(12) Patent Application Publication (10) Pub. No.: US 2007/01544.02 A1 Trumbore Et Al
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US 2007 O1544O2A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/01544.02 A1 Trumbore et al. (43) Pub. Date: Jul. 5, 2007 (54) TOPICAL PHARMACEUTICAL FOAM Publication Classification COMPOSITION (51) Int. Cl. A6II 38/46 (2006.01) A6IR 9/12 (2006.01) (75) Inventors: Mark W. Trumbore, Westford, MA A6II 3/19 (2006.01) (US); Ronald M. Gurge, Franklin, MA A6II 3L/203 (2006.01) (US); Jane C. Hirsh, Wellesley, MA A6IR 36/18 (2006.01) (US) A6II 3/17 (2006.01) (52) U.S. Cl. ..................... 424/45; 424/725.1; 424/94.65; 514/557; 514/559; 514/562; Correspondence Address: 514/588; 424/705 PATREAL PABST PABST PATENT GROUP LLP (57) ABSTRACT 400 COLONY SQUARE, SUITE 1200 A stable topical alcohol-free aerosol foam containing one or 12O1 PEACHTREE STREET more keratolytic agents is provided. The foam-forming ATLANTA, GA 30361 (US) formulation is an emulsion which contains an HFA propel lant and one or more keratolytic agents. The emulsion has an oil phase and an aqueous, i.e. water-containing, phase. The active agent(s) may be present in either phase of the emul (73) Assignee: Collegium Pharmaceutical, Inc. sion or dispersed in the emulsion. The oil phase may consist at least in part of the HFA propellant. Either or both of the oil phase and the aqueous phase may contain one or more (21) Appl. No.: 11/552,457 Surfactants, emulsifiers, emulsion stabilizers, buffers, and/or other excipients. The foam is stable on the skin, for example, for at least 5 minutes at body temperature, preferably at least (22) Filed: Oct. 24, 2006 20 minutes at body temperature, and disappears into the skin upon rubbing or after prolonged standing. In one embodi ment, the formulation contains an HFA propellant which Related U.S. Application Data does not contain additional co-solvents or co-propellants. The formulations demonstrate reduced intensity of the odor and/or color associated with the keratolytic agent(s) as (60) Provisional application No. 60/729,788, filed on Oct. compared to conventional formulations containing kera 24, 2005. tolytic agents. US 2007/01544.02 A1 Jul. 5, 2007 TOPCAL PHARMACEUTICAL FOAM 0006 Since replacing a component of any formulation COMPOSITION means introducing new properties, and HFAs differ in their Solvating power from CFCs and hydrocarbons, providing CROSS-REFERENCE TO RELATED reproducible performance of reformulated aerosols for phar APPLICATIONS maceutical uses represents a challenging task. Co-solvents (such as ethanol) are often incorporated into the formulation 0001. This invention claims the benefit of the priority of in order to arrive at a stable product (Pharmaceutical Aero U.S. Ser. No. 60/729,788, filed Oct. 24, 2005. sols, June 2003, p. 21). Such formulations, however, have a number of undesirable aspects. Alcohol co-solvents can dry FIELD OF THE INVENTION and irritate the skin. U.S. Pat. No. 6,126,920 suggests that 0002 This invention is generally in the field of pharma the use of alcohol co-solvents can lead to burning, itching, ceutical compositions, specifically pharmaceutical foam and irritation observed in the use of topical foam for compositions containing keratolytic agents intended for delivering betamethasone. Further, volatile alcohols are topical administration. highly irritating to mucous membranes. 0007 Formulations that contain volatile alcohols and/or BACKGROUND OF THE INVENTION alkanes are potential safety hazards due to the high flam mability of the product. Moreover, the flammability char 0003 Pharmaceutical foams are pressurized dosage acteristics of the product require expensive precautions forms containing one or more active ingredients that, upon during manufacturing, and may require controlled environ valve actuation, emit a fine dispersion of liquid and/or Solid ments for storage and for disposal of containers after use. materials in a gaseous medium. Foam formulations are For example, WO 85/01876 describes the fire hazards asso generally easier to apply, are less dense, and spread more ciated with alcohol- and alkane-containing aerosol foam easily than other topical dosage forms. Foams may be formulations. formulated in various ways to provide emollient or drying functions to the skin, depending on the formulation con 0008 Pharmaceutical foam formulations containing stituents. Accordingly, this delivery technology is a useful keratolytic agents have not been described in the literature. addition to the spectrum of formulations available for topical Keratolytic agents are agents that soften, separate, and cause use. However, as yet, only a few pharmaceutical foams are descuamation (i.e. Shedding or peeling) of the cornified commercially available. Most commercially available foam epithelium, or horny layer, of the skin. These agents are used dosage forms contain corticosteroids, although some prod to expose mycelia of infecting fungi or to treat corns, warts, ucts have also been used to deliver antiseptics, antifungal and certain other skin diseases. Commonly used keratolytic agents, anti-inflammatory agents, local anesthetic agents, agents include urea, urea in combination with ammonium skin emollients, and protectants (American Journal of Drug lactate, Salicylic acid, papain, papain in combination with Delivery, 2003, vol. 1(1), pp. 71-75). urea, and sulfur. Sulfur is also used in combination with 0004 There is growing interest in converting non-foam Sodium Sulfacetamide to treat acne, rosacea, seborrheic topical treatments to aerosol foam or mousse formulations, dermatitis, eczema, Xerosis, Scabies, pediculosis and psoria which better penetrate the skin, provide faster treatment and S1S. do not leave any greasy residue on skin or clothing com 0009 Keratolyic agents can be administered in the form pared with conventional ointments. Until now, the most of a liquid, cream, lotion or cleanser. Topical formulations common gas propellant used in aerosol products is chlorof containing keratolytic agents typically have an intense color luorocarbon (CFC), an ozone-depleting agent. The Montreal and/or strong odor. For example, Sulfur containing products Protocol International Treaty, signed by 180 nations, banned typically have an intense yellow color and/or a strong odor the use of chlorofluorocarbons (CFCs) as aerosol propellants characteristic of Sulfur. Urea-containing products frequently and mandated the phasing out of CFC agents. No new or exhibit a strong ammonia odor, while papain-containing revised aerosol formulations may contain CFC propellants products exhibit a distinctive papain odor. Current products and alternative propellants must be used that are more on the market typically contain Substantial amounts of odor environmentally friendly. Therefore, manufacturers must masking agents, such as fragrances, in order to mask or reformulate or modify existing products to use non-CFC shield the odor associated with the pharmaceutical agent. propellants, while maintaining important aspects of the However, the use of high concentrations of fragrances can be previous formulation, Such as accuracy of delivery, stability, problematic. The use of fragrances in topical formulations etc. The primary CFC substitute are hydrofluoroalkanes can result in skin sensitizing reactions in which the patient (HFA), also known as hydrofluorocarbons (HFC). develops sensitivity to the odor masking agent. Furthermore, 0005 Although hydrocarbon propellants, such as pro the presence of fragrances, which are often complex mix pane and butane, can be used in the manufacturing of tures of different compounds, may result in undesirable side pharmaceutical foams, these propellants are not suited for reactions between the fragrance and the active agent(s). human use since they are flammable. Just as is the case with 0010. There exists a need for topical keratolytic foam CFC propellants, hydrofluoroalkanes (HFAs) that possess formulations which, once applied to the skin, have little or high chemical stability can be used as a primary Substitute no odor or color and are non-staining and which contain for hydrocarbons. Examples of HFAs are 1,1,1,2,3,3,3- little or no odor masking agents such as fragrances. heptafluoropropane (HFA-134a) and 1,1,1,2-tetrafluoroet hane (HFA-227). Hydrofluoroalkanes (HFAs) are also 0011. It is therefore an object of the invention to provide referred to as hydrofluorocarbons (HFCs) and these terms alcohol-free keratolytic topical foam aerosol formulations are used interchangeably. that use hydrofluoroalkanes (HFAs) as the propellant. US 2007/01544.02 A1 Jul. 5, 2007 0012. It is a further object of the invention to provide 0018. In yet another embodiment, the composition keratolytic topical foam formulations which exhibit reduced includes a proteolytic enzymes such as papain in combina intensity of the odor and/or color associated with the kera tion with urea. The concentration of papain is from about tolytic agent. 0.5% to about 40%, preferably from about 1% to about 20%, more preferably from about 1% to about 1.0% by weight of BRIEF SUMMARY OF THE INVENTION the final composition. The concentration of urea is from about 1% to about 60%, preferably from about 2.5% to about 0013 A stable topical alcohol-free aerosol foam contain 40%, more preferably from about 5% to about 15% by ing one or more keratolytic agents is described herein. The weight of the final composition. In still another embodiment, foam-forming formulation is an emulsion which contains an the composition includes the enzyme papain in combination HFA propellant and one or more keratolytic agents.