U.S. patent application number 12/726804 was filed with the patent office on 2010-07-29 for combination preparation for oral contreaception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same.
Invention is credited to Pol Boudes, Jan Nedrikat, Angelo Secci, Susan Zeun, Holger Zimmermann.
Application Number | 20100190757 12/726804 |
Document ID | / |
Family ID | 46326804 |
Filed Date | 2010-07-29 |
United States Patent
Application |
20100190757 |
Kind Code |
A1 |
Zeun; Susan ; et
al. |
July 29, 2010 |
COMBINATION PREPARATION FOR ORAL CONTREACEPTION AND ORAL THERAPY OF
DYSFUNCTIONAL UTERINE BLEEDING CONTAINING ESTRADIOL VALERATE AND
DIENOGEST AND METHOD OF USING SAME
Abstract
The multiphase combination preparation for oral therapy of
dysfunctional uterine bleeding and for oral contraception contains
a first phase consisting of 2 daily dosage units, each containing 3
mg of estradiol valerate or <3 mg of estradiol; a second phase
consisting of a first group of 5 daily dosage units, each
consisting of a combination of 2 mg of dienogest with 2 mg of
estradiol valerate or <2 mg of estradiol, and a second group
consisting of 17 daily dosage units, each consisting of a
combination of 3 mg of dienogest with 2 mg of estradiol valerate or
<2 mg of estradiol; a third phase consisting of 2 daily dosage
units, each containing 1 mg of estradiol valerate or <1 mg of
estradiol; and another phase consisting of 2 daily dosage units of
a pharmaceutically harmless placebos.
Inventors: |
Zeun; Susan; (Berlin,
DE) ; Boudes; Pol; (Hackettstown, NJ) ; Secci;
Angelo; (Parsippany, NJ) ; Nedrikat; Jan;
(Kirkland, CA) ; Zimmermann; Holger; (Falkensee,
DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
46326804 |
Appl. No.: |
12/726804 |
Filed: |
March 18, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11609705 |
Dec 12, 2006 |
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12726804 |
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11377693 |
Mar 16, 2006 |
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11609705 |
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60727592 |
Oct 17, 2005 |
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Current U.S.
Class: |
514/170 |
Current CPC
Class: |
A61P 15/18 20180101;
A61K 31/56 20130101; A61K 31/57 20130101 |
Class at
Publication: |
514/170 |
International
Class: |
A61K 31/565 20060101
A61K031/565; A61P 15/18 20060101 A61P015/18 |
Claims
1. A multiphase combination preparation for oral contraception and
oral therapy of dysfunctional uterine bleeding, said combination
preparation containing a first phase consisting of two daily dosage
units, each consisting of 3 mg of estradiol valerate or of less
than 3 mg of estradiol; a second phase consisting of two groups of
daily dosage units, a first group of which consisting of 5 daily
dosage units, each consisting of a combination of 2 mg of dienogest
with 2 mg of estradiol valerate or with less than 2 mg of
estradiol, and a second group of which consisting of 17 daily
dosage units, each consisting of a combination of 3 mg of dienogest
with 2 mg of estradiol valerate or with less than 2 mg of
estradiol; a third phase consisting of two daily dosage units, each
consisting of 1 mg of estradiol valerate or of less than 1 mg of
estradiol; and another phase consisting of two daily dosage units
of a pharmaceutically harmless placebo; so that the multiphase
combination preparation consists of a total number of 28 daily
dosage units.
2. The multiphase combination preparation as defined in claim 1,
wherein each of said daily dosage units of said first phase
consists of 2.25 mg of said estradiol; each of said daily dosage
units of said second phase consists of 1.5 mg of said estradiol;
and each of said daily dosage units of said third phase consists of
0.75 mg of said estradiol.
3. The multiphase combination preparation as defined in claim 1,
wherein each of said daily dosage units of said first phase
consists of 3 mg of said estradiol valerate; each of said daily
dosage units of said second phase consists of 2 mg of said
estradiol valerate; and each of said daily dosage units of said
third phase consists of 1 mg of said estradiol valerate.
4. A method of treating dysfunctional uterine bleeding and of oral
contraception, said method comprising the steps of: a) providing a
multiphase combination preparation for oral contraception and oral
therapy of dysfunctional uterine bleeding, said combination
preparation containing a first phase consisting of two daily dosage
units, each consisting of 3 mg of estradiol valerate or of less
than 3 mg of estradiol; a second phase consisting of two groups of
daily dosage units, a first group of which consisting of 5 daily
dosage units, each of which consist of a combination of 2 mg of
dienogest with 2 mg of estradiol valerate or less than 2 mg of
estradiol, and a second group of which consisting of 17 daily
dosage units, each of which consist of a combination of 3 mg of
dienogest with 2 mg of estradiol valerate or less than 2 mg of
estradiol; a third phase consisting of 2 daily dosage units, each
consisting of 1 mg of estradiol valerate or less than 1 mg of
estradiol; and another phase of 2 daily dosage units of a
pharmaceutically harmless placebo; so that the multiphase
combination preparation consists of a total number of 28 daily
dosage units; and b) administering said multiphase combination
preparation to a woman in need of treatment for dysfunctional
uterine bleeding over at least one treatment cycle.
5. The method as defined in claim 4, wherein said at least one
treatment cycle consists of six treatment cycles.
6. The method as defined in claim 4, wherein each of said daily
dosage units of said first phase consists of 2.25 mg of said
estradiol; each of said daily dosage units of said second phase
consists of 1.5 mg of said estradiol; and each of said daily dosage
units of said third phase consists of 0.75 mg of said
estradiol.
7. The method as defined in claim 4, wherein each of said daily
dosage units of said first phase consists of 3 mg of said estradiol
valerate; each of said daily dosage units of said second phase
consists of 2 mg of said estradiol valerate; and each of said daily
dosage units of said third phase consists of 1 mg of said estradiol
valerate.
Description
CROSS-REFERENCE
[0001] This is a continuation-in-part of U.S. patent application
Ser. No. 11/377,693, filed Mar. 16, 2006, which, in turn, claims
the benefit of priority of invention under 35 U.S.C. 119 (e) based
on U.S. Provisional Application, Ser. No. 60/727,592, filed Oct.
17, 2004.
BACKGROUND OF THE INVENTION
[0002] 1. The Field of the Invention
[0003] The subject matter of the present invention comprises the
use of estradiol valerate or estradiol in combination with
17.alpha.-cyanomethyl-17.beta.-hydroxyestra-4, 9-dien-3-one
(dienogest) to make a multiphase combination preparation for oral
therapy of dysfunctional uterine bleeding and for oral
contraception. This multiphase combination preparation contains a
first phase of 2 daily dosage units, each consisting of 3 mg of
estradiol valerate or less than 3 mg of estradiol; a second phase
of two groups of daily dosage units, a first group of which
consists of 5 daily dosage units, each consisting of a combination
of 2 mg of dienogest with 2 mg of estradiol valerate or with less
than 2 mg of estradiol, and a second group of which consists of 17
daily dosage units, each consisting of a combination of 2 mg of
dienogest with 2 mg of estradiol valerate or with less than 2 mg of
estradiol; a third phase of 2 daily dosage units, each consisting
of 1 mg of estradiol valerate or of less than 1 mg estradiol; and
another phase of 2 daily dosage units of pharmaceutically harmless
placebo, which contains a total number of 28 daily dosage units.
The total number of daily dosage units of the multiphase
combination preparation is sufficient for 28 days.
[0004] 2. Description of the Related Art
[0005] Dysfunctional uterine bleeding (DUB) is a frequent clinical
problem in gynecology and affects up to 33% of women presenting
themselves for gynecological medical examinations on an outpatient
basis (Awward J. T., Toth T. L., Schiff I., Abnormal Uterine
Bleeding in the Perimenopause, Int. J. Fertil. 1993; 38, pp.
261-9). The symptoms of DUB are: [0006] extended menstrual bleeding
(>7 days) [0007] frequent bleeding (interval between bleeding
episodes of less than or equal to 21 days) [0008] increased
bleeding (more than or equal to 80 ml).
[0009] DUB requires a diagnosis by exclusion, namely organic causes
such as myoma, polyps or cancer must be excluded before a DUB
diagnosis can be made.
[0010] DUB is associated with anovulation as well as ovulation.
Such bleeding disturbances are due to an imbalance between the
estrogen-stimulating build-up phase (proliferation) of the
endometrium and the gestagenic transformation of the endometrium.
If the DUB symptoms are a result of chronic anovulation, the
endometrium is often exposed to increased gestagenic proliferation.
Such proliferation can lead to hyperplasia of the endometrium
besides the bleeding disturbances (Speroff, et al., Clinical
Gynecologic Endocrinology and Infertility, sixth edition,
Lippincott, Williams and Wilkins, 1999).
[0011] Hyperplasia of the endometrium is a risk factor for the
onset of endometrial cancer.
[0012] Fraser, I. S., Aust. NZ J. Obstet. Gynaecol. (1990) 30 (4),
pp. 353-356, reported the treatment of dysfunctional uterine
bleeding by administration of 5 mg of norethisterone, three times
daily, or 10 mg of medroxyprogesterone acetate, three times daily,
as the only high-dosage gestagen, in each case for 14 days from the
12.sup.th to the 25.sup.th day of the cycle in 6 anovulatory women
and for 20 days from the 5''.sup.1 to the 25.sup.th day of the
cycle in ten ovulatory women. In both groups, the duration of the
bleeding period was reduced. Reliable contraception was not
attained.
[0013] Hickey M., Higham J. and Fraser I S, The Chochrane Library,
Issue 3 2004 (Mickey M, Higham J, Fraser I S, Progestogens Versus
Estrogens and Progestogens for Irregular Uterine Bleeding
Associated with Anovulation (Cochrane Review). In The Cochrane
Library, Issue 3 2004, Chichester, UK: John Wiley & Sons, Ltd)
describe in a review article the low tolerance of women for
irregular and extensive bleeding. They describe the rationale
behind the use of gestagens to achieve a transformation of the
endometrium and thus to create more stable menstruation cycles. The
conclusion of the article is that clinical data from randomized
studies demonstrating the efficacy of the described treatments are
currently not available.
[0014] Steiner, R., Schweiz. Rundsch. Med. Prax. (2000) 91 (46),
pp. 1967-1974, also points out that dysfunctional uterine bleeding
should be treated with, among other methods, high-dosage gestagens,
estrogens or a combination of both.
[0015] Steiner sees a treatment regimen in the oral administration
of 0.01 mg of ethinyl estradiol with 2 mg of norethisterone acetate
for 8 days in decreasing dosages, namely 6, 5, 4, 3, 3, 3, 3,
3/day. Besides the hormonal approach, Steiner postulates the
possibility of treating an acute bleeding situation with
tranexaminic acid, up to 4.times.2 tablets per day.
[0016] Davis, A., Obstet. Gynecol. (2000) 96 (6), pp. 913-920,
describes the treatment of dysfunctional uterine bleedings by a
three-step administration of ethinyl estradiol (EE)/norgestimate
(NGM) followed by hormone-free administration of placebo for three
28-day cycles. According to the treatment regimen, the EE dosage
remains constant over 21 days (0.035 mg of EE), the NGM dose
increases over 21 days (7 daily dosage units of 0.180 mg of NMG and
7 daily dosage units of 0.215 mg of NMG and 7 daily dosage units of
0.250 mg of NMG), followed by a 7-day hormone-free placebo
administration. The placebo-controlled study carried out by Davis
included 45% of women with increased menstrual bleeding
(metrorrhagia, menometrorrhagia and polymenorrhea) and about 55% of
women with reduced menstrual bleeding (oligomenorrhea). The highest
degree of success compared to placebo was achieved in women with
reduced menstrual bleeding in whom regular withdrawal bleeding was
induced. Oligomenorrhea is not necessarily a component of the DUB
symptom group and is not recognized as an ailment worthy of
treatment.
[0017] U.S. Pat. No. 6,782,282 discloses that generally extended
use (3 months) of oral contraceptives can be used for the treatment
of menorrhagia--a form of dysfunctional uterine bleeding.
SUMMARY OF THE INVENTION
[0018] The object of the present invention is to provide a
multiphase combination preparation and a method for using it to
treat dysfunctional uterine bleeding so that the extent of the
bleeding is generally reduced and the recurrence of dysfunctional
bleeding is generally prevented, while at the same time ensuring
reliable, safe and well-tolerated oral contraception.
[0019] By the term "dysfunctional uterine bleeding" here means
extended menstrual bleeding lasting more than 7 days with an
interval between bleeding episodes of less than or equal to 21
days, or increased bleeding of more than or equal to 80 ml without
an organic cause.
[0020] According to the invention this objective is attained by a
multiphase combination preparation for oral therapy of
dysfunctional uterine bleeding and for oral contraception, which is
based on a combination of either estradiol valerate or estradiol
with 17.alpha.-cyano-methyl-17.beta.-hydroxyestra-4, 9-dien-3-one
(dienogest). The multiphase combination preparation contains a
first phase of 2 daily dosage units, each consisting of 3 mg of
estradiol valerate or of less than 3 mg estradiol; a second phase
of 2 groups of daily dosage units, including a first group
consisting of 5 daily dosage units, each consisting of a
combination of 2 mg of dienogest with 2 mg of estradiol valerate or
with less than 2 mg of estradiol, and a second group consisting of
17 daily dosage units, each consisting of a combination of 3 mg of
dienogest with 2 mg of estradiol valerate or with less than 2 mg of
estradiol; a third phase consisting of 2 daily dosage units, each
consisting of 1 mg of estradiol valerate or less than 1 mg of
estradiol and another phase of 2 daily dosage units of a
pharmaceutically harmless placebo. The total number of daily dosage
units of the multiphase combination preparation and the
pharmaceutically harmless placebo should be sufficient for 28
days.
[0021] The duration of use comprises at least one treatment cycle
and depends on the individual desires of the woman regarding
contraception.
[0022] In a preferred embodiment of the multiphase combination
preparation each daily dosage unit of the first phase consists of
2.25 mg of estradiol; each daily dosage unit of the second phase
contains only 1.5 mg of estradiol; and each daily dosage units of
the third phase consists of 0.75 mg of estradiol.
[0023] In another preferred embodiment of the multiphase
combination preparation each daily dosage unit of the first phase
consists of 3 mg of estradiol valerate; each daily dosage unit of
the second phase contains 2 mg of estradiol valerate; and each
daily dosage unit of the third phase consists of 1 mg of estradiol
valerate.
Studies of the Efficacy of the Claimed Formulation
[0024] 180 women 18 to 50 years of age with DUB symptoms, in whom
an organic cause of the symptoms had been excluded by appropriate
diagnostic methods (transvaginal ultrasound, hormone determination
in the blood) and who had given their written consent to
participate in the study, were treated in a randomized,
double-blind, placebo-controlled clinical study. 120 women received
estradiol valerate and dienogest in accordance with the claimed
combination and 60 women received placebo.
[0025] The study comprised a run-in phase of 90 days during which
the severity of the bleeding disturbances was recorded, 6 treatment
cycles and one post-treatment cycle (follow-up phase).
[0026] The extent of bleeding was determined quantitatively by the
alkaline hematin method. To this end, the women collected the
monthly discharges during the entire study period and gave them to
the testing center. The duration of the bleeding and the duration
of the bleeding-free intervals were recorded by daily documentation
in an electronic journal.
[0027] While the invention has been illustrated and described as
embodied in a combination preparation for oral contraception and
oral therapy of dysfunctional uterine bleeding containing estradiol
valerate and dienogest and method of using same, it is not intended
to be limited to the details shown, since various modifications and
changes may be made without departing in any way from the spirit of
the present invention.
[0028] Without further analysis, the foregoing will so fully reveal
the gist of the present invention that others can, by applying
current knowledge, readily adapt it for various applications
without omitting features that, from the standpoint of prior art,
fairly constitute essential characteristics of the generic or
specific aspects of this invention.
[0029] What is claimed is new and is set forth in the following
appended claims.
* * * * *