U.S. patent number RE36,247 [Application Number 08/542,941] was granted by the patent office on 1999-07-06 for method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens.
This patent grant is currently assigned to Pre JAY Holdings, Limited, WOCO Investments, Ltd.. Invention is credited to Earl E. Plunkett, Bernard M. J. Wolfe.
United States Patent |
RE36,247 |
Plunkett , et al. |
July 6, 1999 |
Method of hormonal treatment for menopausal or post-menopausal
disorders involving continuous administration of progestogens and
estrogens
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.
Inventors: |
Plunkett; Earl E. (London,
CA), Wolfe; Bernard M. J. (London, CA) |
Assignee: |
WOCO Investments, Ltd.
(CA)
Pre JAY Holdings, Limited (CA)
|
Family
ID: |
27060286 |
Appl.
No.: |
08/542,941 |
Filed: |
October 13, 1995 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
520834 |
Aug 5, 1983 |
|
|
|
Reissue of: |
635236 |
Jul 24, 1984 |
04826831 |
May 2, 1989 |
|
|
Current U.S.
Class: |
514/170 |
Current CPC
Class: |
A61K
31/57 (20130101); A61K 31/565 (20130101) |
Current International
Class: |
A61K
31/565 (20060101); A61K 31/57 (20060101); A61K
031/56 () |
Field of
Search: |
;514/170 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
OS 2645307 |
|
0000 |
|
DE |
|
1578340 |
|
Nov 1980 |
|
GB |
|
2096462 |
|
Oct 1982 |
|
GB |
|
Other References
Acta Obstet. Gynecol. Sand., 59, 327-329 (1980) [Mugglestone].
.
Abstract--Paper delivered by Dr. Magos to the 23rd British Congress
on the Menopause, Royal College of Obstetrics and Gynecology,
Birmingham, Jul. 1983 [Magos]. .
1984 Physicians' Desk Reference (PDR) pp. 222, 545, 658, 1205, 1513
and 2044. .
Maturitas, 3, 145-156 (1981) [Staland]. .
English translation of Plunkett's Oct. 28, 1993 reply in an
opposition proceeding in the Danish patent application [Danish
Patent Application No. 3770/84 (165,390)] equivalent to Plunkett.
.
FASS, 459 (Mar. 1984) (Pharmaceutical Specialties in Sweden)
[Sweden]. .
English translation of, FASS, 459 (Mar. 1984) (Pharmaceutical
Specialities in Sweden) [Sweden], item (A). .
Minerva Ginecologica, 21(4), 193-7 (1969) [GOISIS]. .
English translation of Minerva Ginecologica, 21(4), 193-7 (1969)
[GOISIS], item (C). .
Aust. N. Z. J. Obstet. Gynaec., 23, 43 (1983) [Smith]. .
Report from Workshop, 157-165 (Aug. 1982)--Socialstyrelsens
komitte' for lakemedelsinformation, workshop, Menopaus
Substitutionsbehandling med ostrogen, Aug. 30-31, 1982 (published
Jan. 1983) [Workshop report]. .
English translation of, Report from Workshop, 157-165 (Aug.
1982)--Socialstyrelsens komitte' for lakemedelsinformation,
workshop, Menopaus Substitutionsbehandling med ostrogen, Aug.
30-31, 1982 (published Jan. 1983) [Workshop Report], item (F).
.
Novo Nordisk's Supplementary Opposition Statement filed Jul. 16,
1997 in Danish Patent Application No. 3770/84. .
English translation of, Novo Nordisk's Supplementary Opposition
Statement filed Jul. 16, 1997 in Danish Patent Application No.
3770/84, item (H). .
Applicants' Agents' Request for Revival and Comments filed Nov. 15,
1996 in Danish Patent Application No. 3770/84 (165,390). .
English translation of, Applicants' Agents' Request for Revival and
Comments filed Nov. 15, 1996, item (J). .
Declaration of Dr. Adam L. Magos signed Jun. 5, 1997. .
Declaration of Ms. Caroline B. Roney signed June. 10, 1997. .
Mugglestone et al., "Combined Estrogen and Progestogen For The
Menopause", Acta Obstet. Gynecol. Scand. 59:327-329, 1980. .
Magos et al., 23rd British Congress, Royal College of Obstetrics
and Gynecology, Birmingham, p. 156, Jul. 1993. .
Chemical Abstracts, vol. 83, No. 9, Sep. 1, 1975, p. 142, Abstract
No. 725288. .
Novo Industri AB, "Kliogest.RTM.: Ostrogenpreparat med
gestagentillsats" Mar. 1984 (Translation provided). .
Eiken, P., N. Kolthoff and S. Pors Nielsen, "Ten Years Effects of
Hormonal Replacement Therapy On Bone Mineral Content in
Post-Menopausal Women," Department of Clinical Physiology, Hillerod
Hospital, DK-3400 Hillerod, Denmark (1996). .
Eiken, P., N. Kolthoff, S. Pors Nielsen and O. Barenholdt, "Eight
Years Effects of Hormonal Replacement Therapy on Mineral Content in
Post-Menopausal Women," Department of Clinical Physiology and
Nuclear Medicine, Hillerod Sygebus, Helsevej 2, DK-3400 Hillerod
(1995). .
Eiken, P. and N. Kolthoff, "Compliance with long-term oral hormonal
replacement therapy," Maturitas, vol. 22: 97-103, Sep. 1995. .
Goisis M. "Treatment of Pre-climacteric and Climacteric introducing
a New Estrogen-progestin Association" Minerva Ginecologica, 21
pages 193-197 (1969). .
Lakartidningen, vol. 81, No. 12, Mar. 21, 1984 (translation
provided). .
Madsen V., Postmenopausal Estrogen Treatment, Manedsskrift for
Praktisk Laegegering, vol. 45 (8) 1967 (translation provided).
.
Magos AL, et al "Amenorrhea and Endometrial Atrophy with Continuous
Oral Estrogen and Progestogen Therapy in Post-Menopausal Women",
Obstet. gynecol 65:496 (1985). .
Maschak CA, et al "Comparison of pharmaceodynamic properties of
various estrogen formulations", Am. J. Obstet. Gynecol. 144:51
(1982). .
Smith M, et al, "A Double-Blind Trial of Ethinyloestradio and
Norethisterone Separately and Together, in Menopausal Women", Aust.
N.Z. J. Obstet. Gynaec. 23: 43 (1983). .
Workshop, Menopause, Substitutional Treatment with Estrogen,
Socialstyrelsens Kommittee for lakemedelsinformation, 1983
(translation provided). .
Mann JI, Vessey MP, Thorogood M, Doll R, Myocardial infarction in
young women with special reference to oral contraceptive practice,
Brit Med J 1975;2:241-245. .
Mattsson L-.ANG., Samsioe G, Estrogen-progestogen replacement in
climacteric women, particularly as regards a new type of continuous
regimen, Acta Obstet Gynecol Scand Suppl 1985;130:53-58. .
Plunkett ER, Contraceptive steroids, age, and the cardiovascular
system, Am J Obstet Gynecol 1982;142:747-751. .
Stolley PD, Tonascia JA, Tockman MS, et al, Thrombosis with
low-estrogen oral contraceptives, Am J Epidemiol 1975;102:197-208.
.
Silfverstolpe G, Gustafson A, Samsioe G, Svanborg A, Lipid
metabolic studies in oophorectomized women: effects induced by two
different estrogens on serum lipids and lipoproteins, Gynecol
obstet Invest 1980;11:161-169. .
Tietze C, Lewit S, Life risks associated with reversible methods of
fertility regulation, Int J Gynaecol Obstet 1979;16:456-459. .
Heiss G, Tamir I, Davis CE, et al., Lipoprotein-cholesterol
distributions in selected North American population: The Lipid
Research Clinics Program Prevalence Study, Circulation,
1980;61:302-315. .
Hiryonen E, Malkonen M, Mannien V, Effects of different
progestogens on lipoproteins during postmenopausal replacement
therapy, N Engl J Med, 1081;304:560-563 (1981). .
Kay CR, The happiness pill? J Roy Coll Gen Pract, 1980;30:8-19.
.
Khoo SK, Hacker N, Chang A, An incremental-dose combined
oestrogen-progestogen oral contraceptive: effects on body weight,
blood pressure, and biochemical parameters, Aust N Z J Obstet
Gynaec, 1980;20:1712-176. .
Larsson-Cohn U, Fahraeus L, Wallentin L, Zador G, Lipoprotein
changes may be minimized by proper composition of a combined oral
contraceptive, Fertil Steril, 1981;35:172-179. .
Mann JI, Inman WHW, Oral contraceptives and death from myocardial
infarction, Brit Med J, 1975;2:245-248. .
Staland B, Continuous Treatment with Natural Oestrogens and
Progestogens, A Method to Avoid Endometrial Stimulation, Maturitas
1981;3:145-156. .
Mattsson L-.ANG., Callberg G, Samsioe G, Evaluation of a Continuous
oestrogen-progestogen regimen for climacteric complaints, Maturitas
1982;4:95-102. .
Bloch B., The effect of cyclical administration of levonorgestrel
and ethinyloestradiol on blood pressure, body mass, blood glucose
and serum triglycerides, S Afr Med J 1979;56:568-570. .
Boston Collaborative Drug Surveillance Program, Boston University
Medical Center, Surgically confirmed gallbladder disease, venous
thromboembolism and breast tumors in relation to postmenopausal
estrogen therapy, N Engl J Med 1974;290:15-19 .
Collaborative Group for the Study of Stroke in Young Men, Oral
contraception and increased risk of cerebral ischemia or
thrombosis, N Engl J Med 1973;288:871-878. .
Gambrell RD Jr, Maier RC, Sanders BI, Decreased incidence of breast
cancer in postmenopausal estrogen-progestogen users, Obstet Gynecol
1983;62:435-443. .
Gambrell RD Jr, Bagnell CA, Greenblatt RB, Role of estrogens and
progesterone in the etiology and prevention of endometrial cancer:
review, Am J Obstet Gynecol 1983;146:696-707. .
Gordon T, Castelli WP, Hjortland MC, Kannel WB, The prediction of
coronary heart disease by high-density and other lipoproteins: an
historical perspective, In:Rifkind BM, (1977). .
Archer, D.F. et al., Bleeding Patterns in Postmenopausal Women
Taking Continuous Combined or Sequential Regimens of Conjugated
Estrogens With Medroxyprogesterone Acetate, Obstet. Gynecol., Vo.
83, No. 5, pp. 686-692 (May 1994) (E14). .
Bewtra, Chhanda et al., Endometrial Histology and Bleeding Patterns
in Menopausal Women Treated With Estrogen and Continuous Cyclic
Progestin, J. Reproductive Med., vol. 33, No. 2, pp. 205-208 (Feb.
1988) (E10). .
Brosens, I.A. et al., Assessment of Incremental Dosage Regimen of
Combined Estrogen-Progestogen Oral Contraceptives, Br. Med. J.,
vol. 4(5945), pp. 643-645 (1974) (P56). .
Christiansen, C.et al., Does Oestriol Add to the Beneficial Effect
of Combined Hormonal Prophylaxis Against Early Postmenopausal
Osteoporosis, Brit. J. Obstet. Gynaecol., vol. 91, pp. 489-493 (May
1984) (P45). .
Clark, James H. et al., Nuclear Binding and Retention of the
Receptor Estrogen Complex: Relation to the Agnostic and
Antagonistic Properties of Estriol, Endo, vol. 1, No. 1, pp. 91-96
(1977) (P27). .
Clisham, P. Ronald et al., Comparison of Continuous Versus
Sequential Estrogen and Progestin Therapy in Postmenopausal Women,
Obstet. Gynecol., vol. 77, No. 2, pp. 241-242 (Feb. 1991) (E9).
.
Dennerstein, Lorraine et al., Menopausal Hot Flushes: A Double
Blind Comparison of Placebo, Ethinyl Oestradiol and Norgestrel,
Brit.J. Obstet. Gynecol., vol. 85, pp. 852-856 (Nov. 1978) (P31).
.
Dennerstein, Lorraine et al, Hormone Therapy and Affect, Maturitas,
vol. 1, pp. 247-259 (1979) (P31a). .
Dennerstein, Lorraine et al., Plasma Levels of Ethinyl Oestradiol
and Norgestrel During Hormone Replacement Therapy, Maturitas, vol.
2, pp. 147-154 (1980) (P32). .
Dickey, Richard P. & Stone, Sergio C., Progestational Potency
of Oral Contraceptives, Obstet. Gynecol., vol. 47, No. 1, pp.
106-112 (Jan. 1976) (P9). .
Dickey, Richard P., Reply to Paper by Dr. Edgren on "Progestational
Potency of Oral Contraceptives: a Polemic", Int. J. Fertil., vol.
23(3), pp. 170-174 (1978) (P11). .
Edgren, Richard A., Progestational Potency of Oral Contraceptives:
a Polemic, Int. J. Fertil., vol. 23(3), pp. 162-169 (1978) (P10).
.
Eizemann, U et al., Abstract: Continuous Treatment of Menopausal
Symptoms with an Estrogen/Progestogen Combinations. Results of a
Multicenter Trial, J. Steroid. Biochem., vol. 17, No. 3, 1982, p.
306 (6th International Congress on Hormonal Steroids, Jerusalem,
Israel, Sep. 5-10, 1982) (P36). .
Englund, D.E. & Johansson, E.D.B., Endometrial Effect of Oral
Estriol Treatment in Postmenopausal Women, Acta Obstet. Gynecol.
Scand, vol. 59, pp. 449-451 (1980) (P26). .
Hammond, Charles B. et al., Effects of Long Term Estrogen
Replacement Therapy, Am. J. Obstet. Gynecol, vol. 133, No. 5, pp.
537-547 (Mar. 1, 1979) (P17). .
Hellberg, D. & Nilsson, S., Comparison of Triphasic
Oestradiol/Norethisterone Acetate Preparation With and Without
Oestriol Component in the Treatment of Climacteric Complaints,
Maturitas, Vol 5, pp. 233-243 (1984) (P44). .
Hillard, T.C. et al., Continuous Combined Conjugated Equine
Estrogen-Progestogen Therapy: Effects of Medroxyprogesterone
Acetate and Norethindrone Acetate on Bleeding Patterns and
Endometrial Histologic Diagnosis, Am J. Obstet. Gynecol., vol. 167,
No. 1, pp. 1-7 (Jul. 1992) (E8). .
Johansson, Elof D.B., Ostrogena Och Gestagena Substansers Effekter
Pa Tumorer I Reproduktionsorganen (The Effects of Estrogenic and
Gestagenic Substances on Tumours in the Reproductory Organs),
Report from Workshop: Menopaus, pp. 129-141 (1982) [with
translation] (Part of P2). .
Johansson, Elof D.B., Nagra Utvecklingslinjer Kring
Substitutions-Behandling Efter Menopaus (A few Courses of
Development for the Substitution Treatment After Menopause), Report
from Workshop: Menopaus, pp. 157-164 (1982) [with translation]
(Part of P2). .
King, Roger J.B. & Whitehead, Malcom I., Assessment of the
Potency of Orally Administered Progestins in Women, Fertility &
Sterility, vol. 48, No. 6, pp. 1062-1066 (Dec. 1986) (E19). .
Lacey, R.W. et al., Safety of Progestins: Effects of Dydrogesterone
on Blood Lipids, Br. J. Clin. Pract. Suppl. 24, pp. 4-10 (1983)
(P23). .
Levrant, Seth G. & Barnes, Randall B., Pharmacology of
Estrogens, in Treatment of Postmenopausal Women: Basic and Clinical
Aspects, ch. 6, pp. 57-67 (Rogerio A. Lobo ed., 1994) (E27). .
Lillienberg, L. et al., Effect of a Sequential Oestrogen-Progestin
Therapy on the Plasma Level of Oestrogens and Lipids in
Post-Menopausal Women, Acta Endocrinologica, vol. 92, pp. 319-329
(1979) (P21). .
Luciano, Anthony Adolph et al., Clinical and Metabolic Responses of
Menopausal Women to Sequential Versus Continuous Estrogen and
Progestin Replacement Therapy, Obstet. Gynecol., vol. 71, No. 1,
pp. 39-43 (Jan. 1988) (E11). .
Luciano, Anthony A. et al., Evaluation of Low-Dose Estrogen and
Progestin Therapy in Postmenopausal Women, J. Reproductive Med.,
vol. 38, No. 3, pp. 207-214 (Mar. 1993) (E7). .
Magos, A.L., Endometrial and Menopausal Response to Continuous
Oestrogen Progestogen Therapy in Post-Menopausal Women, Summary of
Paper to be Presented at Advances in the Management of Menopause
Symposium on Friday, 9th Dec., 1983 (P28). .
Mattsson, L.-A. et al., Effects of a Continuous
Estrogen-Progestogen Therapy for Climacteric Symptoms on
Circulating Sex Steroids and Gonadotrophins, Arch. Gynecol., vol.
233, pp. 101-107 (1983) (P41). .
Merck, pp. CI278, CI102, 454, 3648-49, 3654-55 (1983) (P34). .
Merck, p. 493 (1989) (E23). .
Nand, S.L. et al., Continuous Combined Piperazine Oestrone Sulphate
and Medroxyprogesterone Acetate Hormone Replacement Therapy--A
Study of Bleeding Pattern, Endometrial Response, Serum Lipid and
Bone Density Changes, Aust. and N.Z. J. Obstet. Gynaecol., pp.
92-96 (1995) (E6). .
Neumann, Von F. et al., Probleme der Dosisfindung: Sexualhormone,
Drug. Res., pp. 296-318 (1977) (P20). .
Neumann, F., The physiological Action of Progesterone and the
Pharmacological Effects of Progestogens--a Short Review,
Postgraduate Med. J., vol. 54 (Suppl. 2), pp. 11-24 (1978) (P48).
.
Notelovitz, Morris et al., Oestrogen-Progestin Therapy and the
Lipid Balance of Post-Menopausal Women, Maturitas, vol. 4, pp.
301-308 (1982) (P47). .
Notelovitz, Morris et al., Combination Estrogen and Progestogen
Replacement Therapy Does Not Adversely Affect Coagulation, Obstet.
Gynecol., vol. 62, No. 5, pp. 596-600 (Nov. 1983) (P46). .
Padwick, M.L. et al., Oestriol With Oestradiol Versus Oestradiol
Alone: A Comparison of Endometrial, Symptomatic and Psychological
Effects, British J. Obstet. Gynaecol., vol. 93, pp. 606-612 (Jun.
1986) (E28). .
Physicians' Desk Reference 38th Ed., pp. 424, 1487-1495 (1984)
(P29). .
Rozenbaum, H., Progestatifs de Synthese et Metabolisme Lipidique,
Contraception-Fertilite-Sexualite, Supp. vol. 12, No. 1, pp.
173-180 (1984) (P22). .
Sipinen, S., Plasm Oestrone, Oestradiol and Gonadotrophin
Concentrations in Postmenopausal Patients Treated With Oestradiol
or With a Combination of Oestradiol and Oestriol, Annals of
Clinical Research, vol. 11, pp. 172-178 (1979) (P3). .
Sipinen, Seppo et al., Silastic Implants Releasing Estrone in the
Treatment of Climacteric Complaints, Maturitas, vol. 2, pp. 213-224
(1980) (P35). .
Socialstyrelsens Kommittee for Lakemedelsinformation (Health Board
Committee on Medical Information), Menopaus, Substitutional
Treatment with Estrogen, Workshop, Aug. 30-31, 1982, pp. 27, 30
(published 1983) [with translation] (Part of P2). .
Socialstyrelsens Kommittee for Lakemedelsinformation (Health Board
Committee on Medical Information), Menopaus, Substitutional
Treatment with Estrogen, Workshop, Aug. 30-31, 1982, pp. 121, 161,
167-168 (published 1983) [with translation] (Part of P2). .
Sporrong, T. et al., Comparison of Four Continuously Administered
Progestogen Plus Oestradiol Combinations for Climacteric
Complaints, British J. Obstet. Gynaecol., vol. 95, pp. 1042-1048
(Oct. 1988) (E12). .
Staland, B., Continuous Treatment With a Combination of Estrogen
and Gestagen--A way of Avoiding Endometrial Stimulation, Acta
Obstet Gynecol Scand Suppl 130, pp. 29-35 (1985) (E29). .
Staland, B., Treatment of Menopausal Oestrogen Deficiency Symptoms
in Hysterectomised Women by Means of 17.beta.-Oestradiol Pellet
Implants, Acta. Obstet. Gynecol. Scand., vol. 57, pp. 281-285
(1978) (P18). .
Stanczyk, Frank Z., Structure-Function Relationships, Potency, and
Pharmacokinetics of Progestogens, in Treatment of Postmenopausal
Women: Basic and Clinical Aspects, ch. 7, pp. 69-89 (Rogerio A.
Lobo ed., 1994) (E26). .
Sturdee, D.W. et al., Relations Between Bleeding Pattern,
Endometrial Histology, and Oestrogen Treatment in Menopausal Women,
Brit. Med. J., pp. 1575-1577 (Jun. 17, 1978) (P38). .
Swyer, G.I.M., Potency of Progestogens in Oral
Contraceptives--Further Delay of Menses Data, Contraception, vol.
26, No. 1, pp. 23-27 (Jul. 1982) (P19). .
Swyer, G.I.M., Determination of Progestational Potency: A Review,
J. Roy. Soc. Med., vol. 77, pp. 406-409 (1984) (P59). .
Tausk, Marius, Pharmakologie der Hormone, pp. 83-87, 122-123 (1979)
(P25). .
Upton, Virginia G., Therapeutic Considerations in the Management fo
Climacteric: A Critical Analysis of Prevalent Treatments, J.
Reprod. Med., vol. 29, No. 2, pp. 71-80 (Feb. 1984) (P16). .
Whitehead, M.I. et al., The Effects of Cyclical Oestrogen Therapy
and Sequential Oestrogen/Progestogen Therapy on the Endometrium of
Post-Menopausal Women, Acta Obstet. Gynecol. Scand, Suppl. 65, pp.
91-101 (1977) (P49). .
Whitehead, M.I. & Campbell, S., Endometrial Histology, Uterine
Bleeding and Oestrogen Levels in Menopausal Women Receiving
Oestrogen Therapy and Oestrogen/Progestogen Therapy, Proceedings on
the 2nd Int'l Meeting on Endometrial Cancer and Related Topics, pp.
65-80 (1978) (P50). .
Whitehead, M.I. et al., Effects of Estrogens and Progestins on the
Biochemistry and Morphology of the Postmenopausal Endometrium, New
Eng. J. Med., vol. 305, No. 27, pp. 1599-1605 (Dec. 31, 1981)
(P40). .
Whitehead, M.I. et al., Actions of Progestins on the Morphology and
Biochemistry of the Endometrium of Postmenopausal Women Receiving
Low-Dose Estrogen Therapy, Am. J. Obstet. Gynecol., pp. 791-795
(Mar. 15, 1982) (P4). .
Roger J.B. King, Aug. 29, 1995 (E25). .
Curt Rune, Sep. 24, 1997 (E1 & E17). .
Birgit Kronqvist, Sep. 17, 1997 (with translation) (E2). .
Ruth Skoog, Feb. 3, 1997 (with translation) (E3). .
Malcom Ian Whitehead, Oct. 15, 1997 (E22). .
David W. Sturdee, Nov. 10, 1997 (E30). .
Ove Heide-Jorgensen, Feb. 8, 1998 (with translation) (E31). .
Ib Windfeld, Feb. 4, 1998 (with translation) (E32). .
Bertil Staland, Nov. 24, 1997 (E33). .
DUPHAR International Research B.V., Notice of Opposition to a
European Patent, Oct. 21, 1997 (Party No. 04). .
Novartis AG, Notice of Opposition to a European Patent, Oct. 20,
1997 (Party No. 03). .
Novo Nordisk A/S, Notice of Opposition to a European Patent, Oct.
14, 1997 (Party No. 01). .
Novo Nordisk A/S, Supplemental Notice of Opposition to a European
Patent, Oct. 15, 1997 (Party No. 01). .
Novo Nordisk A/S, Supplemental Notice of Opposition to a European
Patent, Nov. 18, 1997 (Party No. 01). .
Novo Nordisk A/S, Supplemental Notice of Opposition to a European
Patent, Feb. 25, 1998 (Party No. 01). .
Orion Pharma, Notice of Opposition to a European Patent, Oct. 22,
1997 (Party No. 10). .
Ortho Pharmaceutical Corporation, Notice of Opposition to a
European Patent, Oct. 22, 1997 (Party No. 07). .
Pharmacia & Upjohn, Notice of Opposition to a European Patent,
Oct. 21, 1997 (Party No. 06). .
The Procter & Gamble Company, Notice of Opposition to a
European Patent, Oct. 21, 1997 (Party No. 05). .
R.P. Scherer Limited, Notice of Opposition to a European Patent,
Oct. 17, 1997 (Party No. 02). .
Schering AG, Notice of Opposition to a European Patent, Oct. 22,
1997 (Party No. 09). .
Shire Pharmaceutical Contracts Limited, Notice of Opposition to a
European Patent, Oct. 22, 1997 (Party No. 08). .
Warner-Lambert Company, Notice of Opposition to a European Patent,
Oct. 22, 1997 (Party No. 11). .
Goretzlehner G. et al., Treatment of Menopausal Syndrome, Med.
Akt., 8:418-419 (1982) (with English translation). .
Kaiser, R., Hormonale Behandlung von Zyklusstorungen, 4th rev., p.
115 (1970). .
McKay-Hart, D., A Comparative Trial of Kliogest With and Without
Oestriol for the Prevention of Vasomotor Symptoms, Adverse Lipid
Profile Changes and Oestoporosis in Postmenopausal Women (Dec. 15,
1993). .
McKay-Hart, D., A Comparative Trial of Kliogest With and Without
Oestriol Versus Cyclical Hormone Replacement Therapy in Treatment
on Postmenopausal Women (Dec. 15, 1993). .
Nishimo, Y. and Neumann, F., Sialic Acid Content in Mouse Female
Reproductive Organs as a Quantitative Parameter for Testing the
Estrogenicand Antiestrogenic Depot Effect, and Dissociated Effect
of Estrogens on the Uterus and Vagina, Acta Endocrinologica
(Copenhagen) Suppl., vol. 76 (187), p. 62 (1974) (Abstract). .
Paterson, M.E.L. et al., Endometrial Disease After Treatment with
Oestrogens and Progestogens in the Climacteric, Br. Med. J. vol.
280 (6217), pp. 822-824 (Mar. 22, 1980). .
Physicians' Desk Reference 37th Ed., pp. 118, 405, 645-649 (1983).
.
Socialstyrelsens Kommittee for Lakemedelsinformation (Health Board
Committee on Medical Information), Menopaus, Substitutional
Treatment with Estrogen, Workshop, Aug. 30-31, 1982, pp. 1-164, 166
(published 1983). .
Staland, B., Treatment of Climacteric Symptoms by Natural
Oestrogens Without Stimulation of the Endometrium, Cancer Treatment
Reports, vol. 63, No. 7, Abstr. No. 389 (Jul. 1979). .
Whitehead, M.I., The Effects of Estrogens and Progestogens on the
Postmenopausal Endometrium, Maturitas, vol. 1, No. 2, pp. 87-98
(1978) (Abstract). .
Ylostalo, Perra et al., Serum Bile Acids and Lipids During
Treatment of Climacteric Symptoms with Natural Estrogen-Progestin
Combinations, Maturitas, vol. 3, No. 1, pp. 21-24 (1981). .
SDM, Swedish Drug Market, I/1984 and II/1984. .
Merck, p. 360 (1968). .
Unlisted Drugs, vol. 22, No. 10, Oct. 1970, p. 149; Chatham, New
Jersey, US; p. 149e: "Cyclo-Progynova". .
Unlisted Drugs, vol. 25, No. 10, Oct. 1973, p. 160; Chatham, New
Jersey, US; p. 160a: "Microgvnon". .
Unlisted Drugs, vol. 26, No. 11, Nov. 1974, p. 170; Chatham, New
Jersey, US; p. 170b: "WL-20". .
Unlisted Drugs, vol. 27, No. 8, Aug. 1975, p. 130; Chatham, New
Jersey, US; p. 130g: "Nordiol". .
Unlisted Drugs, vol. 28, No. 2, Feb. 1976, p. 20; Chatham, New
Jersey, US; p. 26j: "Minidrill". .
Unlisted Drugs, vol. 29, No. 3, Mar. 1977, p. 41; Chatham, New
Jersey, US; p. 41g: "Adepal". .
Obstetrics and Gyneocology, 63(6), 759-763 (Jun. 1984)..
|
Primary Examiner: Henley, III; Raymond J.
Attorney, Agent or Firm: Pillsbury Madison & Sutro
LLP
Parent Case Text
This is a continuation-in-part of U.S. Ser. No. 520,834, filed Aug.
5, 1983, now abandoned.
Claims
We claim: .[.
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
.beta.-estradiol and said progestogen is dl-norgestrel or
laevo-norgestrel, the daily dosage level of said 17
.beta.-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..].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
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:
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:
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:
7. The method of claim 5 wherein said progestogen is selected from
the following group, with respective daily dosage levels as
follows:
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 17.beta./Laevo-norgestrel
Conjugated equine estrogens/Laevo-norgestrel
Estradiol/dl-norgestrel
Estradiol 17.beta./dl-norgestrel
Estradiol valerate/Laevonorgestrel
Estradiol valerate/dl-norgestrel
Conjugated equine estrogens/dl-norgestrel
Estradiol/Norethindrone (norethisteron)
Estradiol 17.beta./Norethindrone (norethisterone)
Estradiol valerate/Norethindrone (norethisterone)
Conjugated equine estrogens/Norethindrone (norethisterone)
Estradiol/Norethindrone (norethisterone) acetate
Estradiol 17.beta./Norethindrone (norethisterone) acetate
Estradiol valerate/Norethindrone (norethisterone) acetate
Conjugated equine estrogen/Norethindrone (norethisterone)
acetate
Estradiol/Medroxyprogesterone acetate
Estradiol 17.beta./Medroxyprogesterone acetate
Estradiol valerate/Medroxyprogesterone acetate
Conjugated equine estrogen/Medroxyprogesterone acetate. 9. The
method of claim 8 wherein said estrogen is 17.beta.-estradiol and
said progestogen
is dl-norgestrel or laevo-norgestrel. 10. The method of claim 9
wherein the daily dosage level of said 17.beta.-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
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-17.beta. 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-17.beta., 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,
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.
.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:
.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:
.Iadd.33. The method of claim 21, 22, 23, 24 or 25, wherein said
estrogen is selected from the group consisting of estradiol,
estradiol-17.beta., 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:
.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:
.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-.beta., 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-17.beta. 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 17.beta.-estradiol and said progestogen is
dl-norgestrel or laevo-norgestrel, the daily dosage level of said
17.beta.-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.
Description
This invention relates to a method of hormonal treatment for
menopausal (including perimenopausal and post-menopausal) disorders
in women, and particularly to a treatment involving the continuous
administration of a progestogen in conjunction with an estrogen.
The invention further relates to a pharmaceutical composition
comprising selected dosage units of progestogen and estrogen. In
another aspect, the invention is concerned with a regimen
comprising the continuous administration of progestogen in
conjunction with the cyclical administration of estrogen and to a
multi-preparation pack containing selected dosage units of
progestogen and estrogen and particularly adapted to such
regimen.
Perimenopausal (i.e. over approximately forty years of age),
menopausal and post-menopausal women frequently experience a large
variety of conditions and disorders which have been attributed to
estrogen deprivation due to ovarian failure. The duration of these
disorders can be extremely variable, and include hot flushes which
can be devastating in some women and very mild in others. Dryness
of the vagina associated with susceptibility to minor infections,
and frequently associated with discomfort during intercourse, is
another symptom which may be directly related to the decrease is
estrogen availability.
In a long-term sense, one of the most health-threatening aspects of
the menopause is the loss of mineral from bone (osteoporosis) which
produces a decrease in bone mass and generates a serious risk of
fractures. For example, evidence exists that there is a six-fold
increase in fractures in post-menopausal women as opposed to men of
the same age (Garraway et al, Mayo Clinic Proceedings, 54, 701-707,
1979). These fractures, of course, carry a high complication rate
among older people, a marked increase in disability and general
morbidity, and certainly an increased risk of mortality.
Another serious health-threatening aspect of the menopause the
impressive loss of protection against heart attacks which is
enjoyed by younger women up to the age of 60, when compared to men
of the same age. The steep increase in mean serum cholesterol
concentration which occurs around the menopause (during the fourth
and fifth decades) may contribute importantly to the progressive
increase in death from ischemic heart disease in older women. In
the eighth and ninth decades, the incidence of deaths from ischemic
heart disease, approaches that of men (Havlik, R.J. and
Manning-Feinleid, P.H. 1979, NIH Publication No. 79-1610, U.S.
Department of HEW).
In addition to the above-mentioned major physical problems, some
women experience a larger variety of other symptoms ranging from
depression, isomnia, and nervousness, to symptoms of arthritis and
so forth.
It is generally agreed that estrogen is the most effective agent
for the control or prevention of menopausal flushes and vaginal
atrophy. It is effective in retarding or preventing the appearance
of clinical evidence of osteoporosis. In appropriate doses, when
combined with dl-norgestrel (or laevo-norgestrel), a favourable
effect upon blood lipids is also seen. Problems with estrogen
therapy do exist, however, and have been widely explored and
documented in the medical literature. The means by which estrogen
has been administered, generally speaking, involves either the use
of estrogen .[.along.]. .Iadd.alone .Iaddend.or estrogen plus a
progestogen.
Estrogen .[.along.]. .Iadd.alone.Iaddend., given in small doses on
a continuous basis, is effective in most patients for the control
of the above symptoms and problems associated therewith. However,
although the vast majority of women taking continuous low-dose
estrogen will not have bleeding for many months or even years,
there is a distinct risk posed by this routine of silently (i.e.
exhibiting no overt symptoms) developing "hyperplasia of the
endometrium". This term refers, of course, to an overstimulation of
the lining of the uterus which can become pre-malignant, coupled
with the possibility that the patient will eventually develop
cancer of the uterine lining even under such a low-dose regimen
(Gusberg et al, Obstetrics and Gynaecology, 17, 397-412, 1961).
Estrogen .[.along.]. .Iadd.alone .Iaddend.can also be given in
cycles, usually 21-25 days on treatment and 5-7 days off treatment.
Again, if small doses of estrogen are required to control the
symptoms and it is used to this fashion, only about 10% of women
will experience withdrawal bleeding between the cycles of actual
treatment. However, one must again be concerned by the risk of
developing endometrial hyperplasia and by the increased relative
risk of developing cancer of the uterus (Research on the Menopause:
Report of a W.H.O. Scientific Group, 53-68, 1981).
The addition of progestogen for the last 7-10 days of each estrogen
cycle will virtually eliminate the concern about developing
endometrial hyperplasia and probably reduce the risk of developing
endometrial carcinoma below that of the untreated general
population. However, withdrawal bleeding will occur regularly in
this routine and this is highly unacceptable to most older women
(Whitehead, Am. J. Obs/Gyn., 142,6, 791-795, 1982).
Still another routine for estrogen administration would involve a
formulation such as those found in birth control pills which
contain relatively small doses of estrogen over the full 20-21 day
treatment cycle, plus very substantial doses of potent progestogens
over the same period of time. This routine, of course, not only
produces withdrawal bleeding on each cycle, but is further
unacceptable because such formulations have been shown to carry an
increased risk of developing arterial complications such as stroke
or myocardial infaraction in older women about the age of 35-40.
This is especially true if the individual is a smoker of cigarettes
(Plunkett, Am. J. Obs/Gyn. 142, 6, 747-751, 1982).
Therapeutic regimens employing a progestogen along require
relatively large doses in order to control hot flushes. Moreover,
use of a progestogen alone does not prevent atrophy of the vaginal
mucosa, although it may help to prevent osteoporosis. However, a
progestogen administered in large doses, together with large
amounts of a synthetic estrogen, induces changes in blood lipids
which may promote arteriosclerotic changes and have been implicated
in the appearance of strokes and myocardial infarction among women
taking oral contraceptives in their later reproductive years,
(Plunkett, supra).
The present invention provides a novel therapeutic method and
composition involving the use of low dosage levels of estrogens and
progestogens, which method is designed to avoid or minimize
bleeding and prevent overstimulation of the lining of the uterus
while producing favourable changes in blood lipids. In particular,
the method involves continuous and uninterrupted administration of
very small doses of a progestogen along with administration of an
estrogen, the latter being cyclical, where required (for example,
with perimenopausal women). The method specifically provides for
treatment of menopausal or post-menopausal disorders in a women
comprising either:
A. continuously and uninterruptedly administering a progestogen and
an estrogen to said woman, or
B. continuously and uninterruptedly administering a progestogen and
cyclically administering an estrogen to said woman by repetitively
using a dosage regimen comprising:
(i) administering said estrogen continuously for period of time
between about 20 and about 120 days, followed by
(ii) terminating administering said estrogen for a period of time
between about 3 and about 7 days.
The term "perimenopausal" refers to women of approximately forty
years of age and older, who have not yet definitely arrived at
menopause but who are experiencing symptoms associated with
menopause.
The term "continuous" as applied in the specification and the
claims to "administration" means that the frequency of
administration is at least once daily. Thus, administration, e.g.
every other day or once every third day, is not "continuous" for
purposes of this invention. Note, however, that the frequency of
administration may be greater than once daily and still be
"continuous", e.g. twice or even three times daily so long as the
dosage level as specified herein is not exceeded.
The term "uninterrupted" means that there is no break in the
treatment. Thus "continuous, uninterrupted administration" of a
progestogen would mean that the progestogen is administered at
least once daily essentially in perpetuity or until the entire
treatment is ended. In this regard, it should be noted that
"cyclical" administration means that there is a break in
administration and that, therefore, by definition, cyclical
administration cannot be "uninterrupted".
The term "dosage level" means the total amount of estrogen or
progestogen administered per day. Thus, for example, the
"continuous administration" of a progestogen to a women at a
"dosage level" of 75 micrograms means that the women receives a
total of 75 micrograms of progestogen on a daily basis, whether the
progestogen is administered as a single 75 microgram dose or, e.g.
three separate 25 microgram doses. It is noted that the most
conventional means of continuously administering an estrogen or
progestogen is as a single daily oral dose at the prescribed dosage
level. Parenteral modes of administration, which provide a slow
release of the progestogen, could be substituted for the oral
route.
Thus, the invention realizes the objects of providing a therapeutic
method allowing for the administration of an estrogen, controlling
hot flushes, restoring the vaginal mucosa to a healthier state,
preventing the development of the dimineralization of bones as well
as preventing changes in lipids which predispose to cardiovascular
disease, over long periods of treatment, which method does not,
however, initiate bleeding or increase the risk of endometrial
carcinoma.
In another aspect, the invention provides a pharmaceutical
composition for hormonal treatment of menopausal or post-menopausal
disorders in a woman, which comprises a dosage unit of a
progestogen and a dosage unit of an estrogen for continuous
administration wherein the units comprise a progestogen in the
range of 0.025 to 30 mg and an estrogen in the range of 0.005 to
2.5 mg together with a pharmaceutically acceptable inert
carrier.
The actual unit dosages are selected according to conventionally
known methods, e.g. body weight of patient and biological activity
of the hormones, with the ultimate goal of producing the desired
result with the minimum quantities of hormones.
The interruption of the estrogen administration is required in
perimenopausal women to maintain normal periods and may be required
in certain jurisdictions due to health concerns--particularly
overstimulation of the lining of the uterus to cause a
pre-malignant condition. The absence of estrogen for a short period
allows the lining of the uterus to be sloughed and any
pre-malignancy thus avoided. However, the inventors believe that
even with continuous administration of estrogen, the presence of
progestogen will give rise to sufficient atrification of the uterus
that no such condition would be likely to occur.
A further and important object of the invention is to provide the
means whereby a woman may receive the proper quantities and dosage
units of the progestogen and estrogen for adherence to the
prescribed regimen wherein the dosage of estrogen is cyclically
administered. Such means takes the form of a multi-preparation
pack, which facilitates administration by a nurse or physical in
appropriate circumstances or, more usually, self-administration by
the woman.
The multi-preparation pack contains sufficient dosage units of
progestogen and estrogen for continuous administration of both said
progestogen and said estrogen for a period of from about 20 to 120
days plus an additional number of dosage units of progestogen for
administration for an additional period of time of from about 3 to
about 7 days during which administration of said estrogen is
terminated.
The estrogen used in the present disclosure may be those which are
orally active and are suitable for oral contraception and selected
from natural estrogens such as estradiol, estradiol-17.beta.,
estradiol valerate, conjugated equine estrogens, piperazine estrone
sulphate, estrone, estriol, estriol succinate and polyestriol
phosphate, or from synthetic estrogens such as ethinyl estradiol,
quinestranol and mestranol. The natural estrogens are
preferred.
The progestogen is again selected from those which are orally
active and suitable for oral contraceptives and may be, .[.foro.].
.Iadd.for .Iaddend.example, dl-norgestrel, laevo-norgestrel,
norethindrone (norethisterone), norethindrone acetate, ethynodiol
diacetate, medroxyprogesterone acetate, cyproterone acetate or
norethynodrel.
In the following Tables 1A and 1B are listed preferred unit
dosages, minimum unit dosages and maximum unit dosages for the
estrogens and progestogens useful in this invention. The quantities
are determined by the biological activities of the particular
substances as obtained commercially from sources that normally
supply them in micronized form.
TABLE 1A ______________________________________ ESTROGENS Dosage
(mg/day) Preferred Minimum Maximum
______________________________________ Natural estrogens (steroids)
Estradiol 1 0.500 2 Estradiol-17.beta. 1 0.500 2 Estradiol valerate
1 0.500 2 Conjugated equine estrogens 0.600 0.300 2.5 Estrene 0.600
0.300 2.5 Piperazine estrone sulphate 0.500 0.250 2.5 (estropipate)
Estriol* 0.100 0.050 0.500 Estriol succinate* 0.100 0.050 0.500
Polyestriol phosphate* 0.100 0.050 0.500 Synthetic estrogens
(steroids) Ethinyl estradiol 0.010 0.005 0.020 Mestranol 0.015
0.005 0.040 .[.Quinestranol.]. .Iadd.Quinestrol.Iaddend. 0.010
0.005 0.030 ______________________________________
It may be noted that of the estrogens of Table 1A, the estriol
preparations marked with an asterisk (*) have lower preference than
estradiols or estrones because they fail to spare bone in
post-menopausal women. However, they could be combined with natural
or synthetic estrogens for the purpose of the invention. Also, it
is preferable that the following non-steroidal estrogens--although
useful in this invention--be avoided for women who have not
definitely arrived at menopause (who could become
pregnant)--estrogens of this type being known to induce vaginal
cancer and other abnormalities in offspring if taken during the
pregnancy:
______________________________________ Stilboestrol 0.100 0.020 2
Stilboestrol dipropionate 0.100 0.020 2 Diethylstilboestrol 1 0.400
2.5 Chlorotrianiscos 2 1 2.5 Benzoestrol 2 0.5 2.5 Dienoestrol
0.500 0.200 2.5 Hexoestrol 0.500 0.200 2.5 Methallenoestril 1 0.500
2.5 ______________________________________
TABLE 1B ______________________________________ PROGESTOGENS Dosage
(mg/day) Preferred Minimum Maximum
______________________________________ Laevo-norgestrel 0.050 0.025
0.075 dl-norgestrel 0.100 0.050 0.150 Norethindrone
(norethisterone) 0.30 0.15 1.0 Norethindrone (norethisterone) 0.20
0.10 1.0 acetate Dydrogesterone 10 5 30 Medroxyprogesterone acetate
2.5 1 15. Norethynodrel 1 0.200 5 Allylestrenol 2 1 30 Lynoestrenol
0.200 0.100 2 Quingestanol acetate 0.200 0.050 1 Medrogestone 2 1
10 Norgestrienone 0.050 0.020 0.200 Dimethisterone 1 0.500 15
Ethisterone 2.5 1 25 Cyproterone acetate 0.500 0.100 10
Chlormadinone acetate 0.300 0.100 1 Megestrol acetate 1 0.100 10
______________________________________
Although chlormadinone acetate and megestrol are useful in the
context of this invention, it has been speculated that these
progestogens may pre-dispose breast tumors, although no clinical
proof exists to that effect. However, unless and until such
suspicions are proven to be without foundation, these compounds are
clearly of lower preference.
The estrogen/progestogen combinations may be administered
non-orally by implants or intramuscular injections. Generally
speaking, the required dosages are based upon somewhat lower daily
dosage levels that those required for the orally administered
estrogens and progestogens, for the simple reason that the former
are directly released into the bloodstream with consequently
greater activity than the same compounds when orally ingested.
Estradiol, estradiol valerate and estradiol 17-.beta. are suitable
candidates for estrogen implants, in maximum and minimum amounts of
100 mg and 20 mg, with 100 mg preferred. These quantities will be
suitable for slow-release implants intended for replacement every 3
to 12 months.
Suitable progestogen implants and intramuscular injections are set
forth in Table 1C.
TABLE 1C ______________________________________ Total Quantity (mg)
Pre- Min- Max- Period ferred imum imum
______________________________________ Progestogen implants
Loevonorgestrel every 2-5 yr. 50 25 100 dl-norgestrel every 2-5 yr.
100 50 200 Norgestrienone every 1-2 yr. 100 25 200 Norethindrone
acetate every 2-4 mon. 100 25 200 Intramuscular progestogen depots
Medroxyprogesterone acetate every 3 mon. 150 50 500 Norethindrone
enanthate every 3 mon. 50 20 400 Gestrocol hexanoate every 3 mon.
100 50 400 Algestone acetophenide monthly 50 20 300
Hydroxyprogesterone hexanoate weekly 100 50 250 Hydroxyprogesterone
caproate bi-weekly 100 50 250
______________________________________
dl-Norgestrel, laevo norgestrel (the common name for
d-13.beta.-ethyl-17.alpha.-ethinyl-17.beta.-hydroxygon-4-en-3-one),
norethindrone (common name for
17-hydroxy-19-nor-17.alpha.-pregn-4-en-20-yn-3-one), ethynodiol
diacetate (common name for
19-nor-17.alpha.-pregn-4-en-20-yne-3.beta., 17-diol diacetate),
norethindrone acetate, and cyproterone acetate may also be
administered by injection. It will be readily appreciated by those
skilled in the art thay any other synthetic progestogen which is
orally active or effective for use in conjunction with
contraception is also suitable for use in this invention.
Any of the suitable estrogens and progestogens (particularly those
listed in the foregoing tables) may be combined with one another in
the quantities recited to give estrogen/progestogen combinations
within the purview of the invention. Especially preferred
combinations are those containing the estradiols or conjugated
equine estrogens and the norgestrels norethindrones, or
medroxyprogesterones. Thus, especially preferred combinations
are:
Estradiol/Laevo-norgestrel
Estradiol 17.beta./Laevo-norgestrel
Estradiol valerate/Laevo-norgestrel
Conjugated equine estrogens/Laevo-norgestrel
Estradiol/dl-norgestrel
Estradiol 17.beta./dl-norgestrel
Estradiol valerate/dl-norgestrel
Conjugated equine estrogens/dl-norgestrel
Estradiol/Norethindrone (norethisteron)
Estradiol 17.beta./Norethindrone (norethisterone)
Estradiol valerate/Norethindrone (norethisterone)
Conjugated equine estrogens/Norethindrone (norethisterone)
Estradiol/Norethindrone (norethisterone) acetate
Estradiol 17.beta./Norethindrone (norethisterone) acetate
Estradiol valerate/Norethindrone (norethisterone) acetate
Conjugated equine estrogen/Norethindrone (norethisterone)
acetate
Estradiol/Medroxyprogesterone acetate
Estradiol 17.beta./Medroxyprogesterone acetate
Estradiol valerate/medroxyprogesterone acetate
Conjugated equine estrogen/Medroxyprogesterone acetate
The maximum, minimum and preferred dosage levels for the respective
estrogens and progestogens in the foregoing combinations are as
recited in the tables.
The comparison of the invention is usually administered orally in
admixture with a pharmaceutically acceptable inert carrier. The
estrogen and progestogen can be compounded in any pharmaceutically
acceptable inert (non-toxic) form. The packaging can be any system
convenient for proper delivery. With the preferred orally
administrable form, the pharmaceutical carrier can be of any of the
conventionally employed carriers, for example pharmaceutically
grades of mannitol, lactose, starch, magnesium stearate, sodium
saccharin, talcum cellulose, glucose, sucrose, magnesium carbonate,
and similar substances. The compositions may be formulated into
solutions, suspensions, tablets, pills, capsules, powders,
sustained release formulations, etc.
One of the unique aspects of this invention is the adaptation of
the multi-preparation pact to the continuous uninterrupted
administration of a progestogen and an estrogen is administered in
a cyclic fashion. The duration of the estrogen cycle can be very
variable, with continuous administration ranging between 20 and 120
days followed by a break (i.e. interruption) in estrogen
administration ranging anywhere from about 3 to about 7 days.
However, if the estrogen is discontinued for a period longer than 5
days, recurrence of hot flushes is most likely to occur, in a
number of patients.
The multi-pack dispensing system may be accommodated by
conventional packaging equipment, e.g. transparent strip foil
packages continuously arranged in daily dosages or other
conventional means in the art. Where the multi-pack is employed for
the cyclical administration of an estrogen in combination with a
progestogen, the pack would conveniently comprise a transparent
strip foil package with the combined unit daily dosages arranged
continuously with, for example, up to a total of 120 such dosages,
the 3 to 7 unit dosages of progestogen being located at the end of
the combined daily unit dosages whereby they would be taken at the
end of the series.
The inventors have been developed clinical evidence from this
routine that the amounts of estrogen and progestogen required to
control flushes, vaginal symptoms and associated subjective
symptoms are very small. Preliminary metabolic responses of the
subjects indicative favourable changes toward the lower blood lipid
levels found in younger premenopausal women.
EXAMPLE 1
An experimental study of thirty women was instituted under a
randomized double blind protocol with crossover and involved the
administration of placebos, progestogen only, estrogen only and the
combination of the continuous, uninterrupted progestogen/cyclic
estrogen treatment. Treatment comprised administering each hormone
and the combination as follows: (1) estrogen alone for two months;
(2) progestogen alone for two months; (3) combination therapy using
(1) and (2) for six months. Each period of administering a hormone
of the combination was followed by a one month period of placebo
(substance with no endocrine activity) administration. The estrogen
was micronized 17.beta.-estradiol administered at a daily dosage
level of 1 milligram, while the progestogen was dl-norgestrel
administered at a dosage level of 75 micrograms.
Of 30 women who have completed this study, 22, on the basis of
their responses throughout the fourteen months of observation,
selected the combination treatment and requested to continue it.
This represents a high level of acceptability.
EXAMPLE 2
In a follow-up phase of observation, 17 subjects (with intact
uterus) have completed a total of 125 lunar months of the
combination therapy (continuous, uninterrupted administration of
dl-norgestrel, cyclic administration of 17.beta.-estradiol). None
of the patients experienced "bleeding" which required protection.
1.6 percent of the cycles involved spotting requiring no
protection. 98.4 percent of the cycles were completely clear.
The combination therapy has been associated with no evidence
whatsoever of endometrial hyperplasia (over-stimulation of the
lining of the uterus). One patient, after the 2-month phase of
taking estrogen only (in the double blind study) did show evidence
not only of hyperplasia of the endometrium but also had a typical
findings which could be interpreted as indicative of a premalignant
change. Addition of the small (75 microgram) dosage level of
progestogen (dl-norgestrel) for two weeks only followed by full
dilatation and curettage revealed that the endometrium had become
completely atrophic once again and a total reversal of the previous
findings were noted.
As an alternative to dl-norgtestrol, laevo-norgestral may be used.
Since the dl-norgestrol consists of equal parts of the dextro
(inactive) and laevo (active) forms, only half the quantity of
laevo-norgestrol is used with the same effect. Thus, if
laevo-norgestrol is substituted for dl-norgestrol in the foregoing
examples, the laevo-norgestrol dosage level is 37.5 micrograms.
At least five cases of young women who required removal of ovaries
and uterus because of severe endometriosis have also been
successfully treated by the above combination. These women rarely
have total removal of the endometriotic tissue. It is important to
treat these patients with estrogen replacement therapy to prevent
the early appearance of bone demineralization (osteoporosis),
elevation of cholesterol and triglycerides and to control sever hot
flushes and vaginal atrophy. If patients such as these are treated
with estrogen alone, they frequently develop recurrence of pain
symptoms due to residual endometriosis being restimulated by the
administered estrogen. Because the inventors' combination therapy
tends to promote atrophy of the lining of the uterus (endometrium)
no matter whether it is located normally within the uterus or in
the endometriotic tissue in the pelvis, it is found that these
patients tolerate the treatment very well and do not have a
recurrence or reactive of their endometriosis. Furthermore, even
small doses of estrogen in combination with the continuous
progestogen routine is sufficient to control the severe hot flushes
which such patients experience.
Thus this invention permits control of menopausal disorders
including hot flushes and vaginal atrophy along with many of the
subjective symptoms. Further, given that both components of the
combination therapy are considered to be effective in retarding
osteoporosis, long term therapy to prevent this disabling disease
should be effective.
Additionally, the risk of developing endometrial (uterine) cancer
from the combination therapy should, at a minimum, be reduced to
the normal incidence of the general population as opposed to the
increased risk which has in fact been demonstrated to occur using
estrogen-only treatment. The inventors have in fact developed some
evidence suggestive that the combination therapy reduces the risk
of premalignant endometrial changes, which may reduce the risk of
developing endometrial cancer. The reduction in bleeding or
spotting in patients taking the combination therapy makes it much
more desirable relative to known treatments, particularly to older
women.
The following describes directions which may be applied to a
multi-preparation pack specifically adapted to the cyclical
administration of estrogen together with the continuous
administration of progestogen in accordance with one embodiment of
the invention:
ABOUT THESE TABLETS
(The tablet set herein) is used to control menopausal symptoms. It
is not a birth control pill and cannot be relied upon to prevent
pregnancy.
Oral contraceptives should not be taken at the same time as these
tablets and, if necessary, you should therefore ask your doctor
about alternative means of mechanical protection.
When treatment is first started, tingling of the breasts slight
nausea or occasional vaginal bleeding may occur--this should settle
after a short time.
If you have any unusual symptoms, contact your doctor.
To be taken under medical supervision.
HOW TO USE THIS PACK
Whether you are menstrating regularly or not, take the first tablet
on a day suitable to yourself until all the tablets have been
consumed.
The last seven tablets of the different colour are to be taken only
when all others have been consumed.
Alternatively, the foregoing instructions may be printed as a
leaflet, and the package instruction modified as follows:
Before commencing treatment please read the enclosed instruction
leaflet carefully. If you have any difficulties following the
instructions please ask your doctor for assistance.
DIRECTIONS
To remove a tablet, press firmly with your thumb on the appropriate
clear plastic bubble. This may be helped by holding the card so
that your fingers surround the aluminum foil through which the
tablet will emerge.
.Iadd.BRIEF DESCRIPTION OF THE DRAWINGS .Iaddend.
A multi-preparation pack suitable for administration of tablets in
accordance with the regimen described above is illustrated in FIGS.
1 and 2 of the drawings. A bubble pack 10 (which may be folded
along the line 10a) is sold in a protective sleeve 11, upon the
rear of which are printed the directions for use and salient facts
concerning the tablets, as indicated at 12 in the drawing. When
removed from the protective sleeve by the consumer, the bubble pack
contains as many tablets as the number of days which the pack is
intended to cover (in this example, one hundred and twenty days).
Optionally, the individual bubble segments may be numbered from one
to one hundred and twenty but it is important that the last few
segments, which contains the progestogen-only tablets, be clearly
distinguished from the remainder of these segments. In the present
example, the segments 13 containing the first one hundred and
thirteen tablets (combination progestogen/estrogen) are a light
colour (for example, white) whilst the last seven segments 14,
containing the progestogen-only tablets are a dark colour (red, for
example). By following the directions on the sleeve and observing
the colours on the bubble pack (and the "day numbers", if present)
the consumer will take the combination tablets for the first one
hundred and thirteen days and the progestogen tablets for the last
seven days. Thereafter, a new package would be opened, whereby the
cycle is repeated.
Although only a few exemplary embodiments of this invention have
been described in detail above, those skilled in the art will
readily appreciate that many modifications are possible in the
exemplary embodiments without materially departing from the novel
teachings and advantages of this invention.
* * * * *