US 2006O153905A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0153905 A1 Carrara et al. (43) Pub. Date: Jul. 13, 2006 (54) TRANSDERMAL PHARMACEUTICAL Related U.S. Application Data FORMULATION FOR MINIMIZING SKIN RESIDUES (63) Continuation of application No. PCT/EP04/11175, filed on Oct. 6, 2004. (76) Inventors: R. Dario Norberto Carrara, Oberwil Publication Classification (CH); Arnaud Grenier, Steinbrunn le (51) Int. Cl. Haut (FR): Celine Besse, Saint Louis A 6LX 9/70 (2006.01) (FR) (52) U.S. Cl. .............................................................. 424/449 (57) ABSTRACT Correspondence Address: This invention relates to novel transdermal or transmucosal WINSTON & STRAWN LLP pharmaceutical formulation which reduces the occurrences 1700 K STREET, N.W. of contamination of other individuals and the transference to WASHINGTON, DC 20006 (US) clothing of the user. The novel formulation includes at least one pharmacologically active ingredient, and a solvent sys tem having a monoalkylether of diethylene glycol and a (21) Appl. No.: 11/371,042 glycol present in specified ratios, and a mixture of water and alcohol. The invention also relates to a method for inhibiting or delaying crystallization of an active agent in a pharma (22) Filed: Mar. 7, 2006 ceutical formulation. Patent Application Publication Jul. 13, 2006 Sheet 1 of 14 US 2006/O153905 A1 Donor compartment: Excised skin formulation with drug Drug sampling port Diffusion area Y 2%2/ - Fresh receptor solution 3.2%($ Receptor compartment: Receptor medium Thermostatic jacket Magnetic stirrer FIGURE 1 Diffusion Chamber Patent Application Publication Jul. 13, 2006 Sheet 2 of 14 US 2006/O153905 A1 Unabsorbed formulation Normalized recovery per formulation StratumEpidermis-HDerms-Receptor corneum sol 100% S. 60% s is s 40% ths 20% 0% Example 10 example 9. Example 6 Formulation FIGURE 2 In-Vitro 24-Hour Biodistribution of Testosterone Patent Application Publication Jul. 13, 2006 Sheet 3 of 14 US 2006/O153905 A1 Normalized recovery performulation 100% 80% - 60% Unabsorbed formulation Stratum conneum Epidemist Demist-Receptorsol. 40% 20% Example 12 Example 13 Example 14 Formulation FIGURE 3 24-Hour Biodistribution of Minoxidil Patent Application Publication Jul. 13, 2006 Sheet 4 of 14 US 2006/0153905 A1 O -0-Example 3 Relative kinetic profile --Example 5 -a-Example 9 20 18 ---------------------------- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 16 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - --------- : FIGURE 4 In-Vitro Permeation of Testosterone Patent Application Publication Jul. 13, 2006 Sheet 5 of 14 US 2006/O153905 A1 Normalized recovery performulation is Unabsorbed formulation 100% Stratum corneum a Epidermis-Dermist-Receptor sol 80% 60% 40% 20% Example 3 Example 5 Example 9 Formulation FIGURE 5 24-Hour Biodistribution of Testosterone Patent Application Publication Jul. 13, 2006 Sheet 6 of 14 US 2006/0153905 A1 G H Figures 6A - 6H Comparative Crystallization Kinetic Studies Patent Application Publication Jul. 13, 2006 Sheet 7 of 14 US 2006/O153905 A1 FIGURE 7 Flux profile SELEGLINE -o-Formulation A -- Formulation B -a-Formulation C 0.8 (MeantSD) Time (h) Comparative Drug Flux Profile For Selegiline Formulations Patent Application Publication Jul. 13, 2006 Sheet 8 of 14 US 2006/O153905 A1 FIGURE 8 Relative kinetic profile SELEGLINE -- Formulation A --Formulation B -A-Formulation C (MeaniSD) s Time h Comparative Kinetic Profile of In-Vitro Permeation of Selegilline Formulations Patent Application Publication Jul. 13, 2006 Sheet 9 of 14 US 2006/0153905 A1 FIGURE 9 Relative kinetic profile FENTANY -o-Formulation A -- Formulation B -A-Formulaton C (MeantSD) s Comparative Kinetic Profile of In-Vitro Permeation of Fentanyl Formulations Patent Application Publication Jul. 13, 2006 Sheet 10 of 14 US 2006/0153905 A1 FIGURE 10 Comparative Drug Flux Profile of Fentanyl Formulations Flux profile FENTANYL -0-Formulation A --Formulation B -A-Formulation C (MeaniSD) Patent Application Publication Jul. 13, 2006 Sheet 11 of 14 US 2006/O153905 A1 FIGURE 11 Comparative Kinetic Profile of In-Vitro Permeation of Fentanyl Formulations Relative kinetic profile FENTANY -- Formulation A -- Formulation B -A-Formulation C (MeaniSD) s Patent Application Publication Jul. 13, 2006 Sheet 12 of 14 US 2006/0153905 A1 FIGURE 12 Comparative Drug Flux Profile of Fentanyl Formulations Flux profile FENTANYL -0-Formulation A -- Formulation B -A-Formulation C (MeaniSD) Patent Application Publication Jul. 13, 2006 Sheet 13 of 14 US 2006/O153905 A1 FIGURE 13 Comparative Kinetic Profile of In-Vitro Permeation of Buspirone Formulations Relative kinetic profile BUSPIRONE -- Formulation A -- Formulation B -A-Formulation C (MeantSD) Patent Application Publication Jul. 13, 2006 Sheet 14 of 14 US 2006/O153905 A1 FIGURE 14 Comparative Drug Flux Profile of Buspirone Formulations Flux profile BUSPRONE -0-Formulation A -- Formulation B -A-Formulation C (MeantSD) US 2006/0153905 A1 Jul. 13, 2006 TRANSIDERMAL PHARMACEUTICAL contraception, Lancet 1, 276-277). Similarly, Yu et al. FORMULATION FOR MINIMIZING SKIN reported virilization of a two-year-old boy after incidental RESIDUES and unintentional dermal exposure to a testosterone cream applied to his father's arm and back (Yu, Y. M., Punyasa CROSS REFERENCE vatsu, N., Elder, D. & D’Ercole, A. J. (1999): “Sexual 0001. This application is a continuation of International development in a two-year old boy induced by topical application PCT/EP2004/011175 filed Oct. 6, 2004 and exposure to testosterone'. Pediatrics, 104, 23). claims the benefit of U.S. Provisional Application No. 0006 Moreover, the patient information brochure for 60/510,613, filed Oct. 10, 2003, the content of each of which ANDROGEL(R) (1% testosterone gel from Unimed Pharma is expressly incorporated herein by reference. ceuticals Inc.) emphasizes the potential for transfer of test osterone to other people and/or clothing and the brochure FIELD OF INVENTION includes safety measures to be taken by the individual using 0002 The present invention relates to a novel transder the non-occlusive dosage form. mal or transmucosal pharmaceutical formulation comprising 0007 One way to overcome or minimize this contami an active ingredient and a solvent system. The solvent nation issue is to physically protect the transdermal dosage system includes a monoalkyl ether, and glycol in specific form by covering skin with the applied pharmaceutical ratios, as well as mixture of alcohol and water. The invention formulation means of a patch device, a fixed reservoir, an also relates to a method of delaying or inhibiting crystalli application chamber, a tape, a bandage, a sticking plaster, or Zation of an active agent in a transdermal or transmucosal the like, which remain on the skin at the site of application pharmaceutical formulation. of the formulation for a prolonged length of time. This is usually accomplished with occlusive dosage forms. BACKGROUND OF THE INVENTION 0008 Occlusive dosage forms present some advantages 0003. It is known that transdermal or transmucosal dos over non-occlusive dosage forms such as assisting the rate of age forms conveniently deliver drugs across a localized area penetration of drugs across the skin by maintaining the of the skin or the mucosa. One such way of delivering drugs thermodynamic activity of the drug close to its maximum across the skin or mucosa is by way of a non-occlusive (the thermodynamic activity of a drug in a dermal formu transdermal and/or topical dosage form. Some non-limiting lation is proportional to the concentration of the drug and the examples of non-occlusive transdermal and topical semi selection of the vehicle, and according to the laws of Solid dosage forms include creams, ointments, gels, foams, thermodynamics, the maximum activity of a drug is related sprays, solutions, and lotions (i.e. emulsions, or Suspen to that of the pure drug crystal). However occlusive dosage sions). Typically non-occlusive dosage forms are applied to forms also exhibit several major drawbacks. For example, the skin or mucosa and are left uncovered and open in the occlusive dosage forms present a high potential of local skin atmosphere. Because the non-occlusive dosage form is left irritation caused by the prolonged contact on the skin of the uncovered, unwanted transfer of the pharmaceutical formu drug, Volatiles, vehicle excipients, and the adhesive used to lation to the clothing of the user or even to other individuals attach the occlusive device, e.g., the patch, to the skin. In in close proximity to the user is unavoidable. Other draw addition, the occlusive nature of certain occlusive dosage backs of the non-occlusive dosage form include evaporation forms, such as the patch device, also restrict the natural of the formulation, removal of the formulation from the skin ability of the skin to “breathe, and thereby increases the risk or mucosa, for example, by bathing or by other activities, of irritation. and the inabsorption of the formulation through the skin, 0009. In addition to the aforementioned drawbacks of which is discussed below. occlusive dosage forms, significant serious hazards have 0004 The