U.S. patent application number 09/825569 was filed with the patent office on 2001-10-18 for progestin therapy for maintaining amenorrhea.
This patent application is currently assigned to COLUMBIA LABORATORIES (BERMUDA) LIMITED. Invention is credited to Bologna, William J., deZiegler, Dominique, Levine, Howard L..
Application Number | 20010031747 09/825569 |
Document ID | / |
Family ID | 26743461 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031747 |
Kind Code |
A1 |
deZiegler, Dominique ; et
al. |
October 18, 2001 |
Progestin therapy for maintaining amenorrhea
Abstract
The present invention teaches that daily, cyclical vaginal
delivery of progestin may be used to provide regular, predictable
withdrawal bleeding during hormone replacement therapy. The present
invention also teaches that constant administration of progestin in
a water-insoluble, water-swellable cross-linked polycarboxylic acid
polymer may be used to maintain amenorrhea. Either regimen is
accompanied by a significant decrease in adverse side effects.
Inventors: |
deZiegler, Dominique;
(Paris, FR) ; Bologna, William J.; (Paris, FR)
; Levine, Howard L.; (Oceanside, NY) |
Correspondence
Address: |
LYON & LYON LLP
SUITE 4700
633 WEST FIFTH STREET
LOS ANGELES
CA
90071-2066
US
|
Assignee: |
COLUMBIA LABORATORIES (BERMUDA)
LIMITED
14 Bermudiana Road
Pembroke
BM
HM08
|
Family ID: |
26743461 |
Appl. No.: |
09/825569 |
Filed: |
April 3, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09825569 |
Apr 3, 2001 |
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09170326 |
Oct 13, 1998 |
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60063485 |
Oct 21, 1997 |
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Current U.S.
Class: |
514/171 ;
514/177 |
Current CPC
Class: |
A61P 15/00 20180101;
A61K 31/57 20130101; A61P 15/12 20180101; A61K 9/7023 20130101;
A61P 5/24 20180101; A61P 5/00 20180101; Y10S 514/944 20130101; A61K
9/0034 20130101; A61P 15/18 20180101; A61P 5/34 20180101; A61K
47/32 20130101; A61K 31/57 20130101; A61K 31/565 20130101; A61K
31/57 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/171 ;
514/177 |
International
Class: |
A61K 031/57; A61K
031/56 |
Claims
We claim:
1. A method of promoting regular withdrawal bleeding in a woman
undergoing cyclical progestin administration comprising cyclical
vaginal delivery of progestin via a drug delivery system in an
amount sufficient to cause secretory transformation of the
endometrium while avoiding significant adverse side effects.
2. The method of claim 1 wherein the drug delivery system comprises
a water-insoluble, water-swellable cross-linked polycarboxylic acid
polymer.
3. The method of claim 2 wherein the polymer is polycarbophil.
4. The method of claim 3 wherein the progestin is progesterone.
5. The method of claim 4 wherein the amount of progesterone
delivered is about 45 mg to about 90 mg per dose.
6. The method of claim 4 wherein the drug delivery system
additionally comprises at least one adjuvant.
7. The method of either of claims 2 and 5 wherein the drug delivery
system is administered daily during a set portion of every calendar
month.
8. The method of claim 3 wherein the woman is also being treated
with estrogen.
9. The method of claim 7 wherein the woman is also being treated
with estrogen.
10. A method of maintaining amenorrhea in a woman undergoing
constant progestin administration comprising constant vaginal
administration of progestin via a drug delivery system in an amount
sufficient to cause endometrial atrophy while avoiding significant
adverse side effects.
11. The method of claim 10 wherein the drug delivery system
comprises a water-insoluble, water-swellable cross-linked
polycarboxylic acid polymer.
12. The method of claim 11 wherein the polymer is
polycarbophil.
13. The method of either of claims 10 and 12 wherein the progestin
is progesterone.
14. The method of claim 10 wherein the progestin is administered
about twice per week.
15. The method of claim 13 wherein the progestin is administered
about twice per week.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a method of administering
progestin therapy in a manner that promotes controlled bleeding,
rather than the irregular and unpredictable bleeding that normally
accompanies progestin administration.
BACKGROUND OF THE INVENTION
[0002] Progesterone is a naturally occurring steroid which is the
main steroid secreted by women during their reproductive years.
This steroid has been studied extensively and has been found to be
a major precursor in the biosynthesis of most other steroids,
particularly glucocorticoids, androgens and estrogens. Progesterone
also stimulates the growth of the uterus and a number of specific
changes in the endometrium and myometrium. It is essential for the
development of decidual tissue and the differentiation of luminal
and glandular epithelial tissue. Progesterone also plays several
roles in gestation, including breast enlargement, inhibition of
uterine contractility, maintenance of gestation, immunological
protection of the embryo, and inhibition of prostaglandin
synthesis.
[0003] Progestins include the natural progestin, progesterone, as
well as the synthetic progestins, such as medroxyprogesterone
acetate (MPA). Progestins have been used pharmaceutically in the
treatment of a number of clinical disorders such as luteal phase
deficiency, dysfunctional uterine bleeding, endometriosis,
endometrial carcinoma, benign breast disease, pre-eclampsia, and
assisting in vitro fertilization, preventing early abortion and
reducing the occurrence of endometrial hyperplasia in estrogen
replacement therapy (ERT).
[0004] The most common progestational agents used are the synthetic
progestins, which are accompanied by undesirable side effects such
as depression and water retention. Additionally, many of the
synthetic progestins derived from 19-nor-testosterone reverse the
positive effects of estrogen on lipoprotein (HDL) levels. In
contrast, natural progesterone does not cause water retention, is
rarely associated with depression and has no adverse effects upon
lipid levels.
[0005] There have been many difficulties in administering natural
progesterone at the appropriate serum and tissue levels to
patients. When given orally, progesterone is rapidly metabolized.
See e.g., Adlecruz, H. and Martin, F. J. Steroid Biochem.,
13:231-244 (1980) and Maxson, W. S., and Hargrove, J. T., Fertil.
Steril., 44:622-626 (1985).
[0006] Rectal administration of progestins has also been attempted
with 25 mg and 100 mg doses of natural progesterone, which achieved
peak plasma levels at 4 to 8 hours after administration followed by
a gradual decline, but the maintenance of a stable plasma level has
been difficult with this route. Maxson, W. S. Clinical Obstet.
Gynecol., 30: 465-477 (1987); Nillius, S. J. and Johansson, E. D.
B. Am. J. Obstet. Gynecol., 110: 470-479 (1971). Sublingual
administration resulted in rapid appearance of progesterone in the
serum reaching peak values of up to 10 times basal levels, but
returning to basal levels within twenty-four hours. Villanueva, B.,
et al., Fertil. Steril., 35: 433-437 (1981). Nasal administration,
using 20 mg and 30 mg doses, achieved mean maximum concentrations
of 2.1 and 4.1 ng/ml, respectively, at approximately 30 and 240
minutes, respectively.
[0007] Intramuscular administration of progesterone has been
attempted with 100 mg doses which achieved 40 to 50 ng/ml serum
concentrations in two to eight hours. Nillius, S. J. and Johansson,
E. D. B., Am. J. Obstet. Gynecol., 110: 470-479 (1971). Such
administration has shown that such injections need to be given
every day or on alternate days to produce results. Whitehead, M.,
and Godfree, V. in Hornone Replacement Therapy, Churchill
Livingston Edinburgh 1992, pp 91. Subdermal administration has also
been assayed, with six 100 mg progesterone pellets being implanted
in post-partum women. Croxatto, H. B., et al., Acta Endocrinol,
100: 630 (1982). Progesterone levels reached a peak of 4.4 ng/ml
within the first week after insertion and reached a mean peak level
of 1.9 ng/ml six months after implantation. Progestin implants are
not practical in cyclical therapy and moreover, physiological
levels of progestin are not achieved. ("Cyclical" therapy means
that the progestin is administered off and on, typically for a
portion of each 28-day cycle or each calendar month. For example,
cyclical administration could be daily, or every other day, only on
days 15 through 20 of each 28-day cycle, or only for the first five
days each month. "Constant" or "continuous" therapy means that the
drug is administered regularly, whether it is daily, every other
day, weekly, or otherwise, without regard, for example, to the
28-day cycle or the calendar month.)
[0008] It has been demonstrated that topically applied radioactive
progesterone can be absorbed through the skin. Mauvais-Jarvis,
Progesterone., et al., J. Clin. Endocrinol. Metab., 29: 1580-1587
(1969). Labeled metabolites were recovered in the urine at 48 hours
after topical administration. However, the absorption was only 10%
of the applied dose. The high fat solubility of progesterone is
responsible for the prolonged retention of this steroid and the
extensive local metabolism reduces the systemic effect of the
steroid. It has been shown that treatment with topical application
of progesterone to the breast produces no significant endometrial
effects. Sitruk-Ware, R., et al., J. Clin. Endocrin. Metab., 44:
771-774 (1977).
[0009] Progestins have also been administered vaginally to
postmenopausal women receiving ERT. 50 mg/ml of progesterone in a
suspension containing carboxymethyl cellulose and methyl cellulose
which was inserted into the vagina was characterized by a rapid
absorption of the progesterone across the vaginal mucosa. There was
an immediate appearance of the hormone in the peripheral
circulation resulting in a 10-fold increase over the baseline serum
levels (0.34 ng/ml) after 15 minutes. The peak levels were obtained
1 or 2 hours after administration and represented a thirty- to
forty-fold increase over baseline levels (12.25 ng/ml). The serum
levels remained at this level over the next seven hours, declining
over the next ten hours to 3.68 ng/ml. Villanueva, B., et al.,
Fertil. Steril., 35: 433-437 (1981). These results suggested that
the absorption of progestins was enhanced in women also undergoing
ERT.
[0010] As described in U.S. Pat. No. 5,543,150 ("the '150 Patent"),
which is incorporated herein by reference, it now appears that the
bioadhesive formulation used with the instant invention can provide
local vaginal administration of progestins to yield significant
local drug levels while maintaining serum levels low enough to
avoid most of the undesired side effects. See also, Warren, M. P.,
et al., Evaluation of Crinone.RTM., a Transvaginally Administered
Progesterone Containing Bioadhesive Gel, in Women with Secondary
Amenorrhea, Abstract, Presented at the 8th International Congress
on the Menopause, Sydney, Australia, 1996. And as described in U.S.
patent application Ser. No. 08/743,153, which is incorporated
herein by reference, it also appears that progesterone can be
administered for the purpose of treating or reducing ischemia or
incidence of cardiovascular events.
[0011] Treatments of menopausal and post-menopausal women involving
administration of progestins in cyclical association with estrogen
induces the physiological sequence of endometrial changes normally
encountered in the menstrual cycle. Such treatments usually
administer progestins, usually daily, over a period of about 10 to
14 days each month. However, the withdrawal bleeding that results
from such administration is typically irregular and unpredictable,
and often begins as early as about the fourth day following the
first progestin dose. See, Archer, D. F., et al., Bleeding Patterns
in Post-menopausal Women Taking Continuous Combined or Sequential
Regimens of Conjugated Estrogens with Medroxyprogesterone Acetate,
Obstet. Gynecol., 83:686-92 (1994).
SUMMARY OF THE INVENTION
[0012] The present invention comprises a method of cyclical vaginal
administration of progestins daily, while avoiding significant
adverse side effects, in order to avoid the often-erratic monthly
withdrawal bleeding normally associated with cyclical progestin
treatment, and instead to provide regular withdrawal bleeding upon
completion of the progestin-administration period. Thus the
invention provides the benefits of cyclical progestin therapy
without the inconvenience and complications of irregular withdrawal
bleeding, and without common side effects.
[0013] The present invention also comprises a method of constant
vaginal administration to maintain complete amenorrhea while
avoiding significant adverse side effects. Thus, the invention
provides complete amenorrhea without the periodic breakthrough
bleeding or spotting often observed with other methods for three to
six months, and without significant adverse side effects often
resulting from other methods.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 illustrates the bleeding pattern produced by a 45 mg.
dose of progestin (CRINONE.RTM. 4% progesterone gel) cyclically
administered every day vaginally.
[0015] FIG. 2 illustrates the bleeding pattern produced by a 45 mg
. dose of progestin (CRINONE.RTM. 4% progesterone gel) cyclically
administered every other day vaginally, as reported in Warren, M.
P., et al., Evaluation of Crinone.RTM., a Transvaginally
Administered Progesterone Containing Bioadhesive Gel, in Women with
Secondary Amenorrhea, Abstract, Presented at the 8th International
Congress on the Menopause, Sydney, Australia, 1996.
[0016] FIG. 3 illustrates the bleeding pattern produced by a 90 mg.
dose of progestin (CRINONE.RTM. 8% progesterone gel) cyclically
administered every other day vaginally, also as reported in Warren,
M. P., et al., Evaluation of Crinone.RTM. . . . , cited above.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention is related to a method of treating
with progestins comprising use of a therapeutically effective
amount of progestin for vaginal administration to menopausal and
post-menopausal women in an improved regimen in order to promote
regular withdrawal bleeding. Daily vaginal dosing of CRINONE.RTM.
4% progesterone gel to estrogenized women was demonstrated to
produce endometrial transformation, but with monthly withdrawal
bleeding consistently and predictably occurring only after the
progestin administration is complete--only upon true "withdrawal"
from the progestin administered.
[0018] The present invention is also related to a method of
treating with progestins comprising use of a therapeutically
effective amount of progestin for vaginal administration to
menopausal and post-menopausal women in an improved regimen for
maintaining amenorrhea. Constant rather than cyclical association
of estrogens and progestins is proposed in menopausal and
post-menopausal women in order to avoid monthly withdrawal bleeding
altogether. Azzawi, A. J., de Ziegler, D., Vaginal Progesterone
Gel-based Continuous Combined HRT as an Amenorrheic Regimen,
Presented at IV European Congress on Menopause, Vienna, October
1997. Constant, or regular, administration of progestins throughout
the month, without break, promotes amenorrhea, or a total lack of
bleeding. However, just as with pregnancy-induced amenorrhea,
constant administration of progestins does not produce the
often-desired physiological endometrial changes associated with the
menstrual cycle, during which the endometrium undergoes monthly
transformation and shedding. Instead, the endometrium undergoes a
maintained state of atrophy.
[0019] Even when endometrial atrophy, and thus amenorrhea, are
desired to be maintained, continuous daily vaginal administration
of progestins is impractical and inconvenient. We also have studied
the sustained release properties of the progestin gel described in
the '150 Patent, and achieved constant uterine exposure to constant
administration of progesterone while limiting vaginal applications
to a reasonable twice a week. CRINONE.RTM. 8% progesterone gel,
available from Wyeth-Ayerst Laboratories, of Philadelphia, Pa., was
shown to maintain amenorrhea upon bi-weekly dosing to women already
receiving constant transdermal estrogen therapy. This
administration achieved and maintained endometrial atrophy as
expressed by the high incidence of amenorrhea and thin endometrium
as revealed by ultrasound examination. This simple, easy regimen,
devoid of the common side effects and problems encountered with
synthetic progestins or oral administration, is a new clinical
option for menopausal and post-menopausal women wishing to avoid
withdrawal bleeding altogether while receiving progestins. See,
'Fanchin, R., de Ziegler, D., et al., Transvaginal Administration
of Progesterone: Dose-response Data Support a First Uterine Pass
Effect, Obstet. Gynecol., 90:396-401 (1997).
[0020] Contrary to other administrations of progestin discussed in
the art, the regimen of daily cyclical treatment with progestin
produced reliable, regular withdrawal bleeding only after the
progestin administration period. This provides substantial
convenience to women on progestin therapy, without the uncertainty
and inconvenience of irregular and unpredictable onset of bleeding.
And the regimen of constant treatment with progestin maintained
complete amenorrhea. This provides convenience to women seeking
amenorrhea, without the periodic breakthrough bleeding or spotting
common for three to six months with other methods of treatment.
[0021] The invention comprises use of a progestin formulation for
daily vaginal administration while promoting regular withdrawal
bleeding after monthly progestin administration is completed, or
for constant vaginal administration while maintaining complete
amenorrhea. Preferably, the progestin formulation comprises
progesterone and a bioadhesive carrier, which may be in a gel
formulation, containing a polymer base designed to give controlled
and prolonged release of the progesterone through the vaginal
mucosa. This route of administration also avoids first-pass
metabolism problems as well as many significant adverse events.
[0022] The present invention comprises a dosing regimen and manner
of treating with progestin in hormone replacement therapy.
Preferably, about 45 mg to 90 mg of progesterone is administered at
one time. The composition for cyclical administration is preferably
administered daily for part of each cycle, which preferably is
based on calendar months for convenience. The composition for
constant administration is preferably administered about twice per
week. Most preferably, only natural progesterone itself is
used.
[0023] The specific drug delivery formulations preferred, which
were chosen and used in Examples 1 and 2, CRINONE.RTM. 8% and 4 +L%
progesterone gels from Wyeth-Ayerst Laboratories, Philadelphia,
Pa., comprise cross-linked polycarboxylic acid polymer
formulations, generally described in U.S. Pat. No. 4,615,697 to
Robinson (hereinafter "the '697 patent") and in the '150 Patent,
each of which is incorporated herein by reference. In general, at
least about eighty percent of the monomers of the polymer in such a
formulation should contain at least one carboxyl functionality. The
cross-linking agent should be present at such an amount as to
provide enough bioadhesion to allow the system to remain attached
to the target epithelial surfaces for a sufficient time to allow
the desired dosing to take place.
[0024] For vaginal administration, such as in the examples below,
preferably the formulation remains attached to the epithelial
surfaces for a period of at least about twenty-four to forty-eight
hours. Such results may be measured clinically over various periods
of time. This preferred level of bioadhesion is usually attained
when the cross-linking agent is present at about 0.1 to 6.0 weight
percent of the polymer, with about 1.0 to 2.0 weight percent being
most preferred, as long as the appropriate level of bioadhesion
results. Bioadhesion can also be measured by commercially available
surface tensiometers utilized to measure adhesive strength.
[0025] The polymer formulation can be adjusted to control the
release rate of the progesterone by varying the amount of
cross-linking agent in the polymer. Suitable cross-linking agents
include divinyl glycol, divinylbenzene, N,N-diallylacrylamide,
3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene and similar
agents.
[0026] A preferred polymer for use in such a formulation is
Polycarbophil, U.S.P., which is commercially available from B.F.
Goodrich Speciality Polymers of Cleveland, Ohio under the trade
name NOVEON.RTM.-AA1. The United States Pharmacopeia, 1995 edition,
United States Pharmacopeial Convention, Inc., Rockville, Md., at
pages 1240-41, indicates that polycarbophil is a polyacrylic acid,
cross-linked with divinyl glycol.
[0027] Other useful bioadhesive polymers that may be used in such a
drug delivery system formulation are mentioned in the '697 patent.
For example, these include polyacrylic acid polymers cross-linked
with, for example, 3,4-dihydroxy-1,5-hexadiene, and polymethacrylic
acid polymers cross-linked with, for example, divinyl benzene.
[0028] Typically, these polymers would not be used in their salt
form, because this would decrease their bioadhesive capability.
Such bioadhesive polymers may be prepared by conventional free
radical polymerization techniques utilizing initiators such as
benzoyl peroxide, azobisisobutyronitrile, and the like. Exemplary
preparations of useful bioadhesives are provided in the '697
patent.
[0029] The bioadhesive formulation may be in the form of a gel,
cream, tablet, pill, capsule, suppository, film, or any other
pharmaceutically acceptable form that adheres to the mucosa and
does not wash away easily. Different formulations are further
described in the '697 Patent, which is incorporated herein by
reference.
[0030] Additionally, the additives taught in the '697 patent may be
mixed in with the cross-linked polymer in the formulation for
maximum or desired efficacy of the delivery system or for the
comfort of the patient. Such additives include, for example,
lubricants, plasticizing agents, preservatives, gel formers, tablet
formers, pill formers, suppository formers, film formers, cream
formers, disintegrating agents, coatings, binders, vehicles,
coloring agents, taste and/or odor controlling agents, humectants,
viscosity controlling agents, pH-adjusting agents, and similar
agents.
[0031] A preferred progestin composition is CRINONE.RTM. 4% or 8%
progesterone gel, which consists of the following ingredients
discussed further in the '150 Patent: 4 or 8 weight percent
progesterone, 12.9 weight percent glycerin, 4.2 weight percent
mineral oil, 2 weight percent polycarbophil (available from B.F.
Goodrich Specialty Polymers of Cleveland, Ohio), 1 weight percent
hydrogenated palm oil glyceride, 1 weight percent carbomer 934P
(available from B.F. Goodrich), 0.08 weight percent sorbic acid, 0
- 2 weight percent sodium hydroxide, and the remaining part
purified water. (This is the same basic formula discussed in the
'150 Patent at column 6, lines 44-52, except that methylparaben is
not presently included.) Sorbic acid is a preservative, which may
be substituted by any other approved preservative, such as
methylparaben, benzoic acid or propionic acid.
[0032] Carbomer 934P is a gel former, which may be substituted by
other gel formers, such as carbomer 974P, carbomer 980, methyl
cellulose or propyl cellulose.
[0033] Glycerin is a humectant; alternative humectants include, for
example, propylene glycol or dipropylene glycol.
[0034] Mineral oil and hydrogenated palm oil glyceride are
lubricating agents; alternatives include, for example, any mineral
or vegetable oil, such as canola oil, palm oil, or light mineral
oil.
[0035] Sodium hydroxide is simply a strong base for purposes of
controlling the pH level; other bases commonly used for that
purpose may be substituted.
[0036] Preparation of the formulation involves hydration of the
polymers, separate mixing of water-soluble ingredients (the
"polymer phase") and oil-soluble ingredients (the "oil phase"),
heating and mixing of the two phases, and homogenization of the
mixture. All ingredients listed above are well-known and readily
available from suppliers known in the industry.
[0037] The polymer phase may generally be prepared by mixing the
water, sorbic acid, polycarbophil, and carbomer are added. The
polymers are hydrated by mixing for several hours, generally about
2-3 hours until a uniform, smooth, homogenous, lump-free gel-like
polymer mixture is obtained. When the polymers are completely
hydrated, the progesterone is added and mixed in, until a
homogeneous suspension is obtained.
[0038] The oil phase is generally prepared by melting together the
glycerin and mineral oil, by heating to 75 to 78.degree. C. The
mixture is cooled to about 60.degree. C., while the polymer phase
is warmed to about the same temperature. The polymer phase is then
added to the heated oil phase. The two phases are mixed thoroughly,
producing a uniform, creamy white product. If needed, mix in sodium
hydroxide to produce a pH of about 2.5-3.5, generally about 3. When
the mixture has cooled, it is de-aerated. The resulting product is
aseptic because of the nature of the preparation and pH as well as
the presence of the preservative.
[0039] As will be apparent to those skilled in the art, the
composition of the formulation can be varied to affect certain
properties of the formulation. For example, the concentration of
the bioadhesive polymer can be adjusted to provide greater or
lesser bioadhesion. The viscosity can be varied by varying the pH
or by changing the concentration of the polymer or gel former. The
relative concentrations of the oils compared to the water can be
varied to modulate the release rate of the progestin from the drug
delivery system. The pH can also be varied as appropriate or to
affect the release rate or bioadhesiveness of the formulation.
[0040] The progestin formulation may be delivered vaginally in any
of a variety of fashions known in the art, such as by plunger,
douche, suppository, or manually. A preferred method of delivery is
using a device such as that described in U.S. Pat. No. Des.
D345,211 or U.S. Pat. No. Des. D375,352, which disclosures are
incorporated herein by reference. Such a device is an oblong hollow
container, with one end capable of being opened and the other end
containing most of the composition to be delivered and capable of
being squeezed. Such devices allow for pre-measurement of the
amounts of product to be delivered in a single dosage by a sealed
container which may be used relatively easily. The containers also
maintain the product in an aseptic environment until use. Upon use
the container is opened and the open end is inserted into the
vagina, while the other end is squeezed to expel the contents of
the container into the vagina. A `kit` of the product can therefore
contain a single dose or multiple doses of the product.
EXAMPLE 1
Daily vs. Twice-Weekly Cyclical, and Constant, Administration of
Progesterone
[0041] This study was designed to examine the use of CRINONE.RTM.
progesterone gel in menopause as part of hormone replacement
therapy ("HRT") in cyclical association with estrogen therapy, and
in constant combined association with estrogen for a no-bleed
regimen. The results from the first groups of subjects in the study
are reported here. (The study continued with additional subjects;
complete results from all subjects, including those discussed in
Example 1, are reported below at Example 3.)
[0042] Two groups of women were assembled, each with 20 women.
Group I ranged in age from 38 to 55 years old, and each woman
exhibited menopausal symptoms or was already on HRT. Group II
ranged in age from 50 to 64, and each woman was more than 3 years
into menopause (amenorrhea), or on HRT with cyclical bleeding. None
of the woman in either group exhibited abnormal bleeding or any
other uterine pathology.
[0043] Group I received estrogen continuously (PREMARIN.RTM. (0.625
mg) conjugated estrogens (Wyeth-Ayerst Laboratories, Philadelphia,
Pa.), PROGYNOVA.RTM. (2 mg) estradiol valerate (Schering A. G.,
Berlin, Germany), or ESTRADERM.RTM. TTS (50 mg) or ESTRADERM.RTM.
MX 0.05 (0.050 mg) estrogen patches (Novartis Pharmaceutical,
Basel, Switzerland)), and CRINONE.RTM. 4% progesterone gel (45 mg.
progesterone) every day in the morning from cycle days 15 to 24.
(For practical purposes and convenience, administration took place
monthly on calendar days 1 to 10, corresponding to cycle days 15 to
24.) Group II received ESTRADERM.RTM. Mx (50 mg) estrogen patch
(Novartis Pharmaceutical) twice weekly, continuously (or if
intolerant to the patch, OESTROGEL.RTM. estrogen gel
(Besins-Iscovesco Laboratories, Paris, France) every day), and
CRINONE.RTM. 8% progesterone gel (90 mg progesterone) twice a week
in the morning, continuously.
[0044] For all subjects, the baseline clinical assessment included
a clinical exam, and a vaginal ultrasound to screen for women on no
pre-existing treatment less than 5 mm thick, and for women on HRT
or with persistent ovarian function less than 10 mm thick. In Group
1, the women were informed to report any vaginal bleeding other
than withdrawal bleeding defined as menses-like bleeding starting
after the last (tenth) progesterone dose.
[0045] Treatments were administered in months six to twelve, after
baseline was established for months zero to six. At the conclusion,
all women were again clinically examined, including a vaginal
ultrasound, and endometrial sampling if the ultrasound showed for a
group 1 woman an endometrium greater than 10 mm thick, or for a
group 2 woman an endometrium greater than 5 mm thick. The results
are reported in Charts 1 and 2 and in FIG. 1.
1CHART 1 ULTRASOUND - ENDOMETRIAL THICKNESS (mm., mean .+-. SEM) On
treatment Baseline (6-12 months) Group I 4.5 .+-. 1.5 4.5 .+-. 0.8
Group II No HRT 3.2 .+-. 0.6 No bleed 3.3 .+-. 1.0 HRT 6.3 .+-.
1.39 Bleeding 3.5 .+-. 1.1
[0046]
2CHART 2 BLEEDING PATTERN Mean Age Type of bleeding n % Disposition
Group I 46.8 .+-. 4.1 Expected Withdrawal only 19/20 95 100%
Continued HRT Abnormal Breakthrough and/or 1/20 5 n = 1;
discontinued other abnormal HRT bleeding Group II 57.5 .+-. 4.6
Expected Amenorrhea 15/20 75 n = 13 (87%) (no bleed) continued HRT
n = 1: changed regimen n = 1: stopped HRT Acceptable Isolated
spotting/ 4/20 20 n = 4: all mild bleeding continued Unacceptable
Heavy bleeding/ 1/20 5 n = 1: D&C repeated spotting Benign
histology
[0047] FIG. 1 shows the proportion of patients with bleeding, and
the titing of that bleeding, for the Group 1 subjects being
administered daily progesterone. In contrast, FIGS. 2 and 3 show
the proportion of patients with bleeding, and the timing of that
bleeding, for patients receiving, respectively, 45 mg. and 90 mg.
of progesterone (CRINONE.RTM. 4% or 8% progesterone gel) every
other day, as reported by Warren, et al., cited herein
previously.
[0048] As detailed in Chart 2 and FIG. 1, cyclical administration
to Group 1 subjects of daily CRINONE.RTM. progesterone gel resulted
in 95% of the subjects experiencing withdrawal bleeding only after
the monthly progestin dosing periods. Thus daily dosing profoundly
changed the bleeding pattern, resulting in regular bleeding within
1 to 4 days of completing monthly progesterone treatment, with no
other form of bleeding in 95% of the patients. All of these
regularly-bleeding patients continued their HRT program, while the
single irregularly-bleeding patient discontinued HRT
altogether.
[0049] In contrast, CRINONE.RTM. progesterone gel cyclically
administered every other day produced bleeding patterns similar to
those achieved with synthetic progestins (MPA), regardless of the
strength of the CRINONE.RTM. progesterone gel used (4% (45 mg) or
8% (90 mg)). See Warren, et al., cited previously herein regarding
CRINONE.RTM. progesterone gel and reflected in FIGS. 2 and 3, in
comparison with Archer, et al., cited previously herein regarding
MPA. Such a daily regimen is thus very attractive when perfect
control of bleeding is desired.
[0050] For Group 2, with constant CRINONE.RTM. progesterone gel
dosing, 75% of the subjects did not experience withdrawal bleeding,
and only 5% (one of the twenty subjects) experienced heavy bleeding
or repeated spotting. Of the 15 patients without bleeding, 13
continued their HRT program (as did all 4 of the patients with
isolated spotting or mild bleeding), 1 changed her regimen and 1
stopped HRT. The sole subject with heavy bleeding or repeated
spotting underwent a D&C (dilatation and curettage), with
benign histology; her HRT was discontinued.
[0051] Thus, CRINONE.RTM. progesterone gel administered twice a
week continuously in estrogenized menopausal woman maintained
complete amenorrhea in a majority of patients. Pilot data elsewhere
showed similar efficacy with CRINONE.RTM. 4% progesterone gel (45
mg. progesterone). The lack of side effects makes this regimen a
very attractive option for menopausal women who do not wish to have
menses. Prior regimens have often led to periodic breakthrough
bleeding or spotting for three to six months.
EXAMPLE 2
[0052] Constant Administration of Progesterone Eighteen women at
least three years into menopause or at least 53 years of age
received transdermal estrogen therapy (ESTRADERM.RTM. TTS (50 mg)
or ESTRADERM.RTM. Mx (50 mg) estrogen patches) constantly, and
twice per week application of 1.125 g of CRINONE.RTM. 8%
progesterone gel (90 mg. progesterone). An ultrasound was performed
at 6 months.
[0053] After 6 months of treatment, 13 of 18 subjects had remained
amenorrheic during treatment. Of the 5 women who experienced
bleeding, 4 had only mild and intermittent bleeding, and only 1 had
heavier bleeding. At six months, all women had an endometrium less
than 5 mm thick. Of the 13 amenorrheic women, 10 were satisfied and
continued their treatment, 2 switched to a different HRT regimen
and 1 stopped HRT altogether.
[0054] Again, CRINONE.RTM. progesterone gel administered
continuously, twice a week, maintained complete amenorrhea in a
majority of patients.
EXAMPLE 3
Daily vs. Twice-Weekly Cyclical, and Constant, Administration of
Progesterone
[0055] In a continuation of the study reported above in Example 1,
this study continued to examine the use of CRINONE.RTM.
progesterone gel in menopause as part of hormone replacement
therapy ("HRT") in cyclical association with estrogen therapy, and
in constant combined association with estrogen for a no-bleed
regimen. Group I included a total of 69 women, and Group II
included a total of 67 women. Group II women were more than three
years into menopause, or more than 53 years of age, and free of
bleeding disorders.
[0056] Women in both groups were evaluated after six months of
treatment, and at six-month intervals thereafter. Endometrial
thickness was evaluated on ultrasound, and the results through
eighteen months of treatment are reported at Chart 3. Bleeding
patterns through six months are reported at Chart 4. In a subset of
fourteen women evaluated at eighteen months, twelve remained
amenorrheic for the entire observation period.
3CHART 3 ULTRASOUND - ENDOMETRIAL THICKNESS (mm., mean .+-. SEM) On
treatment Baseline (6-18 months) Group I 4.1 .+-. 1.5 4.9 .+-. 0.9
Group II No HRT 3.7 .+-. 0.7 No bleed 3.9 .+-. 1.2 HRT 6.7 .+-.
1.45 Bleeding 3.8 .+-. 1.76
[0057]
4CHART 4 BLEEDING PATTERN Mean Age Type of bleeding n % Group I 50
.+-. 1.5 Expected Withdrawal only 63/69 91.3 Abnormal Breakthrough
6/69 8.7 and/or other abnormal bleeding Group II 58 .+-. 5.3
Expected Amenorrhea 54/67 80.6 (no bleed) Acceptable Isolated
spotting/ 9/67 13.4 mild bleeding Unacceptable Heavy bleeding/ 4/67
6 repeated spotting
[0058] Consistent with Chart 2 and FIG. 1 discussed above in
Example 1, Chart 4 demonstrates that administration to Group 1
subjects of daily CRINONE .RTM. progesterone gel resulted in 91.3%
(sixty three out of sixty nine) of the subjects experiencing
withdrawal bleeding only after each of the six monthly progestin
dosing periods. Thus daily dosing profoundly changed the bleeding
pattern, resulting in regular bleeding within 1 to 4 days of
completing monthly progesterone treatment, with no other form of
bleeding in 91.3% of the patients. Of these sixty three subjects,
fifty eight, or 92%, elected to remain on the vaginal progesterone
for HRT, two opted for another treatment option and three
discontinued all hormone treatment.
[0059] For Group 2 subjects, with constant CRINONE.RTM.
progesterone gel dosing, 80.6% of the subjects did not experience
withdrawal bleeding, only 6% experienced heavy bleeding or repeated
spotting, and 13.4% experienced isolated spotting or mild bleeding
at anytime during the six-month evaluation period.
[0060] Thus, results from the larger pool of test subjects
(relative to the first groups reported above at Example 1) further
demonstrates that progestin administered twice a week continuously
in estrogenized menopausal woman maintained complete amenorrhea in
the vast majority of test subjects. And the cyclical daily
administration of progestin in woman undergoing HRT provided much
more reliable and regular withdrawal bleeding. Especially in
combination with the lower incidence of side effects, either
regimen should lead to improved HRT compliance.
[0061] Any and all publications, patents, and patent applications
mentioned in this specification are indicative of the level of
skill of those skilled in the art to which this patent pertains.
All publications, patents, and patent applications are herein
incorporated by reference to the same extent as if each individual
publication, patent, or patent application was specifically and
individually indicated to be incorporated by reference.
[0062] Reasonable variations, such as those which would occur to a
skilled artisan, can be made without departing from the spirit and
scope of the invention.
* * * * *