PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATING HYPOGONADISM
A pharmaceutical composition useful for treating hypogonadism is disclosed. The composition comprises an androgenic or anabolic steroid, a C1-C4 alcohol, a penetration enhancer such as isopropyl myristate, and water. Also disclosed is a method for treating hypogonadism utilizing the composition.
This application is a continuation of U.S. patent application Ser. No. 10/867,445 filed Jun. 14, 2004, which is a continuation of U.S. patent application Ser. No. 10/248,267 filed Jan. 3, 2003, which is a continuation of U.S. patent application Ser. No. 09/651,777 filed Aug. 30, 2000, now U.S. Pat. No. 6,503,894, the disclosures of which are incorporated herein by reference in their entirety to the extent permitted by law.
FIELD OF THE INVENTIONThe present invention is directed to a pharmaceutical composition comprising testosterone in a gel formulation, and to methods of using the same.
BACKGROUND OF THE INVENTIONA. Testosterone Metabolism in Men.
Testosterone is the major circulating androgen in men. More than 95% of the 6-7 mg of testosterone produced per day is secreted by the approximately 500 million Leydig cells in the testes. 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.
The most important hormone for the regulation of Leydig cell number and function is LH. In eugonadal men, LH secretion from the pituitary is inhibited through a negative-feedback pathway by increased concentrations of testosterone through the inhibition of the release of gonadotropin-releasing hormone (“GRH”) by the hypothalamus. FSH promotes spermatogenesis and is essential for the normal maturation of sperm. FSH secretion from the pituitary normally is inhibited through a negative-feedback pathway by increased testosterone concentrations.
Testosterone is responsible primarily for the development and maintenance of secondary sex characteristics in men. In the body, circulating testosterone is metabolized to various 17-keto steroids through two different pathways. Testosterone can be metabolized to dihydrotestosterone (“DHT”) by the enzyme 5α-reductase. There are two forms of 5α-reductase in the body: one form is found predominately in the liver and non-genital skin while another form is found in the urogenital tract of the male and the genital skin of both sexes. Testosterone can also be metabolized to estradiol (“E2”) by an aromatase enzyme complex found in the liver, fat, and the testes.
Testosterone circulates in the blood 98% bound to protein. In men, approximately 40% of the binding is to the high-affinity sex hormone binding globulin (“SHBG”). The remaining 60% is bound weakly to albumin. Thus, a number of measurements for testosterone are available from clinical laboratories. The term “free” testosterone as used herein refers to the fraction of testosterone in the blood that is not bound to protein. The term “total testosterone” or “testosterone” as used herein means the free testosterone plus protein-bound testosterone. The term “bioavailable testosterone” as used herein refers to the non-SHBG bound testosterone and includes testosterone weakly bound to albumin.
The conversion of testosterone to DHT is important in many respects. For example, DHT binds with greater affinity to SHBG than does testosterone. In addition, in many tissues, the activity of testosterone depends on the reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is then transported to the nucleus where it initiates transcription and cellular changes related to androgen action. DHT is also thought to lower prostate volume and inhibit tumor development in the prostate. Thus, given the importance of DHT and testosterone in normal body functioning, researchers frequently assess and report androgen concentrations in patients as total androgen (“DHT+T”) or as a ratio of DHT to testosterone (“DHT/T ratio”).
The following table from the UCLA-Harbor Medical Center summarizes the hormone concentrations in normal adult men range:
There is considerable variation in the half-life of testosterone reported in the literature, ranging from 10 to 100 minutes. Researchers do agree, however, that circulating testosterone has a diurnal variation in normal young men. Maximum levels occur at approximately 6:00 to 8:00 a.m. with levels declining throughout the day. Characteristic profiles have a maximum testosterone level of 720 ng/dL and a minimum level of 430 ng/dL. The physiological significance of this diurnal cycle, if any, however, is not clear.
B. Hypogonadal Men and Current Treatments for Hypogonadism.
Male hypogonadism results from a variety of patho-physiological conditions in which testosterone concentration is diminished below the normal range. The hypogonadic condition is sometimes linked with a number of physiological changes, such as diminished interest in sex, impotence, reduced lean body mass, decreased bone density, lowered mood, and energy levels.
Researchers generally classify hypogonadism into one of three types. Primary hypogonadism includes the testicular failure due to congenital or acquired anorchia, 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, orchiectomy, 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. However, because of testicular or other failures, the high LH concentrations are not effective at stimulating testosterone production.
Secondary hypogonadism involves an idiopathic gonadotropin or LH-releasing hormone deficiency. 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. Because patients with secondary hypogonadism do not demonstrate an intact feedback pathway, the lower testosterone concentrations are not associated with increased LH or FSH levels. Thus, these men have low testosterone serum levels but have gonadotropins in the normal to low range.
Third, hypogonadism may be age-related. Men experience a slow but continuous decline in average serum testosterone after approximately age 20 to 30 years. Researchers estimate that the decline is about 1-2% per year. Cross-sectional studies in men have found that the mean testosterone value at age 80 years is approximately 75% of that at age 30 years. Because the serum concentration of SHBG increases as men age, the fall in bioavailable and free testosterone is even greater than the fall in total testosterone. Researchers have estimated that approximately 50% of healthy men between the ages of 50 and 70 have levels of bioavailable testosterone that are below the lower normal limit. Moreover, as men age, the circadian rhythm of testosterone concentration is often muted, dampened, or completely lost. The major problem with aging appears to be within the hypothalamic-pituitary unit. For example, researchers have found that with aging, LH levels do not increase despite the low testosterone levels. Regardless of the cause, these untreated testosterone deficiencies in older men may lead to a variety of physiological changes, including sexual dysfunction, decreased libido, loss of muscle mass, decreased bone density, depressed mood, and decreased cognitive function. The net result is geriatric hypogonadism, or what is commonly referred to as “male menopause.” Today, hypogonadism is the most common hormone deficiency in men, affecting 5 in every 1,000 men. At present, it is estimated that only five percent of the estimated four to five million American men of all ages with hypogonadism currently receive testosterone replacement therapy. Thus, for years, researchers have investigated methods of delivering testosterone to men. These methods include intramuscular injections (43%), oral replacement (24%), pellet implants (23%), and transdermal patches (10%). A summary of these methods is shown in Table 2.
As discussed below, all of the testosterone replacement methods currently employed suffer from one or more drawbacks, such as undesirable pharmacokinetic profiles or skin irritation. Thus, although the need for an effective testosterone replacement methodology has existed for decades, an alternative replacement therapy that overcomes these problems has never been developed. The present invention is directed to a 1% testosterone hydroalcoholic gel that overcomes the problems associated with current testosterone replacement methods.
1. Subdermal Pellet Implants.
Subdermal implants have been used as a method of testosterone replacement since the 1940s. The implant is produced by melting crystalline testosterone into a cylindrical form. Today, pellet implants are manufactured to contain either 100 mg (length 6 mm, surface area 1172) or 200 mg of testosterone (length 12 mm, surface area 202 mm2). Patients receive dosages ranging from 100 to 1,200 mg, depending on the individual's requirements. The implants are inserted subcutaneously either by using a trocar and cannula or by open surgery into an area where there is relatively little movement. Frequently, the implant is placed in the lower abdominal wall or the buttock. Insertion is made under local anesthesia, and the wound is closed with an adhesive dressing or a fine suture.
Implants have several major drawbacks. First, implants require a surgical procedure which many hypogonadal men simply do not wish to endure. Second, implant therapy includes a risk of extrusion (8.5%), bleeding (2.3%), or infection (0.6%). Scarring is also a risk. Perhaps most important, the pharmacokinetic profile of testosterone pellet implant therapy fails to provide men with a suitable consistent testosterone level. In general, subdermal testosterone implants produce supra-physiologically high serum testosterone levels which slowly decline so that before the next injection subnormally low levels of testosterone are reached. For example, in one recent pharmacokinetic study, hypogonadal patients who received six implants (1,200 mg testosterone) showed an initial short-lived burst release of testosterone within the first two days after application. A stable plateau was then maintained over then next two months (day 2: 1,015 ng/dL; day 63: 990 ng/dL). Thereafter, the testosterone levels declined to baseline by day 300. DHT serum concentrations also rose significantly above the baseline, peaking at about 63 days after implementation and greatly exceeding the upper limit of the normal range. From day 21 to day 189, the DHT/T ratio was significantly increased. The pharmacokinetic profiles for testosterone, DHT, and DHT/T in this study are shown in
2. Injection of Testosterone Esters.
Since the 1950s, researchers have experimented with the intermuscular depot injection of testosterone esters (such as enanthate, cypionate) to increase testosterone serum levels in hypogonadal men. More recent studies have involved injection of testosterone buciclate or testosterone undecanoate in an oil-based vehicle. Other researchers have injected testosterone microcapsule formulations.
Testosterone ester injection treatments suffer from many problems. Patients receiving injection therapy often complain that the delivery mechanism is painful and causes local skin reactions. In addition, testosterone microcapsule treatment requires two simultaneous intramuscular injections of a relatively large volume, which may be difficult to administer due to the high viscosity of the solution and the tendency to block the needle. Other men generally find testosterone injection therapy inconvenient because injection usually requires the patient to visit his physician every two to three weeks.
Equally important, injection-based testosterone replacement treatments still create an undesirable pharmacokinetic profile. The profile generally shows a supra-physiologic testosterone concentration during the first 24 to 48 hours followed by a gradual fall often to sub-physiologic levels over the next few weeks. These high serum testosterone levels, paralleled by increases in E2, are also considered the reason for acne and gynecomastia occurring in some patients, and for polycythaemia, occasionally encountered especially in older patients using injectable testosterone esters. In the case of testosterone buciclate injections, the treatment barely provides normal androgen serum levels and the maximal increase of serum testosterone over baseline does not exceed 172 ng/dL (6 nmol/dL) on average. Because libido, potency, mood, and energy are thought to fluctuate with the serum testosterone level, testosterone injections have largely been unsuccessful in influencing these variables. Thus, testosterone injection remains an undesirable testosterone replacement treatment method.
3. Oral/Sublingual/Buccal Preparations of Androgens.
In the 1970s, researchers began using oral, sublingual, or buccal preparations of androgens (such as fluoxymesterone, 17α-methyl-testosterone or testosterone undecanoate) as a means for testosterone replacement. More recently, researchers have experimented with the sublingual administration of testosterone-hydroxypropyl-beta-cyclodextrin inclusion complexes. Predictably, both fluoxymesterone and methyl testosterone are 17-alkylated and thus associated with liver toxicity. Because these substances must first pass through the liver, they also produce an unfavorable effect on serum lipid profile, increasing LDL and decreasing HDL, and carbohydrate metabolism. While testosterone undecanoate has preferential absorption through the intestinal lymphatics, it has not been approved in the United States.
The pharmacokinetic profiles for oral, sublingual, and buccal delivery mechanisms are also undesirable because patients are subjected to super-physiologic testosterone levels followed by a quick return to the baseline. For example, one recent testing of a buccal preparation showed that patients obtained a peak serum hormone levels within 30 minutes after administration, with a mean serum testosterone concentration of 2,688+/−147 ng/dL and a return to baseline in 4 to 6 hours. See Dobs et al., Pharmacokinetic Characteristics, Efficacy and Safety of Buccal Testosterone in Hypogonadal Males: A Pilot Study, 83 J. Clinical Endocrinology & Metabolism 33-39 (1998). To date, the ability of these testosterone delivery mechanisms to alter physiological parameters (such as muscle mass, muscle strength, bone resorption, urinary calcium excretion, or bone formation) is inconclusive. Likewise, researchers have postulated that super-physiologic testosterone levels may not have any extra beneficial impact on mood parameters such as anger, nervousness, and irritability.
4. Testosterone Transdermal Patches.
The most recent testosterone delivery systems have involved transdermal patches. Currently, there are three patches used in the market: TESTODERM®, TESTODERM® TTS, and ANDRODERM®.
a. TESTODERM®.
TESTODERM® (Alza Pharmaceuticals, Mountain View, Calif.) was the first testosterone-containing patch developed. The TESTODERM® patch is currently available in two sizes (40 or 60 cm2). The patch contains 10 or 15 mg of testosterone and delivers 4.0 mg or 6.0 mg of testosterone per day. TESTODERM® is placed on shaved scrotal skin, aided by application of heat for a few seconds from a hair dryer.
Several problems are associated with the TESTODERM® patch. Not surprisingly, many men simply do not like the unpleasant experience of dry-shaving the scrotal hair for optimal contact. In addition, patients may not be able to wear close-fitting underwear when undergoing treatment. Men frequently experience dislodgment of the patch, usually with exercise or hot weather. In many instances, men experience itching and/or swelling in the scrotal area. Finally, in a number of patients, there is an inability to achieve adequate serum hormone levels.
b. TESTODERM® TTS.
The most recently developed non-scrotal patch is TESTODERM® TTS (Alza Pharmaceuticals, Mountain View, Calif.). It is an occlusive patch applied once daily to the arm, back, or upper buttocks. The system is comprised of a flexible backing of transparent polyester/ethylene-vinyl acetate copolymer film, a drug reservoir of testosterone, and an ethylene-vinyl acetate copolymer membrane coated with a layer of polyisobutylene adhesive formulation. A protective liner of silicone-coated polyester covers the adhesive surface.
Upon application, serum testosterone concentrations rise to a maximum at two to four hours and return toward baseline within two hours after system removal. Many men, however, are unable to obtain and/or sustain testosterone levels within the normal range. The pharmacokinetic parameters for testosterone concentrations are shown as follows:
The typical 24-hour steady state testosterone concentration achieved with TESTODERM® TTS patch is shown in
Because of TESTODERM® patch is applied to the scrotal skin while the TESTODERM TTS® patch is applied to non-scrotal skin, the two patches provide different steady-state concentrations of the two major testosterone metabolites, DTH and E2:
Likewise, in contrast to the scrotal patch, TESTODERM TTS® treatment creates a DHT/T ratio that is not different from that of a placebo treatment. Both systems, however, suffer from similar problems. In clinical studies, TESTODERM® TTS is associated with transient itching in 12% of patients, erythema in 3% of patients, and puritus in 2% of patients. Moreover, in one 14-day study, 42% of patients reported three or more detachments, 33% of which occurred during exercise.
c. ANDRODERM®.
ANDRODERM® (Watson Laboratories, Inc., Corona, Calif.) is a testosterone-containing patch applied to non-scrotal skin. The circular patch has a total surface area of 37 cm.2 The patch consists of a liquid reservoir containing 12.2 mg of testosterone and a permeation-enhanced vehicle containing ethanol, water, monoglycerides, fatty acid esters, and gelling agents. The suggested dose of two patches, applied each night in a rotating manner on the back, abdomen, upper arm, or thigh, delivers 4.1 to 6.8 mg of testosterone.
The steady state pharmacokinetic profile of a clinical study involving ANDRODERM® is shown in
In clinical trials, ANDRODERM® is associated with skin irritation in about a third of the patients, and 10% to 15% of subjects have been reported to discontinue the treatment because of chronic skin irritation. Preapplication of corticosteroid cream at the site of application of ANDRODERM® has been reported to decrease the incidence and severity of the skin irritation. A recent study, however, found that the incidence of skin reactions sufficiently noxious enough to interrupt therapy was as high as 52%. See Parker et al., Experience with Transdermal Testosterone Replacement in Hypogonadal Men, 50 Clinical Endocrinology (Oxf) 57-62 (1999). The study reported: Two-thirds of respondents found the Andropatch unsatisfactory. Patches were variously described as noisy, visually indiscrete, embarrassing, unpleasant to apply and remove, and generally to be socially unacceptable. They fell off in swimming pools and showers, attracted ribald comments from sporting partners, and left bald red marks over trunk and limbs. Dogs, wives, and children were distracted by noise of the patches with body movements. Those with poor mobility or manual dexterity (and several were over 70 years of age) found it difficult to remove packaging an apply patches dorsally.
d. Transdermal Patch Summary.
In sum, the transdermal patch generally offers an improved pharmacokinetic profile compared to other currently used testosterone delivery mechanisms. However, as discussed above, the clinical and survey data shows that all of these patches suffer from significant drawbacks, such as buritus, burn-like blisters, and erythema. Moreover, one recent study has concluded that the adverse effects associated with transdermal patch systems are “substantially higher” than reported in clinical trials. See Parker, supra. Thus, the transdermal patch still remains an inadequate testosterone replacement therapy alternative for most men.
5. DHT Gels.
Researchers have recently begun investigating the application of DHT to the skin in a transdermal gel. However, the pharmacokinetics of a DHT-gel is markedly different from that of a testosterone gel. Application of DHT-gel results in decreased serum testosterone, E2, LH, and FSH levels. Thus, DHT gels are not effective at increasing testosterone levels in hypogonadal men. Accordingly, there is a definite need for a testosterone formulation that safely and effectively provides an optimal and predictable pharmacokinetic profile.
SUMMARY OF INVENTIONThe foregoing problems are solved and a technical advance is achieved with the present invention. The present invention generally comprises a testosterone gel. Daily transdermal application of the gel in hypogonadal men results in a unique pharmacokinetic steady-state profile for testosterone. Long-term treatment further results in, for example, increased bone mineral density, enhanced libido, enhanced erectile frequency and satisfaction, increased positive mood, increased muscle strength, and improved body composition without significant skin irritation. The present invention is also directed to a unique method of administering the testosterone gel employing a packet having a polyethylene liner compatible with the components of the gel.
While the present invention may be embodied in many different forms, several specific embodiments are discussed herein with the understanding that the present disclosure is to be considered only as an exemplification of the principles of the invention, and it is not intended to limit the invention to the embodiments illustrated.
The present invention is directed to a pharmaceutical composition for percutaneous administration comprising at least one active pharmaceutical ingredient (e.g., testosterone) in a hydroalcoholic gel. In a broad aspect of the invention, the active ingredients employed in the composition may include anabolic steroids such as androisoxazole, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methenolone, methyltrienolone, nandrolone, oxymesterone, quinbolone, stenbolone, trenbolone; androgenic steroids such as boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17 Alpha-methyl-testosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymetholone, prasterone, stanlolone, stanozolol, dihydrotestosterone, testosterone; and progestogens such as anagestone, chlormadinone acetate, delmadinone acetate, demegestone, dimethisterone, dihydrogesterone, ethinylestrenol, ethisterone, ethynodiol, ethynodiol diacetate, fluorogestone acetate, gestodene, gestonorone caproate, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17 Beta-hydroxyprogesterone, 17 Alpha-hydroxyprogesterone caproate, medrogestone, medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethindrone acetate, norethynodrel, norgesterone, norgestimate, norgestrel, norgestrienone, 19-norprogesterone, norvinisterone, pentagestrone, progesterone, promegestone, quingestrone, and trengestone; and all enantiomers, isomers and derivatives of these compounds. (Based upon the list provided in The Merck Index, Merck & Co. Rahway, N.J. (1998)).
In addition to the active ingredient, the gel comprises one or more lower alcohols, such as ethanol or isopropanol; a penetration enhancing agent; a thickener; and water. Additionally, the present invention may optionally include salts, emollients, stabilizers, antimicrobials, fragrances, and propellants.
A “penetration enhancer” is an agent known to accelerate the delivery of the drug through the skin. These agents also have been referred to as accelerants, adjuvants, and absorption promoters, and are collectively referred to herein as “enhancers.” This class of agents includes those with diverse mechanisms of action including those which have the function of improving the solubility and diffusibility of the drug, and those which improve percutaneous absorption by changing the ability of the stratum corneum to retain moisture, softening the skin, improving the skin's permeability, acting as penetration assistants or hair-follicle openers or changing the state of the skin such as the boundary layer.
The penetration enhancer of the present invention is a functional derivative of a fatty acid, which includes isosteric modifications of fatty acids or non-acidic derivatives of the carboxylic functional group of a fatty acid or isosteric modifications thereof. In one embodiment, the functional derivative of a fatty acid is an unsaturated alkanoic acid in which the COOH group is substituted with a functional derivative thereof, such as alcohols, polyols, amides and substituted derivatives thereof. The term “fatty acid” means a fatty acid that has four (4) to twenty-four (24) carbon atoms. Non-limiting examples of penetration enhancers include C8-C22 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C8 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl ethers; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetic ester; N-alkylpyrrolidone; and terpenes.
The thickeners used herein may include anionic polymers such as polyacrylic acid (CARBOPOL® by B.F. Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), carboxymethylcellulose and the like. Additional thickeners, enhancers and adjuvants may generally be found in United States Pharmacopeia/National Formulary (2000); Remington's The Science and Practice of Pharmacy, Meade Publishing Co.
The amount of drug to be incorporated in the composition varies depending on the particular drug, the desired therapeutic effect, and the time span for which the gel is to provide a therapeutic effect. The composition is used in a “pharmacologically effective amount.” This means that the concentration of the drug is such that in the composition it results in a therapeutic level of drug delivered over the term that the gel is to be used. Such delivery is dependent on a number of variables including the drug, the form of drug, the time period for which the individual dosage unit is to be used, the flux rate of the drug from the gel, surface area of application site, etc. The amount of drug necessary can be experimentally determined based on the flux rate of the drug through the gel, and through the skin when used with and without enhancers.
One such testosterone gel has only recently been made available in the United States under the trademark ANDROGEL® by Unimed Pharmaceuticals, Inc., Deerfield, Ill., one of the assignees of this application. In one embodiment, the gel is comprised of the following substances in approximate amounts:
One skilled in the art will appreciate that the constituents of this formulation may be varied in amounts yet continue to be within the spirit and scope of the present invention. For example, the composition may contain about 0.1 to about 10.0 g of testosterone, about 0.1 to about 5.0 g Carbopol, about 0.1 to about 5.0 g isopropyl myristate, and about 30.0 to about 98.0 g ethanol; or about 0.1% to about 10.0% of testosterone, about 0.1% to about 5.0% Carbopol, about 0.1% to about 5.0% isopropyl myristate, and about 30.0% to about 98.0% ethanol, on a weight to weight basis of the composition.
A therapeutically effective amount of the gel is rubbed onto a given area of skin by the user. The combination of the lipophilic testosterone with the hydroalcoholic gel helps drive the testosterone in to the outer layers of the skin where it is absorbed and then slowly released into the blood stream. As demonstrated by the data presented herein, the administration of the gel of the present invention has a sustained effect.
Toxicity and therapeutic efficacy of the active ingredients can be determined by standard pharmaceutical procedures, e.g., for determining LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
The term “treatment” as used herein refers to any treatment of a human condition or disease and includes: (1) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing regression of the condition, or (3) relieving the conditions caused by the disease, i.e., stopping the symptoms of the disease.
Although the examples of the present invention involve the treatment of disorders associated with hypogonadal men, the composition and method of the present invention may be used to treat these disorders in humans and animals of any kind, such as dogs, pigs, sheep, horses, cows, cats, zoo animals, and other commercially bred farm animals.
The present invention is further illustrated by the following examples, which should not be construed as limiting in any way. The contents of all cited references throughout this application are hereby expressly incorporated by reference. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmacology and pharmaceutics, which are within the skill of the art.
Example 1 Treatment of Hypogonadism in Male SubjectsOne embodiment of the present invention involves the transdermal application of ANDROGEL® as a method of treating male hypogonadism. As demonstrated below, application of the gel results in a unique pharmacokinetic profile for testosterone, as well as concomitant modulation of several other sex hormones. Application of the testosterone gel to hypogonadal male subjects also results in (1) increased bone mineral density, (2) enhanced libido, (3) enhanced erectile capability and satisfaction, (4) increased positive mood, (5) increased muscle strength, and (6) better body composition, such increased total body lean mass and decreased total body fat mass. Moreover, the gel is not generally associated with significant skin irritation.
Methods. In this example, hypogonadal men were recruited and studied in 16 centers in the United States. The patients were between 19 and 68 years and had single morning serum testosterone levels at screening of less than or equal to 300 ng/dL (10.4 nmol/L). A total of 227 patients were enrolled: 73, 78, and 76 were randomized to receive 5.0 g/day of ANDROGEL® (delivering 50 mg/day of testosterone to the skin of which about 10% or 5 mg is absorbed), 10.0 g/day of ANDROGEL® (delivering 100 mg/day of testosterone to the skin of which about 10% or 10 mg is absorbed), or the ANDRODERM® testosterone patch (“T patch”) (delivering 50 mg/day of testosterone), respectively.
As shown in the following table, there were no significant group-associated differences of the patients' characteristics at baseline.
Forty-one percent ( 93/227) of the subjects had not received prior testosterone replacement therapy. Previously treated hypogonadal men were withdrawn from testosterone ester injection for at least six weeks and oral or transdermal androgens for four weeks before the screening visit. Aside from the hypogonadism, the subjects were in good health as evidenced by medical history, physical examination, complete blood count, urinalysis, and serum biochemistry. If the subjects were on lipid-lowering agents or tranquilizers, the doses were stabilized for at least three months prior to enrollment. Less than 5% of the subjects were taking supplemental calcium or vitamin D during the study. The subjects had no history of chronic medical illness, alcohol or drug abuse. They had a normal rectal examination, a PSA level of less than 4 ng/mL, and a urine flow rate of 12 mL/s or greater. Patients were excluded if they had a generalized skin disease that might affect the testosterone absorption or prior history of skin irritability with ANDRODERM® patch. Subjects weighing less than 80% or over 140% of their ideal body weight were also excluded.
The randomized, multi-center, parallel study compared two doses of ANDROGEL® with the ANDRODERM® testosterone patch. The study was double-blind with respect to the ANDROGEL® dose and open-labeled for the testosterone patch group. For the first three months of the study (days 1 to 90), the subjects were randomized to receive 5.0 g/day of ANDROGEL®, 10.0 g/day of ANDROGEL®, or two non-scrotal patches. In the following three months (days 91 to 180), the subjects were administered one of the following treatments: 5.0 g/day of ANDROGEL®, 10.0 g/day of ANDROGEL®, 7.5 g/day of ANDROGEL®, or two non-scrotal patches. Patients who were applying ANDROGEL® had a single, pre-application serum testosterone measured on day 60 and, if the levels were within the normal range of 300 to 1,000 ng/dL (10.4 to 34.7 nmol/L), then they remained on their original dose. Patients with testosterone levels less than 300 ng/dL and who were originally assigned to apply 5.0 g/day of ANDROGEL® and those with testosterone levels more than 1,000 ng/dL who had received 10.0 g/day of ANDROGEL® were then reassigned to administer 7.5 of ANDROGEL® for days 91 to 180.
Accordingly, at 90 days, dose adjustments were made in the ANDROGEL® groups based on the pre-application serum testosterone levels on day 60. Twenty subjects in the 5.0 g/day ANDROGEL® group had the dose increased to 7.5 g/day. Twenty patients in the 10.0 g/day ANDROGEL® group had the ANDROGEL® dose reduced to 7.5 g/day. There were three patients in the testosterone patch group who were switched to 5.0 g/day ANDROGEL® because of patch intolerance. One 10.0 g/day ANDROGEL® subject was adjusted to receive 5.0 g/day and one 5.0 ANDROGEL® subject had the dose adjusted to 2.5 g/day. The number of subjects enrolled into day 91 to 180 of the study thus consisted of 51 receiving 5.0 g/day of ANDROGEL®, 40 receiving 7.5 g/day of ANDROGEL®, 52 receiving 10.0 g/day of ANDROGEL®, and 52 continuing on the ANDRODERM® patch. The treatment groups in this example may thus be characterized in two ways, either by “initial” or by the “final” treatment group.
Subjects returned to the study center on days 0, 30, 60, 90, 120, 150, and 180 for a clinical examination, skin irritation and adverse event assessments. Fasting blood samples for calcium, inorganic phosphorus, parathyroid hormone (“PTH”), osteocalcin, type I procollagen, and skeletal specific alkaline phosphatase (“SALP”) were collected on days 0, 30, 90, 120, and 180. In addition, a fasting two-hour timed urine collection for urine creatinine, calcium, and typecollagen cross-linked N-telopeptides (“N-telopeptide”) were collected on days 0, 30, 90, 120, and 180. Other tests performed were as follows: (1) Hematology: hemoglobin, hematocrit, red blood cell count, platelets, white blood cell counts with differential analysis (neutrophils, lymphocytes, monocytes, eosinophils, and basophils); (2) Chemistry: alkaline phosphatase, alanine aminotransferase, serum glutamic pyruvic transaminase (“ALT/SGPT”), asparate aminotransferase/serum glutamin axaloacetic transaminase (“AST/SGOT”), total bilirubin, creatinine, glucose, and elecrolytes (sodium, potassium, chloride, bicarbonate, calcium, and inorganic phosphorus); (3) Lipids: total cholesterol, high-density lipoprotein (“HDL”), low-density lipoprotein (“LDL”), and triglycerides; (4) Urinalysis: color, appearance, specific gravity, pH, protein, glucose, ketones, blood, bilirubin, and nitrites; and (5) Other: PSA (screening days 90-180), prolactin (screening), and testosterone (screening) including electrolytes, glucose, renal, and liver function tests and lipid profile, were performed at all clinic visits. Bone mineral density (“BMD”) was analyzed at day 0 and day 180.
A. ANDROGEL® and ANDRODERM® patch.
Approximately 250 g of ANDROGEL® was packaged in multidose glass bottles that delivered 2.25 g of the gel for each actuation of the pump. Patients assigned to apply 5.0 g/day of ANDROGEL® testosterone were given one bottle of ANDROGEL® and one bottle of placebo gel (containing vehicle but no testosterone), while those assigned to receive 10.0 g/day of ANDROGEL® were dispensed two bottles of the active ANDROGEL®. The patients were then instructed to apply the bottle contents to the right and left upper arms/shoulders and to the right and left sides of the abdomen on an alternate basis. For example, on the first day of the study, patients applied two actuations from one bottle, one each to the left and right upper arm/shoulder, and two actuations from the second bottle, one each to the left and right abdomen. On the following day of treatment, the applications were reversed. Alternate application sites continued throughout the study. After application of the gel to the skin, the gel dried within a few minutes. Patients washed their hands thoroughly with soap and water immediately after gel application.
The 7.5 g/day ANDROGEL® group received their dose in an open-label fashion. After 90 days, for the subjects titrated to the ANDROGEL® 7.5 g/day dose, the patients were supplied with three bottles, one containing placebo and the other two ANDROGEL®. The subjects were instructed to apply one actuation from the placebo bottle and three actuations from a ANDROGEL® bottle to four different sites of the body as above. The sites were rotated each day taking the same sequence as described above.
ANDRODERM® testosterone patches each delivering 2.5 mg/day of testosterone were provided to about one-third of the patients in the study. These patients were instructed to apply two testosterone patches to a clean, dry area of skin on the back, abdomen, upper arms, or thighs once per day. Application sites were rotated with approximately seven days interval between applications to the same site.
On study days when the patients were evaluated, the gel/patches were applied following pre-dose evaluations. On the remaining days, the testosterone gel or patches were applied at approximately 8:00 a.m. for 180 days.
B. Study Method and Results:
1. Hormone Pharmacokinetics.
On days 0, 1, 30, 90, and 180, the patients had multiple blood samples for testosterone and free testosterone measurements at 30, 15 and 0 minutes before and 2, 4, 8, 12, 16, and 24 hours after ANDROGEL® or patch application. In addition, subjects returned on days 60, 120, and 150 for a single blood sampling prior to application of the gel or patch. Serum DHT, E2, FSH, LH and SHBG were measured on samples collected before gel application on days 0, 30, 60, 90, 120, 150, and 180. Sera for all hormones were stored frozen at 20° C. until assay. All samples for a patient for each hormone were measured in the same assay whenever possible. The hormone assays were then measured at the Endocrine Research Laboratory of the UCLA-Harbor Medical Center.
The following table summarizes the pharmacokinetic parameters were measured for each patient:
a. Testosterone Pharmacokinetics:
(1) Methods.
Serum testosterone levels were measured after extraction with ethylacetate and hexane by a specific radioimmunoassay (“RIA”) using reagents from ICN (Costa Mesa, Calif.). The cross reactivities of the antiserum used in the testosterone RIA were 2.0% for DHT, 2.3% for androstenedione, 0.8% for 3-Beta-androstanediol, 0.6% for etiocholanolone and less than 0.01% for all other steroids tested. The lower limit of quantitation (“LLQ”) for serum testosterone measured by this assay was 25 ng/dL (0.87 nmol/L). The mean accuracy of the testosterone assay, determined by spiking steroid free serum with varying amounts of testosterone (0.9 to 52 nmol/L), was 104% and ranged from 92% to 117%. The intra-assay and inter-assay coefficients of the testosterone assay were 7.3 and 11.1%, respectively, at the normal adult male range. In normal adult men, testosterone concentrations range from 298 to 1,043 ng/dL (10.33 to 36.17 nmol/L) as determined at the UCLA-Harbor Medical Center.
(2) Baseline Concentration.
As shown in Table 8 and
(3) Day 1.
(4) Days 30, 90, and 180.
(5) Dose Proportionality for ANDROGEL®.
Table 8(g) shows the increase in AUCO-24 on days 30, 90, and 180 from the pretreatment baseline (net AUCO-24). In order to assess dose-proportionality, the bioequivalence assessment was performed on the log-transformed AUCs using “treatment” as the only factor. The AUCs were compared after subtracting away the AUC contribution from the endogenous secretion of testosterone (the AUC on day 0) and adjusting for the two-fold difference in applied doses. The AUC ratio on day 30 was 0.95 (90% C.I.: 0.75-1.19) and on day 90 was 0.92 (90% C.I.: 0.73-1.17). When the day 30 and day 90 data was combined, the AUC ratio was 0.93 (90% C.I.: 0.79-1.10).
The data shows dose proportionality for ANDROGEL® treatment. The geometric mean for the increase in AUCO-24 from day 0 to day 30 or day 90 was twice as great for the 10.0 g/day group as for the 5.0 g/day group. A 125 ng/dL mean increase in serum testosterone Cavg level was produced by each 2.5 g/day of ANDROGEL®. In other words, the data shows that 0.1 g/day of ANDROGEL® produced, on the average, a 5 ng/dL increase in serum testosterone concentration. This dose proportionality aids dosing adjustment by the physician. Because ANDROGEL® is provided in 2.5 g packets (containing 25 mg of testosterone), each 2.5 g packet will produce, on average, a 125 ng/dL increase in the Cavg for serum total testosterone.
The increase in AUCO-24 from pretreatment baseline achieved by the 10.0 g/day and the 5.0 g/day groups were approximately 2.7 and 1.7 fold higher than that resulting from application of the testosterone patch.
b. Pharmacokinetics of Serum Free Testosterone Concentration:
(1) Methods.
Serum free testosterone was measured by RIA of the dialysate, after an overnight equilibrium dialysis, using the same RIA reagents as the testosterone assay. The LLQ of serum free testosterone, using the equilibrium dialysis method, was estimated to be 22 μmol/L. When steroid free serum was spiked with increasing doses of testosterone in the adult male range, increasing amounts of free testosterone were recovered with a coefficient of variation that ranged from 11.0-18.5%. The intra- and interassay coefficients of free testosterone were 15% and 16.8% for adult normal male values, respectively. As estimated by the UCLA-Harbor Medical Center, free testosterone concentrations range from 3.48-17.9 ng/dL (121-620 μmol/L) in normal adult men.
(2) Pharmacokinetic Results.
In general, as shown in Table 9, the pharmacokinetic parameters of serum free testosterone mirrored that of serum total testosterone as described above. At baseline (day 0), the mean serum free testosterone concentrations (Cavg) were similar in all three groups which were at the lower limit of the adult male range. The maximum serum free testosterone concentration occurred between 8 and 10 a.m., and the minimum about 8 to 16 hours later. This data is consistent with the mild diurnal variation of serum testosterone.
c. Serum DHT Concentrations.
Serum DHT was measured by RIA after potassium permanganate treatment of the sample followed by extraction. The methods and reagents of the DHT assay were provided by DSL (Webster, Tex.). The cross reactivities of the antiserum used in the RIA for DHT were 6.5% for 3-β-androstanediol, 1.2% for 3-α-androstanediol, 0.4% for 3-α-androstanediol glucuronide, and 0.4% for testosterone (after potassium permanganate treatment and extraction), and less than 0.01% for other steroids tested. This low cross-reactivity against testosterone was further confirmed by spiking steroid free serum with 35 nmol/L (1,000 μg/dL) of testosterone and taking the samples through the DHT assay. The results even on spiking with over 35 nmol/L of testosterone was measured as less than 0.1 nmol/L of DHT. The LLQ of serum DHT in the assay was 0.43 nmol/L. The mean accuracy (recovery) of the DHT assay determined by spiking steroid free serum with varying amounts of DI-IT from 0.43 nmol/L to 9 nmol/L was 101% and ranged from 83 to 114%. The intra-assay and inter-assay coefficients of variation for the DHT assay were 7.8 and 16.6%, respectively, for the normal adult male range. The normal adult male range of DHT was 30.7-193.2 ng/dL (1.06 to 6.66 nmol/L) as determined by the UCLA-Harbor Medical Center.
As shown in Table 10, the pretreatment mean serum DHT concentrations were between 36 and 42 ng/dL, which were near the lower limit of the normal range in all three initial treatment groups. None of the patients had DHT concentrations above the upper limit of the normal range on the pretreatment day, although almost half (103 patients) had concentrations less than the lower limit.
The increase in DHT concentrations are likely attributed to the concentration and location of 5α-reductase in the skin. For example, the large amounts of 5α-reductase in the scrotal skin presumably causes an increase in DHT concentrations in the TESTODERM® patch. In contrast, the ANDRODERM® and TESTODERM TTS® patches create little change in DTH levels because the surface area of the patch is small and little 5α-reductase is located in nonscrotal skin. ANDROGEL® presumably causes an increase in DHT levels because the gel is applied to a relatively large skin area and thus exposes testosterone to greater amounts of the enzyme.
To date, elevated DHT levels have not been reported to have any adverse clinical effects. Moreover, there is some evidence to suggest that increased DHT levels may inhibit prostate cancer.
d. DHT/T Ratio.
The UCLA-Harbor Medical Center reports a DHT/T ratio of 0.052-0.328 for normal adult men. In this example, the mean ratios for all three treatments were within the normal range on day 0. As shown in
e. Total Androgen (DHT+T).
The UCLA-Harbor Medical Center has determined that the normal total androgen concentration is 372 to 1,350 ng/dL. As shown in
f. E2 Concentrations.
Serum E2 levels were measured by a direct assay without extraction with reagents from ICN (Costa Mesa, Calif.). The intra-assay and inter-assay coefficients of variation of E2 were 6.5 and 7.1% respectively. The UCLA-Harbor Medical Center reported an average E2 concentration ranging from 7.1 to 46.1 μg/mL (63 to 169 μmol/L) for normal adult male range. The LLQ of the E2 was 18 μmol/L. The cross reactivities of the E2 antibody were 6.9% for estrone, 0.4% for equilenin, and less than 0.01% for all other steroids tested. The accuracy of the E2 assay was assessed by spiking steroid free serum with increasing amount of E2 (18 to 275 μmol/L). The mean recovery of E2 compared to the amount added was 99.1% and ranged from 95 to 101%.
E2 is believed to be important for the maintenance of normal bone. In addition, E2 has a positive effect on serum lipid profiles.
g. Serum SHBG Concentrations.
Serum SHBG levels were measured with a fluoroimmunometric assay (“FIA”) obtained from Delfia (Wallac, Gaithersberg, Md.). The intra- and interassay coefficients were 5% and 12% respectively. The LLQ was 0.5 nmol/L. The UCLA-Harbor Medical Center determined that the adult normal male range for the SHBG assay is 0.8 to 46.6 nmol/L.
As shown in
h. Gonadotropins.
Serum FSH and LH were measured by highly sensitive and specific solid-phase FIA assays with reagents provided by Delfia (Wallac, Gaithersburg, Md.). The intra-assay coefficient of variations for LH and FSH fluoroimmunometric assays were 4.3 and 5.2%, respectively; and the interassay variations for LH and FSH were 11.0% and 12.0%, respectively. For both LH and FSH assays, the LLQ was determined to be 0.2 IU/L. All samples obtained from the same subject were measured in the same assay. The UCLA-Harbor Medical Center reports that the adult normal male range for LH is 1.0-8.1 U/L and for FSH is 1.0-6.9 U/L.
(1) FSH.
Table 15(a)-(d) shows the concentrations of FSH throughout the 180-day treatment depending on the cause of hypogonadism: (1) primary, (2) secondary, (3) age-associated, or (4) unknown.
As discussed above, patients with primary hypogonadism have an intact feedback inhibition pathway, but the testes do not secrete testosterone. As a result, increasing serum testosterone levels should lead to a decrease in the serum FSH concentrations. In this example, a total of 94 patients were identified as having primary hypogonadism. For these patients, the mean FSH concentrations in the three treatment groups on day 0 were 21-26 mlU/mL, above the upper limit of the normal range. As shown in
Patients with secondary hypogonadism have a deficient testosterone negative feedback system. As shown in
Twenty-five patients were diagnosed with age-associated hypogonadism. As shown in
Sixty-four patients in the study suffered from unclassified hypogonadism. As shown in
This data shows that feedback inhibition of FSH secretion functioned to some extent in all four subpopulations. The primary hypogonadal population showed a dose-dependency in both the extent and rate of the decline in FSH levels. The sensitivity of the feedback process appeared to be reduced in the secondary and age-associated groups in that only the highest testosterone doses had a significant and prolonged impact on FSH secretion. In contrast, the feedback inhibition pathway in the patients in the unclassified group was quite responsive at even the lowest dose of exogenous testosterone.
(2) LH.
The response of LH to testosterone was also examined separately for the same four subpopulations. Tables 16(a)-(d) shows the LH concentrations throughout the treatment period.
As shown in
The secondary hypogonadal men were less sensitive to exogenous testosterone. For the 44 patients identified as having secondary hypogonadism, the pretreatment mean concentrations were all within the lower limit normal range. The mean LH concentrations decreased during treatment with all three regimens as shown in
None of the 25 patients suffering from age-associated hypogonadism had pretreatment LH concentrations outside of the normal range as shown in
Of the 64 patients suffering from an unclassified hypogonadism, none of the patients had a pretreatment LH concentration above the upper limit. Fifteen percent, however, had pretreatment concentrations below the normal limit. The unclassified patients showed comparatively rapid LH concentration decreases in all treatment groups as shown in
(3) Summary: LH and FSH.
Patients receiving ANDROGEL® or the testosterone patch achieve “hormonal steady state” only after long-term treatment. Specifically, data involving FSH and LH show that these hormones do not achieve steady-state until many weeks after treatment. Because testosterone concentrations are negatively inhibited by FSH and LH, testosterone levels do not achieve true steady state until these other hormones also achieve steady state. However, because these hormones regulate only endogenous testosterone (which is small to begin with in hypogonadal men) in an intact feedback mechanism (which may not be present depending on the cause of hypogonadism), the level of FSH and/or LH may have little effect on the actual testosterone levels achieved. The net result is that the patients do not achieve a “hormonal steady state” for testosterone even though the Cavg, Cmin, and Cmax for testosterone remains relatively constant after a few days of treatment.
2. Bone Mineral Density (“BMD”) and Similar Markers:
a. BMD.
BMD was assessed by dual energy X-ray absorptiometry (“DEXA”) using Hologic QDR 2000 or 4500 A (Hologic, Waltham, Mass.) on days 0 and 180 in the lumbar spine and left hip regions. BMD of spine was calculated as the average of BMD at L1 to L4. BMD of the left hip, which included Ward's triangle, was calculated by the average of BMD from neck, trochanter, and intertrochanter regions. The scans were centrally analyzed and processed at Hologic. BMD assessments were performed at 13 out of the 16 centers (206 out of 227 subjects) because of the lack of the specific DEXA equipment at certain sites.
Table 17 and
The baseline hip and spine BMD and the change in BMD on day 180 were not significantly correlated with the average serum testosterone concentration on day 0. The changes in BMD in the hip or spine after testosterone replacement were not significantly different in subjects with hypogonadism due to primary, secondary, aging, or unclassified causes; nor were they different between naive and previously testosterone replaced subjects. The change in BMD in the spine was negatively correlated with baseline BMD values, indicating that the greatest increase in BMD occurred in subjects with the lowest initial BMD. The increase in BMD in the hip (but not in the spine) after testosterone treatment was correlated with the change in serum testosterone levels.
b. Bone Osteoblastic Activity Markers.
The results described above are supported by measurements of a number of serum and urine markers of bone formation. Specifically, the mean concentrations of the serum markers (PTH, SALP, osteocalcin, type I procollagen) generally increase during treatment in all treatment groups. In addition, the ratios of two urine markers of bone formation (N-telopeptide/creatinine ratio and calcium/creatinine ratio) suggests a decrease in bone resorption.
(1) PTH (Parathyroid or Calciotropic Hormone).
Serum intact PTH was measured by two site immunoradiometric assay (“IRMA”) kits from Nichol's Institute (San Juan Capistrano, Calif.). The LLC for the PTH assay was 12.5 ng/L. The intra- and inter-assay coefficients of variation were 6.9 and 9.6%, respectively. The UCLA-Harbor Medical Center has reported previously that the normal male adult range of PTH is 6.8 to 66.4 ng/L.
Table 18 provides the PTH concentrations over the 180-day study.
(2) SALP.
SALP was quantitated by IRMA using reagents supplied by Hybritech (San Diego, Calif.). The LLQ for the SALP assay was 3.8 μg/L.; and the intra- and inter-assay precision coefficients were 2.9 and 6.5%, respectively. The UCLA-Harbor Medical Center reported that the adult normal male concentration of SALP ranges from 2.4 to 16.6 μg/L.
The pretreatment SALP concentrations were within the normal range.
(3) Osteocalcin.
Serum osteocalcin was measured by an IRMA from Immutopics (San Clemente, Calif.). The LLQ was 0.45 μg/L. The intra- and inter-assay coefficients were 5.6 and 4.4%, respectively. The UCLA-Harbor Medical Center reports that the normal male adult range for the osteocalcin assay ranges from 2.9 to 12.7 μg/L.
As shown in
(4) Type I Procollagen.
Serum type I procollagen was measured using a RIA kit from Incstar Corp (Stillwater, Minn.). The LLQ of the procollagen assay was 5 μg/L, and the intra- and inter-assay precisions were 6.6 and 3.6%, respectively. The UCLA-Harbor Medical Center reports that the normal adult male concentration of type I procollagen ranges from 56 to 310 μg/L.
c. Urine Bone Turnover Markers: N-Telopeptide/Cr and Ca/Cr Ratios.
Urine calcium and creatinine were estimated using standard clinical chemistry procedures by an autoanalyzer operated by the UCLA-Harbor Pathology Laboratory. The procedures were performed using the COBAS MIRA automated chemistry analyzer system manufactured by Roche Diagnostics Systems. The sensitivity of the assay for creatinine was 8.9 mg/dL and the LLQ was 8.9 mg/dL. According to the UCLA-Harbor Medical Center, creatinine levels in normal adult men range from 2.1 mM to 45.1 mM. The sensitivity of the assay for calcium was 0.7 mg/dL and the LLQ was 0.7 mg/dL. The normal range for urine calcium is 0.21 mM to 7.91N-telopeptides were measured by an enzyme-linked immunosorbant assay (“ELISA”) from Ostex (Seattle, Wash.). The LLQ for the N-telopeptide assay was 5 nM bone collagen equivalent (“BCE”). The intra- and inter-assay had a precision of 4.6 and 8.9%, respectively. The normal range for the N-telopeptide assay was 48-2529 nM BCE. Samples containing low or high serum/urine bone marker levels were reassayed after adjusting sample volume or dilution to ensure all samples would be assayed within acceptable precision and accuracy.
The normal adult male range for the N-telopeptide/Cr ratio is 13 to 119 nM BCE/nM Cr. As shown in
The normal range for Ca/Cr ratio is 0.022 to 0.745 mM/mM.
Interestingly, the change in Ca/Cr ratio from baseline at day 90 was inversely related to the baseline Ca/Cr ratios. Similarly, the change in urine N-telopeptide/Cr ratio was also inversely proportional to the baseline N-telopeptide/Cr ratio (r=−0.80, p=0.0001). Thus subjects with the highest bone resorption markers at baseline showed the largest decreases of these markers during transdermal testosterone replacement. The decreases in urinary bone resorption markers were most prominent in subjects who had highest baseline values, suggesting that hypogonadal subjects with the most severe metabolic bone disease responded most to testosterone replacement therapy.
d. Serum Calcium.
Serum calcium showed no significant inter-group differences at baseline, nor significant changes after testosterone replacement. Serum calcium levels showed insignificant changes during testosterone replacement.
3. Libido, Sexual Performance, and Mood.
Sexual function and mood were assessed by questionnaires the patients answered daily for seven consecutive days before clinic visits on day 0 and on days 30, 60, 90, 120, 150, and 180 days during gel and patch application. The subjects recorded whether they had sexual day dreams, anticipation of sex, flirting, sexual interaction (e.g., sexual motivation parameters) and orgasm, erection, masturbation, ejaculation, intercourse (e.g., sexual performance parameters) on each of the seven days. The value was recorded as 0 (none) or 1 (any) for analyses and the number of days the subjects noted a parameter was summed for the seven-day period. The average of the four sexual motivation parameters was taken as the sexual motivation score and that of the five sexual motivation parameters as the sexual motivation mean score (0 to 7). The subjects also assessed their level of sexual desire, sexual enjoyment, and satisfaction of erection using a seven-point Likert-type scale (0 to 7) and the percent of full erection from 0 to 100%. The subjects rated their mood using a 0 to 7 score. The parameters assessed included positive mood responses: alert, friendly, full of energy, well/good feelings and negative mood responses: angry, irritable, sad, tired, nervous. Weekly average scores were calculated. The details of this questionnaire had been described previously and are fully incorporated by reference. See Wang et al., “Testosterone Replacement Therapy Improves Mood in Hypogonadal Men A Clinical Research Center Study,” 81 J. Clinical Endocrinology & Metabolism 3578-3583 (1996).
a. Libido.
As shown in
Libido was assessed from responses on a linear scale of: (1) overall sexual desire, (2) of sexual activity without a partner, and (3) enjoyment of sexual activity with a partner. As shown in
Similarly the sexual performance score improved significantly in all subjects as a group. The improvement in sexual performance from baseline values was not different between transdermal preparations.
b. Sexual Performance.
The improvement in sexual function was not related to the dose or the delivery method of testosterone. Nor was the improvement related to the serum testosterone levels achieved by the various testosterone preparations. The data suggest that once a threshold (serum testosterone level probably at the low normal range) is achieved, normalization of sexual function occurs. Increasing serum testosterone levels higher to the upper normal range does not further improve sexual motivation or performance.
c. Mood.
The positive and negative mood summary responses to testosterone replacement therapy are shown in
4. Muscle Strength.
Muscle strength was assessed on days 0, 90, and 180. The one-repetitive maximum (“1-RM”) technique was used to measure muscle mass in bench press and seated leg press exercises. The muscle groups tested included those in the hips, legs, shoulders, arms, and chest. The 1-RM technique assesses the maximal force generating capacity of the muscles used to perform the test. After a 5-10 minute walking and stretching period, the test began with a weight believed likely to represent the patient's maximum strength. The test was repeated using increments of about 2-10 pounds until the patient was unable to lift additional weight with acceptable form. Muscle strength was assessed in 167 out of the 227 patients. Four out of 16 centers did not participate in the muscle strength testing because of lack of the required equipment.
The responses of muscle strength testing by the arm/chest and leg press tests are shown in
5. Body Composition.
Body composition was measured by DEXA with Hologic 2000 or 4500A series on days 0, 90, and 180. These assessments were done in 168 out of 227 subjects because the Hologic DEXA equipment was not available at 3 out of 16 study centers. All body composition measurements were centrally analyzed and processed by Hologic (Waltham, Mass.).
At baseline, there were no significant differences in total body mass (“TBM”), total body lean mass (“TLN”), percent fat (“PFT”), and total body fat mass (“TFT”) in the three treatment groups. As shown in
The increase in TLN and the decrease in TFT associated with testosterone replacement therapy showed significant correlations with the serum testosterone level attained by the testosterone patch and the different doses of ANDROGEL®. Testosterone gel administered at 10.0 increased lean mass more than the testosterone patch and the 5.0 g/day ANDROGEL® groups. The changes were apparent on day 90 after treatment and were maintained or enhanced at day 180. Such changes in body composition was significant even though the subjects were withdrawn from prior testosterone therapy for six weeks. The decrease in TFT and PFT was also related to the serum testosterone achieved and were different across the treatment groups. The testosterone patch group did not show a decrease in PFT or TFT after 180 days of treatment. Treatment with ANDROGEL® (5.0 to 10.0 g/day) for 90 days reduced PFT and TFT. This decrease was maintained in the 5.0 and 7.5 g/day groups at 180 days but were further lowered with continued treatment with the higher dose of the ANDROGEL®.
6. Lipid Profile and Blood Chemistry.
The serum total, HDL, and LDL cholesterol levels at baseline were not significantly different in all treatment groups. With transdermal testosterone replacement, there were no overall treatment effects nor inter-group differences in serum concentrations of total, HDL- and LDL-cholesterol (
Approximately 70 to 95% of the subjects had no significant change in their serum lipid profile during testosterone replacement therapy. Total cholesterol levels which were initially high were lowered into the normal range (of each center's laboratory) at day 180 in 17.2, 20.4, and 12.2% of subjects on testosterone patch, ANDROGEL® 5.0 g/day and ANDROGEL® 10.0 g/day, respectively. Serum HDL-cholesterol levels (initially normal) were reduced to below the normal range (of each center's laboratory) in 9.8, 4.0, 9.1, and 12.5% of subjects at day 180 in the testosterone patch, ANDROGEL® 5.0, 7.5, and 10.0 g/day groups, respectively. There was no clinically significant changes in renal or liver function tests in any treatment group.
7. Skin Irritations.
Skin irritation assessments were performed at every clinic visit using the following scale: 0=no erythema; 1=minimal erythema; 2=moderate erythema with sharply defined borders; 3=intense erythema with edema; and 4=intense erythema with edema and blistering/erosion.
Tolerability of the daily application of ANDROGEL® at the tested dosages was much better than with the permeation-enhanced testosterone patch. Minimal skin irritation (erythema) at the application site was noted in three patients in the ANDROGEL® 5.0 g/day group (5.7%) and another three in the ANDROGEL® 10.0 g/day group (5.3%). Skin irritation varying in intensity from minimal to severe (mild erythema to intense edema with blisters) occurred in 65.8% of patients in the patch group. Because of the skin irritation with the testosterone patch, 16 subjects discontinued the study; 14 of these had moderate to severe skin reactions at the medication sites. No patients who received ANDROGEL® discontinued the study because of adverse skin reactions. The open system and the lower concentration of alcohol in the ANDROGEL® formulation markedly reduced skin irritation resulting in better tolerability and continuation rate on testosterone replacement therapy.
Moreover, based on the difference in the weight of the dispensed and returned ANDROGEL® bottles, the mean compliance was 93.1% and 96.0% for the 5.0 g/day and 10.0 g/day ANDROGEL® groups during days 1-90, respectively. Compliance remained at over 93% for the three ANDROGEL® groups from days 91-180. In contrast, based on counting the patches returned by the subjects, the testosterone patch compliance was 65% during days 1-90 and 74% during days 91-180. The lower compliance in the testosterone patch group was mostly due to skin reactions from the subjects' records.
The present invention is also directed to a method for dispensing and packaging the gel. In one embodiment, the invention comprises a hand-held pump capable of delivering about 2.5 g of testosterone gel with each actuation. In another embodiment, the gel is packaged in foil packets comprising a polyethylene liner. Each packet holds about 2.5 g of testosterone gel. The patient simply tears the packet along a perforated edge to remove the gel. However, because isopropyl myristate binds to the polyethylene liner, additional isopropyl myristate is added to the gel in order to obtain a pharmaceutically effective gel when using this delivery embodiment. Specifically, when dispensing the gel via the foil packet, about 41% more isopropyl myristate is used in the gel composition (i.e., about 0.705 g instead of about 0.5 g in Table 5), to compensate for this phenomenon.
The composition can also be dispensed from a rigid multi-dose container (e.g., with a hand pump) having a larger foil packet of the composition inside the container. Such larger packets also comprise a polyethylene liner as above.
Both embodiments permit a patient to deliver accurate but incremental amounts of gel (e.g., either 2.5 g, 5.0 g, 7.5 g, etc.) to the body. These delivery mechanisms thus permit the gel to be administered in unit dose form depending on the particular needs and characteristics of the patient.
Although the invention has been described with respect to specific embodiments and examples, it should be appreciated that other embodiments utilizing the concept of the present invention are possible without departing from the scope of the invention. The present invention is defined by the claimed elements, and any and all modifications, variations, or equivalents that fall within the true spirit and scope of the underlying principles.
Claims
1. A hydroalcoholic gel pharmaceutical composition, comprising: wherein the percentages of components are weight to weight of the composition.
- a. from about 0.5% to about 10% testosterone;
- b. from about 30% to about 98% alcohol selected from the group consisting of ethanol and isopropanol;
- c. from about 0.1% to about 5% of a thickening agent;
- d. from about 0.25% to about 2.5% of at least one penetration enhancer selected from the group consisting of isostearic acid, octanoic acid, lauryl alcohol, isopropyl myristate, butyl stearate, methyl laurate, diisopropyl adipate, glyceryl monolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, dimethyl sulfoxide, glycerol, ethyl acetate, acetoacetic ester, N-alkylpyrrolidone, derivatives thereof, and combinations thereof; and
- e. water in an amount sufficient to make the composition 100%,
2. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the testosterone is present in a concentration of from about 0.5% to about 5% (w/w) of the composition.
3. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the alcohol is ethanol.
4. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the thickening agent is an anionic polymer.
5. The hydroalcoholic gel pharmaceutical composition of claim 4, wherein the anionic polymer is selected from the group consisting of polyacrylic acid, carboxymethyl cellulose, and combinations thereof.
6. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the composition further comprises 0.1N sodium hydroxide.
7. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises isostearic acid.
8. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises octanoic acid.
9. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises lauryl alcohol.
10. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises isopropyl myristate.
11. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises butyl stearate.
12. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises methyl laurate.
13. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises diisopropyl adipate.
14. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises glyceryl monolaurate.
15. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises tetrahydrofurfuryl alcohol polyethylene glycol ether.
16. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises polyethylene glycol.
17. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises propylene glycol.
18. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises 2-(2-ethoxyethoxy)ethanol.
19. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises diethylene glycol monomethyl ether.
20. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises dimethyl sulfoxide.
21. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises glycerol.
22. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises ethyl acetate.
23. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises acetoacetic ester.
24. The hydroalcoholic gel pharmaceutical composition of claim 1, wherein the penetration enhancer comprises N-alkylpyrrolidone.
Type: Application
Filed: Mar 24, 2011
Publication Date: Aug 18, 2011
Inventors: Robert E. Dudley (Rosemary Beach, FL), Dominique Drouin (Verrieres Le Buisson)
Application Number: 13/071,264
International Classification: A61K 31/568 (20060101); A61P 5/00 (20060101);
