Pharmaceutical composition and method for treating hypogonadism

Abstract

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.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 248,267 filed on 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 INVENTION [0002] The present invention is directed to a pharmaceutical composition comprising testosterone in a gel formulation, and to methods of using the same. BACKGROUND OF THE INVENTION [0003] A. Testosterone Metabolism in Men. [0004] 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. [0...

AI Technical Summary

Benefits of technology

[0047] The 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.

Problems solved by technology

However, because of testicular or other failures, the high LH concentrations are not effective at stimulating testosterone production.

Third, hypogonadism may be age-related.

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.

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.

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.

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.

Other studies involving implants have reported similar undesirable pharmacokinetic profiles.

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.

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.

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.

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.

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.

Finally, in a number of patients, there is an inability to achieve adequate serum hormone levels.

Many men, however, are unable to obtain and / or sustain testosterone levels within the normal range.

Both systems, however, suffer from similar problems.

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.

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.

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.

Thus, the transdermal patch still remains an inadequate testosterone replacement therapy alternative for most men.

However, the pharmacokinetics of a DHT-gel is markedly different from that of a testosterone gel.

Thus, DHT gels are not effective at increasing testosterone levels in hypogonadal men.

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