Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens

• US RE36,247 E
• Filed: 10/13/1995
• Issued: 07/06/1999
• Est. Priority Date: 08/05/1983
• Status: Expired due to Term

• Current Assignee: Pre JAY Holdings Limited, WOCO Investments Limited
• Original Assignee: Pre JAY Holdings Limited, WOCO Investments Limited
• Inventors: Wolfe, Bernard M. J., Plunkett, Earl E.
• Primary Examiner(s): Henley, III, Raymond J.
• Application Number:
  US08/542,941
• Time in Patent Office: 1,362 Days
• Field of Search: 514/170
• US Class Current: 514/170
• 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

Abstract

A method of hormonally treating menopausal (including perimenopausal and post-menopausal) disorders in women, a composition, and a multi-preparation pack therefor. The administrative regimen to which the pack is particularly adapted comprises continuously and uninterruptedly administering a progestogen to a woman while cyclically administering an estrogen by using a repetitive dosage regimen. This regimen calls for administering the estrogen continuously for a period of time between about 20 and about 120 days, followed by terminating administering the estrogen for a period of time between about 3 and about 7 days. Alternatively, both the progestogen and estrogen may be administered for the full treatment period without interruption. The regimen avoids many of the problems associated with the administration of estrogen alone or with progestogen administered according to conventional regimens, and also avoids problems associated with such conventional regimens by maintaining the estrogen and progestogen at low daily dosage levels of between 0.005 mg and 2.5 mg estrogen and 0.25 mg and 30 mg progestogen.

Claims

1. A method of hormonally treating menopausal or post-menopausal disorders in a woman, comprising administering to said woman continuously and uninterrupted both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg..!.. .2. The method of claim 1 wherein said estrogen is 17 β

-estradiol and said progestogen is dl-norgestrel or laevo-norgestrel, the daily dosage level of said 17 β

-estradiol being about 1 mg, the daily dosage level of said dl-norgestrel (where present) being about 100 micrograms, and the daily dosage of said laevo-norgestrel

10. about 75 micrograms. 11. The method of claim 10 wherein the daily dosage level of said dl-norgestrel is about 75 micrograms. . .12. The method of claim 1 or 3 wherein said estrogen is a synthetic estrogen..!.. .13. The method of claim 12 wherein said synthetic estrogen is selected from the group consisting of ethinyl estradiol, mestranol and quinestranol..!.. .14. The method of claim 1 or 3 wherein said estrogen is a natural estrogen..!.. .15. The method of claim 14 wherein said natural estrogen is selected from the group consisting of conjugated equine estrogens, estradiol, estradiol-17β

estradiol valerate, estrone, piperazine estrone sulphate, estriol, estriol succinate and polyestrol phosphate..!.. .16. The method of claim 1 or 3, wherein said progestogen is selected from the group consisting of laevo-norgestrel, dl-norge, trel, norethindrone (norethisterone), norethindrone (norethisteron) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, and cyprotecone acetate..!.. .17. A pharmaceutical composition for the hormonal treatment of perimenopausal, menopausal and post-menopausal disorders in a woman, said composition being in implantable or intramuscularly injectable form and comprising, in association with a pharmaceutically acceptable barrier, sufficient progestogen and estrogen to provide dosage levels to said woman equivalent to orally administered daily dosages of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2 mg..!.. .18. The pharmaceutical composition of claim 17 in implantable form, wherein said estrogen is selected from the group consisting of estradiol, estradiol-17β

, and estradiol valerate..!.. .19. The pharmaceutical composition of claim 18 or 17 in implantable form, wherein said progestogen is selected from the group consisting of laevo-norgestrel, dl-norgestrel, norgestrienone, and norethindrone acetate..!.. .20. The pharmaceutical composition of claim 17 in injectable form, wherein said progestogen is selected from the group consisting of medroxyprogesterone acetate, norethindrone enanthate, gestronol hexanoate,

2. (where present being about 50 micrograms..!.3. A method of hormonally treating perimenopausal, menopausal or post-menopausal disorders in a woman, comprising:

A. continuously and uninterruptedly administering a progestogen to said woman in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and

B. cyclically administering an estrogen to said woman by repetitively using a dosage regimen comprising;

(i) administering said estrogen continuously for a period of time between about 20 and about 120 days in daily dosage units of estrogen equivalent to estradiol dosages of from about 0.500 mg to about 2 mg, followed by

(ii) terminating administering said estrogen for a period of time between

3. about 3 and about 7 days. 4. The method of claim 3 wherein said progestogen is selected from the following group, with respective maximum and minimum daily dosage levels as follows:

space="preserve" listing-type="tabular">______________________________________ Dosage (mg/day) Minimum Maximum______________________________________Laeve-norgestrel about 0.025 about 0.075dl-norgestrel about 0.050 about 0.150Norethindrone (norethisterone) about 0.15 about 1.0Norethindrone (norethisterone) about 0.10 about 1.0acetateEthynodiol diacetate about 0.10 about 1.0Dydrogesterone about 5 about 30Medroxyprogesterone acetate about 1 abou 15Norethynodrel about 0.203 about 5Allylestrenol about 1 about 10Lynoestrenol about 0.300 about 2Quingestanol acetate about 0.050 about 1Medrogestone about 1 about 10Norgestrienone about 0.020 about 0.200Dimethisterone about 0.500 about 15Ethisterone about 1 about 25Cyproterone acetate about 0.300 about 10.Iadd...Iaddend.______________________________________

4. 5. The method of claim 3 wherein said estrogen is selected from the following group, with respective maximum and minimum daily dosage levels as follows:

space="preserve" listing-type="tabular">______________________________________ Dosage (mg/day) Minimum Maximum______________________________________Estradiol about 0.500 about 2Estradiol-17β

about 0.500 about 2Estradiol valerate about 0.500 about 2Conjugated equine estrogens about 0.300 about 2.5Estrone about 0.300 about 2.5Piperazine estrone sulphate about 0.250 about 2.5(estropipate)Ethinyl estrodiol about 0.005 about 0.020Mestranol about 0.005 about 0.030. .Quinestranol.!. .Iadd.Quinestrol.Iaddend. about 0.005 about 0.020.Iadd...Iaddend.______________________________________

5. 6. The method of claim 5 or claim 4 wherein said estrogen is selected from the following group, with respective daily dosage levels as follows:

space="preserve" listing-type="tabular">______________________________________ Dosage (mg/day)______________________________________Estradiol about 1Estradiol-17β

about 1Estradiol valerate about 1Conjugated equine estrogens about 0.600Estrone about 0.600Piperazine estrone sulphate (estropipate) about 0.500Ethinyl estradiol about 0.010Mestranol about 0.015. .Quinestranol.!. .Iadd.Quinestrol.Iaddend. about 0.010.Iadd...Iaddend.______________________________________

6. 7. The method of claim 5 wherein said progestogen is selected from the following group, with respective daily dosage levels as follows:

space="preserve" listing-type="tabular">______________________________________ Dosage (mg/day)______________________________________Laevo-norgestrel about 0.050dl-norgestrel about 0.100Norethindrone (norethisterone) about 0.30Norethindrone (norethisterone) abour 0.30Ethynodiol diacetate about 0.30Dydrogestrone about 10Medroxyprogesterone acetate about 2.5Norethynodrel about 1Allylestrenol about 2Lynoestrenol about 0.200Quingestanol acetate about 0.200Medrogestone about 2Norgestrienone about 0.050Dimethisterone about 1Ethisterone about 2.5.Iadd...Iaddend.______________________________________

7. 8. The method of . .any of claims.!. .Iadd.claim .Iaddend.5 wherein said estrogen and said progestogen are selected from the following combination:

Estradiol/Laevo-norgestrel

Estradiol 17β

/Laevo-norgestrel

Conjugated equine estrogens/Laevo-norgestrel

Estradiol/dl-norgestrel

Estradiol 17β

/dl-norgestrel

Estradiol valerate/Laevonorgestrel

Estradiol valerate/dl-norgestrel

Conjugated equine estrogens/dl-norgestrel

Estradiol/Norethindrone (norethisteron)

Estradiol 17β

/Norethindrone (norethisterone)

Estradiol valerate/Norethindrone (norethisterone)

Conjugated equine estrogens/Norethindrone (norethisterone)

Estradiol/Norethindrone (norethisterone) acetate

Estradiol 17β

/Norethindrone (norethisterone) acetate

Estradiol valerate/Norethindrone (norethisterone) acetate

Conjugated equine estrogen/Norethindrone (norethisterone) acetate

Estradiol/Medroxyprogesterone acetate

Estradiol 17β

/Medroxyprogesterone acetate

Estradiol valerate/Medroxyprogesterone acetate

8. Conjugated equine estrogen/Medroxyprogesterone acetate. 9. The method of claim 8 wherein said estrogen is 17β

-estradiol and said progestogen

9. is dl-norgestrel or laevo-norgestrel. 10. The method of claim 9 wherein the daily dosage level of said 17β

-estradiol is between about 0.5 mg and about 2 mg, the daily dosage level of said dl-norgestrel, where present, is between about 50 and about 150 micrograms and the daily dosage level of said laevo-norgestrel, where present, is between about 25 and

11. and algestone acetophenide..!..Iadd.21. A method of hormonally treating menopausal or postmenopausal disorders in a woman to prevent or retard the demineralization of bone, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages and at dosages and a duration sufficient to effectively retard or prevent the demineralization of bone while minimizing spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.05 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg. .Iaddend..Iadd.22. A method of hormonally treating menopausal or postmenopausal disorders in a woman to prevent or retard the demineralization of bone, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages and at dosages and a duration sufficient to effectively retard or prevent the demineralization of bone while minimizing spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg, wherein the progestogen and the estrogen are combined in a single dosage form. .Iaddend..Iadd.23. A method of hormonally treating menopausal or postmenopausal disorders in a woman, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages which minimize spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.05 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 0.25 mg.

12. Iaddend..Iadd.24. A method of hormonally treating menopausal or postmenopausal disorders in a woman, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages which minimize spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg, wherein the progestogen and the estrogen are combined in a single dose form. .Iaddend..Iadd.25. The method of claim 21 or 23, wherein the progestogen and the estrogen are combined in a single dosage form. .Iaddend..Iadd.26. The method of claim 21, 22, 23, 24 or 25, wherein the estrogen consists essentially of a bone-sparing estrogen. .Iaddend..Iadd.27. The method of claim 21, 22, 23, 24 or 25, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.28. The method of claim 21 or 22, wherein the dosages and duration of treatment are effective to prevent or retard osteoporosis. .Iaddend..Iadd.29. The method of claim 21, 22, 23, 24 or 25, wherein the dosages and duration of treatment are sufficient to prevent or retard changes in blood lipids which might otherwise predispose the woman to cardiovascular disease. .Iaddend..Iadd.30. The method of claim 21, 22, 23, 24 or 25, wherein said progestogen is selected from the group consisting of laevo-norgestrel, dl-norgestrel, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, and cyproterone acetate. .Iaddend..Iadd.31. The method of claim 22 or 24, wherein said progestogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows:

space="preserve" listing-type="tabular">______________________________________ .Iadd.Dosage(mg/day) Dosage (mg/day) Minimum Maximum______________________________________Laevo-norgestrel about 0.025 about 0.075dl-norgestrel about 0.050 about 0.150Ethynodiol diacetate about 0.10 about 1.0Dydrogesterone about 5 about 30Medroxyprogesterone acetate about 1 about 15Norethynodrel about 0.200 about 5Allylestrenol about 1 about 10Lynoestrenol about 0.100 about 2Quingestanol acetate about 0.050 about 1Medrogestone about 1 about 10Norgestrienone about 0.020 about 0.200Dimethisterone about 0.500 about 15Ethisterone about 1 about 25Cyproterone acetate about 0.100 about 10..Iaddend.______________________________________

13. Iadd.32. The method of claim 21, 23, 25, wherein said progestogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows:

space="preserve" listing-type="tabular">______________________________________ .Iadd.Dosage(mg/day) Dosage (mg/day) Minimum Maximum______________________________________Laevo-norgestrel about 0.025 about 0.050dl-norgestrel about 0.050 about 0.100Ethynodiol diacetate about 0.10 about 0.30Dydrogesterone about 5 about 10Medroxyprogesterone acetate about 1 about 2.5Norethynodrel about 0.200 about 1Allylestrenol about 1 about 2Lynoestrenol about 0.100 about 0.200Quingestanol acetate about 0.050 about 0.200Medrogestone about 1 about 2Norgestrienone about 0.020 about 0.050Dimethisterone about 0.500 about 1Ethisterone about 1 about 2.5Cyproterone acetate about 0.100 about 0.500..Iaddend.______________________________________

.Iadd.33. The method of claim 21, 22, 23, 24 or 25, wherein said estrogen is selected from the group consisting of estradiol, estradiol-17β

, conjugated equine estrogens, estradiol valerate, estrone, piperazine estrone sulphate, ethinyl estradiol, mestranol, and quinestrol. .Iaddend..Iadd.34. The method of claim 33, wherein said estrogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows;

space="preserve" listing-type="tabular">______________________________________ .Iadd.Dosage(mg/day) Dosage (mg/day) Minimum Maximum______________________________________Estradiol about 0.500 about 2Estradiol-17β

about 0.500 about 2Estradiol valerate about 0.500 about 2Conjugated equine estrogens about 0.300 about 2.5Estrone about 0.300 about 2.5Piperazine estrone sulphate about 0.250 about 2.5(estropipate)Ethinyl estrodiol about 0.005 about 0.020Mestranol about 0.005 about 0.040Quinestrol about 0.005 about 0.030..Iaddend.______________________________________

.Iadd.35. The method of claim 34, wherein said estrogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows;

space="preserve" listing-type="tabular">______________________________________ .Iadd.Dosage(mg/day) Dosage (mg/day) Minimum Maximum______________________________________Estradiol about 0.500 about 1Estradiol-17β

about 0.500 about 1Estradiol valerate about 0.500 about 1Conjugated equine estrogens about 0.300 about 0.600Estrone about 0.300 about 0.600Piperazine estrone sulphate about 0.250 about 0.500(estropipate)Ethinyl estrodiol about 0.005 about 0.010Mestranol about 0.005 about 0.015Quinestrol about 0.005 about 0.010..Iaddend.tz,1/32

14. Iadd.36. The method of claim 30, 31, 32, 33, 34 or 35, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.37. The method of claim 21, 23 or 25, wherein the progestogen is medroxyprogesterone acetate in an amount of from about 1 mg to about 2.5 mg. .Iaddend..Iadd.38. The method of claim 21, 22, 23, 24 or 25, wherein the estrogen is conjugated equine estrogens in an amount of from about 0.300 mg to about 2.5 mg. .Iaddend..Iadd.39. The method of claim 21, 23 or 25, wherein the progestogen is medroxyprogesterone acetate in an amount of from about 1 mg to about 2.5 mg, and the estrogen is conjugated equine estrogens in an amount of from about 0.300 mg to about 2.5 mg. .Iadd.40. The method of claim 39, wherein the estrogen is conjugated equine estrogens in an amount of from about 0.300 to about 0.600. .Iaddend..Iadd.41. The method of claim 39, wherein the progestogen is medroxyprogesterone acetate in an amount of about 2.5 mg and the estrogen is conjugated equine estrogens in an amount of about 0.600 mg. .Iaddend..Iadd.42. The method of claim 39, wherein the progestogen is medroxyprogesterone acetate in an amount of about 2.5 mg and the estrogen is conjugated equine estrogens in an amount of about 0.300 mg. .Iaddend..Iadd.43. The method of claim 37, 38, 39, 40, 41 or 42, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.44. The method of claim 37, 38, 39, 40, 41 or 42, wherein the dosages and duration of treatment are sufficient to prevent or retard changes in blood lipids which might otherwise predispose the woman to cardiovascular disease. .Iaddend..Iadd.45. The method of claim 21, 23 or 25, wherein said progestogen is norethindrone (norethisterone) acetate in an amount of from about 0.10 mg to about 0.20 mg. .Iaddend..Iadd.46. The method of claim 21, 22, 23, 24 or 25, wherein said estrogen is selected from the group consisting of estradiol, estradiol 17-β

, or estradiol valerate and is in an amount of from about 0.500 to about 1 mg. .Iaddend..Iadd.47. The method of claims 22 or 24, wherein the estrogen is estradiol-17β

administered in fixed daily dosages of between about 0.500 and about 1 mg and the progestogen is norethindrone acetate. .Iaddend..Iadd.48. The method of claim 47, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.49. The method of claim 47, wherein the dosages and duration of treatment are sufficient to prevent or retard changes in blood lipids which might otherwise predispose the woman to cardiovascular disease. .Iaddend..Iadd.50. The method of claim 21, 23, 25 or 27, wherein said estrogen is piperazine estrone sulphate (estropipate). .Iaddend..Iadd.51. The method of claim 21, 23, 25 or 27, wherein said estrogen is 17β

-estradiol and said progestogen is dl-norgestrel or laevo-norgestrel, the daily dosage level of said 17β

-estradiol being about 1 mg, the daily dosage level of said dl-norgestrel (where present) being about 100 micrograms, and the daily dosage of said laevo-norgestrel (where present) being about 50 micrograms. .Iaddend..Iadd.52. The method of claim 21, 22, 23, 24 or 25 wherein the selected dosages are the minimum effective quantities of progestogen and estrogen. .Iaddend..Iadd.53. The method of claim 21 or 23, wherein said daily dosages of progestogen and estrogen are administered once daily. .Iaddend..Iadd.54. The method of claim 22, 24 or 25, wherein said single dosage form is a tablet. .Iaddend..Iadd.55. The method of claim 21, 22, 23 or 24, wherein said progestogen is in micronized form. .Iaddend..Iadd.56. The method of claim 21, 22, 23 or 24, wherein said estrogen is a synthetic estrogen. .Iaddend..Iadd.57. The method of claim 21, 22, 23 or 24, wherein the estrogen is a natural estrogen. .Iaddend.