Title of Invention	"A HYDROALCOHOLIC GEL COMPOSITION FOR TREATING ERECTILE DYSFUNCTION IN MALE SUBJECTS"
Abstract	ABSTRACT "A Hydroalcoholic Gel For Improving The Efficacy Of A Pharmaceutical Useful For Treating Erectile Dysfunction" A hydroalcoholic gel for improving the efficacy of a pharmaceutical useful for treating erectile dysfunction in a male subject, comprising, a pharmaceutically effective amount of a steroid in the testosterone synthetic pathway, 40 - 90 % w/w of at least one of a C1-C4 alcohol, 0.10 - 2% w/w of a penetration enhancer, 0.10 - 2 % w/w of thickener; and water qs 100% w/w. O2 O

Title of Invention

"A HYDROALCOHOLIC GEL COMPOSITION FOR TREATING ERECTILE DYSFUNCTION IN MALE SUBJECTS"

Abstract

ABSTRACT "A Hydroalcoholic Gel For Improving The Efficacy Of A Pharmaceutical Useful For Treating Erectile Dysfunction" A hydroalcoholic gel for improving the efficacy of a pharmaceutical useful for treating erectile dysfunction in a male subject, comprising, a pharmaceutically effective amount of a steroid in the testosterone synthetic pathway, 40 - 90 % w/w of at least one of a C1-C4 alcohol, 0.10 - 2% w/w of a penetration enhancer, 0.10 - 2 % w/w of thickener; and water qs 100% w/w. O2 O

Full Text	FIELD OF THE INVENTION The present invention related to a hydroalcoholic gel for improving the efficacy of a pharmaceutical useful for treating erectile dysfunction" RELATED APPLICATIONS This is a continuation-in-part of U.S. Patent Application Serial No. 09/651,777, entitled, "Pharmaceutical Composition and Method for Treating Hypogonadism," filed 30 August 2000, jointly owned by Unimed Pharmaceuticals, Inc., the sole assignee of the instant application. BACKGROUND OF THE INVENTION A. Sexual Performance, Erectile Dysfunction ("ED"), and Libido in Meo 1. Sexual Performance & ED "Sexual performance" as used herein generally refers to a man's ability to have an orgasm, obtain an erection, or erigage in masturbation or intercourse, "Impotence" is a type of deficient sexual performance. Impotence or "erectile dysfunction" as used herein is generally refers to the inability of a man to attain an erection with sufficient rigidity for vaginal penetration 25% or more of the times attempted. As many as 45 million men have some degree of erectile dysfunction. At least 10 million American men - about 9% of the adult population - are thought to have impotence. The rate increases with age. Thus, impotence affects about 10% of men in their sixties, 25% of men in their seventies, 40% of men in their eighties, and more than half of those in their nineties. In young couples, the incidence of impotence is about 7%. One-third of older men receiving medical treatment also have difficulty with erectile function. Over the past decade, the medical perspective on the causes of impotence has shifted. Conventional wisdom used to attribute almost all cases of impotence to psychological factors. Investigators now estimate that between 70% and 80% of impotence cases are caused primarily by medical problems. Risk factors for impotence include hypogonadism, atherosclerosis, hypertension, diabetes mellitus, depression and other emotional or psychological illnesses, pelvic surgery, kidney failure, multiple sclerosis, stroke, some types of epilepsy, and alcoholism. Another risk factor is taking any of a variety of drugs, including cardiovascular medications, drugs that affect the central nervous system, certain hormonal preparations, heroin, and cocaine. Today, 90% of all impotence cases are treated with VIAGRA K (sildenafil citrate USP). Other drugs useful in the treatment of impotence include, but are not limited to: pentoxifylline (TRENTAL®), yohimbine' hydrochloride (ACTIBIME. YOCON. YOHIMEX), apomorphine (UPRIMA®), alprostadil (the MUSE system, TOPIGLAN. CAVERJECT), papavaerine (PAVABID®, CERESPAN), and phentolamine (VASOMAX®, REGITINE). These Pharmaceuticals act by a variety of physiological mechanisms. For example, the physiologic mechanism of erection of the penis involves release of nitric oxide ("NO") in the corpus cavemosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate ("cGMP"), producing smooth muscle relaxation in the corpus cavemosum and allowing inflow of blood. VIAGRA* has no direct relaxant effect on isolated human corpus cavemosum, but enhances the effect of NO by inhibiting phosphodiesterase type 5 ("PDE5"), which is responsible for degradation of cGMP in the corpus cavemosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavemosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavemosum. In contrast, UPRIMA" is a dopamine receptor agonist that acts on the central nervous system. Once absorbed and transported into the brain, UPRIMA® initiates a chain of reactions that result in increased blood flow to the male genital organs and an erection. In accordance with the present invention, testosterone plays a beneficial role physiologically, and stimulates both sexual motivation (i.e., libido) and sexual performance. 2, Sexual Motivation and Libido While the terms "sexual performance" and "impotence" describe physiological effects, the terms "sexual motivation" and "libido" describe psychological effects. "Libido" or "sexual motivation" as used herein is a parameter measured by the duralion, frequency and extent of sexual daydreams, anticipation of sex, flirting, and sexual interaction. As discussed above, while doctors now believe that erectile dysfunction is primarily caused by a physiological mechanism, some cases are still attributable to psychological causes. Moreover, decreased libido may also be a reaction to the experience of impotence. Unfortunately, Pharmaceuticals such as VIAGRA® treat erectile dysfunction by the focusing on the physiological mechanics of attaining and maintaining an erection and do little or nothing to enhance the sexual motivation or libido of men suffering from erectile dysfunction. Thus, there remains a need to treat sexual performance disorders such as impotence in a manner that overcomes both the physiological and psychological problems associated with the disorder. An number of clinical studies involving testosterone replacement in hypogonadal males have provided convincing evidence that testosterone plays a role in both sexual motivation libido and sexual performance. For example, researchers have reported that testosterone replacement results in increased sexual fantasies, sexual arousal and desire, spontaneous erections during sleep and in the morning, ejaculation, sexual activities with and without a partner, and orgasm through coitus or masturbation. See generally Christiansen, Behavioral Correlates of Testosterone, TESTOSTERONE: ACTION, DEFICIENCY, SuBSTiTirnon 109-111 (1998). B. Testosterone Synthesis, Metabolism, and Regulation Testosterone, the major circulating androgen in men, is synthesized from cholesterol. The approximately 500 million Leydig cells in the testes secrete more than 95% of the 6-7 mg of testosterone produced per day. Two hormones produced by the pituitary gland, luteinizing hormone ("LH") and follicle stimulating hormone ("FSH"), are required for the development and maintenance of testicular function and negatively regulate testosterone production. Circulating testosterone is metabolized to various 17- keto steroids through two different pathways. Testosterone can be metabolized to dihydrotestosterone ("DHT") by the enzyme 5a-reductase or to estradiol ("£2") by an aromatase enzyme complex. Testosterone circulates in the blood 98% bound to protein. In men, approximately 40% of the binding is to the high-affinity sex hormone binding globulin ("SHBG"). The remaining 60% is bound weakly to albumin. Thus, a number of measurements for testosterone are available from clinical laboratories. The term "free" testosterone as used herein refers to the fraction of testosterone in the blood that is not bound to protein. The term "total testosterone" or "testosterone" as used herein means the free testosterone plus protein-bound testosterone. The term "bioavailable testosterone" as used herein refers to the non-SHBG bound testosterone and includes that weakly bound to albumin. r The following table from the UCLA-Harbor Medical Center summarizes the hormone concentrations in normal adult men range: Table 1: Hormone Levels in Normal Men Hormone Testosterone Free testosterone DHT DHT/T Ratio DHT + T SHBG FSH LH E2 Normal Range 298 to 1043 ng/dL 3.5 to 17.9 ng/dL 31 to 193 ng/dL 0.052 to 0.33 372 to 1349 ng/dL 10.8 to 46.6 nmol/L 1.0to6.9rnlU/mL 1.0to8.1mlU/mL 17.1 to 46.1 pg/mL There is considerable variation in the half-life of testosterone reported in the literature, ranging from 10 to 100 minutes. Researchers do agree, however, that circulating testosterone has a diurnal variation in normal young men. Maximum levels occur at approximately 6:00 to 8:00 a.m. with levels declining throughout the day. Characteristic profiles have a maximum testosterone level of 720 ng/dL and a minimum level of 430 ng/dL. The physiological significance of this diurnal cycle, if any, however, is not clear. C. Testosterone Levels and Sexual Behavior/Performance Because increasing testosterone concentrations has been shown to alter sexual performance and libido, researchers have investigated methods of delivering testosterone to men. These methods include intramuscular injections (43%), oral replacement (24%), pellet implants (23%), and transdermal patches (10%). A summary of these methods is shown in Table 2. C Table 2: Mode of Application and Dosage of Various Testosterone Preparations Preparation Route Of Application Full Substitution Dose In Clinical Use Testosterone cnanthate Testosterone cypionate Testosterone undecanoate Transdermal testosterone patch Transdermal testosterone patch Testosterone implants Intramuscular injection Intramuscular injection Oral Scrotal skin Non-scrotal skin Implantation under the abdominal skin 200-25.0 g every 2-3 weeks 200 mg every 2 weeks 2-4 capsules at 40 mg per day I membrane per day 1 or 2 systems per day 3-6 implants of 200 mg every 6 months Under Development Testosterone cyclodextrin Testosterone undecanoate Testosterone buciclate Testosterone microspheres Sublingual Intramuscular injection Intramuscular injection Jntramuscular injection 2.5-5.0 mg twice daily 1000 mg every 8-10 weeks 1000 mg every 12-16 weeks 315 mg for 11 weeks Obsolete 17a-Methyltestosterone Fluoxymesterone Oral Sublingual Oral 25-5.0 g per day 10-25 mg per day 10-20 me per day All of the testosterone replacement methods currently employed, however, suffer from one or more drawbacks. For example, subdermal pellet implants and ester injections are painful and require doctor visits. Many of these methods, such as oral/sublingual/buccal preparations, suffer from undesirable pharmacokinetic profile— creating supra-physiologic testosterone concentrations followed a return to baseline. Transdermal patches provide less than optimal pharmacokinetic characteristics, are embarrassing for many patients, and are associated with significant skin irritation. Thus, although the need for an effective testosterone replacement methodology lias existed for decades, an alternative replacement therapy that overcomes these problems has never been developed. SUMMARY OF THE INVENTION The present invention relates to a transdermal hydroalcoholvc testosterone gel formulation that overcomes the problems associated with other testosterone delivery mechanisms by providing, among other things, a desirable pharmacokinetic hormone profile with little or no skin irritation. The gel may be used as a method of improving sexual performance, including treating erectile dysfunction, and increasing libido by increasing testosterone levels in men. In addition, the gel may be used in conjunction with Pharmaceuticals aimed at treating erectile dysfunction, such as VIAGRA®, to enhance their effectiveness. BRIEF DF.gf RfpTTON OF THE DRAWINGS FIG. l(a) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men prior to receiving 5.0 g/day of AndroGcl6, 10.0 g/day of AndroGel, or the testosterone patch (by initial treatment group). FIG. l(b) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men on the first day of treatment with either 5.0 g/day of AndroGel\ 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. l(c) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men on day 30 of treatment with either 5.0 g/day of AndroGel', 10.0 g/day of AndroGel, or the testosterone patch (by initial treatment group). FIG. l(d) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men on day 90 of treatment with either 5.0 g/day of AndroGel, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. l(e) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men on day 180 of treatment with either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (by final treatment group). FIG. l(f) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with 5.0 g/day of AndroGel . FIG. l(g) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men on day 0,1, 30, 90, and 180 of treatment with 10.0 g/day of AndroGel. FIG. l(h) is a graph showing the 24-hour testosterone pharmacokinetic profile for hypogonadal men on day 0,1, 30,90, and 180 of treatment with the testosterone patch. FIG. 2(a) is a graph showing the 24-hour free testosterone pharmacokinetic profile for hypogonadal men on day 1 of treatment with either 5.0 g/day of AndroGel. 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. 2(b) is a graph showing the 24-hour free testosterone pharmacokinetic profile for hypogonadal men on day 30 of treatment with either 5.0 g/day of AndroGer, 10.0 g/day of AndroGer8, or the testosterone patch (by initial treatment group). FIG. 2(c) is a graph showing the 24-hour free testosterone pharmacokinetic profile for hypogonadal men on day 90 of treatment with either 5.0 g/day of AndroGel, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. 2(d) is a graph showing the 24-hour free testosterone pharmacokinetic profile for hypogonadal men on day 180 of treatment with either 5.0 g/day of AndroGel, 10.0 g/day of AndroGel, or the testosterone patch (by final treatment group). FIG. 2(e) is a graph showing the 24-hour free testosterone pharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with 5.0 g/day of AndroGel®. FIG. 2(f) is a graph showing the 24-hour free testosterone pharmacokinetic profile for hypogonadal men on day 0, U 30, 90, and 180 of treatment with 10.0 g/day of AndroGel®. FIG. 2(g) is a graph showing the 24-hour free testosterone pharmacokinetic profile for hypogonadal men on day 0,1, 30,90, and 180 of treatment with the testosterone patch. FIG. 3 is a graph showing the DHT concentrations on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG.4 is a graph showing the DHT/T ratio on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. 5 is a graph showing the total androgen concentrations (DHT +T) on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel, 10.0 g/day of AndroGel18, or the testosterone patch (by initial treatment group). FIG. 6 is a graph showing the Ez concentrations on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel, 10.0 g/day of AndroGel, or the testosterone patch (by initial treatment group). FIG. 7 is a graph showing the SHBG concentrations on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. 8(a) is a graph showing the FSH concentrations on days 0 through 180 for men having primary hypogonadism and receiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel, or the testosterone patch (by initial treatment group). FIG. 8(b) is a graph showing the FSH concentrations on days 0 through 180 for men having secondary hypogonadism and receiving either 5,0 g/day of AndroGel , 10.0 g/day of AndroGel, or the testosterone patch (by initial treatment group). FIG. 8(c) is a graph showing the FSH concentrations on days 0 through 180 for men having age-associated hypogonadism and receiving either 5,0 g/day of AndroGel , 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. 8(d) is a graph showing the FSH concentrations on days 0 through 180 for men having hypogonadism of an unknown origin and receiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. 9(a) is a graph showing the LH concentrations on days 0 through 180 for men having primary hypogonadism and receiving either 5.0 g/day of AndroGel^, 10.0 g/day of AndroGel . or the testosterone patch (by initial treatment group). FIG. 9(b) is a graph showing the LH concentrations on days 0 through 180 for men having secondary hypogonadism and receiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group). FIG. 9(c) is a graph showing the LH concentrations on days 0 through 180 for men having age-associated hypogonadism and receiving either 5.0 g/day of AndroGel, 10.0 g/day of AndroGel, or the testosterone patch (by initial treatment group). FIG. 9(d) is a graph showing the LH concentrations on days 0 through 180 for men having hypogonadism of an unknown origin and receiving either 5.0 g/day of AndroGel , 10.0 g/day of AndroGel18, or the testosterone patch (by initial treatment group). FIG. 10(a) is a graph showing sexual motivation scores on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel, 7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch. FIG. 10(b) is a graph showing overall sexual desire scores on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0 g/day of AndroGel8, or the testosterone patch. II FIG. 10(c) is a graph showing sexual enjoyment (with a partner) scores on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0 g/day of AndroGel, or the testosterone patch. FIG. 11 (a) is a graph showing sexual performance scores on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel1, 7.5 g/day 10.0 g/day of AndroGel, or the testosterone patch. FIG. 11 (b) is a graph showing erection satisfaction performance scores on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0 g/day of AndroGel, or the testosterone patch. FIG. 1 l(c) is a graph showing percent erection scores on days 0 through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0 g/day of AndroGel , or the testosterone patch. DETAILED DESCRIPTION OF THE INVENTION While the present invention may be embodied in many different forms, several specific embodiments are discussed herein with the understanding that the present disclosure is to be considered only as an exemplification of the principles of the invention, and it is not intended to limit the invention to the embodiments illustrated. The present invention is directed to a pharmaceutical composition for percutaneous administration comprising testosterone in a hydroalcoholic gel useful for treating erectile dysfunction and libido deficiencies. In a broad aspect of the invention, other steriods in the testosterone anabolic or catabolic pathway may be used (e.g. androstenedione, androstenediol, dehydroepiandrosterone, prenenolone, and DHT). The gel comprises one or more lower alcohols, such as ethanol or isopropanol; a penetration enhancing agent: a thickener; and water. Additionally, the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants. A "penetration enhancer" is an agent known to accelerate the delivery of the drug through the skin. These agertts also have been referred to as accelerants, adjuvants, and sorption promoters, and are collectively referred to herein as "enhancers." This class of agents includes those with diverse mechanisms of action including those which have the function of improving the solubility and diffusibility of the drug, and those which improve percutaneous absorption by changing the ability of the stratum comeum to retain moisture, softening the skin, improving the skin's permeability, acting as penetration assistants or hair-follicle openers or changing the state of the skin such as the boundary layer. The penetration enhancer of the present invention is a functional derivative of a fatty acid, which includes isosteric modifications of fatty acids or non-acidic derivatives of the carfaoxylic functional group of a fatty acid or isosteric modifications thereof. In one embodiment, the functional derivative of a fatty acid is an unsaturated alkanoic acid in which the —COOH group is substituted with a functional derivative thereof, such as alcohols, polyols, amides and substituted derivatives thereof. The term "fatty acid" means a fatty acid that has four (4) to twenty-four (24) carbon atoms. Non-limiting examples of penetration enhancers include C8-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol: lower alkyl esters of C8-C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C8 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; [& alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl ethers; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetic ester; N-alkylpyrrolidone; and terpenes. The thickeners used herein may include anionic polymers such as polyacrylic acid (CARBOPOL® by Btf. Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), carboxymethylcellulose and the like. Additional thickeners, enhancers and adjuvants may generally be found in Remington's The Science and Practice of Pjiarmacy. Meade Publishing Co., United States Phqirrtacopeia/National Forpiulary. The composition is used in a "pharmacologically effective amount." This means that the concentration of the testosterone is such that in the composition it results in a therapeutic level of drug delivered over the term that the gel is to be used. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the flux rate of the testosterone from the gel, surface area of application site, etc. The amount of testosterone necessary can be experimentally determined based on the flux rate of the drug through the gel, and through the skin when used with and without enhancers. One such testosterone gel has only recently been made available in the United States under the trademark AndroGel® by Unimed Pharmaceuticals, Inc., Deerfleld, Illinois, the assignee of this application. In one embodiment, the gel is comprised of the following substances in approximate amounts: Table 3: Composition of AndroGel* SUBSTANCE Testosterone Carbopol 980 Isopropyl myristate O.lNNaOH AMOUNT (w/w) PERlOOgOFGEL 1.0s 0.90 B 0.50 g 4.72? SUBSTANCE Ethanol (95% w/w) Purified water (qsf) AMOUNT (w/w) PERlOOgOFGEL 72.5 E* 100s Corresponding to 67 g of ethanol. One skilled in the art will appreciate that the constituents of this formulation may be varied in amounts yet continue to be within the spirit and scope of the present invention. For example, the composition may contain about 0.1 to about 10.0 g of testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl rayristate, and about 30.0 to about 98.0 g ethanol, A therapeutic ally effective amount of the gel is rubbed onto a given area of skin by the user. The combination of the lipophilic testosterone with the hydroalcoholic gel helps drive the testosterone in to the outer layers of the skin where it is absorbed and then slowly released into the blood stream. As demonstrated by the data presented herein, the administration of the gel of the present invention has a sustained effect. Toxicity and therapeutic efficacy of the testosterone can be determined by standard pharmaceutical procedures, e.g., for determining LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LDso/EDso. Compounds which exhibit large therapeutic induces are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects. The present invention is further illustrated by the following examples, which should not be construed as limiting in any way. The contents of all cited references throughout this application are hereby expressly incorporated by reference. The practice of the present invention will employ, unless otherwise indicated, conventional techniqu of pharmacology and pharmaceutics, which are within the skill of the art. EXAMPLES Example 1; Method Of Improving Sexual Performance and Increasing Li es Hvoonadal ing Libido in One embodiment of the present invention involves the transdermal application of AndroGel as a method of increasing sexual performance and libido in hypogonadal men without causing significant skin irritation. . In this example, hypogonadal men were recruited and studied in 16 centers in the United States. The patients were between 19 and 68 years and had single morning serum testosterone levels at screening of less than or equal to 300 ng/dL (10.4 nmol/L ). A total of 227 patients were enrolled: 73, 78, and 76 were randomized to receive 5.0 g/day of AndroGel'® (delivering 50 mg/day of testosterone to the skin of which about 10% or 5 mg is absorbed), 10.0 g/day of AndroGel® (delivering 100 mg/day of testosterone to the skin of which about 10% or 10 mg is absorbed), or the ANDRODERM* testosterone patch ("T patch"; delivering 50 mg/day of testosterone), respectively. As shown in the following table, there were no significant group-associated differences of the patients' characteristics at baseline. Table 4. Baseline Characteristics of the Hypogonadal Men Treatment Group No of subjects enrolled Age (years) Range (years) Height (cm) Weight (kg) Serum testosterone (nmol/L") Causes of hypoeonadism T patch 76 51.1 28-67 179.3 ±0.9 92.7 ±1.6 6.40 ±0.41 AndroGel* (5.0 g/day) 73 51.3 23-67 175.8 ±0.8 90.5 ±1.8 6.44 ±0.39 AndroGel* (10.0 g/day) 78 51.0 19-68 178.6±0.8 91.6 ±1.5 6.49 ±0.37 Treatment Group Primary hypogonadism Klinefelter's Syndrome Post Orchidectomy/Anorchia Primary Testicular Failure Secondary hypogonadism Kallman's Syndrome Hypothalimic Pituitary Disorder Pituitary Tumor Aging Not classified Years diagnosed Number previously treated with testosterone Type of Previous Hormonal Treatment Intramuscular injections Transdermal patch All others Duration of treatment (years) T patch 34 9 2 . 23 15 2 6 7 6 21 5.8±1.1 50 (65.8%) 26 12 12 5.8 ± 1.0 AndroGel* (5.0 g/dav) 26 5 1 20 17 2 6 9 13 17 4.4 ±0.9 38(52.1%) 20 7 11 5.4 ± 0.8 AndroGel* (lO.Oq/dav) 34 8 3 23 12 0 3 9 6 26 5.7 ± 1.24 46 (59.0%) 28 8 10 4.6 ±80. 7 Forty-one percent (93/227) of the subjects had not received prior testosterone replacement therapy. Previously treated hypogonadal men were withdrawn from testosterone ester injection fot at least six weeks and oral or transdermal androgens for four weeks before the screening visit. Aside from the hypogonadism, the subjects were in good health as evidenced by medical history, physical examination, complete blood count, urinalysis, and serum biochemistry. If the subjects were on lipid-lowering agents or tranquilizers, the doses were stabilized for at least three months prior to enrollment. Less than 5% of the subjects were taking supplemental calcium or vitamin D during the study. The subjects had no history of chronic medical illness, alcohol or drug abuse. They had a normal rectal examination, a PSA level of less than 4 ng/mL, and a urine flow rate of 12 mL/s or greater. Patients were excluded if they had a generalized skin disease that might affect the testosterone absorption or prior history of skin irritability with ANDRODERM* patch. Subjects weighing less than 80% or over 140% of their ideal body weight were also excluded. The randomized, multi-center, parallel study compared two doses of AndroGel with the ANDRODERM® testosterone patch. The study was double-blind with respect to the AndroGel' dose and open-labeled for the testosterone patch group. For the first three months of the study (days 1 to 90), the subjects were randomized to receive 5.0 g/day of AndroGel , 10.0 g/day of AndroGel®, or two non-scrotal patches. In the following three months (days 91 to 180), the subjects were administered one of the following treatments: 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, 7.5 g/day of AndroGel, or two nonscrotal patches. Patients who were applying AndroGel had a single, pre-application serum testosterone measured on day 60 and, if the levels were within the normal range of 300 to 1,000 ng/dL (10.4 to 34.7 nmol/L ), then they remained on their original dose. Patients with testosterone levels less than 300 ng/dL and who were originally assigned to apply 5.0 g/day of AndroGel* and those with testosterone levels more than 1,000 ng/dL who had received 10.0 g/day of AndroGel® were then reassigned to administer 7.5 g/day ^ of AndroGel* for days 91 to 180. Accordingly, at 90 days, dose adjustments were made in the AndroGel* groups based on the pre-application serum testosterone levels on day 60. Twenty subjects in the 5.0 g/day AndroGel® group had the dose increased to 7.5 g/day. Twenty patients in the 10.0 g/day AndroGel* group had the AndroGel® dose reduced to 7.5 g/day. There were three patients in the testosterone patch group who were switched to 5.0 g/day AndroGel because of patch intolerance. One 10.0 g/day AndroGel* subject was adjusted to receive 5.0 g/day and one 5.0 g/day AndroGel® subject had the dose adjusted to 2.5 g/day. The number of subjects enrolled into day 91 to 180 of the study thus consisted of 51 receiving J8 5.0 g/day of AndroGel®, 40 receiving 7.5 g/day of AndroGel, 52 receiving 10.0 g/day of AndroGel®, and 52 continuing on the ANDRODERM® patch. The treatment groups in this example may thus be characterized in two ways, either by "initial" or by the "final" treatment group. Subjects returned to the study center on days 0, 30, 60, 90,120, 150, and 180 for a clinical examination, skin irritation and adverse event assessments. A. AndroGel and ANDRODERM* patch Approximately 250 g of AndroGel8 was packaged in multidose glass bottles that delivered 2.25 g of the gel for each actuation of the pump. Patients assigned to apply 5.0 g/day of Androgel® testosterone were given one bottle of AndroGel* and one bottle of placebo gel (containing vehicle but no testosterone), while those assigned to receive 10.0 g/day of AndroGel® were dispensed two bottles of the active AndroGel®. The patients were then instructed to apply the bottle contents to the right and left upper arms/shoulders and to the right and left sides of the abdomen on an alternate basis. For example, on the first day of the study, patients applied two actuations from one bottle, one each to the left and right upper arm/shoulder, and two actuations from the second bottle, one each to the left and right abdomen. On the following day of treatment, the applications were reversed. Alternate application sites continued throughout the study. After application of the gel to the skin, the gel dried within a few minutes. Patients washed their hands thoroughly with soap and water immediately after gel application. The 7.5 g/day AndroGel® group received their dose in an open-label fashion. After 90 days, for the subjects titrated to the AndroGel8 7.5 g/day dose, the patients were supplied with three bottles, one containing placebo and the other two AndroGel . The subjects were instructed to apply one actuation from the placebo bottle and three actuations from a AndroGel* bottle to four different sites of the body as above. The sites were rotated each day taking the same sequence as described above. ANDRODEKM® testosterone patches each delivering 2.5 mg/day of testosterone were provided to about one-third of the patients in the study. These patients were instructed to apply two testosterone patches to a clean, dry area of skin on the back, abdomen, upper arms, or thighs once per day. Application sites were rotated with approximately seven days interval between applications to the same site. On study days when the patients were evaluated, the gel/patches were applied following pre-dose evaluations. On the remaining days, the testosterone gel or patches were applied at approximately 8:00 a.m. for 180 days. B. Study Method and Results 1. Hormone Pharmacokinetics On days 0, 1, 30, 90, and 180, the patients had multiple blood samples for testosterone and free testosterone measurements at 30, 15 and 0 minutes before and 2, 4, 8, 12, 16, and 24 hours after AndroGel® or patch application. In addition, subjects returned on days 60, 120, and 150 for a single blood sampling prior to application of the gel or » patch. Serum DHT, E2, FSH, LH and SHBG were measured on samples collected before gel application on days 0, 30, 60, 90, 120, 150, and 180. Sera for all hormones were stored frozen at -20 °C until assay. All samples for a patient for each hormone were measured in the same assay whenever possible. The hormone assays were then measured at the Endocrine Research Laboratory of the UCLA-Harbor Medical Center. The following table summarizes the pharmacokinetic parameters were measured for each patient: 2,0 Table 5: Pharmacokinetic Parameters AUCo-24 Cbase OF C0 v^avg »-TTHU Cmjn Tmax T* mm Fluctuation Index Accumulation ratio Net AUCo-24 area under the curve from 0 to 24 hours, determined using the linear trapezoidal rule. Baseline concentration time-averaged concentration over the 24-hour dosing interval determined by AUCo.24/24 maximum concentration during the 24-hour dosing interval minimum concentration during the 24-hour dosing interval time at which Cmax occurred time at which Cmjn occurred extent of variation in the serum concentration over the course of a single day, calculated as (CTOX -Cmm)/Cavg increase in the daily drug exposure with continued dosing, calculated as the ratio of the AUC at steady on a particular day over the AUC on day 1 (£?.£., AUCday30/AUCd.yl) AUCo-24 on days 30, 90, 180 - AUC0.24 on day 0 a. Testosterone Pharmacokinetics (1) Methods Serum testosterone levels were measured after extraction with ethylacetate and hexane by a specific radioimmunoassay ("RIA") using reagents from ICN (Costa Mesa, CA). The cross reactivities of the antiserum used in the testosterone RIA were 2.0% for DHT, 2.3% for androstenedione, 0.8% for 3-p-androstanediol, 0.6% for etiocholanolone and less than 0.01% for all other steroids tested. The lower limit of quantitation ("LLQ") for serum testosterone measured by this assay was 25 ng/dL (0.87 nmol/L). The mean accuracy of the testosterone assay, determined by spiking steroid free serum with varying amounts of testosterone (0.9 nmol/L to 52 nmol/L), was 104% and ranged from 92% to 117%. The intra-assay and inter-assay coefficients of the testosterone assay were 7.3 and 11.1%, respectively, at the normal adult male range. In normal adult men, testosterone 2.1 concentrations range from 298 to 1,043 ng/dL (10.33 to 36.17 nmol/L) as determined at the UCLA-Harbor Medical Center. (2) Baseline Concentration As shown in Table 6(a)-6(b) and FIG. l(a), at baseline, the average serum testosterone concentrations over 24 hours (Cavg) were similar in the groups and below the adult normal range. Moreover the variations of the serum concentration (based on maximum and minimum concentrations during the 24-hour period, C,™ and (_,,„,,, respectively) during the day were also similar in the three groups. FIG. l(a) shows that the mean testosterone levels had a the maximum level between 8 to 10 a.m. (i.e., at 0 to 2 hours) and the minimum 8 to 12 hours later, demonstrating a mild diurnal variation of serum testosterone. About one-third of the patients in each group had Cavg within the lower normal adult male range on day 0 (24/73 for the 5.0 g/day AndroGel* group, 2£/78 for the 10.0 g/day AndroGelfi group, and 25/76 for testosterone patch group). AH except three of the subjects met the enrollment criterion of serum testosterone less than 300 ng/dL (10.4 runol/L) on admission. Table 6(a): Baseline Phamacokinetic Parameters by Initial Treatment Group (Mean ± SD) N CJV1( (ng/dL) Cm,, (ng/dL) Tm«(hr) Cmin (ng/dL) Tmh (hr) Flue Index (ratio) 5.0g/davT-Gel 73 237 ±130 328 ±178 4.0 (0.0-24.5) 175 ±104 8.01 (0.0-24.1) 0.627 ± 0.479 10.0 g/day T-gel 78 248 ±140 333 ± 194 7.9 (0.0-24,7) 188* 112 8.0 (0.0-24.0) 0.556 ±0.384 T-patch 76 237 ±139 314± 179 4.0 (0.0-24.3) 181±112 8.0 (0.0-23.9) 0.576 ±0.341 Median (Range) Table 6(h): Baseline Testosterone Pharmacokinetic Parameters by Final Treatment Group (Mean ± SD) N C,y, (ng/dL) C^ (ng/dL) T^* (hr) Cmm (n.g/dL) Tmm« (hr) Flue Index (ratio) Doses Received During Initial •> Extended Treatment Phases 5.0 g/day T-Eel 53 247 ±137 333 ±180 4.0(0.0-24.5) 1 85 ± 1 1 1 8.0(0.0-24.1) 0.600 ±0.471 5.0 -> 7.5 g/dav T-eel 20 2121109 313 ± 174 4.0 (0.0-24.0) 150 ±80 11.9(0.0-24.0) 0.699 ± 0.503 1 0.0 -> 7.5 g/day T-j-el 20 282±157 408 ±241 19.7 {0.0-24.3) 206 ± 130 8.0 (0.0-23.3) 0.678 ±0.580 10.0 g/day T-eel 58 236 ± 133 307 ± 170 4.0 (0.0-24.7) 1 82 ± 1 06 8.0(0.0-24.0) 0.514x0.284 T-patch 76 237- 140 314± 179 4.0 (0.0-24.3) 181 ± 112 8.0(0.0-23.9) 0.57610.341 Median (range) (3) Day 1 FIG. l(b) and Tables 6(c)-(d) show the pharmacokinetic profile for all three initial treatment groups after the first application of transdermal testosterone. In general, treatment with AndroGel® and the testosterone patch produced increases in testosterone concentrations sufficiently large to bring the patients into the normal range in just a few hours. However, even on day I, the pharmacokinetic profiles were markedly different in the AndroGel* and patch groups. Serum testosterone rose most rapidly in the testosterone patch group reaching a maximum concentration (Cmax) at about 12 hours (In™). In contrast, serum testosterone rose steadily to the normal range after AndroGel application with C^ax levels achieved by 22 and 16 hours in the 5.0 g/day AndroGel^ group and the 10.0 g/day AndroGel* group, respectively. Table 6(c): Testosterone Pharmacokinetic Parameters on Day 1 by Initial Treatment Group (Mean ± SD) N C,™ C™» (njr/dU 5.0 g/dav T-Gel 73 398 + 156 560 + 269 10.0 g/dav T-gel 76 5 14 ±227 748 ± 349 T-patch 74 482 ± 204 645 ± 280 Tm^Oir) Cmin (ng/dL) Tmin* (hr) 5.0 R/dav T-Gel 22.1 (0.0-25.3) 228 ±122 1.9(0.0-24.0) 10.0 g/dav T-gcl 16.0(0.0-24.3) 250 ± 143 0.0 (0.0-24.2) T-patch 11.8(1.8-24.0) 232+132 1.5(0.0-24.0) Median (Range) Table 6(d): Testosterone Phamacokinetic Parameters on Day 1 by Final Treatment Group (Mean ± SD) N C,v, (ng/dL) C™ (ns/dL) TMJ,(hr) Cn,,.(ng/dU T™* (hr) Flue Index (ratio) Doses Received During Initial •> Extended Treatment Phases 5.0 g/day T-gel 53 41 I t 160 5731285 22.1 (0.0-25.3) 2371125 1.8(0.0-24.0) 0.600 ±0.471 5.0 -> 7.5 g/day T-eel 20 363 ±143 525 ±223 19.5(1.8-24.3) 204±112 3.5 (0.0-24.0) 0.699 ±0.503 10.0-0 7.5 g/day T-gel 19 554 ±243 819±359 15.7(3.9-24.0) 265 ±154 1.9(0.0-24.2) 0.678 ±0.580 10.0 g/day T-gel 57 500 ± 223 724 ± 346 23.0 (0.0-24.3) 245 ±140 0.0 (0.0-23.8) 0.514 ±0.284 T-patch 74 482±2C4 645 ±280 I I . 8 (1.8-24.0) 232 ± 1 3 2 1.5 (0.0-24.0) 0.576 + 0.341 Median (range) (4) Days 30,90, and 180 FIGS. l(c) and l(d) show the unique 24-hour pharmacokinetic profile of AndroGel^-treated patients on days 30 and 90. In the AndroGel groups, serum testosterone levels showed small and variable increases shortly after dosing. The levels then returned to a relatively constant level. In contrast, in the testosterone patch group, patients exhibited a rise over the first 8 to 12 hours, a plateau for another 8 hours, and then a decline to the baseline of the prior day. Further, after gel application on both days 30 and 90, the Cavg in the 10.0 g/day AndroGel® group was 1.4 fold higher than in the 5.0 g/day AndroGel* group and 1.9 fold higher than the testosterone patch group. The testosterone patch group also had a Cmin substantially below the lower limit of the normal range. On day 30, the accumulation ratio was 0.94 for testosterone patch group, showing no accumulation. The accumulation ratios at 1.54 and 1.9 were significantly higher in the 5.0 g/day AndroGel* group and 10.0 g/day AndroGel* group, respectively. The differences in accumulation ratio among the groups persisted on day 90. This data indicates that the AndroGel1 preparations had a longer effective half-life than testosterone patch. FIG. l(e) shows the 24-hour pharmacokinetic profile for the treatment groups on day 180. In general, as Table 6(e) shows, the serum testosterone concentrations achieved and the pharmacokinetic parameters were similar to those on days 30 and 90 in those patients who continued on their initial randomized treatment groups. Table 6(f) shows that the patients titrated to the 7.5 g/day AndroGel® group were not homogeneous. The patients that were previously in the 10.0 g/day group tended to have higher serum testosterone levels than those previously receiving 5.0 g/day. On day 180, the Cavg in the patients in the 10.0 g/day group who converted to 7.5 g/day on day 90 was 744 ng/dL, which was 1.7 fold higher than the. Cavg of 450 ng/dL in the patients titrated to 7.5 g/day from 5.0 g/day. Despite adjusting the dose up by 2.5 g/day in the 5.0 to 7.5 g/day group, the Cavg remained lower than those remaining in the 5.0 g/day group. In the 10.0 to 7.5 g/day group, the C,vg became similar to those achieved by patients remaining in the 10.0 g/day group without dose titration. These results suggest that many of the underresponders may actually be poorly compliant patients. For example, if a patient does not apply AndroGelp properly (e.g., preferentially from the placebo container or shortly before bathing), then increasing the dose will not provide any added benefit. FIGS. l(f)-(b) compare the pharmacokinetic profiles for the 5.0 g/day AndroGel* group, the 10.0 AndroGel® g/day group, and the testosterone patch group at days 0, 1, 30, 90, and 180. In general, the mean serum testosterone levels in the testosterone patch group remained at the lower limit of the normal range throughout the treatment period. In contrast, the mean serum testosterone levels remained at about 490-570 ng/dL for the 5.0 g/day AndroGel* group and about 630-860 ng/dL AndroGel6 for the 10.0 g/day group. Table 6(e): Testosterone Phamacokinetic Parameters on Day 1 by Initial Treatment Group (Mean ± SD) Day 30 Civi (ng/dL) Cmi, (ng/dL) Tm,x(hr) Cn,in (ng/dL) Tmin (hr) Flue Index (ratio) Accum Ratio (ratio) Day 90 CW\| (ng/dL) Cm,x (ng/dL) Tm«(hr) C™ (ng/dL) Tmin (hr) Flue Index (ratio) Accum Ratio (ratio) Day 180 Civ\| (ng/dL) C™ (ng/dL) Tnux(hr) Cmin (ng/dL) Tmin (hr) Flue Index (ratio) Accum Ratio (ratio) 5.0g/davT-Gel N = 66 566 ±262 876 + 466 7.9 (0.0-24.0) 361 + 149 8.0(0.0-24.1) 0.857 + 0.331 1.529+0.726 N = 65 553 + 247 846+444 4.0(0.0-24.1) 354 + 147 4.0 (0.0-25.3) 0.851 +0.402 1.615 ±0.859 N = 63 520+227 779 ±359 4.0 (0.0-24.0) 348 + 164 11.9(0.0-24.0) 0.845 + 0.379 1.523 + 1.024 10.0 g/dav T-ee] N = 74 792 ± 294 1200 + 482 7.8 (0.0-24.3) 505 + 233 8.0 (0.0-25.8) 0.895 + 0.434 1.911 ±1.588 N = 73 792 + 276 1204 + 570 7.9 (0.0-25.2) 501 ±193 8.0 (0.0-24.8) 0.859 + 0.399 1.927+ 1.310 N = 68 722 + 242 1091+437 7.9 (0.0-24.0) 485+184 11.8(0.0-27.4) 0.829 + 0.392 1.897±2.123 T-patch N-70 419+163 576 + 223 11.3(0.0-24.0) 235 + 122 2.0 (0.0-24.2) 0.823 + 0.289 0.937 + 0.354 N = 64 417+157 597 + 242 8.1 (0.0-25.0) 213+105 2.0 (0.0-24.0) 0.937 ± 0.442 0.971 ±0.453 N = 45 • 403 + 163 580 + 240 10.0(0.0-24.0) 223 + 114 2.0 (0.0-25.7) 0.891 ±0.319 0.954 ±0.4105 Median (Range) Table 6(1): Testosterone Pbamacokinetic Parameters on Days 30,90, by Final Treatment Group (Mean ± SD) 180 Doses Received During Initial »> Extended Treatment Phases S.Og/day 5.0 -> 7.5 g/dav 10.0 -> 7.5 g/dav lO.Og/day T-gtl T-eel " T-gel T-Rel l~p"ftt Day 30 CJV1 (ng/dL) Q»i (ng/dL) T^* (hr) C™ (ng/dL) T,™,- (hr) Flue Index (ratio) Accum Ratio (ratio) Diy90 C,V\| (ng/dL) C™ (ng/dL) ?,«,• (hr) C™. (ng/dL) Tmi,* (hr) Flue Index (ratio) Accum Ratio (ratio) N-47 604 ± 288 941 ±509 7.9 (0.0-24.0) 387 ±159 8.1 (0.0-24.1) 0.861 ±0.341 1.543 ±0.747 N = 45 596 ±266 931 ±455 3.8(0.0-24.1) 384 ±147 7.9 (0.0-25.3) 0.886 ±0.391 1.593 ±0.8 13 N- 19 472 ±148 71 6 ±294 8.0(0.0-24.0) 296 ±97 1.7(0.0-24.1) 0.846 ±0.3 15 1.494 ±0.691 N-20 455 ±164 654 ±359 7.7 (0.0-24.0) 286 ±125 0.0 (0.0-24.0) 0.771 ±0.425 1.7371.145 N-19 946 ± 399 1409 ±556 8.0 (0.0-24.3) 600 ±339 11.4(0.0-24.1) 0.927 ± 0.409 2.053 ±1.393 N = I 8 859 ± 298 1398 ±733 7.9 (0.0-24.0) 532 ±181 12.0(0.0-24.1) 0.959 ±0.490 1.752 ±0.700 N = 55 739 ± 230 1 128 ±436 7.8(0.0-24.3) 471 ± 175 8.0 (0.0-25.8) 0.884 ± 0.445 1.864 ±1.657 N-55 77I±26g 1141 ±498 7.9 (0.0-25.2) 492 ±197 4.0(0.0-24.8) 0.826 ±0.363 1.952 ±1.380 N-70 4l9i 163 576 ± 223 11.3(0.0-24.0) 235 ± 122 2.0 (0.0-24.2) 0.823 ± 0.289 0.937 ±0.354 N = 64 417x 157 597 ±242 8.1 (0.0-25.0) 213 ± 105 2.0 (0.0-24.0) 0.937 ± 0.442 0.971 ±0.453 Doses Received During Initial -> Extended Treatment Phases 5.0 g/day 5.0 -> 7.S g/dav I0.0=>7.5g/day 10.0 g/day T-eel T-Eel ' T-«l T-i>el T-Patch Day 180 €„, (ng/dL) C™ (ng/dL) T™' (hr) Cmin (ng/dL) Tmin (hr) Flue Index (ratio) Accum Ratio (ratio) N-44 555 ± 225 803 ± 347 5,8(0.0-24.0) 371 ± 165 11.9(0.0-24.0) 0.853 ± 0.402 1.541 ±0.917 N-18 450±2I9 680 ± 369 2.0 (0.0-24.0) 302 ±150 9.9(0.0-24.0) 0.833 ±0.335 NA N-19 744 ±320 11 10 ±468 7.8 (0.0-24.0) 5 05 ±233 12.0(0.0-24.0) 0.824 ±0.298 NA N=48 713±209 1083 ±434 7.7 (0.0-24.0) 485 ± 156 8.0 (0.0-27.4) 0.81 8 ±0.421 2.061 ±2.445 N = 41 408 ± 105 578 ±245 10.6(0.0-24.0) 222 ± 116 2.0(0.0-25.7) 0.866 ±0.3 I I 0.969 + 0.4 15 Median (range) (5) Dose Proportionality for AndroGel® Table 6(g) shows the increase in AUCo,24 on days 30, 90, and 180 from the pretreatment baseline (net AUCo-24) as calculated using an arithmetic mean. In order to assess dose-proportionality, the bioequivalence assessment was performed on the logtransformed AUCs using "treatment" as the only factor. The AUCs were compared after subtracting away the AUC contribution from the endogenous secretion of testosterone (the AUC on day 0) and adjusting for the two-fold difference in applied doses. The AUC ratio on day 30 was 0.95 (90% C.I.: 0.75-1.19) and on day 90 was 0.92 (90% C.I.: 0.73-1.17). When the day 30 and day 90 data was combined, the AUC ratio was 0.93 (90% C.I.: 0.79- 1.10). The data shows dose proportionality for AndroGel® treatment. The geometric mean for the increase in AUCo-24 from day 0 to day 30 or day 90 was twice as great for the 10.0 g/day group as for the 5.0 g/day group. A 125 ng/dL mean increase in serum testosterone Cavg level was produced by each 2.5 g/day of AndroGel®. In other words, the data shows that 0.1 g/day of AndroGel® produced, on the average, a 5 ng/dL increase in serum testosterone concentration. This dose proportionality aids dosing adjustment by the physician. Because AndroGel is provided in 2.5 g packets (containing 25 mg of testosterone), each 2.5 g packet will produce, on average, a 125 ng/dL increase in the Cjvg • for serum total testosterone. Table 6(g): Net AUQ-24 (nmolh/L) on Days 30,90, and 180 after Transdermal Testosterone Application Day 30 Day 90 Day 180 T Patch 154±18 157 ±20 160 ±25 T gel 5.0 g/day 268 ± 28 263 ± 29 250 ± 32 T gel 10.0 g/day 446 ±30 461 ±28 401 ± 21 The increase in AUC0-24 from pretreatment baseline achieved by the 10.0 g/day and the 5.0 g/day groups were approximately 2.7 and 1.7 fold higher than that resulting from application of the testosterone patch. These figures also indicate that an ANDRODEKM1 patch, which produces an approximately 180 ng/dL increase in Cavg, is equivalent to approximately 3.5 g/day of AndroGel®. b. Pharmacokinetics of Serum Free Testosterone Concentration (1) Methods Serum free testosterone was measured by RIA of the dialysate, after an overnight equilibrium dialysis, using the same RIA reagents as the testosterone assay. The LLQ of serum free testosterone, using the equilibrium dialysis method, was estimated to be 22 pmol/L. When steroid free serum was spiked with increasing doses of testosterone in the adult male range, increasing amounts of free testosterone were recovered with a coefficient of variation that ranged from 11.0-18.5%. The intra- and interassay coefficients of free testosterone were 15% and 16.8% for adult normal male values, respectively. As estimated by the UCLA-Harbor Medical Center, free testosterone concentrations range from 3.48-17.9 ng/dL (121-620 pmol/L) in normal adult men. (2) Pharmacoklnetic Results In general, as shown in Table 7, the pharmacokinetic parameters of serum free testosterone mirrored that of serum total testosterone as described above. At baseline (day 0), the mean serum free testosterone concentrations (C,vg) were similar in all three groups which were at the lower limit of the adult male range. The maximum serum free testosterone concentration occurred between 8 and 10 a.m., and the minimum about 8 to 16 hours later. This data is consistent with the mild diurnal variation of serum testosterone. FIG. 2(a) shows the 24-hour pharmacokinetic profiles for the three treatment groups on day 1, After application of the testosterone patch, the serum free testosterone levels peaked at 12 hours about 4 hours earlier than those achieved by the AndroGel groups The serum free testosterone levels then declined in the testosterone patch group whereas in the AndroGelE groups, the serum free testosterone levels continued to rise. FIGS. 2(b) and 2(c) show the pharmacokinetic profiles of free testosterone in the AndroGel^-treated groups resembled the unique testosterone profiles on days 30 and 90. After AndroGel* application, the mean serum free testosterone levels in the three groups were within normal range. Similar to the total testosterone results, the free testosterone CBVg achieved by the 10.0 g/day group was 1.4 fold higher than the 5.0 g/day group and 1.7 fold higher than the testosterone patch group. Moreover, the accumulation ratio for the testosterone patch was significantly less than that of the 5.0 g/day AndroGel* group and the 10.0 g/day AndroGel^ group. FIG. 2(d) shows the free testosterone concentrations by final treatment groups on day 180. In general, the free testosterone concentrations exhibited a similar pattern as serum testosterone. The 24-hour pharmacokinetic parameters were similar to those on days 30 and 90 in those subjects who remained in the three original randomized groups. Again, in the subjects titrated to receive 7.5 g/day of AndroGel, the group was not homogenous. The free testosterone Cavg in the patients with doses adjusted upwards from 5.0 to 7.5 g/day remained 29% lower than those of subjects remaining in the 5.0 g/day group. The free testosterone C,vg in the patients whose doses were decreased from 10.0 to 7.5 g/day was 11% higher than those in remaining in the 10.0 g/day group. FIGS. 2(e)-(g) show the free testosterone concentrations in the three groups of subjects throughout the 180-day treatment period. Again, the free testosterone levels followed that of testosterone. The mean free testosterone levels in all three groups were within the normal range with the 10.0 g/day group maintaining higher free testosterone levels than both the 5.0 g/day and the testosterone patch groups. Table 7: Free Testosterone Pharmacokinetic Parameters by Final Treatment (Mean ± SD) Doses Received During Initial ->Extended Treatment Phases 5.0 g/day 5.0 -> 7.5 g/dav 1 0.0 -> 7.5 g/day 10/Og/dav T-eel T-eel " T-eel Teel Day 0 Cavg (ng/dL) Cmax (ng/dL) Tmax (hr) Cmin (ng/dL) Tmin* (hr) Flue Index (ratio) Day 1 Cavg (ng/dL) Cmax (ng/dL) Tmax* (hr) Cmin (ng/dL) Tmin' (hr) Day 30 Cavg (ng/dL) Cmax (ng/dL) Tmax* (hr) Cmin (ng/dL) Tmin* (hr) Flue Index (ratio) Accum Ratio (ratio) Day 90 Cavg (ng/dL) Cmax (ng/dL) Tmax* (hr) Cmin (ng/dL) Tmin* (hr) Flue Index (ratio) Accum Ratio (ratio) N-53 4.52 ±3.35 5.98 ±4.25 4.0 (0.0-24.5) 3.23 ±2.74 8.0 (0.0-24.2) 0.604 ±0.342 N-53 7.50 ±4.83 10.86 ±7.45 16.0(0.0-25.3) 4.30 ±3.33 0.0(0.0-24.1) N-47 1I.I2±6.22 l 8.0 (0.0-27.8) 6.99 ± 3.82 4.0 (0-0-24. 1 ) 0.853 ±0.331 1 .635 ± 0.820 N-45 12. 12 ±7.78 18.75 ±12.90 4.0 (0.0-24.0) 7.65 ± 4.74 8.0 (0.0-24.0) 0.9 13 ±0.492 1.75510.983 N=-20 4.27 ±3.45 6.06 ± 5.05 2.0 (0.0-24.0) 3.10 ±2.62 9.9(0.0-16.0) 0.674 ±0.5 12 N-20 6.80 ±4.82 10.10 ±7.79 13.9(0.0-24.3) 3.69 ±3.24 1.8(0.0-24.0) N-= 19 7.8113.94 11. 62 ±6.34 8.0(0.0-26.3) 4.78 ±3. 10 3.5 (0.0-24. 1 ) 0.872 ±0.5 10 1 .479 ± 0.925 N = 20 8.06 ±3.78 10.76 ±4.48 9.7 (0.0-24.0) 4.75 ± 2.86 1.9(0.0-24.0) 0.8 15 ±0.292 I.9I6± 1.816 N = 20 4.64±3.10 6.91 ±4.66 13.5 (0.0-24.2) 3.14±2.14 4.0 (0.0-23.3) 0.756 ±0.597 N- 19 9.94 ±5. 04 15.36±7.31 15.7(2.0-24.0) 3.8S±2.73 0.0 (0.0-24.2) N- 19 16.18±8.18 25.I4± 10.80 8.0 (0.0-24.3) 9.99 ±7. 19 11.4(0.0-24.1) 1.05 1 ±0.449 2.065 ±1.323 N - I S 17.65 ±8.62 25.29 ±12.42 8.0 (0.0-24.0) 10.56 ±6.07 5.9(0.0-24.1) 0.870 ±0.401 1.843 ±0.742 N = 58 4.20 ±3.33 5.84 ± 4.36 :.l (0.0-24.1) 3.12 ±2.68 S.O (0.0-24.0) 0.634 ± 0.420 N-57 8.93 ± 6.09 I3.20±8.6l 23.5ll.S-24.3l 4.40 ±3.94 0.0(0.0-23.9) N-55 I3.37±7.13 19.36 ±9.75 8.0(0.0-24.3) 8.25 ± 5.22 7.8(0.0-25.8) 0.861 ±0.412 1 .953 t 1 .026 N-55 13.11 ±5.97 18.61 ±8.20 8.0(0.0-25.2) 8.40 ± 4.57 4.0(0.0-24.8) 0.812 ±0.335 2.075 ± 1.866 T-patch N- 76 4.82 ± 3 . 64 6.57±4.90 3.8(0.0-24.0) 3.56 ±2.88 7.9 (0.0-24.0) 0.6)410.362 N-74 9.04 ±4.81 12.02 ±6. 14 12.0(1.8-24.0) 4.67 ±3.52 0.0(0.0-24.0) N- 70 S.12±4.I5 11. 48 ±5.78 8.0(0.0-24.0) 4.31 ±3.20 2.0(0.0-24.8) 0.929 ±0.3 11 0.980±0.387 N - 64 8.50 ± 5.04 12.04 ±6. SI 11.6(0.0-25.0) 4.38 ± 3.70 2.0(0.0-24.1) 0.968 ± 0.402 1.054 ±0.498 Doses Received During Initial ->Extended Treatment Phases 5.0g/day 5.0 => 7.5 g/day 10.0 -> 7,5 g/day 10/Oe/day T-erl T-e«l T-gel T gel Day 180 Cavg (ng/dL) Cmax (ng/dL) Tmax* (hr) Cmin (ng/dL) Tmin* (hr) Flue Index (ratio) Accum Ratio (ratio) N = 44 11.0115.24 16.2117.32 7.9 (0.0-24.0) 7.1813.96 9.9 (0.0-24.2) 0.897 ± 0.502 1.71211.071 N- 18 7.80 ± 4.63 11.3616.36 2.0 (0.0-23.9) 5.32 ±4.06 7.9 (0.0-24.0) 0.8380.378 NA N- 19 14.I4±7.73 22.561 12.62 7.8 (0.0-24.0) 9.54 ± 6.45 8.0 (0.0-23.2) 0.950 ±0.501 NA N=48 12.7715.70 18.58 ±9.3 1 8.0(0.0-24.0) 8.2314.01 11.8(0.0-27.4) 0.81510.397 2.1341 1.989 T-patch N = 41 7.25 1 4.90 10.1715.90 11.1 (0.0-24.0) 3.9014.20 2.5(0.0-25.7) 0.96710.370 1.001 10.580 'Median (Range) c. Serum DHT Concentrations Serum DHT was measured by RIA after potassium permanganate treatment of the sample followed by extraction. The methods and reagents of the DHT assay were provided by DSL (Webster, TX). The cross reactivities of the antiserum used in the RJA for DHT were 6.5% for 3-p-androstanediol, 1.2% for 3-a-androstanediol, 0.4% for 3-aandrostanediol glucuronide, and 0.4% for testosterone (after potassium permanganate treatment and extraction), and less than 0.01% for other steroids tested. This low crossreactivity against testosterone was further confirmed by spiking steroid free serum with 35 nmol/L (1,000 pg/dL) of testosterone and taking the samples through the DHT assay. The results even on spiking with over 35 nrnol/L of testosterone was measured as less than 0.1 nmol/L of DHT. The LLQ of serum DHT in the assay was 0.43 nmol/L. The mean accuracy (recovery) of the DHT assay determined by spiking steroid free serum with varying amounts of DHT from 0.43 nmol/L to 9 nmol/L was 101% and ranged from 83 to 114%. The intra-assay and inter-assay coefficients of variation for the DHT assay were 7.8 and 16.6%, respectively, for the normal adult male range. The normal adult male range of DHT was 30.7-193.2 ng/dL (1.06 to 6.66 nmol/L ) as determined by the UCLAHarbor Medical Center. As shown in Table 8, the pretreatment mean serum DHT concentrations were between 36 and 42 ng/dL, which were near the lower limit of the normal range in all three initial treatment groups. None of the patients had DHT concentrations above the upper limit of the normal range on the pretreatment day, although almost half (103 patients) had concentrations less than the lower limit. FIG. 3 shows that after treatment, the differences between the mean DHT concentrations associated with the different treatment groups were statistically significant, with patients receiving AndroGel® having a higher mean DHT concentration than the patients using the patch and showing dose-dependence in the mean serum DHT concentrations. Specifically, after testosterone patch application mean serum DHT levels rose to about 1.3 fold above the baseline. In contrast, serum DHT increased to 3.6 and 4.8 fold above baseline after application of 5.0 glday and 10.0 g/day of AndroGel1, respectively. Table 8: DHT Concentrations (ng/dL) on Each of the Observation Days By Initial Treatment (Mean ± SD) 5.0 g/dav T-«H I0,0j/d»v T-gri T-P»lch Across RX D«v 0 N«73 36.0 ±19.9 N-78 42.0 i 29.4 N-76 37.4 ±21.4 0.6041 Div30 N-69 11 7.6 ±74.9 N-78 200.4 ±127.8 N-73 50.8 ± 34.6 0.0001 Diy60 N-70 t22.4±99.4 N-74 222.0 ±126.6 N-68 49.3127.2 0.0001 D«v90 N-67 130. 1199.2 N-~5 207.7 ± 111.0 N-66 43.6 ±26.9 0.0001 DcvUO N-65 121 .8 ±89.2 N»6g 187.3 ±97.3 N-49 53.0 ±52.8 0.0001 D»y ISO N = 63 144.7 ±110.5 N-67 189.1 ±102.4 N-46 54.0 ±42.5 0.0001 Dav 180 N = 65 143.7 ± 105.9 N-71 206.1 I 105.9 N - 4V 52.1 ±34.3 0.0001 The increase in DHT concentrations are likely attributed to the concentration and location of 5a-reductase in the skin. For example, the large amounts of 5a-reductase in the scrotal skin presumably causes an increase in DHT concentrations in the TESTODERM patch. In contrast, the ANDRODERM* and TESTODERM TTSK patches create little change in DTH levels because the surface area of the patch is small and little 5a-reductase is located in nonscrotal skin. AndroGel® presumably causes an increase in DHT levels because the gel is applied to a relatively large skin area and thus exposes testosterone to greater amounts of the enzyme. To date, elevated DHT levels have not been reported to have any adverse clinical effects. Moreover, there is evidence to suggest that increased DHT levels may inhibit prostate cancer. d. DHTTT Ratio The UCLA-Harbo* Medical Center reports a DHT/T ratio of 0.052-0.328 for normal adult men. In this example, the mean ratios for all three treatments were within the normal range on day 0. As shown in FIG. 4 and Table 9, there were treatment and concentration-dependent increases observed over the 180-day period. Specifically, the AjidroGel® treatment groups showed the largest increase in DHT/T ratio. However, the mean ratios for all of the treatment groups remained within the normal range on all observation days. Table 9: DHT/T Ratio on Each of the Observation Days By Initial Treatment (Mean ± SD) 5.0 g/div T-«tl lO.Og/dtv T-pel T-Patth Acroit RX DtvO N = 73 0.198 ±0.137 N-78 0.206 tO. 163 N-76 0.204 ±0.135 0.7022 Dv 30 Nf-68 0.230 ±0.104 N-77 0.26610.124 N "73 0.1 92 ±0.1 82 0.0001 Div60 N-70 0.2560.132 N- 74 0.313 ±0.160 N-68 O.I7S ±0.102 0.0001 D«v90 N-67 0.248 ±0.1 21 N-74 0.30010.131 N-65 0.17510.092 0.0001 Dtv 110 N-65 0.26610.119 N-68 0.308 ±0.145 N -49 0.18610.134 0.0001 DivlSQ i Ua> 180 N-62 0.200 ±0.14? N-07 0.335 ±0.142 N-46 0.223 + 0.147 0.0001 N = 64 0.27} ±0.100 N - 71 0.291 ±0.i;4 N =40 0.212 ±0.160 00002 e. Total Androgen (DHT + T) The UCLA-Harbor Medical Center has determined that the normal total androgen concentration is 372 to 1,350 ng/dL. As shown in FIG. 5 and Table 10, the mean pre-dose total androgen concentrations for all three treatments were below the lower limit of the normal range on pretreatment day 0. The total androgen concentrations for both AndroGel1® groups were within the normal range on all treatment observation days. In contrast, the mean concentrations for patients receiving the testosterone patch was barely within the normal range on day 60 and 120, but were below the lower normal limit on days 30, 90,150, and 180. Table 10: Total Androgen (DHT +T) (ng/dL) on Each of the Observation Days By Initial Treatment (Mean ± SD) 5.0 g/dv T-gd 10.0 g/day T-RtT T-Patch Across RX DivO N-73 2811150 N-78 307 ±180 N-76 282 ±159 0.7395 Dav 3d N-68 659 ±398 N-77 974 ± 532 N-73 369 ± 206 0.000 1 Dav 60 N-70 6I7±429 N-74 1052 ±806 N-68 392 ± 229 0.0001 Dav90 N-67 690 ±431 N-74 921 ±420 N-65 330 ± 1 73 0.0001 Da v 120 N-65 574 ±331 N-68 827 ±361 N-49 378 ± 250 0.000 1 Dav 150 N-62 63 1 ± 384 N-67 805 + 383 N-46 364220 00001 Dav 180 N -64 694 ± 4 1 2 N» 7] 944 ±432 N-46 355 ±202 0.0001 f. £2 Concentrations Serum E2 levels were measured by a direct assay without extraction with reagents from ICN (Costa Mesa, CA). The intra-assay and inter-assay coefficients of variation of E2 were 6.5 and 7.1% respectively. The UCLA-Harbor Medical Center reported an average £2 concentration ranging from 7.1 to 46.1 pg/mL (63 to 169 pmol/L) for normal adult male range. The LLQ of the Ea was 18 pmol/L. The cross reactivities of the E? antibody were 6.9% for estrone, 0.4% for equilenin, and less than 0.01% for all other steroids tested. The accuracy of the £2 assay was assessed by spiking steroid free serum with increasing amount of E2 (18 to 275 pmol/L). The mean recovery of E2 compared to the amount added was 99.1% and ranged from 95 to 101%. FIG. 6 depicts the E2 concentrations throughout the 180-day study. The pretreatment mean E2 concentrations for all three treatment groups were 23-24 pg/mL. During the study, the E2 levels increased by an average 9.2% in the testosterone patch during the treatment period, 30.9% in the 5.0 g/day AndroGel® group, and 45.5% in the 10.0 g/day AndroGel® group. All of the mean concentrations fell within the normal range. Table 11: Estradiol Concentration (pg/mL) on Each of the Observation Days By Initial Treatment (Mean ± SD) 5.0 g/d«y T-gel lO.Og/day T-g«l T-P»tch Across RX DavO N-73 23.0 ±9.2 N-78 24.5 ± 9.5 N-76 23.8 t 8.2 0.6259 1 l)av 30 N-69 29.2 ±11.0 N-78 33.7 ±11.3 N-72 25-8 ±9.8 0.0001 1 Dav60 N-68 28.1 ± 10.0 N-74 36.5 ±13.5 N-68 74.8 ± 8.0 0.0001 Dav90 N-67 31.4111.9 N-75 37.8 ±13.3 N-66 25.7 ±9.8 0.0001 Davl20 N-64 28.8 ± 9.9 N-71 34 .6 ±10.4 N-50 25.7 S 9.4 0.0001 OavlSO N-6S 30.8 ± I2.S N-66 35.0 i I I . I N-49 27.0 ±9.2 l)«v 180 N-05 32.3 ± 13.8 N - 7 1 36.3 ± 13.9 N-49 26.9 ±9.5 Ej is believed to be important for the maintenance of normal bone. In addition, EZ has a positive effect on serum lipid profiles. g. Serum SHBG Concentrations Serum SHBG levels were measured with a fluoroimmunometric assay ("FIA") obtained from Delfia (Wallac, Gaithersberg, MD). The intra- and interassay coefficients were 5% and 12% respectively. The LLQ was 0.5 nmol/L. The UCLA-Harbor Medical Center determined that the adult normal male range for the SHBG assay is 0.8 to 46.6 nmol/L. As shown in FIG. 7 and Table 12, the serum SHBG levels were similar and within the normal adult male range in the three treatment groups at baseline. None of the treatment groups showed major changes from these the baseline on any of the treatment visit days. After testosterone replacement serum SHBG levels showed a small decrease in all three groups. The most marked change occurred in the 10.0 g/day AndroGel® group. Table 12: SHBG Concentration (nmol/L) on Each of the Observation Days By Initial Treatment (Mean ± SD) 5.0 g/d»y T-el lO.Og/diy Tftl T.P»tch Across RX D«v 0 N-73 26.2 ± 14.9 N-78 26.6 ± 17.8 N-76 30.2 ±22.6 0.3565 D.v 30 N-69 24.9 ± 14.0 N-78 ^24.8 ± 14.5 N-72 28.4 ±21. 3 0.3434 D»v60 N-69 25.9 ± 14.4 N-75 25.2 + 15.5 N-68 28.2 + 23.8 0.5933 Dav 90 N-67 25,5 ±14.7 N-75 23.6 ±14.7 N-66 28.0 ±23.6 0.3459 D»v 120 N-66 25.2 ±14.1 N-72 25.5 1 16.5 N-50 26.7 ±16.0 0.8578 D«v ISO N-6S 24.9 ±12.9 N-68 23.8 ± 12.5 N-49 26.7 ±16.4 0.5280 Dav 180 N-65 24.2 ±13.6 N-71 24.0 ±14.5 N-49 25.8 ±15.1 0.7668 h. Gonadotropins Serum FSH and LH were measured by highly sensitive and specific solid-phase FIA assays with reagents provided by Delfia (Wallac, Gaithersburg, MD). The intra-assay coefficient of variations for LH and FSH fluroimmunometric assays were 4.3 and 5.2%, respectively; and the interassay variations for LH and FSH were 11.0% and 12.0%, respectively. For both LH and FSH assays, the LLQ was determined to be 0.2 IU/L. All samples obtained from the same subject were measured in the same assay. The UCLA- # Harbor Medical Center reports that the adult normal male range for LH is 1.0-8.1 U/L and forFSHisl.O-6.9U/L. (1) FSH Table 13(a)-(d) shows the concentrations of FSH throughout the 180-day treatment depending on the cause of hypogonadism: (1) primary, (2) secondary, (3) age-associated, or (4) unknown. Patients with primary hypogonadism show an intact feedback mechanism in that the low serum testosterone concentrations are associated with high FSH and LH concentrations. However, because of testicular or other failures, the high LH concentrations are not effective at stimulating testosterone production. Secondary hypogonadism involves an idiopathic gonadotropin or LH-releasing hormone deficiency. Because patients with secondary hypogonadism do not demonstrate an intact feedback pathway, the lower testosterone concentrations are not associated with increased LH or FSH levels. Thus, these men have low testosterone serum levels but have gonadotropins in the normal to low range. Hypogonadism may be age-related. Men experience a slow but continuous decline in average serum testosterone after approximately age 20 to 30 years. These untreated testosterone deficiencies in older men may lead to a variety of physiological changes. The net result is geriatric hypogonadism, or what is commonly referred to as "male menopause." As discussed above, patients with primary hypogonadism have an intact feedback inhibition pathway, but the testes do not secrete testosterone. As a result, increasing serum testosterone levels should lead to a decrease in the serum FSH concentrations. In this example, a total ef 94 patients were identified as having primary hypogonadism. For these patients, the mean FSH concentrations in the three treatment groups on day 0 were 21 -26 mlU/mL, above the upper limit of the normal range. As shown in FIG. 8(a) and Table 13(a), the mean FSH concentrations decreased during treatment in all three treatment regimens. However, only the 10.0 g/day AndroGel® group reduced the mean concentrations to within the normal range during the first 90 days of treatment. Treatment with the 10.0 g/day AndroGel® group required approximately 120 days to reach steady state. The mean FSH concentration in patients applying 5.0 g/day of AndroGel showed an initial decline that was completed by day 30 and another declining phase at. day 120 and continuing until the end of treatment. Mean FSH concentrations in the patients receiving the testosterone patch appeared to reached steady state after 30 days but were significantly higher than the normal range. Table 13(a): FSH Concentrations (mlU/mL) on Each of the Observation Days by Initial Treatment Group for Patients Having Primary Hypogonadism (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Dav 150 DavlSO N 26 23 24 24 24 22 24 5 g/day 21.6 ±21.0 10.6 ±15.0 10.8 ±16.9 10.4 ±19.7 8.1 ±15.2 6.7 ±15.0 6.2 ±11.3 N 33 34 32 31 28 29 28 10 e/day 20.9 ±15.9 10.6±14.1 7.2 ±12.6 5.7±10.1 4.6 ±10.2 5.3 ±11.0 5.3 ±11.2 N 34 31 31 30 21 21 22 T-patcb 25.5 ±25.5 2 1.4 ±24.6 21.7 ±23.4 19.5 ±20.0 25.3 ±28.4 18.6 ±24.0 24.5 ±27.4 Patients with secondary hypogonadism have a deficient testosterone negative feedback system. As shown in FIG. 8(b), of 44 patients identified as having secondary hypogonadism, the mean FSH concentrations decreased during treatment, although the decrease over time was not statistically significant for the testosterone patch. The patients in the 5.0 g/day AndroGel* group showed a decrease in the mean FSH concentration by about 35% by day 30, with no further decrease evident by day 60. Beyond day 90. the mean FSH concentration in the patients appeared to slowly return toward the pretreatment value. By day 30, all of the 10.0 g/day AndroGel* group had FSH concentrations less than the lower limit. Table 13(b): FSH Concentrations (mlU/mL) on Each of the Observation Days by Initial Treatment Group for Patients Having Secondary Hypogonadism (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 N 17 16 17 15 14 14 14 5 g/day 4.2 ± 6.6 2.8 ±5.9 2.8 ± 6.1 2.9 ±5.6 3.0 ±6.1 3.5 ±7.5 3.7 ±8.6 N 12 12 12 12 12 12 12 10 g/day 2.1 ±1.9 0.2 ±0.1 0.2 ±0.1 0.2 ±0.1 0.1 ±0.1 0.2 ±0.2 0.1 ±0.1 N 15 14 13 14 12 11 12 T-patch 5.1 ±9.0 4.2 ±8.0 4.2 ±7.4 4.9 ±9.0 6.1 ± 10.7 4.6 ±6.5 4.9 ± 7.4 Twenty-five patients were diagnosed with age-associated hypogonadism. As shown in FIG. 8(c), the 5.0 g/day AndroGel® group had a mean pretreatment FSH concentration above the normal range. The mean concentration for this group was within the normal range by day 30 and had decreased more than 50% on days 90 and 180. The decrease in FSH mean concentration in the 10.0 g/day AndroGel* group showed a more rapid response. The concentrations in all six patients decreased to below the lower normal limit by day 30 and remained there for the duration of the study. The six patients who received the testosterone patch exhibited no consistent pattern in the mean FSH level; however, there was an overall trend towards lower FHS levels with continued treatment. Table 13(c): FSH Concentrations (mlU/mL) on Each of the Observation Days by Initial Treatment Group for Patients Having Age-Related Hypogonadism (Mean ± SD) Day_0 Day 30 Dav60 DayJO Day_120 DayJSO Dav 1 80 N 13 12 12 11 11 11 11 5 g/day 8.0 ±9.1 4.6 ± 7.4 3.9 ±6.6 3.8 ±7.0 4.2 ±8.3 4.3 ±8.1 4.0 ± 7.2 N6 6 6 6 6 5 6 lOg/dav 5.2 ±1.9 0.4 ±0.3 0.3 ± 0.3 0.4 ±0.7 0.4 ± 0.7 0.2 ± 0.2 0.2 ± 0.2 N 6 6 4 4 4 4 4 T-patch 4.7 ±1.7 3. 7 ±2.0 4.3 ±3.3 3.5± 1.9 4.2 ±3.3 3. 4 ±2.7 2.7±2.1 Sixty-four patients in the study suffered from unclassified hypogonadism. As shown in FIG. 8(d), the patients showed a marked and comparatively rapid FSH concentration decrease in all three groups, with the greatest decrease being in the 10.0 g/day AndroGel* group. The 10.0 g/day AndroGel® group produced nearly a 90% decrease in the mean FSH concentration by day 30 and maintained the effect to day 1 SO. The 5.0 g/day AndroGel* group produced about a 75% drop in mean FSH concentration by day 30 and stayed at that level for the remainder of treatment. The 21 patients receiving the testosterone patch had a 50% decrease in the mean FSH concentration by day 30, a trend that continued to day 90 when the concentration was about one-third of its pretreatment value. Table 13(d): Concentrations (mlU/mL) for FSH on Each of the Observation Days by Initial Treatment Group for Patients Having Unknown-Related Hypogonadism (Mean ± SD) Day 0 Day 30 Day 60 Dav 90 N 17 17 16 17 5 g/day 4.0 ±1.8 1.1± 1.0 l . l i l . l l . l i l . l N 26 26 26 25 10 g/day 4.1 ±1.6 0.5 ±0.5 0.3 ± 0.3 0.4 ±0.7 N 21 21 18 18 T-patch 3.7 ±1.4 1.8 ±0.8 1.6± 1.0 1.2 ±0.9 Day 120 Day 150 Day 180 N 16 17 16 5 g/day 1.2 ±1.4 1.4 ±1.4 1.0 ±0.9 N 26 23 24 10 g/day 0.4 ±0.6 0.3 ±0.5 0.4 ±0.4 N 12 13 11 T-patch 1.4 ± 1.0 1.4 ± 1.2 1.3 ±0.9 This data shows that feedback inhibition of FSH secretion functioned to some extent in all four subpopulations. The primary hypogonadal population showed a dose- « dependency in both the extent and rate of the decline in FSH levels. The sensitivity of the feedback process appeared to be reduced in the secondary and age-associated groups in that only the highest testosterone doses had a significant and prolonged impact on FSH secretion. In contrast, the feedback inhibition pathway in the patients in the unclassified group was quite responsive at even the lowest dose of exogenous testosterone. (2) LH The response of LH to testosterone was also examined separately for the same four subpopulations. Table 14(a)-(d) shows the LH concentrations throughout the treatment period. As shown in FIG. 9(a) and Table 14(a), the LH concentrations prior to treatment were about 175% of the upper limit of the normal range in primary hypogonadal patients. The mean LH concentrations decreased during treatment in all groups. However, only the AndroGel® groups decreased the mean LH concentrations enough to fall within the normal range. As with FSH, the primary hypogonadal men receiving AndroGel® showed dosedependence in both the rate and extent of the LH response. Table 14(a): Concentrations for LH (mlU/mL) on Each of the Observation Days for Patients Having Primary Hypogonadism (Summary of Mean ± SD) DayO Day 30 Day 60 Dav90 N 26 23 24 24 5 g/dav 12.2 ±12.1 5.6 ±7.6 6.8 ±9.0 5. 9 ±9.5 N 33 34 32 31 10 g/dav 13.9 ±14.9 5.9 ±8.1 4.8 ±10.0 4.2 ± 1 1 .0 N 33 31 31 30 T-patch 13.3 =t 14.3 10.9 ±12.9 10.8±11.8 10.0 ±11.7 Day 120 Day 150 Day 180 N 24 22 24 5 g/dav 6.4±11.9 4.4 ±8.5 4.8 ±6.8 N 28 29 28 10 g/dav 3.8 ±10.4 4.0±11.3 4.0 ±11. 9 N 71 71 7.7. T-patch 11.5±11.5 7.4 ±6.0 11.2± 10.5 The secondary hypogonadal men were less sensitive to exogenous testosterone. For the 44 patients identified as having secondary hypogonadism, the pretreatment mean concentrations were all within the lower limit normal range. The mean LH concentrations decreased during treatment with all three regimens as shown in FIG. 9(b) and Table 14(b). Table 14(b): Concentrations for LH (mlU/mL) on Each of the Observation Days for Patients Having Secondary Hypogonadism (Summary of Mean ± SD) DayO Dav30 Day 60 Dav90 Day 120 Day 150 Dav 1 80 N 17 16 17 15 14 14 14 5 g/day 1.8 ±2.6 1.1 ±2.2 1.4±3.8 1.2 ±2.4 1.6 ±4.0 1.6 ±3.5 1.5 ±3.7 N 12 12 12 12 12 12 12 lOg/dav 1.4 ±1.8 0.2 ±0.2 0.2 ±0.2 0.2 ± 0.2 0.2 ±0.2 0.2 ± 0.2 0.2 ± 0.2 N 15 14 13 14 12 11 12 T-patch 1.6±3.1 0.4 ±0.4 0.6 ± 0.5 0.7 ±1.0 0.8 ±0.8 1.2 ±2.0 1.4 ±2.1 None of the 25 patients suffering from age-associated hypogonadism had pretreatment LH concentrations outside of the normal range as shown in FIG. 9(c) and Table I4(c). The overall time and treatment effects were significant for the AndroGel® patients but not those patients using the testosterone patch. Table 14(c): Concentrations for LH (mlU/mL) on Each of the Observation Days for Patients Having Age-Related Hypogonadism (Summary of Mean ± SD) DayO Day 30 Day 60 Dav 90 Day 120 Day 150 Dav 180 N 13 12 12 11 11 11 11 5 g/day 3.2±1.1 1.1 ±1.0 0.8 ±0.7 0.9 ±1.2 1.0±1.4 1.3 ±1.5 1.8±2.1 N 6 6 6 6 6 56 10 g/day 2.4 ± 1.8 0.1 ±0.0 0.2 ±0.3 0.1 ±0.0 0.1 ±0.0 0.1 ±0.0 0.1 ±0.0 N 6 6 54 4 4 4 T-patch 2.9 ± 0.6 1.81.1 3. 4 ±2.8 2.3 ±1.4 2.2 ±1.4 1.91.2 1.4 ±1.0 Of the 64 patients suffering from an unclassified hypogonadism, none of the patients had a pretrcatment LH concentration above the upper limit. Fifteen percent, however, had pretreatment concentrations below the normal limit. The unclassified patients showed comparatively rapid LH concentration decreases in all treatment groups as shown in FIG. 9(d) and Table 14(d). Table 14(d): Concentrations for LH (mlU/mL) on Each of the Observation Days for Patients Having Unknown- Related Hypogonadism (Summary of Mean ± SD) DavO Day 30 Day 60 Day 90 Day 120 Day 150 Dav 180 N 17 17 17 17 17 17 15 5 g/day 1.8±1.2 0.3 ±0.3 0.4 ±0.5 0.5 ± 0.5 0.4 ± 0.4 0.8 ±1.1 0.3 ± 0.4 N 26 26 26 26 26 23 25 10 g/day 2.5 ±1.5 0.3 ± 0.3 0.3 ± 0.3 0.3 ± 0.4 0.4 ± 0.5 0.3 ± 0.4 0.4 ±0.4 N 21 21 18 T-patch 2.5 ± 1.5 1.3 ±1.3 1.2± 1.4 18 \| 1.0±1.4 12 13 11 L2±l.l 1.1 ±1.1 1.5± 1.3 (3) Summary: LH and FSH Patients receiving AndroGel* or the testosterone patch achieve "hormonal steady state" only after long-term treatment. Specifically, data involving FSH and LH show that these hormones do not achieve steady-state until many weeks after treatment. Because testosterone concentrations are negatively inhibited by FSH and LG, testosterone levels do not achieve true steady state until these other hormones also achieve steady state. However, because these hormones regulate only endogenous testosterone (which is small to begin with in hypogonadal men) in an intact feedback mechanism (which may not be present depending on the cause of hypogonadism), the level of FSH and/or LH may have little effect on the actual testosterone levels achieved. The net result is that the patients do not achieve a "hormonal steady state" for testosterone even though the C,vg, Cmin, and C^x for testosterone remains relative constant after a few days of treatment. 2. Libido and Sexual Performance Libido and sexual function were assessed by questionnaires the patients answered daily for seven consecutive days before clinic visits on day 0 and on days 30, 60, 90, 120, 150, and 180 days during gel and patch application. The subjects recorded whether they had sexual day dreams, anticipation of sex, flirting, sexual interaction (e.g., sexual motivation parameters) and orgasm, erection, masturbation, ejaculation, intercourse (e.g., sexual performance parameters) on each of the seven days. The value was recorded as 0 (none) or 1 (any) for analyses and the number of days the subjects noted a parameter was summed for the seven-day period. The average of the four sexual motivation parameters was taken as the sexual motivation mean score and that of the five sexual performance parameters as the sexual performance mean score (0 to 7). The subjects also assessed their level of sexual desire, sexual enjoyment, and satisfaction of erection using a seven-point Likcrt-type scale (0 to 7) and the percent of full erection from 0 to 100%. The subjects rated their mood using a 0 to 7 score. Weekly average scores were calculated. The details of this questionnaire had been described previously and are fully incorporated by reference. See Wang et al., Testosterone Replacement Tlierapy Improves Mood in Hypogonadal Men - A Clinical Research Center Study, 81J. CLINICAL ENDOCRINOLOGY & METABOLISM 3578-3583 (1996). a. Libido As shown in FIG. 10(a), at baseline, sexual motivation was the same in all treatment groups. After transdennal testosterone treatment, overall sexual motivation showed significant improvement. The change in the summary score from baseline, however, was not different among the three treatment groups. Libido was also assessed from responses on a linear scale of: (1) overall sexual desire, (2) enjoyment of sexual activity without a partner, and (3) enjoyment of sexual activity with a partner. As shown in FIG. 10(b) and Table 15, as a group, overall sexual desire increased after transdermal testosterone treatment without inter-group difference. Sexual enjoyment with and without a partner (FIG. 10(c) and Tables 14 and 15) also increased as a group. Table 15: Overall Sexual Desire Changes From Day 0 to Day 180 by Initial Treatment Group (Mean ± SD) Initial Treatment Croup 5.0 e/dav T-eel lO.Oe/ayT-gel T-Patch Across-Groups o-value N 69 77 72 Day 0 2.1 ± 1.6 2.0 ±1.4 2.0±].6 0.8955 N 63 68 47 Day 1 80 3.5 ± 1. 6 3.6 ± 1.6 3.1 ± 1.9 0.2247 N 60 67 45 Change From DavOto Dav 130 \A± 1.9 \.5± 1.9 1.6±2.l 0.8579 Wtthin-Group p-value 0.0001 0.0001 0.0001 Table 16: Level of Sexual Enjoyment Without a Partner Changes From Day 0 to Day 180 by Initial Treatment Group (Mean ± SD) Initial Treatment Croup 5.0 c/dav T-eel 1 0.0 e/day T-eel T-Patch Across-Groups p-value N 60 63 66 DayO 1.5 ±1.9 1.2±l.4 1.4± 1.8 0.6506 'N 51 53 44 Day 180 1.9±1.9 2.2 ±1.9 2.2 ±2. 3 0.7461 N 44 48 40 Change From DavOto Dav 180 0.8 ± 1.4 U± 1.6 1.0 ± 1.9 0.6126 Within-Group p-value 0.0051 0.0001 0.0026 Table 17: Level of Sexual Enjoyment With a Partner Change from Day 0 to Day 180 by Initial Treatment Group (Mean ± SD) Initial Treatment Group 5.0a/davT-gcl lO.Oz/dav T-eel T-Patch Across-Groups p-value N C4 66 61 DayO 2.1 ±2.1 1.8 ±1.7 1.5 ±1.7 0.2914 N 55 58 40 Day 180 2.6 ± 2.2 3.0 ±2.2 2.2 ± 2.4 0.1738 N 48 52 35 Change From DavOto Dav 180 0.4 ± 2.2 1.0 ±2.3 0.7 ± 2.3 0.39 II Wlthln-Group p-value 0.0 148 0.0053 0.1170 b. Sexual Performance FIG. 11 (a) shows that while all treatment groups had the same baseline sexual performance rating, the rating improved with transdermal testosterone treatment in all groups. In addition, as a group, the subjects' self-assessment of satisfaction of erection (FIG. ll(b) and Table 18) and percent full erection (FIG. ll(c) and Table 19) were also increased with testosterone replacement without significant differences between groups. The improvement in sexual function was not related to the dose or the delivery method of testosterone. Nor was the improvement related to the serum testosterone levels achieved by the various testosterone preparations. The data suggest that once a threshold (serum testosterone level probably at the low normal range) is achieved, normalization of sexual function occurs. Increasing serum testosterone levels higher to the upper normal range does not further improve sexual motivation or performance. Table 18: Satisfaction with Duration of Erection Change from Day 0 to Day 180 by Initial Treatment Group (Mean ± SD) Initial Treatment Group 5.0g/dayT-gel 10/Og/dayT-gel T-Patch Across-Groups p-value N 55 64 45 DayO 2.5 ±2.1 2.9 ±1.9 3.4 ±2.1 0.1117 N 57 58 34 Day 180 4.3 ±1.8 4.5 ± 1.7 4.5 ± 2.0 0.7093 N 44 53 20 Change From Dav 0 to Dav 1 80 1.9 ±2.0 1.5 ±2.0 1.3 ±2.1 0.5090 Wlthin-Group p-value 0.0001 0.0001 0.0524 Table 19: Percentage of Full Erection Change from Day 0 to Day 180 by Initial Treatment Group (Mean ± SD) Initial Treatment Group 5.0 a/davT-nel 1 0.0 ?/day T-ael T-Patch Across-Groups p- value N 53 62 47 Day 0 53.1 ±24.1 59.6 ±22.1 56.5 ± 24.7 0.3360 N 57 59 33 Day 180 67.4 ± 22.5 72.0 ± 20.2 66.7 ± 26.7 0.4360 N 43 52 19 Changt From Dav 0 to Dav 180 18.7 ±22.1 10.4 ±23.4 12.7120.3 0.1947 VVithin-Group p- value 0.0001 0.0001 0.0064 Example 2: Method of Increasing Libido in Eugonadal Men Having a Diminished Libido As discussed above, transdermal application of testosterone using AndroGel* to hypogonadal men results in improved libido and sexual performance. Researchers have found that eugonadal men having a diminished libido have a significant increase in sexual interest after receiving testosterone injections. See 0'Carrol & Bancroft, Testosterone Therapy for Low Sexual Interest and Erectile Dysfunction in Men: A Controlled Study, Brit. J. Psychiatry 145:146-151 (1984). Thus, the present example is directed to a method of treating a diminished libido in eugonadal men by transdermal application of a hydroalcoholic testosterone gel to such men. In one embodiment, AndroGel® is applied to the body in accordance with the protocol summarized in Example 1. Libido is measured as in Example 1. Men receiving AndroGel are expected to show a increase in their libido. Example 3: Method of Increasing Libido in Eugonadal Men Having a Normal Libido As discussed above, transdermal application of testosterone using AndroGel® to hypogonadal men results in improved libido and sexual performance. Studies have shown that supra-physiological doses of testosterone administered to eugonadal men having a normal libido resulted in a significant increase in libido. See Anderson et al., The Effect of Exogenous Tstoserone on Sexuality and Mood of Normal Men* J. CLINICAL ENDOCRINOLOGY & METABOLISM 75:1505-1507 (1992); Bagatel et al., Metabolic & Behavioral Effects of High-Dose, Exogenous Testosterone in Healthy Men, J. CLINICAL METABOLISM & ENDOCRINOLOGY 79:561-567 (1994). Thus, this example is directed to a method of increasing the libido of normal eugonadal men by application of a transdermal hydroalcoholic testosterone gel. In one embodiment, AndroGel® is applied to the body in duration of erections (RigiScan®) with AndroGel treatment compared with placebo. Applicant expects that all test parameters will show improvement over the placebo. Example 5; Method of Improving Sexual Performance in Eugonadal Mpn Having Normal jErectipns In a prophetic example, 10 eugonadal males age 18 and older having normal erections (i.e. not diagnosed with erectile dysfunction) will be randomized to receive: (a) 5.0 g/day of AndroGel® (delivering 50 mg/day of testosterone to the skin of which about 10% or 5 mg is absorbed) for 30 days or (b) 10.0 g/day of AndroGel® (delivering 100 mg/day of testosterone to the skin of which about 10% or 10 mg is absorbed) for 30 days : or (c) nothing. The effectiveness of AndroGel® will be evaluated using several assessment instrument as discussed in Example 4. Applicant expects that all test parameters will show an increase in sexual performance over the placebo. Accordingly. Applicant expects that AndroGel® can be applied to normal men in order to increase the sexual performance above their normal baseline. Example 6: Method of Treating Men Having Erectile Dysfunction in Conjunction with other Pharmaceuticals As discussed above, transdermal application of testosterone using AndroGel* to hypogonadal men results in improved libido and sexual performance. This example is directed use of AndroGel in combination with pharmaceuticals useful for treating erectile dysfunction. Such pharmaceuticals include any agent that is effective to inhibit the activity of a phosphodiesterase. Suitable phosphodiesterase inhibitors include, but are not limited to, inhibitors of the type III phosphodiesterase (cAMP-specific-cGMP inhibitable form), the type IV phospodiesterase (high affinity-high specificity cAMP form) and the type V phosphodiesterase (the cGMP specific form). Additional inhibitors that may be duration of erections (RigiScan) with AndroGel treatment compared with placebo. Applicant expects that all test parameters will show improvement over the placebo. Example 5; Method ofTmnrovinP Sexual Performance in Eugm^ai p\fn Having Normal Erections In a prophetic example, 10 eugonadal males age 18 and older having normal erections (i.e. not diagnosed with erectile dysfunction) will be randomized to receive: (a) 5.0 g/day of AndroGel® (delivering 50 mg/day of testosterone to the skin of which about 10% or 5 mg is absorbed) for 30 days or (b) 10.0 g/day of AndroGel® (delivering 100 mg/day of testosterone to the skin of which about 10% or 10 mg is absorbed) for 30 days ; or (c) nothing. The effectiveness of AndroGel® will be evaluated using several assessment instrument as discussed in Example 4. Applicant expects that all test parameters will show an increase in sexual performance over the placebo. Accordingly, Applicant expects that AndroGel® can be applied to normal men in order to increase the sexual performance above their normal baseline. Example Conjunction vvitji other Pharmaceuticals As discussed above, transdermal application of testosterone using AndroGel to hypogonadal men results in improved libido and sexual performance. This example is directed use of AndroGel in combination with Pharmaceuticals useful for treating erectile dysfunction. Such Pharmaceuticals include any agent that is effective to inhibit the activity of a phosphodiesterase. Suitable phosphodiesterase inhibitors include, but are not limited to, inhibitors of the type III phosphodiesterase (cAMP-specific-cGMP inhabitable form), the type IV phospodiesterase (high affinity-high specificity cAMP form) and the type V phosphodiesterase (the cGMP specific form). Additional inhibitors that may be allyloxy-5-(4-methyl-l -piperazinylsulfonyO-phenyl]-1 -methyl-3-n-propyl-1,6-dihydro- 7H-Pyrazolo[4,3-d]Pyrimidin-7-one,5-[2-ethoxy-5-[4-(2-ProPyl)-l-Pipcrazinylsulfonyl)- phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyra2olo[4,3-d]pyrimidin-7-one, 5-[2- ethoxy-5-[4-(2-hydroxyethyl)-l-Piperazinylsulfonyl)Phenyl]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4s3-d]pyrirnidin-7-one, 5-[5-[4-(2-hydroxyethyl)-lpiPerazinylsulfonyl]- 2-n-propoxvphenyl]-l-methy l-3-n-Propyl-l,6-dihydro-7Hpyrazolo[ 4,3-d]Pyrimidin-7-one, 5[2-ethoxy-5-(4-methyl-l-piPerazinylcarbonyl)Phenyll- 1 -methyl-3-n-propyl-l,6-dihydro-7H-Pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-5- (l-methyl-2-imidazolyl)Phenyl]-l-methyl-3-n-propyl- 1,6-dihyd ro-7H-pyrazolo[4,3- d]pyrimidin-7-one. The phosphodiesterase inhibitors described in PCT Publication No. WO 96/16644 include griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone derivatives, fused and condensed pyrimidines, pyrimidopyrimidine derivatives, purine compounds, quinazoline compounds, phenylpyrimidinone derivative, imidazoquinoxalinone derivatives or aza analogues thereof, phenylpyridone derivatives. and others. Specific examples of the phosphodiesterase inhibitors disclosed in WO 96/16644 include l,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2- propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-l,2-dihydro-2-oxypyridine-3- carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one, 7-methylthio-4-oxo- 2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine, 6-hydroxy-2-(2- propoxyphenyl)pyrimidine-4-carboxamide, l-ethyl-3-methyHrnidazo[l,5a]quinoxalin- 4(5H)-one, 4-phenylmethylamino-6-chloro-2-( l-imidazoloyl)quinazoline, 5-ethyl-8-[3-(Ncyclohexyl- N-methylcarbamoyl)-proPyloxy]-4,5-dihydro-4-oxo-pyrido[3,2-e]-Pyrrolo[l,2- ajpyrazine, 5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'H)-(3IH)- allyloxy-5-(4-methyl-l-piperazinylsulfonyl)-phenyl]-l-methyl-3-n-propyl-l,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-propyl)-l-piperazinylsulfonyl)- phenyl]-1 -methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2- ethoxy-5-[4-(2-hydroxyethyl)-l-piperazmylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6- dihydro-7H-pyrazolo[4J3-d]pyrimidin-7-one, 5-[5-[4-(2-hydroxyethyl)-lpiperazinylsulfonyl]- 2-n-propoxyphenyl]-l-methy l-3-n-propyl-l,6-dihydro-7Hpyrazolo[ 4,3-d]pyrimidin-7-one, 5[2-ethoxy-5-(4-methyl-l-piperazinylcarbonyl)phenyl]- 1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-5- (l-methyl-2-imidazolyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one. The phosphodiesterase inhibitors described in PCT Publication No. WO 96/16644 include griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone derivatives, fused and condensed pyrimidines, pyrimidopyrirnidine derivatives, purine compounds, quinazoline compounds, phenylpyrimidinone derivative, imidazoquinoxalinone derivatives or aza analogues thereof, phenylpyridone derivatives, and others. Specific examples of the phosphodiesterase inhibitors disclosed in WO 96/16644 include l,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2- propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-l,2-dihydro-2-oxypyridine-3- carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pvrimid-4(3H)-one, 7-methylthio-4-oxo- 2-(2-propoxvphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine, 6-hydroxy-2-(2- propoxyphenyl)pyrimidine-4-carboxamide, l-ethyl-3-methylimidazo[l,5a]quinoxalin- 4(5H)-one, 4-phenylmethylamino-6-chloro-2-(l-imida2oloyl)quinazoline, 5-ethyl-8-[3-(Ncyclohexyl- N-methylcarbamoyl)-propyloxy]-4,5-dihydro-4-oxo-pyrido[3,2-e]-pyrrolo[l,2- a]pyrazine, 5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'I Other phosphodiesterase inhibitors that may be used in the method of this invention include nonspecific phosphodiesterase inhibitors such as theophylline. IBMX, pentoxifylline and papaverine, and direct vasodilators such as hydralazine. The active agents may be administered, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method. Salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms ancj Structure. 4th Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base using conventional methodology, and involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base. Particularly preferred acid addition salts of the active agents herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Conversely, preparation of basic salts of acid moieties which may be present on a phosphodiesterase Other phosphodiesterase inhibitors that may be used in the method of this invention include nonspecific phosphodiesterase inhibitors such as theophylline, IBMX, pemoxifylline and papaverine, and direct vasodilators such as hydralazine. The active agents may be administered, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method. Salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions. Mechanisms and Structure. 4th Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base using conventional methodology, and involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartanc acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base. Particularly preferred acid addition salts of the active agents herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Conversely, preparation of basic salts of acid moieties which may be present on a phosphodiesterase principally by various physiological mechanisms of erection initiation and maintenance, the testosterone gel used in accordance with the present invention plays a beneficial role physiologically, and stimulates both sexual motivation (i.e., libido) and sexual performance. Testosterone controls the expression of the nitric oxide synthase gene. See Reilly et al., Androgenic Regulation of NO Availability in Rat Penile Erection, 38 J. ANDROLOGY 110 (1997); Park et al., Effects of Androgens on the Expression of Nitric Oxide Synthase mRNAs in Rat Corpous Cavernosum, 83 BJU INT'L. 327 (1999). Thus, testosterone and other androgens clearly play a role in erectile dysfunction. See Lugg et al.. We Role of Nitric Oxide in Erectile Function, 16 J. ANDROLOGY 2 (1995); Penson et al., Androgen and Pituitary Control of Penile Nitric Oxide Synthase and Erectile Function In the Rat, 55 BIOLOGY OF REPRODUCTION 576 (1996); Traish et aL, Effects of Castration and Androgen Replacement on Erectile Function in a Rabbit Model, 140 ENDOCRINOLOGY 1861 (1999). Moreover, testosterone replacement restores nitric oxide activity. See Baba et al. Delayed Testosterone Replacement Restores Nitric Oxide Synthase Containing Nerve Fibres and the Erectile Response in Rat Penis, BJU INT'L 953 (2000); Garban et al.. Restoration of Normal Adult Penile Erectile Response in Aged Rats by Long-Term Treatment with Androgens, 53 BIOLOGY OF REPRODUCTION 1365 (1995); Mann et al., Androgen-dependent Nitric Oxide Release in Rat Penis Correlates with Levels of Constitutive Nitric Oxide Synthase Isoenzymes, 61 BIOLOGY OF REPRODUCTION 1012 (1999). As disclosed herein, adequate blood levels of testosterone are important to erection. In one embodiment, AndroGel® is applied to the body in accordance with the protocol summarized in Example 1. The pharmaceutical(s) for erectile dysfunction is taken in accordance with the prescription requirements. For example, VIAGRA® is principally by various physiological mechanisms of erection initiation and maintenance, the testosterone gel used in accordance with the present invention plays a beneficial role physiologically, and stimulates both sexual motivation (i.e., libido) and sexual performance. Testosterone controls the expression of the nitric oxide synthase gene. See Reilly et al., Androgenic Regulation of NO Availability in Rat Penile Erection, 18 J. ANDROLOGY 110 (1997); Park et al., Effects of Androgens on the Expression of Nitric Oxide Synthase mRNAs in Rat Corpous Cavernosum, 83 BJU INT'L. 327 (1999). Thus. testosterone and other androgens clearly play a role in erectile dysfunction. See Lugg et al.. Tlie Role of Nitric Oxide in Erectile Function, 16 J. ANDROLOGY 2 (1995); Penson et al., Androgen and Pituitary Control of Penile Nitric Oxide Synthase and Erectile Function In the Rat, 55 BIOLOGY OF REPRODUCTION 576 (1996); Traish et aL, Effects of Castration and Androgen Replacement on Erectile Function in a Rabbit Model, 140 ENDOCRINOLOGY 1861 (1999). Moreover, testosterone replacement restores nitric oxide activity. See Baba et al. Delayed Testosterone Replacement Restores Nitric Oxide Synthase Containing Nerve Fibres and the Erectile Response in Rat Penis, BJU INT'L 953 (2000); Garban et al.. Restoration of Normal Adult Penile Erectile Response in Aged Rats by Long-Term Treatment with Androgens, 53 BIOLOGY OF REPRODUCTION 1365 (1995); Mann et al., Androgen-dependent Nitric Oxide Release in Rat Penis Correlates with Levels of Constitutive Nitric Oxide Synthase Isoenzymes, 61 BIOLOGY OF REPRODUCTION 1012 (1999). As disclosed herein, adequate blood levels of testosterone are important to erection. In one embodiment, AndroGel® is applied to the body in accordance with the protocol summarized in Example 1. The pharmaceutical(s) for erectile dysfunction is taken in accordance with the prescription requirements. For example, VIAGRA® is invention. The present invention is defined by the claimed elements, and any and all modifications, variations, or equivalents that fall within the true spirit and scope of the underlying principles. We Claim : 1. A hydroalcoholic gel for improving the efficacy of a pharmaceutical useful for treating erectile dysfunction in a male subject, comprising: a. a pharmaceutically effective amount of a steroid in the testosterone synthetic pathway b. 40 - 90 % w/w of at least one of a C1-C4 alcohol, c. 0.10-2% w/w of a penetration enhancer, d. 0.10 - 2% w/w of thickener and e. water qs 100% w/w. 2. The hydroalcoholic gel of claim 1 wherein the pharmaceutical is a phosphodiesterase type 5 inhibitor. 3. The hydroalcoholic gel of claim 1 wherein the pharmaceutical is at least one of sildenafil citrate, pentoxifylline, yohimbine, apomorphine, alprostadil, papavaerine, phentolamine, and combinations, salts, derivatives and enantiomers thereof. 4. The hydroalcoholic gel of claim 1 wherein the Pharmaceuticals are selected from the group consisting of sildenafil, apomorphine, pentoxifylline, or yohimbine. 5. The hydroalcoholic gel of claim 1 wherein the penetration enhancer comprises at least one of a C8-C22 fatty acid. 6. The hydroalcoholic gel of claim 1 wherein the fatty acid comprises an alkyl chain length of at least 12 carbon atoms. 7. The hydroalcoholic gel of claim 1 wherein the lower alcohol comprises at least one of ethanol, 2-propanol, n-propanol, and mixtures thereof. 8. The hydroalcoholic gel of claim 1 wherein the steroid is testosterone and the enhancer is isopropyl myristate. 9. The hydroalcoholic gel of claim 8 wherein the composition comprises about 1.0 % w/w of testosterone. 10. The hydroalcoholic gel of claim 8 wherein the enhancer comprises about 0.5 % w/w of isopropyl myristate. 11. The hydroalcoholic gel of claim 8 wherein the thickener is polyacrylic acid. 12. The hydroalcoholic gel of claim 8 where the steroid comprises about 0.5 to about 5.0 % w/w testosterone, the thickener comprises about 0.10 to about 2 % w/w of polyacrylic acid, the enhancer comprises about 0.1 to about 2 % w/w of isopropyl myristate, the C1-C4 alcohol comprises about 40.0 to about 90 % w/w of ethanol. 13. A composition comprising a pharmaceutical useful for treating erectile dysfunction in a man and a transdermal testosterone gel as separate components to the composition and wherein the transdermal testosterone gel comprises: • 0.5-5% w/w of testosterone, • 40 -90 % w/w of at least one of a C1-C4 alcohol, • 0.10-2% w/w of a penetration enhancer, • 0.10-2% w/w of thickener and • water qs 100% w/w. 14. The composition of claim13 wherein the pharmaceutical is a phosphodiesterase type 5 inhibitor. 15. The composition of claim13 wherein the pharmaceutical is at least one of sildenafil citrate, pentoxifylline, yohimbine, apomorphine, alprostadil, papavaerine, phentolamine, and combinations, salts, derivatives and enantiomers thereof. 16. The composition of claim13 wherein the Pharmaceuticals are selected from the group consisting of sildenafil, apomorphine, pentoxifylline, or yohimbine. 17. The composition of claim 16 wherein the thickener comprises about 0.10 to about 2 % w/w of polyacrylic acid, the enhancer comprises about 0.10 to about 2 % w/w of isopropyl myristate, the C1-C4 alcohol comprises about 40.0 to about 90 % w/w of ethanol Dated this 21st day of November 2003 „ Vidlsha (Jarg Of Anand And Anand Advocates Attorney for the Applicant

Full Text

FIELD OF THE INVENTION
The present invention related to a hydroalcoholic gel for improving the efficacy of a
pharmaceutical useful for treating erectile dysfunction"
RELATED APPLICATIONS
This is a continuation-in-part of U.S. Patent Application Serial No. 09/651,777,
entitled, "Pharmaceutical Composition and Method for Treating Hypogonadism," filed 30
August 2000, jointly owned by Unimed Pharmaceuticals, Inc., the sole assignee of the
instant application.
BACKGROUND OF THE INVENTION
A. Sexual Performance, Erectile Dysfunction ("ED"), and Libido in Meo
1. Sexual Performance & ED
"Sexual performance" as used herein generally refers to a man's ability to have an
orgasm, obtain an erection, or erigage in masturbation or intercourse, "Impotence" is a
type of deficient sexual performance. Impotence or "erectile dysfunction" as used herein
is generally refers to the inability of a man to attain an erection with sufficient rigidity for
vaginal penetration 25% or more of the times attempted.
As many as 45 million men have some degree of erectile dysfunction. At least 10
million American men - about 9% of the adult population - are thought to have
impotence. The rate increases with age. Thus, impotence affects about 10% of men in
their sixties, 25% of men in their seventies, 40% of men in their eighties, and more than
half of those in their nineties. In young couples, the incidence of impotence is about 7%.
One-third of older men receiving medical treatment also have difficulty with erectile
function.
Over the past decade, the medical perspective on the causes of impotence has
shifted. Conventional wisdom used to attribute almost all cases of impotence to
psychological factors. Investigators now estimate that between 70% and 80% of
impotence cases are caused primarily by medical problems. Risk factors for impotence
include hypogonadism, atherosclerosis, hypertension, diabetes mellitus, depression and
other emotional or psychological illnesses, pelvic surgery, kidney failure, multiple
sclerosis, stroke, some types of epilepsy, and alcoholism. Another risk factor is taking any
of a variety of drugs, including cardiovascular medications, drugs that affect the central
nervous system, certain hormonal preparations, heroin, and cocaine.
Today, 90% of all impotence cases are treated with VIAGRA K (sildenafil citrate
USP). Other drugs useful in the treatment of impotence include, but are not limited to:
pentoxifylline (TRENTAL®), yohimbine' hydrochloride (ACTIBIME*. YOCON*.
YOHIMEX*), apomorphine (UPRIMA®), alprostadil (the MUSE* system, TOPIGLAN*.
CAVERJECT*), papavaerine (PAVABID®, CERESPAN*), and phentolamine
(VASOMAX®, REGITINE*).
These Pharmaceuticals act by a variety of physiological mechanisms. For
example, the physiologic mechanism of erection of the penis involves release of nitric
oxide ("NO") in the corpus cavemosum during sexual stimulation. NO then activates the
enzyme guanylate cyclase, which results in increased levels of cyclic guanosine
monophosphate ("cGMP"), producing smooth muscle relaxation in the corpus cavemosum
and allowing inflow of blood. VIAGRA* has no direct relaxant effect on isolated human
corpus cavemosum, but enhances the effect of NO by inhibiting phosphodiesterase type 5
("PDE5"), which is responsible for degradation of cGMP in the corpus cavemosum.
When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil
causes increased levels of cGMP in the corpus cavemosum, resulting in smooth muscle
relaxation and inflow of blood to the corpus cavemosum. In contrast, UPRIMA*" is a
dopamine receptor agonist that acts on the central nervous system. Once absorbed and
transported into the brain, UPRIMA® initiates a chain of reactions that result in increased
blood flow to the male genital organs and an erection. In accordance with the present
invention, testosterone plays a beneficial role physiologically, and stimulates both sexual
motivation (i.e., libido) and sexual performance.
2, Sexual Motivation and Libido
While the terms "sexual performance" and "impotence" describe physiological
effects, the terms "sexual motivation" and "libido" describe psychological effects.
"Libido" or "sexual motivation" as used herein is a parameter measured by the duralion,
frequency and extent of sexual daydreams, anticipation of sex, flirting, and sexual
interaction.
As discussed above, while doctors now believe that erectile dysfunction is
primarily caused by a physiological mechanism, some cases are still attributable to
psychological causes. Moreover, decreased libido may also be a reaction to the experience
of impotence. Unfortunately, Pharmaceuticals such as VIAGRA® treat erectile
dysfunction by the focusing on the physiological mechanics of attaining and maintaining
an erection and do little or nothing to enhance the sexual motivation or libido of men
suffering from erectile dysfunction. Thus, there remains a need to treat sexual
performance disorders such as impotence in a manner that overcomes both the
physiological and psychological problems associated with the disorder.
An number of clinical studies involving testosterone replacement in hypogonadal
males have provided convincing evidence that testosterone plays a role in both sexual
motivation libido and sexual performance. For example, researchers have reported that
testosterone replacement results in increased sexual fantasies, sexual arousal and desire,
spontaneous erections during sleep and in the morning, ejaculation, sexual activities with
and without a partner, and orgasm through coitus or masturbation. See generally
Christiansen, Behavioral Correlates of Testosterone, TESTOSTERONE: ACTION,
DEFICIENCY, SuBSTiTirnon 109-111 (1998).
B. Testosterone Synthesis, Metabolism, and Regulation
Testosterone, the major circulating androgen in men, is synthesized from
cholesterol. The approximately 500 million Leydig cells in the testes secrete more than
95% of the 6-7 mg of testosterone produced per day. Two hormones produced by the
pituitary gland, luteinizing hormone ("LH") and follicle stimulating hormone ("FSH"), are
required for the development and maintenance of testicular function and negatively
regulate testosterone production. Circulating testosterone is metabolized to various 17-
keto steroids through two different pathways. Testosterone can be metabolized to
dihydrotestosterone ("DHT") by the enzyme 5a-reductase or to estradiol ("£2") by an
aromatase enzyme complex.
Testosterone circulates in the blood 98% bound to protein. In men, approximately
40% of the binding is to the high-affinity sex hormone binding globulin ("SHBG"). The
remaining 60% is bound weakly to albumin. Thus, a number of measurements for
testosterone are available from clinical laboratories. The term "free" testosterone as used
herein refers to the fraction of testosterone in the blood that is not bound to protein. The
term "total testosterone" or "testosterone" as used herein means the free testosterone plus
protein-bound testosterone. The term "bioavailable testosterone" as used herein refers to
the non-SHBG bound testosterone and includes that weakly bound to albumin.
r
The following table from the UCLA-Harbor Medical Center summarizes the
hormone concentrations in normal adult men range:
Table 1: Hormone Levels in Normal Men
Hormone
Testosterone
Free testosterone
DHT
DHT/T Ratio
DHT + T
SHBG
FSH
LH
E2
Normal Range
298 to 1043 ng/dL
3.5 to 17.9 ng/dL
31 to 193 ng/dL
0.052 to 0.33
372 to 1349 ng/dL
10.8 to 46.6 nmol/L
1.0to6.9rnlU/mL
1.0to8.1mlU/mL
17.1 to 46.1 pg/mL
There is considerable variation in the half-life of testosterone reported in the
literature, ranging from 10 to 100 minutes. Researchers do agree, however, that
circulating testosterone has a diurnal variation in normal young men. Maximum levels
occur at approximately 6:00 to 8:00 a.m. with levels declining throughout the day.
Characteristic profiles have a maximum testosterone level of 720 ng/dL and a minimum
level of 430 ng/dL. The physiological significance of this diurnal cycle, if any, however,
is not clear.
C. Testosterone Levels and Sexual Behavior/Performance
Because increasing testosterone concentrations has been shown to alter sexual
performance and libido, researchers have investigated methods of delivering testosterone
to men. These methods include intramuscular injections (43%), oral replacement (24%),
pellet implants (23%), and transdermal patches (10%). A summary of these methods is
shown in Table 2.
C
Table 2: Mode of Application and Dosage of Various Testosterone Preparations
Preparation Route Of Application Full Substitution Dose
In Clinical Use
Testosterone cnanthate
Testosterone cypionate
Testosterone undecanoate
Transdermal testosterone patch
Transdermal testosterone patch
Testosterone implants
Intramuscular injection
Intramuscular injection
Oral
Scrotal skin
Non-scrotal skin
Implantation under the
abdominal skin
200-25.0 g every 2-3 weeks
200 mg every 2 weeks
2-4 capsules at 40 mg per day
I membrane per day
1 or 2 systems per day
3-6 implants of 200 mg every 6
months
Under Development
Testosterone cyclodextrin
Testosterone undecanoate
Testosterone buciclate
Testosterone microspheres
Sublingual
Intramuscular injection
Intramuscular injection
Jntramuscular injection
2.5-5.0 mg twice daily
1000 mg every 8-10 weeks
1000 mg every 12-16 weeks
315 mg for 11 weeks
Obsolete
17a-Methyltestosterone
Fluoxymesterone
Oral
Sublingual
Oral
25-5.0 g per day
10-25 mg per day
10-20 me per day
All of the testosterone replacement methods currently employed, however, suffer
from one or more drawbacks. For example, subdermal pellet implants and ester injections
are painful and require doctor visits. Many of these methods, such as
oral/sublingual/buccal preparations, suffer from undesirable pharmacokinetic profile—
creating supra-physiologic testosterone concentrations followed a return to baseline.
Transdermal patches provide less than optimal pharmacokinetic characteristics, are
embarrassing for many patients, and are associated with significant skin irritation. Thus,
although the need for an effective testosterone replacement methodology lias existed for
decades, an alternative replacement therapy that overcomes these problems has never been
developed.
SUMMARY OF THE INVENTION
The present invention relates to a transdermal hydroalcoholvc testosterone gel
formulation that overcomes the problems associated with other testosterone delivery
mechanisms by providing, among other things, a desirable pharmacokinetic hormone
profile with little or no skin irritation. The gel may be used as a method of improving
sexual performance, including treating erectile dysfunction, and increasing libido by
increasing testosterone levels in men. In addition, the gel may be used in conjunction with
Pharmaceuticals aimed at treating erectile dysfunction, such as VIAGRA®, to enhance
their effectiveness.
BRIEF DF.gf RfpTTON OF THE DRAWINGS
FIG. l(a) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men prior to receiving 5.0 g/day of AndroGcl6, 10.0 g/day of AndroGel*, or
the testosterone patch (by initial treatment group).
FIG. l(b) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men on the first day of treatment with either 5.0 g/day of AndroGel\ 10.0
g/day of AndroGel®, or the testosterone patch (by initial treatment group).
FIG. l(c) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men on day 30 of treatment with either 5.0 g/day of AndroGel*', 10.0 g/day
of AndroGel, or the testosterone patch (by initial treatment group).
FIG. l(d) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men on day 90 of treatment with either 5.0 g/day of AndroGel*, 10.0 g/day
of AndroGel®, or the testosterone patch (by initial treatment group).
FIG. l(e) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men on day 180 of treatment with either 5.0 g/day of AndroGel®, 10.0 g/day
of AndroGel®, or the testosterone patch (by final treatment group).
FIG. l(f) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with 5.0 g/day of AndroGel .
FIG. l(g) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men on day 0,1, 30, 90, and 180 of treatment with 10.0 g/day of AndroGel*.
FIG. l(h) is a graph showing the 24-hour testosterone pharmacokinetic profile for
hypogonadal men on day 0,1, 30,90, and 180 of treatment with the testosterone patch.
FIG. 2(a) is a graph showing the 24-hour free testosterone pharmacokinetic profile
for hypogonadal men on day 1 of treatment with either 5.0 g/day of AndroGel*. 10.0
g/day of AndroGel®, or the testosterone patch (by initial treatment group).
FIG. 2(b) is a graph showing the 24-hour free testosterone pharmacokinetic profile
for hypogonadal men on day 30 of treatment with either 5.0 g/day of AndroGer, 10.0
g/day of AndroGer8, or the testosterone patch (by initial treatment group).
FIG. 2(c) is a graph showing the 24-hour free testosterone pharmacokinetic profile
for hypogonadal men on day 90 of treatment with either 5.0 g/day of AndroGel*, 10.0
g/day of AndroGel®, or the testosterone patch (by initial treatment group).
FIG. 2(d) is a graph showing the 24-hour free testosterone pharmacokinetic profile
for hypogonadal men on day 180 of treatment with either 5.0 g/day of AndroGel*, 10.0
g/day of AndroGel*, or the testosterone patch (by final treatment group).
FIG. 2(e) is a graph showing the 24-hour free testosterone pharmacokinetic profile
for hypogonadal men on day 0, 1, 30, 90, and 180 of treatment with 5.0 g/day of
AndroGel®.
FIG. 2(f) is a graph showing the 24-hour free testosterone pharmacokinetic profile
for hypogonadal men on day 0, U 30, 90, and 180 of treatment with 10.0 g/day of
AndroGel®.
FIG. 2(g) is a graph showing the 24-hour free testosterone pharmacokinetic profile
for hypogonadal men on day 0,1, 30,90, and 180 of treatment with the testosterone patch.
FIG. 3 is a graph showing the DHT concentrations on days 0 through 180 for
hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or
the testosterone patch (by initial treatment group).
FIG.4 is a graph showing the DHT/T ratio on days 0 through 180 for hypogonadal
men receiving either 5.0 g/day of AndroGel*, 10.0 g/day of AndroGel®, or the testosterone
patch (by initial treatment group).
FIG. 5 is a graph showing the total androgen concentrations (DHT +T) on days 0
through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel*, 10.0 g/day of
AndroGel18, or the testosterone patch (by initial treatment group).
FIG. 6 is a graph showing the Ez concentrations on days 0 through 180 for
hypogonadal men receiving either 5.0 g/day of AndroGel*, 10.0 g/day of AndroGel*, or
the testosterone patch (by initial treatment group).
FIG. 7 is a graph showing the SHBG concentrations on days 0 through 180 for
hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or
the testosterone patch (by initial treatment group).
FIG. 8(a) is a graph showing the FSH concentrations on days 0 through 180 for
men having primary hypogonadism and receiving either 5.0 g/day of AndroGel®, 10.0
g/day of AndroGel*, or the testosterone patch (by initial treatment group).
FIG. 8(b) is a graph showing the FSH concentrations on days 0 through 180 for
men having secondary hypogonadism and receiving either 5,0 g/day of AndroGel , 10.0
g/day of AndroGel*, or the testosterone patch (by initial treatment group).
FIG. 8(c) is a graph showing the FSH concentrations on days 0 through 180 for
men having age-associated hypogonadism and receiving either 5,0 g/day of AndroGel ,
10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment group).
FIG. 8(d) is a graph showing the FSH concentrations on days 0 through 180 for
men having hypogonadism of an unknown origin and receiving either 5.0 g/day of
AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (by initial treatment
group).
FIG. 9(a) is a graph showing the LH concentrations on days 0 through 180 for men
having primary hypogonadism and receiving either 5.0 g/day of AndroGel^, 10.0 g/day of
AndroGel . or the testosterone patch (by initial treatment group).
FIG. 9(b) is a graph showing the LH concentrations on days 0 through 180 for men
having secondary hypogonadism and receiving either 5.0 g/day of AndroGel®, 10.0 g/day
of AndroGel®, or the testosterone patch (by initial treatment group).
FIG. 9(c) is a graph showing the LH concentrations on days 0 through 180 for men
having age-associated hypogonadism and receiving either 5.0 g/day of AndroGel*, 10.0
g/day of AndroGel*, or the testosterone patch (by initial treatment group).
FIG. 9(d) is a graph showing the LH concentrations on days 0 through 180 for men
having hypogonadism of an unknown origin and receiving either 5.0 g/day of AndroGel ,
10.0 g/day of AndroGel18, or the testosterone patch (by initial treatment group).
FIG. 10(a) is a graph showing sexual motivation scores on days 0 through 180 for
hypogonadal men receiving either 5.0 g/day of AndroGel*, 7.5 g/day 10.0 g/day of
AndroGel®, or the testosterone patch.
FIG. 10(b) is a graph showing overall sexual desire scores on days 0 through 180
for hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0 g/day of
AndroGel8, or the testosterone patch.
II
FIG. 10(c) is a graph showing sexual enjoyment (with a partner) scores on days 0
through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0
g/day of AndroGel*, or the testosterone patch.
FIG. 11 (a) is a graph showing sexual performance scores on days 0 through 180
for hypogonadal men receiving either 5.0 g/day of AndroGel*1, 7.5 g/day 10.0 g/day of
AndroGel*, or the testosterone patch.
FIG. 11 (b) is a graph showing erection satisfaction performance scores on days 0
through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0
g/day of AndroGel*, or the testosterone patch.
FIG. 1 l(c) is a graph showing percent erection scores on days 0 through 180 for
hypogonadal men receiving either 5.0 g/day of AndroGel®, 7.5 g/day 10.0 g/day of
AndroGel , or the testosterone patch.
DETAILED DESCRIPTION OF THE INVENTION
While the present invention may be embodied in many different forms, several
specific embodiments are discussed herein with the understanding that the present
disclosure is to be considered only as an exemplification of the principles of the invention,
and it is not intended to limit the invention to the embodiments illustrated.
The present invention is directed to a pharmaceutical composition for percutaneous
administration comprising testosterone in a hydroalcoholic gel useful for treating erectile
dysfunction and libido deficiencies. In a broad aspect of the invention, other steriods in
the testosterone anabolic or catabolic pathway may be used (e.g. androstenedione,
androstenediol, dehydroepiandrosterone, prenenolone, and DHT). The gel comprises one
or more lower alcohols, such as ethanol or isopropanol; a penetration enhancing agent: a
thickener; and water. Additionally, the present invention may optionally include salts,
emollients, stabilizers, antimicrobials, fragrances, and propellants.
A "penetration enhancer" is an agent known to accelerate the delivery of the drug
through the skin. These agertts also have been referred to as accelerants, adjuvants, and
sorption promoters, and are collectively referred to herein as "enhancers." This class of
agents includes those with diverse mechanisms of action including those which have the
function of improving the solubility and diffusibility of the drug, and those which improve
percutaneous absorption by changing the ability of the stratum comeum to retain moisture,
softening the skin, improving the skin's permeability, acting as penetration assistants or
hair-follicle openers or changing the state of the skin such as the boundary layer.
The penetration enhancer of the present invention is a functional derivative of a
fatty acid, which includes isosteric modifications of fatty acids or non-acidic derivatives of
the carfaoxylic functional group of a fatty acid or isosteric modifications thereof. In one
embodiment, the functional derivative of a fatty acid is an unsaturated alkanoic acid in
which the —COOH group is substituted with a functional derivative thereof, such as
alcohols, polyols, amides and substituted derivatives thereof. The term "fatty acid" means
a fatty acid that has four (4) to twenty-four (24) carbon atoms.
Non-limiting examples of penetration enhancers include C8-C22 fatty acids such
as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl
alcohol and lauryl alcohol: lower alkyl esters of C8-C22 fatty acids such as ethyl oleate,
isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C8
diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as
glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene
glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether;
[&
alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers;
polyethylene oxide dimethyl ethers; dimethyl sulfoxide; glycerol; ethyl acetate;
acetoacetic ester; N-alkylpyrrolidone; and terpenes.
The thickeners used herein may include anionic polymers such as polyacrylic acid
(CARBOPOL® by Btf. Goodrich Specialty Polymers and Chemicals Division of
Cleveland, Ohio), carboxymethylcellulose and the like. Additional thickeners, enhancers
and adjuvants may generally be found in Remington's The Science and Practice of
Pjiarmacy. Meade Publishing Co., United States Phqirrtacopeia/National Forpiulary.
The composition is used in a "pharmacologically effective amount." This means
that the concentration of the testosterone is such that in the composition it results in a
therapeutic level of drug delivered over the term that the gel is to be used. Such delivery
is dependent on a number of variables including the time period for which the individual
dosage unit is to be used, the flux rate of the testosterone from the gel, surface area of
application site, etc. The amount of testosterone necessary can be experimentally
determined based on the flux rate of the drug through the gel, and through the skin when
used with and without enhancers.
One such testosterone gel has only recently been made available in the United
States under the trademark AndroGel® by Unimed Pharmaceuticals, Inc., Deerfleld,
Illinois, the assignee of this application. In one embodiment, the gel is comprised of the
following substances in approximate amounts:
Table 3: Composition of AndroGel*
SUBSTANCE
Testosterone
Carbopol 980
Isopropyl myristate
O.lNNaOH
AMOUNT (w/w)
PERlOOgOFGEL
1.0s
0.90 B
0.50 g
4.72?
SUBSTANCE
Ethanol (95% w/w)
Purified water (qsf)
AMOUNT (w/w)
PERlOOgOFGEL
72.5 E*
100s
*Corresponding to 67 g of ethanol.
One skilled in the art will appreciate that the constituents of this formulation may
be varied in amounts yet continue to be within the spirit and scope of the present
invention. For example, the composition may contain about 0.1 to about 10.0 g of
testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl
rayristate, and about 30.0 to about 98.0 g ethanol,
A therapeutic ally effective amount of the gel is rubbed onto a given area of skin by
the user. The combination of the lipophilic testosterone with the hydroalcoholic gel helps
drive the testosterone in to the outer layers of the skin where it is absorbed and then slowly
released into the blood stream. As demonstrated by the data presented herein, the
administration of the gel of the present invention has a sustained effect.
Toxicity and therapeutic efficacy of the testosterone can be determined by standard
pharmaceutical procedures, e.g., for determining LDso (the dose lethal to 50% of the
population) and the EDso (the dose therapeutically effective in 50% of the population).
The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be
expressed as the ratio LDso/EDso. Compounds which exhibit large therapeutic induces are
preferred. While compounds that exhibit toxic side effects may be used, care should be
taken to design a delivery system that targets such compounds to the site of affected tissue
in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
The present invention is further illustrated by the following examples, which
should not be construed as limiting in any way. The contents of all cited references
throughout this application are hereby expressly incorporated by reference. The practice
of the present invention will employ, unless otherwise indicated, conventional techniqu
of pharmacology and pharmaceutics, which are within the skill of the art.
EXAMPLES
Example 1; Method Of Improving Sexual Performance and Increasing Li
es
Hvoonadal
ing Libido in
One embodiment of the present invention involves the transdermal application of
AndroGel as a method of increasing sexual performance and libido in hypogonadal men
without causing significant skin irritation.
.*
In this example, hypogonadal men were recruited and studied in 16 centers in the
United States. The patients were between 19 and 68 years and had single morning serum
testosterone levels at screening of less than or equal to 300 ng/dL (10.4 nmol/L ). A total
of 227 patients were enrolled: 73, 78, and 76 were randomized to receive 5.0 g/day of
AndroGel'® (delivering 50 mg/day of testosterone to the skin of which about 10% or 5 mg
is absorbed), 10.0 g/day of AndroGel® (delivering 100 mg/day of testosterone to the skin
of which about 10% or 10 mg is absorbed), or the ANDRODERM* testosterone patch ("T
patch"; delivering 50 mg/day of testosterone), respectively.
As shown in the following table, there were no significant group-associated
differences of the patients' characteristics at baseline.
Table 4. Baseline Characteristics of the Hypogonadal Men
Treatment Group
No of subjects enrolled
Age (years)
Range (years)
Height (cm)
Weight (kg)
Serum testosterone (nmol/L")
Causes of hypoeonadism
T patch
76
51.1
28-67
179.3 ±0.9
92.7 ±1.6
6.40 ±0.41
AndroGel*
(5.0 g/day)
73
51.3
23-67
175.8 ±0.8
90.5 ±1.8
6.44 ±0.39
AndroGel*
(10.0 g/day)
78
51.0
19-68
178.6±0.8
91.6 ±1.5
6.49 ±0.37
Treatment Group
Primary hypogonadism
Klinefelter's Syndrome
Post Orchidectomy/Anorchia
Primary Testicular Failure
Secondary hypogonadism
Kallman's Syndrome
Hypothalimic Pituitary Disorder
Pituitary Tumor
Aging
Not classified
Years diagnosed
Number previously treated with
testosterone
Type of Previous Hormonal Treatment
Intramuscular injections
Transdermal patch
All others
Duration of treatment (years)
T patch
34
9
2
. 23
15
2
6
7
6
21
5.8±1.1
50 (65.8%)
26
12
12
5.8 ± 1.0
AndroGel*
(5.0 g/dav)
26
5
1
20
17
2
6
9
13
17
4.4 ±0.9
38(52.1%)
20
7
11
5.4 ± 0.8
AndroGel*
(lO.Oq/dav)
34
8
3
23
12
0
3
9
6
26
5.7 ± 1.24
46 (59.0%)
28
8
10
4.6 ±80. 7
Forty-one percent (93/227) of the subjects had not received prior testosterone
replacement therapy. Previously treated hypogonadal men were withdrawn from
testosterone ester injection fot at least six weeks and oral or transdermal androgens for
four weeks before the screening visit. Aside from the hypogonadism, the subjects were in
good health as evidenced by medical history, physical examination, complete blood count,
urinalysis, and serum biochemistry. If the subjects were on lipid-lowering agents or
tranquilizers, the doses were stabilized for at least three months prior to enrollment. Less
than 5% of the subjects were taking supplemental calcium or vitamin D during the study.
The subjects had no history of chronic medical illness, alcohol or drug abuse. They had a
normal rectal examination, a PSA level of less than 4 ng/mL, and a urine flow rate of 12
mL/s or greater. Patients were excluded if they had a generalized skin disease that might
affect the testosterone absorption or prior history of skin irritability with ANDRODERM*
patch. Subjects weighing less than 80% or over 140% of their ideal body weight were also
excluded.
The randomized, multi-center, parallel study compared two doses of AndroGel
with the ANDRODERM® testosterone patch. The study was double-blind with respect to
the AndroGel' dose and open-labeled for the testosterone patch group. For the first three
months of the study (days 1 to 90), the subjects were randomized to receive 5.0 g/day of
AndroGel , 10.0 g/day of AndroGel®, or two non-scrotal patches. In the following three
months (days 91 to 180), the subjects were administered one of the following treatments:
5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, 7.5 g/day of AndroGel*, or two nonscrotal
patches. Patients who were applying AndroGel* had a single, pre-application
serum testosterone measured on day 60 and, if the levels were within the normal range of
300 to 1,000 ng/dL (10.4 to 34.7 nmol/L ), then they remained on their original dose.
Patients with testosterone levels less than 300 ng/dL and who were originally assigned to
apply 5.0 g/day of AndroGel* and those with testosterone levels more than 1,000 ng/dL
who had received 10.0 g/day of AndroGel® were then reassigned to administer 7.5 g/day
^
of AndroGel* for days 91 to 180.
Accordingly, at 90 days, dose adjustments were made in the AndroGel* groups
based on the pre-application serum testosterone levels on day 60. Twenty subjects in the
5.0 g/day AndroGel® group had the dose increased to 7.5 g/day. Twenty patients in the
10.0 g/day AndroGel* group had the AndroGel® dose reduced to 7.5 g/day. There were
three patients in the testosterone patch group who were switched to 5.0 g/day AndroGel
because of patch intolerance. One 10.0 g/day AndroGel* subject was adjusted to receive
5.0 g/day and one 5.0 g/day AndroGel® subject had the dose adjusted to 2.5 g/day. The
number of subjects enrolled into day 91 to 180 of the study thus consisted of 51 receiving
J8
5.0 g/day of AndroGel®, 40 receiving 7.5 g/day of AndroGel*, 52 receiving 10.0 g/day of
AndroGel®, and 52 continuing on the ANDRODERM® patch. The treatment groups in
this example may thus be characterized in two ways, either by "initial" or by the "final"
treatment group. Subjects returned to the study center on days 0, 30, 60, 90,120, 150, and
180 for a clinical examination, skin irritation and adverse event assessments.
A. AndroGel* and ANDRODERM* patch
Approximately 250 g of AndroGel8 was packaged in multidose glass bottles that
delivered 2.25 g of the gel for each actuation of the pump. Patients assigned to apply 5.0
g/day of Androgel® testosterone were given one bottle of AndroGel* and one bottle of
placebo gel (containing vehicle but no testosterone), while those assigned to receive 10.0
g/day of AndroGel® were dispensed two bottles of the active AndroGel®. The patients
were then instructed to apply the bottle contents to the right and left upper arms/shoulders
and to the right and left sides of the abdomen on an alternate basis. For example, on the
first day of the study, patients applied two actuations from one bottle, one each to the left
and right upper arm/shoulder, and two actuations from the second bottle, one each to the
left and right abdomen. On the following day of treatment, the applications were reversed.
Alternate application sites continued throughout the study. After application of the gel to
the skin, the gel dried within a few minutes. Patients washed their hands thoroughly with
soap and water immediately after gel application.
The 7.5 g/day AndroGel® group received their dose in an open-label fashion. After
90 days, for the subjects titrated to the AndroGel8 7.5 g/day dose, the patients were
supplied with three bottles, one containing placebo and the other two AndroGel . The
subjects were instructed to apply one actuation from the placebo bottle and three
actuations from a AndroGel* bottle to four different sites of the body as above. The sites
were rotated each day taking the same sequence as described above.
ANDRODEKM® testosterone patches each delivering 2.5 mg/day of testosterone
were provided to about one-third of the patients in the study. These patients were
instructed to apply two testosterone patches to a clean, dry area of skin on the back,
abdomen, upper arms, or thighs once per day. Application sites were rotated with
approximately seven days interval between applications to the same site.
On study days when the patients were evaluated, the gel/patches were applied
following pre-dose evaluations. On the remaining days, the testosterone gel or patches
were applied at approximately 8:00 a.m. for 180 days.
B. Study Method and Results
1. Hormone Pharmacokinetics
On days 0, 1, 30, 90, and 180, the patients had multiple blood samples for
testosterone and free testosterone measurements at 30, 15 and 0 minutes before and 2, 4, 8,
12, 16, and 24 hours after AndroGel® or patch application. In addition, subjects returned
on days 60, 120, and 150 for a single blood sampling prior to application of the gel or
»
patch. Serum DHT, E2, FSH, LH and SHBG were measured on samples collected before
gel application on days 0, 30, 60, 90, 120, 150, and 180. Sera for all hormones were
stored frozen at -20 °C until assay. All samples for a patient for each hormone were
measured in the same assay whenever possible. The hormone assays were then measured
at the Endocrine Research Laboratory of the UCLA-Harbor Medical Center.
The following table summarizes the pharmacokinetic parameters were measured
for each patient:
2,0
Table 5: Pharmacokinetic Parameters
AUCo-24
Cbase OF C0
v^avg
»-TTHU
Cmjn
Tmax
T*
mm
Fluctuation
Index
Accumulation
ratio
Net AUCo-24
area under the curve from 0 to 24 hours, determined using the linear
trapezoidal rule.
Baseline concentration
time-averaged concentration over the 24-hour dosing interval determined
by AUCo.24/24
maximum concentration during the 24-hour dosing interval
minimum concentration during the 24-hour dosing interval
time at which Cmax occurred
time at which Cmjn occurred
extent of variation in the serum concentration over the course of a single
day, calculated as (CTOX -Cmm)/Cavg
increase in the daily drug exposure with continued dosing, calculated as
the ratio of the AUC at steady on a particular day over the AUC on day 1
(£?.£., AUCday30/AUCd.yl)
AUCo-24 on days 30, 90, 180 - AUC0.24 on day 0
a. Testosterone Pharmacokinetics
(1) Methods
Serum testosterone levels were measured after extraction with ethylacetate and
hexane by a specific radioimmunoassay ("RIA") using reagents from ICN (Costa Mesa,
CA). The cross reactivities of the antiserum used in the testosterone RIA were 2.0% for
DHT, 2.3% for androstenedione, 0.8% for 3-p-androstanediol, 0.6% for etiocholanolone
and less than 0.01% for all other steroids tested. The lower limit of quantitation ("LLQ")
for serum testosterone measured by this assay was 25 ng/dL (0.87 nmol/L). The mean
accuracy of the testosterone assay, determined by spiking steroid free serum with varying
amounts of testosterone (0.9 nmol/L to 52 nmol/L), was 104% and ranged from 92% to
117%. The intra-assay and inter-assay coefficients of the testosterone assay were 7.3 and
11.1%, respectively, at the normal adult male range. In normal adult men, testosterone
2.1
concentrations range from 298 to 1,043 ng/dL (10.33 to 36.17 nmol/L) as determined at
the UCLA-Harbor Medical Center.
(2) Baseline Concentration
As shown in Table 6(a)-6(b) and FIG. l(a), at baseline, the average serum
testosterone concentrations over 24 hours (Cavg) were similar in the groups and below the
adult normal range. Moreover the variations of the serum concentration (based on
maximum and minimum concentrations during the 24-hour period, C,™ and (_,,„,,,
respectively) during the day were also similar in the three groups. FIG. l(a) shows that
the mean testosterone levels had a the maximum level between 8 to 10 a.m. (i.e., at 0 to 2
hours) and the minimum 8 to 12 hours later, demonstrating a mild diurnal variation of
serum testosterone. About one-third of the patients in each group had Cavg within the
lower normal adult male range on day 0 (24/73 for the 5.0 g/day AndroGel* group, 2£/78
for the 10.0 g/day AndroGelfi group, and 25/76 for testosterone patch group). AH except
three of the subjects met the enrollment criterion of serum testosterone less than 300 ng/dL
(10.4 runol/L) on admission.
Table 6(a): Baseline Phamacokinetic Parameters
by Initial Treatment Group (Mean ± SD)
N
CJV1( (ng/dL)
Cm,, (ng/dL)
Tm«*(hr)
Cmin (ng/dL)
Tmh* (hr)
Flue Index (ratio)
5.0g/davT-Gel
73
237 ±130
328 ±178
4.0 (0.0-24.5)
175 ±104
8.01 (0.0-24.1)
0.627 ± 0.479
10.0 g/day T-gel
78
248 ±140
333 ± 194
7.9 (0.0-24,7)
188* 112
8.0 (0.0-24.0)
0.556 ±0.384
T-patch
76
237 ±139
314± 179
4.0 (0.0-24.3)
181±112
8.0 (0.0-23.9)
0.576 ±0.341
*Median (Range*)
Table 6(h): Baseline Testosterone Pharmacokinetic Parameters
by Final Treatment Group (Mean ± SD)
N
C,y, (ng/dL)
C^ (ng/dL)
T^* (hr)
Cmm (n.g/dL)
Tmm« (hr)
Flue Index (ratio)
Doses Received During Initial •*> Extended Treatment Phases
5.0 g/day
T-Eel
53
247 ±137
333 ±180
4.0(0.0-24.5)
1 85 ± 1 1 1
8.0(0.0-24.1)
0.600 ±0.471
5.0 -> 7.5 g/dav
T-eel
20
2121109
313 ± 174
4.0 (0.0-24.0)
150 ±80
11.9(0.0-24.0)
0.699 ± 0.503
1 0.0 -> 7.5 g/day
T-j-el
20
282±157
408 ±241
19.7 {0.0-24.3)
206 ± 130
8.0 (0.0-23.3)
0.678 ±0.580
10.0 g/day
T-eel
58
236 ± 133
307 ± 170
4.0 (0.0-24.7)
1 82 ± 1 06
8.0(0.0-24.0)
0.514x0.284
T-patch
76
237- 140
314± 179
4.0 (0.0-24.3)
181 ± 112
8.0(0.0-23.9)
0.57610.341
*Median (range)
(3) Day 1
FIG. l(b) and Tables 6(c)-(d) show the pharmacokinetic profile for all three initial
treatment groups after the first application of transdermal testosterone. In general,
treatment with AndroGel® and the testosterone patch produced increases in testosterone
concentrations sufficiently large to bring the patients into the normal range in just a few
hours. However, even on day I, the pharmacokinetic profiles were markedly different in
the AndroGel* and patch groups. Serum testosterone rose most rapidly in the testosterone
patch group reaching a maximum concentration (Cmax) at about 12 hours (In™). In
contrast, serum testosterone rose steadily to the normal range after AndroGel application
with C^ax levels achieved by 22 and 16 hours in the 5.0 g/day AndroGel^ group and the
10.0 g/day AndroGel* group, respectively.
Table 6(c): Testosterone Pharmacokinetic Parameters on Day 1
by Initial Treatment Group (Mean ± SD)
N
C,™ C™» (njr/dU
5.0 g/dav T-Gel
73
398 + 156
560 + 269
10.0 g/dav T-gel
76
5 14 ±227
748 ± 349
T-patch
74
482 ± 204
645 ± 280
Tm^Oir)
Cmin (ng/dL)
Tmin* (hr)
5.0 R/dav T-Gel
22.1 (0.0-25.3)
228 ±122
1.9(0.0-24.0)
10.0 g/dav T-gcl
16.0(0.0-24.3)
250 ± 143
0.0 (0.0-24.2)
T-patch
11.8(1.8-24.0)
232+132
1.5(0.0-24.0)
*Median (Range)
Table 6(d): Testosterone Phamacokinetic Parameters on Day 1
by Final Treatment Group (Mean ± SD)
N
C,v, (ng/dL)
C™ (ns/dL)
TMJ,*(hr)
Cn,,.(ng/dU
T™* (hr)
Flue Index (ratio)
Doses Received During Initial •> Extended Treatment Phases
5.0 g/day
T-gel
53
41 I t 160
5731285
22.1 (0.0-25.3)
2371125
1.8(0.0-24.0)
0.600 ±0.471
5.0 -> 7.5 g/day
T-eel
20
363 ±143
525 ±223
19.5(1.8-24.3)
204±112
3.5 (0.0-24.0)
0.699 ±0.503
10.0-0 7.5 g/day
T-gel
19
554 ±243
819±359
15.7(3.9-24.0)
265 ±154
1.9(0.0-24.2)
0.678 ±0.580
10.0 g/day
T-gel
57
500 ± 223
724 ± 346
23.0 (0.0-24.3)
245 ±140
0.0 (0.0-23.8)
0.514 ±0.284
T-patch
74
482±2C4
645 ±280
I I . 8 (1.8-24.0)
232 ± 1 3 2
1.5 (0.0-24.0)
0.576 + 0.341
*Median (range)
(4) Days 30,90, and 180
FIGS. l(c) and l(d) show the unique 24-hour pharmacokinetic profile of
AndroGel^-treated patients on days 30 and 90. In the AndroGel* groups, serum
testosterone levels showed small and variable increases shortly after dosing. The levels
then returned to a relatively constant level. In contrast, in the testosterone patch group,
patients exhibited a rise over the first 8 to 12 hours, a plateau for another 8 hours, and then
a decline to the baseline of the prior day. Further, after gel application on both days 30
and 90, the Cavg in the 10.0 g/day AndroGel® group was 1.4 fold higher than in the 5.0
g/day AndroGel* group and 1.9 fold higher than the testosterone patch group. The
testosterone patch group also had a Cmin substantially below the lower limit of the normal
range. On day 30, the accumulation ratio was 0.94 for testosterone patch group, showing
no accumulation. The accumulation ratios at 1.54 and 1.9 were significantly higher in the
5.0 g/day AndroGel* group and 10.0 g/day AndroGel* group, respectively. The
differences in accumulation ratio among the groups persisted on day 90. This data
indicates that the AndroGel1 preparations had a longer effective half-life than testosterone
patch.
FIG. l(e) shows the 24-hour pharmacokinetic profile for the treatment groups on
day 180. In general, as Table 6(e) shows, the serum testosterone concentrations achieved
and the pharmacokinetic parameters were similar to those on days 30 and 90 in those
patients who continued on their initial randomized treatment groups. Table 6(f) shows
that the patients titrated to the 7.5 g/day AndroGel® group were not homogeneous. The
patients that were previously in the 10.0 g/day group tended to have higher serum
testosterone levels than those previously receiving 5.0 g/day. On day 180, the Cavg in the
patients in the 10.0 g/day group who converted to 7.5 g/day on day 90 was 744 ng/dL,
which was 1.7 fold higher than the. Cavg of 450 ng/dL in the patients titrated to 7.5 g/day
from 5.0 g/day. Despite adjusting the dose up by 2.5 g/day in the 5.0 to 7.5 g/day group,
the Cavg remained lower than those remaining in the 5.0 g/day group. In the 10.0 to 7.5
g/day group, the C,vg became similar to those achieved by patients remaining in the 10.0
g/day group without dose titration. These results suggest that many of the underresponders
may actually be poorly compliant patients. For example, if a patient does not
apply AndroGelp properly (e.g., preferentially from the placebo container or shortly
before bathing), then increasing the dose will not provide any added benefit.
FIGS. l(f)-(b) compare the pharmacokinetic profiles for the 5.0 g/day AndroGel*
group, the 10.0 AndroGel® g/day group, and the testosterone patch group at days 0, 1, 30,
90, and 180. In general, the mean serum testosterone levels in the testosterone patch
group remained at the lower limit of the normal range throughout the treatment period. In
contrast, the mean serum testosterone levels remained at about 490-570 ng/dL for the 5.0
g/day AndroGel* group and about 630-860 ng/dL AndroGel6 for the 10.0 g/day group.
Table 6(e): Testosterone Phamacokinetic Parameters on Day 1
by Initial Treatment Group (Mean ± SD)
Day 30
Civi (ng/dL)
Cmi, (ng/dL)
Tm,x*(hr)
Cn,in (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
Day 90
CW| (ng/dL)
Cm,x (ng/dL)
Tm«*(hr)
C™ (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
Day 180
Civ| (ng/dL)
C™ (ng/dL)
Tnux*(hr)
Cmin (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
5.0g/davT-Gel
N = 66
566 ±262
876 + 466
7.9 (0.0-24.0)
361 + 149
8.0(0.0-24.1)
0.857 + 0.331
1.529+0.726
N = 65
553 + 247
846+444
4.0(0.0-24.1)
354 + 147
4.0 (0.0-25.3)
0.851 +0.402
1.615 ±0.859
N = 63
520+227
779 ±359
4.0 (0.0-24.0)
348 + 164
11.9(0.0-24.0)
0.845 + 0.379
1.523 + 1.024
10.0 g/dav T-ee]
N = 74
792 ± 294
1200 + 482
7.8 (0.0-24.3)
505 + 233
8.0 (0.0-25.8)
0.895 + 0.434
1.911 ±1.588
N = 73
792 + 276
1204 + 570
7.9 (0.0-25.2)
501 ±193
8.0 (0.0-24.8)
0.859 + 0.399
1.927+ 1.310
N = 68
722 + 242
1091+437
7.9 (0.0-24.0)
485+184
11.8(0.0-27.4)
0.829 + 0.392
1.897±2.123
T-patch
N-70
419+163
576 + 223
11.3(0.0-24.0)
235 + 122
2.0 (0.0-24.2)
0.823 + 0.289
0.937 + 0.354
N = 64
417+157
597 + 242
8.1 (0.0-25.0)
213+105
2.0 (0.0-24.0)
0.937 ± 0.442
0.971 ±0.453
N = 45
• 403 + 163
580 + 240
10.0(0.0-24.0)
223 + 114
2.0 (0.0-25.7)
0.891 ±0.319
0.954 ±0.4105
*Median (Range)
Table 6(1): Testosterone Pbamacokinetic Parameters on Days 30,90,
by Final Treatment Group (Mean ± SD)
180
Doses Received During Initial »> Extended Treatment Phases
S.Og/day 5.0 -> 7.5 g/dav 10.0 -> 7.5 g/dav lO.Og/day
T-gtl T-eel " T-gel T-Rel l~p"ftt
Day 30
CJV1 (ng/dL)
Q*»i (ng/dL)
T^* (hr)
C™ (ng/dL)
T,™,- (hr)
Flue Index (ratio)
Accum Ratio (ratio)
Diy90
C,V| (ng/dL)
C™ (ng/dL)
?,«,• (hr)
C™. (ng/dL)
Tmi,* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
N-47
604 ± 288
941 ±509
7.9 (0.0-24.0)
387 ±159
8.1 (0.0-24.1)
0.861 ±0.341
1.543 ±0.747
N = 45
596 ±266
931 ±455
3.8(0.0-24.1)
384 ±147
7.9 (0.0-25.3)
0.886 ±0.391
1.593 ±0.8 13
N- 19
472 ±148
71 6 ±294
8.0(0.0-24.0)
296 ±97
1.7(0.0-24.1)
0.846 ±0.3 15
1.494 ±0.691
N-20
455 ±164
654 ±359
7.7 (0.0-24.0)
286 ±125
0.0 (0.0-24.0)
0.771 ±0.425
1.737*1.145
N-19
946 ± 399
1409 ±556
8.0 (0.0-24.3)
600 ±339
11.4(0.0-24.1)
0.927 ± 0.409
2.053 ±1.393
N = I 8
859 ± 298
1398 ±733
7.9 (0.0-24.0)
532 ±181
12.0(0.0-24.1)
0.959 ±0.490
1.752 ±0.700
N = 55
739 ± 230
1 128 ±436
7.8(0.0-24.3)
471 ± 175
8.0 (0.0-25.8)
0.884 ± 0.445
1.864 ±1.657
N-55
77I±26g
1141 ±498
7.9 (0.0-25.2)
492 ±197
4.0(0.0-24.8)
0.826 ±0.363
1.952 ±1.380
N-70
4l9i 163
576 ± 223
11.3(0.0-24.0)
235 ± 122
2.0 (0.0-24.2)
0.823 ± 0.289
0.937 ±0.354
N = 64
417x 157
597 ±242
8.1 (0.0-25.0)
213 ± 105
2.0 (0.0-24.0)
0.937 ± 0.442
0.971 ±0.453
Doses Received During Initial -> Extended Treatment Phases
5.0 g/day 5.0 -> 7.S g/dav I0.0=>7.5g/day 10.0 g/day
T-eel T-Eel ' T-«l T-i>el T-Patch
Day 180
€„, (ng/dL)
C™ (ng/dL)
T™' (hr)
Cmin (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
N-44
555 ± 225
803 ± 347
5,8(0.0-24.0)
371 ± 165
11.9(0.0-24.0)
0.853 ± 0.402
1.541 ±0.917
N-18
450±2I9
680 ± 369
2.0 (0.0-24.0)
302 ±150
9.9(0.0-24.0)
0.833 ±0.335
NA
N-19
744 ±320
11 10 ±468
7.8 (0.0-24.0)
5 05 ±233
12.0(0.0-24.0)
0.824 ±0.298
NA
N=48
713±209
1083 ±434
7.7 (0.0-24.0)
485 ± 156
8.0 (0.0-27.4)
0.81 8 ±0.421
2.061 ±2.445
N = 41
408 ± 105
578 ±245
10.6(0.0-24.0)
222 ± 116
2.0(0.0-25.7)
0.866 ±0.3 I I
0.969 + 0.4 15
*Median (range)
(5) Dose Proportionality for AndroGel®
Table 6(g) shows the increase in AUCo,24 on days 30, 90, and 180 from the
pretreatment baseline (net AUCo-24) as calculated using an arithmetic mean. In order to
assess dose-proportionality, the bioequivalence assessment was performed on the logtransformed
AUCs using "treatment" as the only factor. The AUCs were compared after
subtracting away the AUC contribution from the endogenous secretion of testosterone (the
AUC on day 0) and adjusting for the two-fold difference in applied doses. The AUC ratio
on day 30 was 0.95 (90% C.I.: 0.75-1.19) and on day 90 was 0.92 (90% C.I.: 0.73-1.17).
When the day 30 and day 90 data was combined, the AUC ratio was 0.93 (90% C.I.: 0.79-
1.10).
The data shows dose proportionality for AndroGel® treatment. The geometric
mean for the increase in AUCo-24 from day 0 to day 30 or day 90 was twice as great for the
10.0 g/day group as for the 5.0 g/day group. A 125 ng/dL mean increase in serum
testosterone Cavg level was produced by each 2.5 g/day of AndroGel®. In other words, the
data shows that 0.1 g/day of AndroGel® produced, on the average, a 5 ng/dL increase in
serum testosterone concentration. This dose proportionality aids dosing adjustment by the
physician. Because AndroGel* is provided in 2.5 g packets (containing 25 mg of
testosterone), each 2.5 g packet will produce, on average, a 125 ng/dL increase in the Cjvg
•
for serum total testosterone.
Table 6(g): Net AUQ-24 (nmol*h/L) on Days 30,90, and 180
after Transdermal Testosterone Application
Day 30
Day 90
Day 180
T Patch
154±18
157 ±20
160 ±25
T gel 5.0 g/day
268 ± 28
263 ± 29
250 ± 32
T gel 10.0 g/day
446 ±30
461 ±28
401 ± 21
The increase in AUC0-24 from pretreatment baseline achieved by the 10.0 g/day and
the 5.0 g/day groups were approximately 2.7 and 1.7 fold higher than that resulting from
application of the testosterone patch. These figures also indicate that an ANDRODEKM1
patch, which produces an approximately 180 ng/dL increase in Cavg, is equivalent to
approximately 3.5 g/day of AndroGel®.
b. Pharmacokinetics of Serum Free Testosterone
Concentration
(1) Methods
Serum free testosterone was measured by RIA of the dialysate, after an overnight
equilibrium dialysis, using the same RIA reagents as the testosterone assay. The LLQ of
serum free testosterone, using the equilibrium dialysis method, was estimated to be 22
pmol/L. When steroid free serum was spiked with increasing doses of testosterone in the
adult male range, increasing amounts of free testosterone were recovered with a
coefficient of variation that ranged from 11.0-18.5%. The intra- and interassay
coefficients of free testosterone were 15% and 16.8% for adult normal male values,
respectively. As estimated by the UCLA-Harbor Medical Center, free testosterone
concentrations range from 3.48-17.9 ng/dL (121-620 pmol/L) in normal adult men.
(2) Pharmacoklnetic Results
In general, as shown in Table 7, the pharmacokinetic parameters of serum free
testosterone mirrored that of serum total testosterone as described above. At baseline (day
0), the mean serum free testosterone concentrations (C,vg) were similar in all three groups
which were at the lower limit of the adult male range. The maximum serum free
testosterone concentration occurred between 8 and 10 a.m., and the minimum about 8 to
16 hours later. This data is consistent with the mild diurnal variation of serum
testosterone.
FIG. 2(a) shows the 24-hour pharmacokinetic profiles for the three treatment
groups on day 1, After application of the testosterone patch, the serum free testosterone
levels peaked at 12 hours about 4 hours earlier than those achieved by the AndroGel*
groups The serum free testosterone levels then declined in the testosterone patch group
whereas in the AndroGelE groups, the serum free testosterone levels continued to rise.
FIGS. 2(b) and 2(c) show the pharmacokinetic profiles of free testosterone in the
AndroGel^-treated groups resembled the unique testosterone profiles on days 30 and 90.
After AndroGel* application, the mean serum free testosterone levels in the three groups
were within normal range. Similar to the total testosterone results, the free testosterone
CBVg achieved by the 10.0 g/day group was 1.4 fold higher than the 5.0 g/day group and 1.7
fold higher than the testosterone patch group. Moreover, the accumulation ratio for the
testosterone patch was significantly less than that of the 5.0 g/day AndroGel* group and
the 10.0 g/day AndroGel^ group.
FIG. 2(d) shows the free testosterone concentrations by final treatment groups on
day 180. In general, the free testosterone concentrations exhibited a similar pattern as
serum testosterone. The 24-hour pharmacokinetic parameters were similar to those on
days 30 and 90 in those subjects who remained in the three original randomized groups.
Again, in the subjects titrated to receive 7.5 g/day of AndroGel*, the group was not
homogenous. The free testosterone Cavg in the patients with doses adjusted upwards from
5.0 to 7.5 g/day remained 29% lower than those of subjects remaining in the 5.0 g/day
group. The free testosterone C,vg in the patients whose doses were decreased from 10.0 to
7.5 g/day was 11% higher than those in remaining in the 10.0 g/day group.
FIGS. 2(e)-(g) show the free testosterone concentrations in the three groups of
subjects throughout the 180-day treatment period. Again, the free testosterone levels
followed that of testosterone. The mean free testosterone levels in all three groups were
within the normal range with the 10.0 g/day group maintaining higher free testosterone
levels than both the 5.0 g/day and the testosterone patch groups.
Table 7: Free Testosterone Pharmacokinetic Parameters
by Final Treatment (Mean ± SD)
Doses Received During Initial ->Extended Treatment Phases
5.0 g/day 5.0 -> 7.5 g/dav 1 0.0 -> 7.5 g/day 10/Og/dav
T-eel T-eel " T-eel Teel
Day 0
Cavg (ng/dL)
Cmax (ng/dL)
Tmax* (hr)
Cmin (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Day 1
Cavg (ng/dL)
Cmax (ng/dL)
Tmax* (hr)
Cmin (ng/dL)
Tmin' (hr)
Day 30
Cavg (ng/dL)
Cmax (ng/dL)
Tmax* (hr)
Cmin (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
Day 90
Cavg (ng/dL)
Cmax (ng/dL)
Tmax* (hr)
Cmin (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
N-53
4.52 ±3.35
5.98 ±4.25
4.0 (0.0-24.5)
3.23 ±2.74
8.0 (0.0-24.2)
0.604 ±0.342
N-53
7.50 ±4.83
10.86 ±7.45
16.0(0.0-25.3)
4.30 ±3.33
0.0(0.0-24.1)
N-47
1I.I2±6.22
l 8.0 (0.0-27.8)
6.99 ± 3.82
4.0 (0-0-24. 1 )
0.853 ±0.331
1 .635 ± 0.820
N-45
12. 12 ±7.78
18.75 ±12.90
4.0 (0.0-24.0)
7.65 ± 4.74
8.0 (0.0-24.0)
0.9 13 ±0.492
1.75510.983
N=-20
4.27 ±3.45
6.06 ± 5.05
2.0 (0.0-24.0)
3.10 ±2.62
9.9(0.0-16.0)
0.674 ±0.5 12
N-20
6.80 ±4.82
10.10 ±7.79
13.9(0.0-24.3)
3.69 ±3.24
1.8(0.0-24.0)
N-= 19
7.8113.94
11. 62 ±6.34
8.0(0.0-26.3)
4.78 ±3. 10
3.5 (0.0-24. 1 )
0.872 ±0.5 10
1 .479 ± 0.925
N = 20
8.06 ±3.78
10.76 ±4.48
9.7 (0.0-24.0)
4.75 ± 2.86
1.9(0.0-24.0)
0.8 15 ±0.292
I.9I6± 1.816
N = 20
4.64±3.10
6.91 ±4.66
13.5 (0.0-24.2)
3.14±2.14
4.0 (0.0-23.3)
0.756 ±0.597
N- 19
9.94 ±5. 04
15.36±7.31
15.7(2.0-24.0)
3.8S±2.73
0.0 (0.0-24.2)
N- 19
16.18±8.18
25.I4± 10.80
8.0 (0.0-24.3)
9.99 ±7. 19
11.4(0.0-24.1)
1.05 1 ±0.449
2.065 ±1.323
N - I S
17.65 ±8.62
25.29 ±12.42
8.0 (0.0-24.0)
10.56 ±6.07
5.9(0.0-24.1)
0.870 ±0.401
1.843 ±0.742
N = 58
4.20 ±3.33
5.84 ± 4.36
:.l (0.0-24.1)
3.12 ±2.68
S.O (0.0-24.0)
0.634 ± 0.420
N-57
8.93 ± 6.09
I3.20±8.6l
23.5ll.S-24.3l
4.40 ±3.94
0.0(0.0-23.9)
N-55
I3.37±7.13
19.36 ±9.75
8.0(0.0-24.3)
8.25 ± 5.22
7.8(0.0-25.8)
0.861 ±0.412
1 .953 t 1 .026
N-55
13.11 ±5.97
18.61 ±8.20
8.0(0.0-25.2)
8.40 ± 4.57
4.0(0.0-24.8)
0.812 ±0.335
2.075 ± 1.866
T-patch
N- 76
4.82 ± 3 . 64
6.57±4.90
3.8(0.0-24.0)
3.56 ±2.88
7.9 (0.0-24.0)
0.6)410.362
N-74
9.04 ±4.81
12.02 ±6. 14
12.0(1.8-24.0)
4.67 ±3.52
0.0(0.0-24.0)
N- 70
S.12±4.I5
11. 48 ±5.78
8.0(0.0-24.0)
4.31 ±3.20
2.0(0.0-24.8)
0.929 ±0.3 11
0.980±0.387
N - 64
8.50 ± 5.04
12.04 ±6. SI
11.6(0.0-25.0)
4.38 ± 3.70
2.0(0.0-24.1)
0.968 ± 0.402
1.054 ±0.498
Doses Received During Initial ->Extended Treatment Phases
5.0g/day 5.0 => 7.5 g/day 10.0 -> 7,5 g/day 10/Oe/day
T-erl T-e«l T-gel T gel
Day 180
Cavg (ng/dL)
Cmax (ng/dL)
Tmax* (hr)
Cmin (ng/dL)
Tmin* (hr)
Flue Index (ratio)
Accum Ratio (ratio)
N = 44
11.0115.24
16.2117.32
7.9 (0.0-24.0)
7.1813.96
9.9 (0.0-24.2)
0.897 ± 0.502
1.71211.071
N- 18
7.80 ± 4.63
11.3616.36
2.0 (0.0-23.9)
5.32 ±4.06
7.9 (0.0-24.0)
0.838*0.378
NA
N- 19
14.I4±7.73
22.561 12.62
7.8 (0.0-24.0)
9.54 ± 6.45
8.0 (0.0-23.2)
0.950 ±0.501
NA
N=48
12.7715.70
18.58 ±9.3 1
8.0(0.0-24.0)
8.2314.01
11.8(0.0-27.4)
0.81510.397
2.1341 1.989
T-patch
N = 41
7.25 1 4.90
10.1715.90
11.1 (0.0-24.0)
3.9014.20
2.5(0.0-25.7)
0.96710.370
1.001 10.580
'Median (Range)
c. Serum DHT Concentrations
Serum DHT was measured by RIA after potassium permanganate treatment of the
sample followed by extraction. The methods and reagents of the DHT assay were
provided by DSL (Webster, TX). The cross reactivities of the antiserum used in the RJA
for DHT were 6.5% for 3-p-androstanediol, 1.2% for 3-a-androstanediol, 0.4% for 3-aandrostanediol
glucuronide, and 0.4% for testosterone (after potassium permanganate
treatment and extraction), and less than 0.01% for other steroids tested. This low crossreactivity
against testosterone was further confirmed by spiking steroid free serum with 35
nmol/L (1,000 pg/dL) of testosterone and taking the samples through the DHT assay. The
results even on spiking with over 35 nrnol/L of testosterone was measured as less than 0.1
nmol/L of DHT. The LLQ of serum DHT in the assay was 0.43 nmol/L. The mean
accuracy (recovery) of the DHT assay determined by spiking steroid free serum with
varying amounts of DHT from 0.43 nmol/L to 9 nmol/L was 101% and ranged from 83 to
114%. The intra-assay and inter-assay coefficients of variation for the DHT assay were
7.8 and 16.6%, respectively, for the normal adult male range. The normal adult male
range of DHT was 30.7-193.2 ng/dL (1.06 to 6.66 nmol/L ) as determined by the UCLAHarbor
Medical Center.
As shown in Table 8, the pretreatment mean serum DHT concentrations were
between 36 and 42 ng/dL, which were near the lower limit of the normal range in all three
initial treatment groups. None of the patients had DHT concentrations above the upper
limit of the normal range on the pretreatment day, although almost half (103 patients) had
concentrations less than the lower limit.
FIG. 3 shows that after treatment, the differences between the mean DHT
concentrations associated with the different treatment groups were statistically significant,
with patients receiving AndroGel® having a higher mean DHT concentration than the
patients using the patch and showing dose-dependence in the mean serum DHT
concentrations. Specifically, after testosterone patch application mean serum DHT levels
rose to about 1.3 fold above the baseline. In contrast, serum DHT increased to 3.6 and 4.8
fold above baseline after application of 5.0 glday and 10.0 g/day of AndroGel1,
respectively.
Table 8: DHT Concentrations (ng/dL)
on Each of the Observation Days
By Initial Treatment (Mean ± SD)
5.0 g/dav
T-«H
I0,0j/d»v
T-gri
T-P»lch
Across RX
D«v 0
N«73
36.0 ±19.9
N-78
42.0 i 29.4
N-76
37.4 ±21.4
0.6041
Div30
N-69
11 7.6 ±74.9
N-78
200.4 ±127.8
N-73
50.8 ± 34.6
0.0001
Diy60
N-70
t22.4±99.4
N-74
222.0 ±126.6
N-68
49.3127.2
0.0001
D«v90
N-67
130. 1199.2
N-~5
207.7 ± 111.0
N-66
43.6 ±26.9
0.0001
DcvUO
N-65
121 .8 ±89.2
N»6g
187.3 ±97.3
N-49
53.0 ±52.8
0.0001
D»y ISO
N = 63
144.7 ±110.5
N-67
189.1 ±102.4
N-46
54.0 ±42.5
0.0001
Dav 180
N = 65
143.7 ± 105.9
N-71
206.1 I 105.9
N - 4V
52.1 ±34.3
0.0001
The increase in DHT concentrations are likely attributed to the concentration and
location of 5a-reductase in the skin. For example, the large amounts of 5a-reductase in
the scrotal skin presumably causes an increase in DHT concentrations in the
TESTODERM* patch. In contrast, the ANDRODERM* and TESTODERM TTSK
patches create little change in DTH levels because the surface area of the patch is small
and little 5a-reductase is located in nonscrotal skin. AndroGel® presumably causes an
increase in DHT levels because the gel is applied to a relatively large skin area and thus
exposes testosterone to greater amounts of the enzyme.
To date, elevated DHT levels have not been reported to have any adverse clinical
effects. Moreover, there is evidence to suggest that increased DHT levels may inhibit
prostate cancer.
d. DHTTT Ratio
The UCLA-Harbo* Medical Center reports a DHT/T ratio of 0.052-0.328 for
normal adult men. In this example, the mean ratios for all three treatments were within the
normal range on day 0. As shown in FIG. 4 and Table 9, there were treatment and
concentration-dependent increases observed over the 180-day period. Specifically, the
AjidroGel® treatment groups showed the largest increase in DHT/T ratio. However, the
mean ratios for all of the treatment groups remained within the normal range on all
observation days.
Table 9: DHT/T Ratio
on Each of the Observation Days
By Initial Treatment (Mean ± SD)
5.0 g/div
T-«tl
lO.Og/dtv
T-pel
T-Patth
Acroit RX
DtvO
N = 73
0.198 ±0.137
N-78
0.206 tO. 163
N-76
0.204 ±0.135
0.7022
D*v 30
Nf-68
0.230 ±0.104
N-77
0.26610.124
N "73
0.1 92 ±0.1 82
0.0001
Div60
N-70
0.256*0.132
N- 74
0.313 ±0.160
N-68
O.I7S ±0.102
0.0001
D«v90
N-67
0.248 ±0.1 21
N-74
0.30010.131
N-65
0.17510.092
0.0001
Dtv 110
N-65
0.26610.119
N-68
0.308 ±0.145
N -49
0.18610.134
0.0001
DivlSQ i Ua> 180
N-62
0.200 ±0.14?
N-07
0.335 ±0.142
N-46
0.223 + 0.147
0.0001
N = 64
0.27} ±0.100
N - 71
0.291 ±0.i;4
N =40
0.212 ±0.160
00002
e. Total Androgen (DHT + T)
The UCLA-Harbor Medical Center has determined that the normal total androgen
concentration is 372 to 1,350 ng/dL. As shown in FIG. 5 and Table 10, the mean pre-dose
total androgen concentrations for all three treatments were below the lower limit of the
normal range on pretreatment day 0. The total androgen concentrations for both
AndroGel1® groups were within the normal range on all treatment observation days. In
contrast, the mean concentrations for patients receiving the testosterone patch was barely
within the normal range on day 60 and 120, but were below the lower normal limit on
days 30, 90,150, and 180.
Table 10: Total Androgen (DHT +T) (ng/dL)
on Each of the Observation Days
By Initial Treatment (Mean ± SD)
5.0 g/d*v
T-gd
10.0 g/day
T-RtT
T-Patch
Across RX
DivO
N-73
2811150
N-78
307 ±180
N-76
282 ±159
0.7395
Dav 3d
N-68
659 ±398
N-77
974 ± 532
N-73
369 ± 206
0.000 1
Dav 60
N-70
6I7±429
N-74
1052 ±806
N-68
392 ± 229
0.0001
Dav90
N-67
690 ±431
N-74
921 ±420
N-65
330 ± 1 73
0.0001
Da v 120
N-65
574 ±331
N-68
827 ±361
N-49
378 ± 250
0.000 1
Dav 150
N-62
63 1 ± 384
N-67
805 + 383
N-46
364*220
00001
Dav 180
N -64
694 ± 4 1 2
N» 7]
944 ±432
N-46
355 ±202
0.0001
f. £2 Concentrations
Serum E2 levels were measured by a direct assay without extraction with reagents
from ICN (Costa Mesa, CA). The intra-assay and inter-assay coefficients of variation of
E2 were 6.5 and 7.1% respectively. The UCLA-Harbor Medical Center reported an
average £2 concentration ranging from 7.1 to 46.1 pg/mL (63 to 169 pmol/L) for normal
adult male range. The LLQ of the Ea was 18 pmol/L. The cross reactivities of the E?
antibody were 6.9% for estrone, 0.4% for equilenin, and less than 0.01% for all other
steroids tested. The accuracy of the £2 assay was assessed by spiking steroid free serum
with increasing amount of E2 (18 to 275 pmol/L). The mean recovery of E2 compared to
the amount added was 99.1% and ranged from 95 to 101%.
FIG. 6 depicts the E2 concentrations throughout the 180-day study. The
pretreatment mean E2 concentrations for all three treatment groups were 23-24 pg/mL.
During the study, the E2 levels increased by an average 9.2% in the testosterone patch
during the treatment period, 30.9% in the 5.0 g/day AndroGel® group, and 45.5% in the
10.0 g/day AndroGel® group. All of the mean concentrations fell within the normal range.
Table 11: Estradiol Concentration (pg/mL)
on Each of the Observation Days
By Initial Treatment (Mean ± SD)
5.0 g/d«y T-gel
lO.Og/day T-g«l
T-P»tch
Across RX
DavO
N-73
23.0 ±9.2
N-78
24.5 ± 9.5
N-76
23.8 t 8.2
0.6259 1
l)av 30
N-69
29.2 ±11.0
N-78
33.7 ±11.3
N-72
25-8 ±9.8
0.0001 1
Dav60
N-68
28.1 ± 10.0
N-74
36.5 ±13.5
N-68
74.8 ± 8.0
0.0001
Dav90
N-67
31.4111.9
N-75
37.8 ±13.3
N-66
25.7 ±9.8
0.0001
Davl20
N-64
28.8 ± 9.9
N-71
34 .6 ±10.4
N-50
25.7 S 9.4
0.0001
OavlSO
N-6S
30.8 ± I2.S
N-66
35.0 i I I . I
N-49
27.0 ±9.2
l)«v 180
N-05
32.3 ± 13.8
N - 7 1
36.3 ± 13.9
N-49
26.9 ±9.5
Ej is believed to be important for the maintenance of normal bone. In addition, EZ
has a positive effect on serum lipid profiles.
g. Serum SHBG Concentrations
Serum SHBG levels were measured with a fluoroimmunometric assay ("FIA")
obtained from Delfia (Wallac, Gaithersberg, MD). The intra- and interassay coefficients
were 5% and 12% respectively. The LLQ was 0.5 nmol/L. The UCLA-Harbor Medical
Center determined that the adult normal male range for the SHBG assay is 0.8 to 46.6
nmol/L.
As shown in FIG. 7 and Table 12, the serum SHBG levels were similar and within
the normal adult male range in the three treatment groups at baseline. None of the
treatment groups showed major changes from these the baseline on any of the treatment
visit days. After testosterone replacement serum SHBG levels showed a small decrease in
all three groups. The most marked change occurred in the 10.0 g/day AndroGel® group.
Table 12: SHBG Concentration (nmol/L)
on Each of the Observation Days
By Initial Treatment (Mean ± SD)
5.0 g/d»y
T-*el
lO.Og/diy
Tftl
T.P»tch
Across RX
D«v 0
N-73
26.2 ± 14.9
N-78
26.6 ± 17.8
N-76
30.2 ±22.6
0.3565
D.v 30
N-69
24.9 ± 14.0
N-78
^24.8 ± 14.5
N-72
28.4 ±21. 3
0.3434
D»v60
N-69
25.9 ± 14.4
N-75
25.2 + 15.5
N-68
28.2 + 23.8
0.5933
Dav 90
N-67
25,5 ±14.7
N-75
23.6 ±14.7
N-66
28.0 ±23.6
0.3459
D»v 120
N-66
25.2 ±14.1
N-72
25.5 1 16.5
N-50
26.7 ±16.0
0.8578
D«v ISO
N-6S
24.9 ±12.9
N-68
23.8 ± 12.5
N-49
26.7 ±16.4
0.5280
Dav 180
N-65
24.2 ±13.6
N-71
24.0 ±14.5
N-49
25.8 ±15.1
0.7668
h. Gonadotropins
Serum FSH and LH were measured by highly sensitive and specific solid-phase
FIA assays with reagents provided by Delfia (Wallac, Gaithersburg, MD). The intra-assay
coefficient of variations for LH and FSH fluroimmunometric assays were 4.3 and 5.2%,
respectively; and the interassay variations for LH and FSH were 11.0% and 12.0%,
respectively. For both LH and FSH assays, the LLQ was determined to be 0.2 IU/L. All
samples obtained from the same subject were measured in the same assay. The UCLA-
#
Harbor Medical Center reports that the adult normal male range for LH is 1.0-8.1 U/L and
forFSHisl.O-6.9U/L.
(1) FSH
Table 13(a)-(d) shows the concentrations of FSH throughout the 180-day treatment
depending on the cause of hypogonadism: (1) primary, (2) secondary, (3) age-associated,
or (4) unknown.
Patients with primary hypogonadism show an intact feedback mechanism in that
the low serum testosterone concentrations are associated with high FSH and LH
concentrations. However, because of testicular or other failures, the high LH
concentrations are not effective at stimulating testosterone production.
Secondary hypogonadism involves an idiopathic gonadotropin or LH-releasing
hormone deficiency. Because patients with secondary hypogonadism do not demonstrate
an intact feedback pathway, the lower testosterone concentrations are not associated with
increased LH or FSH levels. Thus, these men have low testosterone serum levels but have
gonadotropins in the normal to low range.
Hypogonadism may be age-related. Men experience a slow but continuous decline
in average serum testosterone after approximately age 20 to 30 years. These untreated
testosterone deficiencies in older men may lead to a variety of physiological changes. The
net result is geriatric hypogonadism, or what is commonly referred to as "male
menopause."
As discussed above, patients with primary hypogonadism have an intact feedback
inhibition pathway, but the testes do not secrete testosterone. As a result, increasing serum
testosterone levels should lead to a decrease in the serum FSH concentrations. In this
example, a total ef 94 patients were identified as having primary hypogonadism. For these
patients, the mean FSH concentrations in the three treatment groups on day 0 were 21 -26
mlU/mL, above the upper limit of the normal range. As shown in FIG. 8(a) and Table
13(a), the mean FSH concentrations decreased during treatment in all three treatment
regimens. However, only the 10.0 g/day AndroGel® group reduced the mean
concentrations to within the normal range during the first 90 days of treatment. Treatment
with the 10.0 g/day AndroGel® group required approximately 120 days to reach steady
state. The mean FSH concentration in patients applying 5.0 g/day of AndroGel* showed
an initial decline that was completed by day 30 and another declining phase at. day 120 and
continuing until the end of treatment. Mean FSH concentrations in the patients receiving
the testosterone patch appeared to reached steady state after 30 days but were significantly
higher than the normal range.
Table 13(a): FSH Concentrations (mlU/mL) on Each of
the Observation Days by Initial Treatment Group for
Patients Having Primary Hypogonadism (Mean ± SD)
Day 0
Day 30
Day 60
Day 90
Day 120
Dav 150
DavlSO
N
26
23
24
24
24
22
24
5 g/day
21.6 ±21.0
10.6 ±15.0
10.8 ±16.9
10.4 ±19.7
8.1 ±15.2
6.7 ±15.0
6.2 ±11.3
N
33
34
32
31
28
29
28
10 e/day
20.9 ±15.9
10.6±14.1
7.2 ±12.6
5.7±10.1
4.6 ±10.2
5.3 ±11.0
5.3 ±11.2
N
34
31
31
30
21
21
22
T-patcb
25.5 ±25.5
2 1.4 ±24.6
21.7 ±23.4
19.5 ±20.0
25.3 ±28.4
18.6 ±24.0
24.5 ±27.4
Patients with secondary hypogonadism have a deficient testosterone negative
feedback system. As shown in FIG. 8(b), of 44 patients identified as having secondary
hypogonadism, the mean FSH concentrations decreased during treatment, although the
decrease over time was not statistically significant for the testosterone patch. The patients
in the 5.0 g/day AndroGel* group showed a decrease in the mean FSH concentration by
about 35% by day 30, with no further decrease evident by day 60. Beyond day 90. the
mean FSH concentration in the patients appeared to slowly return toward the pretreatment
value. By day 30, all of the 10.0 g/day AndroGel* group had FSH concentrations less
than the lower limit.
Table 13(b): FSH Concentrations (mlU/mL) on Each of
the Observation Days by Initial Treatment Group for
Patients Having Secondary Hypogonadism (Mean ± SD)
Day 0
Day 30
Day 60
Day 90
Day 120
Day 150
Day 180
N
17
16
17
15
14
14
14
5 g/day
4.2 ± 6.6
2.8 ±5.9
2.8 ± 6.1
2.9 ±5.6
3.0 ±6.1
3.5 ±7.5
3.7 ±8.6
N
12
12
12
12
12
12
12
10 g/day
2.1 ±1.9
0.2 ±0.1
0.2 ±0.1
0.2 ±0.1
0.1 ±0.1
0.2 ±0.2
0.1 ±0.1
N
15
14
13
14
12
11
12
T-patch
5.1 ±9.0
4.2 ±8.0
4.2 ±7.4
4.9 ±9.0
6.1 ± 10.7
4.6 ±6.5
4.9 ± 7.4
Twenty-five patients were diagnosed with age-associated hypogonadism. As
shown in FIG. 8(c), the 5.0 g/day AndroGel® group had a mean pretreatment FSH
concentration above the normal range. The mean concentration for this group was within
the normal range by day 30 and had decreased more than 50% on days 90 and 180. The
decrease in FSH mean concentration in the 10.0 g/day AndroGel* group showed a more
rapid response. The concentrations in all six patients decreased to below the lower normal
limit by day 30 and remained there for the duration of the study. The six patients who
received the testosterone patch exhibited no consistent pattern in the mean FSH level;
however, there was an overall trend towards lower FHS levels with continued treatment.
Table 13(c): FSH Concentrations (mlU/mL) on Each of
the Observation Days by Initial Treatment Group for
Patients Having Age-Related Hypogonadism (Mean ±
SD)
Day_0
Day 30
Dav60
DayJO
Day_120
DayJSO
Dav 1 80
N
13
12
12
11
11
11
11
5 g/day
8.0 ±9.1
4.6 ± 7.4
3.9 ±6.6
3.8 ±7.0
4.2 ±8.3
4.3 ±8.1
4.0 ± 7.2
N6
6
6
6
6
5
6
lOg/dav
5.2 ±1.9
0.4 ±0.3
0.3 ± 0.3
0.4 ±0.7
0.4 ± 0.7
0.2 ± 0.2
0.2 ± 0.2
N
6
6
4
4
4
4
4
T-patch
4.7 ±1.7
3. 7 ±2.0
4.3 ±3.3
3.5± 1.9
4.2 ±3.3
3. 4 ±2.7
2.7±2.1
Sixty-four patients in the study suffered from unclassified hypogonadism. As
shown in FIG. 8(d), the patients showed a marked and comparatively rapid FSH
concentration decrease in all three groups, with the greatest decrease being in the 10.0
g/day AndroGel* group. The 10.0 g/day AndroGel® group produced nearly a 90%
decrease in the mean FSH concentration by day 30 and maintained the effect to day 1 SO.
The 5.0 g/day AndroGel* group produced about a 75% drop in mean FSH concentration
by day 30 and stayed at that level for the remainder of treatment. The 21 patients
receiving the testosterone patch had a 50% decrease in the mean FSH concentration by
day 30, a trend that continued to day 90 when the concentration was about one-third of its
pretreatment value.
Table 13(d): Concentrations (mlU/mL) for FSH on Each
of the Observation Days by Initial Treatment Group for
Patients Having Unknown-Related Hypogonadism
(Mean ± SD)
Day 0
Day 30
Day 60
Dav 90
N
17
17
16
17
5 g/day
4.0 ±1.8
1.1± 1.0
l . l i l . l
l . l i l . l
N
26
26
26
25
10 g/day
4.1 ±1.6
0.5 ±0.5
0.3 ± 0.3
0.4 ±0.7
N
21
21
18
18
T-patch
3.7 ±1.4
1.8 ±0.8
1.6± 1.0
1.2 ±0.9
Day 120
Day 150
Day 180
N
16
17
16
5 g/day
1.2 ±1.4
1.4 ±1.4
1.0 ±0.9
N
26
23
24
10 g/day
0.4 ±0.6
0.3 ±0.5
0.4 ±0.4
N
12
13
11
T-patch
1.4 ± 1.0
1.4 ± 1.2
1.3 ±0.9
This data shows that feedback inhibition of FSH secretion functioned to some
extent in all four subpopulations. The primary hypogonadal population showed a dose-
«
dependency in both the extent and rate of the decline in FSH levels. The sensitivity of the
feedback process appeared to be reduced in the secondary and age-associated groups in
that only the highest testosterone doses had a significant and prolonged impact on FSH
secretion. In contrast, the feedback inhibition pathway in the patients in the unclassified
group was quite responsive at even the lowest dose of exogenous testosterone.
(2) LH
The response of LH to testosterone was also examined separately for the same four
subpopulations. Table 14(a)-(d) shows the LH concentrations throughout the treatment
period.
As shown in FIG. 9(a) and Table 14(a), the LH concentrations prior to treatment
were about 175% of the upper limit of the normal range in primary hypogonadal patients.
The mean LH concentrations decreased during treatment in all groups. However, only the
AndroGel® groups decreased the mean LH concentrations enough to fall within the normal
range. As with FSH, the primary hypogonadal men receiving AndroGel® showed dosedependence
in both the rate and extent of the LH response.
Table 14(a): Concentrations for LH (mlU/mL) on Each
of the Observation Days for Patients Having Primary
Hypogonadism (Summary of Mean ± SD)
DayO
Day 30
Day 60
Dav90
N
26
23
24
24
5 g/dav
12.2 ±12.1
5.6 ±7.6
6.8 ±9.0
5. 9 ±9.5
N
33
34
32
31
10 g/dav
13.9 ±14.9
5.9 ±8.1
4.8 ±10.0
4.2 ± 1 1 .0
N
33
31
31
30
T-patch
13.3 =t 14.3
10.9 ±12.9
10.8±11.8
10.0 ±11.7
Day 120
Day 150
Day 180
N
24
22
24
5 g/dav
6.4±11.9
4.4 ±8.5
4.8 ±6.8
N
28
29
28
10 g/dav
3.8 ±10.4
4.0±11.3
4.0 ±11. 9
N
71
71
7.7.
T-patch
11.5±11.5
7.4 ±6.0
11.2± 10.5
The secondary hypogonadal men were less sensitive to exogenous testosterone.
For the 44 patients identified as having secondary hypogonadism, the pretreatment mean
concentrations were all within the lower limit normal range. The mean LH concentrations
decreased during treatment with all three regimens as shown in FIG. 9(b) and Table 14(b).
Table 14(b): Concentrations for LH (mlU/mL) on Each
of the Observation Days for Patients Having Secondary
Hypogonadism (Summary of Mean ± SD)
DayO
Dav30
Day 60
Dav90
Day 120
Day 150
Dav 1 80
N
17
16
17
15
14
14
14
5 g/day
1.8 ±2.6
1.1 ±2.2
1.4±3.8
1.2 ±2.4
1.6 ±4.0
1.6 ±3.5
1.5 ±3.7
N
12
12
12
12
12
12
12
lOg/dav
1.4 ±1.8
0.2 ±0.2
0.2 ±0.2
0.2 ± 0.2
0.2 ±0.2
0.2 ± 0.2
0.2 ± 0.2
N
15
14
13
14
12
11
12
T-patch
1.6±3.1
0.4 ±0.4
0.6 ± 0.5
0.7 ±1.0
0.8 ±0.8
1.2 ±2.0
1.4 ±2.1
None of the 25 patients suffering from age-associated hypogonadism had
pretreatment LH concentrations outside of the normal range as shown in FIG. 9(c) and
Table I4(c). The overall time and treatment effects were significant for the AndroGel®
patients but not those patients using the testosterone patch.
Table 14(c): Concentrations for LH (mlU/mL) on Each
of the Observation Days for Patients Having Age-Related
Hypogonadism (Summary of Mean ± SD)
DayO
Day 30
Day 60
Dav 90
Day 120
Day 150
Dav 180
N
13
12
12
11
11
11
11
5 g/day
3.2±1.1
1.1 ±1.0
0.8 ±0.7
0.9 ±1.2
1.0±1.4
1.3 ±1.5
1.8±2.1
N
6
6
6
6
6
56
10 g/day
2.4 ± 1.8
0.1 ±0.0
0.2 ±0.3
0.1 ±0.0
0.1 ±0.0
0.1 ±0.0
0.1 ±0.0
N
6
6
54
4
4
4
T-patch
2.9 ± 0.6
1.8*1.1
3. 4 ±2.8
2.3 ±1.4
2.2 ±1.4
1.9*1.2
1.4 ±1.0
Of the 64 patients suffering from an unclassified hypogonadism, none of the
patients had a pretrcatment LH concentration above the upper limit. Fifteen percent,
however, had pretreatment concentrations below the normal limit. The unclassified
patients showed comparatively rapid LH concentration decreases in all treatment groups as
shown in FIG. 9(d) and Table 14(d).
Table 14(d): Concentrations for LH (mlU/mL) on Each
of the Observation Days for Patients Having Unknown-
Related Hypogonadism (Summary of Mean ± SD)
DavO
Day 30
Day 60
Day 90
Day 120
Day 150
Dav 180
N
17
17
17
17
17
17
15
5 g/day
1.8±1.2
0.3 ±0.3
0.4 ±0.5
0.5 ± 0.5
0.4 ± 0.4
0.8 ±1.1
0.3 ± 0.4
N
26
26
26
26
26
23
25
10 g/day
2.5 ±1.5
0.3 ± 0.3
0.3 ± 0.3
0.3 ± 0.4
0.4 ± 0.5
0.3 ± 0.4
0.4 ±0.4
N
21
21
18
T-patch
2.5 ± 1.5
1.3 ±1.3
1.2± 1.4
18 | 1.0±1.4
12
13
11
L2±l.l
1.1 ±1.1
1.5± 1.3
(3) Summary: LH and FSH
Patients receiving AndroGel* or the testosterone patch achieve "hormonal steady
state" only after long-term treatment. Specifically, data involving FSH and LH show that
these hormones do not achieve steady-state until many weeks after treatment. Because
testosterone concentrations are negatively inhibited by FSH and LG, testosterone levels do
not achieve true steady state until these other hormones also achieve steady state.
However, because these hormones regulate only endogenous testosterone (which is small
to begin with in hypogonadal men) in an intact feedback mechanism (which may not be
present depending on the cause of hypogonadism), the level of FSH and/or LH may have
little effect on the actual testosterone levels achieved. The net result is that the patients do
not achieve a "hormonal steady state" for testosterone even though the C,vg, Cmin, and C^x
for testosterone remains relative constant after a few days of treatment.
2. Libido and Sexual Performance
Libido and sexual function were assessed by questionnaires the patients answered
daily for seven consecutive days before clinic visits on day 0 and on days 30, 60, 90, 120,
150, and 180 days during gel and patch application. The subjects recorded whether they
had sexual day dreams, anticipation of sex, flirting, sexual interaction (e.g., sexual
motivation parameters) and orgasm, erection, masturbation, ejaculation, intercourse (e.g.,
sexual performance parameters) on each of the seven days. The value was recorded as 0
(none) or 1 (any) for analyses and the number of days the subjects noted a parameter was
summed for the seven-day period. The average of the four sexual motivation parameters
was taken as the sexual motivation mean score and that of the five sexual performance
parameters as the sexual performance mean score (0 to 7).
The subjects also assessed their level of sexual desire, sexual enjoyment, and
satisfaction of erection using a seven-point Likcrt-type scale (0 to 7) and the percent of full
erection from 0 to 100%. The subjects rated their mood using a 0 to 7 score. Weekly
average scores were calculated. The details of this questionnaire had been described
previously and are fully incorporated by reference. See Wang et al., Testosterone
Replacement Tlierapy Improves Mood in Hypogonadal Men - A Clinical Research Center
Study, 81J. CLINICAL ENDOCRINOLOGY & METABOLISM 3578-3583 (1996).
a. Libido
As shown in FIG. 10(a), at baseline, sexual motivation was the same in all
treatment groups. After transdennal testosterone treatment, overall sexual motivation
showed significant improvement. The change in the summary score from baseline,
however, was not different among the three treatment groups.
Libido was also assessed from responses on a linear scale of: (1) overall sexual
desire, (2) enjoyment of sexual activity without a partner, and (3) enjoyment of sexual
activity with a partner. As shown in FIG. 10(b) and Table 15, as a group, overall sexual
desire increased after transdermal testosterone treatment without inter-group difference.
Sexual enjoyment with and without a partner (FIG. 10(c) and Tables 14 and 15) also
increased as a group.
Table 15: Overall Sexual Desire
Changes From Day 0 to Day 180
by Initial Treatment Group (Mean ± SD)
Initial Treatment
Croup
5.0 e/dav T-eel
lO.Oe/ayT-gel
T-Patch
Across-Groups
o-value
N
69
77
72
Day 0
2.1 ± 1.6
2.0 ±1.4
2.0±].6
0.8955
N
63
68
47
Day 1 80
3.5 ± 1. 6
3.6 ± 1.6
3.1 ± 1.9
0.2247
N
60
67
45
Change From
DavOto Dav 130
\A± 1.9
\.5± 1.9
1.6±2.l
0.8579
Wtthin-Group
p-value
0.0001
0.0001
0.0001
Table 16: Level of Sexual Enjoyment Without a Partner
Changes From Day 0 to Day 180
by Initial Treatment Group (Mean ± SD)
Initial Treatment
Croup
5.0 c/dav T-eel
1 0.0 e/day T-eel
T-Patch
Across-Groups
p-value
N
60
63
66
DayO
1.5 ±1.9
1.2±l.4
1.4± 1.8
0.6506
'N
51
53
44
Day 180
1.9±1.9
2.2 ±1.9
2.2 ±2. 3
0.7461
N
44
48
40
Change From
DavOto Dav 180
0.8 ± 1.4
U± 1.6
1.0 ± 1.9
0.6126
Within-Group
p-value
0.0051
0.0001
0.0026
Table 17: Level of Sexual Enjoyment With a Partner
Change from Day 0 to Day 180
by Initial Treatment Group (Mean ± SD)
Initial Treatment
Group
5.0a/davT-gcl
lO.Oz/dav T-eel
T-Patch
Across-Groups
p-value
N
C4
66
61
DayO
2.1 ±2.1
1.8 ±1.7
1.5 ±1.7
0.2914
N
55
58
40
Day 180
2.6 ± 2.2
3.0 ±2.2
2.2 ± 2.4
0.1738
N
48
52
35
Change From
DavOto Dav 180
0.4 ± 2.2
1.0 ±2.3
0.7 ± 2.3
0.39 II
Wlthln-Group
p-value
0.0 148
0.0053
0.1170
b. Sexual Performance
FIG. 11 (a) shows that while all treatment groups had the same baseline sexual
performance rating, the rating improved with transdermal testosterone treatment in all
groups. In addition, as a group, the subjects' self-assessment of satisfaction of erection
(FIG. ll(b) and Table 18) and percent full erection (FIG. ll(c) and Table 19) were also
increased with testosterone replacement without significant differences between groups.
The improvement in sexual function was not related to the dose or the delivery method of
testosterone. Nor was the improvement related to the serum testosterone levels achieved
by the various testosterone preparations. The data suggest that once a threshold (serum
testosterone level probably at the low normal range) is achieved, normalization of sexual
function occurs. Increasing serum testosterone levels higher to the upper normal range
does not further improve sexual motivation or performance.
Table 18: Satisfaction with Duration of Erection
Change from Day 0 to Day 180
by Initial Treatment Group (Mean ± SD)
Initial Treatment
Group
5.0g/dayT-gel
10/Og/dayT-gel
T-Patch
Across-Groups
p-value
N
55
64
45
DayO
2.5 ±2.1
2.9 ±1.9
3.4 ±2.1
0.1117
N
57
58
34
Day 180
4.3 ±1.8
4.5 ± 1.7
4.5 ± 2.0
0.7093
N
44
53
20
Change From
Dav 0 to Dav 1 80
1.9 ±2.0
1.5 ±2.0
1.3 ±2.1
0.5090
Wlthin-Group
p-value
0.0001
0.0001
0.0524
Table 19: Percentage of Full Erection
Change from Day 0 to Day 180
by Initial Treatment Group (Mean ± SD)
Initial Treatment
Group
5.0 a/davT-nel
1 0.0 ?/day T-ael
T-Patch
Across-Groups
p- value
N
53
62
47
Day 0
53.1 ±24.1
59.6 ±22.1
56.5 ± 24.7
0.3360
N
57
59
33
Day 180
67.4 ± 22.5
72.0 ± 20.2
66.7 ± 26.7
0.4360
N
43
52
19
Changt From
Dav 0 to Dav 180
18.7 ±22.1
10.4 ±23.4
12.7120.3
0.1947
VVithin-Group
p- value
0.0001
0.0001
0.0064
Example 2: Method of Increasing Libido in Eugonadal Men
Having a Diminished Libido
As discussed above, transdermal application of testosterone using AndroGel* to
hypogonadal men results in improved libido and sexual performance. Researchers have
found that eugonadal men having a diminished libido have a significant increase in sexual
interest after receiving testosterone injections. See 0'Carrol & Bancroft, Testosterone
Therapy for Low Sexual Interest and Erectile Dysfunction in Men: A Controlled Study,
Brit. J. Psychiatry 145:146-151 (1984). Thus, the present example is directed to a method
of treating a diminished libido in eugonadal men by transdermal application of a
hydroalcoholic testosterone gel to such men. In one embodiment, AndroGel® is applied
to the body in accordance with the protocol summarized in Example 1. Libido is
measured as in Example 1. Men receiving AndroGel are expected to show a increase in
their libido.
Example 3: Method of Increasing Libido in Eugonadal Men
Having a Normal Libido
As discussed above, transdermal application of testosterone using AndroGel® to
hypogonadal men results in improved libido and sexual performance. Studies have shown
that supra-physiological doses of testosterone administered to eugonadal men having a
normal libido resulted in a significant increase in libido. See Anderson et al., The Effect of
Exogenous Tstoserone on Sexuality and Mood of Normal Men* J. CLINICAL
ENDOCRINOLOGY & METABOLISM 75:1505-1507 (1992); Bagatel et al., Metabolic &
Behavioral Effects of High-Dose, Exogenous Testosterone in Healthy Men, J. CLINICAL
METABOLISM & ENDOCRINOLOGY 79:561-567 (1994). Thus, this example is directed to a
method of increasing the libido of normal eugonadal men by application of a transdermal
hydroalcoholic testosterone gel. In one embodiment, AndroGel® is applied to the body in
duration of erections (RigiScan®) with AndroGel treatment compared with placebo.
Applicant expects that all test parameters will show improvement over the placebo.
Example 5; Method of Improving Sexual Performance in Eugonadal Mpn
Having Normal jErectipns
In a prophetic example, 10 eugonadal males age 18 and older having normal
erections (i.e. not diagnosed with erectile dysfunction) will be randomized to receive: (a)
5.0 g/day of AndroGel® (delivering 50 mg/day of testosterone to the skin of which about
10% or 5 mg is absorbed) for 30 days or (b) 10.0 g/day of AndroGel® (delivering 100
mg/day of testosterone to the skin of which about 10% or 10 mg is absorbed) for 30 days :
or (c) nothing. The effectiveness of AndroGel® will be evaluated using several
assessment instrument as discussed in Example 4. Applicant expects that all test
parameters will show an increase in sexual performance over the placebo. Accordingly.
Applicant expects that AndroGel® can be applied to normal men in order to increase the
sexual performance above their normal baseline.
Example 6: Method of Treating Men Having Erectile Dysfunction in
Conjunction with other Pharmaceuticals
As discussed above, transdermal application of testosterone using AndroGel* to
hypogonadal men results in improved libido and sexual performance. This example is
directed use of AndroGel in combination with pharmaceuticals useful for treating erectile
dysfunction. Such pharmaceuticals include any agent that is effective to inhibit the
activity of a phosphodiesterase. Suitable phosphodiesterase inhibitors include, but are not
limited to, inhibitors of the type III phosphodiesterase (cAMP-specific-cGMP inhibitable
form), the type IV phospodiesterase (high affinity-high specificity cAMP form) and the
type V phosphodiesterase (the cGMP specific form). Additional inhibitors that may be
duration of erections (RigiScan*) with AndroGel treatment compared with placebo.
Applicant expects that all test parameters will show improvement over the placebo.
Example 5; Method ofTmnrovinP Sexual Performance in Eugm^ai p\fn
Having Normal Erections
In a prophetic example, 10 eugonadal males age 18 and older having normal
erections (i.e. not diagnosed with erectile dysfunction) will be randomized to receive: (a)
5.0 g/day of AndroGel® (delivering 50 mg/day of testosterone to the skin of which about
10% or 5 mg is absorbed) for 30 days or (b) 10.0 g/day of AndroGel® (delivering 100
mg/day of testosterone to the skin of which about 10% or 10 mg is absorbed) for 30 days ;
or (c) nothing. The effectiveness of AndroGel® will be evaluated using several
assessment instrument as discussed in Example 4. Applicant expects that all test
parameters will show an increase in sexual performance over the placebo. Accordingly,
Applicant expects that AndroGel® can be applied to normal men in order to increase the
sexual performance above their normal baseline.
Example Conjunction vvitji other Pharmaceuticals
As discussed above, transdermal application of testosterone using AndroGel* to
hypogonadal men results in improved libido and sexual performance. This example is
directed use of AndroGel in combination with Pharmaceuticals useful for treating erectile
dysfunction. Such Pharmaceuticals include any agent that is effective to inhibit the
activity of a phosphodiesterase. Suitable phosphodiesterase inhibitors include, but are not
limited to, inhibitors of the type III phosphodiesterase (cAMP-specific-cGMP inhabitable
form), the type IV phospodiesterase (high affinity-high specificity cAMP form) and the
type V phosphodiesterase (the cGMP specific form). Additional inhibitors that may be
allyloxy-5-(4-methyl-l -piperazinylsulfonyO-phenyl]-1 -methyl-3-n-propyl-1,6-dihydro-
7H-Pyrazolo[4,3-d]Pyrimidin-7-one,5-[2-ethoxy-5-[4-(2-ProPyl)-l-Pipcrazinylsulfonyl)-
phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyra2olo[4,3-d]pyrimidin-7-one, 5-[2-
ethoxy-5-[4-(2-hydroxyethyl)-l-Piperazinylsulfonyl)Phenyl]-l-methyl-3-n-propyl-l,6-
dihydro-7H-pyrazolo[4s3-d]pyrirnidin-7-one, 5-[5-[4-(2-hydroxyethyl)-lpiPerazinylsulfonyl]-
2-n-propoxvphenyl]-l-methy l-3-n-Propyl-l,6-dihydro-7Hpyrazolo[
4,3-d]Pyrimidin-7-one, 5[2-ethoxy-5-(4-methyl-l-piPerazinylcarbonyl)Phenyll-
1 -methyl-3-n-propyl-l,6-dihydro-7H-Pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-5-
(l-methyl-2-imidazolyl)Phenyl]-l-methyl-3-n-propyl- 1,6-dihyd ro-7H-pyrazolo[4,3-
d]pyrimidin-7-one.
The phosphodiesterase inhibitors described in PCT Publication No. WO 96/16644
include griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone
derivatives, fused and condensed pyrimidines, pyrimidopyrimidine derivatives, purine
compounds, quinazoline compounds, phenylpyrimidinone derivative,
imidazoquinoxalinone derivatives or aza analogues thereof, phenylpyridone derivatives.
and others. Specific examples of the phosphodiesterase inhibitors disclosed in WO
96/16644 include l,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2-
propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-l,2-dihydro-2-oxypyridine-3-
carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one, 7-methylthio-4-oxo-
2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine, 6-hydroxy-2-(2-
propoxyphenyl)pyrimidine-4-carboxamide, l-ethyl-3-methyHrnidazo[l,5a]quinoxalin-
4(5H)-one, 4-phenylmethylamino-6-chloro-2-( l-imidazoloyl)quinazoline, 5-ethyl-8-[3-(Ncyclohexyl-
N-methylcarbamoyl)-proPyloxy]-4,5-dihydro-4-oxo-pyrido[3,2-e]-Pyrrolo[l,2-
ajpyrazine, 5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'H)-(3IH)-
allyloxy-5-(4-methyl-l-piperazinylsulfonyl)-phenyl]-l-methyl-3-n-propyl-l,6-dihydro-
7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-propyl)-l-piperazinylsulfonyl)-
phenyl]-1 -methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-
ethoxy-5-[4-(2-hydroxyethyl)-l-piperazmylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-
dihydro-7H-pyrazolo[4J3-d]pyrimidin-7-one, 5-[5-[4-(2-hydroxyethyl)-lpiperazinylsulfonyl]-
2-n-propoxyphenyl]-l-methy l-3-n-propyl-l,6-dihydro-7Hpyrazolo[
4,3-d]pyrimidin-7-one, 5[2-ethoxy-5-(4-methyl-l-piperazinylcarbonyl)phenyl]-
1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-5-
(l-methyl-2-imidazolyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one.
The phosphodiesterase inhibitors described in PCT Publication No. WO 96/16644
include griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone
derivatives, fused and condensed pyrimidines, pyrimidopyrirnidine derivatives, purine
compounds, quinazoline compounds, phenylpyrimidinone derivative,
imidazoquinoxalinone derivatives or aza analogues thereof, phenylpyridone derivatives,
and others. Specific examples of the phosphodiesterase inhibitors disclosed in WO
96/16644 include l,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2-
propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-l,2-dihydro-2-oxypyridine-3-
carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pvrimid-4(3H)-one, 7-methylthio-4-oxo-
2-(2-propoxvphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine, 6-hydroxy-2-(2-
propoxyphenyl)pyrimidine-4-carboxamide, l-ethyl-3-methylimidazo[l,5a]quinoxalin-
4(5H)-one, 4-phenylmethylamino-6-chloro-2-(l-imida2oloyl)quinazoline, 5-ethyl-8-[3-(Ncyclohexyl-
N-methylcarbamoyl)-propyloxy]-4,5-dihydro-4-oxo-pyrido[3,2-e]-pyrrolo[l,2-
a]pyrazine, 5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'I
Other phosphodiesterase inhibitors that may be used in the method of this
invention include nonspecific phosphodiesterase inhibitors such as theophylline. IBMX,
pentoxifylline and papaverine, and direct vasodilators such as hydralazine.
The active agents may be administered, if desired, in the form of salts, esters,
amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or
derivative is suitable pharmacologically, i.e., effective in the present method. Salts, esters,
amides, prodrugs and other derivatives of the active agents may be prepared using
standard procedures known to those skilled in the art of synthetic organic chemistry and
described, for example, by J. March, Advanced Organic Chemistry: Reactions,
Mechanisms ancj Structure. 4th Ed. (New York: Wiley-Interscience, 1992). For example,
acid addition salts are prepared from the free base using conventional methodology, and
involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in
a polar organic solvent such as methanol or ethanol and the acid is added thereto. The
resulting salt either precipitates or may be brought out of solution by addition of a less
polar solvent. Suitable acids for preparing acid addition salts include both organic acids,
e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid,
malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic
acid, salicylic acid, and the like, as well as inorganic acids, e.g.,
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the
like. An acid addition salt may be reconverted to the free base by treatment with a suitable
base. Particularly preferred acid addition salts of the active agents herein are halide salts,
such as may be prepared using hydrochloric or hydrobromic acids. Conversely,
preparation of basic salts of acid moieties which may be present on a phosphodiesterase
Other phosphodiesterase inhibitors that may be used in the method of this
invention include nonspecific phosphodiesterase inhibitors such as theophylline, IBMX,
pemoxifylline and papaverine, and direct vasodilators such as hydralazine.
The active agents may be administered, if desired, in the form of salts, esters,
amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or
derivative is suitable pharmacologically, i.e., effective in the present method. Salts, esters,
amides, prodrugs and other derivatives of the active agents may be prepared using
standard procedures known to those skilled in the art of synthetic organic chemistry and
described, for example, by J. March, Advanced Organic Chemistry: Reactions.
Mechanisms and Structure. 4th Ed. (New York: Wiley-Interscience, 1992). For example,
acid addition salts are prepared from the free base using conventional methodology, and
involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in
a polar organic solvent such as methanol or ethanol and the acid is added thereto. The
resulting salt either precipitates or may be brought out of solution by addition of a less
polar solvent. Suitable acids for preparing acid addition salts include both organic acids,
e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid,
malonic acid, succinic acid, maleic acid, fumaric acid, tartanc acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic
acid, salicylic acid, and the like, as well as inorganic acids, e.g.,
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the
like. An acid addition salt may be reconverted to the free base by treatment with a suitable
base. Particularly preferred acid addition salts of the active agents herein are halide salts,
such as may be prepared using hydrochloric or hydrobromic acids. Conversely,
preparation of basic salts of acid moieties which may be present on a phosphodiesterase
principally by various physiological mechanisms of erection initiation and maintenance,
the testosterone gel used in accordance with the present invention plays a beneficial role
physiologically, and stimulates both sexual motivation (i.e., libido) and sexual
performance. Testosterone controls the expression of the nitric oxide synthase gene. See
Reilly et al., Androgenic Regulation of NO Availability in Rat Penile Erection, 38 J.
ANDROLOGY 110 (1997); Park et al., Effects of Androgens on the Expression of Nitric
Oxide Synthase mRNAs in Rat Corpous Cavernosum, 83 BJU INT'L. 327 (1999). Thus,
testosterone and other androgens clearly play a role in erectile dysfunction. See Lugg et
al.. We Role of Nitric Oxide in Erectile Function, 16 J. ANDROLOGY 2 (1995); Penson et
al., Androgen and Pituitary Control of Penile Nitric Oxide Synthase and Erectile Function
In the Rat, 55 BIOLOGY OF REPRODUCTION 576 (1996); Traish et aL, Effects of Castration
and Androgen Replacement on Erectile Function in a Rabbit Model, 140 ENDOCRINOLOGY
1861 (1999). Moreover, testosterone replacement restores nitric oxide activity. See Baba
et al. Delayed Testosterone Replacement Restores Nitric Oxide Synthase Containing Nerve
Fibres and the Erectile Response in Rat Penis, BJU INT'L 953 (2000); Garban et al..
Restoration of Normal Adult Penile Erectile Response in Aged Rats by Long-Term
Treatment with Androgens, 53 BIOLOGY OF REPRODUCTION 1365 (1995); Mann et al.,
Androgen-dependent Nitric Oxide Release in Rat Penis Correlates with Levels of
Constitutive Nitric Oxide Synthase Isoenzymes, 61 BIOLOGY OF REPRODUCTION 1012
(1999).
As disclosed herein, adequate blood levels of testosterone are important to
erection. In one embodiment, AndroGel® is applied to the body in accordance with the
protocol summarized in Example 1. The pharmaceutical(s) for erectile dysfunction is
taken in accordance with the prescription requirements. For example, VIAGRA® is
principally by various physiological mechanisms of erection initiation and maintenance,
the testosterone gel used in accordance with the present invention plays a beneficial role
physiologically, and stimulates both sexual motivation (i.e., libido) and sexual
performance. Testosterone controls the expression of the nitric oxide synthase gene. See
Reilly et al., Androgenic Regulation of NO Availability in Rat Penile Erection, 18 J.
ANDROLOGY 110 (1997); Park et al., Effects of Androgens on the Expression of Nitric
Oxide Synthase mRNAs in Rat Corpous Cavernosum, 83 BJU INT'L. 327 (1999). Thus.
testosterone and other androgens clearly play a role in erectile dysfunction. See Lugg et
al.. Tlie Role of Nitric Oxide in Erectile Function, 16 J. ANDROLOGY 2 (1995); Penson et
al., Androgen and Pituitary Control of Penile Nitric Oxide Synthase and Erectile Function
In the Rat, 55 BIOLOGY OF REPRODUCTION 576 (1996); Traish et aL, Effects of Castration
and Androgen Replacement on Erectile Function in a Rabbit Model, 140 ENDOCRINOLOGY
1861 (1999). Moreover, testosterone replacement restores nitric oxide activity. See Baba
et al. Delayed Testosterone Replacement Restores Nitric Oxide Synthase Containing Nerve
Fibres and the Erectile Response in Rat Penis, BJU INT'L 953 (2000); Garban et al..
Restoration of Normal Adult Penile Erectile Response in Aged Rats by Long-Term
Treatment with Androgens, 53 BIOLOGY OF REPRODUCTION 1365 (1995); Mann et al.,
Androgen-dependent Nitric Oxide Release in Rat Penis Correlates with Levels of
Constitutive Nitric Oxide Synthase Isoenzymes, 61 BIOLOGY OF REPRODUCTION 1012
(1999).
As disclosed herein, adequate blood levels of testosterone are important to
erection. In one embodiment, AndroGel® is applied to the body in accordance with the
protocol summarized in Example 1. The pharmaceutical(s) for erectile dysfunction is
taken in accordance with the prescription requirements. For example, VIAGRA® is
invention. The present invention is defined by the claimed elements, and any and all
modifications, variations, or equivalents that fall within the true spirit and scope of the
underlying principles.

We Claim :
1. A hydroalcoholic gel for improving the efficacy of a pharmaceutical
useful for treating erectile dysfunction in a male subject, comprising:
a. a pharmaceutically effective amount of a steroid in the
testosterone synthetic pathway
b. 40 - 90 % w/w of at least one of a C1-C4 alcohol,
c. 0.10-2% w/w of a penetration enhancer,
d. 0.10 - 2% w/w of thickener and
e. water qs 100% w/w.
2. The hydroalcoholic gel of claim 1 wherein the pharmaceutical is a
phosphodiesterase type 5 inhibitor.
3. The hydroalcoholic gel of claim 1 wherein the pharmaceutical is at least
one of sildenafil citrate, pentoxifylline, yohimbine, apomorphine,
alprostadil, papavaerine, phentolamine, and combinations, salts,
derivatives and enantiomers thereof.
4. The hydroalcoholic gel of claim 1 wherein the Pharmaceuticals are
selected from the group consisting of sildenafil, apomorphine,
pentoxifylline, or yohimbine.
5. The hydroalcoholic gel of claim 1 wherein the penetration enhancer
comprises at least one of a C8-C22 fatty acid.
6. The hydroalcoholic gel of claim 1 wherein the fatty acid comprises an
alkyl chain length of at least 12 carbon atoms.
7. The hydroalcoholic gel of claim 1 wherein the lower alcohol comprises at
least one of ethanol, 2-propanol, n-propanol, and mixtures thereof.
8. The hydroalcoholic gel of claim 1 wherein the steroid is testosterone and
the enhancer is isopropyl myristate.
9. The hydroalcoholic gel of claim 8 wherein the composition comprises
about 1.0 % w/w of testosterone.
10. The hydroalcoholic gel of claim 8 wherein the enhancer comprises about
0.5 % w/w of isopropyl myristate.
11. The hydroalcoholic gel of claim 8 wherein the thickener is polyacrylic
acid.
12. The hydroalcoholic gel of claim 8 where the steroid comprises about 0.5
to about 5.0 % w/w testosterone, the thickener comprises about 0.10 to
about 2 % w/w of polyacrylic acid, the enhancer comprises about 0.1 to
about 2 % w/w of isopropyl myristate, the C1-C4 alcohol comprises about
40.0 to about 90 % w/w of ethanol.
13. A composition comprising a pharmaceutical useful for treating erectile
dysfunction in a man and a transdermal testosterone gel as separate
components to the composition and wherein the transdermal
testosterone gel comprises:
• 0.5-5% w/w of testosterone,
• 40 -90 % w/w of at least one of a C1-C4 alcohol,
• 0.10-2% w/w of a penetration enhancer,
• 0.10-2% w/w of thickener and
• water qs 100% w/w.
14. The composition of claim13 wherein the pharmaceutical is a
phosphodiesterase type 5 inhibitor.
15. The composition of claim13 wherein the pharmaceutical is at least one
of sildenafil citrate, pentoxifylline, yohimbine, apomorphine,
alprostadil, papavaerine, phentolamine, and combinations, salts,
derivatives and enantiomers thereof.
16. The composition of claim13 wherein the Pharmaceuticals are selected
from the group consisting of sildenafil, apomorphine, pentoxifylline, or
yohimbine.
17. The composition of claim 16 wherein the thickener comprises about 0.10
to about 2 % w/w of polyacrylic acid, the enhancer comprises about 0.10
to about 2 % w/w of isopropyl myristate, the C1-C4 alcohol comprises
about 40.0 to about 90 % w/w of ethanol
Dated this 21st day of November 2003 „
Vidlsha (Jarg
Of Anand And Anand Advocates
Attorney for the Applicant

Documents:

1985-delnp-2003-abstract-(25-10-2007).pdf

1985-DELNP-2003-Assignment-(27-08-2009).pdf

1985-DELNP-2003-Assignment-21-05-2008.pdf

1985-delnp-2003-claims-(25-10-2007).pdf

1985-DELNP-2003-Correspondence-Others-(23-09-2008).pdf

1985-delnp-2003-correspondence-others-(25-10-2007).pdf

1985-DELNP-2003-Correspondence-Others-(27-08-2009).pdf

1985-DELNP-2003-Correspondence-Others-21-05-2008.pdf

1985-delnp-2003-description (complete)-(25-10-2007).pdf

1985-delnp-2003-drawings-(25-10-2007).pdf

1985-delnp-2003-form-1-(25-10-2007).pdf

1985-DELNP-2003-Form-1-21-05-2008.pdf

1985-delnp-2003-form-2-(25-10-2007).pdf

1985-DELNP-2003-Form-2-21-05-2008.pdf

1985-DELNP-2003-GPA-(23-09-2008).pdf

1985-delnp-2003-pct-409-(25-10-2007).pdf

1985-delnp-2003-pct-428-(25-10-2007).pdf

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Patent Number

232906

Indian Patent Application Number

1985/DELNP/2003

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

21-Mar-2009

Date of Filing

21-Nov-2003

Name of Patentee

UNIMED PHARMACEUTICALS INC

Applicant Address

901, SAWYER ROAD, MARIETTA, GA 30062, U.S.A.

Inventors:

#	Inventor's Name	Inventor's Address
1	MR.DUDLEY ROBERT E.	51 JOHNSTOWN LANE,ROSEMARY BEACH,FLORIDA,U.S.A

PCT International Classification Number

A61K 31/565

PCT International Application Number

PCT/US01/27205

PCT International Filing date

2001-08-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	09/651,777	2000-08-30	U.S.A.
2	09/703,753	2000-11-01	U.S.A.