Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-09-16
2004-07-27
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S841000, C514S842000
Reexamination Certificate
active
06767902
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the fields of medicine and pharmaceutical science in providing androgen replacement methods of male contraception and devices useful in accordance with those methods.
BACKGROUND OF THE INVENTION
Male contraception has been enigmatic. Mechanical devices offer reduced sensation and inconvenience. While they may be effective in reducing the transmission of sexually transmitted diseases, they may also be a source of friction in a relationship. Moreover, such contraceptive methods are not without a significant incidence of failure.
For these and other reasons, chemical methods, such as birth control pills for women, have been a long sought after objective. However, chemical protocols for men have been plagued by their own problems. For example, the continuous administration of luteinizing hormone releasing hormone (LHRH) and its analogs have been proposed as an effective way of suppressing spermatogenesis. This is accomplished by blocking gonadotropin secretion. Implants that deliver LHRH and its analogs therefore represent a potential male contraceptive. However, the loss of gonadotropins results in diminished secretion of testosterone which, amongst other things, provides a diminished libido and potential loss of sexual function. Therefore, along with the administration of LHRH, or another sterilant, the art recognizes the need for the co-administration of an androgen. See U.S. Pat. No. 5,733,565. An androgen, often testosterone, is supplied to help bolster the body's testosterone level and sustain normal sexual function. This sort of androgen supplementation, however, brings with it many problems of its own. Testosterone is expensive and relatively large quantities need to be administrated, usually by injection, on a daily basis. Testosterone is also 5&agr;-reduced to DHT (dihydrotestosterone) which is itself a very potent agent. It can over-stimulate prostate growth, potentially leading to complications such as BPH (benign prostate hypoplasia).
In view of the foregoing, there remains a need for an effective method of male contraception with a minimum of health risks and further complications. That need is satisfied by the present invention.
SUMMARY OF THE INVENTION
The present invention is based on, amongst other things, the discovery that an androgen can be used alone as an effective contraceptive, not merely as an androgen supplement. By using an androgen as a contraceptive, one is able to eliminate the need for combination therapies using androgens and sterilants simplifying contraception and lowering costs dramatically. Moreover, the androgens used in accordance with the present invention not only act as contraceptives, but also maintain male sexual function and desire, without the side effects and adversities realized by the administration of 5&agr;-reducible androgens such as testosterone.
In accordance with a preferred embodiment, the present invention relates to methods of male contraception which include administering to a non-sterile male subject a predetermined amount of an androgen which is sufficient to render that male subject reversibly sterile. If the dosage forms used in the methods of the present invention are for daily dosing, then sufficient androgen must be provided for that day. If the dosage form is active over a plurality of days, then sufficient androgen must be provided for the entire period. Stated another way, the amount of androgen administered must be sufficient to render the subject sterile each day over the predetermined period of time.
The androgen, when provided in the amounts contemplated will result in blood levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) of 2.5 International units/liter (“IU/L”) or less and blood levels of testosterone (T) of 10 nmol/L or less. Preferably, the androgen is a non 5&agr;-reducible androgen, such as a 7&agr;-modified androgen. More preferably, the androgen, when provided in the amounts contemplated, will result in blood levels of LH and FSH of 2.0 IU/L or less and blood levels of T of 4 nmol/L or less. Most preferably, the androgen when provided in the amounts contemplated, will result in blood levels of LH and FSH of 1.0 IU/L or less, and blood levels of T of 3 nmol/L or less. Assuming that the androgen used is MENT, a steady-state blood level of more than 1.0 nmol/liter (“nmol/L”) should result. Preferably, blood levels of MENT of 1.5 nmol/L and even more preferably of 2 nmol/L or more will result.
If the goal is to provide contraception over a period of six months, then a sufficient amount of the androgen as described above must be supplied to the subject each day so as to ensure contraceptive efficacy each day for six months. That means that the blood levels should, at least generally, be within the specified limits for LH, FSH and testosterone as discussed above. Of course, day-to-day variation is to be expected based on the subject, the mode of administration, and the like. However, on balance, the subject should receive enough androgen, preferably each day, to ensure that over the six month period the subject is, for all practical purposes, incapable of reproduction.
Dosage forms which contain a sufficient quantity of the specified androgens are also contemplated. These dosage forms, unlike those that have gone before, will provide sufficient androgen to be contraceptively effective without also causing certain side effects such as, for example, overstimulating the prostate. The dosage forms contemplated include, without limitation, the androgen and a pharmaceutically acceptable carrier.
With the understanding that androgens can be used alone as a contraceptive also comes a new understanding of the use of androgens in androgen replacement therapy. There are certainly instances when one would wish to bolster or augment a subject's androgen level to provide a certain therapeutic effect, i.e., enhanced sexual drive, without also providing contraception. Therefore, the present invention also relates to methods of androgen replacement therapy which comprise the administration of androgen to a male subject in an amount which is sufficient to treat the subject's condition without being contraceptively effective. The androgen, when provided in the amounts contemplated in accordance with this aspect of the present invention, will result in blood levels of LH and FSH of greater than 2.5 IU/L and blood levels of testosterone of greater than 10 nmol/liter. Preferably, the androgen is a non-5&agr;-reducible androgen such as a 7&agr;-modified-androgen. This means that the amount of androgen provided is less than that necessary to provide effective contraception, yet sufficient to provide some level of other therapeutic effect. Dosage forms useful in accordance with this aspect of the invention are also contemplated.
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Kumar et al., “The Biological Activity of 7 Alpha-Methyl-19-Nortestosterone Is Not Amplified In Male Reproduction,” WHO Laboratory Manual for the Examination of Human Semen and Sperm—Cervical Mucus Interaction, 3d. Ed. Cambridge Univ. Press 1992.
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Lerner David Littenberg Krumholz & Mentlik LLP
The Population Council, Inc.
Webman Edward J.
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