U.S. patent application number 12/886269 was filed with the patent office on 2011-01-13 for composition comprising a combination of an aromatase inhibitor, a progestin and an oestrogen and its use for the treatment of endometriosis.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Stephen Rubin.
Application Number | 20110009373 12/886269 |
Document ID | / |
Family ID | 9952433 |
Filed Date | 2011-01-13 |
United States Patent
Application |
20110009373 |
Kind Code |
A1 |
Rubin; Stephen |
January 13, 2011 |
COMPOSITION COMPRISING A COMBINATION OF AN AROMATASE INHIBITOR, A
PROGESTIN AND AN OESTROGEN AND ITS USE FOR THE TREATMENT OF
ENDOMETRIOSIS
Abstract
The invention relates to a method of treating endometriosis
using a combination of an aromatase inhibitor, a progestin and an
oestrogen. The invention also relates to pharmaceutical
formulations comprising said combination.
Inventors: |
Rubin; Stephen;
(Southampton, NJ) |
Correspondence
Address: |
ASTRAZENECA R&D BOSTON
35 GATEHOUSE DRIVE
WALTHAM
MA
02451-1215
US
|
Assignee: |
ASTRAZENECA AB
Sodertalje
SE
|
Family ID: |
9952433 |
Appl. No.: |
12/886269 |
Filed: |
September 20, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10543584 |
Jul 27, 2005 |
|
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PCT/GB04/00414 |
Feb 3, 2004 |
|
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12886269 |
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Current U.S.
Class: |
514/170 |
Current CPC
Class: |
A61K 31/4184 20130101;
A61P 19/10 20180101; A61K 31/5685 20130101; A61P 15/00 20180101;
A61K 31/4184 20130101; A61P 5/34 20180101; A61P 5/30 20180101; A61K
31/519 20130101; A61P 15/08 20180101; A61K 31/567 20130101; A61P
15/02 20180101; Y10S 514/899 20130101; A61K 31/5685 20130101; A61P
35/00 20180101; A61K 31/567 20130101; A61K 2300/00 20130101; A61P
5/32 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 31/4196 20130101;
A61K 31/4196 20130101; A61K 31/519 20130101; A61P 43/00
20180101 |
Class at
Publication: |
514/170 |
International
Class: |
A61K 31/56 20060101
A61K031/56; A61K 31/5685 20060101 A61K031/5685; A61P 35/00 20060101
A61P035/00; A61K 31/57 20060101 A61K031/57; A61K 31/566 20060101
A61K031/566 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 5, 2003 |
GB |
0302572.3 |
Claims
1. The use of a combination of an aromatase inhibitor, a progestin
and an oestrogen in the manufacture of a medicament for the
treatment of endometriosis.
2. The use according to claim 1 wherein the aromatase inhibitor is
selected from atamestane, formestane, fadrozole, letrozole,
pentrozole, anastrozole and vorozole.
3. The use according to claim 2 wherein the aromatase inhibitor is
anastrozole.
4. The use according to any one of the preceding claims wherein the
progestin is selected from norgestrel, levonorgestrel,
norethindrone, norethindrone acetate, desogestrel, norgestimate and
ethynodiol diacetate.
5. The use according to claim 4 wherein the progestin is
levonogestrol.
6. The use according to any one of the preceding claims wherein the
oestrogen is selected from ethinyl oestradiol and mestranol.
7. The use according to claim 6 wherein the oestrogen is ethinyl
oestradiol.
8. A pharmaceutical composition comprising a combination according
to any one of claims 1 to 7.
9. A pharmaceutical composition according to claim 8 for the
treatment of endometriosis.
10. A method of the treatment of endometriosis comprising the
administration of a combination of an aromatase inhibitor, a
progestin and an oestrogen.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 10/543,584 (filed Jul. 27, 2005), which is a U.S. National
Stage under 35 USC 371 of International Application No.
PCT/GB2004/000414 (filed Feb. 3, 2004), which claims priority under
35 U.S.C. .sctn.119 (a)-(d) to United Kingdom Application No.
0302572.3 (filed Feb. 5, 2003).
[0002] The present invention relates to a method of treating
endometriosis using a combination of an aromatase inhibitor, a
progestin and an oestrogen. The invention also relates to
pharmaceutical formulations comprising said combination.
[0003] Endometriosis is characterised by the presence of
endometrial-like tissue outside the uterine cavity and is largely a
condition seen in premenopausal women. It is estimated to affect
between 2-10% of women of child-bearing age. This endometrial-like
tissue responds in the same way as the normal endometrium to
changes in the hormonal environment during the menstrual cycle so
that as the concentrations of oestrogen and progesterone change,
the tissue grows and is shed in the same way as the endometrium
itself. Symptoms of endometriosis include pelvic pain,
dysmenorrhoea and dyspareunia and it is often found in association
with infertility although its exact relationship to infertility,
except in severe endometriosis, is uncertain. [For a general review
of endometriosis and current treatment strategies the user is
referred to: Olive D L. Pritts E A. (2001) New England Journal of
Medicine. 345(4):266-75]. Both medical and surgical approaches and
a combination of the two are used in an attempt to eradicate the
disease, however, in many instances treatment is not curative and
the disease and its associated symptoms return.
[0004] Oestrogen is the most well-defined mitogen that enhances
growth and inflammation in this extra-uterine tissue giving rise to
increased pelvic pain. Treatments that inhibit the production of
the major source of oestrogen in premenopausal women, namely the
ovaries, or which create a so-called pseudomenopause have been used
to successfully treat endometriosis. In the former class, the
gonadotrophic hormone releasing hormone agonist analogues (GnRH
analogues) inhibit the production of LH and to a lesser extent FSH
from the pituitary gland leading to inhibition of the production of
oestradiol by the ovaries. This lowering of circulating oestradiol
concentrations into the postmenopausal range results in an
improvement of pelvic pain and pressure symptoms and regression of
endometrial implants. Danazol and progestogenic agents are also
used to treat the disease. Treatment with the GnRH analogues
although effective is limited to 6 months because of the potential
effects on bone mineral density. Treatment with danazol is also
limited because of its androgenic side-effects.
[0005] Not infrequently, patients may not tolerate and/or respond
to currently available medical approaches. Additionally, there is a
high incidence of recurrence.
[0006] For example, 18 months after completing a 6-month course of
Lupron.TM.-depot (which contains the GnRH agonist leuprolide), only
52% of patients had significant relief of pain. The recurrence rate
of pain in the rest of the patients was approximately 5-20% per
year (reaching a cumulative average rate at 5 years as high as
53%). The recurrence rate at 5 years was as high as 75% in severe
forms of endometriosis [see Rice V M (2002) Annals of the New York
Academy of Sciences 955:343-352]. In women treated for pelvic pain,
the symptoms usually return rather quickly after cessation of
therapy. For a period of time after medical treatment, however, the
intensity of symptoms is less severe. The recurrence rates after
treatment with GnRH agonists are similar to those after danazol,
and both are similar to those obtained with surgical excision.
[0007] Recent work has demonstrated that other sources of
oestrogen, in addition to the ovaries, contributes to the
development and continued presence of endometriosis. In particular,
high levels of local aromatase activity and oestrogen production
within the endometriotic tissue per se appear central to the
maintenance and pathophysiology of endometriosis. Thus, aromatase
inhibitors have been suggested for the treatment of endometriosis
[Bulun et al (2000) Human Reproduction Update 6(5), 413-418; Bulun
et al (2000) Trends in Endocrinology and Medicine 11(1),
22-27].
[0008] Given continuously GnRH analogues by inhibiting the
production of gonadotrophins from the pituitary gland, reduce
circulating oestradiol concentrations into the postmenopausal
range. Aromatase inhibitors would not be expected to lower serum
oestradiol concentrations, however, in pre-menopausal women because
of the feedback mechanism, the hypothalamic-pituitary axis, so that
when circulating oestradiol concentrations fall the pituitary gland
produces more gonadotropins, which in turn stimulate the production
of oestrogen by the ovaries. It has been hypothesised that the
increased concentrations of the gonadotrophin, follicle stimulating
hormone (FSH) may result in the formation of cysts in the ovary.
The concomitant use of a progestin agent with the aromatase
inhibitor would be expected to diminish this surge in pituitary
gonadotropins. Another benefit of the concomitant administration of
a progestin is that it would be expected to directly cause thinning
of the eutopic endometrium due to the dominant progestogenic
effect.
[0009] Although oestrogen has a pathological role in endometriosis,
it also has a protective effect in a number of tissues, such as
bone. Thus, treatment of endometriosis with oestrogen lowering
therapies may have side effect due to inhibition of the protective
effects of oestrogen in addition to inhibition of the pathological
effects of oestrogen. For examples treatment of endometriosis with
GnRH analogues leads to castrate levels of oestrogen resulting in
side effects including transient vaginal bleeding, hot flashes,
vaginal dryness, decreased libido, breast tenderness, insomnia,
depression, irritability and fatigue, headache, osteoporosis, and
decreased elasticity of the skin.
[0010] Thus, strategies that inhibit the oestrogen driven symptoms
of endometriosis with minimal side effects are required. The
combination of an aromatase inhibitor with a progestin would be
expected to have some advantage in relation to bone loss. However,
the further addition of an oestrogen to this combination would not
only prevent bone loss more effectively than the addition of a
progestin alone, but would also be expected to stop breakthrough
bleeding commonly seen with progestins. However, the addition of an
oestrogen to patients with endometriosis in combination with the
partial oestrogen-reducing therapy of an aromatase inhibitor in
premenopausal women would be expected to exacerbate the condition
or reduce the efficacy of treatment with the aromatase inhibitor.
Indeed, using an endometriosis model in studies in wild type mice
and aromatase knockout mice Fang et al found that the addition of
oestrogen to the aromatase inhibitor letrozole resulted in
increases in the endometriotic lesion sizes and thus exacerbates
the endometriosis [Fang et al (2002) Journal of Clinical
Endocrinology & Metabolism 87(7), 3460-3466]. We have studied
the combination of an aromatase inhibitor, a progestin and an
oestrogen and we have surprisingly found that the addition of an
oestrogen to the combination of an aromatase inhibitor and a
progestin, contrary to expectations, results in effective
palliation of symptoms in women with severe endometriosis.
Furthermore, this combination therapy was well tolerated with only
mild hot flashes, breakthrough spotting and no significant changes
between baseline and post-treatment hip and spine bone densitometry
measurements.
[0011] Thus, according to the first aspect of the invention there
is provided a method of treatment of endometriosis comprising the
administration of a combination of an aromatase inhibitor, a
progestin and an oestrogen.
[0012] According to a further aspect of the invention there is
provided the use of a combination of an aromatase inhibitor, a
progestin and an oestrogen in the manufacture of a medicament for
the treatment of endometriosis.
[0013] According to a further aspect of the invention there is
provided a pharmaceutical composition comprising a combination of
an aromatase inhibitor, a progestin and an oestrogen in admixture
with a pharmaceutically-acceptable diluent or carrier for the
treatment of endometriosis.
[0014] For the avoidance of doubt in such a pharmaceutical
composition the components may be formulated as follows: [0015] (i)
the aromatase inhibitor, progestin and oestrogen mixed together in
a single formulation; [0016] (ii) two of the components mixed
together in a single formulation and one component formulated
separately, for simultaneous or sequential dosing; or [0017] (iii)
each component formulated separately, for simultaneous or
sequential dosing.
[0018] In this specification an aromatase inhibitor is defined as a
compound that prevents oestrogens from being formed from their
metabolic precursors by inhibiting the enzyme aromatase. Examples
of aromatase inhibitors include: [0019] (i) the testolactone
(17a-oxa-D-homoandrost-1,4-diene-3,17-dione) that is described in
the "Journal of Clinical Endocrinology and Metabolism," 49, 672
(1979); [0020] (ii) the compounds androsta-4,6-diene-3,17-dione,
androsta-4,6-dien-17.beta.-ol-3-one acetate,
androsta-1,4,6-triene-3,17-dione,
4-androstene-19-chloro-3,17-dione, 4-androstene-3,6,17-trione that
are described in "Endocrinology" 1973, Vol. 92, No. 3, page 874,
[0021] (iii) the 19-alkynylated steroids that are described in
German patent application number DE 3124780, [0022] (iv) the
10-(1,2,-propadienyl)-steroids that are described in German patent
application number DE 3124719, [0023] (v) the 19-thio-androstane
derivatives that are described in European patent application,
publication no. EP 100566, [0024] (vi) the
4-androsten-4-ol-3,17-dione and its esters that are described in
"Endocrinology" 1977, Vol. 100, No. 6, page 1684 and U.S. Pat. No.
4,235,893, [0025] (vii) the
1-methyl-15.alpha.-alkyl-androsta-1,4-diene-3,17-dione that is
described in German patent application number DE 3539244, [0026]
(viii) the 10.beta.-alkinyl-4,9(11)-estradiene derivatives that are
described in German patent application number DE 3644358 and [0027]
(ix) the 1,2.beta.-methylene-6-methylene-4-androstene-3,17-dione
that is described in European Patent Application EP 250 262.
[0028] Further examples of aromatase inhibitors include:
atamestane, formestane, fadrozole, letrozole, pentrozole,
anastrozole and vorozole.
[0029] A more preferred aromatase inhibitor is anastrozole.
Anastrozole can be administered at a dose and/or schedule to
deliver between 0.1 and 10 mg/day, preferably, between 0.5 and 5
mg/day, most preferably anastrozole is administered at 1
mg/day.
[0030] In this specification a progestin is defined as a natural or
synthetic progestational substance that mimics some or all of the
actions of progesterone. Examples of progestins include derivatives
of 19-nortestosterone, such as oestranes and gonanes, and
derivatives of 17.alpha.-acetoxyprogesterone (pregnanes). Examples
of oestranes include: norethindrone and its acetates, and
ethynodiol diacetate. Examples of gonanes include norgestrel and
levonorgestrel and the less androgenic derivatives of
levonorgestrel such as desogestrel, norgestimate, and gestodene.
Further examples of progestins include norgestrel, levonorgestrel,
norethindrone, norethindrone acetate, desogestrel, norgestimate and
ethynodiol diacetate. A preferred progestin is levonorgestrel.
Levonorgestrel can be administered at a dose and/or schedule to
deliver between 0.05 and 0.15 mg/day, preferably 0.1 mg/day.
[0031] In this specification oestrogens are defined as compounds
which has agonist activity at the oestrogen receptor. Partial
agonists and full agonists are envisaged but full agonists are
preferred. An example of a partial agonist is tamoxifen. Examples
of full agonists include oestrogen, oestradiol, mestranol and
ethinyl oestradiol. Further examples of full agonists include
oestrogen, oestradiol and ethinyl oestradiol. Preferred oestrogens
include ethinyl oestradiol and mestranol. A more preferred
oestrogen is ethinyl oestradiol. Ethinyl oestradiol can be
administered at a dose and/or schedule to deliver between 0.01 and
0.06 mg/day, preferably 0.02 mg/day.
[0032] Conveniently the progestin and oestrogen components of the
combination of the invention could be provided by a combination
birth control pill comprising an oestrogen and a progestin.
Examples of such birth control pills include tablets comprising:
[0033] (i) ethinyl oestradiol and norethindrone; [0034] (ii)
ethinyl oestradiol and norgestimate; [0035] (iii) ethinyl
oestradiol and desogestrel; [0036] (iv) ethinyl oestradiol and
levonogestrel; [0037] (v) ethinyl oestradiol and gestodene; [0038]
(vi) ethinyl oestradiol and norgestrel; and [0039] (vii) mestranol
and norethindrone.
[0040] A preferred combination birth control pill comprises ethinyl
oestradiol and levonogestrel.
[0041] In one aspect of the invention, the administration is
carried continuously, for at least 6 months. However, treatment for
1 to 2 years is also envisaged. Treatment for greater than 2 years
is also contemplated.
[0042] Treatment of pre-menopausal women is most preferred, however
treatment of post-menopausal women would also be contemplated in
those women for whom oestrogen replacement therapy would be
considered yet currently thought contraindicated due to concerns
regarding endometriosis.
[0043] In another aspect the combination of the invention is
contemplated for patients who are refractory to a combination of
surgical resection and/or one or more course of prior or subsequent
hormonal treatment. Examples of such hormonal therapy include
treatment with GnRH analogues.
[0044] The term `surgical resection` refers to surgical removal of
endometriotic implants and/or lysis of adhesions caused by scarring
from endometriosis. Such removal could comprise ablation by for
example a laser.
[0045] In order to carry out the invention the combination could be
provided in a single formulation or in multiple formulations,
comprising one or more of the components of the combination.
Administration of the elements of the combination could be
administered simultaneously or each component could be administered
at different times. Simultaneous administration is preferred. The
combination may be provided in various formulations such as
parentally (e.g. aqueous or oily suspensions) or orally (e.g.,
tablets, powders, capsules, granules, aqueous or oily suspensions).
Preferably, the combination is provided in an orally available
formulation to be administered daily. However, slow release
formulation or depot or transdermal formulations could also be used
to administer the combination.
[0046] Thus, according a further feature of the invention there is
provided a pharmaceutical formulation comprising an aromatase
inhibitor, a progestin and an oestrogen, preferably a
pharmaceutical formulation for the treatment of endometriosis.
[0047] For preparing pharmaceutical formulations of the invention,
inert, pharmaceutically acceptable carriers can be added to the
components of the composition which can either be solid or liquid.
Solid form preparations include powders, tablets, dispersible
granules, capsules and cachets.
[0048] A solid carrier can be one or more substances which may also
act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or tablet disintegrating agents; it can
also be an encapsulating material.
[0049] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component. In tablets,
the active component is mixed with the carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0050] Suitable carriers include magnesium carbonate, magnesium
stearate, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
[0051] The term formulation is intended to include the mixture of
the active component with encapsulating material as a carrier
providing a capsule in which the active component (with or without
other carriers) is surrounded by a carrier which is thus in
association with it. Similarly, cachets are included. Tablets,
powders, cachets, and capsules can be used as solid dosage forms
suitable for oral administration.
[0052] Liquid form compositions include solutions, suspensions, and
emulsions. Sterile water or water-propylene glycol solutions of the
active compounds may be mentioned as an example of liquid
preparations suitable for parenteral administration. Liquid
compositions can also be formulated in solution in aqueous
polyethylene glycol solution. Aqueous solutions for oral
administration can be prepared by dissolving the active component
in water and adding suitable colorants, flavoring agents,
stabilizers, and thickening agents as desired. Aqueous suspensions
for oral use can be made by dispersing the finely divided active
component in water together with a viscous material such as natural
synthetic gums, resins, methyl cellulose, sodium carboxymethyl
cellulose, and other suspending agents known to the pharmaceutical
formulation art.
[0053] The pharmaceutical formulation can be in unit dosage form.
In such form, the composition is divided into unit doses containing
appropriate quantities of the active component. The unit dosage
form can be a packaged preparation, the package containing discrete
quantities of the preparations, for example, packeted tablets,
capsules, and powders in vials or ampoules. The unit dosage form
can also be a capsule, cachet, or tablet itself, or it can be the
appropriate number of any of these packaged forms.
[0054] The invention will now be illustrated with reference to the
following non-limiting example.
[0055] A clinical trial was designed to assess the efficacy of a
combination of an aromatase inhibitor, a progestin and an oestrogen
in the treatment of endometriosis. 18 patients with severe
endometriosis-related pelvic pain, who previously have not
responded to a combination of surgical resection and one or more
courses of hormonal treatment were included in the trial. The
patients had an age range of 23 to 46, and all patients had normal
ovarian function. These patients were treated with the oral
aromatase inhibitor, anastrozole [Arimidex.TM.] at 1 mg/day in
combination with an oestrogen-containing birth control pill, Alesse
21.TM. one tablet per day [Alesse 21.TM. contains levonorgestrel
(0.1 mg), a progestin and ethinyl oestradiol (0.02 mg), an
oestrogen]. Patients were assessed for severity of pain and for
severity of side effects. Of these 18 patients, 9 patients
completed the study.
Pain
[0056] A self-assessment visual analog pain scoring system (VAS),
varying in severity from 0 (no pain) to 10 (maximum pain) was used,
which was recorded daily. All patients had baseline pain scores
between 7 and 10. Tables 1 and 2 show the results of the pain
measurements in the trial. Table 1 shows the data for the 9
patients who completed the study, Table 2 shows the data for all
the patients in the study, the number of patients at each time
point is indicated. The results show a significant decrease in pain
in the patients at each time point, with an increase in pain relief
up to the final 6 month time point.
TABLE-US-00001 TABLE 1 Average Monthly Pain Scores for the 9
patients that completed the study Statistical significance was
assessed by ANOVA followed by Newman-Keuls multiple comparisons
test Statistical Significance Statistical Mean Pain vs Significance
Score pre-treatment vs 1.sup.st month Pre-treatment 8.6 1.sup.st
month 6.1 p < 0.01 2.sup.nd month 5.3 p < 0.001 p < 0.05
6.sup.th month 4.6 p < 0.0005
TABLE-US-00002 TABLE 2 Average Monthly Pain Scores for all patients
in trial Mean Pain Number of Score.sup.1 patient Pre-treatment 8.3
15 1.sup.st month 5.8 14 2.sup.nd month 5.2 14 6.sup.th month 4.6 9
.sup.1All results showed statistical significance between each
other.
Side Effects
[0057] Side effects were captured in the scheduled office visits
and recorded in patient charts. Potential side effects which were
monitored included lack of tolerability (i.e. lack of
hypoestrogenemic symptoms, for example those associated with GnRH
treatment such as transient vaginal bleeding, hot flashes, vaginal
dryness, decreased libido, breast tenderness, insomnia, depression,
irritability and fatigue, headache, osteoporosis, breakthrough
spotting and decreased elasticity of the skin) and safety issues
(i.e. no surge in gonadotropins leading to ovarian stimulation and
cyst formation and preserved bone densitometry measurements).
[0058] The most consistently observed side effects were mild hot
flashes and breakthrough spotting, although breakthrough spotting
occurred in a few patients almost exclusively as a result of
inadvertent interruptions of the oestrogen-containing birth control
pill.
[0059] No significant changes were detected between baseline and
post treatment DEXA bone densitometry measurements of the hip and
spine.
[0060] Monthly measurements of FSH, LH, oestradiol and oestrone did
not show significant alterations from the baseline. Thus no surge
in gonadotropins was observed.
Thus, the combination of an aromatase inhibitor, oestrogen and
progestin results in an efficaceous treatment of the symptoms of
endometriosis, with a relatively benign side effect profile.
* * * * *