RU2303981C2 - Method for treating male patients for erectile dysfunction and high libido - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves transcutaneously introducing testosterone preparation as water-and alcohol gel having (in % by weight) testosterone 0.1-10; isopropyl myristate 0.1-5; ethanol 30-98 and thickener 0.1-5 in combination with type 5 phosphodiesterase inhibitor. Sildenaphil citrate is applied as type 5 phosphodiesterase inhibitor.

EFFECT: enhanced effectiveness of treatment.

Description

FIELD OF THE INVENTION

The present invention relates to a method for treating erectile dysfunction and increasing libido in men.

BACKGROUND OF THE INVENTION

A. Sexual activity, erectile dysfunction ("ED") and male libido

1. Sexual activity and ED

The term "sexual activity", as used in this description, usually refers to the ability of men to experience a state of orgasm, the ability to erection, or the ability to masturbate or engage in sexual intercourse. "Impotence" is a type of lack of sexual activity. Impotence, or “erectile dysfunction,” as used herein, generally refers to a man’s inability to achieve an erection with sufficient rigidity with vaginal penetration in 25% of cases or more of the number of attempts.

Approximately 45 million American men have some degree of erectile dysfunction. An estimated 10 million American men — about 9% of the adult population — are impotent. The number of (patients) increases with age. Thus, impotence affects 10% of sixty-year-old men, 25% of seventy-year-olds, 40% of eighty-year-olds, and more than half of ninety-year-olds. In young couples, cases of impotence make up about 7%. One third of older men receiving medication also have difficulty with erection.

Over the past decade, there have been prospects for treating cases of impotence. Normal common sense is used to attribute almost all cases of impotence to psychological factors. Currently, according to researchers, about 70-80% of cases of impotence is caused primarily by medical problems. Risk factors for impotence include hypogonadism, atherosclerosis, hypertension, diabetes mellitus, depression and other emotional or psychological diseases, renal pelvis surgery, kidney failure, multiple sclerosis, stroke, some types of epilepsy, and alcoholism. Another risk factor is the intake of a number of drugs, including cardiovascular drugs, drugs that act on the central nervous system, some hormones, heroin and cocaine.

Currently, 90% of all cases of impotence are treated with VIAGRA® (USP sildenafil citrate). Other drugs useful in treating impotence include, but are not limited to: pentoxifylline (TRENTAL ^® ), yohimbine hydrochloride (ACTIBINE ^® , YOCON ^® , YOHIMEX ^® ), apomorphine (UPRIMA ^® ), alprostadil (MUSE ^® system, TOPIGLAN ^® , CAVERJECT ^® ), papaverine (PAVABID ^® , CRESPAN ^® ) and phentolamine (VASOMAX ^® , REGITIN ^® ).

These pharmaceutical preparations have various physiological mechanisms of action. For example, the physiological mechanism of penile erection involves the release of nitric oxide ("NO") into the cavernous body during sexual stimulation. Then NO activates the guanylate cyclase enzyme, which causes an increased level of cyclic guanosine monophosphate ("cGMP"), relaxation of smooth muscles in the cavernous body, and causes blood flow. VIAGRA ^® does not have a relaxing effect on a single human cavernous body, but increases NO exposure by inhibiting type 5 phosphodiesterase ("PDA5"), which is responsible for the decomposition of cGMP in the cavernous body. When sexual stimulation causes local NO release, inhibition of PDE5 with sildenafil leads to elevated levels of cGMP in the cavernous body, causing relaxation of smooth muscles and blood flow to the cavernous body. In contrast, UPRIMA ^® is a dopamine receptor agonist that acts on the central nervous system. When absorbed and transported to the brain, UPRIMA ^® initiates chain reactions that, as a result, increase blood flow to the male genitalia and erection. In accordance with the present invention, testosterone has a beneficial physiological effect and stimulates both sexual motivation (i.e., libido) and sexual activity.

2. Sexual motivation and libido.

While the terms “sexual activity” and “impotence” describe a physiological effect, the terms “sexual motivation” and “libido” describe a psychological effect. "Libido" or "sexual motivation" used in this description is a parameter measured by the duration, frequency and measure of sexual dreams, anticipation of sex, flirting and sexual interaction.

As discussed above, although doctors believe that erectile dysfunction is primarily caused by a physiological mechanism, some cases are still attributed to psychological reasons. In addition, decreased libido may also be a reaction to impressions of impotence. Unfortunately, the main focus in the treatment of erectile dysfunction with pharmaceuticals such as VIAGRA ^® is on the physiological mechanics of achieving and maintaining an erection, and there is little or no attention paid to increasing sexual motivation or libido of men suffering from erectile dysfunction. Consequently, there remains a need for the treatment of disorders of sexual activity, such as impotence, in a way that overcomes both the physiological and psychological problems associated with the violation.

A number of clinical studies, including testosterone replacement in hypogonadal men, have provided convincing evidence that testosterone plays a role in both sexual libido motivation and sexual activity. For example, researchers reported that testosterone replacement leads to increased sexual fantasies, sexual arousal and desire, spontaneous erections during sleep and morning, ejaculation, sexual activity in the presence or absence of a partner, orgasm during coition or masturbation. See generally Christiansen, Behavioral Correlates of Testosterone, Testosterone: Action, Deficiency, Substitution 109-111 (1998).

B. Synthesis, metabolism and regulation of testosterone

Testosterone, the main androgen in the blood of men, is synthesized from cholesterol. About 500 million Leydig cells in the testes secrete more than 95% of 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 to develop and maintain testicular function and negatively regulate testosterone production. Circulating testosterone is converted (metabolized) to various 17-ketosteroids in two different ways. Testosterone can be metabolized to dihydrotestosterone ("DHT") under the action of 5α-reductase or to estradiol ("E ₂ ") under the action of an aromatase complex.

98% of testosterone circulates in the blood as protein bound testosterone. In men, about 40% is associated with sex hormone-binding globulin ("SHBG"), which has a high affinity. The remaining 60% are weakly bound to albumin. Therefore, a number of indicators can be obtained in clinical laboratories. The term "free" testosterone is used in this description to the part of testosterone in the blood that is not associated with the protein. The term "total testosterone" or "testosterone", as used herein, means free testosterone plus testosterone bound to a protein. The term “bioavailable testosterone,” as used herein, refers to non-SHBG-related testosterone and includes testosterone weakly bound to albumin.

The intervals of hormone concentrations in normal (healthy) adult men are given in the table below of the UCLA-Harbor Medical Center:

Table 1 Hormone levels in healthy men Hormone Normal interval Testosterone 298-1043 ng / dl Free testosterone 3.5-17.9 ng / dl DHT 31-193 ng / dl DHT / T Ratio 0.052-0.33 DHT + T 372-1349 ng / dl SHBG 10.8-46.6 nmol / L FSH 1.0-6.9 mU / ml Lh 1.0-8.1 mU / ml E ₂ 17.1-46.1 pg / ml

In the information reported in the literature on the half-life of testosterone in the body, there is a large scatter from 10 to 100 minutes. Researchers, however, agree that testosterone levels in the blood of healthy young people change throughout the day. The maximum levels are observed around 6.00-8.00 in the morning, and during the day they decrease. On the characteristic curves, the maximum testosterone level is 720 ng / dl, and the minimum 430 ng / dl. However, the physiological significance of this diurnal cycle, if one exists, is unclear.

C. Testosterone Levels and Sexual Behavior / Sexual Activity

Since it has been shown that increasing testosterone concentrations changes sexual activity and libido, researchers have studied ways to deliver testosterone to men. These methods include intramuscular injections (43%), oral replacement (24%), pellet implantation (23%), and transdermal patches (10%). These methods are summarized in Table 2.

table 2 Method of administration and dosage of various testosterone preparations A drug Mode of application Full replacement dose Clinic Application Testosterone enanthate Intramuscular injection 200-25.0 g every 2-3 weeks Testosterone cypionate Intramuscular injection 200 mg every 2 weeks Testosterone undecanoate Orally 2-4 capsules of 40 mg per day Transdermal membrane with testosterone Through the scrotal skin 1 membrane per day Transdermal membrane with testosterone Through necrotic skin 1 or 2 systems per day Testosterone implants Abdominal implantation 3-6 implants of 20 mg every 6 months During development Testosterone cyclodextrin Sublingually 2.5-5 mg twice daily Testosterone undecanoate Intramuscular injection 1000 mg every 8-10 weeks Testosterone bicyclate Intramuscular injection 1000 mg every 12-16 weeks Testosterone microspheres Intramuscular injection 315 mg for 11 weeks Disused 17α-methyltestosterone Orally 25-5.0 g per day Fluoxymestron Sublingually 10-25 mg per day Orally 10-20 mg per day

However, all modern methods of compensation (replenishment) of testosterone have one drawback or more. For example, subcutaneous implants in the form of granules or injections of esters are painful and require a visit to the doctor. Many of these methods, such as oral / sublingual / buccal preparations, have an undesirable pharmacokinetic curve - the formation of testosterone concentrations below physiological levels after returning to the baseline. Transdermal patches (membranes) give pharmacokinetic characteristics below optimal, putting many patients in a difficult position and associated with significant skin irritation. Therefore, although the need for an effective testosterone replenishment methodology has existed for decades, an alternative replacement therapy that would overcome these difficulties has not yet been created.

SUMMARY OF THE INVENTION

The present invention relates to a transdermal preparation of testosterone in the form of a water-alcohol gel, the use of which allows to overcome the difficulties associated with other testosterone delivery mechanisms, due, inter alia, to a given pharmacokinetic curve in the absence of skin irritation. The gel can be used as a way to increase sexual activity, including the treatment of erectile dysfunction, and increase libido by increasing testosterone levels in men. In addition, the gel can be used in combination with pharmaceutical drugs that help in the treatment of erectile dysfunction, such as VIAGRA ^® , to increase their effectiveness.

Brief Description of the Figures

FIG. 1 (a) depicts 24-hour pharmacokinetic curves for testosterone in hypogonadal men before treatment with 5.0 g / day AndroGel, or 10 g / day AndroGel ^® , or a patch with testosterone (starting treatment group).

FIG. 1 (b) shows 24-hour pharmacokinetic curves for testosterone in hypogonadal men on the first day of treatment with 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (group starting treatment )

FIG. 1 (c) shows 24-hour pharmacokinetic curves for testosterone in hypogonadal men on the 30th day of treatment with 5.0 g / day AndroGel ^® , 10 g / day AndroGel ^® or a patch with testosterone (the group starting treatment).

FIG. 1 (d) shows 24-hour pharmacokinetic curves for testosterone in hypogonadal men on the 90th day of treatment with 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (group starting treatment )

FIG. 1 (e) shows 24-hour pharmacokinetic curves for testosterone in hypogonadal men at 180 days of treatment with 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or patch with testosterone (group finishing treatment )

FIG. 1 (f) depicts 24-hour pharmacokinetic curves for testosterone in hypogonadal men at 0, 1, 30, 90, and 180 days of treatment with 5.0 g / day AndroGel ^® .

FIG. 1 (g) shows 24-hour pharmacokinetic curves for testosterone in hypogonadal men at 0, 1, 30, 90, and 180 days of treatment with 10.0 g / day AndroGel ^® .

FIG. 1 (h) depicts 24-hour pharmacokinetic curves for testosterone in hypogonadal men at 0, 1, 30, 90, and 180 days of treatment with a testosterone patch.

FIG. 2 (a) shows 24-hour pharmacokinetic curves for free testosterone in hypogonadal men at 1 day of treatment with 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or patch with testosterone (starting group treatment).

FIG. 2 (b) shows 24-hour pharmacokinetic curves for free testosterone in hypogonadal men on the 30th day of treatment with 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (starting group treatment).

FIG. 2 (c) shows 24-hour pharmacokinetic curves for free testosterone in hypogonadal men on the 90th day of treatment with 5.0 g / day AndroGel ^® , 10 g / day AndroGel ^® or a patch with testosterone (group starting treatment) .

FIG. 2 (d) shows 24-hour pharmacokinetic curves for free testosterone in hypogonadal men on day 180 of treatment with 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or patch with testosterone (group ending treatment).

FIG. 2 (e) depicts 24-hour pharmacokinetic curves for free testosterone in hypogonadal men at 0, 1, 30, 90, and 180 days of treatment with 5.0 g / day AndroGel ^® .

FIG. 2 (f) depicts 24-hour pharmacokinetic curves for free testosterone in hypogonadal men at 0, 1, 30, 90, and 180 days of treatment with 10.0 g / day AndroGel ^® .

FIG. 2 (g) shows 24-hour pharmacokinetic curves for testosterone in hypogonadal men at 0, 1, 30, 90, and 180 days of treatment with a testosterone patch.

FIG. 3 shows DHT concentration curves on days 0 through 180 in hypogonadal men receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (treatment initiating group).

Figure 4 shows the curves of the concentration of DHT / T on days 0 to 180 in hypogonadal men receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel, or a patch with testosterone (the group starting treatment).

Figure 5 shows the concentration curves of total (total) androgen (DHT / T + T) on days 0 to 180 in hypogonadal men receiving either 5.0 g / day AndroGel, or 10 g / day AndroGel, or a patch with testosterone (group starting treatment).

Figure 6 shows the concentration curves of E ₂ on days 0 to 180 in hypogonadal men receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (the group starting treatment).

FIG. 7 shows SHBG concentration curves on days 0 through 180 in hypogonadal men receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (treatment initiation group).

FIG. 8 (a) shows FSH concentration curves on days 0 to 180 in men with primary hypogonadism receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (starting group treatment).

FIG. 8 (b) shows FSH concentration curves on days 0 through 180 in men with secondary hypogonadism receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (starting group treatment).

FIG. 8 (c) depicts FSH concentration curves on days 0 through 180 in men with age-related hypogonadism receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (starting group treatment).

FIG. 8 (d) depicts FSH concentration curves on days 0 to 180 in men with hypogonadism of unknown origin receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (group, beginning treatment).

Figure 9 (a) shows the curves of LH concentration on days 0 to 180 in men with primary hypogonadism receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel, or a patch with testosterone (the group starting treatment )

FIG. 9 (b) shows LH concentration curves on days 0 through 180 in men with secondary hypogonadism receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (starting group treatment).

FIG. 9 (c) shows LH concentration curves on days 0 through 180 in men with age-related hypogonadism receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (starting group treatment).

FIG. 9 (d) shows LH concentration curves on days 0 through 180 in men with hypogonadism of unknown origin receiving either 5.0 g / day AndroGel ^® , or 10 g / day AndroGel ^® , or a patch with testosterone (group, beginning treatment).

Figure 10 (a) shows the curves of estimates (values) of sexual motivation in days 0 to 180 in men with hypogonadism receiving either 5.0 g / day AndroGel ^® , 7.5 g / day, 10 g / day AndroGel ^® , or a patch with testosterone.

FIG. 10 (b) shows curves of general estimates (values) of sexual desire on days 0 through 180 for hypogonadal men receiving either 5.0 g / day AndroGel ^® , 7.5 g / day, 10 g / day AndroGel ^® , or a patch with testosterone.

In FIG. 10 (c) shows curves of estimates (values) of sexual satisfaction on days 0 through 180 in hypogonadal men receiving either 5.0 g / day AndroGel ^® , 7.5 g / day, 10 g / day AndroGel ^® , or patch with testosterone.

In FIG. 11 (a) shows curves of estimates (values) of sexual activity on days 0 through 180 for hypogonadal men receiving either 5.0 g / day AndroGel ^® , 7.5 g / day, 10 g / day AndroGel ^® , or patch with testosterone.

11 (b) shows the curves of estimates (values) of the effect of satisfying an erection on days 0 to 180 in hypogonadal men receiving either 5.0 g / day AndroGel ^® , 7.5 g / day, 10 g / day AndroGel ^® , or a patch with testosterone.

11 (c) shows the curves of estimates (in percent) of an erection on days 0 to 180 in hypogonadal men receiving either 5.0 g / day AndroGel ^® , 7.5 g / day, 10 g / day AndroGel ^® or patch with testosterone.

DETAILED DESCRIPTION OF THE INVENTION

Although the present invention can be embodied in many different forms, several specific embodiments of the invention are discussed in this description, but in view of the fact that the present description should be considered only as an explanation of examples of principles of the invention, not intended to limit the invention to illustrative examples.

The present invention relates to a pharmaceutical composition for administration through the skin, containing testosterone in a water-alcohol gel, suitable for the treatment of erectile dysfunction and libido disorders. In a broad aspect of the present invention, other steroids (e.g., androstenedione, androstenediol, dehydroepiandrosterone, prenolone and DHT) may be used in the anabolic or catabolic pathway of testosterone metabolism. The gel contains one or more lower alcohol, such as ethanol or isopropanol; absorption enhancer; thickener; and water. In addition, the present invention may, if necessary, contain salts, emollients, stabilizers, antimicrobial agents, aromatic substances and dispersants.

A substance that enhances absorption (penetration), "absorption enhancer", is an agent known as an accelerator of drug delivery through the skin. These agents are also called accelerators, adjuvants and sorption promoters, and in this description they are combined under the general name "enhancers". This class of agents includes agents with various mechanisms of action, including mechanisms that improve the solubility and diffusion ability of a drug substance, and mechanisms that increase absorption through the skin by changing the ability of the corneous layer to retain moisture, soften the skin, increase skin permeability, acting as penetration agents (absorption), or opening hair follicles, or changing the condition of the skin, such as the boundary layer.

The absorption enhancer (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 a fatty acid at a carboxy functional group or their isosteric modifications. In one embodiment of the invention, the functional derivative of the fatty acid is an unsaturated alkanoic acid in which the —COOH group is substituted with its functional derivative, such as alcohols, polyols, amides and substituted derivatives thereof. The term "fatty acid" means a fatty acid containing from four (4) to twenty-four (24) carbon atoms.

Non-limiting examples of absorption 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; C8-C22 lower fatty acid alkyl esters such as ethyl oleate, isopropyl myristate, butyl stearate and methyl laurate; C6-C8 di (lower) alkyl esters of dicarboxylic acids, such as diisopropyl adipate; C8-C22 fatty acid monoglycerides, such as glyceryl monolaurate; tetrahydrofurfuryl alcohol ether and polyethylene glycol; polyethylene glycol, propylene glycol; 2- (2-ethoxyethoxy) ethanol; diethylene glycol monomethyl ether; polyethylene oxide alkylaryl ethers; polyethylene oxide monomethyl esters; polyethylene oxide dimethyl esters; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetate ether; N-alkylpyrrolidone; and terpenes.

The thickeners used herein may include anionic polymers such as polyacrylic acid (CARBPOL ^® from BFGoodrich Specialty Polymers and Chemicals Division of Cleveland , Ohio), carboxymethylcellulose and the like Other thickeners, enhancers and adjuvants can typically be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary.

The composition is used in a "pharmacologically effective amount." This means that the concentration of testosterone is such that in the composition it results in a therapeutic level of the drug substance delivered over the time determined by the gel used. Such delivery depends on a number of variables, including the time during which an individual standard dose should be used, the rate of testosterone release from the gel, the surface area of the application, etc. The required amount of testosterone can be determined experimentally, based on the speed of passage of the drug through the gel and through the skin in the case of use with enhancers and without them.

One such gel has recently started to be sold in the United States under the AndroGel ^® trademark by Unimed Pharmaceuticals, Inc., Deerfield, Illinois, the holder of this application. In one embodiment of the invention, the gel contains the following substances in exemplary amounts:

Table 3 Composition AndroGel ^® Substance Amount (weight / weight) per 100 g of gel Testosterone 1.0 g Carbopol 980 0.90 g Isopropyl myristate 0.50 g 0.1 N NaOH 4.72 g Ethanol (95 wt.%) 72.5 g * Purified Water (qs) 100 g * Corresponds to 67 g of ethanol

The person skilled in the art understands that the quantitative composition of this formulation may change, continuing to be consistent with the spirit and remaining within the scope of this invention. For example, the composition may contain about 0, -10.0 g of testosterone, about 0.1-5.0 g of CARBOPOL, about 0.1-5.0 g of isopropyl myristate and about 30.0-98 g of ethanol.

A therapeutically effective amount of gel is rubbed by the user on a given area of the skin. The combination of lipophilic testosterone with a water-alcohol gel helps to promote testosterone to the outer layers of the skin, where it is absorbed and then slowly released into the bloodstream. As shown by the data given in this description, the gel according to this invention has a prolonged effect.

The toxicity and therapeutic efficacy of testosterone can be determined by standard pharmaceutical methods, for example, determination of LD ₅₀ (lethal dose for 50% of the population) and ED ₅₀ (therapeutically effective dose in the case of 50% of the population). The ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio of LD ₅₀ / ED ₅₀ . Compounds with a large therapeutic index are preferred. Although compounds with toxic side effects can be used, care must be taken when creating a delivery system that delivers these compounds to the affected tissue in order to minimize the 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 the practical application of the present invention, unless otherwise indicated, use the usual methods of pharmacology and pharmaceuticals known to specialists in this field of technology.

Examples

Example 1: Method for increasing sexual activity and libido in hypogonadal men

One embodiment of the present invention includes the transdermal use of AndroGel ^® as a method of increasing sexual activity and libido in hypogonadal men without causing noticeable skin irritation.

In this example, men are selected and studied at 16 centers in the United States. Patients are 19–68 years old, and upon screening, their single morning serum testosterone levels are less than or equal to 300 ng / dl (10.4 nmol / L). A total of 227 patients were registered, randomly divided into groups: 73, 78 and 76 people receiving 5.0 g / day AndroGel ^® (delivering 50 mg / day of testosterone to the skin, of which about 10% or 5 mg is absorbed), 10 g / day AndroGel ^® (delivering 100 mg / day of testosterone to the skin, of which about 10% or 10 mg is absorbed) or patch (patch) with ANDRODERM ^® testosterone ("T-pad (patch)" delivering 50 mg / day of testosterone), respectively .

As shown in the table below, there are no significant group-related differences between the baseline characteristics.

Table 4 Basic characteristics of hypogonadal men Processing group T-patch AndroGel ^® (5.0 g / day) AndroGel ^® (10.0 g / day) The number of patients in the group 76 73 78 Age (years) 51 51.3 51.0 Scatter (years) 28-67 23-67 19-68 Height (cm) 179.3 ± 0.9 175.8 ± 0.8 178.6 ± 0.8 Weight, kg) 92.7 ± 1.6 90.5 ± 1.8 91.6 ± 1.5 Serum Testosterone (nmol / L) 6.40 ± 0.41 6.44 ± 0.39 6.49 ± 0.37 Causes of Hypogonadism Primary hypogonadism 34 26 34 Kleinfelter's syndrome 9 5 8 Postorchiectomy / Anorchia 2 one 3 Primary testicular dysfunction 23 twenty 23 Secondary hypogonadism fifteen 17 12 Kallman's syndrome 2 2 2 Hypothalamic pituitary disorder 6 6 3 Pituitary cancer 7 9 9 Age 6 13 6 Not classified 21 17 26 When diagnosed (years) 5.8 ± 1.1 4.4 ± 0.9 5.7 ± 1.24 The number of testosterone previously given 50 (65.8%) 38 (52.1%) 46 (59.0%) Earlier Treatment Intramuscular injection 26 twenty 28 Transdermal patch 12 7 8 Rest 12 eleven 10 Treatment duration 5.8 ± 1.0 5.4 ± 0.8 4.6 ± 0.7

Forty-one percent (94/227) of the number of patients did not receive previous testosterone replacement therapy. Previously treated patients with hypogonadism stopped injecting testosterone ester at least six weeks, and oral or transdermal administration of androgens four weeks before the examination. In addition to hypogonadism, patients have good health, as can be seen from the medical history, physical examination, complete blood count, urinalysis, and biochemical blood test. If study participants take lipid lowering agents or tranquilizers, their doses will be stabilized at least three months before selection. Less than 5% of the participants in the experiment receive additional calcium or vitamin D during the study. There is no history of chronic diseases, alcohol or drug dependence in the history of the study participants. The rectal examination is normal, the PSA level is less than 4 ng / ml, and the urine flow rate is 12 ml / s or more. Patients are not included in the study if they have a common skin disease that can affect the absorption of testosterone, or if a history of skin irritation by the patch (lining) with ANDRODERM ^{® is} noted. Also excluded are patients whose weight is less than 80% or more than 140% of the ideal body weight.

In a randomized, multicenter parallel study, the effect of two doses of AndroGel ^{® is} compared with the action of a patch (patch) with ANDRODERM ^® testosterone. A double-blind AndroGel ^® dose-response study and an open-label study were conducted for the testosterone patch group. During the first three months of the study (days 1-90), patients are randomly divided into groups that use 5.0 g / day AndroGel ^® , 10.0 g / day AndroGel ^® or two non-scrotal patches (patches). In the next three months (days 91-180), patients undergo one of the following courses of treatment: 5.0 g / day AndroGel ^® , 7.5 g / day AndroGel ^® , 10.0 g / day AndroGel ^®, or two non-scrotal patches (patches ) In patients receiving AndroGel ^® , serum testosterone is determined once before use on the 60th day and, if it is normal, from 300 to 1000 ng / dl (10.4-34 nmol / l), they are left with the initial dose. Patients whose testosterone level is below 300 ng / dl and who initially took 5.0 g / day of AndroGel ^® , and those who have a testosterone level above 1000 ng / dl and who first took 10.0 g / day of AndroGel ^® , are changed dose and appoint 7.5 g / day AndroGel ^® from 91 to 180 days.

Accordingly, based on the levels of serum testosterone measured before use (of the drug substance) on day 60, after 90 days the dose is adjusted in the groups receiving AndroGel ^® . Twenty patients from the group receiving 5.0 g / day AndroGel ^® , the dose is increased to 7.5 g / day. Twenty patients from the group receiving 10.0 g / day AndroGel ^® , the dose is reduced to 7.5 g / day. Three patients from the group receiving the patch with testosterone are prescribed 5.0 g / day AndroGel ^® due to the intolerance of the patch (patch). One patient receiving 10.0 g / day AndroGel ^® is prescribed 5.0 g / day, and one patient receiving 5.0 g / day AndroGel ^® is adjusted the dose to 2.5 g / day. The number of patients registered for the study on days 91-180, therefore, is 51, receiving 5.0 g / day AndroGel ^® , 40, receiving 7.5 g / day AndroGel ^® , 52, receiving 10.0 g / day AndroGel ^® , and 52, continuing treatment with the lining with ANDRODERM ^® .

A. AndroGel ^® and ANDRODERM ^® patch

Approximately 250 g of AndroGel ^{® is} packaged in refillable vials that dispense 2.25 g of gel each time the pump is started. Patients who are scheduled to receive testosterone in the form of 5.0 g / day AndroGel ^® are given one vial of AndroGel ^® and one bottle of placebo gel (containing a vehicle but not containing testosterone), while patients who are prescribed 10.0 g / day AndroGel ^® , give two bottles of active AndroGel ^® . Then the patients are instructed how to apply the contents of the vials on the right and left shoulder / forearm and on the right and left sides of the abdomen alternately. For example, on the first day of the study, patients make two inlets from one bottle, one on the right and left shoulder / forearm, and two inlets from the second bottle, one on the right and left half of the abdomen. The next day, the application is reversed. Alternation of application sites continues throughout the study. After applying the gel to the skin, it is dried for several minutes. Patients wash their hands thoroughly with soap and water immediately after applying the gel.

The AndroGel ^® 7.5 g / day group does not receive their dose blindly (with an open label). After 90 days, patients given a dose of 7.5 g / day AndroGel ^® are given three vials, one containing a placebo and two other AndroGel ^® . Patients are instructed to make one inlet from the placebo vial and three inlets (three presses) from the AndroGel ^® vial, applied to four different parts of the body as described above.

ANDRODERM ^® patches with testosterone, each of which delivers 2.5 mg / day of testosterone, appoint approximately one third of the study participants. These patients are instructed to apply two patches of testosterone to the clean, dry skin of their back, abdomen, forearms, or hips once a day. Overlay locations change with approximately a seven-day interval between overlays at the same location.

In those days when a medical examination occurs, gel / patches are applied / applied after it. On the remaining days, gel or patches with testosterone are applied / applied at about 8:00 a.m. for 180 days.

B. Research Method and Results.

1. Pharmacokinetics of hormones

On days 0, 1, 30, 90, and 180, blood tests for testosterone and free testosterone are taken repeatedly from patients 30, 15, and 0 minutes before and 2, 4, 8, 12, 16, and 24 hours after AndroGel ^® application or application patch. In addition, patients arrive on days 60, 120 and 150 to take one blood test before applying the gel or applying a patch. Serum DHT, E ₂ , FSH, LH, and SHBG are determined in samples taken before gel application on days 0, 30, 60, 90, 120, 150, and 180. Serum for analysis of homons is stored frozen at -20 ° C until analysis. All measurements with samples taken from the patient for each hormone, if possible, are carried out during the same analysis. Then hormone analyzes are carried out in the laboratory of endocrine studies of the Medical Center UCLA-Harbor.

The following table summarizes the pharmacokinetic parameters for each patient:

Table 5 Pharmacokinetic parameters AUC _0-24 area under the curve from 0 to 24 hours, determined by the linear trapezoidal formula C _base or C _about Base concentration C _avg time-averaged concentration over a 24-hour dosing interval, defined as AUC _0-24 / 24 C _max maximum concentration over a 24-hour interval between doses C _min minimum concentration over a 24-hour interval between doses T _max time when C _max is observed T _min time when C _min is observed Fluctuation index the change in serum concentration over one day, calculated as (C _max -C _min ) / C _avg Accumulation Ratio the increase in the daily effect of the drug with prolonged use, calculated as the ratio of the steady state AUC on a particular day to the AUC on day 1 (for example, AUC _{day 30} / AUC _{day 1} ) Net AUC _0-24 AUC _0-24 on days 30, 90, 180 - AUC _0-24 on day 0

but. Pharmacokinetics of Testosterone

(1) Methods

Serum testosterone levels were determined after extraction with ethyl acetate and hexane by specific radioimmunoassay ("RIA", "RIA") using reagents from ICN (Costa Mesa, CA). The cross-reactivity of the antiserum used for RIA of testosterone is 2% for DHT, 2.3% for androsterone, 0.8% for 3-β-androstanediol, 0.6% for etiocholanolone, and less than 0.01% in against other tested steroids. The lower measurement limit (“LLQ”) for serum testosterone determined by this assay is 25 ng / dl (0.87 nmol / L). The average accuracy of testosterone analysis, determined by adding increasing amounts of testosterone (0.9 nmol / L - 52 nmol / L) to serum free of steroids, is 104% and is in the range of 92-117%. When analyzing testosterone, the coefficients (divergence of results) in one analysis and between analyzes are 7.3 and 11.1%, respectively, in the normal interval for adult men. In normal adult males, the concentration of testosterone is in the range of 298-1043 ng / dl (10.33 -36.17 nmol / L), as determined by the UCLA-Harbor Medical Center.

(2) Base (initial) concentration

As shown in Tables 6 (a) -6 (b) and FIG. 1 (a), on the baseline, mean serum testosterone concentrations over 24 hours (C _avg ) are similar in groups and below the normal interval for adults. Moreover, changes in serum concentration (based on the maximum and minimum concentrations within 24 hours, C _max and C _min , respectively) during the day are also similar in the three groups. Figure 1 (a) shows that average testosterone levels have a maximum value between 8 and 10 hours of the morning (i.e., after 0-2 hours) and a minimum value after 8-12 hours, showing a slight change in serum testosterone during the day . In about a third of patients in each group, the C _avg value is in the lower interval for normal adult men on day 0 (24/73 for the group receiving 5.0 g / day AndroGel ^® , 26/78 for the group receiving 10.0 g / AndroGel ^® day and 25/76 for the group using testosterone patches). In all patients, except three, at the time of admission (registration), the level of serum testosterone is less than 300 ng / dl (10.4 nmol / l).

Table 6 (a) Basic pharmacokinetic parameters of the treatment initiation group (Mean ± SD) 5.0 g / day T-gel 10.0 g / day T-gel T-patch N 73 78 76 C _avg (ng / dl) 237 ± 130 248 ± 140 237 ± 130 C _max (ng / dl) 328 ± 178 333 ± 194 314 ± 179 T _max * (h) 4.0 (0.0-24.5) 7.9 (0.0-24.7) 4.0 (0.0-24.3) C _min (ng / dl) 175 ± 104 188 ± 112 181 ± 112 T _min (h) 8.01 (0.0-24.1) 8.0 (0.0-24.0) 8.0 (0.0-23.9) Fluctuation Index (ratio) 0.627 ± 0.479 0.556 ± 0.384 0.576 ± 0.341 * Median value (median) (Interval *)

Table 6 (b) Basic pharmacokinetic parameters of the group completing treatment (Mean ± SD) Doses received in the initial ⇒ continuing stage of treatment 5.0 g / day T-gel 5.0⇒7.5 g / day T-gel 10.0⇒7.5 g / day T-gel 10.0 g / day T-gel T-patch N 53 twenty twenty 58 76 C _avg (ng / dl) 247 ± 137 212 ± 109 282 ± 157 236 ± 133 237 ± 140 C _max (ng / dl) 333 ± 180 313 ± 174 408 ± 241 307 ± 170 314 ± 179 T _max * (h) 4.0 (0.0-24.5) 4.0 (0.0-24.0) 19.7 (0.0-24.3) 4.0 (0.0-24.7) 4.0 (0.0-24.3) C _min (ng / dl) 185 ± 111 150 ± 80 206 ± 130 182 ± 106 181 ± 112 T _min (h) 8.0 (0.0-24.1) 11.9 (0.0-24.0) 8.0 (0.0-23.3) 8.0 (0.0-24.1) 8.0 (0.0-24.1) Fluctuation Index (ratio) 0.600 ± 0.471 0.699 ± 0.503 0.678 ± 0.580 0.514 ± 0.284 0.576 ± 0.341 * Median value (median, interval)

(3) Day 1

FIG. 1 (b) and Tables 6 (c) to (d) show the pharmacokinetic parameters for all three treatment groups after the first transdermal administration of testosterone. As a rule, treatment with AndroGel ^® and a patch with testosterone leads to an increase in testosterone concentrations, which is large enough to bring it to a level in a normal interval within a few hours. However, even on day 1, the pharmacokinetic curves differ markedly in the groups using AndroGel ^® and the patch. The level of serum testosterone rises most quickly in the group using the patch with testosterone, reaching a maximum concentration (C _max ) in about 12 hours (T _max ). In contrast, serum testosterone levels after application of AndroGel ^® evenly increase, reaching C _max , after 22 and 16 hours in the group using 5.0 g / day AndroGel ^® and in the group using 10.0 g / day AndroGel ^® , respectively.

Table 6 (c) Pharmacokinetic parameters of testosterone on day 1 in the treatment initiation group (Mean ± SD) 5.0 g / day T-gel 10.0 g / day T-gel T-patch N 73 76 74 C _avg (ng / dl) 398 ± 156 514 ± 227 482 ± 204 C _max (ng / dl) 560 ± 269 748 ± 349 645 ± 280 T _max * (h) 22.1 (0.0-25.3) 16.0 (0.0-24.3) 11.8 (1.8-24.0) C _min (ng / dl) 228 ± 122 250 ± 143 232 ± 132 T _min (h) 1.9 (0.0-24.0) 0.0 (0.0-24.2) 1.5 (0.0-24.0)

Table 6 (d) Pharmacokinetic parameters of testosterone on day 1 in the group completing treatment (Mean ± SD) Doses received in the initial ⇒ continuing treatment 5.0 g / day T-gel 5.0⇒7.5 g / day T-gel 10.0⇒7.5 g / day T-gel 10.0 g / day T-gel T-patch N 53 twenty 19 57 74 C _avg (ng / dl) 411 ± 160 363 ± 143 554 ± 243 500 ± 223 482 ± 204 C _max (ng / dl) 573 ± 285 525 ± 223 819 ± 359 724 ± 346 645 ± 280 T _max * (h) 22.1 (0.0-25.3) 19.5 (1.8-24.3) 15.7 (3.9-24.0) 23.0 (0.0-24.3) 11.8 (1.8-24.0) C _min (ng / dl) 237 ± 125 204 ± 112 265 ± 154 245 ± 140 232 ± 132 T _min (hour) 1.8 (0.0-24.0) 3.5 (0.0-24.0) 1.9 (0.0-24.2) 0.0 (0.0 - 23.8) 1.5 (0.0-24.0) Fluctuation Index (ratio) 0.600 ± 0.471 0.699 ± 0.503 0.678 ± 0.580 0.514 ± 0.284 0.576 ± 0.341 * Median value (median, interval)

(4) Days 30, 90 and 180

FIGS. 1 (c) and 1 (d) show a unique 24-hour pharmacokinetic curve for patients using AndroGel ^® on days 30 and 90. In groups using AndroGel ^® , a slight and unstable increase in serum testosterone levels is observed shortly after the dose . Then the levels return to a relatively constant value. In contrast, in the group using the patch with testosterone, patients observed an increase in the first 8-12 hours, a plateau in the next 8 hours, and then decrease to the baseline of the previous day. In addition, after applying the gel on day 30 and day 90, C _avg in the group using 10.0 g / day AndroGel ^® is 1.4 times higher than in the group using 5.0 g / day AndroGel ^® , and 1.9 times higher than in the group using the patch with testosterone. In the group using the patch with testosterone, C _{min is} significantly lower than the lower limit of the normal interval. On day 30, the accumulation ratio is 0.94 for the group using the patch with testosterone, which indicates the absence of accumulation. The accumulation ratios of 1.54 and 1.9 are significantly higher in the group using 5.0 g / day AndroGel ^® and in the group using 10.0 g / day AndroGel ^® , respectively. The difference in the accumulation ratio between the groups persists even on day 90. These data show that AndroGel ^® preparations have a longer effective half-life than a testosterone patch.

FIG. 1 (e) shows a 24-hour pharmacokinetic curve for treatment groups on day 180. As a rule, as shown in Table 6 (e), the achieved serum testosterone concentrations and pharmacokinetic parameters are similar to serum testosterone concentrations and pharmacokinetic parameters in days 30 and 90 in those patients who continue treatment in the groups to which they are initially randomly assigned. From Table 6 (f) it can be seen that the group of patients using 7.5 g / day AndroGel ^® is heterogeneous. Patients who were previously in the group using 10.0 g / day tend to have higher levels of serum testosterone than patients previously using 5.0 g / day. On day 180 C _avg in patients who previously applied 10 g / day and switched to a regimen of 7.5 g / day on day 90, is 744 ng / dl, which is 1.7 times higher than C _avg 450 ng / dl in patients who switched to 7.5 g / day from the group using 5.0 g / day. Despite a dose adjustment of 2.5 g / day in the group that switched from 5.0 g / day to 7.5 g / day, the C _avg value remains lower than in patients remaining in the 5.0 g group /day. In the 10 g / day group, ⇒ 7.5 g / day, the C _avg value is similar to the C _avg value achieved in patients remaining in the group that continues to use 10 g / day. These results suggest that many of these respondents with poor results may in fact be not very obedient, malleable patients. For example, if the patient does not apply AndroGel ^® properly (for example, preferably uses a container with a placebo or applies the gel shortly before bathing), then increasing the dose will not give an additional positive effect.

FIG 1 (f) - (h) compares the pharmacokinetic curves for groups using 5.0 g / day AndroGel ^® , 10.0 g / day AndroGel ^® and a patch with testosterone on days 0, 1, 30, 90 and 180 As a rule, the average serum testosterone levels in the group using the testosterone patch remain at the lower limit of the normal interval throughout the treatment period. In contrast, average serum testosterone levels persist around 490-570 ng / dl for the AndroGel ^® 5.0 g / day group and 630-860 ng / dl for the AndroGel ^® 10.0 g / day group.

Table 6 (e) Pharmacokinetic parameters of testosterone on day 1 in the treatment initiation group (Mean ± SD) 5.0 g / day T-gel 10.0 g / day T-gel T-patch Day 30 N = 66 N = 74 N = 70 C _avg (ng / dl) 566 ± 262 792 ± 294 419 ± 163 C _max (ng / dl) 876 ± 466 1200 ± 482 576 ± 223 T _max * (h) 7.9 (0.0-24.0) 7.8 (0.0-24.3) 11.3 (0.0-24.0) C _min (ng / dl) 361 ± 149 505 ± 233 235 ± 122 T _min (h) 8.0 (0.0-24.1) 8.0 (0.0-25.8) 2.0 (0.0-24.2) Fluct. index (rel.) 0.857 ± 0.331 0.895 ± 0.434 0.823 ± 0.289 Rel accumulation (rel.) 1.529 ± 0.726 1.911 ± 1.588 0.937 ± 0.354 Day 90 N = 65 N = 73 N = 64 C _avg (ng / dl) 553 ± 247 792 ± 276 417 ± 157 C _max (ng / dl) 846 ± 444 1204 ± 570 597 ± 242 T _max * (h) 4.0 (0.0-24.1) 7.9 (0.0-25.2) 8.1 (0.0-25.0) C _min (ng / dl) 354 ± 147 501 ± 193 213 ± 105 T _min (h) 4.0 (0.0-25.3) 8.0 (0.0.-24.8) 2.0 (0.0-24.0) Fluct. index (rel.) 0.851 ± 0.402 0.859 ± 0.399 0.937 ± 0.442 Rel accumulation (rel.) 1.615 ± 0.859 1.927 ± 1.310 0.971 ± 0.453 Day 180 N = 63 N = 68 Number 45 C _avg (ng / dl) 520 ± 227 722 ± 242 403 ± 163 C _max (ng / dl) 779 ± 359 1091 ± 437 580 ± 240 T _max * (h) 4.0 (0.0-24.0) 7.9 (0.0-24.0) 10.0 (0.0-24.0) C _min (ng / dl) 348 ± 164 485 ± 184 223 ± 114 T _min (h) 11.9 (0.0-24.0) 11.8 (0-0-27.4) 2.0 (0.0-25.7) Fluct. index (rel.) 0.845 ± 0.379 0.829 ± 0.392 0.891 ± 0319 Rel accumulation (rel.) 1.523 ± 1.024 1.897 ± 2.123 0.954 ± 0.4105 * Median value (median, interval)

Table 6 (f) Pharmacokinetic parameters of testosterone on days 30, 90, 180 in the group completing treatment (Mean ± SD) Doses obtained in the initial⇒continuing stage of treatment 5.0 g / day T-gel 5.0⇒7.5 g / day T-gel 10.0⇒7.5 g / day T-gel 10.0 g / day T-gel T-patch Day 30 N = 47 N = 19 N = 19 N = 55 N = 70 C _avg (ng / dl) 604 ± 288 472 ± 148 946 ± 399 739 ± 230 419 ± 163 C _max (ng / dl) 941 ± 509 716 ± 294 1409 ± 556 1128 ± 436 576 ± 223 T _max * (h) 7.9 (0.0-24.0) 8.0 (0.0-24.0) 8.0 (0.0-24.3) 7.8 (0.0-24.3) 11.3 (0.0-24.0) C _min (ng / dl) 387 ± 159 296 ± 97 600 ± 339 471 ± 175 235 ± 122 T _min (h) 8.1 (0.0-24.1) 1.7 (0.0-24.1) 11.4 (0.0-24.1) 8.0 (0.0-25.8) 2.0 (0.0-24.2) Flux index (rel) 0.861 ± 0.341 0.846 ± 0.315 0.927 ± 0.409 0.884 ± 0.445 0.823 ± 0.289 Relative Acc. (Rel) 1.543 ± 0.747 1.494 ± 0.691 2.053 ± 1.393 1.864 ± 1.657 0.937 ± 0.354 Day 90 N = 45 N = 20 N = 18 N = 55 N = 64 C _avg (ng / dl) 596 ± 266 455 ± 164 859 ± 298 771 ± 268 417 ± 157 C _max (ng / dl) 931 ± 455 654 ± 359 1398 ± 733 1141 ± 498 597 ± 242 T _max * (h) 3.8 (0.0-24.1) 7.7 (0.0-24.0) 7.9 (0.0-24.0) 7.9 (0.0-25.2) 8.1 (0.0-25.0) C _min , (ng / dl) 384 ± 147 286 ± 125 532 ± 181 492 ± 197 213 ± 105 T _min (h) 7.9 (0.0-25.3) 0.0 (0.0-24.0) 12.0 (0.0-24.1) 4.0 (0.0-24.8) 2.0 (0.0-24.0) Fluk. index (rel) 0.886 ± 0.391 0.771 ± 0.425 0.959 ± 0.490 0.826 ± 0.363 0.937 ± 0.442 Rel accumulated (rel) 1.593 ± 0.813 1.737 ± 1.145 1.752 ± 0.700 1.952 ± 1.380 0.971 ± 0.453 Day 180 N = 44 N-18 N = 19 N = 48 N = 41 C _avg (ng / dl) 555 ± 225 450 ± 219 744 ± 320 7l3 ± 209 408 ± 165 C _max (ng / dl) 803 ± 347 680 ± 369 1110 ± 468 1083 ± 434 578 ± 245 T _max * (h) 5.8 (0.0-24.0) 2.0 (0.0-24.0) 7.8 (0.0-24.0) 7.7 (0.0-24.0) 10.6 (0.0-24.0) C _min (ng / dl) 371 ± 165 302 ± 150 505 ± 233 485 ± 156 222 ± 116 T _min (h) 11.9 (0.0-24.0) 9.9 (0.0-24.0) 12.0 (0.0-24.0) 8.0 (0.0-27.4) 2.0 (0.0-25.7) Flux index (rel) 0.853 ± 0.402 0.833 ± 0.335 0.824 ± 0.298 0.818 ± 0.421 0.866 ± 0.311 Rel accumulated (rel.) 1.541 ± 0.917 NA NA 2.061 ± 2.445 0.969 ± 0.415 * Median value (median, interval)

(5) AndroGel ^® Dose Proportionality

Table 6 (g) shows the increase in AUC _0-24 , calculated as the arithmetic mean, on days 30, 90 and 180 compared to the baseline (net AUC _0-24 ). To determine dose proportionality, an AUC _0-24 bioequivalence is evaluated in a logarithmic format using “treatment (treatment)” as the only factor. AUC is compared after subtracting the contribution to the AUC of endogenous testosterone secretion (AUC on day 0) and adjusting for the twofold difference in the applied doses. The AUC ratio on day 30 is 0.95 (90% CI: 0.75-1.19), and on day 90 it is 0.92 (90% CI: 0.73-1.17). When the data of day 30 and day 90 are combined, the AUC ratio is 0.93 (90% CI: 0.79-1.10).

Data show dose proportionality in the treatment of AndroGel ^® . The geometric mean AUC increase of _0-24 from day 0 to day 30 or day 90 is twice as large for the 10 g / day group compared to the 5.0 g / day group. An average increase in serum testosterone C _{avg of} 125 ng / dl is obtained with AndroGel ^® every 2.5 g / day. In other words, the data show that 0.1 g / day AndroGel ^® gives a serum testosterone concentration of 5 ng / dl. This dose proportionality helps doctors adjust the dose. Since AndroGel ^{® is} available in 2.5 g packages (containing 25 mg), each 2.5 g package gives an average increase in C _{avg of} total serum testosterone of 125 ng / dl.

Table 6 (g) Net AUC _0-24 (nmol * h / l) on days 30, 90, and 180 after transdermal testosterone administration T-patch T-gel 5.0 g / day T-gel 10.0 g / day Day 30 154 ± 18 268 ± 28 446 ± 30 Day 90 157 ± 20 263 ± 29 461 ± 28 Day 180 160 ± 25 250 ± 32 401 ± 27

The increase in AUC _0-24 compared with the baseline before the start of the study in the groups of 10.0 g / day and 5.0 g / day is approximately 2.7 and 1.7 times greater than when using a patch with testosterone. These figures also indicate that the ANDRODERM ^® patch, which causes an increase in C _{avg of} about 180 ng / dl, is equivalent to about 3.5 g / day of AndroGel ^® .

b. Pharmacokinetics of serum free testosterone concentration

(1) Methods

Serum free testosterone is determined by the RIA dialysate method after equilibrium dialysis overnight using the same RIA reagents as in the testosterone assay. The LLQ value of free serum testosterone, determined by equilibrium dialysis, is 22 pmol / L. When increasing doses of testosterone are added to the steroid-free serum in the range corresponding to the concentration range in an adult male, increasing amounts of free testosterone are regenerated with a scattering coefficient in the range of 11.0-18.5%. External and internal (between analyzes and in one analysis) free testosterone ratios are 15% and 16.8% for values for healthy adult men. The UCLA-Harbor Medical Center estimates that free testosterone concentrations in normal adult males are 3.48-17.9 ng / dL (121-620 pmol / L).

(2) Pharmacokinetic results

In general, as shown in Table 7, the pharmacokinetic parameters of free serum testosterone, as in a mirror, reflect the pharmacokinetic parameters of total testosterone, as described above. On the baseline (day 0), average serum free testosterone concentrations (C _avg ) are similar in all three groups and correspond to the lower limit for adult men. The maximum concentration of free serum testosterone is observed between 8 and 10 in the morning, and the minimum concentration is observed after about 8-16. These data are consistent with weak daily variability of serum testosterone.

FIG. 2 (a) shows 24-hour pharmacokinetic curves for all three groups participating in the experiment. After applying testosterone patches, serum free testosterone levels peak 12 hours later, about 4 hours earlier than peaks achieved in the AndroGel ^® groups. Serum free testosterone levels then fall in the group using the testosterone patch, while in the AndroGel ^® groups, serum free testosterone levels continue to rise.

FIGS. 2 (b) and 2 (c) show the pharmacokinetic curves of free testosterone in the AndroGel ^® groups, resembling the unique testosterone curves on days 30 and 90. After AndroGel ^® application, the average serum free testosterone levels in the three groups are in the normal range . Similar to the results obtained for total testosterone, C _avg achieved in the group using 19.0 g / day is 1.4 times higher than in the group using 5.0 g / day, and 1.7 times higher. than in the group using the testosterone patch. In addition, the accumulation ratio in the group using the patch with testosterone is significantly lower than in the group using 5.0 g / day AndroGel ^® and in the group using 10.0 g / day AndroGel ^® .

FIG. 2 (d) shows the concentrations in the final experimental groups on day 180. Typically, the concentrations of free testosterone exhibit the same features as the concentrations of serum testosterone. 24-hour pharmacokinetic parameters are similar to those on days 30 and 90 in those patients who remain in three initially randomly formed groups. Again, the group of patients who are prescribed 7.5 g / day AndroGel ^® is not uniform. C _avg free testosterone in patients with a dose adjustment of 5.0⇒7.5 g / day remains 29% lower than C _avg free testosterone in patients remaining in the 5.0 g / day AndroGel ^® group. C _{avg of} free testosterone in patients whose doses are reduced from 10.0 to 7.5 g / day is 11% higher than in patients remaining in the group taking 10.0 g / day.

Figure 2 (e) - (g) shows the concentration of free testosterone in three groups of patients during the 180-day treatment period. And again, free testosterone levels "follow the example" of testosterone levels. The average levels of free testosterone in all three groups were in the normal range, while in the group using 10.0 g / day, higher testosterone levels remained than in the groups using 5.0 g / day and a patch with testosterone.

Table 7 Pharmacokinetic parameters of free testosterone during final treatment Doses received in the initial ⇒ Continuing stages of treatment 5.0 g / day T-gel 5.0⇒7.5 g / day T-gel 10.0⇒7.5 g / day T-gel 10.0 g / day T-gel T-patch Day 0 N = 53 N = 20 N = 20 N = 58 N = 76 C _avg (ng / dl) 4.52 ± 3.35 4.27 ± 3.45 4.64 ± 3.10 4.20 ± 3.33 4.82 ± 3.64 C _max (ng / dl) 5.98 ± 4.25 6.06 ± 5.05 6.91 ± 4.66 5-84 ± 4.36 6.57 ± 4.90 T _max * (h) 4.0 (0.0-24.5) 2.0 (0.0-24.0) 13.S (0.0-24.2) 2.1 (0.0-24.1) 3.8 (0.0-24.0) C _min (ng / dl) 3.23 ± 2.74 3.10 ± 2.62 3.14 ± 2.14 3.12 ± 2.68 3.56 ± 2.88 T _min (h) 8.0 (0.0.-24.2) 9.9 (0.0-16.0) 4.0 (0.0-23.3) 8.0 (0.0-24.0) 7.9 (0.0-24.0) Flux index (rel) 0.604 ± 0.342 0.674 ± 0.512 0.756 ± 0.597 0.634 ± 0.420 0.614 ± 0.362 Day 1 N = 53 N = 20 N = 19 N = 57 N = 74 C _avg (ng / dl) 7.50 ± 4.83 6.80 ± 4.82 9.94 ± 5.04 8.93 ± 6.09 9.04 ± 4.81 C _max (ng / dl) 10.86 ± 7.45 10.10 ± 7.79 15.36 ± 7.31 13.20 ± 8.61 12.02 ± 6.14 T _max * (h) 16.0 (0.0-25.3) 13.9 (0.0-24.3) 15.7 (2.0-24.0) 23.5 (1.8-24.3) 12.0 (1.8-24.01) C _min (ng / dl) 4.30 ± 3.33 3.69 ± 3.24 3.88 ± 2.73 4.40 ± 3.94 4.67 ± 3.52 T _min (h) 0.0 (0.0-24.1) 1.8 (0.0-24.0) 0.0 (0.0-24.2) 0.0 (0.0-23.9) 0.0 (0.0-24-0) Day 30 N = 47 N = 19 N = 19 N = 55 N = 70 C _avg (ng / dl) 11.12 ± 6.22 7.81 ± 3.94 16.18 ± 8.18 13.37 ± 7.13 8.12 ± 4.15 C _max (ng / dl) 16.93 ± 10.47 11.62 ± 6.34 25.14 ± 10.80 19.36 ± 9.75 11.48 ± 5.78 T _max * (h) 8.0 (0.0-27.8) 8.0 (0.0-26.3) 8.0 (0.0-24.3) 8.0 (0.0-24.3) 8.0 (0.0-24.0) C _min (ng / dl) 6.99 ± 3.82 4.78 ± 3.10 9.99 ± 7.19 8.25 ± 5.22 4.31 ± 3.20 T _min (h) 4.0 (0.0-24.1) 3.5 (0.0-24.1) 11.4 (0.0-24.1) 7.8 (0.0-25.8) 2.0 (0.0-24.8) Fluk. index (rel) 0.853 ± 0.331 0.872 ± 0.510 1.051 ± 0.449 0.861 ± 0.412 0.929 ± 0.311 Rel accumulated (rel) 1,635 ± 0.820 1.479 ± 0.925 2.065 ± 1.523 1.953 ± 1.626 0.980 ± 0.387 Day 90 N = 45 N = 20 N = 18 N = 55 N-64 C _avg (ng / dl) l2.12 ± 7.78 8.06 ± 3.78 17.65 ± 8.62 13.11 ± 5.97 8.50 = 5.04 C _max (ng / dl) 18.75 ± 1.90 10.76 ± 4.48 25.29 ± 12.42 18.61 ± 8.20 12.04 ± 6.81 T _max * (h) 4.0 (0.0.24.0) 9.7 (0.0-24.0) 8.0 (0.0-24.0) 8.0 (0.0-25.2) 11.6 (0.0-25.0) C _min (ng / dl) 7.65 ± 4.74 4.75 ± 2.86 10.56 ± 6.07 8.40 ± 4.57 4.38 ± 3.70 T _min (h) 8.0 (0.0-24.0) 1.9 (0.0-24.0) 5.9 (0.0-24.1) 4.0 (0.0-24.8) 2.0 (0.0-24.1) Fluk. index (rel) 0.913 ± 0.492 0.815 ± 0.292 0.870 ± 0.401 0.812 ± 0.335 0.968 ± 0.402 Rel accumulated (rel) 1.755 ± 0.983 1.916 ± 1.816 1.843 ± 0.742 2.075 ± 1.866 1.054 ± 0.498 Day 180 N = 44 N = 18 N = 19 N = 48 N = 41 C _avg (ng / dl) 11.01 ± 5.24 7.80 ± 4.63 14.14 ± 7.73 12.77 ± 5.70 7.25 ± 4.90 C _max (ng / dl) 16.21 ± 7.32 11.36 ± 6.36 22.56 ± 12.62 18.58 ± 9.31 10.17 ± 5.90 T _max * (h) 7.9 (0.0-24.0) 2.0 (0.0-23.9) 7.8 (0.0-24.0) 8.0 (0.0-24.0) 11.1 (0.0-24.0) C _min (ng / dl) 7.18 ± 3.96 5.32 ± 4.06 9.54 ± 6.45 8.23 ± 4.01 3.90 ± 4.20 T _min (h) 9.9 (0.0-24.2) 7.9 (0.0-24.0) 8.0 (0.0-23.2) 11.8 (0.0-27.4) 2.5 (0.0-25.7) Fluk. index (rel) 0.897 ± 0.502 0.838 ± 0.378 0.950 ± 0.501 0.815 ± 0.397 0.967 ± 0.370 Rel accumulated (rel) 1.712 ± 1.071 NA NA 2.134 ± 1.989 1.001 ± 0.580 * Median value (median, interval)

from. Serum DHT concentrations

Serum DHT is determined by RIA after treatment with a potassium permanganate sample after extraction. Methods and reagents for DHT analysis provided by DSL (Webster, TX). The cross-reactivity of the antiserum used in RIA for DHT analysis is 6.5% for 3-β-androstandiol, 1.2% for 3-α-androstanediol, 0.4% for 3-α-androstanediol glucuronide and 0 , 4% for testosterone (after treatment with potassium permanganate and extraction) and less than 0.01% for other steroids. This low cross-reactivity for testosterone is further confirmed by adding 35 nmol / L (1000 pg / dl) of testosterone to steroid-free serum and analyzing samples for DHT. The results, even with the addition of more than 35 nmol / L testosterone, are less than 0.1 nmol DHT. The serum DHT LLQ in the assay is 0.43 nmol / L. The average accuracy (yield) of the DHT analysis, determined by adding various amounts from steroid-free serum from 0.43 nmol / L to 9 nmol / L, DHT, is 101% and ranges from 83-114%. The dispersion coefficient (scatter) in one analysis and between analyzes (within groups and between groups) of DHT is 7.8 and 16.6%, respectively, for the interval of normal adult men. The normal range for adult males is 30.7-193.2 ng / dl (1.06-6.66 nmol / L) as defined by the UCLA-Harbor Medical Center.

As shown in Table 8, pre-experimental mean serum DHT concentrations are 36-42 ng / dl, which is close to the lower limit of the normal interval in all three treatment initiation groups. In none of the patients did DHT concentrations exceed the upper limit of the normal interval on the day before treatment, although almost half (103 patients) had concentrations lower than the lower limit.

FIG. 3 shows that after treatment, the difference between the average concentrations of DHT associated with the different treatment groups is statistically significant, while patients receiving AndroGel ^® have an average concentration of DHT higher than patients using the patch and average DHT concentrations serum is dose dependent. Specifically, after applying a patch with testosterone, the average levels of serum DHT increase by about 1.3 times compared to the baseline. In contrast, serum DHT rises to 3.6 and 4.8 times compared to the baseline after application of 5.0 g / day and 10.0 g / day AndroGel ^®, respectively.

Table 8 DHT concentrations (ng / dl) on each day of the examination from the start of treatment (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 5,0 N = 73 N = 69 N = 70 N = 65 N = 65 N = 63 N = 65 g / day T-gel 36.0 ± 19.9 117.6 ± 74.9 122.4 ± 99.4 130.1 ± 99.2 121.8 ± 89.2 144.7 ± 110.5 143.7 ± 105.4 10.0 N = 78 N = 78 N = 74 N = 75 N = 68 N = 67 N = 71 g / day T-gel 42 ± 29.4 200.4 ± 127.8 222.0 ± 126.6 207.7 ± 110.0 187.3 ± 97.3 189.1 ± 102.4 206.1 ± 105.4 T- N = 76 N = 73 N = 68 N = 66 N = 49 N = 46 N = 49 Patch 37.4 ± 21.4 50.8 ± 34.6 49.3 ± 27.2 43.6 ± 26.9 53.0 ± 52.8 54.0 ± 42.5 52.1 ± 34.3 Cross RX 0.6041 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

The increase in DHT concentrations should apparently be attributed to the concentration and localization of 5α-reductase in the skin. For example, large amounts of 5α-reductase in the scrotal skin are likely to cause an increase in DHT concentrations in the TESTODERM ^® patch. In contrast, ANDRODERM ^® and TESTODERM TTS ^® patches cause a slight change in DHT levels due to the small surface area of the patch and a little 5α-reductase localized in the non-scrotal skin. AndroGel ^® appears to cause an increase in DHT levels due to the fact that the gel is applied to a relatively large surface of the skin and therefore exposes testosterone with large amounts of the enzyme.

To date, there are no reports that elevated levels of DHT cause harmful clinical effects. Moreover, there is evidence that elevated levels of DHT can inhibit prostate cancer.

d. DHT / T Ratio

UCLA Medical Center - Harbor reports that the DHT / T ratio for normal adult males is 0.052-0.328. In this example, the average ratio values for all three treatment groups on day 0 correspond to the normal interval. As shown in FIG. 4 and Table 9, increases are observed over a 180-day period depending on treatment and concentration. Specifically, in the groups using AndroGel ^® , the largest increase in the DHT / T ratio is observed. However, the average ratio for all treated groups remains in the normal interval all days of the examination (examination).

Table 9 The ratio of DHT / T on each day of the examination from the start of treatment (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 5,0 N = 73 N = 68 N = 70 N = 67 N = 65 N = 62 N = 64 g / day T-gel 0.198 ± 0.137 0.230 ± 0.104 0.256 ± 0.132 0.248 ± 0.121 0.266 ± 0.119 0.290 ± 0.119 0.273 ± 0.160 10.0 N = 78 N = 77 N = 74 N = 74 N = 68 N = 67 N = 71 g / day T-gel 0.206 ± 0.163 0.266 ± 0.124 0.313 ± 0.160 0.300 ± 0.131 0,308 ± 0,145 0.325 ± 0.142 0.291 ± 0.124 T- N = 76 N = 73 N = 68 N = 65 N = 49 N = 46 N = 46 Patch 0.204 ± 0.135 0.192 ± 0.182 0.175 ± 0.102 0.175 ± 0.092 0.186 ± 0.134 0.223 ± 0.147 0.212 ± 0.160 Cross RX 0.7922 0.0001 0.0001 0.0001 0.0001 0.0001 0,0002

e. General androgen (DHT + T)

According to the definition of the UCLA - Harbor Medical Center, the normal concentration of total androgen is 372-1350 ng / dl. As shown in FIG. 5 and Table 10, the average “pre-dosage” concentrations of total androgen are below the lower limit per day before treatment. The concentrations of total androgen in both groups using AndroGel ^® correspond to the normal interval on all days of the examination. In contrast, the average concentrations in patients using a testosterone patch are very difficult to fit into the normal interval on days 60 and 120, but below the lower normal limit on days 30, 90, 150 and 180.

Table 10 Total androgen (DHT + T) (ng / dl) on each day of the examination from the start of treatment (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 5,0 N = 73 N = 68 N = 70 N = 67 N = 65 N = 62 N = 64 g / day T-gel 281 ± 150 659 ± 398 617 ± 429 690 ± 431 574 ± 331 631 ± 384 694 ± 412 10.0 N = 78 N = 77 N = 74 N = 74 N = 68 N = 67 N = 71 g / day T-gel 307 ± 180 974 ± 532 1052 ± 806 921 ± 420 827 ± 361 805 ± 383 944 ± 432 T- N = 76 N = 73 N = 68 N = 65 N = 49 N = 46 N = 46 Patch 282 ± 159 369 ± 206 392 ± 229 330 ± 173 378 ± 250 364 ± 220 355 ± 202 Cross RX 0.7395 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

f. Concentration E ₂

E ₂ levels are determined directly, without extraction, by analysis using ICN reagents (Costa Mesa, CA). The coefficient of variation of E ₂ in one analysis and between analyzes is 6.5 and 7.1, respectively. According to reports of the UCLA - Harbor Medical Center, the interval of the average concentration of E ₂ is 7.1-46.1 pg / ml (63-169 pmol / l) for normal adult men). LLQ E ₂ is 18 pmol / L. The cross-reactivity of the anti-E ₂ antibody is 6.9% with respect to estrone, 0.4% with respect to equilenine and less than 0.01% with respect to other tested steroids. The accuracy of the E ₂ assay is evaluated by injecting increasing amounts of E ₂ (18-275 pmol / L) into steroid-free serum. Regeneration (yield) E ₂ relative to the input amount is on average 99.1%, the interval 95 - 101%.

FIG. ₆ shows E ₂ concentrations over a 180-day study. The average concentrations of E ₂ before the study in all groups are 23-24 pg / ml. During the study, E ₂ levels increase on average by 9.2% in the group using the patch with testosterone, by 30.9% in the group using 5.0 g / day AndroGel ^® , and 45.5% in the group using 10 , 0 g / day AndroGel ^® . All average concentrations are within the normal range.

Table 11 The concentration of estradiol (pg / dl) on each day of the examination from the start of treatment (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 5,0 N = 73 N = 69 N = 69 N = 67 N = 64 N = 65 N = 65 g / day T-gel 23.0 ± 9.2 29.2 ± 11.0 28.1 ± 10.0 31.4 ± 11.9 28.8 ± 9.9 30.8 ± 12.5 32.3 ± 13.8 10.0 N = 78 N = 78 N = 74 N = 75 N = 71 N = 66 N = 71 g / day T-gel 24.5 ± 9.5 33.7 ± 11.5 36.5 ± 13.5 37.8 ± 13.3 34.6 ± 10.4 35.0 ± 11.1 36.3 ± 13.9 T- N = 76 N = 72 N = 68 N = 66 N = 50 N = 49 N = 49 Patch 23.8 ± 8.2 25.8 ± 9.8 24.8 ± 8.0 25.7 ± 9.8 25.7 ± 9.4 27.0 ± 9.2 26.9 ± 9.5 Cross RX 0.6259 0.0001 0.0001 0.0001 0.0001 0,0009 0,0006

It is believed that E _{2 is} important for maintaining bone strength. In addition, E ₂ has a positive effect on serum lipids.

g. Serum SHBG concentrations

Serum SHBG levels are determined by immunofluorescence analysis (ELISA, "FIA") with reagents from Delfia (Wallac, Gaithersberg, MD). Coefficients within and between analyzes are 5% and 12%, respectively. LLQ is 0.5 nmol / L. According to the UCLA - Harbor Medical Center, the interval for healthy adult men in the SHBG analysis is 0.8-46.6 nmol / L.

As shown in FIG. 7 and Table 12, serum SHBG levels are similar and are in the range of values for healthy adult males in the three treatment groups on the baseline. None of the treated groups showed significant changes compared with the baseline on any day of the visit to the doctor. After testosterone replacement, a slight decrease in serum SHBG levels is observed in all three groups. The most noticeable change is observed in the group using 10.0 g / day AndroGel ^® .

Table 12 The concentration of SHBG (nmol / l) on each day of the examination from the start of treatment (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 5,0 N = 73 N = 69 N = 69 N = 67 N = 66 N = 65 N = 65 g / day T-gel 26.2 ± 14.9 24.9 ± 14.0 25.9 ± 14.4 25.5 ± 14.7 25.2 ± 14.1 24.9 ± 12.9 24.2 ± 13.6 10.0 N = 78 N = 78 N = 75 N = 75 N = 72 N = 68 N = 71 g / day T-gel 26.6 ± 17.8 24.8 ± 14.5 25.2 ± 15.5 23.6 ± 14.7 25.5 ± 16.5 23.8 ± 12.5 24.0 ± 14.5 T- N = 76 N = 72 N = 68 N = 66 N = 50 N = 49 N = 49 Patch 30.2 ± 22.6 28.4 ± 21.3 28.2 ± 23.8 28.0 ± 23.6 26.7 ± 16.0 26.7 ± 16.4 25.8 ± 15.1 Cross RX 0.3565 0.3434 0.5933 0.3459 0.8578 0.5280 0.7668

b. Gonadotropins

Serum FSH (FSH) and LH (LH) are determined by highly sensitive and specific methods of solid-phase ELISA ("FIA") with reagents provided by Delfia (Wallac, Gaithersberg, MD). The coefficient of variation in one analysis for immunofluorescence analysis for LH and FSH is 4.3% and 5.2%, respectively, and the coefficient of variation between analyzes for LH and FSH is 11.0 and 12.0%, respectively. In both the LH analysis and the FSH analysis, the LLQ is 0.2 IU / L. Analysis of all samples from the same patient is carried out in one series. According to the UCLA - Harbor Medical Center, the interval for healthy adult men in the LH analysis is 1.0-8.1 U / L, and for FSH this interval is 1.0-6.9 U / L.

(1) FSH (FSH)

Table 13 (a) - (d) shows the concentration of FSH during a 180-day treatment depending on the cause of hypogonadism: (1) primary, (2) secondary, (3) age-related, or (4) the cause is unknown.

Patients with primary hypogonadism exhibit an intact feedback mechanism in the sense that low concentrations of serum testosterone are associated with high concentrations of FSH and LH. However, due to testicular or some other deficiency, high LH concentrations are ineffective in stimulating testosterone production.

Secondary hypogonadism includes a deficiency of idiopathic gonadotropin or LH releasing factor. Since patients with secondary hypogonadism do not have an intact feedback mechanism, lower testosterone concentrations are not associated with elevated levels of LH and FSH. Consequently, these men have low levels of serum testosterone, but the concentration of gonadotropins in the normal range.

Hypogonadism may be associated with age. In men, a slow but continuous decrease in the average level of serum testosterone is observed, after about 20-30 years. This testosterone deficiency in the absence of its treatment can lead to a number of physiological changes in older men. The end result is senile hypogonadism, or what is commonly called "male menopause."

As discussed above, patients with primary hypogonadism have a metabolic pathway for inhibiting intact feedback, but the testes do not secrete testosterone. As a result, rising serum testosterone levels result in lower serum FSH concentrations. In this example, a total of 94 patients with primary hypogonadism were identified. In these patients, the average FSH concentrations in the three treatment groups on day 0 are 21-26 IU / ml, above the upper limit of the normal interval. As shown in FIG. 8 (a) and Table 13 (a), the average FSH concentrations during the experiment are reduced with all three treatment regimens. However, only in the group receiving 10.0 g / day AndroGel ^® , the average concentrations are reduced to the normal interval during the first 90 days of treatment. When treated with 10.0 g / day, AndroGel ^® takes approximately 120 days to reach a steady state. The average concentration of FSH in patients receiving AndroGel ^® 5.0 g / day first decreases, the decline is compensated by day 30, and then another phase of decrease on day 120, which continues until the end of treatment. The average FSH concentrations in patients using a testosterone patch reach a steady state, apparently after 30 days, but these concentrations are well above the normal range.

Table 13 (a) Concentrations of FSH (FSH) (IU / ml) on each day of the examination in groups from the start of treatment in patients with primary hypogonadism (Mean ± SD) N 5 g / day N 10 g / day N T-patch Day 0 26 21.6 ± 21.0 33 20.9 ± 15.9 34 25.5 ± 25.5 Day 30 23 10.6 ± 15.0 34 10.6 ± 14.1 31 21.4 ± 24.6 Day 60 24 10.8 ± 16.9 32 7.2 ± 12.6 31 21.7 ± 23.4 Day 90 24 10.4 ± 19.7 31 5.7 ± 10.1 thirty 19.5 ± 20.0 Day 120 24 8.1 ± 15.2 28 4.6 ± 10.2 21 25.3 ± 28.4 Day 150 22 6.7 ± 15.0 29th 5.3 ± 11.0 21 18.6 ± 24.0 Day 180 24 6.2 ± 11.3 28 5.3 ± 11.2 22 24.5 ± 27.4

In patients with secondary hypogonadism, the mechanism of negative feedback with testosterone deficiency. As shown in FIG. 8 (b), in 44 patients with identified secondary hypogonadism, the average FSH concentration decreases during the experiment, although the decrease in time is not statistically significant in the case of a testosterone patch. In patients in the group receiving 5.0 g / day AndroGel ^® , there was a decrease in the average concentration of FSH by about 35% on day 30, then on day 60 there was no obvious decrease. After approximately 90 days, the average concentration of FSH in patients appears to slowly return to its value before treatment. At day 30, all patients in the AndroGel ^® 10.0 g / day group received FSH concentrations below the lower limit.

Table 13 (b) Concentrations of FSH (FSH) (mU / ml) on each day of the examination in groups from the start of treatment in patients with secondary hypogonadism (Mean ± SD) N 5 g / day N 10 g / day N T-patch Day 0 17 4.2 ± 6.6 12 2.1 ± 1.9 fifteen 5.1 ± 9.0 Day 30 16 2.8 ± 5.9 12 0.2 ± 0.1 fourteen 4.2 ± 8.0 Day 60 17 2.8 ± 6.1 12 0.2 ± 0.1 13 4.2 ± 7.4 Day 90 fifteen 2.9 ± 5.6 12 0.2 ± 0.1 fourteen 4.9 ± 9.0 Day 120 fourteen 3.0 ± 6.1 12 0.1 ± 0.1 12 6.1 ± 10.7 Day 150 fourteen 3.5 ± 7.5 12 0.2 ± 0.2 eleven 4.6 ± 6.5 Day 180 fourteen 3.7 ± 8.6 12 0.1 ± 0.1 12 4.9 ± 7.4

Twenty-five patients were diagnosed with age-related hypogonadism. As shown in FIG. 8 (c), in the group receiving 5.0 g / day AndroGel ^® , the average concentration of FSH before the experiment was above the normal range. The average concentration in this group becomes normal by day 30 and decreases by more than 50% on days 90 and 180. The decrease in the average concentration of FSH in the group receiving 10.0 g / day AndroGel ^® is faster. Concentrations in all six patients fall below the lower normal limit on day 30 and remain at that level during the study. Six patients who use a testosterone patch have conflicting mean FSH levels; however, there is a general tendency to lower FSH levels with continued treatment.

Table 13 (c) Concentrations of FSH (FSH) (mU / ml) on each day of the examination in groups from the start of treatment in patients with age-related hypogonadism (Mean ± SD) N 5 g / day N 10 g / day N T-patch Day 0 13 8.0 ± 9.1 6 5.2 ± 1.9 6 4.7 ± 1.7 Day 30 12 4.6 ± 7.4 6 0.4 ± 0.3 6 3.7 ± 2.0 Day 60 12 3.9 ± 6.6 6 0.3 ± 0.3 four 4.3 ± 3.3 Day 90 eleven 3.8 ± 7.0 6 0.4 ± 0.7 four 3.5 ± 1.9 Day 120 eleven 4.2 ± 8.3 6 0.4 ± 0.7 four 4.2 ± 3.3 Day 150 eleven 4.3 ± 8.1 5 0.2 ± 0.2 four 3.4 ± 2.7 Day 180 eleven 4.0 ± 7.2 6 0.2 ± 0.2 four 2.7 ± 2.1

Sixty-four patients participating in the study suffer from unclassified hypogonadism. As shown in FIG. 8 (d), patients showed a noticeable and relatively rapid decrease in the concentration of FSH in all three groups, with the greatest decrease observed in the group receiving 10.0 g / day AndroGel ^® . In the group receiving 10.0 g / day AndroGel ^® , the decrease in the average concentration of FSH on day 30 is about 90%, and this effect persists until day 180. In the group receiving 5.0 g / day AndroGel ^® , the average concentration of FSH in day 30 falls by about 75% and remains at this level until the end of treatment. In 21 patients in the group using the testosterone patch, the decrease in the average FSH concentration on day 30 is 50%, this trend continues until day 90, when the concentration is about one third of the value before the start of the experiment.

Table 13 (d) Concentrations of FSH (FSH) (mU / ml) on each day of the examination in groups from the start of treatment in patients with unclassified hypogonadism (Mean ± SD) N 5 g / day N 10 g / day N T-patch Day 0 17 4.0 ± 1.8 26 4.1 ± 1.6 21 3.7 ± 1.4 Day 30 17 1.1 ± 1.0 26 0.5 ± 0.5 21 1.8 ± 0.8 Day 60 16 1.1 ± 1.1 26 0.3 ± 0.3 eighteen 1.6 ± 1.0 Day 90 17 1.1 ± 1.1 25 0.4 ± 0.7 eighteen 1.2 ± 0.9 Day 120 16 1.2 ± 1.4 26 0.4 ± 0.6 12 1.4 ± 1.0 N 5 g / day N 10 g / day N T-patch Day 150 17 1.4 ± 1.4 23 0.3 ± 0.5 12 1.4 ± 1.0 Day 180 16 1.0 ± 0.9 24 0.4 ± 0.4 eleven 1.3 ± 0.9

These data show that inhibition of FSH secretion by the feedback mechanism to some extent works in all four groups. In the group of primary hypogonadal patients, there is a dose dependence of both the degree and the rate of decrease in FSH levels. The sensitivity of the feedback process seems to decrease in groups with secondary and age-related hypogonadism, in them only the highest doses of testosterone have a significant and lasting effect on FSH secretion. In contrast, inhibition by the feedback mechanism in patients not assigned to any group is very sensitive even with the lowest dose of exogenous testosterone.

(2) LH (LH)

Separately, the reaction of LH (LH) to testosterone is studied for the same four subpopulations. Tables 14 (a) - (d) show LH concentrations over the entire treatment period.

As shown in FIG. 9 (a) and Table 14 (a), LH concentrations before treatment were 175% of the upper limit of the normal interval in primary hypogonadal patients. Average LH concentrations decrease during treatment in all groups. However, only in the groups receiving AndroGel ^® , the decrease in LH concentrations is large enough so that these concentrations become normal. As in the case of FSH, in men with primary hypogonadism receiving AndroGel ^® , a dose dependence of both the rate and degree of LH response is observed.

Table 14 (a) The concentration of LH (LH) (mU / ml) on each day of the examination in patients with primary hypogonadism (total Average ± SD) N 5 g / day N 10 g / day N T-patch Day 0 26 12, ± 12.1 33 13.9 ± 14.9 33 13.3 ± 14.3 Day 30 23 5.6 ± 7.6 34 5.9 ± 8.1 31 10.9 ± 12.9 Day 60 24 6.8 ± 9.0 32 4.8 ± 10.0 31 10.8 ± 11.8 Day 90 24 5.9 ± 9.5 31 4.2 ± 11.0 thirty 10.0 ± 11.7 Day 120 24 6.4 ± 11.9 28 3.8 ± 10.4 21 11.5 ± 11.5 Day 150 22 4.4 ± 8.5 29th 4.0 ± 11.3 21 7.4 ± 6.0 Day 180 24 4.8 ± 6.8 28 4.0 ± 11.9 22 11.2 ± 10.5

Men with secondary hypogonadism are less susceptible to exogenous testosterone. In all 44 patients with diagnosed secondary hypogonadism, preliminary (before the start of the study) average concentrations correspond to the lower limit of the normal interval. Average LH concentrations are reduced during the experiment with all three treatment regimens, as shown in FIG. 9 (b) and Table 14 (b).

Table 14 (b) The concentration of LH (LH) (mU / ml) on each day of the examination in patients with secondary hypogonadism (total Average ± SD) N 5 g / day N 10 g / day N T-patch Day 0 17 1.8 ± 2.6 12 1.4 ± 1.8 fifteen 1.6 ± 3.1 Day 30 16 1.1 ± 2.2 12 0.2 ± 0.2 fourteen 0.4 ± 0.4 Day 60 17 1.4 ± 3.8 12 0.2 ± 0.2 13 0.6 ± 0.5 Day 90 fifteen 1.2 ± 2.4 12 0.2 ± 0.2 fourteen 0.7 ± 1.0 Day 120 fourteen 1.6 ± 4.0 12 0.2 ± 0.2 12 0.8 ± 0.8 Day 150 fourteen 1.6 ± 3.5 12 0.2 ± 0.2 eleven 1.2 ± 2.0 Day 180 fourteen 1.5 ± 3.7 12 0.2 ± 0.2 12 1.4 ± 2.1

In none of the 25 patients with age-related hypogonadism, LH concentrations before the study did not go beyond the normal interval, as shown in FIG. 9 (c) and Table 14 (c). The effects of total time and treatment are significant for patients receiving AndroGel ^® , but not for patients using a testosterone patch.

Table 14 (c) The concentration of LH (LH) (mU / ml) on each day of the examination in patients with age-related hypogonadism (total Average ± SD) N 5 g / day N 10 g / day N T-patch Day 0 13 3.2 ± 1.1 6 2.4 ± 1.8 6 2.9 ± 0.6 Day 30 12 1.1 ± 1.0 6 0.1 ± 0.0 6 1.8 ± 1.1 Day 60 12 0.8 ± 0.7 6 0.2 ± 0.3 5 3.4 ± 2.8 Day 90 eleven 0.9 ± 1.2 6 0.1 ± 0.0 four 2.3 ± 1.4 Day 120 eleven 1.0 ± 1.4 6 0.1 ± 0.0 four 2.2 ± 1.4 Day 150 eleven 1.3 ± 1.5 5 0.1 ± 0.0 four 1.9 ± 1.2 Day 180 eleven 1.8 ± 2.1 6 0.1 ± 0.0 four 1.4 ± 1.0

Of the 64 patients with unclassified hypogonadism, none of them had a preliminary (before the start of the study) concentration of LH does not exceed the upper limit of normal. However, in fifteen percent of patients, the concentration before the study is below normal. In patients with unclassified hypogonadism, a relatively rapid decrease in LH concentration is observed in all treated groups, as shown in FIG. 9 (d) and Table 14 (d).

Table 14 (d) The concentration of LH (LH) (mU / ml) on each day of the examination in patients with unclassified hypogonadism (sum Average ± SD) N 5 g / day N 10 g / day N T-patch Day 0 17 1.8 ± 1.2 26 2.5 ± 1.5 21 2.5 ± 1.5 Day 30 17 0.3 ± 0.3 26 0.3 ± 0.3 21 1.3 ± 1.3 Day 60 17 0.4 ± 0.5 26 0.3 ± 0.3 eighteen 1.2 ± 1.4 Day 90 17 0.5 ± 0.5 26 0.3 ± 0.4 eighteen 1.0 ± 1.4 Day 120 17 0.4 ± 0.4 26 0.4 ± 0.5 12 1.2 ± 1.1 Day 150 17 0.8 ± 1.1 23 0.3 ± 0.4 13 1.1 ± 1.1 Day 180 fifteen 0.3 ± 0.4 25 0.4 ± 0.4 eleven 1.4 ± 1.3

(3) Summary: LH and FSH (LH and FSH)

In patients using AndroGel ^® or a patch with testosterone, the "stationary hormonal state" is achieved only after prolonged treatment. More specifically, data on FSH and LH show that these hormones do not provide a steady state before treatment lasts for many weeks. Since the inhibition of testosterone concentration by FSH and LH occurs through a negative feedback mechanism, testosterone levels do not reach a valid steady state until these other hormones also reach a steady state. However, since these hormones regulate only endogenous testosterone (which is too insignificant for its regulation to begin in hypogonadal men) via an intact feedback mechanism (which may be absent depending on the cause of hypogonadism), the level of FSH and / or LH may slightly affect the achieved in fact testosterone levels. Ultimately, patients do not achieve a "hormonal stationary state" for testosterone, even though C _avg , C _min and C _max for testosterone remain relatively constant after several days of treatment.

(4) Libido and sexual activity

Libido and sexual function are evaluated using questionnaires with questions that patients answer daily for seven consecutive days before visiting the clinic on day 0 and on days 30, 60, 90, 120, 150 and 180 during the treatment period using gel and overlay patch. Patients record whether they have daytime sexual dreams, a premonition of sex, courtship, sexual interaction (i.e. indicators of sexual motivation) and orgasm, erection, masturbation, ejaculation, coitus (i.e. indicators of sexual activity) in each of the seven days. Estimates are recorded in figures as 0 (there is nothing) or 1 (there is something) for analyzes and the number of days when the indicator is recorded is added up over a seven-day period. The average of the four indicators of sexual motivation is taken as the average value of sexual motivation, and the average of the five indicators of sexual activity is taken as the average value of sexual activity (0-7).

Patients also evaluate their level of sexual desire, sexual pleasure and satisfaction with an erection on the Likert scale (0-7) and the completeness of an erection as a percentage from 0 to 100%. Patients evaluate their mood from 0 to 7. Weekly averages are calculated. Details of this profile are given earlier and are incorporated into this description by reference. See Wang et al., Testosterone Replacement Therapy Improves Mood in Hypogonadal Men- A Clinical Research Center Study, 81 J. Clinical Endocrinology & Metabolism 3578-3583 (1996).

(a) Libido (sex drive)

As shown in FIG. 10 (a), on the baseline, sexual motivation is similar in all treatment groups. After transdermal treatment with testosterone, there is a significant improvement in overall sexual motivation. However, the change in the total score compared with the baseline does not differ in the three groups processed.

Libido is also determined on a linear scale by answering questions: (1) general 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, in the group as a whole, overall sexual desire increases after transdermal administration of testosterone, there is no difference between the groups. Sexual pleasure in the presence and absence of a partner (FIG. 10 (c) and Tables 14 and 15) also increases in the group as a whole.

Table 15 Change in general sexual desire from day 0 to day 180 in groups with an initial treatment regimen (Mean ± SD) The group with the initial scheme - N Day 0 N Day 180 N Change from day 0 to day 180 P value in the group 5.0 g / day T-gel 69 2.2 ± 1.6 63 3.5 ± 1.6 60 1.4 ± 1.9 0.0001 10.0 g / day T-gel 77 2.0 ± 1.4 68 3.6 ± 1.6 67 1.5 ± 1.9 0.0001 T-patch 72 2.0 ± 1.6 47 3.1 ± 1.9 45 1.6 ± 2.1 0.0001 P value between groups 0.8955 0.2247 0.8579

Table 16 Change in the level of sexual pleasure without a partner from day 0 to day 180 in groups with an initial treatment regimen (Average ± SD) Initial Scheme Group N Day 0 N Day 180 N Change from day 0 to day 180 P value in the group 5.0 g / day T-gel 60 1.5 ± 1.9 51 1.9 ± 1.9 44 0.8 ± 1.4 0.0051 10.0 g / day T-gel 63 1.2 ± 1.4 53 2.2 ± 1.9 48 1.1 ± 1.6 0.0001 T-patch 66 1.4 ± 1.8 44 2.2 ± 1.8 40 1.0 ± 1.9 0.0026 P value between groups 0.6506 0.7461 0.6126

Table 17 Change in the level of sexual pleasure with a partner from day 0 to day 180 in groups with an initial treatment regimen (Average ± SD) Initial Scheme Group N Day 0 N Day 180 N Change from day 0 to day 180 P value in the group 5.0 g / day T-gel 64 2.1 ± 2.1 55 2.6 ± 2.2 48 0.4 ± 2.2 0.0148 10.0 g / day T-gel 66 1.8 ± 1.7 58 3.0 ± 2.2 52 1.0 ± 2.3 0.0053 T-patch 61 1.5 ± 1.7 40 2.2 ± 2.4 35 0.7 ± 2.3 0.1170 P value between groups 0.2914 0.1738 0.3911

(b) Sexual activity

11 (a) shows that, although all treated groups on the baseline have a similar indicator of sexual (sexual) activity, the indicators increase with transdermal use of testosterone in all groups. In addition, in the group, the patient’s self-assessment of satisfaction with an erection (FIG. 11 (b) and Table 18) and the percentage of completeness of an erection (FIG. 11 (b) and Table 19) also increases with testosterone replacement in the absence of significant differences between the groups. Increased sexual function is not related to the dose or method of testosterone delivery. This improvement is also not related to the level of serum testosterone achieved with various testosterone preparations. These data suggest that when the threshold is reached (the level of serum testosterone is supposedly in the normal range), normalization of sexual function occurs. An increase in serum testosterone levels above the upper limit of the normal interval does not provide an additional improvement in sexual motivation or sexual activity.

Table 18 Change in satisfaction with the duration of an erection from day 0 to day 180 in groups with an initial treatment regimen (Mean ± SD) Initial Scheme Group N Day 0 N Day 180 N Change from day 0 to day 180 P value in the group 5.0 g / day T-gel 55 2.5 ± 2.1 57 4.3 ± 1.8 44 1.9 ± 2.0 0.0001 10.0 g / day T-gel 64 2.9 ± 1.9 58 4,5 ± 1,7 53 1.5 ± 2.0 0.0001 T-patch 45 3.4 ± 2.1 34 1.3 ± 2.1 twenty 1.3 ± 2.1 0,0524 P value between groups 0.1117 0.7093 0.5090

Table 19 Change in erection as a percentage of a complete erection from day 0 to day 180 in groups with an initial treatment regimen (Mean ± SD) Initial Scheme Group N Day 0 N Day 180 N Change from day 0 to day 180 P value in the group 5.0 g / day T-gel 53 53.1 ± 24.1 57 67.4 ± 22.5 43 18.7 ± 22.1 0.0001 10.0 g / day T-gel 62 59.6 ± 22.1 59 72.0 ± 20.2 52 10.4 ± 24.4 0.0001 T-patch 47 56.5 ± 24.7 33 66.7 ± 26.7 19 12.7 ± 20.3 0.0064 P value between groups 0.3360 0.4360 0.1947

Example 2: Method for increasing libido in eugonadal men with reduced sex drive (libido)

As discussed above, the transdermal use of testosterone with AndroGel ^{® by} hypogonadal men leads to an increase in libido and sexual activity. Researchers have found that eugonadal men with reduced libido show a significant increase in sexual interest after injecting testosterone. See O'Carrol & Bancroft, Testosterone Therapy for Low Sexual Interest and Erectile Disfunction in Men: A Controlled Study, Brit. J. Psychiatry 145: 146-151 (1984). Thus, the present example relates to a method for treating decreased libido in eugonadal men with the transdermal use of an aqueous-alcohol testosterone gel to treat such men. In one embodiment of the invention, AndroGel ^® is applied to a body area according to the protocol set forth in Example 1. Libido is defined as in Example 1. Men using AndroGel ^® are believed to have an increased sex drive.

Example 3: Method for increasing libido in eugonadal men with normal libido

As discussed above, the transdermal use of testosterone when using AndroGel ^® leads to an increase in sexual desire (libido) and sexual activity in hypogonadal men. Studies have shown that doses of testosterone higher than physiological given to eugonadal men with normal libido lead to a significant increase in libido. See Anderson et al., The effect of Exogenous Testosterone 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 relates to a method for increasing libido in normal eugonadal men using transdermal application of an aqueous-alcohol testosterone gel. In one embodiment of the invention, AndroGel ^® is applied to the body in accordance with the protocol presented in Example 1. Applicants believe that men receiving AndroGel ^® increase libido.

Example 4: Method for increasing sexual activity of eugonadal men with erectile dysfunction

In a predictive example, 10 eugonadal men with erectile dysfunction aged 18 years and older are randomly divided into groups receiving: (a) 5.0 g / day AndroGel ^® (delivers 50 mg / day of testosterone to the skin, of which about 10% is absorbed or 5 mg) within 30 days; or (b) 10.0 g / day AndroGel ^® (delivers 100 mg / day of testosterone to the skin, of which 10% or 10 mg is absorbed) for 30 days; or (c) nothing. The effectiveness of AndroGel ^® to increase sexual activity and to treat erectile dysfunction is determined using several methods. An initial assessment is carried out using the Sexual Function Questionnaire of the International Index of Erectile Function ("IIEF"). Two questions from the IIEF serve as study endpoints; unambiguous answers to questions about (1) the ability to achieve an erection sufficient for sexual intercourse, and (2) maintaining an erection after penetration should be achieved. Possible clear answers to these questions: (0) there is no attempt at sexual intercourse, (1) never or almost never, (2) rarely, (3) sometimes, (4) in most cases and (5) almost always or always. As part of the IIEF, information is collected about other aspects of sexual function, including information on erectile dysfunction, orgasm, desire, sexual intercourse satisfaction, and general sexual satisfaction. Patient data is also recorded daily in a diary about sexual function. In addition, patients are asked a question about overall effectiveness and use the questionnaire of a possible partner. In addition, a decrease in erectile dysfunction (improvement) is assessed by objective determination of the hardness and duration of an erection (RigiScan ^® ) using AndroGel ^® compared to placebo. The applicant believes that all the characteristics obtained during testing show an improvement compared with placebo.

Example 5: Method for increasing the sexual activity of eugonadal men with normal erections

In a predictive example, 10 eugonadal men with normal erections (i.e. they are not diagnosed with erectile dysfunction) aged 18 years and older are randomly divided into groups receiving: (a) 5.0 g / day AndroGel ^® (delivers 50 to the skin) mg / day of testosterone, of which about 10% or 5 mg is absorbed) for 30 days; or (b) 10.0 g / day AndroGel ^® (delivers 100 mg / day of testosterone to the skin, of which 10% or 10 mg is absorbed) for 30 days; or (c) nothing. The effectiveness of the use of AndroGel ^® to increase sexual activity and to treat erectile dysfunction is determined using several methods, as described in Example 4. The applicant believes that all characteristics show an increase in sexual activity compared to placebo. Accordingly, the applicant believes that AndroGel ^® can be used in the treatment of healthy (normal) men to increase sexual activity above their normal baseline.

Example 6: A Method for the Treatment of Men with Erectile Dysfunction in Combination with Other Pharmaceuticals

As discussed above, the transdermal use of testosterone by hypogonadal men in the form of AndroGel ^® leads to an increase in sexual desire (libido) and sexual activity. This example relates to the use of AndroGel ^® in combination with pharmaceutical preparations suitable for the treatment of erectile dysfunction. Such pharmaceutical preparations include any agent that effectively inhibits phosphodiesterase activity. Suitable phosphodiesterase inhibitors include, but are not limited to, type III phosphodiesterase inhibitors (cAMP (cAMP) -specific-cGMP (cGMP) inhibited form), type IV phosphodiesterase (high affinity - highly specific cAMP) and type V phosphodiesterase specific cGMP. Additional inhibitors that can be used together according to this invention are inhibitors of cGMP-specific phosphodiesterase other than phosphodiesterase type V inhibitors.

Examples of type III phosphodiesterase inhibitors that may be used include, but are not limited to, bipyridines, such as milrinone and amirinone, imidazolones, such as pyroximon and enoximon, dihydropyridazinones, such as imazodane, 5-methyl-imazodane, indolidan and ICI11182inone, compounds x such as cilostamide, cilostazol and springrinone, and such as bemoradan, anergrelide, siguazodan (siguazodan), trequinzin, pimobendan, SKF-914120, SKF-95654, lixazinone and isomazole.

Examples of type IV phosphodiesterase inhibitors useful herein include, but are not limited to, rolipram and rolipram derivatives such as RO20-1724, nitraquazone and nitraquazone derivatives such as CP-77059 and RS-25344-00, xanthine derivatives such as denbufillin and ICI63197, and other compounds such as EMD54622, LAS-31025 and etazolate.

Examples of type V phosphodiesterase inhibitors include, but are not limited to, zaprinast, MY5445, dipyridamole, and sildenafil. Other type V phosphodiesterase inhibitors are described in PCT International Applications WO 94/28902 and WO 96/16644. In a preferred embodiment used phosphodiesterase type 5 inhibitor ( "FDEV"), such as Viagra (VIAGRA ^®, sildenafil citrate USP).

The compounds described in PCT International Application WO 94/28902 are pyrazolopyrimidinones. Examples of inhibitors include 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- ( 5-morpholinoacetyl-2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- [2-ethoxy- 5- (4-methyl-1-piperazinyl sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- [2-allyloxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7- he, 5- [2-ethoxy-5- [4- (2-propyl) -1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one, 5- [2-et hydroxy-5- [4- (2-hydroxyethyl) -1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7 -one, 5- [5- [4- (2-hydroxyethyl) -2-n-propoxyphenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- [2-ethoxy-5- (4-methyl-1-piperazinylcarbonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one and 5- [2-ethoxy-5- (1-methyl-imidazolyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one.

The phosphodiesterase inhibitors described in PCT International Application WO 96/16644 include griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridine derivatives, pyrimidopyrimidine derivatives, purine compounds, quinazolines, analog phenylpyrimidinimidinides, and phenylpyrimidinidinimidinones, derivatives of phenylpyrimidinidinidinides and others. Specific examples of phosphodiesterase inhibitors described in WO 96/16644 include 1,3-dimethyl-5-benzylpyrazolo [4,3-d] pyrimidin-7-one, 2- (2-propoxyphenyl) -6-purinone, 6- ( 2-propoxyphenyl) pyrido [ 2,3-d] pyrimide-4 (3H) -one, 7-methylthio-4-oxo-2- (2-propoxyphenyl) -3,4-dihydropyrido [4,5-d] pyrimidine, 6-hydroxy-2 - (2-propoxyphenyl) pyrimidine-4-carboxamide, 1-ethyl-3-methylimidazo [1,5-a] quinoxaline-4 (5H) -one, 4-phenylmethylamino-6-chloro-2- (1-imidazoloyl) quinazoline, 5-8- [3- (N-cyclohexyl-N-methylcarbamoyl) propyloxy] -4,5-dihydro-4-oxo-pyrido [3,2-e] pyrrolo [1,2-a] pyrazine, 5'-methyl-3- (phenylmethyl) -spiro [cyclopentane-1,7 '(8'H) - (3'H) -imidazo [2,1-b] purine] 4' (5'H) -one , 1- [6-chloro-4- (3,4-methylenedioxybenzyl) aminoquinazolin-2-yl) piperidin-4-carboxylic acid, (6R, 9S) -2- (4-trifluoromethyl-phenyl) methyl-5- methyl 3,4,5,6a, 7,8,9,9a-octahydra cyclopent [4,5] imidazo [3,1-b] purin-4-one, 1-tert.butyl-3-phenylmethyl-6- (4-pyridyl) pyrazolo [3,4-d] pyrimid-4-one , 1-Cyclopentyl-3-methyl-6- (4-pyridyl) -4,5-dihydro-1H-pyrazolo [3,4-d] pyrimid-4-one, 2-butyl-1- (2-chlorobenzyl) -6-ethoxycarbonylbenzimidazole and 2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-nitroquinazoline and 2-phenyl-8-ethoxycycloheptimidazole.

Other type V phosphodiesterase inhibitors useful in the combination of this invention include: IC-351 (ICOS); 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) propoxy] -3 (2H) pyridazinone; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid monosodium salt; (+) - cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) phenylmethyl-5-methylcyclopent [4,5] imidazo [2,1-b] purin-4 (3H) he; furazocillin; cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] imidazo [2,1-b] purin-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Shering Plow); GF-196960 (Glaxo Wellcome); and Sch-51866.

Other phosphodiesterase inhibitors that may be used in the method of this invention include non-specific phosphodiesterase inhibitors such as theophylline, IBMX, pentoxifylline and papaverine, and direct-acting vasodilators such as hydralazine.

Active agents can be used, if required, in the form of salts, esters, amides, prodrugs, derivatives, etc., provided that the salt, ester, prodrug or derivative is acceptable from the point of view of pharmacology, i.e. effective in this method. Salts, esters, amides, prodrugs and other derivatives of active agents can be obtained by standard methods known to specialists in the field of synthetic organic chemistry and described, for example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4 ^th Ed. _ (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base in a conventional manner by reaction with an appropriate acid. Typically, the drug substance in the form of a base is dissolved in a polar organic solvent such as methanol or ethanol, and acid is added to it. The resulting salt either precipitates or can be precipitated out of solution by adding a less polar solvent. Suitable acids for the preparation of acid addition salts include organic acids, for example, 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 acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like, and inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. The acid addition salt can again be converted to the free base by treatment with an appropriate base. Particularly preferred salts of the addition of active agents as described herein are salts of hydrohalic acids, such as those obtained using hydrochloric or hydrobromic acid. Conversely, base salts from acidic moieties that may be present in the phosphodiesterase inhibitor molecule are obtained in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine and the like. Particularly preferred basic salts as described herein are alkali metal salts, for example sodium salt, copper salt. Obtaining esters includes the functionalization of the hydroxyl and / or carboxyl groups that may be present in the drug molecule. Esters are typically acyl substituted by free alcohol groups, i.e. these are carboxylic acid derivatives of the formula RCOOH, where R is alkyl, preferably lower alkyl. Esters can, if required, be converted back to the free acids by conventional hydrogenolysis or hydrolysis. Amides and prodrugs can also be obtained using methods known to specialists in this field of technology or described in the relevant literature. For example, amides can be obtained from esters using the corresponding amines, or they can be obtained from acid anhydrides or acid chlorides by reaction with ammonia or lower alkyl amine. Prodrugs, as a rule, are obtained by covalently bonding a fragment, which results in a compound that is therapeutically inactive until it is modified during the metabolism of the patient.

Other compounds may also be used to treat erectile dysfunction. These compounds include: (a) pentoxifylline (TRENTAL ^® ); (b) yohimbine hydrochloride (ACTIBINE ^® , YOCON ^® , YOHIMEX ^® ); apomorphine (UPRIMA ^® ); (d) alprostadil (MUSE ^® system, TOPILGAN ^® , CAVERJECT ^® ); (e) papaverine (PAVABID ^®, CERESPAN ^®); (f) phentolamine (VASOMAX ^®, REGITINE ^®), and combinations, salts, derivatives and enantiomers of all the above compounds.

A gel containing testosterone, such as AndroGel ^® , is used to increase the therapeutic efficacy of such drugs in both hypogonadal and eugonadal patients with erectile dysfunction. While the effects of pharmaceuticals such as VIAGRA ^® are predominantly based on various physiological mechanisms for initiating and maintaining an erection, the testosterone gel used in this invention has a positive physiological effect and stimulates sexual motivation (i.e., libido), and sexual activity. 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 Corpus Cavernosum, 83 BJU Int'l. 327 (1999). Thus, testosterone and other androgens undoubtedly play a role in erectile dysfunction. See Lugg et al., The 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 Rabbit Model, 140 Endocrinology 1861 (1999). In addition, testosterone replacement restores nitric oxide activity. See Baba et al., Delayed Testosterone Replacement Restores Nitric Oxide Synthase Containing Nerve Fibers 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); Marine et al., Androgen-dependent Nitric Oxide Release, in Rat Penis Correlates with Levels of Constitutive Nitric Oxide Synthase Isoensymes, 61 Biology of reproduction 1-12 (1999).

As indicated in this description, adequate testosterone levels are important for erection. In one embodiment, the AndroGel ^® applied to the body surface in accordance with the protocol summarized in Example 1. The pharmaceutical (s), drug (s) for erectile dysfunction is taken in accordance with the prescribed requirements. For example, doses of 50 mg VIAGRA ^® are usually used 20-40 minutes before sexual intercourse. The combination approach is particularly useful for the treatment of hypogonadal men who require elevated testosterone levels to optimize the effect of VIAGRA ^® and overall sexual experience. In essence, a synergistic effect is achieved. AndroGel ^®, preferably applied to the body surface for a time sufficient to achieve steady-state levels of testosterone.

In a predictive example, 10 men aged 18 years and older are randomly divided into groups receiving: (a) 5.0 g / day AndroGel ^® (delivers 50 mg / day of testosterone to the skin, of which about 10% or 5 mg is absorbed) for 30 days plus 50 mg of sildenafil citrate 1 hour before sexual intercourse, at least 1 day after AndroGel ^® therapy; or (b) 10.0 g / day AndroGel ^® (delivers 100 mg / day of testosterone to the skin, of which about 10% or 10 mg is absorbed) for 30 days plus 50 mg of sildenafil citrate 1 hour before sexual intercourse, at least , 1 day after AndroGel ^® therapy; or (c) 5.0 g / day AndroGel ^® (delivers 50 mg / day of testosterone to the skin, of which about 10% or 5 mg is absorbed) for 30 days and nothing before sexual intercourse. Libido, erection and sexual activity are studied as described in the previous Examples. The applicant believes that all test characteristics show an increase in sexual activity and synergism in combination.

In another embodiment of the invention, combination therapy is carried out using a kit containing both a testosterone gel and a pharmaceutical preparation for treating erectile dysfunction in quantities sufficient for an appropriate dosage of drug substances. Kits also contain a set of instructions for the patient.

Although the invention has been described with reference to specific embodiments of the invention and specific examples, it should be appreciated that other variations are possible without departing from the scope of the invention using the concept of the invention.

One embodiment of the present invention includes the transdermal use of a testosterone gel, administered in conjunction with an oral dose of sildenafil, as a method of erecting an erectile response in hypogonadal men (men with weakened sexual function) who do not respond to the treatment of erectile dysfunction with sildenafil alone.

In this example, volunteers were selected from among men who did not respond to the treatment of erectile dysfunction with one sildenafil alone, and studied at several centers throughout the United States. The study was a double-blind study of a 1% testosterone gel (AndroGel ^® ) and a placebo gel. The mean age of the patients was 58.5 years. The selection criteria for patients included: erectile dysfunction for at least the last 3 months, participation in constant heterosexual relationships, lack of response to treatment with 100 mg of sildenafil (score in points 2 or 3 for each of questions 3 and 4 of the International Erectile Function Index (IIEF), see below) and low to lower normal serum testosterone levels (<400 ng / dl collected until 10:00 in the morning).

IIEF is a concise, reliable, self-administered erectile function questionnaire used in mixed cultural communities to detect changes in patients caused by treatment. The IIEF consists of 15 questions related to individual sexual behavior. Each question includes 6 possible answers (0-5, and 0 means no effect, as a rule, and 5 means no signs (indications), as a rule). Based on the analysis of the main components of the scale, five factors or areas (domains) of responses are determined: (1) Erectile function (EF); (2) Orgasmic function (OF); (3) Libido (sexual desire) (SD); (4) Sexual Satisfaction (IS); (5) General satisfaction (OS).

A total of 75 patients were enrolled and randomly divided into groups receiving 5.0 g / day AndroGel ^® (50 mg / day testosterone delivery to the skin, of which 10% or 5 mg is absorbed) plus 100 mg sildenafil (1 hour before sexual intercourse) or 5.0 g / day placebo gel plus 100 mg sildenafil (1 hour before sexual intercourse). Subjects received 5 g / day AndroGel ^® or a placebo gel through clean, dry skin of the shoulder blades, shoulders, and / or stomach and orally received 100 mg / day of sildenafil. Patients were treated for 12 weeks. A preliminary analysis of 67 subjects at week 4 showed that AndroGel ^® significantly increased the response to sildenafil in the EF, OF, and OS regions and the overall IIEF score in points compared to placebo gel. Key findings included a mean change from baseline (BL) in the IIEF erectile function domain. Secondary (additional) indicators obtained included the average change compared to the baseline in each of the other four domains and the overall IIEF score. Safety assessments included physical examination, urological examination, PSA, vital signs, laboratory tests, and side effects.

The table below shows the obtained IIEF indicators:

Table 20 The resulting IIEF IIEF domain Change compared to BL (mean ± SD) R* AndroGel ^® + Sildenafil Placebo + Sildenafil Erectile function 5.65 ± 6.66 2.97 ± 5.13 0,037 Orgasmic Funct. 1.53 ± 2.38 0.36 ± 2.03 0.019 Sexual desire 0.44 ± 2.02 0.00 ± 1.68 0.211 Satisfaction from intercourse 2.21 ± 2.33 0.70 ± 1.94 0.250 General satisfaction 1.62 ± 2.26 0.61 ± 1.98 0,046 Overall rating (points) 10.44 ± 13.21 4.64 ± 9.88 0,022 * By the method of analysis of variance (ANOVA).

As shown in this table, testosterone therapy with testosterone gel increases the erectile response to sildenafil and can be used in the treatment of erectile dysfunction in men with low or lower normal testosterone levels who were not helped by previous treatment with sildenafil alone. Although testosterone sildenafil was used in this study, the present invention is not limited to just this one type of phosphodiesterase type 5 inhibitor. Other type 5 phosphodiesterase inhibitors, in particular VIAGRA, may be used in the practice of the invention.

Claims (22)

1. A method of increasing the effectiveness of type 5 phosphodiesterase inhibitors used to treat erectile dysfunction in a man, comprising administering through the patient’s skin a pharmaceutically effective amount of testosterone in an aqueous-alcohol gel in the form of a pharmaceutical composition containing at least one of the C1- alcohols C4, absorption enhancer, thickener and water, along with the patient's use of type 5 phosphodiesterase inhibitors. 2. The method according to claim 1, characterized in that the patient is eugonadal. 3. The method according to claim 1, characterized in that the type 5 phosphodiesterase inhibitor is sildenafil citrate and its salts, derivatives and enantiomers. 4. The method according to claim 1, characterized in that the type 5 phosphodiesterase inhibitor is VIAGRA. 5. The method according to claim 1, characterized in that the absorption enhancer is at least one of the C8-C22 fatty acids. 6. The method according to claim 5, characterized in that the fatty acid contains an alkyl chain with a length of at least 12 carbon atoms. 7. The method according to claim 1, characterized in that the C1-C4 alcohol is at least one of the following alcohols: ethanol, 2-propanol, n-propanol and mixtures thereof. 8. The method according to claim 1, characterized in that the suction enhancer is isopropyl myristate. 9. The method of claim 8, wherein the composition contains about 1.0 wt.% Testosterone. 10. The method according to claim 8, characterized in that the isopropyl myristate is contained in an amount of about 0.5 wt.%. 11. The method according to claim 1, characterized in that the thickener is CARBOPOL. 12. The method according to claim 1, characterized in that the pharmaceutical composition contains, wt.%: testosterone 0,1-10 isopropyl myristate 0.1-5 ethanol 30-98 thickener 0.1-5 13. The method according to claim 1, characterized in that the patients are men suffering from hypogonadism. 14. The method according to claim 1, characterized in that the patients are men suffering from primary hypogonadism. 15. The method according to claim 1, characterized in that the pharmaceutical composition is administered daily. 16. The method according to claim 1, characterized in that the introduction is the application of the composition to the right or left forearm or shoulder and to the right or left side of the abdomen once a day, alternately. 17. The method according to claim 1, characterized in that the pharmaceutically effective amount of testosterone is 75 mg per day. 18. The method according to claim 1, characterized in that they provide stable testosterone levels. 19. A kit for the treatment of erectile dysfunction, containing a type 5 phosphodiesterase inhibitor and a pharmaceutical composition for transdermal administration in the form of a water-alcohol gel containing testosterone, at least one of C1-C4 alcohols, an absorption enhancer, a thickener and water. 20. The kit according to claim 19, characterized in that the type 5 phosphodiesterase inhibitor is sildenafil citrate and its salts, derivatives and enantiomers. 21. The kit according to claim 19, characterized in that the type 5 phosphodiesterase inhibitor is VIAGRA. 22. The kit according to claim 19, characterized in that the water-alcohol gel contains, wt.%: testosterone 0,1-10 isopropyl myristate 0.1-5 ethanol 30-98 thickener 0.1-5

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