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 inefficiencies of drug permeation across or been documented regarding the high drug loading that is through the skin or mucosa barriers are known. It is also specific to patches. For example, several cases of abuses known that the permeation of a drug in a non-occlusive with remaining fentanyl in fentanyl patches have been transdermal or transmucosal dosage form can be as little as reported. See, Marquardt K. A., Tharratt R. S., “Inhalation 1% and usually is no more than 15%. Thus, a vast majority abuse of fentanyl patch.”. J. Toxicol Clin. Toxicol. of the active drug remains unabsorbed on the skin or mucosa 1994:32(1): 75-8.: Marquardt K. A., Tharratt R. S., Musal Surface. Because the vast majority of the drug remains on the lam N. A., “Fentanyl remaining in a transdermal system skin and does not penetrate the skin or mucosa Surfaces, the following three days of continuous use.'. Ann Pharmaco bioavailability of the particular drug is not optimal, and also ther. 1995 Oct:29(10):969-71.; Flannagan L. M. Butts J D, a high risk of contamination of other individuals in close Anderson W. H., “Fentanyl patches left on dead bodies— proximity to the user is presented by the unwanted transfer potential source of drug for abusers.”. J. Forensic Sci. 1996 of the pharmaceutical formulation in the non-occlusive Mar; 41(2):320-1. Severe incidental intoxication cases have dosage form. also been documented. See Hardwick Jr., W. King, W., 0005 Problems associated with the unwanted transfer of Palmisano, P., “Respiratory Depression in a Child Uninten a particular pharmaceutical formulation to others are well tionally Exposed to Transdermal Fentanyl Patch”, Southern documented. For example, Delanoe et al. reported the andro Medical Journal, September 1997. genization of female partners of Volunteers applying a 0010 Patch products typically contain patient informa testosterone gel preparation during contraceptive studies. tion, which clearly indicate the risks discussed above. For (Delanoe, D., Fougeyrollas, B., Meyer, L. & Thonneau, P. instance, OXYTROLTM (an oxybutynin patch commercial (1984): “Androgenisation of female partners of men on ized by WATSON Pharmaceuticals, Inc. USA) contains medroxyprogesterone acetate/percutaneous testosterone patient information that indicates the following warning: US 2006/0153905 A1 Jul. 13, 2006

“Since the patch will still contain some oxybutynin, throw it Solvent may be defined as a solvent that changes readily away so that it can not be accidentally worn or swallowed by from Solid or liquid to a vapor, that evaporates readily at another person, especially a child.” The high level of active normal temperatures and pressures. Here below is presented drug residues is thus a critical drawback of patches. Such data for some usual solvents, where volatility is reflected by accidents could not occur with the use of gel formulations. the molar enthalpy of vaporization AH, defined as the 0011 Although attempts have been made to overcome enthalpy change in the conversion of one mole of liquid to drawbacks associated with both occlusive and non-occlusive gas at constant temperature. Values are given, when avail drug forms, such attempts have been futile. For example, as able, both at the normal boiling point t referred to a noted above, one drawback of non-occlusive dosage forms pressure of 101.325 kPa (760 mmHg), and at 25°C. (From is evaporation of the formulation, which is left open in the “Handbook of Chemistry and Physics, David R. Lide, 79" atmosphere. The formulation of non-occlusive Supersatu edition (1998-1999) Enthalpy of vaporization (6-100 to rated systems could have achieved an ideal merge but 6-115). Stanislaus et al. (U.S. Pat. No. 4,704,406 on Oct. 9, transdermal formulations, which rely on Supersaturation 2001) defined as volatile solvent a solvent whose vapor technologies, present a major drawback of formulation pressure is above 35 mm Mg when the skin temperature is instability, both prior to and during application to the skin 32° C., and as non-volatile solvent a solvent whose vapor due to solvent evaporation. Davis A F and Hadgraft J Su pressure is below 10 mm Mg at 32° C. skin temperature. persaturated Solutions as topical drug delivery systems, Examples of non-volatile solvents include, but are not Pharmaceutical Skin Penetration Enhancement, Marcel limited to, propylene glycol, glycerin, liquid polyethylene Dekker Inc, New York (1993). 243-267 ISBN 082479017 glycols, or polyoxyalkylene glycols. Examples of volatile 0, which is incorporated herein by reference. Solvents include, but are not limited to, ethanol, propanol, or 0012 Notably, extraordinary physicochemical changes isopropanol. occur with the evaporation of the solvent system, which TABLE 1. result in modifications of the concentration of the active agent, which may even lead to drug precipitation, thereby Enthalpy of vaporization of certain solvents altering the diffusional driving force of the formulation. See Ma et al. Proceed. Intern. Symp. Control. Rel. Bioact. ti, AH (t) AH (25 C.) Mater, 22 (1995). Consequently, the percutaneous absorp Ethanol 78.3 38.6 423 tion of the active agent may be quite different from that Propan-2-ol (isopropanol) 82.3 39.9 45.4 Propanol 97.2 41.4 47.5 when the solvent was present. Butan-2-ol 99.5 40.8 49.7 0013 In addition, controlling drug crystallization is of Butan-1-ol 117.7 43.3 52.4 particular interest for non-occlusive transdermal systems. Ethylene glycol monomethyl ether 124.1 37.5 45.2 Ethylene glycol monoethyl ether 135.0 39.2 48.2 Campbell et al. resorted to a method of heating a crystalline Ethylene glycol monopropyl ether 149.8 41.4 52.1 hydrate to a temperature above the melting point in order to 1,2-Propylene glycol 187.6 52.4 Not available prevent the crystallization of the formulation. See, U.S. Pat. Diethylene glycol monomethyl ether 193.0 46.6 Not available No. 4,832,953. Maetal found that PVP added to the matrix Diethylene glycol monoethyl ether 196.O 47.5 Not available acts as an effective crystallization inhibitor for norethin 1,3-Propylene glycol 214.4 57.9 Not available drone acetate transdermal delivery systems. See, Int. J. of Glycerin 29O.O 61.0 Not available Pharm. 142 (1996) pp. 115-119). DE-A-42.10711 affirms that cholesterol and SiO, are crystallization inhibitors for 0017 Numerous authors have investigated evaporation 17-beta.-estradiol transdermal delivery system. WO and transdermal penetration from solvent systems. For 95/18603 describes soluble PVP as crystal inhibitor for Example, Spencer et al. (Thomas S. Spencer, "Effect of patch devices and affirms that soluble PVP increases the volatile penetrants on in vitro skin permeability', AAPS solubility of a drug without negatively affecting the adhe workshop held in Washington D.C. on Oct. 31-Nov. 1, 1986) sivity or the rate of drug delivery from the pressure-sensitive established that the relationship between volatility and pen adhesive composition. etration is not absolute and depends on many parameters 0014) Additionally, the inhibition of crystallization in such as for instance hydration of the tissue or the solubility transdermal devices was reported by Biali et al. See, U.S. of the penetrant in the tissue. Stinchcomb et al. reported that Pat. No. 6,465,005 in which it is described that the use of a the initial uptake of a chemical (hydrocortisone, flurbipro steroid (estradiol for instance) as an additive in a process of fen) from a volatile solvent system (acetone) is more rapid manufacture or storage of a transdermal device acts as a than that from a non-volatile solvent system (aqueous solu crystallization inhibitor during storage of the device. tion). With an aqueous solution, close to the Saturation 0.015 Further, transdermal delivery from semi-solid for solubility of the chemical, the driving force for uptake mulations faces antinomic requirements. The drug delivery remains more or less constant throughout the exposure system should enable absorption of an extensive amount of period. Conversely, for a volatile vehicle which begins active drug through the skin within the shortest period of evaporating from the moment of application, the Surface time in order to prevent contamination of individuals, trans concentration of the chemical increases with time up to the fer to clothing or accidental removing. The drug delivery point at which the solvent has disappeared; one is now left system should also provide Sustained release of the active with a solid film of the chemical from which continued drug over 24 hours ideally, so that only once-daily applica uptake into the stratum corneum may be very slow and tion is required. This drug delivery system should also dissolution-limited. prevent drug crystallization at the application Surface area. 0018 Risk assessment following dermal exposure to 0016 Drug delivery systems having such properties may volatile vehicles should pay particular attention, therefore, to be achieved by combining various solvents. A volatile the duration of contact between the evaporating solvent and US 2006/0153905 A1 Jul. 13, 2006

the skin (Audra L. Stinchcomb, Fabrice Pirot, Gilles D. for oral administration of macrollide containing a hydrophilic Touraille, Annette L. Bunge, and Richard H. Guy, "Chemi carrier medium consisting of diethylene glycol monoethyl cal uptake into human Stratum corneum in vivo from volatile ether, glycofurol, 1,2-propylene glycol, or mixtures thereof. and non-volatile solvents'. Pharmaceutical Research, Vol. 0026 U.S. Pat. Nos. 6,267,985 and 6,383,471 to Chen et 16, No 8, 1999). Kondo et al. studied bioavailability of al. disclose pharmaceutical compositions and methods for percutaneous nifedipine in rats from binary (acetone and improved solubilization of triglycerides and improved deliv propylene glycol PG or isopropyl myristate IPM) or ternary ery of therapeutic agents containing diethylene glycol mono (acetone-PG-IPM) solvent systems, compared with the ethyl ether and propylene glycol as solubilizers of ionizable results from simple PG or IPM solvent systems saturated hydrophobic therapeutic agents. with the drug. (Kondo et al. S. Yamanaka C. Sugimoto I. "Enhancement of transdermal delivery by superfluous ther 0027 U.S. Pat. No. 6,426,078 to Bauer et al. discloses an modynamic potential. III. Percutaneous absorption of nife oil-in water microemulsion containing diethylene glycol dipine in rats', J Pharmaco Biodyn. 1987 Decem monoethyl ether or propylene glycol as co-emulsifier of ber; 10(12):743-9). lipophilic vitamins. 0019 U.S. Pat. No. 6,299,900 to Reed et al. discloses a 0028 Many research experiments have been carried out non-occlusive, percutaneous, or transdermal drug delivery on diethylene glycol monoethyl ether (marketed under the system-having active agent, safe and approved Sunscreen as trademark TRANSCUTOLTM by Gattefossé) as an intracu penetration enhancer, and optional volatile liquid. The taneous drug depot builder. For example, Ritschel, W. A., invention describes a transdermal drug delivery system, Panchagnula, R., Stemmer, K., Ashraf, M., “Development of which comprises at least one physiologically active agent or an intracutaneous depot for drugs. Binding, drug accumu prodrug thereof and at least one penetration enhancer of low lation and retention studies, and mechanism depot for toxicity being a safe skin-tolerant ester Sunscreen. The drugs'. Skin Pharmacol, 1991; 4: 235-245; Panchagnula, R. composition comprises an effective amount of at least one and Ritschel, W. A., “Development and evaluation of an physiologically active agent, at least one non-volatile dermal intracutaneous depot formulation of corticosteroids using penetration enhancer; and at least one volatile liquid. TRANSCUTOL(R) as a cosolvent, in vitro, ex vivo and in-vivo rat studies'. J. Pharm. Pharmacology. 1991: 43:609-614; 0020 U.S. Pat. No. 5,891.462 to Carrara discloses a Yazdanian, M. and Chen, E., “The effect of diethylene glycol pharmaceutical formulation in the form of a gel suitable for monoethyl ether as a vehicle for topical delivery of iver the transdermal administration of an active agent of the class mectin", Vetemary Research Corn. 1995; 19:309-319; Pav of estrogens or of progestin class or of a mixture of both, liv, L., Freebem, K., Wilke, T., Chiang, C-C. Shetty, B., comprising lauryl alcohol, diethylene glycol monoethyl Tyle, P., “Topical formulation development of a novel ether and propylene glycol as permeation enhancers. thymidylate synthase inhibitor for the treatment of psoria 0021 Mura et al. describe the combination of diethylene sis', Int. J. Pharm., 1994; 105: 227-233; Ritschel, W. A., glycol monoethyl ether and propylene glycol as a transder Hussain, A. S., “In vitro skin permeation of griseofulvin in mal permeation enhancer composition for clonazepam rat and human skin from an ointment dosage form , Arz (Mura P. Faucci M. T., Bramanti G., Corti P., “Evaluation of neimeittelforsch/Drug Res. 1988; 38: 1630-1632: Touitou, transcutol as a clonazepam transdermal permeation E., Levi-Schaffer, F., Shaco-Ezra, N., Ben-Yossef, R. and enhancer from hydrophilic gel formulations”, Eur. J. Pharm. Fabin, B., “Enhanced permeation of theophylline through Sci., 2000 Feb; 9(4): 365-72) the skin and its effect on fibroblast proliferation'. Int. J. Pharm., 1991: 70: 159-166; Watkinson, A. C., Hadgraft, J. 0022 Williams et al. reports the effects of diethylene and Bye, A., “Enhanced permeation of prostaglandin E glycol monoethyl ether (TRANSCUTOLTM) in binary co through human skin in vitro '. Int. j. Pharm., 1991; 74: Solvent systems with water on the permeation of a model 229-236; Rojas, J., Falson, F., Courraze, G., Francis, A., and lipophilic drug across human epidermal and Silastic mem Puisieux, F. “Optimization of binary and ternary solvent branes (A. C. Williams, N. A. Megrab and B. W. Barry, systems in the percutaneous absorption of morphine base'. “Permeation of Oestradiol through human epidermal and STP Pharma Sciences, 1991; 1: 71-75; Ritschel, W. A., Silastic membranes from saturated TRANSCUTOL(R/water Barkhaus, J. K. "Use of absorption promoters to increase systems', in Prediction of Percutaneous Penetration, Vol. systemic absorption of coumarin from transdermal drug 4B, 1996). Many references may also illustrate the effect of delivery systems', Arzneimeittelforsch/Drug Res. 1988; 38: TRANSCUTOLTM as an intracutaneous drug depot builder well known to one skilled in the art. 1774-1777. 0023 U.S. Pat. No. 5,658,587 to Santus et al. discloses 0029. Thus there remains a need to provide a pharma transdermal therapeutic systems for the delivery of alpha ceutically acceptable transdermal or transmucosal pharma adrenoceptor blocking agents using a solvent enhancer sys ceutical formulation or drug delivery system that exhibits tem comprising diethylene glycol monoethyl ether and pro the advantages of both occlusive systems (high thermody pylene glycol. namic activity) and non-occlusive systems (low irritation and sensitization potential, and excellent skin tolerance) 0024 U.S. Pat. No. 5,662,890 to Punto et al. discloses an while overcoming the disadvantages of these systems. The alcohol-free cosmetic compositions for artificially tanning novel transdermal or transmucosal pharmaceutical formula the skin containing a combination of diethylene glycol tion of the present invention satisfies this need. monoethyl ether and dimethyl isosorbide as permeation enhancer. SUMMARY OF INVENTION 0025 U.S. Pat. No. 5,932.243 to Fricker et al. discloses 0030 The transdermal or transmucosal pharmaceutical a pharmaceutical emulsion or microemulsion preconcentrate formulation of the present invention comprises at least one US 2006/0153905 A1 Jul. 13, 2006 active agent; and a solvent system present in an amount 0038 FIG. 4 is a kinetic profile of in-vitro permeation of sufficient to solubilize the at least one active ingredient and Testosterone of selected formulation examples disclosed inhibit crystallization of the at least one active ingredient on herein; a skin or mucosal Surface of a mammal. Other advantages of the transdermal or transmucosal pharmaceutical formulation 0.039 FIG. 5 is a graph illustrating in vitro 24 hour of the invention include reducing or preventing the transfer biodistribution of Testosterone of the formulation examples of the formulation to clothing or another, minimizing con shown in FIG. 4; tamination of clothing by the formulation, modulation of 0040 FIGS. 6A to 6H illustrate results of crystallization biodistribution of the active agent within different layers of kinetic studies of prior art compositions compared to for the skin and facilitation of absorption of the active agent by mulations in accordance with the present invention. the skin or mucosa Surface to name a few. 0041 FIG. 7 is a comparative drug flux of selegilline 0031. The novel solvent system of the present invention formulations comprising the present invention compared to includes a monoalkyl ether, present in an amount of between other formulations; about 1% and 30% by weight of the solvent system, a glycol, present in an amount of between about 1% and 30% by 0042 FIG. 8 is an absolute kinetic profile of selegilline weight of the solvent system. The monoalkyl ether and formulations comprising the present invention with other glycol are present in a weight ratio of 10:1 to 2:1 or 1:2 to formulations; 1:10. The solvent system further includes a mixture of an 0.043 FIG. 9 is an absolute kinetic profile of fentanyl alcohol and water. The mixture present in an amount of formulations comprising the present invention compared to between about 40% and 98% of the solvent system, wherein other formulations; and the alcohol is present in an amount of about 5% to 80% of the mixture, and the water is present in an amount of about 0044 FIG. 10 is a drug flux profile of fentanyl formu 20% to 95% of the mixture. lations comprising the present invention with other formu lations. 0032 Surprisingly, it has been discovered that the com binative use of a monoalkyl ether of diethylene glycol and 004.5 FIG. 11 is an absolute kinetic profile of fentanyl a glycol at specified ratios, preferably in hydro-alcoholic formulations comprising the present invention compared to formulations, prevents or significantly reduces the transfer other formulations; and of active drug(s) from transdermal semi-solid formulations 0046 FIG. 12 is a drug flux profile of fentanyl formu to clothing or other surfaces, significantly reduces the trans lations comprising the present invention with other formu fer to individuals; and also prevents or significantly reduces lations. the loss of active drug(s)—and therefore the loss of thera peutic efficiency—consecutive to accidental removing due 0047 FIG. 13 is an absolute kinetic profile of buspirone to daily activities such as washing, Swimming or the like. formulations comprising the present invention compared to 0033. Other advantages of the present invention include other formulations; and the discovery that the association of a monoalkyl ether and 0048 FIG. 14 is a drug flux profile of buspirone formu a glycol at specified ratios exhibit a synergic effect and lations comprising the present invention with other formu inhibits crystallization of the active ingredient(s) in trans lations. dermal semi-solid formulations. In addition, it has been discovered, against the background described above, a DETAILED DESCRIPTION OF THE totally unexpected control of the active drug(s) distribution PREFERRED EMBODIMENTS in the different layers of the skin is achieved when modi fying the range of the monoalkyl ether:glycol ratio described 0049. The present invention is directed to a novel trans in the present invention, simultaneously but independently dermal or transmucosal pharmaceutical formulation. The from the crystallization inhibitor effect above mentioned. formulation comprises at least one active ingredient and a 0034) Further, it has also been found that the glycol acts Solvent system. The solvent system including a monoalkyl as a modulator of the capability of monoalkyl ether to build ether, a glycol and a hydro-alcohol mixture. In accordance a drug depot in the different layers of the skin. Also, the with the present invention, the transdermal or a transmu significant reduction of unabsorbed active drug(s) remaining cosal drug delivery formulation is in the form of a semi-solid at the application Surface area results from the simultaneous formulation, gel, a cream, an ointment, a lotion (i.e. an although independent inhibition of crystallization and trans emulsion or a dispersion), a solution, a foam, or a spray. dermal drug penetration, enhanced or not by additional Although alternatives are also in the scope of the claims. permeation enhancer(s). 0050. The phrase “semi-solid formulation means a het BRIEF DESCRIPTION OF THE DRAWINGS erogeneous system in which one solid phase is dispersed in 0035 FIG. 1 is schematically illustrates a diffusion a second liquid phase. chamber used for vertical diffusion cell used for in vitro 0051. The phrase “transdermal delivery, applicants testing of oxybutynin transdermal formulations; intend to include both transdermal (or “percutaneous') and 0.036 FIG. 2 is a graph illustrating in-vitro 24-hour transmucosal administration, i.e., delivery by passage of a biodistribution of Testosterone of selected formulation drug through the skin or mucosal tissue and into the blood examples disclosed herein; Stream. 0037 FIG. 3 is a graph illustrating in-vitro 24-hour 0052 The phrase “pharmacologically active' or “physi biodistribution of Minoxidil of selected formulation ologically active' to describe “ingredient’ or "agent’ as examples disclosed herein; used herein means any chemical material or compound US 2006/0153905 A1 Jul. 13, 2006

Suitable for transdermal or transmucosal administration being comprised of a lipid matrix made primarily from which induces a desired systemic effect. cholesterol, ceramides and long chain fatty acids. The Stra 0053) The phrase “therapeutically effective” amount of a tum comeum creates the rate-limiting barrier for diffusion of pharmacologically active agent means a non toxic but Suf the active agent across the skin. ficient amount of a compound to provide the desired thera 0063. The phrase “skin-depot’ as used herein means a peutic effect. reservoir or deposit of active agent and dermal penetration enhancer within the stratum comeum, whether it is intra 0054 The phrase “non-occlusive' system as used herein cellular (within keratinocytes) or inter-cellular. means a system that does not trap nor segregate the skin from the atmosphere by means of for instance a patch 0064. As stated above, the present invention relates to a device, a fixed reservoir, an application chamber, a tape, a transdermal or a transmucosal drug delivery formulation. bandage, a sticking plaster, or the like which remains on the The invention relates more specifically to a non-occlusive skin at the site of application for a prolonged period of time. transdermal or transmucosal formulation, preferably in the form of a gel, for use in the delivery of at least one 0055. The phrase “contamination” or “transfer” as used pharmaceutical active ingredient to a warm-blooded animal. herein means the unintended presence of harmful Substances Formulations of the present invention may be used for local in individuals or surfaces by direct contact between indi or systemic delivery. viduals, between surfaces, or between individuals and Sur 0065. The formulation may include a permeation faces (and reciprocally). enhancer, gelling agent, preservative, antioxidant, buffer, 0056. The phrase “synergy”, “synergism”,99 &g“synergistic humectant, sequestering agent, moisturizer, Surfactant, effect” or “synergistic action” as used herein means an effect emollient, or any combination thereof. The active agent may of the interaction of the actions of two agents such that the be local anaesthetics; general anaesthetics; muscle relaxant result of the combined action is greater than expected as a drugs; diuretics; angiotension converting enzyme inhibitors; simple additive combination of the two agents acting sepa calcium-channel blockers; anti-arythmics; anti-angina rately. drugs; anti-migraine drugs; antiemetic drugs; anti-hista minic drugs and anti-asthma drugs; thrombolytics; analge 0057 The phrase “modulate”, “regulate” or “control” as sics; antitussive agents; tricyclic antidepressants; amphet used herein means to adjust, or maintain, with respect to a amines; anorectics; psychodysleptics; nootropics; desired rate, degree, or condition, as to adjust permeation hypnotics; analeptics; tricyclic neuroleptics; anti-psychotic rate, crystallization speed, repartition of an active pharma drugs; anti-convulsive drugs; hypothalamo-hypophysis ceutical ingredient in the layers of the skin. regulators; corticosteroids; glucocorticoids; mineralocorti 0058. The phrase “effective” or “adequate” permeation coids; glycemic regulators; hypolipidemia drugs; phospho enhancer or combination as used herein means a permeation calcic metabolism regulators; anti-inflammatory drugs; anti enhancer or a combination that will provide the desired secretive gastric drugs; laxatives; gastric mucosa protectors; increase in skin permeability and correspondingly, the gastric motricity modulators; bile salt adsorbants; chelators; desired depth of penetration, rate of administration, and gall Stone dissolvants; anti-anemia drugs; cutaneous dis amount of drug delivered. eases drugs; alpha antagonist drugs; anti-parasitic drugs. 0059) The phrase “monoalkylether of diethylene glycol” 0066. In one embodiment, the pharmaceutical formula means a chemical having general formula CHO(CH2) tion includes testosterone as an active agent and the wherein n=1-4. Further, the term “glycol encompasses a monoalkyl ether of diethylene glycol and the glycol are in a broad range of chemicals including but not limited to weight ratio of 1:4. In another embodiment, the active agent propylene glycol, dipropylene glycol, butylene glycol, and is selegilline hydrochloride or fentanyl and the monoalkyl polyethyleneglycols having general formula ether of diethylene glycol and glycol are in a weight ratio HOCH (CHOH), CH2OH wherein n (number of oxyethyl between about 1:2 to 1:10. ene groups)=4-200. 0067. In another aspect of the invention, a method for delaying or inhibiting crystallization of an active agent in a 0060. The phrase “thermodynamic activity” of a sub transdermal or transmucosal formulation is provided. It has stance means the energy form involved in skin permeation surprisingly been found that the present invention inhibits or of this substance. The chemical potential of a substance is delays for a significant period of time crystallization of the defined in thermodynamics as the partial molar free energy active agent on the skin or mucosal Surface. One problem of the substance. The difference between the chemical associated with crystallization of the drug on the skin is that potentials of a drug outside and inside the skin is the energy the crystals have difficulty crossing the skin or mucosal Source for the skin permeation process. barrier. Thus, the active agent is left on the skin surface for 0061 The phrase “permeation enhancer as used herein an extended period of time. As such, there is an increase in means an agent which improves the rate of percutaneous the likelihood that the active agent is transferred to clothing transport of active agents across the skin or use and delivery or contaminates another being that comes in contact with the of active agents to organisms such as animals, whether for user of the pharmaceutical formulation. The present inven local application or systemic delivery. tion by inhibiting or delaying crystallization of the active agent has at least three advantage. The delay or inhibition of 0062) The phrase “stratum corneum” as used herein the active agent will increase absorption of the drug across means the outer layer of the skin, which comprised approxi the skin or mucosal barrier. Accordingly, there is a minimi mately 15 layers of terminally differentiated keratinocytes zation of transfer of the pharmaceutical formulation to made primarily of the proteinaceous material keratin clothing. Moreover, there is a minimization of contamina arranged in a brick and mortar fashion with the mortar tion of active agent to others. US 2006/0153905 A1 Jul. 13, 2006

0068. In accordance with the present invention, the trans include but is not limited to an estrogen, androgen, or dermal or a transmucosal pharmaceutical formulation is a progestogen, an anti estrogen Such as tamoxifen, 4—OH drug delivery formulation comprising an active ingredient tamoxifen, anti progestogens and anti androgens. and a solvent system. The solvent system of the invention includes a pharmaceutically acceptable monoalkyl ether, a 0073. Also in accordance with the invention, the phar pharmaceutically acceptable glycol, and a mixture of an maceutical active agent may include anti-gout drugs such as alcohol and water. colchicine and derivatives, Sulfinpyrazone, probenecid, ben Zbromarone, allopurinol; local anaesthetics such as ben 0069. For example, the monoalkyl ether is diethylene Zocaine, procaine, tetracaine, lidocaine, etidocaine, glycol monomethyl ether, diethylene glycol monoethyl ether prilocaine, mepivacaine, bupivacaine, butanilicaine, artic or mixtures thereof Also for example the glycol is propylene aine, fomocaine; general anaesthetics Such as methohexital, glycol, dipropylene glycol or mixtures thereof. The monoak thiamylal, thiopenthal, ketamine, etomidate, propofol, mida lyl ether and glycol are present in an amount between about Zolam, flumazenil, droperidol, fentanyl, alfentanil, Sufenta 1% and 30% w/w each, and are present in a ratio ranging nil; muscle relaxant drugs such as curare derivatives, hexac from 10:1 to 2:1 or 1:2 to 1:10. In a preferred embodiment arbacholine, dantrolene, tetrazepam, carisoprodol. the pharmaceutically acceptable monoalkyl ether is diethyl chlorZoxaZone, baclofen, memantine, tiZandine; diuretics ene glycol monoethyl ether and the glycol is propylene such as hydrochlorothiazide and derivatives, chlortalidone, glycol. indapamide, furosemide, bumetanide, piretanide, aZosemide, etoZolin, ethacrynic acid, amiloride, triamterene, 0070 Preferably, the solvent system includes a combina spironolactone; angiotensin converting enzyme inhibitors tion of volatile and non-volatile solvents. Examples of Such as captopril, enalapril, trandolapril, lisinopril, perin non-volatile solvents include but are not limited to propy dopril, benazepril, cilaZepril, fosinopril, moexipril, lene glycol, glycerin, liquid polyethylene glycols, or poly quinapril, ramipril; calcium-channel blockers such as bepri oxyalkylene glycols. Examples of Volatile solvents include dil, diltiazem, felodipine, flunarizine, isradipine, nicar but are not limited to ethanol, propanol, or isopropanol. dipine, nitrendipine, nifedipine, nimodipine, Verapamil, Preferably, the volatile solvent is a C-C alcohol. For amlodipine, lacidipine, buflomedil, anti-arythmics such as example, the C-C alcohol is preferably ethanol, isopro quinidine, ajmaline, procainamide, disopyramide, pro panol, or mixtures of thereof. The C-C alcohol is present pafenone, tocainide, phenytoin, aprindine, mexiletine, in an amount between about 5 and 80% w/w, and preferably flecainide, lorcainide, propafenone, Sotalol, amiodarone, between 15 and 65%, and more preferably between 20 and verapamil, diltiazem; anti-angina drugs such as nitrate 50%. derivatives, molsidomine; anti-migraine drugs such as, pizo 0071. The active ingredient of the formulation includes tifene, oxetorone, methysergide Sumatriptan, Zolmitriptan, but is not limited to a hormone such as nonsteroidal estro naratriptan, eletriptan, almotriptan, rizatriptan; antiemetic gens such as benzestrol, broparoestrol, chlorotrianisene, drugs such as chlorphenoxamine, dimenhydramine, mecloz dienestrol, diethylstilboestrol, diethylstilboestrol dipropi ine, triethylperazine, triflupromazine, metoclopramide, bro onate, dimestrol, fosfestrol, hexoestrol, methallenestril and mopride, domperidone, granisetron, ondansetron, tro methestrol, and steroidal estrogens such as colpormon, con pisetron, dolasetron, alosteron, tegaserod; anti-histaminic jugated estrogenic hormones, equilenin, equilin, estradiol, and anti-asthma drugs such as cromoglycate, nedocromil. 17 beta-estradiol, estriol, estrone, ethinyl estradiol, estradiol tritoqualine, ketotifene, lodoxamide, Salbutamol, terbuta benzoate, estradiol 17 beta-cypionate, polyestradiol phos line, pirbuterol, salmeterol, formoterol, bambuterol, mon phate, mestranol, moxestrol, my tatrienediol, quinestradiol. telukast, pranlukast, theophylline, ipratropium, oxitropium, quinestrol; progestogens such as allylestrenol, anagestone, beclometaSone, dexamethasone, fluticaSone, budesonide, chlomardinone acetate, delmadinone acetate, demegestone, flunisolide; thrombolytics such as alteplase and derivatives, desogestrel, dimethisterone, drospirenone, dydrogesterone, streptokinase, urokinase; analgesics such as morphine, ethynilestrenol, ethisterone, ethynodiol, ethynodiol diac codeine, diamorphine, dihydrocodeine, hydromorphone, etate, flurogestone acetate, gestodene, gestonorone caproate, hydrocodone, oxycodone, oxymorphone, levorphanol, haloprogesterone, 17-hydroxy-16-methylene-delta.-proges pethidine, levomethadone, fenpipramine, piritramide, terone, 17.alpha-hydroxyprogesterone, 17.alpha-hydrox clofedanol, pentazocine, buprenorphine, butorphanol, nal ygesterone caproate, lynestrenol, medrogestone, medroX buphine, tilidine, tramadol, nefopam, Salicylic acid and yprogesterone, megestrol acetate, melengestrol, derivatives, Salsalate, diflunisal, acetaminophen, benorylate, norethindrone, norethindrone acetate, norethynodrel, norg mefenamic acid, flufenamic acid, niflumic acid, metamizole, esterone, norgestimate, norgestrel, norgestrienone, 19 nor phenaZone, phenylbutyaZone, aminophenaZone, oxyphenb progesterone, norvinisterone, pentagestrone, progesterone, utaZone, azapropaZone, indometacin, diclofenac, Sulindac, natural progesterone, promegestone, quingestrone, trenge felbinac, ibuprofen, naproxen, fenoprofen, flurbiprofen, stone; androgens such as boldenone, cloXotestosterone, flu ketoprofen, tiaprofenic acid, nabumetone, piroxicam, oxymesterone, mestanolone, mesteronolone, 17-methyltes tenoxicam, meloxicam, antitussive agents such as codeine tosterone, testosterone 17 beta-cypionate, testosterone and derivatives, clobutinol, isoaminile, pentoxyverine, enanthate, testosterone nicotinate, testosterone phenylac butamirate, Oxeladine, pipaZetate; tricyclic antidepressants etate, testosterone propionate, 17.alpha.-methyltestosterone Such as imipramine, desipramine, trimipramine, 3-cyclopentyl enol ether, norethandrolone, normethandrone, lofepramine, clomipramine, opipramol, amitriptyline, ami Oxandrolone, oxymesterone, oxymetholone, prasterone, triptylinoxide, nortriptyline, dibenzepin, doxepin, meli tracen; tetracyclic antidepressants such as maprotiline, stanolone, stanoloZol, testosterone, tiomesterone. mianserin; atypical antidepressants such as fluvoxamine, 0072 Moreover, the active agent may be an anti-hor traZodone, Viloxacin, fluoxetine; monoamine oxidase inhibi mone. For example, the pharmaceutical active agent may tors such as tranylcipromine; serotonin precursors such as US 2006/0153905 A1 Jul. 13, 2006 oxitriptan; lithium salts; tranquilizers such as meprobamate, mides; quinolones; isoniazide, ethambutol; antineoplasic hydroxy Zine, chlordiazepoxide, temazepam, flurazepam, drugs such as chlormethine, chlorambucil, melphalan, lormetazepam, nitrazepam, flunitrazepam, diazepam, cyclophosphamide, ifosfamide, estramustine, carnustine, prazepam, oxazepam, lorazepam, clonazepam, bro lomustine, fotemustine, carbazine derivatives, cisplatine and mazepam, clotiazepam, alprazolam, triazolam, oxazolam, derivatives, thiothepa, daunorubicine and derivatives, midazolam, ketazolam, brotizolam, clobazam, cloraZepate, mitoxantrone, 5-fluorouracil, capecitabine, cytarabine, gem buspirone; amphetamines and related compounds such as citabine, mercaptiopurine azathioprine, fludarabine, amfetamine, metamfetamine, fenetylline, methylphenidate, thioguanine, pentostatine, cladribine, raltitrexed; anti virus prolintane; anorectics Such as cathine, amfepramone, drugs such as zidovudine and derivatives, aciclovir and mefenorex, propylhexedrine, fenfluramine; psychodyslep derivatives, foscarnet, ritonavir and derivatives; antifungus tics Such as N-dimethyltryptamine, psilocin, psilocybin, drugs such as nystatine, terbinafine, micanazole, ketocona bufotenin, lysergide, mescaline, tetrahydrocannabinol; noo Zole, fluconazole, itraconazole, bifonazole, econazole, omo tropics such as pyritinol, piracetam, meclofenoxate; hypnot conazole, Sulconazole, tioconazole, isoconazole, fenticona ics such as carbromal, bromisoval, vinylbital, aprobarbital, Zole, Sertaconazole. secbutabarbital, pentobarbital, cyclobarbital, phenobarbital, 0074 The active agent may also be selected from an glutethimide, methyprylon, methaqualone; analeptics Such anti-Parkinson drug, an anti-Alzheimer's drug or an opioid as doxapram; tricyclic neuroleptics such as chlorpromazine, analgesic. For example, the opioid analgesic may be fenta promazine, triflupromazine, alimemazine, levomepro nyl. mazine, chlorprothixene, pecazine, thioridazine, perphena Zine, trifluoperazine periciazine, perazine, fluphenazine, dix 0075. The term “anti-Parkinson drugs' as used herein yrazine, clopenthixol, dixyrazine, prothipendyl, thithixene, means any drug administered to a patient for the treatment chlorprothixene, clopenthixol, flupentiXol; butyrophenones of Parkinson's Disease or the symptoms associated with and diphenylbutylpiperidines neuroleptics such as haloperi Parkinson's Disease, such as but not limited to trihex dol, bromperidol, droperidol, trifluperidol, pipamperone, yphenidyl, tropatepione, biperiden, procyclidine, benzatro melperone, benperidol, pimozide, fluspirilene; benzamide pine, orphenadrine, bornaprine, metixene, levodopa, or a neuroleptics such as Sulpiride; anti-psychotic drugs such as pharmaceutically acceptable salt thereof. The anti-Parkinson clozapine, haloperidol, olanzapine, quetiapine, risperidone; drug may be in the fomulation alone or in combination with anti-convulsive drugs such as carbamazepine, Valproic acid a decarboxylase inhibitor Such as carbidopa or benserazide, and its derivatives, primidone, phenytoin, ethoSuximide, bromocriptine, lisuride, amantadine, or Selegiline. trimethadione, Sultiame, hypothalamo-hypophysis regula 0076. The term “anti-Alzheimer drug” as used herein tors such as gonadoreline, triptoreline, leupropreline, buser means any drug administered to a patient for the treatment eline, gosereline, nafareline, gonadotrophins, follitropins, of Alzheimer's Disease or the symptoms associated with danazol, clomifene, quinagoline, bromocriptine, lisuride; Alzheimer's Disease. Such as but not limited to galantamine, antihypo- and antihyperthyroidy drugs such as thyreotropin rivastigmine, doneZepil, tacrine, or memantine, or a phar releasing hormone, thyreoStimuline hormone, triiodothyro maceutically acceptable salt thereof. nine, thyroxine, tiratricol, benzylthiouracile, clotrimazole, corticosteroids; glucocorticoids and mineralocorticoids; gly 0077. Further, the active agent may be an alpha-adrener cemia regulators such as insuline, glipizide, glibenclamide, gic agonists such as budralazine, clonidine, epinephrine, glibomuride, gliclazide, carbutamide, glimepiride, repaglin fenoxazoline, naphazoline, phenylephrine, phenylpropano ide, metformine, acarbose, miglitol, glucagon, diaZoxide; lamine, beta-adrenergic agonists Such as formoterol, meth hypolipidemia drugs such as orlistat, simvastatine, pravas oxyphenamine, alpha-adrenergic blockers such as dox tatine, fluvastatine, atorvastatine, tiadenol, cholestyramine, aZosin, praZosin, teraZosin, trimaZosin, yohimbine, beta fenofibrate, ciprofibrate, bezafibrate, gemfibrozil, ursodiol; adrenergic blockers such as abenolol, bisoprolol, carteolol. phosphocalcic metabolism regulators such as ergocalciferol, carvedilol.metoprolol, nadolol, penbutolol, nerve agents for cholecalciferol calcitriol, alfacalcidol, calcifediol, calcipot Smoking cessation Such as nicotine, nicotine citrate and riol, tacalcitol; anti-inflammatory drugs such as nabume nicotine tartrate, anticholinergic agents; antiepileptic agents; tone, meloxicam, nimeSulide, etodolac, alminoprofene, Sul antiparkinson agents; bronchodilators; narcotic antagonists; fasalazine, mefasalazine, olSalazine, rofecoxib, celecoxib, amides Such as butoctamide, diethylbromoacetamide, Valdecoxib, nefopam; antisecretive gastric drugs such as ibrotamide, isovaleryl diethylamide, niaprazine, tricetamide, omeprazole, lanSoprazole, pantoprazole, rabeprazole, miso trimetozine, Zolpidem, Zopiclone, guanidine derivatives prostol; laxatives; gastric mucosa protectors such as cime Such as guanethidine; quinazoline derivatives such as alfu tidine, famotidine, ranitidine, nizatidine, gastric motricity Zosin; reserpine derivatives such as reserpine, Sulfonamide modulators; bile salts adsorbants; chelators; gall Stone dis derivatives Such as furosemide; others such as minoxidil, Solvants; anti-anemia drugs; cutaneous diseases drugs; alpha doxazosin mesylate, moXonidine, and dihydropyridine antagonist drugs such as urapidil and derivatives, praZosine derivatives such as nilvadipine, nisoldipine, piperazine; and derivatives, nicergoline, moxisylyte, antiparasitic drugs derivatives Such as flunarisine; others such as perhexiline; Such as albendazole, atovaquone, chloroquine, dehydro calcium regulator Such as calcitonin, clodronic acid, dihy emetine, diloxanide, furazolidone, halofantrine, iodoquinol, drotachysterol, elcatonin, etidronic acid, ipriflavone, pam ivermectin, mebendazole, mefloquine, metronidazole, nifur idronic acid, parathyroid hormone, teriparatide acetate, or timox, primaquine, pyrantel, pyrimethamine, quinine, qui selegilline hydrochloride. However, the present invention nidine, penicillins; cephalosporins; aminosids; polypeptides; could be applied to other groups of pharmaceutical active Sulfamides; diaminopyrimidines; tetracyclins; chloram agents not previously mentioned. It is to be understood that phenicol; thiamphenicol; macrollides; Vancomycin; teicopla the “active agent' is intended to mean a single active agent nin: rifampicin; fusidic acid; 5-nitro-imidazoles; lincosa or a combination of more than one active agent. The amount US 2006/0153905 A1 Jul. 13, 2006 of the systemically and/or topically active agent included in noxyethanol, phenylethyl alcohol, phenylmercuric salts, the formulation is subject to the degree to which penetration thimerosal, sorbic acid and derivatives. The preservative is enhancement is achieved. present from about 0.01 to about 10% w/w depending on the 0078. Also in accordance with the invention, permeation type of compound. enhancers may be additionally incorporated to the pharma 0081. The transdermal or transmucosal pharmaceutical ceutical formulation. Permeation enhancers include but are formulation may further comprise an antioxidant Such as but not limited to sulfoxides such as dimethylsulfoxide and not limited to tocopherol and derivatives, ascorbic acid and decylmethylsulfoxide; Surfactants such as Sodium laurate, derivatives, butylated hydroxyanisole, butylated hydroxy Sodium lauryl Sulfate, cetyltrimethylammonium bromide, toluene, fumaric acid, malic acid, propyl gallate, metabisul benzalkonium chloride, poloxamer (231, 182, 184), tween fates and derivatives. The antioxidant is present from about (20, 40, 60, 80) and lecithin; the 1-substituted azacyclohep 0.001 to about 5.0% w/w depending on the type of com tan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2- pound. one; fatty alcohols such as lauryl alcohol, myristyl alcohol, oleyl alcohol and the like; fatty acids such as lauric acid, 0082 Also in accordance with the invention, the formu oleic acid and Valeric acid; fatty acid esters such as isopropyl lation may further comprise buffers such as carbonate buff myristate, isopropyl palmitate, methylpropionate, and ethyl ers, citrate buffers, phosphate buffers, acetate buffers, hydro oleate; polyols and esters thereof Such as propylene glycol, chloric acid, lactic acid, tartaric acid, diethylamine, ethylene glycol, glycerol, butanediol, polyethylene glycol, triethylamine, diisopropylamine, aminomethylamine. and polyethylene glycol monolaurate, amides and other Although other buffers as known in the art may be included. nitrogenous compounds such as urea, dimethylacetamide The buffer may replace up to 100% of the water amount (DMA), dimethylformamide (DMF). 2-pyrrolidone, 1-me within the formulation. thyl-2-pyrrolidone, ethanolamine, diethanolamine and tri ethanolamine, terpenes; alkanones, and organic acids, par 0083. In one embodiment, the transdermal or transmu ticularly Salicylic acid and Salicylates, citric acid and cosal pharmaceutical formulation further comprises humec succinic acid. As noted earlier herein, "Percutaneous Pen tant such as glycerin, propylene, glycol, Sorbitol, triacetin. etration Enhancers’, eds. Smith et al. (CRC Press, 1995), The humectant is present from about 1 to 10% w/w depend which is incorporated herein by reference thereto, provides ing on the type of compound. an excellent overview of the field and further information 0084. The present formulation may further comprise concerning possible secondary enhancers for use in con sequestering agent such as edetic acid. The sequestering junction with the present invention. More permeation agent is present from about 0.001 to about 5% w/w depend enhancer(s) suitable to be used with the present invention ing on the type of compound. may be known by those skilled in the art. The permeation enhancer is present from about 0.1 to about 30.0% w/w 0085 Also in accordance with the invention, the formu depending on the type of compound. Preferably the perme lation includes a moisturizer Such as docusate Sodium, ation enhancers are fatty alcohols and fatty acids, and more polyoxyethylene alkyl ethers, polyoxyethylene castor oil preferably fatty alcohols. Preferably, the fatty alcohols have derivatives, polyoxyethylene Stearates, polyoxyethylene Sor the formula the CH3(CH2)n(CH)mCH2OH wherein n bitan fatty acid esters, sodium lauryl sulfate. The moisturizer ranges from (8-m) to (16-m) and m=0-2. is present from about 1.0 to about 5% w/w depending on the type of compound. 0079 The pharmaceutical formulation of the invention may further include a gelling agent or thickener, e.g. car 0086) The formulation may further comprise anionic, bomer, carboxyethylene or polyacrylic acid such as car nonionic, or cationic Surfactants. The Surfactant is present bomer 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 from about 0.1 to about 30% w/w depending on the type of or 934 NF, ETD 2020, 2050, 934P NF, 971P NF, 974P NF compound. and carbomer derivatives; cellulose derivatives such as ethylcellulose, hydroxypropylmethylcellulose (HPMC), 0087 Also in accordance with the present invention, the ethyl-hydroxyethylcellulose (EHEC), carboxymethylcellu formulation comprises emollients such as but not limited to lose (CMC), hydroxypropylcellulose (HPC), hydroxyethyl cetostearyl alcohol, cetyl esters wax, cholesterol, glycerin, cellulose (HEC), etc.; natural gums such as arabic, Xanthan, fatty esters of glycerol, isopropyl myristate, isopropyl palmi guar gums, alginates, etc., polyvinylpyrrolidone derivatives; tate, lecithins, light mineral oil, mineral oil, petrolatum, polyoxyethylene polyoxypropylene copolymers, etc.; others lanolins, and combinations thereof. The emollient is present like chitosan, polyvinyl alcohols, pectins, veegum grades, from about 1.0 to about 30.0% w/w depending on the type and the like. Other Suitable gelling agents to apply the of compound. present invention include, but are not limited to, carbomers. 0088. In another aspect of the present invention a method Alternatively, other gelling agents or viscosant known by is provide for delaying or inhibiting crystallization of an those skilled in the art may also be used. The gelling agent active agent in a transdermal or transmucosal pharmaceuti or thickener is present from about 0.2 to about 30% w/w cal formulation. The method includes preparing a formula depending on the type of polymer, as known by one skilled tion comprising at least one active agent and a solvent in the art. system, which includes a pharmaceutically acceptable 0080. The transdermal or transmucosal pharmaceutical monoalkyl ether of diethylene glycol and a glycol present in formulation may further include preservatives such as ben a weight ratio of 10:1 to 2:1 or 1:2 to 1:10. In one Zalkonium chloride and derivatives, benzoic acid, benzyl embodiment of the method, the monoalkyl ether of dieth alcohol and derivatives, bronopol, parabens, centrimide, ylene glycol and the glycol are present in an ratio of 10:1 to chlorhexidine, cresol and derivatives, imidurea, phenol, phe 2:1. In another embodiment of the method, the monoalkyl US 2006/0153905 A1 Jul. 13, 2006 ether of diethylene glycol and the glycol are present in an Example 5 amount of about. 1:2 to 1:10. 0096. A gel composed by testosterone 1.00% w/w, dieth 0089 Preferably, the monoalkyl ether of diethylene gly ylene glycol monoethyl ether 5.00% w/w, propylene glycol col and the glycol in combination are present in an amount 15.0% w/w, ethanol 42.56% w/w, purified water 34.82% of at least 15% and no more than 60% of the formulation. w/w, carbomer (CARBOPOLTM 980 NF) 1.20% w/w, tri 0090 Advantageously, the method decreases or inhibits ethanolamine 0.35% w/w, disodium EDTA 0.06% w/w, was crystallization of the active agent such that absorption and prepared according to the manufacturing technique permeation through the skin or mucosal Surface to which it described in Example 1. is applied is facilitated or increased. Preferably, the formu lation includes a permeation enhancer to increase perme Example 6 ability of the active agent across a dermal or mucosal 0097 Agel composed by testosterone 1.00% w/w, dieth surface. For example, the formulation may further include ylene glycol monoethyl ether 30.0% w/w, propylene glycol lauryl alcohol or myristyl alcohol in an amount between 0.5 6.00% w/w, ethanol 33.76% w/w, purified water 27.62% to 2% by weight of the total formulation. w/w, carbomer (CARBOPOLTM 980 NF) 1.20% w/w, tri ethanolamine 0.35% w/w, disodium EDTA 0.06% w/w, was EXAMPLES prepared according to the manufacturing technique 0.091 The following examples are illustrative, and should described in Example 1. not be interpreted as limitations to the invention. Example 7 Example 1 0098. A gel composed by testosterone 1.00% w/w, dieth 0092. A gel containing testosterone 1.00% weight by ylene glycol monoethyl ether 5.00% w/w, propylene glycol weight (w/w), diethylene glycol monoethyl ether 5.00% 6.00% w/w, ethanol 47.40% w/w, purified water 38.79% w/w, propylene glycol 6.00% w/w, ethanol 46.28% w/w, w/w, carbomer (CARBOPOLTM 980 NF) 1.20% w/w, tri purified water 38.11% w/w, carbomer (CARBOPOLTM 980 ethanolamine 0.35% w/w, disodium EDTA 0.06% w/w, NF) 1.20% w/w, triethanolamine 0.35% w/w, disodium lauryl alcohol 0.20% w/w, was prepared according to the edetic acid (EDTA) 0.06% w/w, lauryl alcohol 2.00% w/w manufacturing technique described in Example 1. was prepared by dissolving the active ingredient (if not hydrosoluble) in the ethanol/propylene glycol/diethylene Example 8 glycol monoethyl ether/lauryl alcohol mixture. The diso dium EDTA solution was then added and carbomer thor 0099 Agel composed by testosterone 1.00% w/w, dieth oughly dispersed in the hydro-alcoholic Solution under ylene glycol monoethyl ether 5.00% w/w, ethanol 50.81% mechanical stirring at room temperature at a Suitable speed w/w, purified water 38.87% w/w, carbomer (CARBOPOLTM ensuring good homogenization of the formulation while 980 NF) 1.20% w/w, triethanolamine 0.35% w/w, disodium avoiding lumps formation and air entrapment. Triethanola EDTA 0.06% w/w, was prepared according to the manufac mine was finally added under stirring to form the gel. turing technique described in Example 1. Example 2 Example 9 0093. A gel composed by testosterone 1.00% w/w, dieth 0.100 Agel composed by testosterone 1.00% w/w, dieth ylene glycol monoethyl ether 5.00% w/w, propylene glycol ylene glycol monoethyl ether 5.00% w/w, propylene glycol 6.00% w/w, ethanol 46.96% w/w, purified water 38.43% 30.0% w/w, ethanol 34.31% w/w, purified water 28.07% w/w, carbomer (CARBOPOLTM 980 NF) 1.20% w/w, tri w/w, carbomer (CARBOPOLTM 980 NF) 1.20% w/w, tri ethanolamine 0.35% w/w, disodium EDTA, 0.06% w/w ethanolamine 0.35% w/w, disodium EDTA 0.06% w/w, was lauryl alcohol 1.00% w/w was prepared according to the prepared according to the manufacturing technique manufacturing technique described in Example 1. described in Example 1. Example 3 Example 10 0094. A gel composed by testosterone 1.00% w/w, dieth 0101 Agel composed by testosterone 1.00% w/w, etha ylene glycol monoethyl ether 5.00% w/w, propylene glycol nol 53.56% w/w, purified water 43.83% w/w, carbomer 6.00% w/w, ethanol 47.52% w/w, purified water 38.87% (CARBOPOLTM 980 NF) 1.20% w/w, triethanolamine w/w, carbomer (CARBOPOLTM 980 NF) 1.20% w/w, tri 0.35% w/w, disodium EDTA 0.06% w/w, was prepared ethanolamine 0.35% w/w, disodium EDTA 0.06% w/w, was according to the manufacturing technique described in prepared according to the manufacturing technique Example 1. described in Example 1. Example 11 Example 4 0102) A gel composed by testosterone 1.00% w/w, dieth 0.095 A gel composed by testosterone 1.00% w/w, pro ylene glycol monoethyl ether 15.0% w/w, propylene glycol pylene glycol 6.00% w/w, ethanol 50.26% w/w, purified 6.00% w/w, ethanol 42.00% w/w, purified water 34.39% water 41.13% w/w, carbomer (CARBOPOLTM 980 NF) w/w, carbomer (CARBOPOLTM 980 NF) 1.20% w/w, tri 1.20% w/w, triethanolamine 0.35% w/w, disodium EDTA, ethanolamine 0.35% w/w, disodium EDTA 0.06% w/w, was was prepared according to the manufacturing technique prepared according to the manufacturing technique described in Example 1. described in Example 1. US 2006/0153905 A1 Jul. 13, 2006

Example 12 30.0% w/w ethanol 37.50% w/w, purified water 25.00% 0103) A gel composed by minoxidil 2.00% w/w, ethanol w/w, hydroxypropylcellulose (KLUCELTM MF Pharm) 58.50% w/w, purified water 39.00% w/w, hydroxypropyl 0.50% w/w, was prepared according to the manufacturing cellulose (KLUCELTMMF Pharm) 0.50% w/w, % w/w, was technique described in Example 12. prepared by dissolving the active ingredient (if not hydro soluble) in the ethanol/propylene glycol/diethylene glycol Example 20 monoethyl ether/lauryl alcohol mixture. Purified water was 0.111 Agel composed by estradiol 2.00% w/w, diethylene then added and hydroxypropylcellulose thoroughly dis glycol monoethyl ether 30.0% w/w, propylene glycol 6.00% persed in the hydro-alcoholic Solution under mechanical w/w ethanol 36.90% w/w, purified water 24.60% w/w, stirring at room temperature at a suitable speed ensuring hydroxypropylcellulose (KLUCELTM MF Pharm) 0.50% good homogenization of the formulation while avoiding W/w, was prepared according to the manufacturing tech lumps formation and air entrapment until complete Swelling. nique described in Example 12. Example 13 Example 21 0104. A gel composed by minoxidil 2.00% w/w, dieth 0112 A gel composed by fentanyl base 3.00% w/w, ylene glycol monoethyl ether 5.00% w/w, propylene glycol ethanol 58.00% w/w, purified water 38.60% w/w, hydrox 30.0% w/w ethanol 37.50% w/w, purified water 25.00% ypropylcellulose (KLUCELTM MF Pharm) 0.50% w/w, was w/w, hydroxypropylcellulose (KLUCELTM MF Pharm) prepared according to the manufacturing technique 0.50% w/w, was prepared according to the manufacturing technique described in Example 12. described in Example 12. Example 14 Example 22 0105. A gel composed by minoxidil 2.00% w/w, dieth 0113. A gel composed by fentanyl base 5.00% w/w, ylene glycol monoethyl ether 30.0% w/w, propylene glycol diethylene glycol monoethyl ether 5.00% w/w, propylene 6.00% w/w ethanol 36.90% w/w, purified water 24.60% glycol 30.0% w/w ethanol 36.00% w/w, purified water w/w, hydroxypropylcellulose (KLUCELTM MF Pharm) 23.50% w/w, hydroxypropylcellulose (KLUCELTM MF 0.50% w/w, was prepared according to the manufacturing Pharm) 0.50% w/w, was prepared according to the manu technique described in Example 12. facturing technique described in Example 12. Example 15 Example 23 0106 Agel composed by oxybutynin base 2.00% w/w, 0114. A gel composed by fentanyl base 2.00% w/w, ethanol 58.50% w/w, purified water 39.00% w/w, hydrox diethylene glycol monoethyl ether 30.0% w/w, propylene ypropylcellulose (KLUCELTM MF Pharm) 0.50% w/w, was glycol 6.00% w/w ethanol 36.90% w/w, purified water prepared according to the manufacturing technique 24.60% w/w, hydroxypropylcellulose (KLUCELTM MF described in Example 12. Pharm) 0.50% w/w, was prepared according to the manu facturing technique described in Example 12. Example 16 0107 Agel composed by oxybutynin base 2.00% w/w, Example 24 diethylene glycol monoethyl ether 5.00% w/w, propylene 0.115. A gel composed by testosterone 1.00% w/w, estra glycol 30.0% w/w ethanol 37.50% w/w, purified water diol 0.10% w/w, ethanol 59.00% w/w, purified water 39.40% 25.00% w/w, hydroxypropylcellulose (KLUCELTM MF w/w, hydroxypropylcellulose (KLUCELTM MF Pharm) Pharm) 0.50% w/w, was prepared according to the manu 0.50% w/w, was prepared according to the manufacturing facturing technique described in Example 12. technique described in Example 12. Example 17 Example 25 0108) A gel composed by oxybutynin base 2.00% w/w, diethylene glycol monoethyl ether 30.0% w/w, propylene 0116. A gel composed by testosterone 1.00% w/w, estra glycol 6.00% w/w ethanol 36.90% w/w, purified water diol 0.10% w/w, diethylene glycol monoethyl ether (TRAN 24.60% w/w, hydroxypropylcellulose (KLUCELTM MF SCUTOLTM P) 5.00% w/w, propylene glycol 30.0% w/w Pharm) 0.50% w/w, was prepared according to the manu ethanol 38.00% w/w, purified water 25.40% w/w, hydrox facturing technique described in Example 12. ypropylcellulose (KLUCELTM MF Pharm) 0.50% w/w, was prepared according to the manufacturing technique Example 18 described in Example 12. 0109) A gel composed by estradiol 2.00% w/w, ethanol 58.50% w/w, purified water 39.00% w/w, hydroxypropyl Example 26 cellulose (KLUCELTM MF Pharm) 0.50% w/w, was pre 0117. A gel composed by testosterone 1.00% w/w, estra pared according to the manufacturing technique described in diol 0.10% w/w, diethylene glycol monoethyl ether 30.00% Example 12. w/w, propylene glycol 6.00% w/w ethanol 37.40% w/w, purified water 25.00% w/w, hydroxypropylcellulose Example 19 (KLUCELTMMF Pharm) 0.50% w/w, was prepared accord 0110. A gel composed by estradiol 2.00% w/w, diethyl ing to the manufacturing technique described in Example ene glycol monoethyl ether 5.00% w/w, propylene glycol 12. US 2006/0153905 A1 Jul. 13, 2006

Example 27 under non-occlusive conditions and at 600 rpm of stirring speed. At given time points, samples were withdrawn from 0118. A gel composed by estradiol 0.06% w/w, diethyl the receptor Solution and the receptor chamber was imme ene glycol monoethyl ether 5.00% w/w, propylene glycol diately refilled with fresh solution. All samples taken from 6.0% w/w, ethanol 46.28% w/w, purified water 41.05% w/w, the receptor Solution (permeated drug) were analyzed using carbomer (CARBOPOLTM 980 NF) 1.20% w/w, triethano a high performance liquid chromatography (HPLC) method. lamine 0.35% w/w, disodium EDTA 0.06% w/w, lauryl After completion of the permeation study, and utilizing alcohol 2.00% w/w, was prepared according to the manu appropriate solvents formulation, all skin disk pieces were facturing technique described in Example 1. analysed in drug distribution within the skin layers: dermis, Example 28 epidermis and stratum comeum. Unabsorbed formulation was also assessed. Then, balance mass was performed in 0119) A gel composed by alprazolam 2.00% w/w, ethanol order to assess total recovery/distribution of drug after 58.50% w/w, purified water 39.00% w/w, hydroxypropyl certain time following drug product administration/applica cellulose (KLUCELTMMF Pharm) 0.50% w/w, % w/w, was tion, considering unabsorbed formulation, the amount of prepared according to the manufacturing technique drug in the stratum comeum and the amount of drug within described in Example 12. the innermost layers of the skin (epidermis, dermis, and receptor solution representing the bloodstream). The differ Example 29 ent compartments were analyzed using a high performance 0120) A gel composed by alprazolam 2.00% w/w, dieth liquid chromatography (HPLC) method. ylene glycol monoethyl ether 5.00% w/w, propylene glycol Cumulated Drug Permeated and Drug Flux Determination 30.0% w/w ethanol 37.50% w/w, purified water 25.00% (in vitro Permeation Study) w/w, hydroxypropylcellulose (KLUCELTM MF Pharm) 0.50% w/w, was prepared according to the manufacturing 0.124. The total amount of drug permeated (mcg/cm2) technique described in Example 12. during the study duration and the transdermal flux (mcg/ sqcm/h) were determined for each study. Example 30 0.125 Biodistribution Study 0121 Agel composed by alprazolam 2.00% w/w, dieth 0.126. After completion of the in vitro permeation study, ylene glycol monoethyl ether 30.0% w/w, propylene glycol distribution of the active compound was assessed for the 6.00% w/w ethanol 36.90% w/w, purified water 24.60% different compartments as explained before. In order to w/w, hydroxypropylcellulose (KLUCELTM MF Pharm) demonstrate the improvements in the permeation perfor 0.50% w/w, was prepared according to the manufacturing mance applying the invention herein discloses, as well as technique described in Example 12. improvements in minimizing amount of drug that can poten tially being transferred to clothes or partners, in vitro per COMPARATIVE EXAMPLES OF-IN VITRO meation studies and drug biodistribution studies of examples DRUG BIODISTRIBUTION AND PERMEATION using the inventive means were compared with examples STUDIES made without using this invention. Example 31 0127. It was an objective to demonstrate the results 0122) In vitro drug biodistribution and permeation obtained applying the invention herein disclose. By carrying experiments through ear pig skin were made using the out drug biodistribution studies in vitro and though, assess diffusion chamber that is schematically shown in FIG. 1 ing the amount of drug remaining on the skin Surface which (Franz Vertical Diffusion Cell). Cutaneous penetration stud can potentially be transmitted or transferred to other surfaces ies in vitro through human skin are limited due to the lack or partners when the formulation is used “in vivo”. of availability of the human skin. It is largely described in Example 32 the literature that ear pig skin can be used as the closest model to human skin in the assessment of percutaneous Comparison Between a Formulation of the Present absorption of chemicals. Invention and a Prior Art Formulation 0123 Fresh cadaver ear pig skin obtained from slaugh 0.128 Refer to “Examples’ above for the quali-quantita terhouses was processed according to standard operating tive formulations of the examples cited below. procedures. The ears were evaluated on their integrity (no bites, Scratches or redness) and condition. The skin was 0129 Testosterone 24-Hour Biodistribution excised from the ears with the help of Scalpels, avoiding perforations or any damage. The excised skin Samples were TABLE I rinsed with PBS solution and placed on a surface for Testosterone in vitro 24-hour biodistribution Successive punching of skin disks. The skin disk pieces were Normalized recovery (% of total relative recovery mounted between the sections of a vertical diffusion cell having 1.77 sqcm of Surface area, the epidermal facing up. Example 10 Example 9 Example 6 50 mg of the transdermal devices exemplified previously control TCPG ratio 1:9) (TCPG ratio 5:1 was applied over the epidermal layer whilst the dermal layer Mean SD Mean SD Mean SD contact with the receptor solution: 2.0% weight by volume Compartments % % N % % N % % N polyoxyethylene 20 oleyl ether (Oleth 20), with phosphate Unabsorbed 92.5 20.1 4 66.5 32.2 4 82.4 15.9 buffer solution PBS 10 mM, pH 7.4. The receptor chamber formulation 4 was maintained at 35° C. and the studies were conducted US 2006/0153905 A1 Jul. 13, 2006

TABLE I-continued TABLE II-continued

Testosterone in vitro 24-hour biodistribution Minoxidil 24-hour biodistribution Normalized recovery (% of total relative recovery Normalized recovery (% of total relative recovery Example 10 Example 9 Example 6 Example 12 Example 13 Example 14 control TCPG ratio 1:9) (TCPG ratio 5:1 (control) (TC:PG ratio 1:6) (TC:PG ratio 5:1) Mean SD Mean SD Mean SD Compartments % % N % % N % % N Mean SD Mean SD Mean SD Compartments % % N % % N % % N Stratum 5.7 3.0 4 12.6 8.3 4 6.6 4.0 4 COilell Epidermis 15 O2 4 9.S. S.1 4 5.1 2.8 4 Epidermis 18 OS 4 20.9 4.8 4 11.1 5.5 4 Dermis Dermis Receptor Receptor TOTAL 1OO.O 1OOO 1OO.O TOTAL 1OO.O 1OO.O 1OOO

0130 Table 1 above clearly shows a significant decrease 0.134 Table II illustrates the results of a 24-hour biodis in the amount of drug that is unabsorbed when a transdermal tribution study using Minoxidil as the active agent. The or transmucosal formulation of the present invention is used results clearly confirm a significant decrease in the amount compared a transdermal or transmucosal formulation that of drug unabsorbed when the invention is present in the does not include the novel ratio of monoalkyl ester and formulation. As shown in Table II and also in FIG. 3 (in glycol. As shown, after 24 h, a huge amount of testosterone graphic form), after 24 h. 94.2% of minoxidil remained (92.5%) remained unabsorbed from example 10, which does unabsorbed from example 12, but examples 14 and more not include the novelty of the present invention, conversely, particularly example 13 both of which are preferred embodi examples 9 and 6, both embodiments of the present inven ments of the present invention, more minoxidil was tion had significantly less unabsorbed drug, 66.5% and absorbed. Specifically, example 14 had 90.5% of unab 82.4% respectively. FIG. 2 illustrates these results in sorbed drug, and example 13 had 85.9%. Table II and FIG. graphic format. 3 also show a higher amount of minoxidil (6.2% versus 0131 Table 1 above and FIG. 2 show that a higher 2.1%) was present in the stratum comeum in example 13, amount of testosterone (12.6% versus 6.6%) is present in the wherein the monoalkyl ether and the glycol are present in a stratum corneum in example 9 where the invention is present ratio of 1:6, and example 14 where the monoalkyl ether and in a ratio of 1:6 than in example 6 where the invention is the glycol are present in a ratio of 5:1. Thus, again it is present in a ratio of 5:1. This result shows that accumulation shown that accumulation of active drug in the outermost of active drug in the outermost layer of the skin or the layer of the skin or the mucosa does result from the mucosa does result from the combination of diethylene synergistic combination of diethylene glycol monoethyl glycol monoethyl ether propylene glycol in defined ratios, and does not only depend on diethylene glycol monoethyl ether propylene glycol in defined ratios, in which crystalli ether concentration as expected by the background described zation is inhibited. As shown herein, crystallization inhibi previously. tion does not only depend on diethylene glycol monoethyl ether concentration as expected by the background described 0132) This biodistribution study demonstrates the useful previously, but on the specified ratios of the present inven ness of the present invention (i.e. a combination of diethyl tion. ene glycol monoethyl ether and propylene glycol tested in this case at two extreme ratios: 1:6 and 5:1) and that the 0.135 Therefore, these in vitro permeation and biodistri present invention significantly reduces formulation skin bution studies demonstrate the unexpected results of the a residues. combination of diethylene glycol monoethyl ether propy 0.133 Minoxidil 24-hour biodistribution lene glycol tested in this case at two extreme ratios: 1:6 and 5:1, which significantly reduces formulation skin residues. TABLE II Example 33 Minoxidil 24-hour biodistribution Normalized recovery (% of total relative recovery Comparison between Formulation Containing the Invention Example 12 Example 13 Example 14 Herein Described in Different Ratios control TCPG ratio 1:9) (TCPG ratio 5:1 0.136 Three different formulations, each of which con Mean SD Mean SD Mean SD tained a fixed concentration of diethylene glycol monoethyl Compartments % % N % % N % % N ether (5% w/w) and a variable concentration of propylene Unabsorbed 95.5 2.7 4 84.4 93 4 92.8 4.9 4 glycol (6, 15 or 30% w/w) were prepared, and compared in formulation Stratum 3.1 1.6 4 6.1 1.5 4 2.1 1.5 4 a drug permeation and a drug biodistribution after 24 hours; COilell Examples, 3, 5, and 9 above. The results of the permeation study are found in Table III below. US 2006/0153905 A1 Jul. 13, 2006 13

These in vitro permeation and biodistribution studies also TABLE III clearly demonstrate that changes of the ratio in which the novel formulation of the present invention do not result in Testosterone 24-hour in vitro permeation significantly different permeation performances. Addition Testosterone 24-hour in vitro permeation ally, these in vitro permeation and biodistribution studies Testosterone Cumulative Amount - 24 hours (ug/cm) clearly demonstrate that the novel formulation of the present Mean SD invention has an independent effect. Time (h) Example 3 Example 5 Example 9 Example 34 O O O O 6 3.9 3.1 2.1 1.7 1.5 + 1.O In Vitro Permeation of Selegilline Hydrochloride 12 10.9 6.1 9.9 8.3 7.2 - 5.6 18 16.9 6.5 21.4 + 13.4 18.1 - 12.0 0.142 Investigations were undertaken to compare the 24 20.7 6.7 31.0 - 14.5 29.5 - 14.6 permeation results of one simple hydroalcholic gel formu lation (formulation A) and two gel formulations containing the present invention (formulations B and C). All three 0137 Table III shows that three different embodiments of formulations comprised selegilline HCl in 1% ww (corre the present invention, each of which have different ratios sponding to 0.84% w/w selegilline base). ranging from 1:1.2 to 1:6 of diethylene glycol monoethyl ether propylene glycol, result in significantly similar cumu 0.143. The components of each of Formulations A, B, and lated amounts of permeated testosterone. FIG. 4 illustrates C, are represented below. the relative kinetic profile of each of these three embodi ments of the present invention. 0138 Changes in the quantitative formulation of the Formulation present invention do not result in any significant permeation A. B C variation. % Wiw % Wiw % Wiw 0139 Testosterone 24-hour biodistribution Selegilline HCI 1.OO 1.00 1.OO Diethylene glycol ethyl ether S.OO S.OO (Transcutol P) TABLE IV Propylene glycol 1O.O 1O.O Lauryl alcohol 1.OO Testosterone 24-hour biodistribution Hydroxypropyl cellulose 1...SO 1...SO 1...SO Normalized recovery (% of total relative recovery (Klucel HF) Ethanol 40.O 40.00 40.O Example 3 Example 5 Example 9 Triethanolamine q.S. pH 6.5 control TCPG ratio 1:9) (TCPG ratio 5:1

Mean SD Mean SD Mean SD Compartments % % N % % N % % N The following conditions and parameters were used for the Unabsorbed 88.6 4.1 4 79.0 18.5 4 75.1 16.0 4 in-vitro permeation of selegilline hydrochloride examples A, formulation B, and C, described above. Stratum 2.6 1.5 4 4.8 22 4 8.1 3.1 4 COilell 0144. The data obtained in this Study illustrates the Epidermis 8.8 2.3 4 16.2 4.8 4 16.8 3.5 4 beneficial effect of the diethylene glycol ethyl ether and Dermis propylene glycol in a 1:2 ratio and present in an amount of Receptor 15% of the total formulation. As shown in FIG. 7, the TOTAL 1OO.O 1OO.O 1OOO percentage of cumulated drug permeated is greater for the formulations comprising the present invention. In addition, as shown in FIGS. 6, a maximum drug instant flux is 0140. As shown in Table IV above, and in FIG. 5, attained after 6 hours for both Formulation A, which does increasing the ratio of the present formulation from 1:3 (5% not comprise the present invention, and Formulation B. w/w diethylene glycol monoethyl ether/ 15% w/w propylene which contains the present invention. However, the drug flux glycol) in example 5 to 1:6 in example 9 (5% w/w diethylene drops 4.5 times quicker for Formulation A as compared to glycol monoethyl ether/30% w/w propylene glycol) only Formulation B within 6 hours. The drug instant flux resulted in a 5% decrease of unabsorbed drug, but resulted decreases by 68% for Formulation A, and by 15% for in a about 66% increase of drug distributed in the stratum Formulation B, between T=6 and T=12 hours. Thus, the drug comeum. Drug distributed deeper in the skin layers can be instant flux between T=6 hours and T=12 hours is 2.2 times considered as unchanged. This study demonstrates that it is higher for Formulation B (0.31 ug/cm2h) than for Formu possible to modify the distribution of the active drug within lation A (0.14 ug/cm2/h). The slower depletion of the active the outermost layers of the skin or the mucosa while agent from Formulation B illustrates a better sustained simultaneously not affecting significantly drug distribution release of active agent over time, which would be a benefit in the innermost layers of the skin or the mucosa (example for long-term treatment drugs. Advantageously, formula tions of the present invention and use of the same may 5 and 9). require less frequent administration and may avoid 0141. This set of in vitro permeation and biodistribution unwanted blood level variations, such as the plasmatic peaks studies clearly demonstrate that drug distribution is modu and valleys responsible for undesired adverse effects, and lated by the ratio of the formulation of the present invention. decreased therapeutic efficacy. US 2006/0153905 A1 Jul. 13, 2006

Example 35 In vitro Permeation of Fentanyl Formulation 0145 Investigations were undertaken to compare the permeation results of one simple hydroalcholic gel formu A. B C lation (formulation A) and two gel formulations containing % Wiw % Wiw % Wiw the present invention (formulations B and C). All three Fentanyl base 1.OO 1.00 1.OO Diethylene glycol ethyl ether S.OO 2.50 formulations comprised fentanyl in 1% w/w. The compo (Transcutol P) nents of each of Formulations A, B, and C, are represented Propylene glycol 2O.OO 2O.OO below. Hydroxypropyl cellulose 1...SO 1...SO 1...SO (Klucel HF) Ethanol 40.OO 40.00 40.OO Water 57.50 32.50 35.00 Formulation A. B C 0150. The data obtained in this Study illustrates the % Wiw % Wiw % Wiw beneficial effect of the diethylene glycol ethyl ether and Fentanyl base 1.00 1.OO 1.00 propylene glycol in a 1:4 or 1:8 ratio and present in an Lauryl alcohol 1.OO 1.00 amount of about 25% of the total formulation. Diethylene glycol ethyl ether S.OO S.OO (Transcutol P) 0151. As shown in FIGS. 10 and 11, the addition of the Propylene glycol 10.00 invention in a ratio of diethylene glycol monoethyl ether Hydroxypropyl cellulose 1...SO 1...SO 1...SO ..propylene glycol 1:4 (respectively 1:8) in a simple hydroal (Klucel HF) Ethanol 40.00 40.OO 40.00 coholic gel of fentanyl 1% w/w statistically increases the Water 57.50 51.50 41.50 transdermal absorption of the drug by, respectively, 2.8-fold (respectively, 3.0-fold). Furthermore, this addition allows to reach the steady-state 4h sooner (at 12 h instead of 16 h) and 0146 The data obtained in this Study illustrates the to significantly increase the steady-state flux value: at the beneficial effect of the diethylene glycol ethyl ether and steady-state, the absorption rate is, respectively, 3.3-fold and 3.0-fold higher for B and C than for A. The addition of a propylene glycol in a 1:2 ratio and present in an amount of combination of diethylene glycol ethyl ether and propylene 15% of the total formulation. glycol to a simple hydroalcoholic gel has a significant 0147 As shown in FIGS. 8 and 9, the addition of a positive effect on fentanyl systemic absorption. diethylene glycol ethyl ether 5% and lauryl alcohol % w/w Example 37 leads to an increase of 76% of the absolute permeated In vitro Permeation of Buspirone amount of fentanyl, of 68% of the relative permeated amount offentanyl, and of 55% of the steady-state flux for 0152 Investigations were undertaken to compare the fentanyl. Thus, the data show that in combination, diethyl permeation results of one simple hydroalcholic gel formu ene glycol ethyl ether and lauryl alcohol have a positive lation (formulation A) and two gel formulations containing the present invention (formulations B and C) in different effect on the transdermal absorption offentanyl. ratios, and in absence or in presence of a further permeation 0148. Further the addition of propylene glycol in an enhancer (myristyl alcohol). All three formulations com amount of 10% w/w leads to a two-fold increase of the prised buspirone hydrochloride in 3% w/w corresponding to absolute and relative permeated amounts offentanyl, as well 2.74% w/w buspirone base. The components of each of as steady-state flux. Despite the lipophilic feature offentanyl Formulations A, B, and C, are represented below. (LogKo?w=4.05), the addition of a combination of diethyl ene glycol ethyl ether, lauryl alcohol, and propylene glycol to a simple hydroalcoholic gel has a significant positive effect on drug systemic absorption and to increase three-fold Formulation the steady-state flux. A. B C % Wiw % Wiw % Wiw Example 36 Buspirone hydrochloride 3.00 3.00 3.00 Diethylene glycol ethyl ether S.OO S.OO In vitro Permeation of Fentanyl (Transcutol P) Propylene glycol 1S.OO 1S.OO 0149 Investigations were undertaken to compare the Myristyl alcohol 1.OO permeation results of one simple hydroalcholic gel formu Hydroxypropyl cellulose 1...SO 1...SO 1...SO (Klucel (R) HF) lation (formulation A, same as formulation. A disclosed in Ethanol 30.00 30.00 35.00 previous Example 35) and two gel formulations containing Water 65.50 4SSO 39.50 the present invention (formulations B and C) in different ratios and in absence of a further permeation enhancer (for instance lauryl alcohol, as in disclosed in previous Example 0153. The data obtained in this Study illustrates the 35). All three formulations comprised fentanyl in 1% w/w. beneficial effect of the diethylene glycol ethyl ether and The components of each of Formulations A, B, and C, are propylene glycol in a 1:3 ratio and present in an amount of represented below. 20% of the total formulation. US 2006/0153905 A1 Jul. 13, 2006

0154). As shown in FIGS. 12 and 13, the addition of the 0162 FIGS. 6a-6h show the crystallization status of invention in a ratio of diethylene glycol monoethyl ether Some formulations not containing the present invention :propylene glycol 1:3 (formulation B) in a simple hydroal (Examples 9 and 12) 30 minutes after spreading of the coholic gel of buspirone hydrochloride 3% w/w allows to formulations on the glass plate. improve the drug absorption by 60% compared-to the ref erence (formulation A). Incorporation of a permeation Crystallization of Testosterone Formulations enhancer—myristyl alcohol (Formulation C) further 0.163 A comparative study focusing on the crystallization improves drug absorption about twice, representing a 3.2- rate of testosterone formulations was undertaken in which fold increase of buspirone hydrochloride transdermal the rate of crystallization of testosterone formulations of the absorption in comparison with the reference. present invention were compared to other testosterone for 0155 The steady-state absorption rate is also improved mulations not comprising the present invention. In this by 2.2-fold when adding diethylene glycol monoethyl ether regard, formulations (solutions or semi-solid) were spread : propylene glycol 1:3 (Formulation B versus Formulation over a cover glass and were observed under a microscope for A), and by 3.8-fold when further adding myristyl alcohol the occurrence of crystal formation. (Formulation C versus Formulation A). 0164. In the first study, the Gel formulation of Example A was compared to the Gel formulation of Example B for Example 38 crystallization rate. Example A was ANDROGEL(R) a 1% Crystallization Study testosterone gel marketed in US for male hypogonadism. The ANDROGEL(R) composition is as follows: 0156 Investigations on drug crystallization kinetics were also carried out for the present invention in which the novel formulation of the present invention was compared to for mulations not having the novel specified ratio. The objective Ingredient % Wiw was to establish a correlation between crystallization kinet Testosterone 1.00 ics of the novel formulations of the present invention Carbomer C980 NF O.90 (“slow' or “fast' crystallization rate) with in vitro perme Isopropyl myristate OSO Ethanol 96% 71.4 ation and biodistribution results, and therefore to determine Sodium Hydroxide 4.72 the partner/surfaces transfer potential of the formulations Purified water C.S. (“low” or “high” potential). 0157 Different active compounds were evaluated in for mulations containing the invention herein disclosed in com Example A: Composition of ANDROGEL(R) parison to formulations without containing the invention. The invention relates to the use of certain combination of 0.165 Androgel(R) (Example A), which does not comprise vehicles which enhance or promote drug uptake from the the present invention was compared with Example B, which skin while minimizing the amounts of skin residual after also does not comprise the present invention. As noted application of the drug product onto the skin. below. Example B is a testosterone gel comprising a dieth ylene glycol monoethyl ether and propylene glycol in a 0158 Microscopic examination was done on several gel weight ratio (TC:PG) of 1:1.2. Example A does not comprise formulations containing the invention herein described and either a diethylene glycol monoethyl ether nor propylene an active compound, compared to formulations which do not glycol. contain the invention and the same active compound. Pla cebo formulations were used for blank comparison as well. 0159 Anandrogen compound, testosterone (octanol:wa ter partition coefficient, or Log P about 3.3) and minoxidil Ingredient % ww (Log Pabout 1.2, thus less lipophilic than testosterone) were Testosterone 1.OO Carbomer C980 NF 1.2O used as drug models to exemplify the invention. Diethylene glycol monoethyl ether S.OO (TRANSCUTOL (R), “TC) 0160 An aliquot (1 mL) of the tested formulations was Propylene glycol (“PG') 6.OO placed on a glass plate and immediately spread with the help Disodium edetate O.O6 of a cover slip to form a homogenous layer of gel. Glass Ethanol 96% 47.5 plates holding the sample were, in all cases, let evaporated Triethanolamine O3S at controlled room temperature (25° C.) and observations Purified water C.S. and pictures were made at different times of exposure. 0161 Picture illustrated herein as FIGS. 6a through 6h 0166 Results of Example A compared to Example B. were taken under the same conditions, i.e., same time points (typically less than 5 minutes; 30 minutes; 2 hours for 0.167 Crystallization was observed in Example A after 10 fast-crystallizing formulations or 4 hours for slow-crystal minutes of application of the gel formulation to the glass lizing formulations; more than 8 hours in Some case), same cover. Likewise, crystallization was also observed in magnification (total x6.5), same location: the glass plate was Example B in 10 minutes. Thus, no significant difference in positioned once when initiating the study, and then was not the crystallization rate was observed between Example A, further moved until the completion of the study. Some slight ANDROGEL(R), and the gel formulation of Example B. differences in contrast and texture are imputable to solvent which comprises dietheylene glycol monoethyl ether and evaporation. propylene glycol in a 1:1.2 weight ratio. US 2006/0153905 A1 Jul. 13, 2006

0168 A comparison study was also undertaken for solu Crystallization was not observed in Example E after four tion formulations Examples C and D, represented below. hours of application of the formulation to a glass cover. Crystallization was observed after 30 minutes in Example F. 0169. Example C Thus, when both the gel formulation and the solution formulation comprise diethylene glycol monoethyl ether and propylene glycol in a ratio of 1:4, the crystallization rate of both formulations were significantly lower compared to Ingredient % Wiw other examples tested. Testosterone 1.OO Isopropyl myristate OSO What is claimed is: Ethanol 96% 71.4 1. A transdermal or transmucosal pharmaceutical formu Purified water C.S. lation comprising: at least one active agent; and 0170 Example D a solvent system present in an amount Sufficient to solu bilize the at least one active ingredient and character ized in that it includes: Ingredient % Wiw (i) a pharmaceutically acceptable monoalkyl ether of Testosterone 1.OO diethylene glycol present in an amount of between Diethylene glycol monoethyl ether S.OO about 1% and 30% by weight of the solvent system; (TRANSCUTOL (R), “TC) Propylene glycol (“PG') 6.OO (ii) a pharmaceutically acceptable glycol present in an Disodium edetate O.O6 Ethanol 96% 47.5 amount of between about 1% and 30% by weight of the Purified water C.S. solvent system, with the monoalkyl ether of diethylene glycol and glycol being present in a weight ratio of 10:1 to 2:1 or 1:2 to 1:10; and 0171 Crystallization was observed in Example C after (iii) a mixture of a C to C alcohol and water which only one minute, and in Example D after four minutes. Thus, mixture is present in an amount of between about 40% formulations containing diethylene glycol monoethyl ether and 98% of the solvent system, wherein the C2 to C4 and propylene glycol in a 1:1.2 weight ratio do not differ alcohol is present in an amount of about 5% to 80% of significantly from reference example A, either as a gel the mixture, and the water is present in an amount of formulation or as a solution formulation. A third compara about 20% to 95% of the mixture, tive study was undertaken in which the propylene glycol was increased from 6.00% ww to 20% ww in Examples E and F. so that, compared to formulations containing the same (The viscosity was adjusted to the ANDROGEL(R); about components but in different amounts and ratios, the 8000 cP). present solvent system (a) inhibits crystallization of the at least one active ingredient on a skin or mucosal EXAMPLE E Surface of a mammal, (b) reduces or prevents transfer of the formulation to clothing or to another being, (c) Ingredient % Wiw modulates biodistribution of the at least one active Testosterone 1.OO agent within different layers of skin, (d) facilitates Carbomer C980 NF O.6O absorption of the at least one active agent by a skin or Diethylene glycol monoethyl ether S.OO a mucosal Surface of a mammal, or (e) provides a (TRANSCUTOL (R), “TC) Propylene glycol (“PG') 2O.O combination of one or more of (a) through (d). Disodium edetate O.O6 2. The pharmaceutical formulation of claim 1, wherein the Ethanol 96% 47.5 monoalkyl ether of diethylene glycol and the glycol are Triethanolamine O3S present in a weight ratio of 10:1 to 2:1. Purified water C.S. 3. The pharmaceutical formulation of claim 1, wherein the monoalkyl ether of diethylene glycol and the glycol are present in a weight ratio of 1:2 to 1:10. 0172 4. The pharmaceutical formulation of claim 1, wherein the monoalkyl ether of diethylene glycol is selected from the EXAMPLE F group consisting of diethylene glycol monomethyl ether, and diethylene glycol monoethyl ether or mixtures thereof. Solution 5. The pharmaceutical formulation of claim 1, wherein the Ingredient % Wiw glycol is selected from the group consisting of propylene Testosterone 1.OO glycol, dipropylene glycol or mixtures thereof. Diethylene glycol monoethyl ether S.OO 6. The pharmaceutical formulation of claim 1, wherein the (TRANSCUTOL (R), “TC) glycol modulates the capacity of diethylene glycol mono Propylene glycol (“PG') 2O.O ethyl ether to build a skin depot. Disodium edetate O.O6 Ethanol 96% 47.5 7. The pharmaceutical formulation of claim 1, wherein the Purified water C.S. C. to C alcohol is selected from the group consisting of ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or mixtures thereof. US 2006/0153905 A1 Jul. 13, 2006

8. The pharmaceutical formulation of claim 1, further 17. The pharmaceutical formulation of claim 14, wherein including a permeation enhancer present in an amount the anti-Alzheimer drug is galantamine, rivastigmine, don Sufficient to increase permeability of the active agent across eZepil, tacrine, or memantine, or a pharmaceutically accept a dermal or mucosal Surface of a mammal. able salt thereof. 9. The pharmaceutical formulation of claim 1, wherein the 18. The pharmaceutical formulation of claim 14, wherein formulation further includes lauryl alcohol or myristyl alco the analgesic is an opioid analgesic, and further wherein the hol present in an amount from 0.5 to 2% by weight of the opioid analgesic is fentanyl, alfentanil, Sufentanil, or a total formulation. pharmaceutically acceptable salt thereof. 19. The pharmaceutical formulation of claim 11, wherein 10. The pharmaceutical formulation of claim 1, wherein at least one active agent is testosterone, the monoalkyl ether the at least one active ingredient includes a hormone or an of diethylene glycol and the glycol are present in a weight anti-hormone. ratio of 1:4, and the monoalkyl ether of diethylene glycol 11. The pharmaceutical formulation of claim 10, wherein and the glycol in combination are present in an amount of a the hormone or anti-hormone is an estrogen, an androgen, a least 15% of the total formulation by weight. progestogen, an anti-estrogen, an anti-androgen, or an anti 20. The pharmaceutical formulation of claim 14, wherein progestogen. the at least one active agent is selegilline or a pharmaceu 12. The pharmaceutical formulation of claim 11, wherein tically acceptable salt thereof, and the monoalkyl ether of the estrogen is selected from the group consisting of colpor diethylene glycol and the glycol are present in a weight ratio mon, conjugated estrogenic hormones, equilenin, equilin, of 1:2 to 1:10. estradiol, estrone, ethinyl estradiol, estradiol benzoate, 21. The pharmaceutical formulation of claim 18, wherein mestranol, moxestrol, mytatrienediol, quinestradiol, and the at least one active agent is fentanyl or a pharmaceutically quinestrol; and the androgen is selected from the group acceptable salt thereof, and the monoalkyl ether of diethyl consisting of cloXotestosterone, fluoxymesterone, ene glycol is monoethyl ether of diethylene glycol, the mestanolone, mesteronolone, 17-methyltestosterone, 17-O- glycol is propylene glycol, present in a weight ratio of 1:2 methyltestosterone 3-cyclopentyl enol ether, nore to 1:10. thandrolone, normethandrone, Oxandrolone, oxymesterone, 22. The pharmaceutical formulation of claim 1, further oxymetholone, prasterone, stanolone, stanoloZol, testoster comprising an agent selected from the group consisting of one, and tiomesterone. gelling agents; permeation enhancers, preservatives, anti 13. The pharmaceutical formulation of claim 1, wherein Oxidants, buffers, humectants, Sequestering agents, moistur the at least one active ingredient is a therapeutic agent izers, Surfactants, emollients, and any combination thereof. selected from the group consisting of sympathomimetics, 23. A method of delaying or inhibiting crystallization of sympatholytics, parasympathomimetics, parasympatholyt an active agent in a transdermal or transmucosal pharma ics, ganglioplegics, local anaesthetics, myorelaxants, anti ceutical formulation, characterized in that the formulation hypertensives, diuretics, cardiotonics, anti-arythmics, anti comprises at least one active agent and a solvent system, the angina drugs, cerebral and peripheric vasodilatators, anti Solvent system comprising a pharmaceutically acceptable migraine drugs, anti-histaminic drugs, anti-asthma drugs, monoalkyl ether of diethylene glycol and a glycol present in thrombolytics, general anaesthetics, anxiolytics, antidepres a weight ratio of 10:1 to 2:1 or 1:2 to 1:10. sants, neuroleptics, anti-convulsive drugs, hypothalamo-hy 24. The method of claim 23, wherein the monoalkyl ether pophysis regulators, hypo and hyperthyroidics, corticoster of diethylene glycol and the glycol are present in an ratio of oids, glycemia regulators, hypolipidemia drugs, 10:1 to 2:1. phosphocalcic metabolism regulators, antipyretics, anti-in 25. The method of claim 23, wherein the monoalkyl ether flammatory drugs, anti-acids, antisecretive gastric drugs, of diethylene glycol and the glycol are present in an amount laxatives, gastric mucosa protectors, gastric motricity modu of about. 1:2 to 1:10. lators, bile salts adsorbants, chelators, gall stone dissolvants, 26. The method of claim 23, wherein the monoalkyl ether anti-anemia drugs, cutaneous diseases drugs, antiparasit of diethylene glycol and the glycol in combination are drugs, antibiotics, penicillins, cephalosporins, aminosids, present in an amount of at least 15% and no more than 60% polypeptides, Sulfamides, diaminopyrimidines, tetracyclins, of the formulation. chloramphenicol, thiamphenicol, macrollides, Vancomycin, 27. The method of claim 13, wherein the solvent system teicoplanin, rifampicin, fusidic acid, 5-nitro-imidazoles, lin further comprises a mixture of a C to Calcohol and water, cosamides, quinolones, anticancer drugs, anti virus drugs, the mixture present in an amount of between 40% and 98% and antifungus drugs. of the solvent system. 14. The pharmaceutical formulation of claim 1, wherein 28. The method of claim 23, wherein the C to C alcohol the active agent is an anti-Parkinson drug, an anti-Alzheimer is present in an amount between 5% and 80% of the mixture, drug, or an analgesic drug. and the water is present in an amount between 20% and 95% 15. The pharmaceutical formulation of claim 14, wherein of the mixture. the anti-Parkinson drug is selected from the group consisting 29. The method of claim 23, wherein the decrease or of selegilline, trihexyphenidyl, tropatepione, bipeiden, pro inhibition of crystallization of the active agent is sufficient to cyclidine, benzatropine, orphenadrine, bomaprine, metix facilitate or increase absorption of the active agent across a ene, or levodopa, or a pharmaceutically acceptable salt skin or mucosal Surface to which it is applied. thereof. 30. The method of claim 23, wherein the monoalkyl ether 16. The pharmaceutical formulation of claim 14, wherein of diethylene glycol is selected from the group consisting of the anti-Parkinson drug is in combination with a decarboxy diethylene glycol monomethyl ether, and diethylene glycol lase inhibitor. monoethyl ether or mixtures thereof. US 2006/0153905 A1 Jul. 13, 2006

31. The method of claim 23, wherein the glycol is selected 37. The method of claim 36, wherein the hormone or from the group consisting of propylene glycol, dipropylene anti-hormone is an estrogen, an androgen, a progestogen, an glycol or mixtures thereof. anti-estrogen, or an anti-androgen, or an anti progestogen. 32. The method of claim 23, which further comprises 38. The method of claim 1, wherein the active agent is an providing a permeation enhancer present in an amount anti-Parkinson drug, an anti-Alzheimer drug, or an analge Sufficient to increase permeability of the active agent across sic. a dermal or mucosal Surface of a mammal. 33. The method of claim 23, wherein the formulation 39. The method of claim 38, wherein the anti-Parkinson further includes lauryl alcohol or myristyl alcohol present in drug is selected from the group consisting of selegilline, an amount from 0.5 to 2% by weight of the total formulation. trihexyphenidyl, tropatepione, bipeiden, procyclidine, ben 34. The method of claim 23, characterized in that the C. Zatropine, orphenadrine, bomaprine, metixene, or levodopa, to C alcohol is selected from the group consisting of or a pharmaceutically acceptable salt thereof. ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or 40. The method of claim 38, wherein the anti-Parkinson mixtures thereof. drug is in combination with a decarboxylase inhibitor. 35. The method of claim 23, characterized in that the at 41. The method of claim 38, wherein the anti-Alzheimer least one active ingredient is selected from the group includ drug is galantamine, rivastigmine, doneZepil, tacrine, or ing sympathomimetics, sympatholytics, parasympathomi memantine, or a pharmaceutically acceptable salt thereof. metics, parasympatholytics, ganglioplegics, myorelaxants, 42. The method of claim 38, wherein the analgesic is an antihypertensives, diuretics, cardiotonics, anti-arythmics, opioid analgesic, and further wherein the opioid analgesic is anti-angina drugs, cerebral and peripheric vasodilatators, fentanyl, alfentanil, Sufentanil, or a pharmaceutically accept anti-migraine drugs, anti-histaminic drugs, anti-asthma able salt thereof. drugs, thrombolytics, general anaesthetics, anxiolytics, anti depressants, neuroleptics, anti-convulsive drugs, hypo 43. The method of claim 42, wherein the active agent is thalamo-hypophysis regulators, hypo and hyperthyroidics, fentanyl, the monoalkyl ether of diethylene glycol is mono corticosteroids, glycemia regulators, hypolipidemia drugs, ethyl ether of diethylene glycol, the glycol is propylene phosphocalcic metabolism regulators, antipyretics, anti-in glycol, present in a weight ratio of 1:2 to 1:10. flammatory drugs, anti-acids, antisecretive gastric drugs, 44. The method of claim 39, characterized in that the laxatives, gastric mucosa protectors, gastric motricity modu active agent is selegilline hydrochloride, the monoalkyl lators, bile salts adsorbants, chelators, gall stone dissolvants, ether of diethylene glycol and the glycol are present in a anti-anemia drugs, cutaneous diseases drugs, antiparasit weight ratio of 1:2 to 1:10. drugs, antibiotics, penicillins, cephalosporins, aminosids, 45. The method of claim 37, wherein at least one active polypeptides, Sulfamides, diaminopyrimidines, tetracyclins, agent is testosterone, the monoalkyl ether of diethylene chloramphenicol, thiamphenicol, macrollides, Vancomycin, glycol and the glycol are present in a weight ratio of 1:4, and teicoplanin, rifampicin, fusidic acid, 5-nitro-imidazoles, lin the monoalkyl ether of diethylene glycol and the glycol in cosamides, quinolones, anticancer drugs, anti virus drugs, combination are present in an amount of a least 15% of the and antifungus drugs. total formulation by weight. 36. The method of claim 1, wherein the at least one active ingredient includes a hormone or an antihormone.