JP2010521519A - Composition for treating pediatric hypogonadism and method of treatment - Google Patents

Abstract

  The present invention provides, inter alia, a composition for treating prepubertal adult men who are deficient in testosterone production using hydroalcoholic testosterone gel formulations that provide desirable hormonal pharmacokinetic profiles and said adolescents Relates to the treatment of males.

Description

  The present invention provides, inter alia, a composition for treating prepubertal adult men who are deficient in testosterone production using hydroalcoholic testosterone gel formulations that provide desirable hormonal pharmacokinetic profiles and said adolescents Relates to the treatment of males.

The age at which adolescence begins in boys ranges from 9 to 14 years, and is characterized by testicular swelling, followed by the appearance of pubic hair 18 to 24 months after testicular development. Adolescence is characterized by skeletal growth with a linear growth rate that begins to increase in Tanner Genital Stage III and Tanner Pubic Stage II. Tanner period (I to V) is a period of body growth in children and adolescents. These periods define physical measurements of development based on apparent primary and secondary sexual characteristics, such as pubic hair development. Due to the natural variations, depending on the puberty period, the Tanner period passes at different rates depending on the individual. The maximum stature growth rate typically reaches 14 years. See Wheeler, MD, Endocrinol and Metab CHn N. Am., 20 (1): 1-14 (1991). Boys whose secondary sexual characteristics do not begin by the age of 14 or boys who have not undergone stage V of pubertal development within 4 and a half years after puberty began are evaluated for hypogonadism, ie a decrease in testosterone levels. Should be. Styne, D., Puberty, Basic and Clinical Endocrinology, 6 th Edition, Greenspan FS and Gardner DG, ed. McGraw- Hill, New York, 2001 see.

  Testosterone is the major circulating androgen in men and is synthesized from cholesterol. Testosterone is mainly secreted from the male testis. In adult males, approximately 500 million Leydig cells in the testis secrete more than 95% of the 6-7 mg testosterone produced per day. Two hormones produced by the pituitary gland, luteinizing hormone ("LH") and follicle stimulating hormone ("FSH") are required for the development and maintenance of testicular function and are produced by circulating concentrations of hormones. Feedback mechanism negatively controls testosterone production. Circulating testosterone is metabolized to various 17-ketosteroids by two different pathways. Testosterone is metabolized to dihydrotestosterone by the enzyme 5α-reductase or to estradiol (“E2”) by the aromatase enzyme complex.

  Testosterone circulates in the blood with 98% bound to protein. In men, about 40% of the binding is to high affinity hormone binding globulin (“SHBG”). The remaining 60% binds weakly to albumin. Thus, numerous testosterone measurements are available for clinical studies. As used herein, the term “free” testosterone refers to the fraction of blood testosterone that is not bound to protein. As used herein, the term “total testosterone” or “testosterone” refers to free testosterone and testosterone bound to a protein. As used herein, the term “bioavailable testosterone” refers to non-SHBG-bound testosterone and includes testosterone that is weakly bound to albumin.

  The table below summarizes the range of normal testosterone concentrations for each Tanner phase.

  The table below summarizes the range of serum hormone concentrations in normal men by age.

  There is a very large variation in the half-life of testosterone reported in the literature, ranging from 10 to 100 minutes. However, researchers have admitted that circulating testosterone has diurnal variation in normal young men. The maximum level occurs approximately from 6 am to 8 am, and the level decreases during the day.

  Adolescent delay in adolescent men (ie, boys) can result from a variety of different conditions. For example, from sexual characteristics and adolescent constitutional delay (CDGP), gonadotropin excess hypogonadism (primary hypogonadism), or hypogonadotropic hypogonadism (secondary hypogonadism) there is a possibility. For patients not taking testosterone, pre-pubertal maturity can be indicated, inter alia, by (i) a testicular volume of 3 mL or less and (ii) a testosterone concentration of 50 ng / dL or less.

  Hypogonadism results from a variety of pathophysiological conditions in which testosterone levels are reduced below the normal range. A hypogonadal state may be associated with a number of physiological changes, such as a reduction in the body without fat, a reduction in bone density, a decrease in mood, and a decrease in energy levels.

  Researchers generally classify hypogonadism into one of three types. Primary hypogonadism is congenital or acquired adolescence, XYY syndrome, XX male, Noonan syndrome, gonadal dysgenesis, Leydig cell tumor, poorly descending testis, sexual varices, Sertoli cell alone syndrome, stationary testis Intestinal disorders, bilateral torsion, disappearing testicular syndrome, Kleinfelter syndrome, chemotherapy, toxic disorders due to alcohol or heavy metals, and testicular disorders due to systemic diseases (renal failure, cirrhosis, dystrophic myotonia). Patients with primary hypogonadism show a complete feedback mechanism associated with high FSH and LH concentrations with low serum testosterone concentrations. However, due to testis or other dysfunction, high LH concentrations are not effective in stimulating testosterone production.

  Secondary hypogonadism includes idiopathic gonadotropin or LH-releasing hormone release disease. This type of hypogonadism may include Kalman syndrome, Prader-Lovehart-Uri syndrome, Lawrence-Moon-Beedle syndrome, pituitary dysfunction / adenoma, Pasqualini syndrome, hemochromatosis, hyperprolactinemia, or tumor, trauma, Includes pituitary-hypothalamic injury resulting from irradiation or obesity. Since patients with secondary hypogonadism do not show a complete feedback pathway, a decrease in testosterone levels is not accompanied by an increase in LH or FSH levels. Thus, these men have low testosterone serum levels but have gonadotropins in the normal to low range.

  Adolescent men with adolescent delay with the above conditions may be treated with androgens (eg, testosterone) or anabolic steroids. Adolescent men with persistent hypogonadism will require prolonged androgen administration. Such treatment will typically give rise to secondary sexual characteristics and increase in height. The most common form of testosterone used to treat puberty delay is the form of injection. This is a depot formulation in which a testosterone ester (eg, testosterone enanthate) is dissolved in oil and injected once every few weeks deep into the gluteal muscle. This dosing regime requires frequent visits to medical personnel and is painful. Testosterone injection also results in serum testosterone concentrations that vary widely over the dosing interval from concentrations higher than desired immediately after injection to concentrations lower than desired prior to the next injection. Concentrations that vary over these dosing intervals complicate the use of serum testosterone concentration as a meaningful indicator for dosing adjustment. Because of the risk of liver side effects, oral products of halogenated or methylated testosterone are not common in the United States. Furthermore, the use of anabolic steroids does not promote increased growth hormone secretion, as does testosterone. Thus, several drawbacks are associated with each of the products typically used to treat adolescent delays.

  In 2000, 1% testosterone gel was approved for replacement therapy in adult men over 18 years of age with a deficiency or deficiency of endogenous testosterone (primary or secondary hypogonadism). 73 men with hypogonadism using 5 g testosterone gel 1% (containing 50 mg testosterone) once daily and 10 g testosterone gel 1% (containing 100 mg testosterone) once daily The results of a testosterone supplementation test in 78 men with hypogonadism using testosterone showed that testosterone gel 1% was well tolerated and was effective in increasing serum testosterone concentrations within the normal range of testicular function It was. Normal concentrations of testicular function were achieved within hours of the first donation in most men, and these concentrations were maintained up to 180 days with once daily dosing. The most commonly reported side effects (AE) associated with testosterone gel 1% are acne (less than 8%); abnormal laboratory tests (6%) including increased red blood cells, increased hemoglobin, increased hematocrit, and decreased serum lipids. Less than); site response (5% or less); prostate disorder (5% or less); and headache (4% or less).

  There is evidence that with administration of 5 g or more testosterone gel, serum testosterone concentrations in adult men over the age of 18 years with hypogonadism increased within the normal range of testicular function, but at lower levels There is no evidence that, at doses, serum testosterone concentrations in adolescent males younger than 18 years with hypogonadism will increase within the normal range of testicular function, and such doses cannot be predicted. Specifically, the manner in which young male skin absorbs testosterone gel is unclear. In general, the skin of an adolescent male differs from the skin of an adult male over 18 years of age when acting as a reservoir. Thus, at lower dose levels of testosterone gel, there is no evidence that serum testosterone levels in hypogonadic adolescent men increase in a safe and effective manner. Furthermore, the uptake of testosterone in the skin reservoir depends on the individual metabolism. The metabolism of young men is dramatically different from that of adult men over 18 years of age.

  Testosterone gel may provide several benefits for the treatment of delayed puberty in adolescent boys. Most importantly, the relatively constant serum testosterone concentration achieved by the product is such that the health care professional obtains a meaningful measurement of serum testosterone concentration and is appropriate for a given stage of pubertal development. Allows the dose to be adjusted to obtain testosterone concentrations. Testosterone concentrations gradually increase as the boy transitions from Tanner pubic period I to Tanner pubic period V. The ability to obtain consistent testosterone concentrations over time and the use of concentrations that allow for proper adjustment of the dose is important for health professionals to induce secondary sexual characteristics and to make the boy more physiological It should be possible to shift to various stages of puberty.

  An additional consideration in the use of testosterone gel in the treatment of adolescent delay in adolescent boys is ease of use. The use of the gel would not require returning the boy to a health care worker every 2 to 4 weeks to make an injection. This is important for both the boy and his family. Ultimately, the gel should be well tolerated by this population. Its use would avoid the pain and discomfort associated with parental compliance with testosterone injections and testosterone therapy treatment plans. There is also no risk of liver side effects associated with the use of oral anabolic agents. The gel is very well tolerated by the adult population, with a small number of subjects showing application site reactions.

Wheeler, MD, Endocrinol and Metab CHn N. Am., 20 (1): 1-14 (1991) Styne, D., Puberty, Basic and Clinical Endocrinology, 6th Edition, Greenspan FS and Gardner DG, ed. McGraw- Hill, New York, 2001

  Therefore, there is a need for safe and effective treatment of pediatric hypogonadism, ie low testosterone levels in adolescent men aged 9 to 17 years.

  The present invention provides, inter alia, a composition for treating prepubertal adolescent men with inadequate testosterone production using hydroalcoholic testosterone gel formulations that provide the pharmacokinetic profile of the desired hormone, as well as said adolescents It relates to a treatment method for men.

FIG. 1 is a graph showing the observed mean serum concentration versus time profile for total or free testosterone, dihydrotestosterone, bioavailable testosterone. FIG. 2 is a graph showing the mean baseline adjusted serum concentration versus time profile for total or free testosterone, dihydrotestosterone, bioavailable testosterone. FIG. 3 is a graph showing pre-dose testosterone concentrations observed or adjusted at baseline.

  Although the present invention may be implemented in a multitude of different aspects, several specific embodiments are discussed herein and the present disclosure should be considered only as an illustration of the subject matter of the present invention. It is not intended to be limited to the embodiments described.

  The present invention provides, among other things, a prepubescent adolescent male with insufficient testosterone production (ie, pediatric hypogonadism) using an aqueous alcohol testosterone gel formulation that provides the desired hormonal pharmacokinetic profile, That is, it relates to compositions for treating men between the ages of 9 and 17 (including boundaries) and methods of using such compositions for such treatment.

  For subjects not taking testosterone, premature pubertal maturity is indicated, inter alia, by (i) a testicular volume of 3 mL or less and (ii) a testosterone concentration of 50 ng / dL or less.

  In one embodiment, the present invention relates to a method for transdermal administration of testosterone in a hydroalcoholic gel. The gel includes testosterone (or testosterone derivative), one or more lower alcohols such as ethanol or isopropanol; penetration enhancers such as isopropyl myristate; thickener; and water. In addition, the present invention may optionally include salts, emollients, stabilizers, antibacterial agents, perfumes, and propellants.

  The present invention treats, prevents, ameliorates, halts, or slows the progression of gonadal dysfunction or other low testosterone-related diseases in subjects that are clinically apparent or Also included are kits, methods, combinations, and pharmaceutical compositions for treating symptoms associated with or associated with. The subject may have already been diagnosed with hypogonadism and / or low testosterone at the time of administration, or may be at risk of developing hypogonadism and / or low testosterone. The present invention is preferably for the treatment of adolescent subjects under 18 years of age. More preferably, the present invention is for the treatment of a prepubertal subject between 9 and 17 years of age (including the border).

  The term “derivative” means a compound made from another compound of similar structure by substituting one atom, molecule or group substituent for another. For example, the hydrogen atom of a compound may be substituted with alkyl, acyl, amino, etc. to produce a derivative of the compound.

  The term “lower alcohol” as used herein, alone or in combination, means a straight or branched alcohol moiety containing from 1 to about 6 carbon atoms. In one embodiment, the lower alcohol contains 1 to about 4 carbon atoms, and in another embodiment the lower alcohol contains 2 to about 3 carbon atoms. Examples of such alcohol moieties include methanol, ethanol, ethanol USP (ie, 95% v / v), n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.

  The term “lower alkyl” as used herein, alone or in combination, means a straight or branched alkyl group containing from 1 to about 6 carbon atoms. In one embodiment, the lower alkyl contains 1 to about 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

The term “ethanol” as used herein means C ₂ H ₅ OH. It may be used in any general form including dehydrated alcohol USP, alcohol USP, or in combination with various amounts of water.

  The composition is used in a “pharmacologically effective amount”. The term refers to the drug concentration administered in the composition that results in the delivery of a therapeutic level of drug over the period of use of the drug. Such delivery depends on a number of variables, including the period during which the individual dosage unit is used, including the rate at which the drug, eg, testosterone, flows out of the gel from the composition, the surface area of the application site, and the like. For testosterone, for example, the amount of testosterone required may be determined empirically based on the testosterone efflux rate from the gel and the testosterone efflux rate through the skin when used with and without a promoter.

The term “prodrug” means a drug or compound whose pharmacological action (active therapeutic agent) is derived from conversion by metabolic action in the body. Prodrugs are generally understood to be drug precursors that are converted to an active or more active species by some process, such as a metabolic process, after administration to a subject and after absorption. Other products derived from the conversion process are easily handled by the body. Prodrugs generally have chemical groups present on the prodrug that render the drug more inactive and / or provide some other property. When the chemical group is cleaved from the prodrug, a more active drug is produced. Prodrugs may be designed as reversible drug derivatives and utilized as modifiers to facilitate drug delivery to site-specific tissues. To date, prodrug designs increase the effective water solubility of therapeutic compounds to target areas where water is the primary solvent. For example, Fedorak, et al., Am. J. Physiol, 269: G210-218 (1995) discloses dexamethasone-β-D-glucuronide. McLoed, et al., Gastroenterol., 106: 405-413 (1994) discloses dexamethasone-succinate-dextran. Hochhaus, et al., Biomed. Chrom., 6: 283-286 (1992) discloses dexamethasone-21-sulfobenzoate sodium and dexamethasone-21-isonicotinate. In addition, J. Larsen and H. Bundgaard [Int. J. Pharmaceutics, 37, 87 (1987)] discloses the evaluation of N-acylsulfonamides as potential prodrug derivatives. J. Larsen et al., [Int. J. Pharmaceutics, 47, 103 (1988)] discloses the evaluation of N-methylsulfonamide as a potential prodrug derivative. Prodrugs are also disclosed, for example, in Sinkula et al., J. Pharm. ScL, 64: 181-210 (1975). Other non-limiting examples of “prodrugs” that may be used in combination or in the methods of the present invention include parecoxib (propanamide, N-[[4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] Sulfonyl]-) and MAG-camptothecin.

  In one embodiment, the present invention relates to a method for transdermal administration of testosterone in a hydroalcoholic gel. The gel includes one or more alcohols, such as ethanol or isopropanol; penetration enhancers; thickeners; and water. In one embodiment, the gel comprises an anionic polymer thickener precursor neutralized, preferably neutralized with a hydroxide releasing agent such as sodium hydroxide. In addition, the present invention may optionally include salts, emollients, stabilizers, antibacterial agents, perfumes, and propellants.

  The isomers and tautomers of the disclosed compounds and their pharmaceutically acceptable salts are included in the methods and pharmaceutical compositions of the invention. Exemplary pharmaceutically acceptable salts are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid , Pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, Prepared from benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, argenic acid, b-hydroxybutyric acid, galactaric acid, and galacturonic acid.

  Non-limiting examples of penetration enhancers include C8-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; ethyl oleate, isopropyl myristate, butyl stearate And lower alkyl esters of C8-C22 fatty acids such as methyl laurate; di-lower alkyl esters of C6-C22 dibasic acids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene Polyethylene glycol; propylene glycol; 2- (2-ethoxyethoxy) ethanol; diethylene glycol monomethyl ether; Including and terpene; chromatography ether; polyethylene oxide monomethyl ether; polyethylene oxide dimethyl ether; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetate; N- alkylpyrrolidones.

  Thickeners (also known as gelling agents) suitable for use in the present invention include neutralized anionic polymers such as polyacrylic acid. Preferably, carbomer polyacrylic acid, especially Noveon Inc. of Cleveland, Ohio. Manufactured and sold as Carbopol® (see http://www.noveon.com, which is incorporated herein by reference). Particularly preferred are Carbopol (R) Ultrez 10, 940, 941, 954, 980, 981, ETD 2001, EZ-2, and EZ-3. Most preferred are Carbopol (R) 940 and Carbopol (R) 980. Other suitable anionic polymers include carboxypolymethylene and carboxymethylcellulose. Other known thickening agents such as Pemulen® polymer emulsifier and Noveon® polycarbophil are also suitable. Additional thickeners, accelerators, and excipients may also generally be referred to Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary, which is incorporated herein by reference. .

  In one embodiment, the formulation comprises sodium hydroxide, ammonium hydroxide, water, in an amount sufficient to neutralize the anionic polymer thickener precursor and form a gel in the process of forming the composition. Neutralization selected from the group consisting of potassium oxide, arginine, aminomethylpropanol, tetrahydroxypropylethylenediamine, triethanolamine (TEA), tromethamine, PEG-15 cocamine, diisopropanolamine, and triisopropanolamine, or combinations thereof. Contains an anionic polymer thickener precursor such as carbomer in combination with an agent. Suitable neutralizing agents and their use with selected anionic thickener precursors are incorporated herein by reference, “Neutralizing Carbopol® and Pemulen® Polymers in Aqueous and Hydroalcoholic Systems,” Commercial Brochure TDS-237 (October 1998) by Noveon Inc. of Cleveland, Ohio.

  In other embodiments, the formulations of the invention deliver from about 0.5 mg to about 50 mg of testosterone, or equivalent thereof, to the subject per unit dose. In another embodiment of the invention the formulation provides from about 5 mg to about 25 mg testosterone or equivalent per unit dose. In yet another embodiment of the invention, the formulation delivers about 5 mg to about 15 mg of testosterone or equivalent thereof to the subject per unit dose. In another embodiment of the invention, the formulation delivers about 15 mg to about 25 mg testosterone or equivalent thereof to the subject per unit dose. In still other embodiments of the invention, the formulation delivers about 25 mg to about 50 mg of testosterone or equivalent thereof to the subject per unit dose. Thus, for example, a testosterone gel, ointment, cream, or patch formulated for once daily administration may contain about 5 mg, or about 15 mg, or about 25 mg, or about 50 mg of testosterone.

  In one embodiment, the formulation is a gel, ointment, cream, or patch, testosterone; a penetration enhancer, such as isopropyl myristate; a thickener, such as a neutralized carbomer; a lower alcohol, such as ethanol. Or isopropanol; and water. In another embodiment, the formulation is a gel, ointment, cream, or patch and contains the following substances in appropriate proportions.

  In another embodiment, the formulation contains an anionic polymer thickener precursor, such as a carbomer, in combination with a neutralizing agent in an amount sufficient to form a gel during the formation of the composition.

  In still other embodiments, the formulation is in an amount sufficient for gelation and is a neutralizing agent, an aqueous hydroxy sodium solution, such as 0.1 N sodium hydroxide, or 1.5 N sodium hydroxide, or 2.0 N. Contains an anionic polymer thickener precursor, such as carbomer, in combination with sodium hydroxide or any other convenient strength aqueous solution. In one embodiment, the composition was prepared using about 1.0% to 10.0% 0.1N hydroxy sodium. Thus, embodiments using any proportion of 0.1 N NaOH between about 1.0% and about 10.0% may be used, for example, 1.0%, 2.0%, 3.0% %, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% 0.1N NaOH may be used.

  In one embodiment, in a 100 g composition, the gel, ointment, cream, or patch comprises about 0.01 g to about 15 g testosterone, about 0.01 g to about 50 g penetration enhancer, about 0.1 g to about It may contain 50 g of gelling agent and about 30 g to about 98 g of lower alcohol. In another embodiment, in a 100 g composition, the gel, ointment, cream, or patch comprises about 0.1 g to 10 g testosterone, about 0.1 g to about 5 g penetration enhancer, about 0.1 to about 5 g. And about 45 g to about 90 g of a lower alcohol, and water.

  In another embodiment, the composition comprises from about 0.75% to about 1.2% (w / w) testosterone; from about 0.6% to about 1.2% (w / w) isopropyl myristate. An alcohol selected from the group consisting of about 60% to about 80% (w / w) ethanol and isopropanol; a thickener sufficient to provide the composition with a viscosity greater than about 9000 cps; and water .

  In one embodiment, the viscosity of the composition of the present invention is from about 9000 cps to about 29000 cps. Thus, the viscosity of the composition of the present invention can be any amount between about 9000 cps and about 29000 cps, such as 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15 , 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000 , 28,000, or 29,000 cps.

  In one embodiment of the invention, the composition comprises about 1.0% (w / w) testosterone; about 0.6% to about 1.4% (w / w) isopropyl myristate; about 67% From about 74% (w / w) ethanol; from about 0.6% to about 1.4% (w / w) carbomer; from about 6.5% to about 7.5% (w / w) 0.1 N NaOH; And additional water.

  In another embodiment of the invention, the composition comprises about 0.9% to 1.1% (w / w) testosterone; about 0.4% to about 0.6% (w / w) isopropyl myristate. From about 68% to about 73% (w / w) ethanol; from about 0.85 to about 0.95% (w / w) carbomer; from about 4.6% to about 4.9% (w / w). Obtained by combining 1N NaOH; and additional water.

  In various cases, it may be preferable to use higher concentrations of testosterone. Thus, in yet another embodiment of the invention, the composition comprises about 1.15% to 1.8% (w / w) testosterone; about 0.6% to about 1.2% (w / w) ) Isopropyl myristate; about 60% to about 80% (w / w) ethanol; about 0.6% to about 1.4% (w / w) carbomer; and additional water. In other examples, the composition is in an amount sufficient to form a gel and is a neutralizing sodium hydroxide aqueous solution, such as 0.1 N sodium hydroxide or 1.5 N sodium hydroxide or 2.0 N. It may further contain sodium hydroxide or other convenient strength aqueous solutions. In one embodiment, the composition was prepared using about 1.0% to 10.0% 0.1N sodium hydroxide. Thus, embodiments using any proportion of 0.1N NaOH between about 1.0% and about 10.0% may be used, for example, 1.0%, 2.0%, 3.0% %, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% 0.1 N NaOH may be used. Thus, in another embodiment, the composition comprises about 1.15% to 1.8% (w / w) testosterone; about 0.6% to about 1.2% (w / w) isopropyl myristate; About 60% to about 80% (w / w) ethanol; about 0.6% to about 1.4% (w / w) carbomer; about 6.5% to about 7.5% (w / w) 0. It is obtained by combining 1N NaOH and additional water.

In yet another embodiment, the pharmaceutical composition comprises testosterone in an aqueous alcohol gel. The concentration of testosterone in the gel may vary. For example, the testosterone may be about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8% by weight of the composition. %, About 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8% %, About 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8% %, About 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8% %, About 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8% % By weight, about 4.9% by weight, about 5% by weight, about 5.1% by weight, about 5.2% by weight , About 5.3 wt%, about 5.4 wt%, about 5.5 wt%, about 5.6 wt%, about 5.7 wt%, about 5.8 wt%, about 5.9 wt%, about 6 wt%, about 6.1 wt%, about 6.2 wt% About 6.3 wt%, about 6.4 wt%, about 6.5 wt%, about 6.6 wt%, about 6.7 wt%, about 6.8 wt%, about 6.9 wt%, about 7 wt%, about 7.1 wt%, about 7.2 wt% , 7.3 wt%, 7.4 wt%, about 7.5 wt%, about 7.6 wt%, about 7.7 wt%, about 7.8 wt%, about 7.9 wt%, about 8 wt%, about 8.1 wt%, about 8.2 wt% Approx. 8.3 wt%, 8.4 wt%, 8.5 wt%, 8.6 wt%, 8.7 wt%, 8.8 wt%, 8.9 wt%, 9 wt%, 9.1 wt%, 9.2 wt% About 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, or about 10% by weight. The accelerator in this embodiment is about 0.5%, about 0.65%, about 0.75%, about 0.85%, about 0.95%, about 1%, about 2% by weight of the composition. Isopropyl myristate, which may be present at a concentration of about 3%, about 4%, or about 5% by weight. The pharmaceutical composition is about 70%, about 71%, about 71.4%, about 71.8%, about 72%, about 72.3%, about 72.5%, about 72.7% by weight of the composition. Also included are C1-C4 alcohols present in concentrations of weight percent, about 73 weight percent, about 73.5 weight percent, about 74 weight percent, about 74.5 weight percent, about 75 weight percent, or about 75 weight percent. Furthermore, the said pharmaceutical element obtained product contains polyacrylic acid and / or carboxymethylcellulose as a gelling agent. In one embodiment, the gelling agent is polyacrylic acid present at a concentration of about 1% by weight relative to the weight of the composition.

  One such testosterone gel is available from Unimmed Pharmaceuticals, Inc., the assignee of the present application. , Recently available in the United States with AndroGel® by Marietta, Georgia. In one embodiment, the gel comprises the following substances in appropriate amounts.

  Those skilled in the art will appreciate that the amounts of the components of the formulation may vary and still be within the spirit and scope of the invention. For example, the composition comprises about 1% (w / w) testosterone, about 0.9% (w / w) Carbopol 980, about 0.5% (w / w) isopropyl myristate, about 4.72% (w / W) 0.1N NaOH, about 71.4% (v / v) ethanol (about 96% purity), and up to 100% purified water. In various cases, it may be preferable to use higher concentrations of testosterone. Thus, in another example, the composition comprises about 1.15% to about 1.8% (w / w) testosterone, about 0.6% to about 1.4% (w / w) Carbopol 980, about 0 .6% to about 1.2% (w / w) isopropyl myristate, about 6.5% (w / w) to about 7.5% 0.1 NaOH, about 60% to about 80% (v / w) v) ethanol (about 96% purity) and up to 100% purified water. In another example, the composition comprises about 0.1 to 10.0 g testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl myristate, and about 30 0.0 to about 98.0 g of ethanol may be contained.

  In yet another embodiment, the composition comprises testosterone in an amount greater than 0.01 wt%, a penetration enhancer in an amount greater than about 0.1 wt%, and about 0.1 wt%, based on the weight of the composition. % Thickener and lower alcohol in an amount greater than about 30.0% by weight.

  The gel may be rubbed or placed in the area of the subject's skin and dried. The gel dries rapidly, i.e. within about 30 seconds to about 3 minutes after application. Illustratively, the gel is rubbed once a day into an area of skin, for example, the outside of the upper thigh and / or the buttocks. After application, subjects wash their hands. Application of the gel results in an increase in testosterone levels having the desired pharmacokinetic profile and treats symptoms associated with or associated with hypogonadism and / or low testosterone or hypogonadism and / or low testosterone in a subject Or it is effective for prevention. Thus, the composition is useful for the treatment of a number of conditions or diseases both in adolescents younger than 18 years and in adults 18 years and older.

  In one embodiment, the present invention uses a sachet having a polyethylene backing that is compatible with the components of the testosterone gel described above. The sachet may hold a unit dose or multiple doses.

  In other embodiments, the methods and compositions use a composition dispensed from a solid multi-dose container (eg, a hand pump), for example with a large foil sachet of the composition inside the container. Such large parcels may be provided with a polyethylene backing as described above. In one embodiment, the multi-dose container comprises an airless pump with a polyethylene lined foil pouch in the container with an inserted hand pump. In one embodiment, the polyethylene-lined foil pouch comprises 44g to 88g of product. In one embodiment, the pump allows a total amount of about 75 g of gel to be dispensed. In one embodiment, the pump is prepared prior to use, for example, by depressing the pump three times to discard the gel. In one embodiment, the pump contains sufficient product for preparation and a predetermined number of appropriate doses. In one embodiment, each full pump depression provides 1.25 g of testosterone gel. In this embodiment, a 3.75 g dose of gel would require the pump to be depressed three times. A 5 g dose of gel requires 4 pump depressions. A 7.5 g dose of gel would require 6 pump depressions. A 10 g dose of gel would require 8 depressions. Of course, each pump depression may supply any amount of testosterone gel suitable to deliver the desired dose. In fact, in other embodiments, each full depression of the pump delivers 0.5 g of testosterone gel. In this embodiment, a 5 g dose of gel would require 10 pump depressions. The pouch size, ie, the amount and volume delivered per depression, is not limited to these embodiments and may be varied or adjusted to meet the needs of the patient population.

  U.S. Patent No. 6,503,894, U.S. Published Patent Application Nos. 2002/0183296, 2003/0022877, 2003/0050292, 2003/0139384, 2003/0232072, which is hereby incorporated by reference in its entirety. 2004/0002482, 2004/0092494, and U.S. patent applications 09 / 703,753, 10 / 787,071, 10 / 825,540, 10 / 828,678, 10 / 829,618, 10 / 867,435 , 10 / 924,421, and 10 / 925,421, testosterone transdermal application using AndroGel® to hypogonadal patients improves testosterone levels, mood, libido, and sexual performance Has been shown and disclosed. As disclosed herein, AndroGel® has been found to be used for the treatment of pediatric hypogonadism.

  The methods and compositions of the present invention treat hypogonadism or other low testosterone-related diseases in patients, for example, adolescent men between the ages of 9 and 17 years (including boundaries) compared to those currently available Providing improved treatment options for preventing, preventing, recovering, stopping, or delaying their progression.

  In one embodiment, the pharmaceutical composition of the present invention is administered once, twice, three times a day or as many times as necessary to achieve the desired therapeutic effect. In other embodiments, the compositions of the invention are administered once, twice, or three times daily. In other embodiments, the compositions of the invention are administered once, twice, or three times daily, weekly, biweekly, or monthly.

  In one embodiment, the therapeutically effective amount is between about 0.5 g and less than about 5.0 g, preferably between 0.5 and 2.5 g.

  The composition allows release of the steroid after application to the skin in one embodiment of the invention at a rate and duration that delivers at least about 10 μg of steroid to the subject's serum each day.

  In another embodiment of the invention, the composition releases testosterone after application of the composition to the skin of a subject at a rate and duration that achieves a circulating serum concentration of testosterone greater than about 100 ng / dL. enable.

  In another embodiment of the invention, the composition comprises a circulating serum concentration of total testosterone greater than about 100 ng / dL (serum) over a period from about 0.5 hours after administration to about 24 hours after administration. Allows the testosterone to be released after application of the composition to the subject's skin at a rate and duration to achieve

In another embodiment of the invention, after administration of the composition, the C _max obtained is between about 100 and 1000 ng / dL.

  In other embodiments of the invention, the composition is administered daily at a dose of about 0.5 g to about 2.5 g, such as about 0.5 g, or about 1.5 g, or about 2.5 g. To be provided to the subject. Any other suitable dose may also be administered.

  In yet another embodiment of the invention, the subject in need of treatment has a serum testosterone level prior to the first application (pretreatment) of the composition of the invention of less than about 100 ng / dL. In another embodiment of the invention, a subject in need of treatment is a subject of less than the normal range of adolescent males in Tanner stage II, ie, between about 5 and less than about 70 ng / dL as shown in Table 1. Serum testosterone levels prior to the first application (pretreatment) of the inventive composition.

  In another embodiment of the invention, the subject's serum testosterone concentration is at least about 100 ng / dL to about 1000 ng / dL, such as about 100 ng, after at least about 30 days of daily administration of the composition of the invention. / DL to about 500 ng / dL, about 200 ng / dL to about 300 ng / dL, about 200 ng / dL to about 400 ng / dL, or about 200 ng to about 500 ng / dL.

  In yet another embodiment of the invention, the total testosterone concentration in the patient is greater than about 100 ng / dL after daily administration of the composition of the invention. In one embodiment, the total serum testosterone concentration in the patient is about 200 ng / dL, about 300 ng / dL, about 400 ng / dL, or greater than about 500 ng / dL. In one embodiment, total testosterone concentration is measured 24 hours after administration. In one embodiment, the total testosterone concentration is measured after 2 days of daily administration, such as 10 days, 14 days, 20 days, or 30 days.

  In other embodiments of the methods, kits, combinations, and compositions of the invention, the compositions of the invention are administered to the subject once, twice, or three times daily for at least about 4 days. In one embodiment, the composition is administered once a day.

  The invention is further illustrated by the following examples, which are not intended to be limiting in any manner. The contents of all documents cited throughout this application are expressly incorporated herein by reference. In practicing the invention, unless otherwise indicated, conventional pharmacological and pharmaceutical techniques within the ordinary skill in the art are used.

Example 1
Pharmacokinetics of testosterone gel (1%) in adolescent males before puberty Serum testosterone concentration at steady state, pharmacokinetics of testosterone gel 1% (PK) in adolescent males with insufficient testosterone production Evaluate properties as well as safety and durability. The primary assessment of PK properties was based on steady-state PK parameters determined from serum total testosterone concentrations.

Methods Formulation: AndroGel®, 1% testosterone, is available from Solvay Pharmaceuticals, Inc. Prepared and supplied by

  Design: A multi-center, non-blind dose escalation study was conducted on 18 pre-pubertal adult boys. For one treatment group and one of three dose escalations of testosterone gel 1% for 4 consecutive days (0.5 g, 1.5 g, and 2.5 g containing 5 mg, 15 mg, and 25 mg testosterone, respectively) There were three stages of processing periods (processing periods 1, 2, and 3) that apply to. Each treatment period was separated by a washing period of up to 14 days.

  The test design scheme is shown in Table 5.

  Treatment applied: Three different doses of testosterone gel 1% were used in this study (0.1 g, 1.5 g, and 2.5 g) and administered topically for three treatment periods as shown in Table 6 did. Testosterone gel 1% was supplied in multi-dose bottles with pumps adjusted to dispense 0.5 g of testosterone gel 1% as shown in Table 6.

  Each subject received a single dose of 1% testosterone gel over each period of 4 days with a 14-day washout period between treatments. Study drug was applied topically once a day in the morning. The following table is a list of ingredients that were combined to produce the test formulations used.

Main criteria adopted:
(A) Subject parent or court guardian signed informed consent, subject signed consent form in accordance with local law. ;
(B) recruited men aged 13 to 17 years with primary or secondary hypogonadism or CFGP;
(C) performed on testosterone-free subjects in prepubertal maturity as indicated by (i) testis volume of 3 mL or less and (ii) testosterone concentration of 50 ng or less;
(D) had a bone age of at least 10.5 years; and (e) had at least 12 g / dL of hemoglobin and at least 36% hematocrit.

  Subjects: A total of 17 prepubertal adolescent boys were employed to obtain serum concentration data for evaluation at levels of 0.5 g / day and 1.5 g / day. Four of the 17 subjects did not take a dose level of 2.5 g / day because they achieved serum testosterone levels greater than 200 ng / dL. Therefore, serum concentration data was obtained from 13 subjects at a dose level of 2.5 g / dL. Subjects who did not continue testing due to exceeding 200 ng / dL of serum testosterone levels were considered completed by the protocol that defined an upper limit of 200 ng / dL. Of the 17 subjects who participated, 13 subjects were diagnosed for primary or secondary hypogonadism, and 4 subjects were diagnosed for CDGP.

  Target layers: Table 8 lists the characteristics of all target layers and baselines.

Procedure and Evaluation Administration: Three escalating doses of testosterone gel 1% (0.5 g, 1.5 g, and 2.5 g containing 5 mg, 15 mg, and 25 mg testosterone, respectively) washed between each administration It was applied once a day in the morning for 4 consecutive days with a period. Subjects were instructed to wash the application site with soap and water 8 to 10 hours after each dose.

  The wash period was defined as the period (including boundaries) between the day after the last application of the test medication at the visit in the last treatment period and the day before the first application in the next treatment period. Each treatment facility was separated by a cleaning period of up to 14 days.

  Pharmacokinetic sample collection: Blood samples for pharmacokinetic (PK) measurements of total testosterone, bioavailable testosterone and free testosterone and serum concentration of total DHT, before application of testosterone gel 1% (pre-dose), treatment period Recovered after 1, 2, 4, 8, 12, and 24 hours of application on days 1, 2, and 3. Samples were also collected at the same nominal time on day 0, the day before the first dose, based on the “scheduled dose time” during the treatment period. Optionally, blood samples may be collected between 2 and 12 hours of application of 1% testosterone gel on the first day of treatment periods 1, 2, and 3.

  Bioanalytical Methods: Total testosterone, free testosterone, and bioavailable testosterone, and total DHT, E2, FSH, LH, and SHBG measurements were performed at Esterix Laboratory Services, 4301 Lost Hills Road, Calif. Hills, CA 91.

Criteria for evaluation Safety: vital signs, ECG, health check, clinical laboratory measurements (including PSA measurements), DRE and IPSS, safe testosterone and hematocrit measurements.

Pharmacokinetic analysis: Serum concentrations (ie, observed concentrations) for total testosterone, free testosterone, and bioavailable testosterone, and total DHT, as well as each successive sample collection time and each treatment at baseline (day 0) Periods (4th day of treatment periods 1, 2 and 3) were explicitly summarized (n, average, SD, CV%, minimum, maximum, median, and geometric mean). In addition, baseline adjusted concentrations were explicitly summarized for each treatment period for total testosterone, free testosterone, and bioavailable testosterone, and total DHT. The summarized data were presented separately for all subjects (17 subjects), subjects with hypogonadism (13 subjects), and subjects with CDGP (4 subjects). Pharmacokinetic parameters include the following:
(A) AUC _{0-24, ss} : area under the curve from 0 to 24 hours determined using the first-order trapezoidal formula; at least 4 data points are needed for the AUC calculation; Stipulated that AUC is unknown;
(B) C _{max, ss} : maximum concentration observed in the 24 hour dosing period;
(C) t _{max, ss} : time when C _max occurs;
(D) C _{min, ss} : minimum concentration observed in the 24 hour dosing period;
(E) t _{min, ss} : time when Cmin occurs;
(F) C _{avg. , Ss} : time-average concentration over the period of administration measured by AUC _0-24 / 24;
(E) Fluctuation index: (C _max −C _min ) / C _avg. The degree of variation in serum concentration over the course of the day, calculated as

  Statistical methods: Statistics compiled for the given data collected during the study are presented to give an overview of the general characteristics and PK and safe results of the tested subjects. Variability of categories is summarized by presenting the number and proportion of subjects in each category. Continuous variations are summarized using n, average, minimum, and maximum values.

Screening for basic testosterone levels In screening, all subjects who did not receive testosterone had a testosterone concentration of 50 ng / dL or less, and their sexual function status was confirmed before exposure to the test drug. . Approximately two-thirds of subjects did not receive androgen before entering the study (11 subjects, 64.7%). Table 9 shows screening of serum hormone reference concentrations for all subjects.

  The average serum total concentration was 70.5 ng / dL, but the median serum total concentration was 19.0 ng / dL, so the average value is biased.

Pharmacokinetic and pharmacodynamic results Of the 17 subjects who participated in the study, 13 subjects received all three treatment periods (0.5 g, 1.5 g, and 2 using testosterone 1%). 0.5 g of treatment) was completed. Four subjects did not complete the last treatment period because serum testosterone exceeded the level of 200 ng / dL.

Testosterone Concentration-Time Data FIG. 1 shows the average concentration profiles observed for all treatment groups of total testosterone, free testosterone, bioavailable testosterone, and total DHT. FIG. 2 shows baseline adjusted mean concentration profiles for all treatment groups of total testosterone, free testosterone, bioavailable testosterone, and total DHT.

  Referring to FIGS. 1 and 2, dose-related increases in total testosterone concentration (observation) over the entire concentration-time profile include each increase in dose (each containing 5, 15, and 25 mg testosterone. Testosterone gel 1%) at doses of 5, 1.5 and 2.5 g. At all testosterone gel dose levels, the total testosterone concentration was significantly increased compared to the baseline. The average serum concentration-time profile is very flat, indicating that testosterone concentration was maintained at a very constant level throughout the day. The concentration 24 hours after administration was similar to that before administration of each dose group except for the 2.5 g dose group, indicating that the total testosterone concentration represents a stable state on the fourth day. ing. The mean concentration 24 hours after administration in the 2.5 g treatment group was higher than before administration, which was 2 to 5 times higher than other subjects in the same treatment group. This may be due to an abnormal total testosterone concentration derived from 2004. The observed concentration profiles for free and bioavailable testosterone and total DHT were similar to those observed for total testosterone. The “baseline-adjusted” concentration-time profiles for all treatment groups and all specimens were in a similar pattern.

  FIG. 3 shows observed total testosterone and baseline adjusted total testosterone levels for all treatment periods prior to treatment with 1 g of 0.5 g, 1.5 g, and 2.5 g of testosterone gel. Indicates. In general, the average pre-dose concentration increased with increasing dose.

Pharmacokinetic parameters Table 10 summarizes the observed PK parameters for total testosterone, free testosterone, and total DHT after treatment.

Referring to Table 10, the median T _max observed for total testosterone ranged from 2 to 12 hours over the three treatment periods. A dose-related increase in mean exposure to total testosterone (AUC _{0-24, ss} , C _{max, ss} , and C _{avg, ss} ) was observed with increasing dose, but this increase is proportional to dose It was smaller than that. The AUC _{0-24, ss} , C _{max, ss} , and C _{avg, ss} parameters each showed a 2.3 fold increase with a 5 fold increase in testosterone dose (5 mg to 25 mg). Similar results were observed for free testosterone and bioavailable testosterone.

For total DHT, the observed median t _max ranged from 8 to 12 hours over the three treatment periods. The AUC _{0-24, ss} , C _{max, ss} , and C _{avg, ss} parameters each showed a 2.5-fold increase with a 5-fold increase in testosterone dose (5 mg to 25 mg).

Table 11 provides baseline adjusted PK parameters for total testosterone, free testosterone, bioavailable testosterone, and total DHT. The median t _max for total testosterone adjusted at baseline ranged from 2 to 8.08 over three treatment periods. For parameters adjusted at baseline for total testosterone, free testosterone, bioavailable testosterone, and total DHT, the trend was similar to that of the “observed” PK parameters.

CONCLUSION Characterization of total and free testosterone and total DHT pharmacokinetics in a young male pediatric population with reduced sexual function after topical application of 0.5%, 1.5g, and 2.5g testosterone gel 1% did.

  The steady state concentration-time profile is relatively flat in all subjects, indicating that the concentration of these analytes remains at a very stable level over the administration period.

The dose-related increase in exposure (AUC _{0-24, ss} , C _{max, ss} , and C _{avg, ss} ) increased in total testosterone and free with increasing testosterone dose compared to baseline concentration. Observed for testosterone. The increase was not proportional to dose, but there was no indication that it deviated from linear pharmacokinetics.

  Testosterone gel 1% appears to be safely and well tolerated in the pediatric subject population since there were no deaths and other malignant side effects during the study period. There were no clinically meaningful changes from baseline to the last visit during the pharmacokinetic assessment period for any hematological, blood chemistry, urinalysis, or lipid parameter.

  All references, including documents, patent applications, and patents, are incorporated by reference so that each document is individually and specifically incorporated by reference and is as if fully set forth herein. Incorporated herein.

  The use of individual numerical values is an approximation so that the value precedes the term “about” or “approximately”. Similarly, numerical values in the various ranges specified herein are preceded by the term “about” or “approximately” where the minimum and maximum values in the stated range are both “unless”, unless explicitly stated otherwise. As shown, it is an approximate value. Thus, the above and below variations of the stated range may be used such that substantially the same result as the value of the range is obtained. As used herein, the terms “about” and “approximately”, when referring to a numerical value, are common and usual for those skilled in the art to which the particular subject matter is most relevant or the scope or element thereof. Has the meaning of The amount that spreads from a particular numerical boundary depends on a number of factors. For example, a number of factors that may be taken into account are the effects of a given amount of variation and / or the importance of factors on the implementation of the claimed subject matter, as well as other known to those skilled in the art. Includes consideration factors. As used herein, different numbers of significant digits are not intended to limit the extent to which the use of the term “about” or “approximately” serves to expand a particular number. Thus, as a general problem, “about” or “approximately” extends the numerical value. Range disclosure is also intended as a continuous range including all values between the minimum and maximum values and the extension of the range obtained by use of the term “about” or “approximately”. Thus, the description of a range of values herein is intended only to serve as a simplified method of separately referring to each individual number included in the range, unless otherwise indicated. Each individual value is included herein as described separately herein.

  The use of the term “invention” is not intended to limit the scope of the claims in any way, and any and all statements and discussions relating to a particular use of the term “invention” are either or all No conclusion should be drawn that it applies to the following claims. The use of the term “invention” is used only for linguistic or grammatical convenience and does not limit the essence of any claim.

  Alternative embodiments of the claims are described herein, including the best mode known to the inventors for carrying out the claimed invention. Of these, variations of the disclosed embodiments will be apparent to persons of ordinary skill in the art who have touched this specification. The present inventor expects those skilled in the art to appropriately implement such modifications, and the present inventor believes that the claimed invention is not described in the present specification. It is intended to be implemented. Accordingly, the claimed invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof, unless otherwise indicated herein and not clearly contradicting the background, claims It is included in the invention described in.

  Any ranges, ratios, and ratio ranges formed in or derived from the data disclosed herein represent further embodiments of the specification, and are hereby expressly set forth. Included as part of This includes the formation of ranges that include or do not include an upper limit and / or a lower limit. Accordingly, those skilled in the art that are most closely related to a particular range, ratio, or range of ratios will understand that such values can be clearly derived from the data presented herein. Let's go.

  The use of the terms "a" and "an" and [the] and similar terms herein (especially the appended claims) is not indicated herein or otherwise from the background. Unless clearly contradicted, it should be understood to include both singular and plural. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by background. The use of any and all examples given herein or the exemplified terms (eg, etc., preferably, preferably) are intended only to further exemplify what is disclosed herein; It is not intended to limit the scope of the claims. The matter described in this specification should not be construed as any element not recited in any claims essential to the practice of the invention recited in the claims.

Claims (20)

  Use of testosterone for the manufacture of a topical pharmaceutical composition in the form of a hydroalcoholic gel containing testosterone for the treatment of hypogonadism in adolescent boys.   The use according to claim 1, wherein the treatment of hypogonadism is further characterized by pre-determining that the adolescent boy has serum testosterone levels below the appropriate level at that age.   The use according to claim 1 or 2, wherein the treatment of hypogonadism is characterized by raising the serum testosterone level of the boy to a level within the normal range of testicular function at that age.   4. The age of the adolescent boy is between about 9 and about 17, in particular between about 11 and about 17, especially between about 15 and about 17 years (including boundaries). Use as described in.   Serum testosterone levels with normal testicular function range from about 5 to about 50 ng / dL total testosterone for ages of about 10 to about 11 years, and about 10 to about 570 ng for ages of about 12 to about 14 years. 4. Use according to any one of claims 1 to 3, wherein the total testosterone is in the range of / dL total testosterone and for the age of about 15 to about 17 years is in the range of about 220 to about 800 ng / dL total testosterone.   Use of testosterone for the manufacture of a topical pharmaceutical composition in the form of a hydroalcoholic gel containing testosterone for treating adolescent boys' developmental delay in puberty.   7. Use according to claim 6, wherein the treatment of developmental delay is further characterized by measuring in advance that the adolescent boy has serum testosterone levels that cannot progress to an appropriate Tanner stage at that age.   Use according to claim 6 or 7, wherein the treatment of developmental delay is characterized by raising the serum testosterone level of the boy to a level within a range appropriate for the Tanner phase of that age.   Use of testosterone for the manufacture of a topical pharmaceutical composition in the form of a hydroalcoholic gel containing testosterone for treating an adolescent boy who cannot progress to puberty by the age of 14.   The use according to claim 9, wherein the treatment of the adolescent boy's inability to progress in puberty is further characterized by pre-determining serum testosterone levels in such a boy.   11. The treatment of the adolescent boy's failure to progress to puberty is characterized by raising the boy's serum testosterone to a level sufficient to initiate progression to puberty. Use as described in.   12. Use according to any one of claims 9 to 11, wherein the adolescent boy is pre-pubertal.   13. The testosterone according to any of claims 1 to 12, wherein the testosterone is administered to the skin at a daily dose of about 5 mg to about 25 mg testosterone, preferably a daily dose of about 5 mg, about 15 mg, or about 25 mg testosterone. Use according to one paragraph. The topical pharmaceutical composition in the form of an hydroalcoholic gel,
(A) about 0.01 to about 15% (w / w) testosterone;
(B) about 0.01 to about 50% (w / w) penetration enhancer,
(C) about 0.01 to about 50% (w / w) gelling agent;
(D) about 30 to about 98% (w / w) lower alcohol, and (e) 100% (w / w) purified water,
14. Use according to any one of claims 1 to 13, comprising: The topical pharmaceutical composition in the form of an hydroalcoholic gel,
(A) about 0.9 to about 1.1% (w / w) testosterone;
(B) about 0.85 to about 0.95% (w / w) Carbopol 980,
(C) about 0.4 to about 0.6% (w / w) isopropyl myristate;
(D) about 4.6 to about 4.9% (w / w) 0.1 N NaOH,
(E) about 68 to about 73% (v / v) ethanol (96% purity), and (e) up to 100% purified water,
15. Use according to any one of claims 1 to 14, comprising: The topical pharmaceutical composition in the form of an hydroalcoholic gel,
(A) about 1.15 to about 1.8% (w / w) testosterone;
(B) about 0.6 to about 1.4% (w / w) Carbopol 980,
(C) about 0.6 to about 1.2% (w / w) isopropyl myristate;
(D) about 6.5 to about 7.5% (w / w) 0.1 N NaOH,
(E) about 60 to about 80% (v / v) ethanol (96% purity), and (e) up to 100% purified water,
15. Use according to any one of claims 1 to 14, comprising:   The topical pharmaceutical composition in the form of a hydroalcoholic gel is about 1.0% (w / w) testosterone, about 0.90 g Carbopol 980, about 0.50 g isopropyl myristate, about 4.72 g 0.7. 16. Use according to any one of the preceding claims comprising 1 N NaOH, about 71.4 g 96% (v / v) ethanol, and up to 100 g purified water.   The topical pharmaceutical composition in the form of a hydroalcoholic gel comprises about 1.15 to about 1.80% (w / w) testosterone, about 0.6 to about 1.4 g Carbopol 980, about 0.6 to about 2. 1.2 g of isopropyl myristate, about 6.5 to about 7.5 g of 0.1 N NaOH, about 60 to about 80 g of 96% (v / v) ethanol, and up to 100 g of purified water. Use according to any one of 1 to 14 and 16.   Pharmaceutical sachet containing an hydroalcoholic gel comprising about 5 mg, about 15 mg, or about 25 mg testosterone.   A multi-dose container containing a hydroalcoholic gel that can dispense a fixed amount of gel with each pump operation to deliver about 5 mg, about 15 mg, or about 25 mg of testosterone.