EP2136813A2 - Compositions and method for treating pediatric hypogonadism - Google Patents

Compositions and method for treating pediatric hypogonadism

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Publication number
EP2136813A2
EP2136813A2 EP08718089A EP08718089A EP2136813A2 EP 2136813 A2 EP2136813 A2 EP 2136813A2 EP 08718089 A EP08718089 A EP 08718089A EP 08718089 A EP08718089 A EP 08718089A EP 2136813 A2 EP2136813 A2 EP 2136813A2
Authority
EP
European Patent Office
Prior art keywords
testosterone
use according
treatment
age
boy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08718089A
Other languages
German (de)
English (en)
French (fr)
Inventor
Robert E. Dudley
Alan D. Rogol
Janet Benesh
Troy L. Zumbrunnen
Gregg Pratt
John J. Brennan
Hjalmar Lagast
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Besins Healthcare Luxembourg SARL
Unimed Pharmaceuticals LLC
Original Assignee
Laboratoires Besins International SAS
Unimed Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires Besins International SAS, Unimed Pharmaceuticals LLC filed Critical Laboratoires Besins International SAS
Priority to EP08718089A priority Critical patent/EP2136813A2/en
Publication of EP2136813A2 publication Critical patent/EP2136813A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the age of onset of puberty in boys ranges from nine to fourteen years and is characterized by testicular enlargement followed by the appearance of pubic hair eighteen to twenty-four months after the onset of testicular growth.
  • Puberty can be characterized by skeletal growth, with linear growth velocity beginning to increase at Tanner Genital Stage III and Tanner Pubic Hair Stage II.
  • the Tanner Stages (I to V) are stages of physical development in children and adolescents. The stages define physical measurements of development based on external primary and secondary sex characteristics, such as the development of pubic hair. Due to natural variation, indi- viduals pass through the Tanner Stages at different rates, depending in particular on the timing of puberty. Peak height velocity is typically reached at 14 years of age.
  • Testosterone the major circulating androgen in males, is synthesized from cholesterol. It is primarily secreted in the testes of males. In the adult male, the ap- proximately 500 million Leydig cells in the testes secrete more than 95% of the 6-7 mg of testosterone produced per day. Two hormones produced by the pituitary gland, luteinizing hormone (“LH”) and follicle stimulating hormone (“FSH”), are required for the development and maintenance of testicular function and negatively regulate testosterone production via a feedback mechanism driven by circulating concentrations of the hormone. Circulating testosterone is metabolized to various 17-keto steroids through two different pathways. Testosterone can be metabolized to dihydrotestosterone ("DHT”) by the enzyme 5 ⁇ -reductase or to estradiol (“E2”) by an aromatase enzyme complex.
  • DHT dihydrotestosterone
  • E2 estradiol
  • Testosterone circulates in the blood 98% bound to proteins. In males, approximately 40% of the binding is to the high-affinity sex hormone binding globulin ("SHBG"). The remaining 60% is bound weakly to albumin. Thus, a number of measurements for testosterone are available from clinical laboratories.
  • the term “free” testosterone as used herein refers to the fraction of testosterone in the blood that is not bound to protein.
  • total testosterone or “testosterone” as used herein means the free testosterone plus protein-bound testosterone.
  • bioavailable testosterone refers to the non-SHBG bound testosterone and includes testosterone weakly bound to albumin.
  • Table 1 Testosterone Levels in Males by Tanner Stage
  • Table 2 Hormone Levels in Adolescent Males by Age Group
  • prepubertal maturation status can be indicated by, among other things: (i) testis volume of ⁇ 3 ml. and (ii) testosterone concentration of ⁇ 50 ng/dL.
  • testis volume ⁇ 3 ml.
  • testosterone concentration ⁇ 50 ng/dL.
  • Hypogonadism results from a variety of patho-physiological conditions in which testosterone concentration is diminished below the normal range. The hypo- gonadic condition is sometimes linked with a number of physiological changes, such as reduced lean body mass, decreased bone density, lowered mood, and decreased energy levels.
  • researchers generally classify hypogonadism into one of three types.
  • Pri- mary hypogonadism includes the testicular failure due to congenital or acquired anor- chia, XYY Syndrome, XX males, Noonan's Syndrome, gonadal dysgenesis, Leydig cell tumors, maldescended testes, varicocele, Sertoli-Cell-Only Syndrome, cryptorchidism, bilateral torsion, vanishing testis syndrome, Klinefelter's Syndrome, chemotherapy, toxic damage from alcohol or heavy metals, and general disease (renal failure, liver cirrhosis, diabetes, myotonia dystrophica). Patients with primary hypogonadism show an intact feedback mechanism in that the low serum testosterone concentrations are associated with high FSH and LH concentrations.
  • Secondary hypogonadism involves an idiopathic gonadotropin or LH-releasing hormone deficiency.
  • This type of hypogonadism includes Kallman's Syndrome, Prader-Labhart-Willi's Syndrome, Laurence-Moon-Biedl's Syndrome, pituitary insufficiency/adenomas, Pasqualini's Syndrome, hemochromatosis, hyperprolactinemia, or pituitary-hypothalamic injury from tumors, trauma, radiation, or obesity.
  • Adolescent males with delayed puberty associated with the conditions de- scribed above may be treated with androgens (e.g., testosterone) or anabolic steroids. Adolescent males with permanent hypogonadism will require long-term androgen supplementation. Such treatment will typically produce secondary sexual development and an increase in stature.
  • the most common form of testosterone used for treatment of delayed puberty is the injectable form.
  • a testos- terone ester e.g., testosterone enanthate
  • This regimen requires frequent visits to the physician's office and is painful.
  • Injections of testosterone also result in serum testosterone concentrations that fluctuate widely over the dosing interval, from higher than desired immediately after an injection to lower than desired before the next injection. These fluctuating concentrations over the dosing interval complicate the use of serum testosterone concentrations as a meaningful indicator for dosage adjustments.
  • Oral halo- genated or methylated testosterone products are not popular in the United States because of the risk of hepatic complications.
  • use of the anabolic steroids does not promote increased secretion of growth hormone, as does testosterone.
  • disadvantages are associated with each of the products typically used to treat delayed puberty.
  • Eugonadal concentrations were achieved within a few hours of the first application in the majority of the men, and these concentrations were maintained for up to 180 days with once daily dosing.
  • the most frequently reported adverse events (AEs) related to the use of testosterone gel 1 % were acne (up to 8%); clinical laboratory test abnormalities (up to 6%) that included increased red blood cells, hemoglobin, hematocrit, and decreased serum lipids; applica- tion site reactions (up to 5%); prostate disorder (up to 5%); and headache (up to 4%).
  • Testosterone gel could provide several advantages for the treatment of delayed puberty in boys of adolescent age. Most importantly, the relatively consistent serum testosterone concentrations achieved with this product would allow a clinician to obtain meaningful measurements of serum testosterone concentrations to adjust the dose to attain a testosterone concentration appropriate for a given stage of pubertal development.
  • Testosterone concentrations gradually increase as boys move from Tanner Pubic Hair Stage I through Tanner Pubic Hair Stage V.
  • the ability to attain consistent testosterone concentrations over time and to use those concentrations to make appropriate adjustments in dose should allow clinicians to induce secondary sexual development and to move these boys through the various stages of puberty in a more physiologic manner.
  • testosterone gel for the treatment of delayed puberty in adolescent boys is convenience of use. Use of the gel would not require that the boys return to the physician's office every two to four weeks, as they do for injections. This is an important factor for both the boys and their families. Finally, the gel should be well-tolerated in this population. Its use will avoid the pain and discomfort associated with the testosterone injections and foster compliance with a testosterone therapy treatment plan. Neither will there be the risk of hepatic complications associated with the use of oral anabolic agents. The gel has been very well tolerated in the adult population, and few subjects experience application site reactions.
  • the present invention relates to compositions for treating prepubertal males of adolescent age with insufficient testosterone production using a hydroalcoholic testosterone gel formulation that provides, among other things, a desirable pharmacokinetic hormone profile, and methods of treating said adolescent males.
  • FIG. 1 is a graph showing the mean observed serum concentration versus time profile for total and free testosterone, dihydrotestosterone, and bioavailable testos- terone.
  • FIG. 2 is a graph showing the mean baseline-adjusted serum concentration versus time profile for total and free testosterone, dihydrotestosterone, and bioavailable testosterone.
  • FIG. 3 is a graph showing the observed and baseline-adjusted mean predose testosterone concentrations.
  • the present invention relates to compositions for treating prepubertal males of adolescent age, i.e., between 9 and 17 years of age (inclusive), with insufficient testosterone production (i.e., pediatric hypogonadism) using a hydroalcoholic testosterone gel formulation that provides, among other things, a desirable pharmacokinetic hormone profile, and methods using such compositions for such treatment.
  • the present invention is directed to a method for percutaneous administration of testosterone in a hydroalcoholic gel.
  • the gel comprises testosterone (or a testosterone derivative), one or more lower alcohols, such as ethanol or isopropanol; a penetration enhancing agent such as isopropyl myristate; a thickener; and water.
  • the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
  • the present invention also includes kits, methods, combinations, and pharmaceutical compositions for treating, preventing, reversing, halting or slowing the progression of hypogonadism or other low-testosterone-associated disorders in a subject once it becomes clinically evident, or treating the symptoms associated with, or related to the hypogonadism or low-testosterone-associated disorder.
  • the subject may already have a diagnosis of hypogonadism and/or low testosterone at the time of administration, or be at risk of developing hypogonadism and/or low testosterone.
  • the present invention preferably is for treatment of adolescent subjects under 18 years of age. Even more preferably, the present invention is for treatment of prepubertal subjects between 9 and 17 years of age (inclusive).
  • the term “derivative” refers to a compound that is produced from another compound of similar structure by the replacement of substitution of one atom, molecule or group by another.
  • a hydrogen atom of a compound may be substituted by alkyl, acyl, amino, etc., to produce a derivative of that compound.
  • the term "lower alcohol,” alone or in combination means a straight-chain or branched-chain alcohol moiety containing one to about six carbon atoms. In one embodiment, the lower alcohol contains one to about 4 carbon atoms, and in another embodiment the lower alcohol contains two to about 3 carbon atoms.
  • alcohol moieties examples include methanol, ethanol, ethanol USP (i.e., 95% v/v), n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.
  • lower alkyl means a straight-chain or branched-chain alkyl radical containing one to about six carbon atoms. In one embodiment, the lower alkyl contains one to about four carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, and tert-butyl.
  • the term "ethanol” refers to C 2 H5OH. It may be used as dehydrated alcohol USP, alcohol USP, or in any common form including in combination with various amounts of water.
  • the composition is used in a "pharmacologically effective amount.” This means that the concentration of the drug administered is such that in the composition it results in a therapeutic level of drug delivered over the term that the drug is to be used. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the flux rate of the drug from the composition, for example, testosterone, from the gel, surface area of application site, etc. For testosterone, for example, the amount of testosterone necessary can be experimentally determined based on the flux rate of testosterone through the gel, and through the skin when used with and without enhancers.
  • prodrug refers to a drug or compound in which the pharmacological action (active curative agent) results from conversion by metabolic processes within the body.
  • Prodrugs are generally considered drug precursors that, following administration to a subject and subsequent absorption, are converted to an active or a more active species via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body.
  • Prodrugs generally have a chemical group present on the prodrug which renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved from the prodrug the more active drug is generated.
  • Prodrugs may be designed as reversible drug derivatives and utilized as modifiers to enhance drug transport to site-specific tissues.
  • prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent.
  • Fedorak, et al., Am. J. Physiol, 269:G210-218 (1995) describe dexamethasone- beta -D-glucuronide.
  • McLoed, et al., Gastroenterol., 106:405-413 (1994) describe dexamethasone-succinate-dextrans.
  • Hochhaus, et al., Biomed. Chrom., 6:283-286 (1992) describe dexamethasone-21-sulphobenzoate sodium and dexamethasone-21-isonicotinate.
  • Bundgaard Int. J. Pharmaceutics, 37, 87 (1987)] describe the evaluation of N-acylsulfonamides as potential prodrug derivatives. J. Larsen et al., [Int. J. Pharmaceutics, 47, 103 (1988)] describe the evaluation of N-methylsulfonamides as potential prodrug derivatives. Prodrugs are also described in, for example, Sinkula et al., J. Pharm. ScL, 64:181-210 (1975).
  • the present invention is directed to a method for percutaneous administration of testosterone in a hydroalcoholic gel.
  • the gel comprises one or more lower alcohols, such as ethanol or isopropanol; a penetration enhancing agent; a thickener; and water.
  • the gel comprises an anionic polymer thickening agent precursor neutralized, preferably neutralized with a hydroxide releasing agent, such as sodium hydroxide.
  • the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
  • the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
  • Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.
  • Non-limiting examples of penetration enhancing agents include C8-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C22 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene gly- col monomethyl ether; alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; poly
  • the thickening agents (aka gelling agents) suitable for use in the present invention include neutralized anionic polymers such as polyacrylic acid.
  • Preferred are the carbomer polyacrylic acids, especially those made and sold by Noveon Inc. of Cleveland, Ohio under the trademark Carbopol®. (See information at http://www.noveon.com, incorporated herein by reference.)
  • Particularly preferred are Carbopols® Ultrez 10, 940, 941 , 954, 980, 981 , ETD 2001 , EZ-2 and EZ-3.
  • Carbopol® 940 and Carbopol® 980 are particularly preferred.
  • Other suitable anionic polymers include carboxypolymethylene and carboxymethyl cellulose.
  • polymeric thickening agents such as Pemulen® polymeric emulsifiers, and Noveon® polycarbophils. Additional thickening agents, enhancers and adjuvants may generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia/National Formulary, all incorporated herein by refer- ence.
  • the formulation contains an anionic polymer thickening agent precursor such as a carbomer which has been combined with a neutralizer selected from the group consisting of sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, triethanolamine ("TEA"), tromethamine, PEG-15 cocamine, diisopropanolamine, and triisopropanolamine, or combinations thereof in an amount sufficient to neutralize the anionic polymer thickening agent precursor to form a gel in the course of forming the composition.
  • a neutralizer selected from the group consisting of sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, triethanolamine (“TEA”), tromethamine, PEG-15 cocamine, diisopropanolamine, and triisopropanolamine, or combinations thereof in an
  • the formulation of the present invention delivers about 0.5 mg to about 50 mg testosterone, or the equivalent thereof, to a subject per dosage unit. In another embodiment of the present invention, the formulation delivers from about 5 mg to about 25 mg testosterone, or the equivalent thereof, to a subject per dosage unit. In yet another embodiment of the present invention, the formulation delivers from about 5 mg to about 15 mg testosterone, or the equivalent thereof, to a subject per dosage unit.
  • the formulation delivers from about 15 mg to about 25 mg testosterone, or the equivalent thereof, to a subject per dosage unit. In still another embodiment of the present invention, the formulation delivers from about 25 mg to about 50 mg testosterone, or the equivalent thereof, to a subject per dosage unit.
  • a testosterone gel, ointment, cream or patch formulated for once a day administration can contain about 5 mg, or about 15 mg, or about 25 mg, or about 50 mg testosterone.
  • the formulation is a gel, an ointment, a cream or a patch and is comprised of testosterone; a penetration enhancing agent, such as isopropyl myristate; a thickening agent, such as a neutralized carbomer; a lower alcohol, such as ethanol or isopropanol; and water.
  • the formulation is a gel, an ointment, a cream or a patch and is comprised of the following substances in approxi- mate percentages:
  • the formulation contains an anionic polymer thickening agent precursor such as a carbomer which has been combined with a neutralizer in an amount sufficient to form a gel in the course of forming the composition.
  • the formulation contains an anionic polymer thickening agent precursor such as a carbomer which has been combined with a neutralizer which is an aqueous solution of sodium hydroxide such as 0.1 N sodium hydroxide, or 1.5 N sodium hydroxide, or 2.0 N sodium hydroxide or any other convenient strength aqueous solution in an amount sufficient to form a gel.
  • the composition was prepared using between about 1.0% and 10.0% 0.1 N sodium hydroxide.
  • embodiments employing any percentage between about 1.0% and about 10.0% 0.1 N NaOH may be used, such as, e.g., 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.
  • the gel, ointment, cream, or patch may contain about 0.01 g to about 15 g of testosterone, about 0.01 g to about 50 g penetration enhancing agent, about 0.1 g to about 50 g gelling agent, and about 30 g to about 98 g lower alcohol.
  • the gel, ointment, cream, or patch may contain about 0.1 g to 10 g of testosterone, about 0.1 g to about 5 g of penetration enhancing agent, about 0.1 g to about 5 g of gelling agent, and about 45 g to about 90 g lower alcohol and water.
  • the composition comprises about 0.75 % to about 1.2 % (w/w) testosterone; about 0.6 % to about 1.2 % (w/w) isopropyl myristate; about 60 % to about 80 % (w/w) alcohol selected from the group consisting of ethanol and iso- propanol; a sufficient amount of a thickening agent to give the composition a viscosity in excess of about 9000 cps; and water.
  • the viscosity of the composition of the present invention is about 9,000 cps to about 29,000 cps.
  • the viscosity of the composition of the present invention may be any amount between about 9,000 cps and 29,000 cps, such as, e.g., 9,000, 10,000, 1 1 ,000, 12,000, 13,000, 14,000, 15,000, 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.
  • the composition is obtained by combining about 1.0 % (w/w) testosterone; about 0.6 % to about 1.4 % (w/w) isopropyl myristate; about 67 % to about 74 % (w/w) ethanol; about 0.6 % to about 1.4 % (w/w) carbomer; about 6.5 % to about 7.5 % (w/w) 0.1 N NaOH; and additional water.
  • the composition is obtained by combining about 0.9 % to 1.1 % (w/w) testosterone; about 0.4 % to about 0.6 % (w/w) isopropyl myristate; about 68 % to about 73 % (w/w) ethanol; about 0.85 % to about 0.95 % (w/w) carbomer; about 4.6 % to about 4.9 % (w/w) 0.1 N NaOH; and addi- tional water.
  • the composition is obtained by combining 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.
  • the composition may additionally contain a neutralizer which is an aqueous solution of sodium hydroxide such as 0.1 N sodium hydroxide, or 1.5 N sodium hydroxide, or 2.0 N sodium hydroxide or any other convenient strength aqueous solution in an amount sufficient to form a gel.
  • a neutralizer which is an aqueous solution of sodium hydroxide such as 0.1 N sodium hydroxide, or 1.5 N sodium hydroxide, or 2.0 N sodium hydroxide or any other convenient strength aqueous solution in an amount sufficient to form a gel.
  • the composition was prepared using between about 1.0% and 10.0% 0.1 N sodium hydroxide. Accordingly, embodiments employing any percentage between about 1.0% and about 10.0% 0.1 N NaOH may be used, such as, e.g., 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.
  • the composition is obtained by combining 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; from about 6.5 % to about 7.5 % (w/w) 0.1 N NaOH and additional water.
  • the pharmaceutical composition includes testosterone in a hydroalcoholic gel. The concentration of testosterone in the gel can be varied.
  • the testosterone may be present in a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, 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%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about
  • the enhancer in this embodiment includes isopropyl myristate, which may be present in a concentration of about 0.5%, about 0.65%, about 0.75%, about 0.85%, about 0.95%, about 1 %, about 2%, about 3%, about 4%, or about 5% weight to weight of the composition.
  • the pharmaceutical composition also includes a C1-C4 alcohol present in a concentration of about 70%, about 71 %, about 71.4%, about 71.8%, about 72%, about 72.3%, about 72.5%, about 72.7%, about 73%, about 73.5%, about 74%, about 74.5%, about 75% or about 75% weight to weight of the composition.
  • the pharmaceutical composition includes polyacrylic acid and/or carboxymethylcellulose as the gelling agent.
  • the gelling agent is polyacrylic acid present in a concentration of about 1 % weight to weight of the composition.
  • the gel is comprised of the following substances in approximate amounts:
  • the constituents of this formulation may be varied in amounts yet continue to be within the spirit and scope of the present invention.
  • the composition may contain about 1% (w/w) Testosterone, about 0.9% (w/w) Carbopol 980, about 0.5% (w/w) Isopropyl myristate, about 4.72% (w/w) 0.1 N NaOH, about 71.4% (v/v) Ethanol (about 96% pure), and purified water up to 100%. In various instances, it may be preferable to utilize higher testosterone concentrations.
  • the composition may contain from about 1.15 % to about 1.8 % (w/w) Testosterone, from about 0.6% to about 1.4% (w/w) Carbopol 980, from about 0.6% to about 1.2% (w/w) lsopropyl myristate, from about 6.5% (w/w) to about 7.5% 0.1 N NaOH, from about 60% to about 80% (v/v) Ethanol (about 96% pure), and purified water up to 100%.
  • Testosterone from about 0.6% to about 1.4% (w/w) Carbopol 980, from about 0.6% to about 1.2% (w/w) lsopropyl myristate, from about 6.5% (w/w) to about 7.5% 0.1 N NaOH, from about 60% to about 80% (v/v) Ethanol (about 96% pure), and purified water up to 100%.
  • the composition may contain about 0.1 to about 10.0 g of testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl myristate, and about 30.0 to about 98.0 g ethanol.
  • the composition comprises testosterone in an amount greater than 0.01%, a penetration enhancing agent in an amount greater than about 0.1%, a thickening agent in an amount greater than about 0.1 %, and a lower alcohol in an amount greater than about 30% w/w of the composition.
  • the gel is rubbed or placed onto an area of skin of the subject and allowed to dry.
  • the gel dries rapidly, i.e., within about 30 seconds to about 3 minutes after appli- cation.
  • the gel is rubbed onto an area of skin, for example, on the upper outer thigh and/or hip once daily. Following application the subject washes his or her hands.
  • Application of the gel results in an increased testosterone level having a desirable pharmacokinetic profile and is effective to treat or prevent hypogonadism and/or low testosterone, or the symptoms associated with, or related to hypogonadism and/or low testosterone in the subject.
  • the composition is thus useful for treating a number of conditions or diseases in both adolescents under 18 years of age and adults 18 years of age and older.
  • the present invention employs a packet having a polyethylene liner compatible with the components of a testosterone gel, as described below.
  • the packet may hold a unit dose or multiple dose.
  • the methods and compositions employ a composition that is dispensed from a rigid multi-dose container (for example, with a hand pump) having a larger foil packet, for example, of the composition inside the container.
  • a rigid multi-dose container for example, with a hand pump
  • a larger foil packet for example, of the composition inside the container.
  • larger packets can also comprise a polyethylene liner as above.
  • the multi-dose container comprises an airless pump that comprises a polyethylene lined foil pouch within a canister with a hand pump inserted.
  • the polyethylene lined foil pouch comprises 44 g or 88 g of product.
  • the pump is capable of dispensing a total amount of about 75 g of gel.
  • the pump is primed before use, such as, e.g., by fully depressing the pump three times and discarding the gel.
  • the pump contains enough product to allow for priming and a set number of precise doses.
  • each full pump depression delivers 1.25 g of testosterone gel.
  • a 3.75 g dose of gel would require 3 pump depressions.
  • a 5 g dose of gel would require 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, and so on.
  • each pump depression can deliver any amount of testosterone gel suitable for delivering the desired dose.
  • each full pump depression delivers 0.5 g of testosterone gel.
  • a 5 g dose of gel would require 10 pump depressions, and so on.
  • the pouch size, amount dispensed and the delivery volume per depression are not limited to these embodiments and may be changed or adjusted to meet the needs of the patient population.
  • compositions of the present invention provide enhanced treatment options for treating, preventing, reversing, halting or slowing the progression of hypogonadism or another low-testosterone-associated disorder in a subject, for example, an adolescent male between 9 and 17 years of age (inclusive), as compared to those currently available.
  • the pharmaceutical composition of the present invention is administered once, twice, or three times a day, or as many times necessary to achieve the desired therapeutic effect. In another embodiment the composition of the present invention is administered once, twice, or three times a day on alternate days. In another embodiment the composition of the present invention is administered once, twice, or three times a day on a weekly, biweekly, or monthly basis. [057] In one embodiment, a therapeutically effective dose is between about 0.5 g and under about 5.0 g, preferably between about 0.5 g and 2.5 g.
  • the composition is capable of releasing the steroid after applying the composition to the skin at a rate and duration that delivers in one embodiment of the present invention at least about 10 ⁇ g per day of the steroid to the blood serum of the subject.
  • the composition is capable of releasing the testosterone after applying 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 serum.
  • the composition is capable of releasing the testosterone after applying the composition to the skin of a subject at a rate and duration that achieves a circulating serum concentration of total testosterone greater than about 100 ng/dL serum during a time period beginning about 0.5 hours after administration and ending about 24 hours after administration.
  • an obtained C max is between about 100 and 1000 ng/dL.
  • the composition is provided to a subject for daily administration in about a 0.5 g to about a 2.5 g dose, such as, e.g., about 0.5 g, or about 1.5 g, or about 2.5 g. Any other suitable dose may be also be administered.
  • the subject in need of treatment has a serum testosterone level before the first application (pretreatment) of the composition of the present invention of less than about 100 ng/dL.
  • the subject in need of treatment has a serum testosterone level before the first application (pretreatment) of the composition of the present invention of less than the normal range of an adolescent male in Tanner Stage II, i.e., less than between about 5 and about 70 ng/dL, as shown in Table 1.
  • the serum testosterone concentration in a subject is at least about 100 ng/dL to about 1000 ng/dL, such as, for example, about 100 ng/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/dL to about 500 ng/dL.
  • the total testosterone concentration in a subject is greater than about 100 ng/dL.
  • the total serum tes- tosterone concentration in the subject is greater than about 200 ng/dL, about 300 ng/dL, about 400 ng/dL or about 500 ng/dL.
  • the total testosterone concentration is measured after 24 hours of administration.
  • the total testosterone concentration is measured after more than 2 days of daily administration, such as, for example, after 10 days, 14 days, 20 days, or 30 days.
  • the composition of the present invention is administered once, twice, or three times daily to a subject for at least about 4 days. In one embodiment, the composition is administered once a day.
  • Example 1 Pharmacokinetic Evaluation of Testosterone gel (1%) in Prepubertal Males of Adolescent Age
  • Treatments Administered Three different doses of testosterone gel 1 % were utilized in this study (0.5 g, 1.5 g, and 2.5 g), and administered topically during three treatment periods as indicated in Table 6. Testosterone gel 1 % was supplied in multi-dose bottles with attached pumps calibrated to dispense 0.5 g of testosterone gel 1% as shown in Table 6.
  • Treatment Period 1 Treatment Period 2: Treatment Period 3:
  • Subjects A total of seventeen (17) prepubertal boys of adolescent age were enrolled and provided serum concentration data for evaluation at the 0.5g/day and 1.5 g/day dose levels. Four of 17 subjects did not complete the 2.5g/day dose level due to achieving serum testosterone values greater than 200 ng/dL. Therefore thirteen (13) subjects provided serum concentration data at the 2.5 g/day dose level. Subjects who were discontinued due to exceeding a serum testosterone level of 200 ng/dL were considered study completers due to the protocol defined upper limit of 200 ng/dL. Of the seventeen (17) subjects enrolled, thirteen (13) subjects were diagnosed with primary or secondary hypogonadism and four (4) subjects were diagnosed with CDGP. [076] Subject Demographics: Table 8 provides the summary statistics of demographic and Baseline characteristics for all subjects.
  • Washout Period was defined as the period between the day after the last ap- plication of study medication in the last treatment period visit and the day before the first application in the next treatment visit (inclusive). Each treatment period was separated by a washout period of up to 14 days.
  • Bioanalytical Method Measurements of total, free, and bioavailable testosterone, as well as total DHT, E2, FSH, LH, and SHBG were performed at Esoterix Laboratory Services, 4301 Lost Hills Road, Calabasas Hills, CA 91301.
  • Pharmacokinetic parameters included the following: (a) AUCo- 24 ,s S : area under the curve from O to 24 hours, determined using the linear trapezoidal rule; a minimum of four data points were required for the calculation of AUC; otherwise AUC was defined as missing;
  • the mean serum total concentration was 70.5 ng/dL, but the mean appears to be skewed as the median serum total concentration was 19.0 ng/dL.
  • FIG. 1 shows the observed mean concentration profiles for total, free, bioavailable testosterone and total DHT for all treatment groups.
  • FIG. 2 shows the Baseline-adjusted mean concentration profiles for total, free, bioavailable testosterone and total DHT for all treatment groups.
  • FIG. 3 shows the predose levels of observed and Baseline adjusted total tes- tosterone for all treatment periods before treatment with 0.5 g, 1.5 g, and 2.5 g of testosterone gel 1 %. In general, the mean predose concentrations increased with increase in dose.
  • Table 10 summarizes the observed PK parameters for total testosterone, free testosterone, and total DHT after treatment.
  • the observed median t max for total testosterone ranged from 2 to 12 hours across the 3 treatment periods.
  • a dose-related increase in mean exposure (mean AUC 0 -24,ss, C max ,ss, and C avg ,ss) to total testosterone was observed with increasing dose, though this increase was less than dose-proportional.
  • the parameters Cmax.ss, and Cavg.ss showed a 2.3-fold increase over a 5-fold increase in dose (5 mg to 25 mg) of testosterone, respectively. Similar results were observed for free and bioavailable testosterone.
  • the observed median t max ranged from 8 to 12 hours across the three treatment periods.
  • the parameters AUC 0 -24,ss, C max ,ss, and C avg ,ss showed a 2.5- fold increase over a 5-fold increase in dose (5 mg to 25 mg) of testosterone, respectively.
  • Table 11 provides the Baseline-adjusted PK parameters for total, free and bioavailable testosterone and total DHT.
  • the Baseline-adjusted median t max for total testosterone ranged from 2 to 8.08 hrs across the 3 treatment periods.
  • Testosterone gel 1 % appears to be safe and well-tolerated in this pediatric subject population as there were no deaths or other significant adverse events during this study. There were also no clinically meaningful changes from Baseline to Final Visit during the Pharmacokinetic Evaluation Phase for any hematology, blood chemistry, urinalysis, or lipid parameters.
  • the amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art. As used herein, the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words “about” or “approximately” will serve to broaden a particular numerical value. Thus, as a general matter, "about” or “approximately” broaden the numerical value.
  • ranges is intended as a continuous range including every value between the minimum and maximum values plus the broadening of the range afforded by the use of the term "about” or “approximately.”
  • ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it there individually recited herein.

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US20040072810A1 (en) * 2001-11-07 2004-04-15 Besins International Belgique Pharmaceutical composition in the form of a gel or a solution based on dihydrotestosterone, process for preparing it and uses thereof
US7138389B2 (en) * 2004-02-09 2006-11-21 University Of Washington Oral androgen therapy using modulators of testosterone bioavailability
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