Drug – bio-affecting and body treating compositions – Contraceptive
Reexamination Certificate
1999-01-26
2001-01-30
Dodson, Shelley A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Contraceptive
C424S435000, C424S464000
Reexamination Certificate
active
06180682
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to pharmaceutical compositions and methods for administering pharmacologically active agents. More particularly, the invention relates to buccal drug delivery, and to a buccal dosage unit and method for administering a contraceptive composition to a mammalian male.
BACKGROUND
To date, there are no commercially available oral contraceptive methods for males which are safe, reliable, and effective. Currently available male contraceptive methods suffer from the disadvantages of being unreliable, cumbersome, or, in the case of vasectomy, generally irreversible. In spite of these drawbacks, approximately 35% of contraception worldwide involves male practices.
Popul. Rep
. (1986)14: J889.
It has been proposed that spermatogenesis is driven by gonadotropins. Gonadotropin releasing hormone (GnRH), a decapeptide released in bi-hourly pulses from the hypothalamus, pituitary secretion of fofficle-stimulating hormone (FSH) and luteinizing hormone (LH) regulate the functioning of the gonads to produce testosterone in the testes and the production and maturation of gametes. Within the testis, FSH binds to specific receptors on Sertoli cells, and LH stimulates Leydig cells. In addition, LH stimulates cells to produce testosterone, which interacts with intracellular androgen receptors in testicular Sertoli and peritubular cells. Spermatogenesis is thus thought to be driven by both FSH and testosterone. Accordingly, most hormonal approaches to male contraception have focused on inhibition of G gonadotropins, or both.
Exogenously administered androgens inhibit gonadotropin secretion, consequently inhibiting spennatogenesis, and have been studied as potential contraceptive agents in men. Cummings et al. (1994)
Clin. Androl
. 23:893-992. An intramuscular (IM) injection of 200 mg per week of testosterone enanthate results in azoospermia in 50% to 70% of Caucasian men and 95% of Asian men after approximately 4 months. Side effects included oily skin, acne, irritation of the injection site, an increase in aggressiveness, a decrease of the high-density lipoprotein (HDL)-cholesterol and possible adverse effects on the prostate gland.
The effect of lower doses of testosterone enanthate in combination with prosgestogenic agents has also been studied and has been reported to produce azoospermia comparable to those obtained with high doses of testosterone enanthate alone. An IM injection of 100 mg per week of testosterone enanthate in combination with 500 &mgr;g per day of levonorgestrel administered orally resulted in about 67% of the males achieving azoospermia in about 10 weeks. The side effects included a slight gain in weight and a significant decrease in the serum HDL-cholesterol. Bebb et al. (1996)
J. Clin. Endocr. Metab
. 81:757-762.
Co-administration of testosterone enanthate (100 mg/week, IM injection) with the synthetic steroid cyproterone acetate (100 mg/day or 50 mg per day) has been evaluated and was found to result in azoospernia within 7 to 8 weeks. However, the side effects included a slight decrease in body weight and a significant decrease in testis size during treatment. Meriggiola et al. (1996)
J. Clin. Endocr. Metab
. 81:3018-3023; Meriggiola et al. (1997)
J. Androl
. 18:240-244.
In another study, testosterone enanthate (25 mg/week, IM injection) was co-administered with a GnRH antagonist Nal-Glu (10 mg/day, subcutaneous injection). This combination resulted in azoospermia in approximately 75% of the men tested. However, the major side effect was an increase in the concentration of HDL-cholesterol. Pavlou et al. (1991)
J. Clin. Endocr. Metab
. 73:1360-1369; Tom et al. (I992)
J. Clin. Endocr. Metab
. 75:476-483.
The methods of effecting male contraception using testosterone enanthate currently being studied require intramuscular or a subcutaneous injection that can be painful. In addition, self-administration of an injectable composition typically suffers from low user acceptance.
Attempts at alternative routes of administration have not been successful for a number of reasons. Testosterone, for example, is well absorbed after oral administration but is quickly metabolized during passage through the liver and intestine. Therefore, it is not possible to achieve effective blood levels of testosterone via oral administration. 17&agr;-alkylated derivatives of testosterone can be administered orally and are resistant to hepatic metabolism, but are not recommended for clinical use because of their potential hepatoxicity. Bhasin et al. (1997)
J. Clin. Endocr. Metab
. 82:3-8. Delivery of testosterone through the skin has been achieved using conventional transdenmal patches. However, transdermal administration of steroids requires a permeation enhancer, which can result in skin irritation and sensitization.
Drug therapy involving buccal administration of steroid hormones has been described. For example, U.S. Pat. No. 4,755,386 to Hsiao et al. generally describes the buccal administration of various medicaments, including estrogens, progestins and androgens; however, male contraceptive compositions are not contemplated. U.S. Pat. No. 4,764,378 to Keith et al. describes rapidly disintegrating dosage forms utilizing a combination of high and low molecular weight polyethylene glycols; the dosage forms, which are preferably 50 mg to 100 mg tablets, may be administered orally or through the buccal mucosa. Similarly, U.S. Pat. No. 5,135,752 to Snipes et al. describes buccal delivery systems containing polyethylene glycols of varying molecular weights for the delivery of methyl testosterone or estadiol. U.S. Pat. No. 4,877,774 to Pitha et al. describes crystalline complexes of steroid hormones and gamma-cydodextrin for administration of steroids through mucosal tissue.
The present male contraceptive compositions and methods are, however, new and completely unsuggested by the art. Applicants' contraceptive compositions are in the form of a compact drug dosage unit to be applied to the buccal mucosa, wherein the dosage unit comprises an androgenic agent and a progestin in a bioerodible polymeric carrier that facilitates adhesion to the buccal mucosa. The present buccal dosage units provide for a highly effective method of male contraception, and overcome a number of the disadvantages associated with prior male contraceptive compositions and methods. In particular, the present buccal dosage units, in contrast to the prior art, are simple in design and easily manufactured, are pharmacologically reliable, and do not result in the side effects associated with intramuscular injection, transdermal drug delivery or other modes of administration.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to address the aforementioned need in the art by providing a drug dosage unit for buccally administering to a male individual a pharmaceutical composition comprising an androgenic agent and a progestin.
It is another object of the invention to provide a method for effecting contraception in a male individual by buccally administering a contraceptive composition using the aforementioned drug dosage unit.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
Accordingly, in a first embodiment, then, a pharmaceutical composition is provided in the form of a simple, compact buccal dosage unit comprising therapeutically effective amounts of an androgenic agent and a progestin in a bioerodible polymeric carrier, wherein the carrier is such that it enables the dosage unit to adhere to the buccal mucosa. Following application to the buccal mucosa, gradual and complete erosion of the unit occurs over a predetermined time period, thus providing drug delivery throughout that time period. In a preferred embodiment, the dosage unit contains only the active agents to be administered and the polymeric carrier. However, other compone
Dodson Shelley A.
George Konata M.
Place Virgil A.
Reed Dianne E.
Reed & Associates
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