US 20110245215A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245215 A1 Carrara et al. (43) Pub. Date: Oct. 6, 2011

(54) TRANSIDERMAL DELIVERY SYSTEMIS FOR (60) Provisional application No. 60/453,604, filed on Mar. ACTIVE AGENTS 11, 2003, provisional application No. 60/510,613, filed on Oct. 10, 2003, provisional application No. (75) Inventors: Dario Norberto R. Carrara, 60/510,613, filed on Oct. 10, 2003. Oberwil (CH); Arnaud Grenier, Steinbrunn le Haut (FR): Celine (30) Foreign Application Priority Data Besse, Saint Louis (FR); Stephen M. Simes, Long Grove, IL (US); Aug. 3, 2000 (EP) ...... PCT/EPOO/O7533 Leah M. Lehman, Green Oaks, IL (US) Publication Classification (51) Int. Cl. (73) Assignee: ANTARES PHARMA, IPL, AG A6II 3/568 (2006.01) A6IP5/26 (2006.01) (21) Appl. No.: 13/106,715 A6IP 5/00 (2006.01) (52) U.S. Cl...... S14/178 (22) Filed: May 12, 2011 (57) ABSTRACT Related U.S. Application Data A formulation for transdermal or transmucosal administra (63) Continuation of application No. 13/044,447, filed on tion of an active agent. The formulation includes an active Mar. 9, 2011, which is a continuation of application agent and a delivery vehicle comprising a C to C alkanol, a No. 12/614,216, filed on Nov. 6, 2009, which is a polyalcohol, and a permeation enhancer of monoalkyl ether continuation-in-part of application No. 10/798,111, of diethylene glycol present in an amount Sufficient to provide filed on Mar. 10, 2004, said application No. 12/614, permeation enhancement of the active agent through dermal 216 is a continuation-in-part of application No. or mucosal surfaces. The formulation is substantially free of 11/755,923, filed on May 31, 2007, which is a continu long-chain fatty alcohols, long-chain fatty acids, and long ation-in-part of application No. 1 1/371,042, filed on chain fatty esters in order to avoid undesirable odor and Mar. 7, 2006, now Pat. No. 7,335,379, which is a irritation effects caused by Such compounds during use of the continuation of application No. PCT/EP04/11175, formulation. Also, the active agent is testosterone that is filed on Oct. 6, 2004, said application No. 1 1/755,923 present in an amount of about 1%, the alkanol is ethanol that is a continuation-in-part of application No. 1 1/634, is present in an amount of about 46.28% to about 47.5% of the 005, filed on Dec. 4, 2006, now Pat. No. 7,404,965, formulation; the polyalcohol is propylene glycol that is which is a continuation of application No. 10/343,570, present in an amount of about 6% of the formulation; and the filed on May 19, 2003, now Pat. No. 7,214,381, filed as permeation enhancer is diethylene glycol monoethyl ether application No. PCT/EP01/09007 on Aug. 3, 2001. that is present in an amount of about 5% of the formulation. Patent Application Publication Oct. 6, 2011 Sheet 1 of 11 US 2011/0245215 A1

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TRANSIDERMAL DELIVERY SYSTEMIS FOR 0005. In addition to reduced levels of endogenous steroid ACTIVE AGENTS hormones Such as those described above, adrenal insuffi ciency leads to reduced levels of dehydroepiandrosterone CROSS-REFERENCE TO RELATED (DHEA) in men and women. The adrenal glands are also APPLICATIONS involved in the production of many hormones in the body, 0001. This application is a continuation of application Ser. including DHEA and sex hormones such as estrogen and No. 13/044,447 filed Mar. 9, 2011, which is a continuation of testosterone. Consequently, adrenal insufficiency can lead to application Ser. No. 12/614,216 filed Nov. 6, 2009, which is a reduced levels of DHEA and sex hormones which can lead to continuation-in-part of application Ser. No. 10/798,111 filed the clinical symptoms described above. Mar. 10, 2004, which claims the benefit of each of application 0006 Although steroid hormone concentrations may be No. 60/453,604 filed Mar. 11, 2003 and 60/510,613 filed Oct. restored to normal or near-normal levels by hormone replace 10, 2003. Application Ser. No. 12/614,216 is also a continu ment therapy, the current forms of treatment (i.e., oral, intra ation-in-part of application Ser. No. 1 1/755,923 filed May 31, muscular, Subcutaneous, transdermal patches and topical for 2007, which is a continuation-in-part of U.S. patent applica mulations) have several disadvantages. For example, orally tion Ser. No. 1 1/371,042 filed Mar. 7, 2006, now U.S. Pat. No. administered testosterone is largely degraded in the liver, and 7.335,379, which is a continuation of International applica tion no. PCT/EP2004/011175 filed Oct. 6, 2004, which is therefore not a viable option for hormone replacement claims the benefit of U.S. provisional patent application No. since it does not allow testosterone to reach systemic circu 60/510,613, filed Oct. 10, 2003. Application Ser. No. 1 1/755, lation. Further, analogues of testosterone modified to reduce 923 is also a continuation-in-part of U.S. patent application degradation (e.g., methyltestosterone and methandros tenolone) have been associated with abnormalities to liver Ser. No. 1 1/634,005 filed Dec. 4, 2006, now U.S. Pat. No. function, such as elevation of liver enzymes and conjugated 7,404.965, which is a continuation of application Ser. No. bilirubin. Injected testosterone produces wide peak-to-trough 10/343,570 filed May 19, 2003, now U.S. Pat. No. 7,214,381, variations in testosterone concentrations that do not mimic which is the U.S. national stage of International application the normal fluctuations of testosterone making maintenance no. PCT/EP01/09007 filed Aug. 3, 2001 which claims prior of physiological levels in the plasma difficult. Testosterone ity to International application no. PCT/EP00/07533 filed injections are also associated with mood Swings and Aug. 3, 2000. Each prior application is expressly incorpo increased serum lipid levels. Injections require large needles rated herein in its entirety by reference thereto. for intramuscular delivery, which leads to diminished patient compliance due to discomfort. Commonly, estrogen is often TECHNICAL FIELD administered orally. This route of administration has been 0002 The present invention relates to a novel transdermal also associated with complications related to hormone or transmucosal pharmaceutical formulation comprising at metabolism, resulting in inadequate levels of circulating hor least one active ingredient and a solvent system. The inven mone. Further, side-effects seen with the use of oral estrogen tion reveals a pharmaceutical formulation that administers the include gallstones and blood clots. To overcome these prob active drug(s) at a permeation rate that would ensure thera lems, transdermal delivery approaches have been developed peutically effective systemic concentration. The formulations to achieve therapeutic effects in a more patient friendly man of the present invention contain defined amounts of chemicals . that minimize the barrier characteristics of the most upper 0007. The art recognizes that the transdermal and/or trans most layer of the epidermis and provide Sustained permeation mucosal delivery of active agents provide a convenient, pain rate. This invention relates generally to a novel delivery free, and non-invasive method of administering active agents vehicle and preferably one that is substantially free of long to a subject. Topical or transdermal delivery systems for the chain fatty alcohols, long chain fatty acids, and long-chain administration of drugs are known to offer several advantages fatty esters. over oral delivery of the same drugs. For example, the admin istration of active agents through the skin or mucosal Surface BACKGROUND avoids the well-documented problems associated with the 0003. The present invention relates to formulations and “first pass effect encountered by oral administration of methods of treatment using a wide variety of active agents. Of active agents. course, many existing agents and treatments are currently 0008 Generally, the advantages of topical or transdermal known. delivery of drugs relate to pharmacokinetics. More specifi 0004. In the area of hormones, for example, reduced levels cally, one common problem associated with the oral delivery of endogenous steroid hormones in humans often leads to a of drugs is the occurrence of peaks in serum levels of the drug, variety of undesirable clinical symptoms. For example, men which is followed by a drop in serum levels of the drug due to with low testosterone levels (hypogonadism) may result in its elimination and possible metabolism. Thus, the serum clinical symptoms including impotence, lack of sex drive, level concentrations of orally administered drugs have peaks muscle weakness, and osteoporosis. Similarly, in women, and Valleys after ingestion. These highs and lows in serum reduced levels of testosterone and/or estrogen may result in level concentrations of drug often lead to undesirable side female sexual disorder, which include clinical symptoms effects. Such as lack of sex drive, lack of arousal or pleasure, low 0009. In contrast, topical and transdermal delivery of energy, reduced sense of well-being, and osteoporosis. More drugs provides a relatively slow and steady delivery of the over, reduced levels of estrogen and/or progesterone in drug. Accordingly, unlike orally administered drugs, the women, Such as that due to menopause, often result in clinical serum concentrations of topically or transdermally delivered symptoms including hot flashes, night Sweats, vaginal atro drugs are substantially Sustained and do not have the peaks phy, decreased libido, and osteoporosis. associated with oral delivery. US 2011/02452.15 A1 Oct. 6, 2011

0010 Although the transdermal and/or transmucosal enhancer. It is a very odoriferous compound. Also, delivery of active agents overcome some of the problems TESTIMR) is not desirable because it contains undesirable associated with oral administration of the same agents, this amounts of glycerin which are not well tolerated by the skin. route of administration is not free of its own drawbacks. 0016 For these reasons, other penetration enhancers have Transdermal patches very often cause allergic reactions and skin irritations due to their occlusive nature, or due to their been used to increase the permeability of the dermal surface composition (incompatibility reactions with the polymers or to drugs. Many of these are proton accepting solvents such as adhesives that are used). dimethyl sulfoxide (DMSO) and dimethylacetamide. Other 0011. In addition to skin irritation and tolerance consider penetration enhancers that have been studied and reported as ations, another issue of transdermal drug delivery systems is effective include 2-pyrrolidine, N,N-diethyl-m-toluamide that these systems are typically restricted to low-molecular (Deet), 1-dodecal-azacycloheptane-2-one N,N-dimethylfor weight drugs and those with structures having the proper mamide, N-methyl-2-pyrrolidine, calcium thioglycolate, lipophilic/hydrophilic balance. High molecular weight drugs, hexanol, fatty acids and esters, pyrrolidone derivatives, or drugs with too high or too low hydrophilic balance, often derivatives of 1,3-dioxanes and 1,3-dioxolanes, 1-N-dodecyl cannot be incorporated into current transdermal systems in 2-pyrrolidone-5-carboxylic acid, 2-pentyl-2-oxo-pyrro concentrations high enough to overcome their impermeabil lidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, ity through the stratum corneum. Efforts have been made in 1-azacycloheptan-2-one-2-dodecylacetic acid, and aminoal the art to chemically modify the barrier properties of skin to cohol derivatives, including derivatives of 1,3-dioxanes, permit the penetration of certain agents (since diffusion is among others. Some of these permeation enhancers also primarily controlled through the stratum corneum), enhance present odor or even taste disadvantages. the effectiveness of the agent being delivered, enhance deliv 0017. In addition, transdermal drug delivery systems are ery times, reduce the dosages delivered, reduce the side typically restricted to low-molecular weight drugs and those effects from various delivery methods, reduce patient reac with structures having the proper lipophilic/hydrophilic bal tions, and so forth. In this regard, penetration enhancers have ance. High molecular weight drugs, or drugs with too high or been used to increase the permeability of the dermal surface low hydrophilic balance, often cannot be incorporated into to drugs. current transdermal systems in concentrations high enough to 0012 Efforts have been made in the art to chemically modify the barrier properties of skin to permit the penetration overcome their impermeability through the stratum corneum. of certain agents (since diffusion is primarily controlled Specifically, polar drugs tend to penetrate the skin too slowly, through the stratum corneum), enhance the effectiveness of and since most drugs are of a polar nature, this limitation is the agent being delivered, enhance delivery times, reduce the significant. dosages delivered, reduce the side effects from various deliv 0018. Further, transdermal delivery from semi-solid for ery methods, reduce patient reactions, and so forth. mulations faces antinomic requirements. The drug delivery 0013 The most common penetration enhancers, however, system should enable absorption of an extensive amount of are toxic, irritating, oily, odiferous, or allergenic. Specifically, active drug through the skin within the shortest period of time the penetration enhancers used and thought to be necessary to in order to prevent contamination of individuals, transfer to transdermally deliver hormones or other active agents such as clothing or accidental removing. The drug delivery system oxybutynin, namely, long-chain acids Such as oleic acid or should also provide Sustained release of the active drug over lauric acid, long-chain alcohols such as lauryl or myristyl 24 hours ideally, so that only once-daily application is alcohol, and long-chain esters such as triacetin (the glycerol required. This drug delivery system should also prevent drug trimester of acetic acid), glycerol monolaurate or glycerol crystallization at the application Surface area. monooleate, tend to include aliphatic groups that make the 0019 Drug delivery systems having such properties may formulations oily and malodorous. beachieved by combining various solvents. A volatile solvent 0014 For example, U.S. Pat. No. 5,891,462 teaches the may be defined as a solvent that changes readily from Solid or use of lauryl alcohol as a permeation enhancer for estradiol liquid to a vapor, that evaporates readily at normal tempera and norethindrone acetate. Such formulations are not appeal ing to the user nor to anyone else in close proximity to the tures and pressures. Here below is presented data for some user. Although this particular patent discloses three examples usual solvents, where volatility is reflected by the molar of estradiol or norethindrone acetate formulations having no enthalpy of vaporization A.H, defined as the enthalpy lauryl alcohol component, such formulations are comparative change in the conversion of one mole of liquid to gas at examples that are intended to illustrate the long held position constant temperature. Values are given, when available, both that long chain fatty alcohols such as lauryl alcohol are nec at the normal boiling point t referred to a pressure of 101. essary to transdermally deliver norethindrone acetate in com 325 kPa (760 mmHg), and at 25° C. (From “Handbook of bination with estradiol to a subject. Chemistry and Physics, David R. Lide, 79 edition (1998 0015. Additionally, for example, the known testosterone 1999)—Enthalpy of vaporization (6-100 to 6-115). Stanis gel formulations FORTIGEL(R) and TOSTRELLER (Celegy laus et al. (U.S. Pat. No. 4,704,406 on Oct. 9, 2001) defined as Pharma, South San Francisco, Calif.), both include ethanol, volatile solvent a solvent whose vapor pressure is above 35 propanol, propylene glycol, carbomer, triethanolamine, puri mm Mg when the skin temperature is 32° C., and as non fied water, and oleic acid as a permeation enhancer, the latter volatile solvent a solvent whose vapor pressure is below 10 being responsible for the irritating and malodorous charac mm Mg at 32°C. skin temperature. Examples of non-volatile teristics of these formulations. Also, TESTIMOR (Auxilium Solvents include, but are not limited to, propylene glycol, Pharmaceuticals, Norristown, Pa.) is a 1% testosterone gel glycerin, liquid polyethylene glycols, or polyoxyalkylene and includes pentadecalactone, acrylates, glycerin, polyeth glycols. Examples of Volatile solvents include, but are not ylene glycol (PEG), and pentadecalactone as a permeation limited to, ethanol, propanol, or isopropanol. US 2011/02452.15 A1 Oct. 6, 2011

Enthalpy of Vaporization of Certain Solvents comprises an effective amount of at least one physiologically active agent, at least one non-volatile dermal penetration 0020 enhancer, and at least one volatile liquid. (0024 U.S. Pat. No. 5,891.462 to Carrara discloses a phar maceutical formulation in the form of a gel suitable for the transdermal administration of an active agent of the class of t, AH (tr.) AH (25 C.) estrogens or of progestin class or of a mixture of both, com Ethanol 78.3 38.6 423 prising lauryl alcohol, diethylene glycol monoethyl ether and Propan-2-ol (isopropanol) 82.3 39.9 45.4 propylene glycol as permeation enhancers. Propanol 97.2 41.4 47.5 Butan-2-ol 99.5 40.8 49.7 0025 Mura et al. describe the combination of diethylene Butan-1-ol 117.7 43.3 52.4 glycol monoethyl ether and propylene glycolas a transdermal Ethylene glycol monomethyl ether 124.1 37.5 45.2 permeation enhancer composition for clonazepam (Mura P. Ethylene glycol monoethyl ether 135.0 39.2 48.2 Ethylene glycol monopropyl ether 149.8 41.4 52.1 Faucci M.T., Bramanti G., Corti P., “Evaluation of transcutol 1.2-Propylene glycol 187.6 52.4 Not available as a clonazepam transdermal permeation enhancer from Diethylene glycol monomethyl ether 193.0 46.6 Not available hydrophilic gel formulations”, Eur. J. Pharm. Sci., 2000 Feb Diethylene glycol monoethyl ether 196.O 47.5 Not available ruary: 9(4): 365-72) 1,3-Propylene glycol 214.4 57.9 Not available 0026. Williams et al. reports the effects of diethylene gly Glycerin 29O.O 61.0 Not available col monoethyl ether (TRANSCUTOLTM) in binary co-sol vent systems with water on the permeation of a model lipo 0021 Numerous authors have investigated evaporation philic drug across human epidermal and Silastic membranes and transdermal penetration from solvent systems. For (A. C. Williams, N. A. Megrab and B. W. Barry, “Permeation Example, Spencer et al. (Thomas S. Spencer, “Effect of vola of Oestradiol through human epidermal and Silastic mem tile penetrants on in vitro skin permeability”, AAPS work branes from saturated TRANSCUTOL(R)/water systems', in shop held in Washington D.C. on Oct. 31-Nov. 1, 1986) Prediction of Percutaneous Penetration, Vol. 4B, 1996). established that the relationship between volatility and pen Many references may also illustrate the effect of TRANSCU etration is not absolute and depends on many parameters such TOLTM as an intracutaneous drug depot builder well known to as for instance hydration of the tissue or the solubility of the one skilled in the art. penetrant in the tissue. Stinchcomb et al. reported that the 0027 U.S. Pat. No. 5,658,587 to Santus et al. discloses initial uptake of a chemical (hydrocortisone, flurbiprofen) transdermal therapeutic systems for the delivery of alpha from a volatile solvent system (acetone) is more rapid than adrenoceptor blocking agents using a solvent enhancer sys that from a non-volatile solvent system (aqueous solution). tem comprising diethylene glycol monoethyl ether and pro With an aqueous solution, close to the saturation solubility of pylene glycol. the chemical, the driving force for uptake remains more or 0028 U.S. Pat. No. 5,662.890 to Punto et al. discloses an less constant throughout the exposure period. Conversely, for alcohol-free cosmetic compositions for artificially tanning a volatile vehicle which begins evaporating from the moment the skin containing a combination of diethylene glycol mono of application, the Surface concentration of the chemical ethyl ether and dimethyl isosorbide as permeation enhancer. increases with time up to the point at which the solvent has 0029 U.S. Pat. No. 5,932.243 to Fricker et al. discloses a disappeared; one is now left with a solid film of the chemical pharmaceutical emulsion or microemulsion preconcentrate from which continued uptake into the stratum corneum may for oral administration of macrollide containing a hydrophilic be very slow and dissolution-limited. carrier medium consisting of diethylene glycol monoethyl 0022 Risk assessment following dermal exposure to vola ether, glycofurol, 1,2-propylene glycol, or mixtures thereof. tile vehicles should pay particular attention, therefore, to the 0030 U.S. Pat. Nos. 6,267,985 and 6,383,471 to Chen et duration of contact between the evaporating solvent and the al. disclose pharmaceutical compositions and methods for skin (Audra L. Stinchcomb, Fabrice Pirot, Gilles D. Touraille, improved solubilization of triglycerides and improved deliv Annette L. Bunge, and Richard H. Guy, "Chemical uptake ery of therapeutic agents containing diethylene glycol mono into human stratum corneum in vivo from volatile and non ethyl ether and propylene glycol as solubilizers of ionizable volatile solvents’. Pharmaceutical Research, Vol. 16, No 8, hydrophobic therapeutic agents. 1999). Kondo et al. studied bioavailability of percutaneous 0031 U.S. Pat. No. 6,426,078 to Bauer et al. discloses an nifedipine in rats from binary (acetone and propylene glycol oil-in water microemulsion containing diethylene glycol PG or isopropyl myristate IPM) or ternary (acetone-PG-IPM) monoethyl ether or propylene glycolas co-emulsifier of lipo solvent systems, compared with the results from simple PG or philic vitamins. IPM solvent systems saturated with the drug. (Kondo et al. S. 0032. Many research experiments have been carried out Yamanaka C. Sugimoto I., “Enhancement of transdermal on diethylene glycol monoethyl ether (marketed under the delivery by superfluous thermodynamic potential. III. Percu trademark TRANSCUTOLTM by Gattefossé) as an intracuta taneous absorption of nifedipine in rats'. J Pharmaco Bio neous drug depot builder. For example, Ritschel, W. A., Pan dyn. 1987 December; 10(12):743-9). chagnula, R., Stemmer, K., Ashraf. M., “Development of an 0023 U.S. Pat. No. 6,299,900 to Reed et al. discloses a intracutaneous depot for drugs. Binding, drug accumulation non-occlusive, percutaneous, or transdermal drug delivery and retention studies, and mechanism depot for drugs'. Skin system-having active agent, safe and approved Sunscreen as Pharmacol, 1991; 4: 235-245; Panchagnula, R. and Ritschel, penetration enhancer, and optional volatile liquid. The inven W. A., “Development and evaluation of an intracutaneous tion describes a transdermal drug delivery system, which depot formulation of corticosteroids using TRANSCUTOL(R) comprises at least one physiologically active agent or prodrug as a cosolvent, in vitro, ex vivo and in-vivo rat Studies'. J. thereof and at least one penetration enhancer of low toxicity Pharm. Pharmacology. 1991:43: 609-614:Yazdanian, M. and being a safe skin-tolerant ester Sunscreen. The composition Chen, E., “The effect of diethylene glycol monoethyl ether as US 2011/02452.15 A1 Oct. 6, 2011 a vehicle for topical delivery of ivermectin, Veternary vehicle facilitates absorption of the active agent by the dermal Research Com. 1995; 19:309-319; Pavliv, L., Freebern, K., or mucosal surfaces so that transfer or removal of the formu Wilke, T., Chiang, C-C. Shetty, B., Tyle, P., “Topical formu lation from Such surfaces is minimized. lation development of a novel thymidylate synthase inhibitor 0036. The invention also relates to a non-occlusive formu for the treatment of psoriasis'. Int. J. Pharm., 1994; 105: lation comprising a delivery vehicle as disclosed herein along 227-233; Ritschel, W. A., Hussain, A. S., “In vitro skin per with an active agent or a pharmaceutically acceptable salt meation of griseofulvin in rat and human skin from an oint thereof present in an amount of between about 1 to 20% by ment dosage form”, Arzneimeittelforsch/Drug Res. 1988; 38: weight of the formulation. Like the delivery system, the for 1630-1632: Touitou, E., Levi-Schaffer, F., Shaco-Ezra, N., mulation is substantially free of long-chain fatty alcohols, Ben-Yossef, R. and Fabin, B., “Enhanced permeation of theo long-chain fatty acids, and long-chain fatty esters in order to phylline through the skin and its effect on fibroblast prolifera avoid undesirable odor and irritation effects caused by such tion', Int. J. Pharm., 1991: 70: 159-166; Watkinson, A. C., compounds during use. As disclosed herein, a wide range of Hadgraft, J. and Bye, A., “Enhanced permeation of prostag active agents can be delivered by the formulations of the landin E through human skin in vitro, Int. j. Pharm., 1991; invention. 74: 229-236; Rojas, J., Falson, F., Courraze, G., Francis, A., 0037 Preferably, the formulation includes testosterone as and Puisieux, F., “Optimization of binary and ternary solvent the active agent present in an amount of about 1%, ethanol as systems in the percutaneous absorption of morphine base'. the alkanol that is present in an amount of about 46.28% to STP Pharma Sciences, 1991; 1: 71-75; Ritschel, W. A., about 47.5% of the formulation; propylene glycolas the poly Barkhaus, J. K. "Use of absorption promoters to increase alcohol that is present in an amount of about 6% of the systemic absorption of coumarin from transdermal drug formulation; and diethylene glycol monoethyl ether as the delivery systems”, Arzneimeittelforsch/Drug Res. 1988; 38: permeation enhancer that is present in an amount of about 5% 1774-1777. of the formulation. 0033. Thus there remains a need to provide a pharmaceu 0038. To facilitate application of the active agent, the tically acceptable transdermal or transmucosal pharmaceuti formlulation may further comprise at least one excipient cal formulation or drug delivery system that exhibits the selected from the group consisting of gelling agents, solvents, advantages of both occlusive systems (high thermodynamic cosolvents, antimicrobials, preservatives, antioxidants, buff activity) and non-occlusive systems (low irritation and sensi ers, humectants, sequestering agents, moisturizers, emol tization potential, and excellent skin tolerance) while over lients, film-forming agents, or permeation enhancers. Thus, coming the disadvantages of these systems such as low skin the formulation may be provided in the form of a topical gel, tolerability and unpleasant odors. The novel transdermal or lotion, foam, cream, spray, aerosol, ointment, emulsion, transmucosal pharmaceutical formulations of the present microemulsion, nanoemulsion, Suspension, liposomal sys invention satisfies this need. tem, lacquer, or non-occlusive dressing. 0039. The invention also relates to a method for adminis SUMMARY OF INVENTION tering an active agent to a mammal in need thereof which comprises topically or transdermally administering to the 0034. The present invention relates to a delivery vehicle for topical pharmaceutical formulations. The delivery vehicle skin or the mucosa of the mammal one of the formulations comprises a C2 to C4alkanol, a polyalcohol, and a monoalkyl according to invention as disclosed hereinto deliver the active ether of diethylene glycol present in relative amounts suffi agent to the mammal. Preferably, the active agent is present in cient to provide permeation enhancement of an active agent an amount of about 0.01 to about 10% of the composition and through mammalian dermal or mucosal Surfaces. Preferably, between about 40 and about 250 mg of the composition is the delivery vehicle as well as the formulations that contain it administered daily upon the abdomen, shoulder, arm, or thigh are substantially free of long-chain fatty alcohols, long-chain of the mammal to effectuate the treatment. fatty acids and long-chain fatty esters in order to avoid poten BRIEF DESCRIPTION OF THE DRAWINGS tial undesirable odor and irritation effects caused by such compounds during use of the formulation. These preferred 0040. The features and benefits of the invention will now formulations advantageously do not include the undesirable become more clear from a review of the following detailed odor-causing and irritation-causing permeation enhancers description of illustrative embodiments and the accompany that were once thought to be necessary for Such transdermal ing drawings, wherein: or transmucosal formulations. Without these additives, use of 0041 FIG. 1 is a graph depicting drug flux over time for the formulations is facilitated and patient compliance is testosterone in formulations including various amounts of greater. lauryl alcohol (LA) in an in vitro model using human excised 0035 Certain advantageous delivery system components skin and 10 mg testosterone/cm2 in the loading chamber and amounts are disclosed herein. The alkanol may be (n=3-4+SD). selected from the group consisting of ethanol, isopropanol, 0042 FIG. 2 is a graph depicting drug flux over time for n-propanol, and mixtures thereof; the polyalcohol from the testosterone in formulations including various amounts of group consisting of propylene glycol and dipropylene glycol lauryl alcohol (LA) in an in vitro model using human excised and mixtures thereof; and the monoalkyl ether of diethylene skin and 50 mg testosterone/cm2 in the loading chamber glycol is selected from the group consisting of monomethyl (n=3-4+SD). ether of diethylene glycol, monoethyl ether of diethylene 0043 FIGS. 3A, B & C are graphs depicting median total, glycol, and mixtures thereof. The alkanol is typically present free and bioavailable testosterone serum concentrations fol in an amount between about 5 to 80% by weight, the polyal lowing administration of 1% T+0% LA gel in vivo over a cohol in an amount between about 1% to 30% by weight, and sampling period on days 1, 7, 14, and 21, respectively. the monoalkyl ether of diethylene glycol in an amount 0044 FIGS. 3D, E & F are graphs depicting mean bio between about 0.2 to 30% by weight so that the delivery available and free testosterone serum concentrations after US 2011/02452.15 A1 Oct. 6, 2011

different dose regimens and treatments with a 1% T+2% LA the formulation is a clear, water-washable, quick-drying, gel in vivo over a sampling period on days 1, 7, 14, respec spreadable, non-greasy, non-occlusive topical gel which is tively. free of fatty permeation enhancers. 0045 FIG. 4A is a graph depicting mean serum concen 0060 Advantageously, the substantial omission of the trations of estradiol (E2) following single dose administration long-chain fatty alcohols, long-chain fatty acids, and long of E2+0% LA gel (a 0.75 mg E2; b=1.50 mg E2). chain fatty esters provides a formulation that does not have 0046 FIG. 4B is a graph depicting mean trough concen the unpleasant odor, irritation, and/or greasy texture caused trations of E2 over time following repeated administration of by formulations of the prior art that include one or more of E2+0% LA gel (a=0.75 mg E2; b=1.50 mg E2). Such compounds. Thus, the formulation in accordance with 0047 FIG. 4C is a graph depicting mean trough concen the present invention will result in greater patient compliance. trations of E2 over time following repeated administration of The inventive formulations are substantially free of such alco E2+0% LA gel in one subject (2.5 g.: +SD; 240.0 H-value out hols, acids, and esters so that the odors associated with those of scale (28.0 mg/dl)). compounds do not emanate from the formulation. In this 0048 FIG. 4D is a graph depicting individual trough con regard, “substantially free” means an amount which does not centrations of E2 overtime following repeated administration impart a perceptible odor to the formulation at a distance of of E2+0% LA gel at both doses. one meter. Such formulations are also deemed to be substan 0049 FIG. 4E is a graph depicting mean serum concen tially odor-free. For the purpose of example and illustration, a trations of E2 following multiple dose administration of formulation comprising fatty alcohols, fatty acids and/or fatty E2+0% LA gel (a=0.75 mg E2; b=1.50 mg E2). 0050 FIG. 4F is a graph depicting mean serum concentra esters in an amount of less than about 0.1% by weight of the tions of estrone (E1) following single dose administration of formulation is substantially odor-free. E2+0% LA gel (a=0.75 mg E2; b=1.50 mg E2). 0061. It is to be understood that the terminology used 0051 FIG. 4G is a graph depicting mean trough concen herein is for the purpose of describing particular embodi trations of E1 following repeated administration of E2+0% ments only, and is not intended to be limiting. As used in this LA gel (a-0.75 mg E2; b=1.50 mg E2). specification, description of specific embodiments of the 0052 FIG. 4H is a graph depicting mean serum concen present invention, and any appended claims, the singular trations of E1 following multiple dose administration of forms “a,” “an and “the include plural referents unless the E2+0% LA gel (a=0.75 mg E2; b=1.50 mg E2). context clearly dictates otherwise. Thus, for example, refer 0053 FIG. 4I is a graph depicting mean serum concentra ence to “a compound includes one or more compounds, tions of estrone-sulfate (E1-sulfate) following single dose mixtures of compounds, and the like. administration of E2+0% LA gel (a 0.75 mg E2; b=1.50 mg 0062 Unless defined otherwise, all technical and scien E2). tific terms used herein have the same meaning as commonly 0054 FIG. 4J is a graph depicting mean trough concentra understood by one of ordinary skill in the art to which the tions of E1-sulfate following multiple dose administration of invention pertains. Although other methods and materials E2+0% LA gel (a=0.75 mg E2; b=1.50 mg E2). similar, or equivalent, to those described herein can be used in 0055 FIG. 4K is a graph depicting mean serum concen the practice of the present invention, the preferred materials trations of E1-sulfate following multiple dose administration and methods are described herein. of E2+0% LA gel (a 0.75 mg E2; b=1.50 mg E2). 0063. In describing and claiming the present invention, the 0056 FIG. 5A is a graph depicting mean change from following terminology will be used in accordance with the baseline in daily moderate-to-severe hot flush rate after definitions set out below. E2+0% LA gel at various doses. (Intent-to-treat efficacy 0064. The term “dosage form as used herein refers to a population (“ITT); Method of last observation carried for pharmaceutical composition comprising an active agent and ward for subjects who discontinued early ("LOCF). optionally containing inactive ingredients, e.g., pharmaceu 0057 FIG. 5B is a graph depicting mean change from tically acceptable excipients such as Suspending agents, Sur baseline in daily moderate-to-severe hot flush rate after factants, disintegrants, binders, diluents, lubricants, stabiliz E2+0% LA gel at various doses (Evaluable-LOCF). ers, antioxidants, osmotic agents, colorants, plasticizers, 0058 FIG. 5C is a graph depicting mean change from coatings and the like, that may be used to manufacture and baseline in daily hot flush mean severity after E2+0% LA gel deliver active pharmaceutical agents. at various doses (ITT-LOCF). 0065. The term “gel” as used herein refers to a semi-solid dosage form that contains a gelling agent in, for example, an DETAILED DESCRIPTION OF THE PREFERRED aqueous, alcoholic, or hydroalcoholic vehicle and the gelling EMBODIMENTS agent imparts a three-dimensional cross-linked matrix ('gel 0059. The present invention relates generally to composi lified') to the vehicle. ? The term “semi-solid’ as used herein tions or formulations that contain an active agent for admin refers to a heterogeneous system in which one solid phase is istration to subjects in need thereof. The invention further dispersed in a second liquid phase. relates to preferred formulations for the transdermal or trans 0066. The term “vehicle' as used herein refers to carrier mucosal administration of Such agents wherein the formula materials (other than the pharmaceutically active agent) Suit tion is substantially free of malodorous, and irritation-caus able for transdermal administration of a pharmaceutically ing permeation enhancers. Surprisingly, the formulations of active agent. A vehicle may comprise, for example, Solvents, the present invention can achieve Sufficient absorption to cosolvents, permeation enhancers, pH buffering agents, anti result in an effective dosage of the active agent or its metabo oxidants, gelling agents, additives, or the like, wherein com lites circulating in serum without the inclusion of the mal ponents of the vehicle are nontoxic and do not interact with odorous and irritation-causing permeation enhancers that other components of the total composition in a deleterious have been used to date. In a preferred aspect of the invention, a. US 2011/02452.15 A1 Oct. 6, 2011

0067. The phrase “non-occlusive, transdermal drug deliv selected from the group including: carbomer 980 or 940 NF, ery” as used herein refers to transdermal delivery methods or 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, systems that do not occlude the skin or mucosal Surface from 2050, 934P NF, 971P NF, 974P NF, Noveon AA-1 USP; contact with the atmosphere by structural means, for cellulose derivatives such as ethylcellulose, hydroxypropyl example, by use of a patch device, a fixed application cham methylcellulose (HPMC), ethylhydroxyethylcellulose ber or reservoir, a backing layer (for example, a structural (EHEC), carboxymethylcellulose (CMC), hydroxypropyl component of a device that provides a device with flexibility, cellulose (HPC) (Klucel grades), hydroxyethylcellulose drape, or occlusivity), a tape or bandage, or the like that (HEC) (Natrosol grades), HPMCP 55, Methocel grades: remains on the skin or mucosal Surface for a prolonged period natural gums such as arabic, Xanthan, guar gums, alginates: of time. Non-occlusive, transdermal drug delivery includes polyvinylpyrrolidone derivatives such as Kollidon grades; delivery of a drug to skin or mucosal Surface using a topical polyoxyethylene polyoxypropylene copolymers such as medium, for example, creams, ointments, sprays, Solutions, Lutrol F grades 68, 127. Other gelling agents include chito lotions, gels, and foams. Typically, non-occlusive, transder san, polyvinyl alcohols, pectins, Veegum grades. A tertiary mal drug delivery involves application of the drug (in a topical amine. Such as triethanolamine or trolamine, can be included medium) to skin or mucosal Surface, wherein the skin or to thicken and neutralize the system. The amount and the type mucosal Surface to which the drug is applied is left open to the of the gelling agent in the formulation may be selected by the atmosphere. man skilled in the art to provide the desired product consis 0068. The term “transdermal delivery, as used herein tency and/or viscosity to facilitate application to the skin. The refers to both transdermal (and "percutaneous') and transmu gelling agent is present from about 0.2 to about 30% w/w of cosal administration, that is, systemic delivery by passage of the formulation depending on the type of polymer. For a drug through a skin or a mucosal tissue surface and ulti example, the gelling agent is preferably present in an amount mately into the bloodstream. between about 0.3% to 2% for carbomers, and between about 0069. The term “topical” delivery, as used herein refers to 1% to 5% for hydroxypropylcellulose derivatives. local delivery of a drug into a skin Surface or a mucosal tissue 0075. In preferred embodiments, as noted, the composi Surface with minimal passage into the bloodstream. tion is non occlusive. The penetration enhancing system of 0070 The phrase “therapeutically effective amount’ as the present invention can also be used for mucosal delivery used herein refers to a nontoxic but sufficient amount of a through the buccal, Sublingual, auricular, nasal, ophthalmic, drug, agent, or compound to provide a desired therapeutic rectal, or vaginal mucosa. effect 0076. The formulation may further include preservatives 0071. In accordance with the invention, the delivery such as, but not limited to, benzalkonium chloride and deriva vehicle of the present invention preferably comprises a C2 to tives, benzoic acid, benzyl alcohol and derivatives, bronopol, C4 short-chain alkanol, a polyalcohol, and a monoalkyl ether parabens, centrimide, chlorhexidine, cresol and derivatives, of diethylene glycol in an amount Sufficient to provide per imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phe meation enhancement of the oxybutyninthrough mammalian nylmercuric salts, thimerosal, sorbic acid, derivatives thereof dermal or mucosal Surfaces. For the purpose of illustration and the like. The preservative is present from about 0.01 to and not limitation, the alkanol may be ethanol, isopropanol, about 10% w/w depending on the type of compound. or n-propanol. The alkanol is preferably ethanol. The alkanol 0077. The formulation may further include antioxidants is present in an amount between about 45 to 75% w/w, pref Such as but not limited to, tocopherol, ascorbic acid, butylated erably between about 50% to 70%, and more preferably hydroxyanisole, butylated hydroxytoluene, fumaric acid, between about 55% and 65% w/w. As known in the art, the malic acid, propyl gallate, Sulfites, derivatives thereof and the amount of the alkanol may be selected to maximize the dif like. The antioxidant is present from about 0.001 to about fusion of the active agent through the skin while minimizing 5.0% w/w of the formulation depending on the type of com any negative impact on the active agent itself or desirable pound. properties of the formulation. The alkanol can be present in a mixture with water. 0078. The formulation may further include a buffer such 0072 The polyalcohol is preferably propylene glycol or as carbonate buffers, citrate buffers, phosphate buffers, dipropylene glycol. The polyalcohol may also be a polyeth acetate buffers, hydrochloric acid, lactic acid, tartric acid, ylene glycol having general formula CH-OH(CHOH) diethylamine, triethylamine, diisopropylamine, aminom CHOH wherein the number of oxyethylene groups repre ethylamine. Although other buffers as known in the art may sented by n is between 4 to 200, propylene glycol, be included. The buffer may replace up to 100% of the water dipropylene glycol, butylene glycol, hexylene glycol, and amount within the formulation. mixtures thereof. The polyalcohol is advantageously present 007.9 The formulation may further include a humectant. in an amount between about 1% and 30% of the vehicle, The formulation may further include humectant, such as but preferably from 2.5% to 20% w/w, and more preferably from not limited to glycerin, propylene, glycol, Sorbitol, triacetin. about 5% to 10% w/w. The humectant is present from about 1 to 10% w/w of the 0073. The monoalkyl ether of diethylene glycol is prefer formulation depending on the type of compound. ably selected from the group consisting of monomethyl ether 0080. The formulation may further include a sequestering of diethylene glycol, monoethyl ether of diethylene glycol, agent Such as edetic acid. The sequestering agent is present and mixtures thereof. It is present in an amount of about 1% from about 0.001 to about 5% w/w of the formulation depend and 15%, preferably between about 2.5% to 10% w/w and ing on the type of compound. more preferably between about 2.5% to 5% w/w. I0081. The formulation may further include anionic, non 0074 The formulation may further include a thickening ionic or cationic Surfactants. The Surfactant is present from agent or gelling agent present in an amount Sufficient to alter about 0.1% to about 30% w/w of the formulation depending the viscosity of the formulation. A gelling agent can be on the type of compound. US 2011/02452.15 A1 Oct. 6, 2011

0082. The formulation may further include a pH regulator, active drugs by only once-a-day application of the formula generally, a neutralizing agent, which can optionally have tion. Thus, the present invention relates to a method for cross-linking function. By way of example and not limitation, administering topically or systemically different active Sub the pH regulator may include a ternary amine Such as mono stance(s). ethanolamine, diethanolamine, triethanolamine, I0089. The delivery vehicle may further include moisturiz tromethamine, tetrahydroxypropylethylendiamine, aminom ers and emollients to soften and smoothen the skin or to hold ethyl propanol, diisopropanolamine, or an inorganic alkali and retain moisture. By way of example and not limitation, such as NaOH solution, KOH solution, or NH-OH solution. moisturizers and emollients may include cholesterol, leci The pH regulator is present in the formulations in variable thin, light mineral oil, petrolatum, and urea. amounts depending on the nature and the relative strength of 0090 The present formulations advantageously (a) inhib the pH regulator. The optimum pH may also be determined its crystallization of the at least one active ingredient on a skin and may depend on, for example, the nature of the active or mucosal Surface of a mammal, (b) reduces or prevents agent and the degree of flux required. transfer of the formulation to clothing or to another being, (c) 0083. For some lesser preferred embodiments, the deliv modulates biodistribution of the at least one active agent ery vehicle may contain a saturated fatty alcohol or fatty acid, within different layers of skin, (d) facilitates absorption of the or mixtures thereof in an amount of from about 0.4 to 10%, at least one active agent by a skin or a mucosal Surface of a wherein the fatty alcohol or fatty acid have the formula mammal, or (e) provides a combination of one or more of (a) CH (CH), CH-OH or CH (CH), HCOOH, through (d). respectively, in which n is an integer from 8 to 22; or an 0091 For any particular formulation, the active agent, unsaturated fatty alcohol or fatty acid, or mixtures thereof, delivery vehicle and other ingredients may be selected to wherein said unsaturated fatty alcohol and/or fatty acid have achieve the desired drug delivery profile and the desired pen the formula CH-(CH2-)-OH or CH-(CH2)— etration. COOH, respectively, in which n is an integer from 8 to 22. Of 0092. In accordance with the invention, the active agent these, lauryl alcohol or myristyl alcohol present in an amount may be present in an amount between about 0.1% to 20% by from 0.5 to 2% by weight of the total formulation can be used. weight of the delivery vehicle. The active agent may be 0084. Further, it has also been found that the glycol acts as present in the form of a pharmaceutically acceptable salt a modulator of the capability, of the monoalkyl ether of dieth thereof. Examples of such salts comprise, but are not limited ylene glycol to build a drug depot within the different layers to, acetate, bitartrate, citrate, edetate, edisylate, estolate, esy of the skin. Also, the significant reduction of unabsorbed late, fumarate, gluceptate, gluconate, glutamate, hydrobro active drug(s) remaining at the application Surface area mide, hydrochloride, lactate, malate, maleate, mandelate, results from the simultaneous although independent inhibi mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate, tion of crystallization and transdermal drug penetration, pantothenate, phosphate, Salicylate, Stearate. Succinate, Sul enhanced or not by additional permeation enhancer(s). fate, tannate and tartrate. The invention is applicable to com 0085 Additional advantages of the present invention binations of active agents, where a primary active agent is include the discovery that the association of a monoalkyl present in combination with a secondary active agent for ether of diethylene glycol and the preferred propylene glycol concurrent administration to the Subject. component at specified ratios exhibits a synergic effect and 0093. The active agent may be a hormone selected from inhibits crystallization of the active ingredient(s) in transder the group consisting of an androgen, estrogen, progestin, or a mal semi-solid formulations. In addition, it has been discov combination thereof. The androgen may be selected from the ered that a totally unexpected control of the active drug(s) group consisting of testosterone, 17-B-hydroxyandrostenone, distribution in the different layers of the skin is achieved when testosterone esters, methyl testosterone, testolactone, modifying the range of the monoalkyl ether:glycol ratio, oxymetholone, fluoxymesterone, androsterone, androsterone simultaneously but independently from the crystallization acetate, androsterone propionate, androsterone benzoate, inhibitor effect above mentioned. androstenediol, androstenediol-3-acetate, androstenediol I0086. The monoalkyl ether of diethylene glycol and the 17-acetate, androstenediol-3,17-diacetate, androstenediol glycol are generally present in a weight ratio of 10:1 to 1:10 17-benzoate, androstenediol-3-acetate-17-benzoate, andros and preferably in a ratio ranging from 10:1 to 2:1 or 1:2 to tenedione, Sodium dehydroepiandrosterone Sulfate, 1:10, although ratios between 3:1 and 1:1 or 2:1 to 1:1 are 4-dihydrotestosterone, 5 adihydrotestosterone, dromo preferred. stanolone, dromostanolone propionate, ethylestrenol, nan 0087. It has been surprisingly discovered that it is possible drolone phenpropionate, nandrolone decanoate, nandrolone to achieve a therapeutically effective, Sustained and con furylpropionate, nandrolone cyclohexanepropionate, nan trolled penetration rate of diverse active substances into the drolone benzoate, nandrolone cyclohexanecarboxylate, skin with the aid of the inventive delivery system. It has also Oxandrolone, and Stanozolol or any combination thereof. The been discovered Surprisingly that the formulations composi estrogen may be selected from the group consisting of 17 tions disclosed herein exert higher permeation rates when beta-estradiol, estradiol, estradiolbenzoate, estradiol 17beta compared with compositions that do not contain the delivery cypionate, estriol, estrone, ethynil estradiol, mestranol, mox system of the invention. estrol, mytatrienediol, polyestradiol phosphate, quinestra 0088. It also has been surprisingly discovered also that by diol, and quinestrol or any combination thereof. The utilizing the combination of diethylene glycol monoethyl progestin may be selected from the group consisting of ether and propylene glycol as permeation enhancers in the allylestrenol, anagestone, chlormadinone acetate, delmadi delivery system of the invention herein disclosed, an adequate none acetate, demegestone, desogestrel, dimethisterone, penetration enhancement factor and a Sustained flux of the dydrogesterone, ethynilestrenol, ethisterone, ethynodiol. active agent is attained, thereafter reflected in achieving ethynodiol diacetate, flurogestone acetate, gestodene, gesto therapeutic effective, controlled and sustained levels of the norone caproate, haloprogesterone, 17-hydroxy-16-methyl US 2011/02452.15 A1 Oct. 6, 2011

ene-progesterone, 17 alpha-hydroxyprogesterone, 17 alpha acceptable salts, isomers, and mixtures thereof, or even an hydroxygesterone caproate, lynestrenol, medrogestone, anti-depressant drug selected from the group consisting of medroxyprogesterone, megestrol acetate, melengestrol, citalopram, escitalopram oxalate, fluoxetine, fluvoxamine, 16-methylene-17-alpha-acetoxy-19-nor-pregn-4-ene.3.20 paroxetine, Sertraline, dapoxetine; Venlafaxine and dulloxet dione, norethindrone, norethindrone acetate, norethynodrel, ine; harmaline, iproniazid, isocarboxazid, nialamide, par norgesterone, norgestimate, norgestrel, norgestrienone, gyline, phenelzine, selegiline, toloxatone, tranylcypromine, 19-norprogesterone, norvinisterone, pentagestrone, progest brofaromine, moclobemide; amitriptyline, amoxapine, erone, natural progesterone, promegestone, quingestrone, butriptyline, clomipramine, desipramine, dibenzepin, dothi and trengestone or any combination thereof. Preferably, the epin, doxepin, imipramine, iprindole, lofepramine, meli combination of estrogen and progestin is not present in the tracen, nortriptyline, opipramol, protriptyline, trimipramine; formulation. maprotiline, mianserin, nefazodone, traZodone, and pharma 0094. The active agent may also be any of the following: ceutically acceptable salts, isomers, and mixtures thereof. drugs to treat Parkinson disease; drugs to treat Alzheimer 0097. The active agent may also be a drug for treating disease and senile dementia; Attention Deficit and Hyperac ADHD selected from the group consisting of methylpheni tivity Disorders (ADHD) drugs; drugs to treat narcolepsy; date, and pharmaceutically acceptable salts, isomers, and anti-anxiety drugs; anti-depression drugs; drugs to treat epi mixtures thereof, or an anti-insomnia drug selected from the lepsy; drugs to treat insomnia; drugs to treat motor neurone group consisting of Zolpidem, Zopiclone, and pharmaceuti diseases; drugs to treat multiple Sclerosis; anti-nausea and cally acceptable salts, isomers, and mixtures thereof, or a anti-Vomiting drugs; anti-psychotic drugs; hypnotics; anti 5-alpha-reductase inhibitor Such as the azasteroid com depressants; tranquilizers; drugs to treat Restless Legs Syn pounds, namely, finasteride or dutasteride. drome (RLS); drugs to treat alcohol addiction, nicotine addic 0098. Also in accordance with the invention, the pharma tion, drug addiction, or food addiction; central analgesics; ceutical active agent may include anti-gout drugs such as drugs to treat central metabolism disorders; or a combination colchicine and derivatives, Sulfinpyrazone, probenecid, ben of one of the previously mentioned drugs with another drug. Zbromarone, allopurinol; local anaesthetics such as ben 0095. The active agent may also be an anti-Parkinson drug Zocaine, procaine, tetracaine, lidocaine, etidocaine, selected from the group consisting of amantadine, benser prilocaine, mepivacaine, bupivacaine, butanilicaine, artic azide, carbidopa, levodopa, benztropine, biperiden, ben aine, fomocaine; general anaesthetics such as methohexital, Zhexol, procyclidine, bornaprine, budipine, entacapone, etho thiamylal, thiopenthal, ketamine, etomidate, propofol, mida propazine, laZabemide, memantine, orphenadrine, Selegiline, Zolam, flumazenil, droperidol, fentanyl, alfentanil, Sufenta tolcapone, trihexyphenidyl, modafinil, talampanel, altini nil; muscle relaxant drugs such as curare derivatives, hexac cline, brasofensine, Safinamide, droxidopa, rasagline, bro arbacholine, dantrolene, tetrazepam, carisoprodol. mocriptine, cabergoline, pergolide, piribedil, pramipexole, chlorZoxaZone, baclofen, memantine, tiZandine; diuretics quinagolide, terguride, rotigotine, riluzole, talipexole, piro such as hydrochlorothiazide and derivatives, chlortalidone, heptine, bifeprunoX, spheramine, lisuride, Sumanirole, ropin indapamide, furosemide, bumetanide, piretanide, azosemide, irole, rotigotine, and pharmaceutically acceptable salts, iso etoZolin, ethacrynic acid, amiloride, triamterene, spironolac mers, and mixtures thereof, an anti-Alzheimer drug selected tone; angiotensin converting enzyme inhibitors such as cap from the group consisting of tacrine, donepezil, rivastigmine, topril, enalapril, trandolapril, lisinopril, perindopril, galantamine, amantadine, memantine, rimantadine, and phar benazepril, cilaZepril, fosinopril, moexipril, quinapril, rami maceutically acceptable salts, isomers, and mixtures thereof; pril; calcium-channel blockers such as bepridil, diltiazem, or an analgesic drug selected from the group consisting of felodipine, flunarizine, isradipine, nicardipine, nitrendipine, alfentanil, buprenorphine, butorphanol, codeine, dextro nifedipine, nimodipine, Verapamil, amlodipine, lacidipine, moramide, dextropropoxyphene, dezocine, diamorphine, buflomedil; anti-arythmics Such as quinidine, ajmaline, dihydrocodeine, fentanyl, flupirtine, hydrocodone, hydro procainamide, disopyramide, propafenone, tocainide, pheny morphone, ketobemidone, levomethadyl, mepiridine, toin, aprindine, mexiletine, flecainide, lorcainide, pro meptazinol, methadone, morphine, nalbuphine, oxycodone, pafenone, Sotalol, amiodarone, Verapamil, diltiazem; anti oxymorphone, papaveretum, pentazocine, pethidine, pheno angina drugs such as nitrate derivatives, molsidomine; anti peridine, piritramide, remifentanil, tilidine, tramadol, Sufen migraine drugs such as, pizotifene, oxetorone, methysergide tanil and pharmaceutically acceptable salts, isomers, and Sumatriptan, Zolmitriptan, naratriptan, eletriptan, almotrip mixtures thereof. tan, rizatriptan; antiemetic drugs such as chlorphenoxamine, 0096. The active agent may also be an anti-addiction drug dimenhydramine, meclozine, triethylperazine, triflupro selected from the group consisting of nicotine, buprenor mazine, metoclopramide, bromopride, domperidone, granis phine, naloxone, and pharmaceutically acceptable salts, iso etron, ondansetron, tropisetron, dolasetron, alosteron, tegas mers, and mixtures thereof, oran anti-psychotic drug selected erod; anti-histaminic and anti-asthma drugs such as from the group consisting of chlorpromazine, fluphenazine, cromoglycate, nedocromil, tritoqualine, ketotifene, lodoxa perphenazine, prochlorperazine, thioridazine, trifluopera mide, salbutamol, terbutaline, pirbuterol, salmeterol, formot Zine, butyrophenones, haloperidol, droperidol, pimozide, erol, bambuterol, montelukast, pranlukast, theophylline, clozapine, olanzapine, mirtanzapine, tinaeptine, bupropion, ipratropium, oxitropium, beclometaSone, dexamethasone, risperidone, quetiapine, Ziprasidone, amisulpride, melper fluticasone, budesonide, flunisolide; thrombolytics such as one, paliperidone, aripiprazole, and pharmaceutically accept alteplase and derivatives, streptokinase, urokinase; analge able salts, isomers, and mixtures thereof, or an anti-anxiety sics such as morphine, codeine, diamorphine, dihydroco drug selected from the group consisting of alprazolam, bro deine, hydromorphone, hydrocodone, oxycodone, oxymor mazepam, diazepam, lorazepam, clonazepam, temazepam, phone, levorphanol, pethidine, levomethadone, oxazepam, flunitrazepam, triazolam, chlordiazepoxide, flu fenpipramine, piritramide, clofedanol, pentazocine, razepam, estazolam, nitrazepam, and pharmaceutically buprenorphine, butorphanol, nalbuphine, tilidine, tramadol, US 2011/02452.15 A1 Oct. 6, 2011 nefopam, Salicylic acid and derivatives, Salsalate, diflunisal, coxib, nefopam; antisecretive gastric drugs such as omepra acetaminophen, benorylate, mefenamic acid, flufenamic Zole, lanSoprazole, pantoprazole, rabeprazole, misoprostol; acid, niflumic acid, metamizole, phenaZone, phenylbutya laxatives; gastric mucosa protectors such as cimetidine, Zone, aminophenaZone, oxyphenbutaZone, azapropaZone, famotidine, ranitidine, nizatidine, gastric motricity modula indometacin, diclofenac, Sulindac, felbinac, ibuprofen, tors; bile salts adsorbants; chelators; gall stone dissolvants; naproxen, fenoprofen, flurbiprofen, ketoprofen, tiaprofenic anti-anemia drugs; cutaneous diseases drugs; alpha antago acid, nabumetone, piroxicam, tenoxicam, meloxicam, anti nist drugs such as urapidil and derivatives, prazosine and tussive agents such as codeine and derivatives, clobutinol, derivatives, nicergoline, moxisylyte, antiparasitic drugs such isoaminile, pentoxyverine, butamirate, Oxeladine, pipaZetate; as albendazole, atovaquone, chloroquine, dehydroemetine, tricyclic antidepressants such as imipramine, desipramine, diloxanide, furazolidone, halofantrine, iodoquinol, ivermec trimipramine, lofepramine, clomipramine, opipramol, ami tin, mebendazole, mefloquine, metronidazole, nifurtimox, triptyline, amitriptylinoxide, nortriptyline, dibenzepin, dox primaquine, pyrantel, pyrimethamine, quinine, quinidine, epin, melitracen, tetracyclic antidepressants such as mapro penicillins; cephalosporins; aminosids; polypeptides; Sulfa tiline, mianserin; atypical antidepressants such as mides; diaminopyrimidines; tetracyclins; chloramphenicol; fluvoxamine, traZodone, Viloxacin, fluoxetine; monoamine thiamphenicol; macrollides; Vancomycin; teicoplanin; oxidase inhibitors such as tranylcipromine; serotonin precur rifampicin; fusidic acid; 5-nitro-imidazoles; lincosamides; sors such as oxitriptan; lithium salts; tranquilizers such as quinolones; isoniazide, ethambutol; antineoplasic drugs such meprobamate, hydroxy Zine, chlordiazepoxide, temazepam, as chlormethine, chlorambucil, melphalan, cyclophospha flurazepam, lormetazepam, nitrazepam, flunitrazepam, diaz epam, prazepam, oxazepam, lorazepam, clonazepam, bro mide, ifosfamide, estramustine, carmustine, lomustine, fote mazepam, clotiazepam, alprazolam, triazolam, oxazolam, mustine, carbazine derivatives, cisplatine and derivatives, midazolam, ketazolam, brotizolam, clobazam, cloraZepate, thiothepa, daunorubicine and derivatives, mitoxantrone, buspirone; amphetamines and related compounds such as 5-fluorouracil, capecitabine, cytarabine, gemcitabine, mer amfetamine, metamfetamine, fenetylline, methylphenidate, captiopurine azathioprine, fludarabine, thioguanine, pen prolintane; anorectics Such as cathine, amfepramone, to statine, cladribine, raltitrexed; anti virus drugs such as mefenorex, propylhexedrine, fenfluramine; psychodysleptics Zidovudine and derivatives, aciclovir and derivatives, foscar Such as N-dimethyltryptamine, psilocin, psilocybin, bufote net, ritonavir and derivatives; antifungus drugs such as nys nin, lysergide, mescaline, tetrahydrocannabinol; nootropics tatine, terbinafine, micanazole, ketoconazole, fluconazole, such as pyritinol, piracetam, meclofenoxate; hypnotics such itraconazole, bifonazole, econazole, omoconazole, Sulcona as carbromal, bromisoval, vinylbital, aprobarbital, secbut Zole, tioconazole, isoconazole, fenticonazole, Sertaconazole. abarbital, pentobarbital, cyclobarbital, phenobarbital, glute 0099. The active agent may also be oxybutynin or another thimide, methyprylon, methaqualone; analeptics such as dox anticholinergic drug. Although oxybutynin is the preferred apram; tricyclic neuroleptics such as chlorpromazine, anti-cholinergic agent that is disclosed herein, other Such promazine, triflupromazine, alimemazine, levomepro agents, among which those having an antimuscarinic activity mazine, chlorprothixene, pecazine, thioridazine, perphena are preferred, can be used in place of oxybutynin. Preferred Zine, trifluoperazine periciazine, perazine, fluphenazine, dix anti-cholinergic drugs with antimuscarinic activity include, yrazine, clopenthixol, dixyrazine, prothipendyl, thithixene, without limitation, tolterodine, trospium, propiverine, flavox chlorprothixene, clopenthixol, flupentiXol; butyrophenones ate, emepronium, propantheline, darifenacin, and Solifena and diphenylbutylpiperidines neuroleptics such as haloperi cin. These can be used, for example, in the treatment of dol, bromperidol, droperidol, trifluperidol, pipamperone, hyperactivity of the detrusor muscle (over activity of the melperone, benperidol, pimozide, fluspirilene; benzamide bladder muscle) with frequent urge to urinate, increased uri neuroleptics such as Sulpiride; anti-psychotic drugs such as nation during the night, urgent urination, involuntary urina clozapine, haloperidol, olanzapine, quetiapine, risperidone; tion with or without the urge tourinate (incontinence), painful anti-convulsive drugs such as carbamazepine, Valproic acid or difficulturination. and its derivatives, primidone, phenytoin, ethoSuximide, tri methadione, Sultiame, hypothalamo-hypophysis regulators 0100 Preferably, the formulations of the invention pro Such as gonadoreline, triptoreline, leupropreline, busereline, vides therapeutic levels of the active agent or metabolite for at gosereline, nafareline, gonadotrophins, follitropins, danazol. least 24 hours. More preferably, the method provides sus clomifene, quinagoline, bromocriptine, lisuride; antihypo tained therapeutic levels for at least 48 hours. Most prefer and antihyperthyroidy drugs such as thyreotropin releasing ably, the method provides sustained therapeutic levels for at hormone, thyreostimuline hormone, triiodothyronine, thy least 72 hours. Thus, the formulations of the invention only roXine, tiratricol, benzylthiouracile, clotrimazole, corticos need to be administrated every once a day, every other day, teroids; glucocorticoids and mineralocorticoids; glycemia every third day or twice per week. regulators such as insuline, glipizide, glibenclamide, glib 0101 The present invention further provides various treat ornuride, gliclazide, carbutamide, glimepiride, repaglinide, ment methods for administering the active agent to a subject metformine, acarbose, miglitol, glucagon, diazoxide; hypo in need thereof via the topical or transdermal formulations lipidemia drugs such as orlistat, simvastatine, pravastatine, disclosed herein. For example, methods for treating hormonal fluvastatine, atorvastatine, tiadenol, cholestyramine, fenofi diseases, disorders, or conditions in a subject are disclosed. brate, ciprofibrate, bezafibrate, gemfibrozil, ursodiol; phos These methods generally comprise administering to the Sub phocalcic metabolism regulators such as ergocalciferol, ject a formulation comprising an effective dosage of at least cholecalciferol calcitriol, alfacalcidol, calcifediol, calcipot one active agent of a hormone and the delivery vehicle. riol, tacalcitol; anti-inflammatory drugs such as nabumetone, 0102 The subject in need of treatment may be male or meloxicam, nimeSulide, etodolac, alminoprofene, Sulfasala female. Thus, the type of active agents selected for the for Zine, mefasalazine, olSalazine, rofecoxib, celecoxib, Valde mulation and method of treatment, and the effective dosages US 2011/02452.15 A1 Oct. 6, 2011 of the active agents is in part dependent on the sex of the symptoms, vaginal dryness, and general well-being, little subject to be treated, and the type of hormonal disorder being improvement in libido has been observed. Increased sexual treated. drive, arousal, and frequency of sexual fantasies were 0103 For the purpose of illustration and not limitation, observed in hysterectomized and oophorectomized women and in accordance with the invention, for example, a woman with testosterone-enanthate injections over and above those undergoing treatment may be of childbearing age or older, in observed with ERT alone. Therefore, in accordance with the whom ovarian estrogen, progesterone and/or androgen pro method of the invention, treating female Subjects comprising duction has been interrupted either because of natural meno administration of formulations comprising active agents pause, Surgical procedures, radiation, chemical ovarian abla including both an androgen, preferably testosterone, and an tion or extirpation, or premature ovarian failure. In addition to estrogen, as well as treating female Subjects comprising natural menopause and aging, a decline in total circulating administering formulations comprising estradiol alone as the androgens leading to testosterone deficiency can be attributed active agent. to conditions that Suppress adrenal androgen secretion (i.e., 0108. Another study in women who were naturally or acute stress, anorexia nervosa, Cushing's syndrome, and pitu Surgically menopausal with inadequate ERT for 24 months itary renal insufficiency), conditions that can decrease ova showed significant improvements in sexual sensation and rian androgen secretion (i.e., ovarian failure and the use of desire after 4 and 8 weeks of androgen/estrogen treatment vs. pharmacologic doses of glucocorticoids), and chronic illness placebo or estrogen treatment alone. Sexual desire, arousal, Such as muscle-wasting diseases like Acquired Immune Defi well-being, and energy levels were enhanced with androgen/ ciency Syndrome (AIDS). Thus, the term “hormonal disor estrogen therapy in Studies in Surgically menopausal women. der” as used herein means any condition that causes a Sup Results of improved libido with subcutaneous testosterone pression or reduction of hormonal Secretions in a subject. implants in combination with Subcutaneous estrogen 0104. In addition to treating female subjects for female implants in postmenopausal women have also been reported. menopausal symptoms due to aging and other factors as dis In women who have undergone oophorectomy and hysterec cussed above, reduced levels of androgens (and estrogens) in tomy, transdermal testosterone improved sexual function and women may lead to female sexual dysfunction (FSD) result psychological well-being. To achieve good response in terms ing in clinical symptoms such as lack of sex drive, arousal or of libido, plasma testosterone levels need to be restored to pleasure; low energy, reduced sense of well-being and near the upper end of the normal physiologic range observed osteoporosis. Preferred results of using the formulations of in young ovulating women. the invention to treat FSD in women may include one or more 0109 Therefore, treatment with a separate or the same of the following: increased energy, increased sense of well composition including estrogen may be desirable to achieve being, decreased loss of calcium from bone, and increased at least the preferred results described above. A pre-meno sexual activity and desires. pausal female Subject generally has a serum concentration of 0105. In pre-menopausal women, total plasma testoster estradiol from about 30 to 100 pg/mL, whereas normal post one concentrations generally range from 15-65 ng/dL (free menopausal levels are below 20 pg/mL. testosterone in pre-menopausal women is approximately 1.5 0110. Further, reduced levels of estrogens (and progestin) to 7 pg/ml) and fluctuate during the menstrual cycle, with in women, such as due to aging, leads to menopause resulting peaks of androgen concentration corresponding to those of in clinical symptoms such as hot flashes and night Sweats, plasma estrogens at the pre-ovulatory and luteal phases of the vaginal atrophy, decreased libido, increased risk of heart dis cycle. In the years leading to postmenopausal transition, lev ease and osteoporosis. Preferred results of using a composi els of circulating androgens begin to decline as a result of tion of the present invention may include one or more of the age-related reductions of both ovarian and adrenal Secretion. following: decreased incidence and severity of hot flashes and There are reports in studies that 24-hour mean plasma test night Sweats, decreased loss of calcium from bone, decreased osterone levels in normal pre-menopausal women in their risk of death from ischemic heart disease, increased vascu 40’s are half that of women in their early 20's. It has been larity and health of the vaginal mucosa and urinary tract are generally accepted, however, that women with androgen defi and increased sexual activity and desires. Thus, in another ciency have total testosterone levels <25 ng/dL (<50-years preferred embodiment, the method include administering to a old) or <20 ng/dL (250-years-old) while oophorectomized female Subject in need of treatment, a formulation comprising women can have total testosterone levels <10 ng/dL. both an estrogen in combination with a progestin as active 0106. In this regard, the method may include administer agents. ing to the female Subject a therapeutically effective dosage of 0111. As stated above, the methods include treating male testosterone from about 1 mg to about 3 mg each 24 hours. subjects for hormonal disorders. For example, the male is Therefore, the formulation preferably provides the subject treated for hypogonadism (low testosterone levels). Hypogo with a total serum concentration of testosterone from at least nadism in men may result in clinical symptoms including about (>30 ng/dL) 15 to about 55 ng/dL, or a free serum impotence, lack of sex drive, muscle weakness and concentration of testosterone from about 2 to about 7 pg/mL. osteoporosis. Preferred results of using the compositions of 0107 Moreover, studies have shown that testosterone the invention to treat hypogonadism in men may include one replacement combined with estrogen replacement therapy or more of the following: decreased incidence and severity of (“ERT) improves parameters of sexual function and well impotence, decreased loss of calcium from bone, increased being versus ERT alone. A decline in rates of sexual inter muscle strength, and increased sexual activity and desires. course and fewer sexual thoughts and fantasies has been 0112 A normal male subject generally has a total serum associated with significant decreases in estradiol and test concentration of testosterone from about 300 to 1050 ng/dL, osterone. A decrease in testosterone has also been associated whereas hypogonadal men have levels below 300 ng/dL. with decreased frequency of coitus. Although estradiol treat Therefore, the composition of the invention may be used to ment alone in oophorectomized women improved vasomotor provide the subject with a therapeutically effective dosage of US 2011/02452.15 A1 Oct. 6, 2011

testosterone of about 50 mg/day. Therefore, in use the com position preferably provides the subject with a free serum TABLE 5 concentration of testosterone from at least about 300 to 1000 Testosterone 196 ng/dL. Carbomer 980 1.2% Triethanolamine (adjust to pH 5.9) O.4% 0113. The invention also relates to a method for adminis Ethanol 47.5% tering oxybutynin or other anticholinergic agent to a mammal Propylene glycol 6% in need thereof comprising topically or transdermally admin Diethylene glycol monoethyl ether 59 Disodium EDTA O.06% istering to the skin or the mucosa of a mammal one of the Ion Exchange Purified Water q. ad. 100% compositions disclosed herein. Preferably, the mammal is a human. For example, the treatments methods include treating 0115 The preferred formulations of the present invention hyperactivity of the detrusor muscle with frequent urge to are advantageous at least for the following reasons. First, the urinate, increased urination during the night, urgenturination, formulations of the present invention are substantially free of involuntary urination with or without the urge to urinate, long-chain fatty alcohols, long-chain fatty acids, and long painful or difficult urination, detrusor hyperreflexia and chain fatty esters. Surprisingly, the formulations exhibit skin detrusor instability. Typically, not more than 200 mg of the penetration sufficient to deliver an effective dosage of the active agent is administered per day, with a daily dose of active agent to the user. This is an unexpected advantage that between about 40 and about 100 mg being preferred. The those of ordinary skill in the art would not have readily composition is advantageously administered upon the abdo discovered since it had been generally understood that per meation enhancers, and more particularly long-chain fatty men, shoulder, arm, or thigh of the Subject. alcohols, long-chain fatty acids, and long chain fatty esters, 0114. The preferred formulations for these treatments would be required to enhance skin penetration of certain include the following: active agents such as oxybutyninto permitan effective dose to penetrate the skin. Second, because the formulation does not TABLE 1. include aliphatic acid groups, such as fatty acids, that are Estradiol O.01%-296 commonly included in topical gels, it does not have the odor Carbomer O.05%-49 or oily texture which is associated with that ingredient as in Triethanolamine (adjust to pH 5.9) O.05%-49 presently-available gels. Numerous studies acknowledge the Alcohol 20%-65% irritation-causing potential of unsaturated fatty acids such as Propylene glycol 190-15% Diethylene glycol monoethyl ether 190-15% oleic acid. See, Tanojo H. Boelsma E, Junginger H E. Ponec Ion Exchange Purified Water q. ad. 20%-65% M. Bodde H E, “In vivo human skin barrier modulation by topical application offatty acids. Skin Pharmacol Appl. Skin Physiol. 1998 March April; 11 (2)8797. Third, the absence of long-chain fatty alcohols, long-chain fatty acids, and long TABLE 2 chain fatty esters means that the irritation potential is lower Testosterone O.01%-10% and that there is less chance for the components to interact, Carbomer O.05%-49 reducing the need for stabilizers in the formulation. It is to be Triethanolamine (adjust to pH 5.9) O.05%-1.96 Alcohol 20%-65% understood, however, that if such stabilizers are desired, the Propylene glycol 190-15% invention encompasses formulations which include antioxi Diethylene glycol monoethyl ether 190-15% dants, chelators or preservatives. The reduction in the number Ion Exchange Purified Water q. ad. 20%-65% of ingredients is advantageous at least in reducing manufac turing costs, possible skin irritation. 0116. Additionally, the reduced number of ingredients increases the storage stability of the formulation by decreas TABLE 3 ing the chance that the ingredients will interact prior to being Estradiol O.01%-1% delivered to the patient in need thereof. This does not, how Carbomer 940 1.2% ever, imply that additional ingredients cannot be included in Triethanolamine (adjust to pH 5.9) O.4% Alcohol 46.28% the formulation for particular aesthetic and/or functional Propylene glycol 6% effects. For example, the formulation may optionally include Diethylene glycol monoethyl ether 59% one or more moisturizers for hydrating the skin or emollients Disodium EDTA O.06% for softening and Smoothing the skin. Glycerin is an example Ion Exchange Purified Water q. ad. 100% of such a suitable moisturizing additive. 0117 The formulation may be applied once daily, or mul tiple times per day depending upon the condition of the TABLE 4 patient. The formulation of the invention may be applied topically to any body part, such as the thigh, abdomen, shoul Testosterone O.O1%-10% Carbomer 980 1.2% der, and upper arm. In one embodiment, up to 10 grams of a Triethanolamine (adjust to pH 5.9) O.4% formulation in the form of a gel is applied to an area of skin. Alcohol 46.28% In a preferred embodiment of the invention, not more than 5 Propylene glycol 6% Diethylene glycol monoethyl ether 59 grams of a formulation in the form of a gel is applied to about Disodium EDTA O.06% an area of skin for about 1 g of gel. In a most preferred Ion Exchange Purified Water q. ad. 100% embodiment of the invention, about 1 to 3 grams of a formu lation in the form of a gel is applied to about a 100 square centimeter to a 1000 square-centimeter area of skin. Formu US 2011/02452.15 A1 Oct. 6, 2011 lation of the present invention may be applied on alternate 2" Ed., edited by J. Swarbrick and J. C. Boylan, Marcel areas of the body as applications alternate. For example, the Dekker, Inc., 2002, the content of which is incorporated gel may be applied to the abdomen for the first application, herein by reference. the upper arm for the second application, and back to the abdomen for the third application. This may be advantageous EXAMPLES in alleviating any sensitivity of the skin to repeated exposure to components of the formulation. Alternatively, the formu 0.122 The following examples are merely illustrative of lation of the present invention may be applied always on the the present invention and they should not be considered as same area of the body. limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent 0118. The invention includes the use of the formulations to those skilled in the art in light of the present disclosure and described above to treat subjects to increase circulating levels the accompanying claims. of the active agent or a metabolite thereof within the patient. Preferred dosage units are capable of delivering an effective amount of the active agent or metabolite over a period of Example 1 about 24 hours. By an “effective' or “therapeutically effec I0123. One embodiment of the formulation according to tive' amount of the active agent or metabolite means a non the invention is a topical gel having Testosterone 1.25% w/w, toxic, but sufficient amount to provide the desired effect. propylene glycol 5.95% w/w, Ethyl alcohol 45.46% w/w, However, it will be appreciated by those skilled in the art that Distilled water 45.67% w/w, Carbomer (Carbopol 980 NF) the desired dose will depend on the specific form of the active 1.21% w/w, Triethanolamine 0.39% w/w, Disodium EDTA agent or metabolite as well as on other factors. The formula 0.06% WFw. tion is preferably applied on a regularly-timed basis so that administration of the active agent or metabolite is Substan Example 2 tially continuous. 0119 The composition may be applied directly or indi 0.124 One embodiment of the formulation according to rectly to the skin or mucosal surfaces. Preferably, the com the invention is a gel composed by testosterone 1.00% w/w, position is non occlusive. The phrase “non-occlusive' as used diethylene glycol monoethyl ether 5.00% w/w, propylene herein refers to a system that does not trap nor segregate the glycol 6.00% w/w, ethanol 47.52% w/w, purified water skin from the atmosphere. 38.87% w/w, carbomer (CARBOPOLTM 980 NF) 1.20% 0120. The composition of the invention can be in a variety wfw, triethanolamine 0.35% w/w, and disodium EDTA of forms suitable for transdermal or transmucosal adminis 0.06% WFw. tration. For purpose of illustration and not limitation, the various possible forms for the present composition include Example 3 gels, ointments, creams, lotions, microspheres, liposomes, micelles, foams, lacquers, and non-occlusive transdermal 0.125 One embodiment of a formulation according to the patches, bandages, or dressings, or combinations thereof. invention is a topical hydroalcoholic gel formulation with 1% testosterone as the active ingredient. The formulation has Alternatively, the composition may be in the form of a spray, been studied in one Phase I/II multiple dose, dose escalating aerosol, Solution, emulsion, nanosphere, microcapsule, nano clinical study in women. The study was conducted to deter capsule, as well as other topical or transdermal forms known mine the effectiveness of the formulation for the treatment of in the art. In a preferred embodiment, the invention is a gel, a hypoactive sexual desire disorder (“HSDD), in subjects lotion, or a cream. In a most preferred embodiment, the inven including Surgically menopausal women with low testoster tion is a non-occlusive gel. Gels are semisolid, Suspension one levels. type systems. Single-phase gels comprise macromolecules 0.126 This study showed that the testosterone gel dosing (polymers) distributed substantially uniformly throughout between about 0.22 g to about 0.88 g formulation (2.2 to 8.8 the carrier liquid, which is typically aqueous. However, gels mg/day testosterone) daily for 7 days resulted in average total preferably comprise alcohol and, optionally, oil. Preferred and free testosterone serum concentrations within the normal polymers, also known as gelling agents, are crosslinked range or somewhat above the normal range for pre-meno acrylic acid polymers, polyethylene oxides, polyoxyethyl pausal women. ene-polyoxypropylene copolymers and polyvinylalcohol; cellulosic polymers (hydroxypropyl cellulose, hydroxyethyl Example 4 cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methyl cellulose); gums such as 0127. In vitro studies were conducted to determine the tragacanth and Xanthan gum, Sodium alginate; and gelatin. In permeability profile of testosterone in human Surgically order to prepare a uniform gel, dispersing agents such as excised skin using the testosterone formulation of Table 5 alcohol or glycerin can be added, or the gelling agent can be above (containing no lauryl alcohol, “1% T+0% LA”), as dispersed by trituration, mechanical mixing or stirring, or compared with other testosterone formulations containing combinations thereof. 1% and 2% lauryl alcohol (“1% T+1% or 2% LA'). The 0121 The compositions of the present invention may be results of these studies are presented below in Tables 6, 7 and manufactured by conventional techniques of drug formula 8 tion, particularly topical and transdermal drug formulation, I0128. In the first study pieces of excised human skin were which are within the skill of the art. Such techniques are mounted in Franz Vertical Diffusion Cells (Hansen Research disclosed in “Encyclopedia of Pharmaceutical Technology, Inc.). Approximately 10 mg of testosterone/cm (1%T+0, 1 US 2011/02452.15 A1 Oct. 6, 2011 13 or 2% LA), were loaded in the loading chamber over the skin, which was maintained at 35° C. Sampling of the receptor TABLE 9 Solution was performed at selected intervals after loading. Flux h cm Cum. Igen Amt. (SD The testosterone flux and cumulative amount in the perme ability study are shown below in Table 6. Time (h) O% LA 1% LA 2% LA O% LA 1% LA 2% LA 3.0 O448 O.872 O.900 1.345 2.617 2.700 TABLE 6 6.O O.S21 1.216 1.336 2.908 5.732 6.709 9.0 OSO4 O.914 O.801 4.421 8.473 9.112 Flux (Ligh cm Cum. Amt. (SD /cm Time (h) O% LA 1% LA 2% LA O% LA 1% LA 2% LA I0132 FIG. 2 is a graph depicting drug flux over time for 3 O.043 O.159 O.101 O.129 O.478 O.303 testosterone in formulations including various amounts of 6 O.093 O468 O.307 O.410 1884 1.225 lauryl alcohol (LA) in an in vitro model using human excised 9 O.062 O.329 O.172 0.595 2.871 1.740 12 O.OS1 O.16S O.121 O.748 3.368 2.104 skin and 50 mg testosterone/cm in the loading chamber 18 O.O27 O.049 O.047 O.911 3.664 2.388 (n=3-4+SD). This study shows that the 1% T+0% LA has a 24 O.O26 O.036 O.OS2 1.070 3.883 2.699 lower permeation rate. However, the permeation profile was less variable making it potentially more desirable for use in women since testosterone levels must be titrated within a 0129. The testosterone flux and cumulative amount for the narrow range. Thus, these in vitro studies would lead one of gel comprising approximately 1.25% testosterone, 5.00% ordinary skill in the art to believe that the inclusion of lauryl Transcutol, 5.95% propylene glycol, 43.09% ethyl alcohol, alcohol in the formulation is required in the formulation in 43.07% distilled water, 1.20% Carbopol 980NF, 0.38% tri order to achieve suitable circulating levels of hormones. ethanolamine, 0.059% EDTA are represented below in Tables However, Applicants have unexpectedly found that the inclu 7 and 8. sion of lauryl alcohol is not required intopical formulations to achieve an effective dose of circulating active agent penetra TABLE 7 tion. This is especially true for Female Sexual Dysfunction Testosterone where required testosterone plasmatic levels are lower than In vitro flux (ugh * cm)* testosterone therapeutic plasmatic levels observed to treat Mean +/- S.D. hypogonadism. Example 1 described above 1.12+f- 0.36 *(Slope of cumulative amount of permeated drug vs. time between 12 and 24 h) Example 5 0.133 Experience with gel formulations and transdermal TABLE 8 patches generally show low rates of mild dermal toxicity with Testosterone the gels and extensive skin reactions with the patches, prob Cumulative Amount (ig/cm) ably related to the adhesive used or the occlusive nature of the Mean +f- S.D. patch. For instance, with a topical gel formulation of test osterone, a few patients had skin reactions, none of which Time (h) Example 1 described above required treatment or discontinuation of drug. In contrast, O O transient mild to moderate erythema was observed in the 6 10.25 +f- 4.97 12 20.40+f- 6.75 majority of patients treated with a transdermal patch, and 18 27.84+f- 8.70 Some patients had more severe reactions including blistering, 24 33.80+f- 10.45 necrosis, and ulceration. See for example, Gelas B, Thébault J. Roux I, Herbrecht F. Zartarian M.. “Comparative study of 0130 FIG. 1 is a graph depicting drug flux over time for the acceptability of a new estradiol TX 11323 (A) gel and a testosterone in formulations including various amounts of transdermal matrix system. Contraception, fertilité, sexual lauryl alcohol (LA) in an in vitro model using human excised ité 1997 June; 25 (6):470-474). skin and 10 mg testosterone/cm in the loading chamber (n=3-4+SD). The profile of 1%T+0%LA is different than the Example 6 formulations containing lauryl alcohol. The profile is about 4 times lower at 6 hours than the 2% LA formulation, but I0134. The objective of this study was to evaluate the safety overall more consistent. All profiles showed a decrease in and pharmacokinetic profiles of multiple doses of a 1%T+0% testosterone flux after 6 hours of permeation, possibly due to LA hydroalcoholic gel, in postmenopausal women. During drug depletion. the first 7 days of the study, the subjects received daily topical applications of 0.22 g of a formulation including 1% T+0% 0131) Another permeation study was conducted using the LA (2.2 mg/day testosterone). On Days 8-14, the subjects method described above, except that approximately 50 mg of received 0.44 g of a formulation including 1%T+0% LA (4.4 testosterone/cm were loaded in the loading chamber over the mg/day testosterone), and on Days 15-21, the Subjects skin. Sampling of the receptor Solution was performed at received 0.88g of a formulation including 1%T+0% LA (8.8 selected intervals hours after loading. The testosterone flux mg/day testosterone). There was no washout period, prior to and cumulative amount in the permeability study are shown each dose escalation. The pharmacokinetic results for total, below. free and bioavailable testosterone are shown below. US 2011/02452.15 A1 Oct. 6, 2011

TABLE 10

Total Testosterone Parameter Day 1 Day 7 Day 14 Day 31 Daily Dose 2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7 C (ng dL) 21.00 (6.0) 42.43 (14.8) 68.71 (35.6) 87.00 (41.6) C (ng/dL) 38.49 (17.0) 56.03 (24.5) 91.99 (51.2) 141.49 (72.0) C. (ng/dL) 69.86 (33.0) 113.57 (92.9) 165.57 (113.8) 203.86 (128.3) C., (ng Dl) 19.00 (6.2) 31.14. (15.6) 43.14 (20.6) 77.57 (27.9) T* (hr) 20 (20-24) 16 (1-24) 16 (1-24) 20 (3-24) T* (hr) 1 (0-6) 6 (0-20) 6 (0-12) 0 (0-12) AUC (ngi hr/dL) 923.79 (408.3) 1344.71 (588.5) 2207.79 (1228.1) 3395.64 (1728.8) AR (ratio) 1.59 (0.7) 2.32 (0.5) 3.59 (0.6) Parameter Day 1 Day 7 Day 14 Day 21

Free Testosterone Daily Dose 2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7 C. (pg/mL) 2.64 (1.0) 5.24 (1.8) 7.87 (3.2) 10.80 (7.4) C. (pg/mL) 4.81 (1.8) 6.96 (1.9) 11.13 (5.4) 16.69 (7.3) C. (pg/mL) 8.84 (3.6) 15.79 (14.3) 21.31 (19.5) 25.80 (16.0) C. (pg/mL) 2.26 (0.9) 3.67 (1.3) 5.53 (2.2) 9.23 (4.9) T* (hr) 20 (20-24) 20 (3-24) 16 (1-24) 20 (3-24) T* (hr) 1 (0-12) 9 (0-20) 9 (0-12) O (O-6) AUC (pg.hr/mL) 1.57 (0.6) 2.28 (0.5) 3.43 (0.8) Bioavailable Testosterone Daily Dose 2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7 C (ng/dL) 4.01 (2.1) 7.94 (3.7) 12.56 (5.8) 16.27 (12.1) C (ng/dL) 7.48 (3.4) 10.81 (3.6) 16.47 (8.1) 25.04 (11.5) C (ng/dL) 13.33 (6.7) 25.57 (28.5) 32.14 (29.4) 39.13 (27.1) C., (ng/dL) 3.69 (1.7) 5.84 (2.7) 8.43 (3.6) 13.84 (7.7) T* (hr) 20 (20-24) 16 (1-24) 16 (9-24) 20 (3-24) AUC (nghridL) 179.4 (81.4) 259.52 (87.1) 395.23 (195.0) 600.94 (276.2) AR (ratio) 1.59 (0.7) 2.26 (0.7) 3.48 (1.2)

0135 FIGS. 3A-C are graphs depicting median total, free age free testosterone concentrations towards the upper limit and bioavailable testosterone serum concentrations following of normal. For the 0.44 g dose, average free testosterone administration of 1% T+0% LA in vivo over a sampling concentrations were 1.6 times the upper limit of normal while period on days 1, 7, 14, and 21, respectively. average free testosterone concentrations for the 0.88 g dose 0136. The average baseline total testosterone and free tes were approximately 2.4 times the upper limit of normal. tosterone concentrations were 21.0 ng/dL and 2.6 pg/mL, 0.139. Further, the 1% T+0% LA formulation has been respectively. After one week of 0.22 g daily doses of 1% administered in daily testosterone doses of 2.2, 4.4, and 8.8 T+0% LA, the average total testosterone and free testosterone mg (doses of 0.22 g/day, 0.44 g/day, and 0.88 g/day, each concentrations were 56.0 mg/dL and 7.0 pg/mL, respectively. applied for 7 days, respectively) in one Phase I/II study. The One week of daily 0.44 g doses of 1% T+0% LA increased the formulation was well tolerated in this study. No serious or average total testosterone and free testosterone concentra significant adverse events were reported. No significant tions to 92.0 ng/dL and 11.1 pg/mL, respectively. Daily doses changes in clinical laboratory variables, vital signs, ECG of 0.88 g 1% T+0% LA for 7 days increased the average parameters or physical findings were detected in any of the testosterone and free testosterone concentrations to 141.5 treatment groups. ng/dL and 16.7 pg/mL in the 7 subjects. 0.137 FIGS. 3D-F are graphs depicting mean bioavailable Example 7 and free testosterone serum concentrations after different dose regimens and treatments with 1% T+2% LA in vivo over 0140. The primary objectives of this study were to evalu a sampling period on days 1, 7, 14, respectively. When like ate the safety, tolerability, and pharmacokinetic profile of two testosterone dosages are compared, this data shows that in different, multiple topical doses of an estradiol gel including vivo testosterone levels are not substantially changed by the in terms of the PK variables AUC and C with and without inclusion of lauryl alcohol. Therefore, contrary to the in vitro corrections for endogenous estradiol concentrations in post findings, lauryl alcohol was not necessary to achieve effective menopausal female Subjects. Each subject received one of serum levels in vivo. two estradiol treatments for 14 consecutive days; either 1.25 0.138. This study demonstrated that 1% T 0% LA has the gestradiol gel 0.06% (0.75 mg estradiol/day) or 2.5 g estra potential to elevate free testosterone concentrations in women diol gel 0.06% (1.5 mg estradiol/day). with low endogenous testosterone production. The 0.22 g 0141 Multiple doses of 0.75 mg E2/day maintained aver dose, corresponding to 2.2 mg testosterone, resulted in aver age concentrations (AUCL/24) of 2.4 ng/dl (24 pg/ml). The US 2011/02452.15 A1 Oct. 6, 2011

double dose of 1.5 mg E2/day resulted in an average concen by Day 14 (312 H). The mean E2 concentrations at the begin tration of 5.3 ng/dl (53 pg/ml). The values correspond very ning of this interval (treatmenta: 2.0 ng/dl E2, treatment b: well to those observed after transdermal patches such as 5.0 ng/dl E2) and at the end of this sampling interval (treat Estraderm R. When using a patch with a nominal delivery rate menta: 2.4 ng/dl E2, treatment b: 5.5 ng/dl E2) were compa of 25 ug/day, an average maintenance concentration of 23 rable. Average maximum E2 concentrations were 3.7 ng/dl pg/ml has been reported. For patches with a delivery rates of and 8.8 ng/dl., respectively (Day 14 data). 50 g/day or 100 ug/day, average concentrations of 40 pg/ml 0147 Estradiol Pharmacokinetic Parameters on Day 1 and and 75 pg/ml have been reported, respectively. EstradermR) Day 14. The pharmacokinetic parameters for E2 following has been registered in the European Community and in the single and multiple applications of Bio-E-Gel at 1.25 g and United States as being efficacious for postmenopausal disor 2.5 g are presented in Table 10a. A descriptive summary of the ders including reduction in hot flashes, and for osteoporosis pharmacokinetic parameters, uncorrected and baseline-ad prophylaxis. Therefore, it is predicted that the E2 gel formu justed, are presented in Table 10c and 10d, respectively. lation will be safe and effective for treatment of menopausal symptoms including reduction of hot flashes, and for TABLE 10a osteoporosis prophylaxis. 0142. Estradiol Concentration Time Data (0-24 hours) E2 - PK Variables by Dose Regimens Following a Single Dose (Day 1). FIG. 4A is a graph depict 1.25g 2.5g 2.5g ing mean serum concentrations of estradiol (E2) following 1.25g Bio-E- Bio-E- Bio-E- single dose administration of E2+0% LA gel (a–0.75 mg E2: Bio-E-Gel, Gel, Gel, Gel, b=1.50 mg E2). Following administration of the lower dose Single Multiple Single Multiple (treatment a), the concentration-time profile demonstrates Variable Statistic Dose Dose Dose Dose that an increase in E2 concentrations was observed. On aver AUC N 6 6 6 6 ng/dl * H. Mean 27.5 57.0 49.7 128.2 age, E2 concentrations increased from a baseline value of 0.4 SD 17.2 29.9 48.1 SO.O ng/dl E2 at OH to 2.1 ng/dl E2 at 24 H. Following application GeoM 19.2 51.9 38.4 117.6 of the higher dose, (treatment b) an increase from 0.5 ng/dl E2 G CV 173.5 48.0 79.0 53.1 at baseline at OH to 3.0 ng/dl E2 at 24 H was observed. Cmax N 6 6 6 6 ng/dl. Mean 2.3 3.7 3.7 8.8 0143 Estradiol Trough Concentration Data (Days 1-20). SD 1.8 2.3 2.7 4.8 FIG. 4B is a graph depicting mean trough concentrations of GeoM 1.7 3.2 3.1 7.6 E2 over time following repeated administration of E2+0% G CV 110.1 54.2 75.9 67.0 LAgel. On average, the trough concentrations increased until "max N 6 6 6 6 H Mean 17.67 327.83 18.00 330.33 approximately 24 H after application (Day 2, predose). SD 8.62 9.85 4.90 8.62 Thereafter a plateau in concentrations was observed and lev Min 2.OO 313.OO 12.00 3.14.OO els fluctuated between 2.1 ng/dl at 24H and 2.4 ng/dl E2 on Med 2O.OO 332.OO 16.00 334.OO the day after the last dose was applied (336 H-Day 15, OH). Max 24.00 336.OO 24.00 336.OO Baseline, N 6 6 6 6 Within this sampling interval, the trough concentrations were Co Mean O.S O.S 0.4 0.4 variable and fluctuated between a minimum of 1.3 ng/dl E2 ng/dl. SD 0.4 0.4 O.3 O.3 observed at 48 H (Day 3 predose) to a maximum of 2.4 ng/dl Min O.O O.O O.O O.O at 336 H (Day 15, OH). Following the last administration, Med O.S O.S 0.4 0.4 average E2 concentrations declined to 0.8 ng/dland were near Max 1.3 1.3 O.8 O.8 predose baseline levels (0.6 ng/dl) at 456 H (Day 20, 0 H: 5 days after discontinuation of drug application). 0.148. Following a single application of 1.25 g of E2 gel, 014.4 FIG. 4D is a graph depicting individual trough con maximum concentrations (C) on Day 1 were 2.3 mg/dl. On centrations of E2 overtime following repeated administration average, the time to maximum concentrations, t, was of E2+0% LA gel at both doses. On average, E2 concentra achieved by 17.67 H. The exposure to E2, as measured by tions continued to increase until approximately 240 H (Day AUCL was 27.5 ng/dl.H. Following multiple applications, 11 predose). Concentrations increased from 0.5 ng/dlat base C concentrations increased to 3.7 ng/dl on Day 14. The line (OH) to 8.7 ng/dl at 240 H. testimates were approximately 16 Hon Day 14 and were 0145 The median trough values were also examined and comparable to those observed on Day 1. The exposure to E2 these reached a plateau of approximately 5.1 ng/dl E2 at 96 H was 57.0 ng/dlH on Day 14 and was higher than that (Day 5 predose) after application. Thereafter, the trough con observed on Day 1, demonstrating the accumulation of E2 in centrations were variable and fluctuated between a minimum the serum following repeated applications. of 4.2 ng/dl E2 (median at 288 H. Day 13 predose) to a 0149 Following a single application of 2.5 g of E2 gel, maximum of 5.3 ng/dl at 336 H (Day 15, OH). Following the maximum concentrations (C) on Day 1 were 3.7ng/dl. On last administration, average E2 concentrations declined to 0.8 average, the time to maximum concentrations, t, was ng/dland were near predose baseline levels (0.5 ng/dl) at 456 achieved by 18 H. The exposure to E2, as measured by AUC H (Day 20, 0H; 5 days after discontinuation of drug applica was 49.7 ng/dl. Following multiple application, C con tion). Examination of median trough concentrations indicate centrations increased to 8.8 ng/dl on Day 14. The testi that steady state E2 concentrations are reached by 4 and 5 mates were approximately 18 H on Day 14 and were compa days for the E2 gel 1.25 g and 2.5g doses, respectively. rable to those observed on Day 1. The exposure to E2 was 0146 Estradiol Concentration Time Data (0-24 hours) 128.2 mg/dl. Hon Day 14 and was higher than that observed Following 14 Doses (Day 14). FIG. 4E is a graph depicting on Day 1, demonstrating the accumulation of E2 in the serum mean serum concentrations of E2 following multiple dose following repeated applications. administration of E2+0% LA gel. The profiles on Day 14 0150. The ratio of geometric means of E2 gel 2.5 g/1.25g demonstrate that steady state E2 concentrations were reached was used to assess the dose proportionality of E2 following US 2011/02452.15 A1 Oct. 6, 2011

the two doses of E2 gel. After single dose application, the 0154 Estrone Trough Concentration Data (Days 1-20). mean AUC ratio (E2 gel 2.5 g/1.25 g) was 38.4/19.2=2.0 and FIG. 4G is a graph depicting mean trough concentrations of after multiple doses it was 117.6/51.9=2.3, indicating dose E1 following repeated administration of E2+0% LA gel. On proportionality. average, the trough concentrations increased to approxi 0151. Baseline Adjusted Estradiol Pharmacokinetic mately 72 H (Day 4 predose) after application. Thereafter a Parameters on Day 1 and Day 14. Baseline concentrations of plateau in concentrations was observed and levels fluctuated E2 were similar for both groups and were calculated as 0.5 between 4.3 ng/dl at 72 Hand 5.2 ng/dl E1 on the day after the ng/dl and 0.4 ng/dl for the 1.25 g and 2.5 g E2 gel, respec last dose was applied (336 H=Day 15, 0 H). Within this tively. In order to correct for endogenous E2 concentrations, sampling interval, the trough concentrations were variable the baseline E2 concentration (E2 gel 1.25 g.: 0.5 ng/dland 2.5 and fluctuated between a minimum of 4.1 ng/dl E1 observed g: 0.4 ng/dl) was Subtracted from the total concentration at 96 H (Day 5 predose) to a maximum of 5.3 ng/dl at 288 H measured after application and the AUCT and C were (Day 13 predose). Following the last administration, average recalculated based on the baseline-adjusted concentration. E1 concentrations declined to 3.0 ng/dland were near predose The results of the baseline-adjusted pharmacokinetic vari baseline levels (2.4 ng/dl) at 456 H (Day 20,0H; 5 days after ables are summarized in Table 10b. The baseline-adjusted discontinuation of drug application). C. estimates were 1.8 ng/dl and 3.4 ng/dl following single applications of the 1.25 g and 2.5 g E2 gel, respectively. For 0155 The mean E1 trough concentrations following AUCL, the baseline-adjusted values were 14.9 mg/dL*H and repeated administration of Bio-E-Gel 2.5 g are also presented 41.4 ng/dlH for the 1.25 g and 2.5 g E2 gel, respectively. in FIG. 4G. On average, E1 concentrations continued to Following repeated applications, C. estimates increased to increase until approximately 240 H (Day 11 predose). Con 3.1 ng/dland 8.4 ng/dland AUC estimates increased to 44.2 centrations increased from 2.4 ng/dl at baseline (OH) to 10.4 ng/dl.H and 119.6 ng/dl.H for 1.25 g and 2.5 g E2 gel, ng/dl at 240 H. Thereafter, the trough concentrations were respectively. These increases reflect the accumulation of drug variable and fluctuated between 9.1 ng/dl E1 (at 288 H-Day in the serum following repeated application of the gel. 13 predose) to 7.8 ng/dlat 336 H (Day 15,0H). Following the last administration, average E1 concentrations declined to 3.1 0152 The terminal elimination half-life (t/2) of E2 was ng/dland were near predose baseline levels (4.0 ng/dl) at 456 calculated from the baseline-adjusted concentrations follow ing the last dose (at 312 H. Day 14 predose) by log-linear H (Day 20, 0H; 5 days after discontinuation of drug applica regression from the linear portion of the logarithmic trans tion). Examination of mean trough concentrations indicate formed concentration-time plot. The individual and mean that steady state E1 concentrations are reached by 11 and 13 estimates of half-life following the application of 1.25 g and days for the Bio-E-Gel 2.5 g and 1.25 g doses, respectively. 2.5 g E2 gel are presented in Table 10d. The median half-life 0156 Estrone Concentration Time Data (0-24 hours) Fol was 22.15 H (range: 13.11-76.71) for E2 gel 1.25g and 35.58 lowing 14 Doses (Day 14). FIG. 4H is a graph depicting mean H (range: 26.60-51.59) for 2.5 g. The half-life estimates for serum concentrations of E1 following multiple dose admin both treatment groups were comparable. istration of E2+0% LA gel. The profiles on Day 14 demon strate that steady state E1 concentrations were reached by Day 14 (312 H). The E1 concentrations at the beginning of TABLE 1 Ob this interval (treatmenta: 4.8 mg/dl., treatment b: 8.2 ng/dl) and E2 - PK Variables, Baseline Adiusted at the end of this sampling interval (treatment a: 5.2 mg/dl. treatment b: 7.8 ng/dl) were comparable. Average maximum 1.25 g, 2.5g, 2.5g, 1.25 g, Multiple Single Multiple E1 concentrations on Day 14 (312 to 336 H) were 6.0 ng/dl Variable Statistic Single Dose Dose Dose Dose and 9.2 ng/dl., respectively. 0157 Estrone Pharmacokinetic Parameters on Day 1 and 8AUC N ng/dl * H. Mean 14.9 44.2 41.4 119.6 Day 14. Following a single application of 1.25 g of E2 gel. SD 13.3 22.2 51.1 51.2 maximum concentrations (C) on Day 1 were 3.6 ng/dl. On GeoM 9.8 39.7 25.2 108.9 average, the time to maximum concentrations, t, was G CV 147.3 56.1 1396 53.5 achieved by 12.67 H. The exposure to E1, as measured by 6C,na. N 6 6 6 6 ng/dl. Mean 1.8 3.1 3.4 8.4 AUCL was 56.2 ng/dl.H. Following multiple applications, SD 1.8 2.0 2.9 4.7 Cmax concentrations increased to 6.0 ng/dl on Day 14. The GeoM 1.2 2.7 2.4 7.3 testimates were approximately 11 Hon Day 14 and were G CV 132.8 56.4 118.5 68.5 comparable to those observed on Day 1. The exposure to E1 t1/2 N 4 4 H Mean 33.53 37.34 was 111.4 ng/dlH on Day 14 and was higher than that SD 29.16 12.41 observed on Day 1, demonstrating the accumulation of E1 in Min 13.11 26.60 the serum following repeated applications. Med 22.15 35.58 0158. Following a single application of 2.5 g of E2 gel, Max 76.71 51.59 maximum concentrations (C) on Day 1 were 4.1 ng/dl. On average, the time to maximum concentrations, t, was 0153. Estrone Concentration Time Data (0-24 hours) Fol achieved by 21 H. The exposure to E1, as measured by AUC lowing a Single Dose (Day 1). FIG. 4F is a graph depicting was 62.2 ng/dl.H. Following multiple application, Cmax mean serum concentrations of estrone (E1) following single concentrations increased to 9.2 mg/dl on Day 14. The t dose administration of E2+0% LA gel. On average, E1 con estimates were approximately 2 Hon Day 14 and were lower centrations increased from a baseline value of 2.4 ng/dl E1 at than those observed on Day 1. The exposure to E1 was 179.7 0 H to 3.4 ng/dl E1 at 24 H. Following application of the ng/dl. Hon Day 14 and was higher than that observed on Day higher dose, (treatment b) an increase from 2.4 ng/dl E1 at 1, demonstrating the accumulation of E1 in the serum follow baseline (OH) to 4.0 ng/dl E1 at 24 H was observed. ing repeated applications. US 2011/02452.15 A1 Oct. 6, 2011

TABLE 1 Oc TABLE 10d-continued El - PKVariables by Dose Regimens El - PK Variables, Baseline Adiusted 1.25g 2.5g 2.5g 1.25g 1.25g 2.5g 2.5g 1.25g Multiple Single Multiple Single Multiple Single Multiple Variable Statistic Single Dose Dose Dose Dose Variable Statistic Dose Dose Dose Dose AUC N 6 6 6 6 Med 1.7 3.6 2.0 8.0 ng/dl * H. Mean 56.2 111.4 62.2 179.7 GeoM 1.6 4.0 2.0 6.4 SD 31.2 54.2 3O.O 67.6 G CV 47.2 34.7 30.6 57.5 GeoM 49.6 100.8 56.2 167.1 G CV 59.2 S1.9 53.2 46.3 Cmax N 6 6 6 6 0160 Estrone-Sulfate Concentration Time Data (0-24 ng/dl. Mean 3.6 6.0 4.1 9.2 hours) Following a Single Dose (Day 1). FIG. 4I is a graph SD 1.6 2.7 O.6 3.1 GeoM 3.2 S.6 4.0 8.7 depicting mean serum concentrations of estrone-sulfate (E1 G CV 56.3 45.O 13.2 4O.S sulfate) following single dose administration of E2+0% LA max N 6 6 6 6 gel (a–0.75 mg E2; b=1.50 mg E2). On average, E1-S con H Mean 12.67 323.33 21.01 3.14.33 SD 1242 9.93 7.33 1.51 centrations increased from a baseline value of 45.8 ng/dl E1 at Min 1.OO 3.12.00 6.OS 3.12.00 OH to 79.0 ng/dl El-Sat 24 H. Following application of the Med 13.00 322.OO 24.00 3.14.OO higher dose, (treatment b) an increase from 34.7 ng/dl El-Sat Max 24.00 336.OO 24.00 316.00 baseline at 0 H to 70.7 ng/dl E1-S at 24 H was observed. Baseline, N 6 6 6 6 Co Mean 1.8 1.8 2.0 2.O 0.161 Estrone-Sulfate Trough Concentration Data (Days ng/dl. SD 1.4 1.4 O.9 O.9 1-20). FIG. 4J is a graph depicting mean trough concentra Min O.S O.S 1.1 1.1 tions of E1-sulfate following multiple dose administration of Med 1.5 1.5 1.8 1.8 E2+0% LA gel (a 0.75 mg E2; b=1.50 mg E2). On average, Max 4.4 4.4 3.2 3.2 the trough concentrations continued to increase with repeated applications although the mean plot suggested a change in the rate of increase by approximately 192 H (Day 9 predose). 0159 Baseline Adjusted Estrone Pharmacokinetic Param E1-S serum concentrations fluctuated between 133.8 ng/dl at eters on Day 1 and Day 14. Baseline concentrations of E1 192 Hand 117.8 ng/dl E1-S on the day after the last dose was were similar for both groups and were calculated as 1.8 ng/dl applied (336 H; Day 15, OH). Following the last administra and 2.0 ng/dl for the 1.25 g and 2.5 g E2 gel, respectively. In tion, average E1-S concentrations declined to 77.0 ng/dland order to correct for endogenous E1 concentrations, the base were higher than predose baseline levels (45.8 ng/dl) at 456 H line E1 concentration (E2 gel 1.25 g: 1.8 ng/dland E2 gel 2.5 (Day 20, 0 H; 5 days after discontinuation of drug applica g: 2.0 ng/dl) was Subtracted from the total concentration tion). measured after application and the AUCT and C were 0162. On average, E1-S concentrations continued to recalculated based on the baseline-adjusted concentration. increase until approximately 312 H (Day 14 predose) The results of the baseline-adjusted pharmacokinetic vari although a change in the rate of increase was evident at ables are summarized in Table 10d. The baseline-adjusted approximately 240 H (Day 11 predose). Concentrations increased from 34.7 ng/dl at baseline (OH) to 193.5 ng/dl at C. estimates were 1.8 ng/dl and 2.0 ng/dl following single 240 H. Thereafter, the trough concentrations were variable applications of the 1.25 g and 2.5 g E2 gel respectively. For and fluctuated between 193.5 ng/dl E1 (at 240 H) to 155.7 AUCL, the baseline-adjusted values were 14.5 mg/dL*H and ng/dl at 336 H (Day 15, OH). Following the last administra 17.9 ng/dlH for the 1.25 g and 2.5 g E2 gel, respectively. tion, average E1-S concentrations declined to 60.3 ng/dland Following repeated applications, C. estimates increased to were higher than predose baseline levels (34.7 ng/dl) at 456 H 4.2 ng/dland 7.2 mg/dland AUC estimates increased to 67.1 (Day 20, 0 H; 5 days after discontinuation of drug applica ng/dl.H and 131.2 ng/dl.H for 1.25 g and 2.5 g E2 gel, tion). Examination of mean trough concentrations indicate respectively. These increases reflect the accumulation of drug that steady state E1-sulfate concentrations are reached by 13 in the serum following repeated application of the gel. and 14 days for the E2 gel 1.25 gand 2.5g doses, respectively. 0163 Estrone-Sulfate Concentration Time Data (0-24 TABLE 10d hours) Following 14 Doses (Day 14). FIG. 4K is a graph depicting mean serum concentrations of El-Sulfate following El - PK Variables, Baseline Adiusted multiple dose administration of E2+0% LA gel. The profiles 1.25g 1.25g 2.5g 2.5g on Day 14 demonstrate that steady state E1-S concentrations Single Multiple Single Multiple were essentially reached by Day 14 (312 H). The mean E1-S Variable Statistic Dose Dose Dose Dose concentrations at the beginning of this interval (treatment a: 130.7 ng/dl., treatment b: 200.3 ng/dl) and at the end of this 8AUC N 6 6 6 6 ng/dl * H. Mean 14.5 67.1 17.9 1312 sampling interval (treatment a: 117.8 ng/dl., treatment b: SD S.6 27.1 6.O 68.4 155.7 ng/dl) were slightly different. However, the range of the Med 14.6 63.9 16.2 139.6 values overlapped thereby suggesting the comparability of GeoM 13.6 63.0 17.2 113.8 the results. Average maximum El-S concentrations on Day G CV 42.1 39.9 31.3 68.0 6C,na. N 6 6 6 6 14 were 163.5 ng/dl E1-S for E2 gel 1.25 g and 253.8 ng/dl ng/dl. Mean 1.8 4.2 2.0 7.2 E1-S for E2 gel 2.5 g. SD O.8 1.7 O.S 3.2 (0164. Estrone-Sulfate Pharmacokinetic Parameters on Day 1 and Day 14. The pharmacokinetic parameters for El-S US 2011/02452.15 A1 Oct. 6, 2011 following single and multiple applications of E2 gel at 1.25g mates were 28.8 ng/dl and 37.7 ng/dl following single appli and 2.5 g are presented in Table 10e. A descriptive summary cations of the 1.25g and 2.5g E2 gel, respectively. For AUCT, of the pharmacokinetic parameters, uncorrected and base the baseline-adjusted values were 165.7 ng/dL*H and 325.5 line-adjusted, are presented in Table 10c and 10d, respec ng/dl.H for the 1.25 g and 2.5 g E2 gel, respectively. Follow tively. ing repeated applications, C. estimates increased to 112.2 0.165 Following a single application of 1.25 g of E2 gel, ng/dl and 216.9 ng/dl and AUC estimates increased to maximum concentrations (C) on Day 1 were 80.2 ng/dl. 1602.1 ng/dl. Hand 3192.5 ng/dl.H for 1.25 g and 2.5g E2 On average, the time to maximum concentrations, t, was gel, respectively. These increases reflect the accumulation of achieved by 20.67 H. The exposure to E1-S, as measured by drug in the serum following repeated application of the gel. AUCt was 1359.2 mg/dl.H. 0166 Following multiple applications, Cmax concentra tions increased to 163.5 ng/dl on Day 14. The testimates TABLE 1 Of were approximately 5 Hon Day 14 and were lower than those El-Sulfate - PK Variables. Baseline Adusted observed on Day 1. The exposure to E1-S was 2834.1 ng/dlh on Day 14 and was higher than that observed on Day 1, 1.25g 1.25g 2.5g 2.5g demonstrating the accumulation of E1-S in the serum follow Single Multiple Single Multiple ing repeated applications. Variable Statistic Dose Dose Dose Dose 0167 Following a single application of 2.5 g of E2 gel, 8AUC N 6 6 6 6 ng/dl * H. Mean 165.7 16O2.1 325.5 31925 maximum concentrations (Cmax) on Day 1 were 74.7 ng/dl. SD 63.7 878.6 267.1 1543.4 On average, the time to maximum concentrations, t, was GeoM 153.9 1403.2 256.1 2893.6 achieved by 20 H. The exposure to E1-S, as measured by G CV 46.4 61.9 87.6 51.8 AUCL was 1207.4 ng/dl. H. Following multiple applications, 6Ca N 6 6 6 6 ng/dl. Mean 28.8 112.2 37.7 216.9 Cmax concentrations increased to 253.8 ng/dl on Day 14. The SD 19.3 61.0 16.0 120.4 to estimates were approximately 3 H on Day 14 and were GeoM 24.1 97.0 33.7 192.9 lower than those observed on Day 1. The exposure to E1-S G CV 71.7 67.2 63.6 55.7 was 4079.2 ng/dlH on Day 14 and was higher than that observed on Day 1, demonstrating the accumulation of El-S in the serum following repeated applications. (0169. Sex Hormone Binding Globulin (SHBG). The SHBG concentrations in the subsequent table were deter mined in addition to the study protocol, specially in order TABLE 1 Oe enable the interpretation of the unexpected accumulation of El-Sulfate - PKVariables by Dose Regimens E2 in Subject 04. The data are tabulated in Table 10g. Gen erally the mean SHBG concentrations increased with time, 1.25g 2.5g 2.5g 1.25g Multiple Single Multiple after E2 gel 1.25 g from mean 72.5 nmol/l at 0 H over 80.17 Variable Statistic Single Dose Dose Dose Dose nmol/l to 84.00 nmol/l and after E2 gel 2.5 g from mean 72.5 nmol/l at 0 H over 77.83 nmol/l to 88.83 nmol/l. Subject 04 AUC N 6 6 6 6 ng/dl * H. Mean 1359.2 2834.1 12O7.4 4O79.2 who received E2 gel 2.5 g showed a similar pattern. The SD 4O7.8 1219.O 243.6 1674.5 pre-treatment SHBG-concentrations were 58 nmol/l and 53 GeoM 1302.6 26111 1184.3 3798.7 nmol/l, respectively. 192 H (Day 9 predose) after the first G CV 33.9 47.2 22.6 43.4 application the SHBG concentration was 58 nmol/l and after Cmax N 6 6 6 6 ng/dl. Mean 80.2 163.5 74.7 253.8 360 H (Day 16, 0 H) it was increase to 71 nmol/l. Subject 04 SD 3O.S 75.5 12.1 1242 thus did not appear to differ from the other subjects and the GeoM 75.2 148.2 73.8 231.3 SHBG concentration do not explain the excessive E2 concen G CV 41.5 S2.6 17.0 49.0 trations in this subject. max N 6 6 6 6 H Mean 20.67 316.67 2O.OO 3.15.33 SD 8.16 3.93 6.20 4.46 TABLE 10g Min 4.OO 314.00 12.00 312.00 Med 24.00 315.00 24.00 313.50 SHBG Mof Max 24.00 324.00 24.00 324.00 Baseline, N 6 6 6 6 Scheduled time relative Co Mean 51.3 51.3 36.9 36.9 to first application ng/dl. SD 17.9 17.9 10.7 10.7 Min 23.3 23.3 23.3 23.3 Treatment Statistic -16 -10 192 360 Med 55.5 55.5 38.0 38.0 E2 gel, N 6 6 6 6 Max 71.O 71.O 53.0 53.0 1.25 Mean 72.33 72.50 80.17 84.00 SD 23.73 24.83 28.53 29.18 GeoM 69.12 69.02 75.94 79.73 0168 Baseline Adjusted Estrone-Sulfate Pharmacoki GCV 34.09 35.54 37.59 36.85 netic Parameters on Day 1 and Day 14. Baseline concentra E2 gel, N 6 6 6 6 tions of E1-S were similar for both groups and were measured 2.5g Mean 74.OO 72.50 77.83 88.83 as 51.3 ng/dl and 36.9 ng/dl for the 1.25 g and 2.5 g E2 gel, SD 29.64. 30.34 32.17 38.97 GeoM 68.91 67.20 72.20 81.17 respectively. In order to correct for endogenous E1-S concen GCV 43.88 45.1O 45.01 50.71 trations, the baseline E1-S concentration (E2 gel 1.25 g: 51.3 ng/dl and Bio-E-Gel 2.5 g.: 36.9 ng/dl) was subtracted from the total concentration measured after application and the 0170 Pharmacokinetics Conclusions. The pharmacoki AUC and C were recalculated based on the baseline netic characteristics were calculated as Surrogates for the adjusted concentration. The baseline-adjusted Cmax esti evaluation of the efficacy. It could be shown that multiple US 2011/02452.15 A1 Oct. 6, 2011 doses of 0.75 mg and 1.5 mg E2 gel resulted in average serum proven safe and effective for treatment of menopausal Symp concentrations of about 2.4 ng/dl E2 and 5.3 ng/dl E2, respec toms including reduction of hot flashes and osteoporosis. tively. These values are of a magnitude which are obtained after transdermal patches with a delivery rate of 25 and 50 ug Example 8 E2 per day and are approved for postmenopausal disorders, (0176) Study of the Safety and Efficacy of Topical E2 Gel including reduction of hot flashes. Versus Placebo for Treatment of Vasomotor Symptoms in 0171 Safety Conclusions. Eight adverse events were Postmenopausal Females. The objectives of this study were to observed; 7 of them were classified as (possibly) related to the evaluate the safety and efficacy, and determine the lowest study treatments: 3 and 4 events after the administration of effective dose of E2 gel, administered as a daily regimen, as 1.25 g and 2.5 g E2 gel, respectively. Both treatments regi compared to that of placebo gel in the treatment of vasomotor mens showed excellent skin tolerability. No severe, serious, symptoms in postmenopausal women. Eligible Subjects were or significant adverse events occurred. No drop outs were equally randomized to one of four treatment arms: E2 gel observed. There were no significant changes in Vital signs, 0.625/day (0.375 mg estradiol), E2 gel 1.25 g/day (0.75 mg estradiol), E2 gel 2.5 g/day (1.5 mg estradiol) or matching ECG, clinical laboratory variables or physical findings. The placebo gel. Eligible Subjects were healthy postmenopausal study medication was well tolerated. There were no relevant women, with an estradiol level <20 pg/mL, who exhibited 27 differences in safety profile of the two treatments investi moderate to severe hot flushes each day or 260 moderate to gated. severe hot flushes total during 7 days of Screening. 0172 Conclusions. The mean and individual serum con 0177 E2 gel consisted of 0.06% estradiol in a hydroalco centration-time profiles for E2, E1 and E1-S from 1.25 g and holic gel formulation Supplied in single-dose Sachets: E2 gel 2.5 g E2 gel showed that the two treatments provided drug 0.625 g/day (0.375 mg/day E2), E2 gel 1.25 g/day (0.75 concentrations that were above the measured baseline levels. mg/day E2), or E2 gel 2.5 g/day (1.5 mg/day E2). Daily The pharmacokinetics of the gel product demonstrate that topical applications of E2 gel was administered by the Subject upon repeated administration a plateau in drug levels is gen on the thigh. erally reached. In addition, once drug is discontinued, drug 0.178 Parameters were evaluated including: hot flush levels return to or are near baseline levels within 5 days. The occurrence rates and severity. Adverse events, safety labora pharmacokinetics of E2, E1 and El-S Suggested dose propor tory tests, vitals signs, weight, physical examinations, breast tionality for the 1.25 and 2.5g gel products. Mean parameter examinations, skin irritation were assessed. estimates in the 2.5 g treatment group were approximately (0179 Results of the primary analyses of the co-primary double the estimates in the 1.25 g treatment group on Days 1 efficacy endpoints indicate that the lowest effective dose of and 14. E2 gel in the treatment of vasomotor symptoms in postmeno pausal women is E2 gel 2.5 g/day (1.5 mg/day E2). In the E2 0173 Estimates of t were variable in both treatment gel 2.5 g/day treatment group, the difference from placebo of groups. At steady-state on Day 14, Some estimates oft 2.7 in mean change from baseline in the moderate-to-Severe occurred at the beginning of the dosing interval. In these hot flush rate at Week 4 was clinically meaningful (i.e., 22.0), cases, it is possible that serum concentrations continued to with a complimentary Superiority to placebo in mean change rise immediately after a dose due to continued presence of from baseline in daily hot flush mean severity (placebo -0.6; drug from the previously administered dose. The time to E2 gel 2.5 g/day, -0.9). The analogous differences from pla maximum concentration following administration of both cebo in daily hot flush rate for the other E2 gel dose groups treatments occurred within 16-20H after the first application. were not clinically meaningful (E2 gel 0.625 g/day, 0.7: E2 0.174. The achievement of steady-state was assessed pri gel 1.25 g/day, 0.0). marily by graphical methods. Mean trough concentrations for E2 in both treatment groups were highly variable but showed TABLE 11 no significant increasing trend over the study period. The median trough concentration plots Suggested that steady Daily Moderate-to-Severe Hot Flush Rates: state was reached for E2 by Day 5 in both treatment groups. Mean Change from Baseline Based upon the estimates oft/2 for E2 obtained in this study E2 Gel E2 Gel E2 Gel (approximately 33 H), steady-state would be achieved after Placebo 0.625 g/day 1.25 g/day 2.5 g/day approximately 9 to 10 days of dosing, a finding which is Evaluation (N = 42) (N = 41) (N = 39) (N = 38) consistent with the results of the graphical analysis. Thus, the Baseline 16.0 9.88 1255.60 12.37.26 13.05.97 pharmacokinetic measurements conducted on Day 14 of (Mean + SD) treatment should be representative of steady-state. Similar Week-1 -53 -3.9 -4.7 -50 (Placebo results were observed for E1 and E1-S although concentra Lead-In) tions did appear to be more variable and to fluctuate more for Week 1 -7.3 -58 -5.9 -7.5 these two analytes. Week 2 -7.9 -7.5 -7.2 -9.4 0.175. The pharmacokinetic characteristics were calcu Week 3 -8.5 -8.5 -7.4 -10.5 lated as surrogates for the evaluation of the efficacy. It could Week 4 -8.5 -9.2 -8.5 -11.2 be shown that multiple doses of 0.75 mg and 1.5 mg E2 gel For Week -1 through Week 4, means are least squares means derived from the ANCOVA model with factors for treatment, site, and treatment-by-site interaction, with baseline hot resulted in average serum concentrations of about 2.4 ng/dl flush rate as the covariate. E2 and 5.3 mg/dl E2, respectively. These values are of a Unadjusted means and standard deviations. Baseline based on the first 7 days of the magnitude, which are obtained after transdermal patches with Screening Period. a delivery rate of 25 and 50 ug E2 per day and are approved for 0180. As in the primary efficacy analyses, comparison of postmenopausal disorders, including reduction of hot flashes treatment groups with respect to the proportion of Subjects and osteoporosis. Therefore, it is predicted that E2 gel will be with a 290% reduction in daily moderate-to-severe hot flush US 2011/02452.15 A1 Oct. 6, 2011 20 rate at Week 4 indicates effectiveness in the E2 gel 2.5 g/day 0187 FIG. 5A is a graph depicting mean change from group (55% of subjects), while the other E2 gel dose groups baseline in daily moderate-to-severe hot flush rate after estra performed similar to placebo (27% to 35%). Furthermore, the diol at various doses (ITT-LOCF). median estradiol concentration at Week 4 for the E2 gel 2.5 g/day dose group (33 pg/mL) is in the low end of the expected TABLE 11a therapeutic range, with the median concentrations falling Mean Change from Baseline in Daily Moderate-to-Severe below the range for the other E2 gel dose groups (E2 gel 0.625 Hot Flush Rate (ITT-LOCF g/day, 12 pg/mL, E2 gel 1.25 g/day, 23 pg/mL). 0181 Analyses of Efficacy. The primary efficacy evalua Mean Change from Baseline tion of the clinical effectiveness of E2 gel 0.625 g/day (0.375 E2 Gel E2 Gel E2 Gel mg E2), E2 gel 1.25 g/day (0.75 mg E2), and E2 gel 2.5 g/day Placebo 0.625 g/day 1.25 g/day 2.5 g/day (1.5 mg E2) as compared to placebo was determined with Evaluation (N = 42) (N = 41) (N = 39) (N = 38) respect to change from baseline in daily (moderate-to-severe) Baseline 16.0 9.88 1255.60 12.37.26 13.05.97 hot flush rate at Week 4 and change from baseline in daily hot (Mean + SD) flush mean severity at Week 4 evaluated in the ITT LOCF Week-1 -53 -3.9 -4.7 -50 (Placebo Data Set. The baseline measures used in these analyses are Lead-In) based on data obtained during the Screening Period analyses Week 1 -7.3 -58 -5.9 -7.5 with baseline measures based on data obtained during the Week 2 -7.9 -7.5 -7.2 -9.4 Placebo Lead In Period were not included. Week 3 -8.5 -8.5 -7.4 -10.5 0182. The primary analysis of change from baseline in Week 4 -8.5 -9.2 -8.5 -11.2 daily hot flush mean severity was based on unadjusted means For Week -1 through Week 4, means are least squares means derived from the ANCOVA model with factors for treatment, site, and treatment-by-site interaction, with baseline hot from the one-way ANOVA model with treatment as the factor. flush rate as the covariate. Though 40 subjects are in the ITTBio-E-Gel 1.25 gfday treatment group, Subject 102 is not However, in consideration of dissimilarity across treatment included in the hot flush analyses due to intractable baseline data. groups with respect to mean baseline daily hot flush rates, as For the evaluation at Week 1, N=37 for the E2 gel 2.5 gfday treatment group since the hot flush diary for Subject 187 for that week was lost. well as an apparent treatment-by-site interaction, the primary “Unadjusted means and standard deviations. Baseline based on the first 7 days of the analysis of change from baseline in daily hot flush rate was Screening Period. based on least-squares means derived from the ANCOVA model with factors for treatment, site, and treatment-by-site 0188 Evaluable Subject Dataset-LOCF Analyses. In the interaction, with baseline hot flush rate as the covariate. Only LOCF analyses of the Evaluable Subject Data Set, mean these primary analysis results are discussed. reductions from baseline in daily moderate-to-severe hot 0183. As secondary efficacy analyses, the analyses of the 2 flush rates were observed for all 4 treatment groups, with a co-primary endpoints described above were performed on the more pronounced reduction observed in the E2 gel 2.5 g/day Evaluable Subject LOCF Data Set. Additional analyses dose group (see Table 11b and FIG.5b). A clinically signifi included the proportions of subjects who had a 250%, cant difference (i.e., 22.0) was observed between the E2 gel 260%, 2.70%, 280%, 290%, 2.95% or 100% reduction 2.5 g/day dose group and placebo in the mean reduction of from baseline in daily moderate-to-severe hot flush rate at daily hot flush rate at Week 4 (difference between groups=- Week 4, conducted for the ITT LOCF and the Evaluable 3.2), while the two lower doses of E2 gel did not show a Subject LOCF Data Sets. For the ITT Data Set, the results of clinically meaningful difference from placebo. these proportion analyses are presented in a text table. 0189 FIG. 5B is a graph depicting mean change from 0184. Descriptive analyses of the 2 co-primary endpoints baseline in daily moderate-to-severe hot flush rate after estra were performed for the ITT Observed-Case DataSet and the diol at various doses (Evaluable-LOCF). Evaluable Subject Observed-Case Data Set at Week 1, Week 2, Week 3, and Week 4. Since only 4 subjects discontinued TABLE 11b. treatment prematurely, the results of the observed-case analy ses on these data sets are nearly identical to those from the Mean Change from Baseline in Daily Moderate-to-Severe Hot Flush LOCF analyses and are therefore not discussed explicitly in Rate (Evaluable-LOCF this report. Mean Change from Baseline 0185. Mean Change from Baseline in Daily Moderate-to E2 Gel E2 Gel E2 Gel Severe Hot Flush Rates. Intent-to-Treat Data Set-LOCF Placebo 0.625 g/day 1.25 g/day 2.5 g/day Analyses. In the LOCF analyses of the ITT Data Set, mean Evaluation (N = 28) (N = 38) (N = 33) (N = 30) reductions from baseline in daily moderate-to-severe hot Baseline 1539.35 12.3 5.11 12.87.73 13.45.91 flush rates were observed for all four treatment groups, with a (Meant SD) more pronounced reduction observed in the E2 gel 2.5 g/day Week-1 -4.8 -3.7 -50 -4.8 dose group (see Table 11a and FIG. 5a). (Placebo Lead-In) 0186. A clinically significant difference (i.e., 22.0) was Week 1 -6.7 -5.9 -6.0 -7.6 observed between the E2 gel 2.5 g/day group and placebo in Week 2 -7.1 -7.6 -7.3 -9.4 the mean reduction of daily hot flush rate at Week 4 (differ Week 3 -7.9 -8.5 -7.6 -10.6 ence between groups=-2.7), while the two lower doses of E2 Week 4 -8.0 -9.1 -9.0 -11.2 gel did not show a clinically meaningful difference from For Week -1 through Week 4, means are least squares means derived from the ANCOVA model with factors for treatment, site, and treatment-by-site interaction, with baseline hot placebo. Therefore, the two lower E2 gel doses are non flush rate as the covariate. effective and the E2 gel 2.5 g/day dose is demonstrated to be Unadjusted means and standard deviations. Baseline based on the first 7 days of the the lowest effective dose for the treatment of moderate-to Screening Period. severe hot flushes. US 2011/02452.15 A1 Oct. 6, 2011 21

(0190. Proportion of Subjects with 290% or 100% Percent Reductions in Daily Moderate-to-Severe Hot Flush Rates at TABLE 11d Week 4. Intent-to-Treat Data Set-LOCF Analyses. In the Mean Change from Baseline in Daily Hot Flush Mean Severity LOCF analyses of the ITT Data Set, the majority (55%, ITT LOCF 21/38) of subjects in the E2 gel 2.5 g/day dose group experi enced a 290% reduction in daily moderate-to-severe hot Mean Change from Baseline flush rate at Week 4, compared to approximately a third of E2 Gel E2 Gel E2 Gel Subjects in placebo and the two lower E2 gel dose groups (see Placebo 0.625 g/day 1.25 g/day 2.5 g/day Table 11c). Twenty-four percent (24%) of subjects in the E2 Evaluation (N = 42) (N = 41) (N = 39) (N = 38) gel 2.5 g/day dose group had a 100% reduction (i.e., no Baseline 2.3 - 0.31 22 O.30 23 O.33 2.2 0.33 (Mean + SD) moderate-to-severe hot flushes) at Week 4. Week-1 -0.2 -0.2 -0.2 -0.1 (Placebo Lead-In) TABLE 11 c Week 1 -0.5 -0.2 -0.3 -0.3 Week 2 -0.6 -0.3 -0.5 -0.6 Week 3 -0.6 -0.4 -0.6 -O.7 Number and Proportion of Subjects with a 250% to a Week 4 -0.6 -0.6 -0.8 -0.9 100% Reduction in Daily Moderate-to-Severe Hot Flush Rates at Week 4 (ITT-LOCF) Severity scale; 1 = mild, 2 = moderate, 3 = severe. Though 40 subjects are in the ITTBio-E-Gel 1.25 gfday treatment group, Subject 102 is not included in the hot flush analyses due to intractable baseline data. Number (%) of Subjects For the evaluation at Week 1, N=37 for the Bio-E-Gel 2.5 gfday treatment group since the hot flush diary for Subject 187 for that week was lost. “Unadjusted means and standard deviations. Baseline based on the first 7 days of the E2 Gel E2 Gel E2 Gel Screening Period. Placebo 0.625 g/day 1.25 g/day 2.5 g/day 0193 Drug Dose, Drug Concentration, and Relationships Evaluation (N = 42) (N = 41) (N = 39) (N = 38) to Response. Estradiol, Estrone, and Estrone Sulfate. Trough serum samples were obtained prior to dosing on Day 1 and 25.0% Reduction 32 (76%) 31 (76%) 32 (82%) 33 (87%) upon study completion for determination of estradiol. 260% Reduction 29 (69%) 29 (71%) 28 (72%) 32 (84%) estrone, and estrone sulfate concentrations. For Summariza 2.70% Reduction 24 (57%) 21 (51%) 23 (59%) 29 (76%) tion, all assay results below the detection limit of 5 pg/mL 280% Reduction 19 (45%) 15 (37%) 17 (44%) 24 (63%) were set equal to the limit (i.e., assigned a value of 5 pg/mL). 290% Reduction 13 (31%) 11 (27%) 14 (36%) 21 (55%) Trough concentrations of estradiol, estrone, and estrone sul 295% Reduction 8 (19%) 7 (17%) 12 (31%) 19 (50%) fate at Day 1 and Week 4 were highly variable within treat 100% Reduction 4 (10%) 4 (10%) 8 (21%) 9 (24%) ment groups (see Table 11e). In consideration of the variabil ity and the moderate sample sizes, median values will be Though 40 subjects are in the ITT E2 Gel 1.25 gfday treatment group, Subject 102 is not discussed. included in the hot flush analyses due to intractable baseline data. 0194 Across all treatment groups, median values at Day 1 forestradiol (5 pg/mL), estrone (18.5 to 22.0 pg/mL), and the (0191 Mean Change from Baseline Severity of Hot estradiol-to-estrone ratio (0.29 to 0.42) were consistent with Flushes. Intent-to-Treat Data Set-LOCF Analyses. In the a postmenopausal profile (see Table 11e). However, note that some subjects who met the inclusion criterion of <20 pg/mL LOCF analyses of the ITT Data Set, mean reductions from estradiol at screening failed to meet this criterion at Day 1. baseline daily hot flush mean severity were observed for all Apart from variability inherent to the assay, speculative rea four treatment groups, with a more pronounced reduction sons for this are instability of hormone levels for subjects with observed in the E2 gel 2.5 g/day dose group, and to a lesser menopause onset within the prior year, hysterectomy without degree, in the E2 gel 1.25 g/day dose group (see Table 11 dand oopherectomy in Subjects <50 years of age, or possible unre ported noncompliance regarding use of an estrogen product FIG. 5c). The decrease in daily hot flush mean severity over during the Screening Period. time in the E2 gel 2.5 g/day dose group is complimentary to 0.195. After therapy with E2 gel, median estradiol, estrone, the clinically meaningful difference from placebo seen at and estrone sulfate concentrations at Week 4 showed separa Week 4 in mean reduction of daily hot flush rate. tion between treatment groups in accord with E2 gel dose administration (see Table 11e). The median estradiol values at 0.192 FIG. 5C is a graph depicting mean change from Week 4 were 12 pg/mL, 23 pg/mL, and 33 pg/mL, respec baseline in daily hot flush mean severity after estradiol at tively, for the E2 gel 0.625 g/day, 1.25 g/day, and 2.5 g/day various doses (ITT-LOCF). dose groups.

TABLE 11E

Trough Estradiol, Estrone, and Estrone Sulfate at Day 1 and Week 4 (ITT)

E2 Gel E2 Gel E2 Gel Hormone Evaluation Placebo 0.625 g/day 1.25 g/day 2.5 gfday

E2 Day 1 (N = 41) (N = 41) (N = 39) (N = 38) (pg/mL) Mean + SD 12.2 18.5 15.3 24.5 10.3 13.5 12.3 20.3 Median 5 5 5 5 Range S-110 S-120 5-64 S-110 Week 4 (N = 40) (N = 41) (N = 37) (N = 37) US 2011/02452.15 A1 Oct. 6, 2011 22

TABLE 11 E-continued Trough Estradiol. Estrone, and Estrone Sulfate at Day 1 and Week 4 (ITT E2 Gel E2 Gel E2 Gel Hormone Evaluation Placebo 0.625 g/day 1.25 g/day 2.5 gfday Mean SD 114 15.4 24.1 + 41.6 34.833.O 46.8 44.6 Median 5 12 23 33 Range 5-85 5-240 5-170 5-250 E1 Day 1 (N = 41) (N = 41) (N = 39) (N = 38) (pg/mL) Mean it SD 22.3 - 13.9 29.928.1 24.3 15.8 22.4 - 13.9 Median 19.0 22.O 22.0 18.5 Range 5-65 6-160 S-93 5-67 Week 4 (N = 40) (N = 41) (N = 37) (N = 36) Mean SD 21.6 15.3 36.3 15.7 51.929.1 723 - 43.8 Median 19.5 3S.O 44.0 6O.S Range S-82 5-78 13-130 17-200 E2, E1 Day 1 (N = 41) (N = 41) (N = 39) (N = 38) Ratio Mean SD O.S.S. O.S2 O49, O-36 O43 - 0.29 O.47 O.33 Median O42 O.3 O.29 O.39 Range O.2-2.9 O.0-1.6 0.1-1.2 O.2-2.O Week 4 (N = 40) (N = 41) (N = 37) (N = 36) Mean O.S9 O.S9 O.S.S. O.S6 O.67 O.S9 O64 O.33 Median 0.37 O.35 O.S1 O.S4 Range O.2-3.2 O.2-3.3 O.2-3.8 O.2-1.7 E1-S Day 1 (N = 41) (N = 41) (N = 39) (N = 38) (pg/mL) Mean SD 532.4 - 350.2 691.0 815.5 457.4 1939 523.2443.5 Median 41O.O 48O.O 430 43 O.O Range 150-2100 170-4760 190-940 18O-26SO Week 4 (N = 40) (N = 40) (N = 38) (N = 36) Mean SD 573 616.6 944-4579.1 1562 1610 2283 1884 Median 400.O 740.O 995.0 1765 Range 11O-402O 300-2870 280-8020 330-7040

0196. Safety Conclusions. Daily application of 0.625-2.5 shifts to above normal cholesterol levels in E2 gel groups, and g E2 gel (0.375-1.5 mg estradiol) for approximately 4 weeks an apparent E2 gel dose-related increased incidence of shifts was safe and well-tolerated in this population of postmeno to above normal BUN levels; however, only about 10 subjects pausal females. The overall incidence of treatment-emergent per group were included in the cholesterol comparison (since adverse events among the E2 gel groups was not increased most subjects had above normal baseline cholesterol levels), with dose level (approximately 50% in each dose group), and and the BUN shifts were not associated with corresponding compared well to the incidence in the placebo group (40%). shifts in other renal function indicators or clinical manifesta Adverse events associated with reproductive system and tions of renal insufficiency. breast disorders were reported more frequently in the E2 gel 0200 No clinically important effects of E2 gel were groups (10%, 18%, and 13% in the 0.625 g/day, 1.25 g/day, observed for vital signs, body weight, physical examinations, and 2.5 g/day E2 gel groups, respectively) versus placebo or skin irritation assessment. (5%), as would be expected in this class of drugs. These 0201 Conclusion. Transdermal ET delivers estradiol events reported in 2 or more E2 gel subjects included: breast directly into the systemic circulation via the skin, thus avoid tenderness, metrorrhagia (vaginal spotting), nipple pain, uter ing the first-pass hepatic metabolism that occurs with oral ET ine spasm, and vaginal discharge. No relationship was appar and avoiding the effects on the hepatobiliary system seen with ent between the incidence of these events and E2 gel dose or oral ET. No statistically significant or clinically meaningful estradiol level. No subjects discontinued the study due to changes noted in the mean change from baseline to Week 4 these events. evaluation were observed for any liver function parameters. 0.197 Breast examination indicated no effect of E2 gel at One subject in the E2 gel 0.625 g/day dose group experienced final evaluation for all but one subject; the change observed an increased AST that the investigator felt was clinically for this subject (E2 gel 2.5 g/day) corresponded to one of the significant; also this Subject had an elevated ALT (44 u/L) at reported adverse events of mild breast tenderness, which baseline that increased to 70 u/L at final evaluation. No Sub resolved one week after final study drug administration. jects were observed to have clinically significant increases in 0198 No deaths or serious adverse events occurred during liver function tests in the E2 gel 1.25 g/day or E2 gel 2.5 g/day the study. Two (2) subjects (both E2 gel 1.25 g/day) discon dose groups. tinued double-blind treatment due to an adverse event, only 0202 Adverse events associated with the topical applica one of which (dizziness) was considered possibly related: tion of the study gel were minimal and were more frequently both subjects recovered. reported in the E2 gel 1.25 g/day dose group. Dry skin at the 0199 No clinically meaningful effects of E2 gel on clini application site was the most frequently reported event asso cal laboratory results were observed in analyses of mean ciated with the application of study drug, occurring in two change from baseline to Week 4 evaluations. Comparisons of subjects. These events were considered mild, with the onset proportions of subjects with shifts from normal baselines to greater than 2 weeks on study drug, and the events lasted no abnormal levels at Week 4 indicated a higher incidence of longer than 7 days. Other skin related events reported US 2011/02452.15 A1 Oct. 6, 2011 included burning or itching at the application site, occurring and multiple activations of the pump. Such as three times, may in one Subject for each event. No treatment-emergent dispense the desired dosage of the formulation for the appli erythema at application site occurred. cation by the Subject. In one example, the kit includes a gel 0203 Oral ET has been shown to produce an increase in formulation included within a container Such as an Orion the biliary cholesterol saturation index, and is associated with metered dose pump bottle. Although containers other than an increased risk of gallstones disease; however, this effect pump bottle type container may be used, e.g., Stick, or roll-on containers, and the like. does not appear to be evident in transdermal ET. No subjects 0209 Additional examples of formulations have been pre in the E2 gel dose groups were noted to have clinically sig sented in Additional examples of formulations of other active nificant changes in bilirubin levels, and no adverse events agents, such as Oxybutynin, selegilline, fentanyl, and bus related to increased cholesterol, bilirubinemia, or gallstones pirone, can be found in U.S. application Ser. No. 12/614,216 were reported. and U.S. Pat. No. 7,335,379 and are expressly adopted herein 0204 While it was initially thought that the use of trans by reference thereto. dermal ET would avoid the increases in serum lipids and 0210 While the invention has been described and pointed lipoproteins seen with oral ET, studies have shown that out in detail with reference to operative embodiments thereof, changes in serum lipids and lipoproteins do occur, but with it will be understood by those skilled in the art that various onset and progression that is slower than with oral ET. In this changes, modifications, Substitutions, and omissions can be 4 week study, clinically meaningful mean changes were not made without departing from the spirit of the invention. It is observed in these parameters, though overall changes would intended therefore, that the invention embrace those equiva not be expected in just a 4-week duration of treatment. One lents within the scope of the claims that follow. Subject in the E2 gel 2.5 g/day dose group had a clinically What is claimed is: significant change from baseline in triglycerides; however, 1. A gel formulation for transdermal or transmucosal the subject's final laboratory blood draw was non-fasting. administration of an active agent, the formulation compris Incidentally, this subject's baseline cholesterol was 287 ing: an active agent; a gelling agent of a carbomer present in mg/dL and LDL was 172 mg/dL. an amount of about 1.2% of the formulation; and a delivery 0205 The results of this study demonstrate that E2 gel vehicle comprising a C to C alkanol, a polyalcohol, and a administered daily in doses of 0.625-2.5 g/day for 4 weeks is permeation enhancer of monoalkyl ether of diethylene glycol safe and well-tolerated. present in an amount Sufficient to provide permeation 0206. In accordance with the invention, the formulation enhancement of the active agent through dermal or mucosal may be provided in a kit including the formulations described surfaces; wherein the formulation is substantially free of above, as well as instructions for use of the same. The kit long-chain fatty alcohols, long-chain fatty acids, and long generally includes a container that retains the formulation and chain fatty esters in order to avoid undesirable odor and has a dispenser for releasing or applying a predetermined irritation effects caused by Such compounds during use of the dosage or predetermined Volume of the formulation upon formulation, wherein the active agent is testosterone that is demand. The dispenser can also automatically release the present in an amount of about 1%, the wherein the alkanol is predetermined dosage or Volume of the composition upon ethanol present in an amount of about 46.28% to about 47.5% activation by the user. of the formulation; the polyalcohol is propylene glycol that is 0207. The kit of the present may include the formulations present in an amount of about 6% of the formulation; and the in a pouch, tube, bottle, or any other appropriate container. permeation enhancer is diethylene glycol monoethyl ether The kit may include a single doses of the formulation pack that is present in an amount of about 5% of the formulation. aged in individual Sachets, such that each day a user opens and 2. The formulation of claim 1, further comprising at least applies the amount of the composition included in the Sachet one excipient selected from the group consisting of antimi as the dosage of the active ingredient. The kit may also crobials, preservatives, antioxidants, buffers, humectants, include multiple doses of the composition packaged in a sequestering agents, moisturizers, emollients, or film-form container. During use, the Subject may be instructed to dis ing agents. pense a given amount of the composition from the container 3. The formulation of claim 1, further comprising a neu for application to the skin (Such as a “dime-sized amount’, or tralizing agent of triethanolamine present in an amount of the like). Storage of the compositions according to this inven about 0.4% of the formulation, disodium EDTA present in an tion may be in aluminum tubes at about 25° C. and 60% amount of about 0.06%, and water. relative humidity as well as 40°C. and 75% relative humidity 4. A method for administering testosterone to a mammal in at least for about 6 weeks. need thereof which comprises topically or transdermally 0208. The container may include a metered dispenser, administering to the skin or the mucosa of the mammal a Such that a known Volume or dosage of the formulation is formulation according to claim 1. dispensed by the user at each activation of the dispenser. In 5. The method of claim 4, wherein between about 40 and one example, the formulation may be supplied in a metered about 250 mg of the formulation is administered daily upon dose pump bottle. The formulation provided may be in a the abdomen, shoulder, arm, or thigh of the mammal. concentration Such that a certain weight or Volume (such as 0.87 g) may be dispensed from each depression on the pump, c c c c c