Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-02-02
2003-05-27
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S179000, C514S182000, C514S841000, C514S842000, C514S843000
Reexamination Certificate
active
06569844
ABSTRACT:
DESCRIPTION
This invention relates to pharmaceutical preparations containing active ingredients that are estra-1,3,5(10)-triene derivatives having an R—SO
2
—O group at their C3 position.
Estrogens play a major role in hormonal contraception, in menopausal hormone replacement therapy (HRT), and for treating gynecologic (e.g. mammary carcinoma) and andrologic (e.g. prostatic carcinoma) diseases.
For HRT and contraception, estrogens are mainly used together with a gestagen, e.g. levornogestrel, desogestrel, gestodene, drospirorenone, norethisterone, cyproterone acetate, chlormadinone acetate, dienogest.
When used for contraception, estrogens are needed for safely suppressing follicle maturation and ovulation, but in addition they replace the endogenous ovarian secretion of estradiol which is suppressed to a major extent. This replacement is important for maintaining an artificial menstrual cycle and other genital functions, which could not be done to any satisfactory extent by just using a gestagen.
Moreover, endogenous estrogens have important central nervous and metavolic functions in female organism.
Normal estrogen levels contribute very much to a person's well-being (L. Zichella; Clinical Management of the Menopausal Woman; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 (1993), pp. 15-22). Estrogens antagonize the development of cardiovascular diseases through various mechanisms, that is, by creating “favourable” lipoprotein patterns in the blood (G. Samsioe; Hormone Replacement and Cardiovascular Disease; Int. J. of Fertil. and Menop. Studies, 39, Suppl. 1 (1993), pp. 23-29), by inhibiting lipid deposits in the vessel wall (B. Clarkson; Experimental Effects of Progesterone versus Progestins on Arterial Wall; Gynecol. Endocrinol., 6, Suppl. 1 (1992), p. 15), by exerting a favourable influence on vascular tonus, thus reducing blood pressure (R. A. Lobo; Estrogen and Cardiovascular Disease; Ann. New York Acad. Sciences, 592 (1990), pp. 286-294), by reducing resistance to perfusion in important vessel sections and sedating contractile stimuli to the vascular muscle (C. Jiang et al.; Acute effect of 17&bgr;-estradiol on rabbit coronary artery contractile responses to endothelin-1; Am. J. Physiol., 263 (1992), H271-H275). The interior walls of vessels release factors (prostacyclin) under the influence of estrogens that counteract the development of blood clots.
Estrogens are indispensable for preserving the bone structure in women. If they are gone, this may cause destruction of the bone (osteoporosis) (C. Christiansen; Prevention and Treatment of Osteoprosis with Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 (1993), pp. 45-54). These latter “central nervous” and “metabolic” effects of estrogens are a main aspect of HRT.
But notwithstanding all positive aspects of estrogen therapy there are unsolved problems, too, which restrict the therapeutic use of estrogens or entail undesired effects.
Natural estrogens (estradiol, estrone, estrone sulfate, esters of estradiol, estriol) become bioavailable only to a very low degree when taken orally (K. B. Lokind et al.; Oral bioavailability of 17&bgr;-estradiol and various ester prodrugs in the rat; Int. J. Pharmaceutics, 76 (1991), pp. 177-182). This degree may vary so much from person to person that general dosage recommendations cannot be given. These pharmacokinetic factors resulted in a negative evaluation of natural estrogens for contraception (W. Kuhnz et al.; Pharmacokinetics of Estradiol, Free and Total Estrone, in Young Women Following Single Intravenous and Oral Administration of 17&bgr;-Estradiol; Arzneimittel-Forschung/Drug Res., 43 (II), 9, (1993), pp. 966-973). Fast elimination of the substances from the blood is another problem. Estrogen replacement under HRT often has to be adjusted to the individual. Development of an estradiol prodrug designed to improve bioavailability therefore proved to be unsuccessful (K. B. Lokind et al.; see above).
Synthetic estrogens also have considerable disadvantages. The most important synthetically altered estrogenic steroid is ethinyl estradiol (EE). This estrogen is dominant in oral contraception. Apart from EE, mestranol is used in a few cases; this is a “prodrug” that is metabolized to EE in the organism (J. W. Goldzieher; Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications; Am. J. Obstet. Gynecol., 163 (1990), pp. 318-322). When applied orally to humans, EE has a much better bioavailability than the natural estrogens mentioned above, but its oral bioavailability varies to an extraordinary extent from individual to individual. Goldzieher pointed out the negative meaning, from a pharmacodynamic point of view, of the variation of the area under the curve (AUC), of half-life and the time at which maximum concentrations in the blood are reached. The highest AUC found in this study, measured 0 to 24 hours after application, was 2121 pg×h/ml. The lowest AUC was 284 pg×h/ml. A similar variation of the AUC around a factor of 6 or 7 was described in Hümpel et al. (M. Hümpel et al.; Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives; Horm. Res., 33 (1990), pp. 35-39).
After resorption from the intestinal lumen, orally applied active ingredients enter the organism via the liver. This fact is of specific importance for estrogenic agents as the liver is a target organ for estrogens; oral intake of estrogens results in strong estrogenic effects in the liver. The secretion activity that is controlled by estrogens in the human liver includes synthesis of transport proteins CBG, SHBG, TBG, angiotensinogen, several factors that are important for the physiology of blood clotting, and lipoproteins.
If natural estrogens are introduced to the female organism while avoiding passage through the liver (e.g. by transdermal application), the liver functions mentioned remain virtually unchanged (U. Larsson-Cohn et al.; Some biochemical consequences of post-menopausal hormone replacement treatment; in: The Controversial Climacteric, Ed.: P. A. van Keep et al.; MTP Press Ltd. (1982)). Therapeutically equivalent doses of natural estrogens, when applied orally, result in clear responses of hepatic parameters: increase of SHBG, CBG, angiotensinogen, HDL (high density lipoprotein) (J. C. Stevenson et al.; Oral Versus Transdermal Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 (1993), pp. 30-35). These hepatic effects of estrogen are clearly stronger when, instead of natural estrogens, equine estrogen formulations (so-called conjugated estrogens) are used (C. A. Mashchak et al.; Comparison of pharmacodynamic properties of various estrogen formulations; Am. J. Obstet. Gynecol., 144 (1982) pp. 511-518). Ethinyl estradiol and DES have an even greater hepatic estrogenicity. When referring to antigonadotropic properties, EE is about 8 to 10 times more estrogenic in the liver than orally applied natural estrogens are. This is a very unfavourable dissociation of properties (B. von Schoultz et al.; Estrogen Therapy and Liver Function—Metabolic Effects of Oral and Parenteral Administration; The Prostate, 14, (1989), pp. 389-395).
The following observation shows that undesired hepatic responses to estrogen cannot be avoided by lowering EE doses in contraceptives. A reduction from 30 &mgr;g to 20 &mgr;g of EE, each time combined with 150 &mgr;g of the same gestagen, showed no reduction of the considerably increased angiotensin level after three months, and just marginally reduced values after 6 months (A. Basdevant et al.; Hemostatic and metabolic effects of lowering the ethinyl estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel; Contraception, 48 (1993), pp. 193-204).
A known complication that may occur after applying high doses of estrogen to males suffering from prostatic carcinoma is fatal thromboembolism (B. von Schoultz et al.; see
Elger Walter
Lucas Margit
Reddersen Gudrun
Schneider Birgitt
Schwarz Sigfrid
Badio Barbara P.
Jenapharm GmbH & Co. KG
Lucas Margit
Siemann Christel
Siemann Frank
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