Estrogen replacement regimen

• US 20060089337A1
• Filed: 08/28/2003
• Published: 04/27/2006
• Est. Priority Date: 08/28/2002
• Status: Active Grant

• Current Assignee: Gideon Kopernik, Robert Casper, Zeev Shoham
• Original Assignee: Gideon Kopernik, Robert Casper, Zeev Shoham
• Inventors: Casper, Robert, Kopernik, Gideon, Shoham, Zeev
• Granted Patent: US 8,946,198 B2
• Time in Patent Office: Days
• US Class Current: 514/170
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61P 15/12 for climacteric disorders

Abstract

The present invention provides an improved method to deliver estrogen to menopausal women comprising administering ultra-low dose estradiol alternating with standard-dose estradiol.

Claims

1. An improved pharmaceutical preparation, for administration to a female in need of estrogen replacement, comprising a plurality of doses arranged in alternating standard dose estrogen phases and ultra low dose estrogen phases, each phase consisting of from about 1 to about 4 consecutive daily unit doses or an equivalent thereof, wherein the daily unit doses of the standard dose estrogen phases contain an amount of a substance exhibiting estrogenic activity equivalent to from at or about 0.5 mg to at or about 5.0 mg of estradiol, and the daily unit doses of the ultra-low dose estrogen phases contain an amount of a substance exhibiting estrogenic activity equivalent to at or about 0.005 mg to at or about 0.5 mg of estradiol.

2. A pharmaceutical preparation according to claim 1, wherein the daily unit doses are in at least one of orally, transdermally and buccally administerable form.

3. A pharmaceutical preparation according to claim 1, comprising administering a series of consecutive daily doses arranged in standard dose estrogen phases of two daily unit doses each alternating with ultra low dose estrogen phases of two daily unit doses each.

4. A pharmaceutical preparation according to claim 1, comprising administering a series of consecutive daily doses arranged in standard dose estrogen phases of three daily unit doses each alternating with ultra low dose estrogen phases of three daily unit doses each.

5. A pharmaceutical preparation according to claim 1, comprising administering a series of consecutive daily doses arranged in standard dose estrogen phases of four daily unit doses each alternating with ultra low dose estrogen phases of four daily unit doses each.

6. An improved pharmaceutical preparation according to claim 1 wherein the substance exhibiting estrogenic activity is selected from 17α

-ethinylestradiol, esters and ethers of 17α

-ethinylestradiol, 17α

-ethinylestradiol 3-dimethylamino propionate, 17α

-ethinylestradiol 3-cyclopentyl ether (quienestrol) and 17α

-ethinylestradiol 3-methyl ether (mestranol);

natural estrogens, estrone, estrone sulfate, estrone sulfate peperazine salt, estradiol and estriol, and their esters, conjugated equine estrogens and any components thereof with estrogenic activity, as well as the synthetic estrogens, and the substance exhibiting progestogenic activity is selected from desogestrel, norgestimate, gestodene, dydrogesterone, medroxyprogesterone acetate, norethynodrel, norethinedrone, norethinedrone acetate, levonorgestrel, dl-norgestrel, cyproterone acetate, chlormadinone acetate, magestrol acetate, 17 D-acetyl norgestimate, dienogest, trimegestone, drosperinone and nomagestrel.

7. An improved pharmaceutical preparation, for administration to a female in need of estrogen and progesterone replacement therapy, comprising a plurality of doses arranged in alternating standard dose estrogen phases and ultra low dose estrogen phases, each phase consisting of from about 1 to about 4 consecutive daily unit doses or an equivalent thereof, wherein the daily unit doses of the standard dose estrogen phases contain an amount of a substance exhibiting estrogenic activity equivalent to from at or about 0.5 mg to at or about 5.0 mg of estradiol and a substance exhibiting progestogenic activity equivalent to from 0 mg to at or about 300 mg of micronized progesterone and the daily unit doses of the ultra low dose estrogen phases contain a substance exhibiting estrogenic activity equivalent to from at or about 0.005 mg to at or about 0.5 mg and a substance exhibiting progestogenic activity equivalent to from at or about 50 mg to at or about 300 mg of micronized progesterone.

8. A pharmaceutical preparation according to claim 7, wherein the substance exhibiting estrogenic activity is selected from 1 7α

-ethinylestradiol, esters and ethers of 17α

-ethinylestradiol, 17α

-ethinylestradiol 3-dimethylamino propionate, 17α

-ethinylestradiol 3-cyclopentyl ether (quienestrol) and 17α

-ethinylestradiol 3-methyl ether (mestranol);

natural estrogens, estrone, estrone sulfate, estrone sulfate peperazine salt, estradiol and estriol, and their esters, conjugated equine estrogens and any components thereof with estrogenic activity, as well as the synthetic estrogens, and the substance exhibiting progestogenic activity is selected from desogestrel, norgestimate, gestodene, dydrogesterone, medroxyprogesterone acetate, norethynodrel, norethinedrone, norethinedrone acetate, levonorgestrel, dl-norgestrel, cyproterone acetate, chlormadinone acetate, magestrol acetate, 17 D-acetyl norgestimate, dienogest, trimegestone, drosperinone and nomagestrel.

9. A pharmaceutical preparation according to claim 7, wherein the substance exhibiting progestin activity is selected on the basis that it binds to progestin receptors, demonstrates poor affinity for androgen receptors and has a lack of affinity for sex-hormone-binding globulin.

10. A pharmaceutical preparation according to claim 7, wherein the daily unit doses are in at least one of orally, transdermally and buccally administerable form.

11. A pharmaceutical preparation according to claim 7, comprising administering a series of consecutive daily doses arranged in standard dose estrogen phases of two daily unit doses each alternating with ultra low dose estrogen phases of two daily unit doses each.

12. A pharmaceutical preparation according to claim 7, comprising administering a series of consecutive daily doses arranged in standard dose estrogen phases of three daily unit doses each alternating with ultra low dose estrogen phases of three daily unit doses each.

13. A pharmaceutical preparation according to claim 7, comprising administering a series of consecutive daily doses arranged in standard dose estrogen phases of four daily unit doses each alternating with ultra low dose estrogen phases of four daily unit doses each.

14. An improved pharmaceutical preparation for administration to a female in need of estrogen and progesterone replacement therapy comprising a plurality of doses arranged in alternating standard dose estrogen phases and ultra low dose estrogen phases, each phase consisting of from at or about 1 to at or about 4 consecutive daily unit doses or an equivalent thereof, wherein the daily unit doses of the standard dose estrogen phases contain an amount of a substance exhibiting estrogenic activity, or an amount of a substance exhibiting estrogenic activity and an amount of a substance exhibiting progestogenic activity, and the daily unit doses of the ultra low dose estrogen phases contain an amount of a substance exhibiting estrogenic activity and an amount of a substance exhibiting progestogenic activity, the amount of the substance exhibiting progestogenic activity being alternately increased in the ultra low dose estrogen phases to provide daily unit doses exhibiting progestin dominant activity and decreased in the standard dose estrogen phases to provide daily unit doses exhibiting lower progestin activity relative to the ultra low dose phases, and wherein the amount of substance exhibiting estrogenic activity per unit dose in the standard dose estrogen phase exhibits an estrogen activity equivalent to from at or about 0.5 mg to at or about 5.0 mg of estradiol, and the amount of substance exhibiting estrogenic activity per unit dose in the ultra low dose estrogen phase exhibits an estrogen activity equivalent to from at or about 0.0005 mg to at or about 0.5 mg of estradiol the amount of substance exhibiting progestogenic activity per unit dose ranges from 0 to an amount which exhibits a progestin activity equivalent to at or about 300 mg of micronized progesterone.

15. A pharmaceutical preparation according to claim 14, wherein the substance exhibiting progestin activity is selected on the basis that it binds to progestin receptors, demonstrates poor affinity for androgen receptors and has a lack of affinity for sex-hormone-binding globulin.

16. A pharmaceutical preparation according to claim 14, the daily unit doses are in at least one of orally, transdermally and buccally administerable form.

17. A pharmaceutical preparation according to claim 14, wherein the substance exhibiting estrogenic activity is selected from 17α

-ethinylestradiol, esters and ethers of 17α

-ethinylestradiol, 17α

-ethinylestradiol 3-dimethylamino propionate, 17α

-ethinylestradiol 3-cyclopentyl ether (quienestrol) and 17α

-ethinylestradiol 3-methyl ether (mestranol);

natural estrogens, estrone, estrone sulfate, estrone sulfate peperazine salt, estradiol and estriol, and their esters, conjugated equine estrogens and any components thereof with estrogenic activity, as well as the synthetic estrogens, and the substance exhibiting progestogenic activity is selected from desogestrel, norgestimate, gestodene, dydrogesterone, medroxyprogesterone acetate, norethynodrel, norethinedrone, norethinedrone acetate, levonorgestrel, dl-norgestrel, cyproterone acetate, chlormadinone acetate, magestrol acetate, 17 D-acetyl norgestimate, dienogest, trimegestone, drosperinone and nomagestrel.

18-104. -104. (canceled)