Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1996-01-25
2002-07-23
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C552S638000
Reexamination Certificate
active
06423701
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to novel water-soluble prodrugs of testosterone suitable for intranasal administration to mammals, including humans, in need of testosterone replacement therapy. More specifically, this invention relates to a water-soluble form of testosterone which is suitable for intranasal administration. This invention also relates to a testosterone replacement therapy which comprises intranasal administration of one or more of the water-soluble forms of testosterone of the present invention.
BACKGROUND
Testosterone (17&bgr;-hydroxyandrost-4-en-3-one) and its metabolite, dihydrotestosterone, are the primary endogenous androgenic hormones (androgens). Endogenous androgens are responsible for the normal growth and development of the male sex organs and for development and maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in body musculature, and fat distribution.
These compounds also cause retention of nitrogen, sodium, potassium phosphorous, and decreased urinary excretion of calcium. Androgens have also been reported to increase protein anabolism and decrease protein catabolism. Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rate but may cause a disproportionate advancement in bone maturation. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietin.
The range of plasma testosterone levels in normal adult men is from 10 to 35 nmol/L (3 to 10 ng/ml). There are clinical conditions in which testosterone levels are decreased from normal levels. Disorders associated with hypotestosteronemia include primary hypogonadism (congenital or acquired), testicular failure due to cryptorchidism, bilateral torsion, Cushing's syndrome, congenital adrenal hyperplasia, hyperprolactinemia, Kinefelter's syndrome, orchitis, sickle cell anemia, Hodgkin's disease, amyloidosis, cirrhosis of the liver, and chronic renal failure. Decreases in plasma testosterone may also accompany surgery, chemotherapy, spinal cord injury, myocardial infarction, severe burns, and toxic damage from exposure to alcohol or heavy metals. In any or all of these conditions it may be desirable for the patient to undergo testosterone replacement therapy.
Testosterone also antagonizes a number of the effects of estrogens, and sometimes is employed clinically for this purpose. This is especially important in the suppression of metastatic carcinoma of the breasts. Testosterone and its esters (e.g., testosterone propionate) and derivatives (e.g., methyltestosterone) also promotes retention of calcium, and may be useful in treatment of osteoporosis.
However, oral administration of testosterone itself is generally ineffective as a means for increasing circulating testosterone levels. When testosterone per se is administered by mouth, it is absorbed into the portal blood and degraded promptly by the liver so that insignificant amounts reach the systemic circulation; when injected parenterally, testosterone is rapidly absorbed from the injection vehicle and rapidly degraded. As a consequence, effective androgen therapy requires either the administration of testosterone in a slowly absorbed dosage form or the administration of modified analogs of testosterone dissolved in oil vehicle. Such chemical modifications represent attempts to retard the rate of metabolism of testosterone, so as to sustain effective blood levels, due to slow conversion of the ester. Three types of modification of the molecule have received widespread clinical application, namely, esterification of the 17&bgr;-hydroxyl group, alkylation at the 17&agr; position, and modification of the ring structure, particularly substitutions at the 2, 9, and 11 positions. Most agents actually contain combinations of ring structure alterations and either 17&agr;-alkylation or esterification of the 17&bgr;-hydroxyl moiety. Esterification serves to decrease the polarity of the molecule. Consequently, the steroid is more soluble in the fat vehicles used for injection, and release of the steroid into the circulation is slowed. Most esters must be injected parenterally, a route of administration which, because it is painful and inconvenient, is difficult for patients to self-administer in a chronic therapeutic regimen. Furthermore, the more carbon molecules in the acid esterified, the more prolonged is the action of the modified compound. Esters such as testosterone cypionate (testosterone cyclopentanepropionate) and testosterone enanthate (testosterone heptanoate) are typically injected every 1 to 3 weeks. These esters are hydrolyzed before the hormones act; thus the effectiveness of therapy must be monitored by assaying plasma testosterone level with time following administration.
The oral effectiveness of 17&agr;-alkylated androgens (such as methyl-testosterone and methandrostenolone) is due to slower hepatic catabolism than occurs with testosterone itself, so that the alkylated derivatives escape degradation by the liver and reach the systemic circulation. For this reason, 17&agr;-methyl or -ethyl substitution is a common feature of most orally active androgens. Unfortunately, all 17&agr;-alkylated steroids can produce cholestatic hepatitis and jaundice, and other liver function abnormalities such as elevation of plasma alkaline phosphatase and conjugated bilirubin, even at low doses. The most serious complications of 17&agr;-alkylated androgen therapy are the development of peliosis hepatitis (blood-filled cysts in the liver) and hepatoma. While patients with preexisting liver disease are particularly susceptible to these serious side effects, they are frequently seen even in patients without a history of clinical liver disease. 17&agr;-Alkylated drugs also cause an increase in a variety of plasma proteins that are synthesized in the liver. Finally, the relatively infrequent administration of these drugs results in a wide range in postadministration plasma testosterone values.
Although testosterone is known to be absorbed from the nasal cavity, its insolubility in water makes its intranasal administration impractical (see, e.g., Hussain et al.,
J. Pharm. Sci.
73: 1300-1301, 1984). Transdermal preparations of testosterone in which a testosterone-loaded patch is applied each day have recently become available (Testoderm®, Alza Corporation, Palo Alto, Calif.). This therapy avoids the wide swings in serum testosterone values that occur between injections of testosterone esters, and allows for self-administration by the patient. However, the transdermal patch will not produce adequate serum testosterone concentration if applied to nongenital skin. In order to deliver an effective amount of testosterone into the bloodstream, the transdermal patch must be applied directly to a shaved area of the scrotum, where it must be worn for 22-24 hours per day. Furthermore, any testosterone remaining on the skin following removal of the patch may be transferred to the patient's sexual partner. Finally, the transdermal patch suffers from the disadvantage of being extremely expensive.
In view of the foregoing, it is apparent that there exists a need in the art for an improved method of delivery of testosterone for use in testosterone replacement therapy.
Surprisingly, the present inventor has found that intranasal administration of a novel form of testosterone offers significant advantages over the prior art. Those advantages include rapid absorption, and easy and reliable self-administration.
SUMMARY OF THE INVENTION
Accordingly, since parenteral administration of testosterone analogs results in wide swings in plasma testosterone levels, and since
Badio Barbara P.
Burns Doane , Swecker, Mathis LLP
University of Kentucky
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