including but not limited to proliferative, inflammatory and allergic dermatoses such as psoriasis (vulgaris), eczema atopic dermatitis; parasitic infestations; fungal skin infections; bacterial or fungal overgrowth; acne; rosacea and erythematotelangiectatic rosacea; and lichen sclerosus. The following examples are provided to enable those of ordinary skill in the art to make and use the methods and compositions of the invention. These examples are not intended to limit the scope of what the inventor regards as the invention. Additional advantages and modifications will be readily apparent to those skilled in the art. Examples Example 1 Eight different hydrocarbon propellants, a 47/53 wt/wt blend of N-Butane/dimethyl ether and the hydrofluorocarbon HFA 134a were added to the foam concentrate [either Formulation 1 or Formulation 2] listed in Table 8 and the emitted foam appearance was noted after gentle shaking of the canister. Target proportions were 5 grams propellant added to 62 grams foam concentrate. As seen in Table 6, the use of either N-Butane or Isobutane alone as a propellant and blends of propane and isobutane produced a runny product that did not meet appearance requirements for a foam. However, a Propane/Isobutane/N-Butane blended propellant produced an emitted foam that was smooth, white and uniform. This foam using the three-hydrocarbon propellant blend initially supported its own weight but readily broke during rub-in. The addition of isopentane to the Propane/Isobutane/N-Butane propellant blend destabilized the emitted foam and produced a runny looking product. Table 8. Dimethyl ether is commonly added to a hydrocarbon propellant to increase solubility in the canister of water-insoluble actives, especially if 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 looking product upon dispensing that did not meet appearance requirements for a foam. HFA-134a (1,1,1,2- tetrafluoroethane), the 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 that did not comprise gas bubbles distributed in a liquid. Example 2 Determining the Dispersed Content Uniformity Throughout Canister Life The appearance of 64 grams foam concentrate (Formulation 1 containing 0.15% roflumilast) when gassed with 5, 6, 8 or 10 grams of AP-70 propellant were compared. The emitted foam appearance for these four foam concentrate to propellant ratios was indistinguishable smooth, white foam products having gas bubbles that were small and uniform in size. Additional analytical testing was completed on formulation 1 (containing 0.3% roflumilast) to determine dispersed roflumilast content uniformity throughout the canister life. Two clinically relevant doses (~1 gram) were dispensed from the beginning of the can (initial actuations after ~ 5 hand shakes of the can). The amount of foam dispensed was quantified by completing a difference weighing of the can and the assay results of the two separate foam extractions were averaged to give the “Beginning Average” value. 15 grams of foam was dispensed, and the canister was allowed to return to room temperature. An additional 5-6 hand shakes of the canister was followed by dispensing two clinically relevant doses (~1 gram) from the middle of the canister. Assay results of the two separate foam extractions were averaged to give the “Middle Average” value. An additional 15 grams of foam was dispensed, the canister allowed to return to room temperature. This sequence of sampling was repeated to give the “End Average” data. Data comparing the “Beginning Average”, Middle Average” and “End Average” for lot PGX-C containing 10 grams of AP-70 propellant compared to a lot that contains 8 grams of AP-70 propellant is shown in Table 9. According to USP<607> Pharmaceutical Foams—Product Quality Tests the dispersed content uniformity throughout canister life must not exceed 10%. This compendial method instructs to dispense quantities according to the labeled instructions separately collecting an appropriate amount of individually weighed foam drug product. The sample size should not exceed the maximum dose recommended by the product labeling for a single application. The labeled use instructions determine if the can should be shaken prior to expelling foam and the orientation (upright or inverted) when dispensing. Portions of foam should be retained corresponding to: 1) an initial portion from the filled canister, 2) a portion from the middle of the canister (in the range of 40%– 60% of labeled canister content), and 3) the portion corresponding to the canister contents with 85% of the labeled contents delivered. The canister should be dispensed at room temperature. If the canister cools as a result of dispensing, the canister should be warmed to room temperature before subsequent delivery. Using an appropriate sample preparation (such as outgassing) and analytical method, determine the drug substance concentration in each of the three portions. None of the three results are outside of the product assay range. The maximum difference in the amount of active ingredient determined within the canister is NMT 10.0%, beginning, middle and end. 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) and causes the now swollen emulsion globules to rise (creaming of the emulsion) away from the inverted valve/actuator. Since the water insoluble active disproportionately resides surrounding the oil phase of the emulsion, repeating this process of shaking the canister and emitting the foam serves to concentrate active in the canister. When the O/W emulsion is destabilized to the point of exceeding the maximum difference limit (not more than 10%) specified for content uniformity throughout canister life according to USP<607>, the aerosol foam drug product is no longer commercially viable. For a target 64-gram fill of 0.3% roflumilast Formulation 1, increasing the amount of AP-70 hydrocarbon propellant, suddenly and unexpectantly destabilized the emulsion of the foam concentrate to make this foam drug product no longer acceptable for commercial pharmaceutical products. Table 9.
Example 3 Effect of Increasing the Concentration of Diethylene Glycol Monoethyl Ether Using the same USP<607> Pharmaceutical Foams—Product Quality Tests as detailed in Example 2 for determining the dispersed content uniformity throughout canister life, the effect of increasing the concentration of diethylene glycol monoethyl ether (Table 10) was determined. Table 10. When the O/W emulsion is destabilized to the point of exceeding the maximum difference limit (not more than 10%) specified for content uniformity throughout canister life in USP<607>, the aerosol foam drug product is no longer commercially viable. For a target 64-gram fill of 0.3% roflumilast foam concentrate and 8-gram fill of AP-70 hydrocarbon propellant, the emulsion in the canister suddenly and unexpectantly destabilizes when the DEGEE concentration is increased from 35% to 40% (Table 10). The emulsion of this foam drug product containing 40% DEGEE is not acceptable for pharmaceutical commercialization. Table 11. Example 4 As detailed in Example 2, two clinically relevant doses (~1 gram) were dispensed from the beginning, middle and end of the can. The amount of foam dispensed was quantified by completing a difference weighing of the can and the assay results of the two separate foam extractions were averaged to give 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 as the beginning retain (BR), middle retain (MR) and end retain (ER). The six assay values (which represents assay of the entire contents of the canister) for FORMULATION 4 from Table 10 is shown in Table 12. Table 12. The data shown in Table 12 provides a dramatic example of how creaming of a foam concentrate emulsion within the canister can cause dramatic changes in dosing levels of active to the patient. From development of roflumilast emulsion formulations it is known that increasing the amount of DEGEE from 25% to 40% will increase the solubility of roflumilast in the foam concentrate, but increasing DEGEE above 35% also destabilizes the emulsion. The assay pattern after fully assaying the canister (Table 12) indicates that active is migrating to the portion of the emulsion containing roflumilast that is being retained in the canister during actuation. By walking through the assay steps, the data from Table 12 can be understood. The full can of product is shaken, and the beginning one-gram samples are dispensed with an assay value of 96.4%. The can is again shaken and approximately 15-grams of foam is dispensed into a jar in a single actuation—the roflumilast-rich, propellant swollen globules of the destabilized emulsion phase separate (creaming) and migrate away from the valve of the inverted canister. Creaming of the emulsion carries a disproportionate amount of roflumilast toward the interface between the emulsion and liquid propellant which assures that the “Beginning Retain” has a very low assay value of 69.4%. The can is allowed to return to room temperature, shaken and the short actuation, 1-gram middle samples are taken and assayed at 99.0 % of label. Once again, due to the destabilized emulsion, roflumilast evades being dispensed from the canister during the long actuation during dispensing of the “Middle Retain” (72.2% of label). With about two-thirds of the three-phase pharmaceutical aerosol having been dispensed at low potency, the 1-gram end actuations have the highest assay value of 131.3 % of label. The final long actuation to produce the “End Retain” assay value maintains the trend of having a lower roflumilast assay value (111.0 % label) compared to end sample (131.3 % label). Depending on how long the canister is held inverted after shaking, a physically unstable emulsion foam product could deliver 69% of the labeled dose or 131% of the labeled dose. Formulation 4 would not be a commercially viable pharmaceutical aerosol foam product. Example 5 Ratio of the Hydrocarbon Blend The aesthetics of ARQ-154 foam formulation shown in Table 2 (64 grams concentrate) when gassed 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 AP-70 propellant is a 55:15:30 blend of Propane:Isobutane:N-Butane. While both foams were found completely acceptable, the firmer appearance and slightly slower breaking of the AP-48 propellant foam was preferred by about two-thirds of the individuals testing the products. The other third of the testers had either no preference or a slight preference for the quicker breaking AP-70 foam. It was concluded that both the AP-48 and AP-70 hydrocarbon blends show good topical foam characteristics and excellent aesthetics. By adjusting the ratio of propane to the isobutane:N-Butane mixtures, any pressure between 48 and 70 psig can be achieved. In terms of aesthetics, any ratio of the hydrocarbon propellant blend of Propane/Isobutane/N-Butane that gives a pressure around 48-70 psig at 70°F has been shown acceptable. Example 6. Formulations with Various Low Water Soluble APIs Table 13
Table 14
Table 15 Table 16
Example 7 Can Liner Compatibility Testing Since introduction of a hexane extraction step significantly decreased variability in assay results, a sampling of commercially available can liners were filled with 0.3% foam concentrate and gassed with AP-70 propellant. Three different can sizes were compared to the glass compatibility bottle. The current roflumilast foam 60 gram can was compared to the larger Trivium Cans (PPG-2845 and PPG-8900) that were 53 mm X 235 mm cans filled with 275.2 grams concentrate (equivalent to 64 g concentrate for the 60 gram can) and 34.4 grams of AP-70 propellant (equivalent to 8 g or propellant for the 60 gram can). The smaller roflumilast foam 10 gram sample can was filled with 12.0 g concentrate and 2.3 g AP-70 propellant. The bulk concentrate was packaged, and propellant added. The cans were stored inverted and upright at ambient conditions. Bottles were gassed and sent the same days, but were stored upright and horizontal. The assay results for roflumilast, methylparaben and propylparaben are shown in Table 18. Table 18. Results from can liner compatibility study after ambient storage for over one month.
Variability in the results and the lower than expected values for the glass bottle samples makes it difficult to precisely determine loss to the can liner. However, trends in the data indicate that in terms of retaining near target roflumilast values the epoxy phenolic liner is best, MPE and BPA are similar, but slightly inferior to the epoxy phenolic liner and the current PAM liner is the least compatible liner for the roflumilast foam product. From the data in Table 18 it appears the epoxy phenolic liner may not be compatible with the parabens, especially propyl paraben. If this incompatibility between the preservatives and the epoxy phenolic can liner is confirmed, an overage of roflumilast may be required to compensate for the slight roflumilast loss due to use of the PAM can liner in the primary container for the roflumilast foam. Example 8 Roflumilast Foam Final Formulation Experiment To select the final roflumilast formulation for the manufacture of the three primary stability batches, a matrix of four packaging/propellant combinations is being placed on stability. The four configurations are: 1) current PAM lined can gassed with the AP-70 propellant (The phase 2 IP), 2) current PAM lined can gassed with the AP-48 propellant, 3) epoxy phenolic lined can gassed with AP-70 propellant and 4) epoxy phenolic can gassed with AP-48 propellant. The product concentrate will have the composition shown in Table 2 with the IPP added to the active phase during processing. Target fill weights will be 64.0 grams for the product concentrate and 8.0 grams for the propellant. Forty (40) cans of each of the four configurations will be filled, gassed and placed on stability. Three (3) cans from each configuration will be pulled at each time and tested for assay, impurities, and preservatives. Example 9 Storage Stability The following formulations were prepared and mixed with propellant AP-48 or AP-70 to determine whether a stable foam is formed after storage under ambient conditions for more than 30 days. Table 19
Example 10 Evaluation of Foam Quality Foams were prepared and assessed using foam quality and foam expansion techniques. Five foam formulations containing an active pharmaceutical ingredient which has low solubility in water were prepared to determine whether a suitable foam product is produced. The APIs included ivermectin, clobetasol proprionate, oxymetazoline free base, ketoconazole and econazole nitrate. The product concentrates containing the APIs were mixed with NIP-70 propellant at a ratio of 88.9% product concentrate to 11.1% propellant. All five of the formulations resulted in a foam product as shown in figures 2-6. The foam quality was assessed visually and by using foam density and foam expansion techniques. Aerosol can components were prepared according to the following table. Table 20 The sample variable tolerances were as follows. Table 21 Example 11 Four formulations were tested for each of five different low water soluble actives including ivermectin, clobetasol propionate,oxymetazoline, ketoconazole, and econazole nitrate. Samples were prepared for each variable. Each can was filled with 64 g of the product concentrate containing the API, followed by crimping. The cans were subsequently pressurized with 8 g of NIP-70 propellant. The propellant was filled manually using a burette system followed by weight analysis of individual samples. A+/- 5% range from the target weights was deemed acceptable. No sample deviated more than 3% from the target values. The finished aerosol products utilized 75% of the specified can’s brim filled capacity. The finished cans were tested for leaks by submerging 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 no more than 10 seconds and allowed to rest for at least 2 days to ensure complete mixing of the propellant and product concentrate. The samples were studied using visual analysis to determine the presence or absence of a foam after dispensing. A foam was defined as the visual presence of multiple bubbles sharing a minimum of 1 liquid film wall which may be broken when agitated by an external force. The foams were visually analyzed immediately after dispensing and again five minutes after dispensing. Formulations 5-8, 10, 12-21,23, and 24 were found to produce acceptable foams immediately after dispensing and 5 minutes after dispensing. The acceptable foams were smooth white or off-white foams having uniform bubbles and were able to support their own weight. The foam half-life was more than 60 seconds. The resulting foams are shown in Figures 2-6. All five APIs produced foams for all of the formulations that were tested. A wide range of foam structures were observed for the different formulations showcasing the range of foams which can be produced using the tested APIs. The foam structures can be optimized for specific indications.