Note: Descriptions are shown in the official language in which they were submitted.
CA 02501846 2002-06-26
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THERAPEUTIC COMB1NATIONS FOR THE TREATMENT
OF HORMONE DEFICIENCIES
FIELD OF THE INVENTION
The present invention relates to methods, combinations, and compositions for
treating,
preventing,lor reducing the risk of developing an androgenic or estrogenic
hormone deficiency in
a riiale or female subject, or for treating, preventing, or reducing the risk
of developing the
symptoms associated with, or related to, an androgenic or estrogenic
deficiency in a male or
female subject.
BACKGROUND OF THE INVENTION
Research into "male menogaaase" or "andropause" shows that these is a drastic
drop of
serum levels of free testosterone of about 1.5% per year after puberty. While
the total
testosterone of a male does not drop drastically, the free testosterone, which
is the biologically
active part of the testosterone, does drop precipitously with aging. In fact,
a significant drop of
free testosterone can occur as early as the early forties. Studies have shown
that men with high
testosterone levels live longer, healthier lives and maintain sexual potency.
Studies have also
shown that testosterone has the ability to stop the spread of breast cancer in
females.
Additionally, research has shown that testosterone has a protective effect
against sutoimmune
diseases.
The female hormones, estrogen and progesterone, are known to drop drastically
to very
low levels after menopause. The American College of Physicians and the
American College of
Obstetricians and Gynecologists has released position papers saying post-
menopausal women
should seriously consider preventive estrogen/progesterone hormone replacement
therapy for
their benefit in reducing osteoporosis and heart disease. Maintaining estrogen
and progesterone
levels has also been shown to improve a number of key risk factors for heart
disease in post-
menopausal women. The benefits of estrogen/progesterone hormone replenishment
therapy
include prevention of osteoporosis and heart disease, prevention of vaginal
dryness and thinning
of the vaginal wall, relief from menopausal symptoms and hot flashes, and the
possible benefit of
reducing the onset of Alzheimer's disease, dementia, and cataracts. Studies
have shown that
CA 02501846 2002-06-26
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when estrogen is replenished in conjunction with progesterone, the rislc~ of
uterine or breast
cancer is nullified.
A. Androgen Synthesis, Metabolism and Regulation
Androgens constitute a group of 19-carbon steroid hormones that exert
influence on the
male genital tract and are involved with the development and maintenance of
secondary male sex
characteristics such as beard growth, deepening of the voice at puberty,
muscle and bone
development, body strength, and sexual drive. Androgens are synthesized in the
male testis, in
the female ovary, and in the adrenal cortex of both sexes. Once released into
the blood, these
endogenous androgens serve both as hormones and as prohormones for the
formation of two
different classes of steroids: 5 alpha -reduced androgens, which act as the
intracellular mediators
of must actions of the male sex'hormunes, and estrogens, which enhance some
androgenic
effects and block others.
Testosterone, the major circulating androgen in men, is synthesized from
cholesterol.
The approximately S00 million Leydig cells in the testes secrete more than 95%
of the 6-7 mg of
testosterone produced per day. In women, the ovary and adrenals synthesize
small amounts of
testosterone. Typically, testosterone is reduced at the 5 alpha position into
dihydrotestosterone,
which serves as the intracellular mediator of most hormone actions. Although a
variety of other
naturally occurring androgens have been identified, these are generally weak
in potency; and it is
now generally believed that they are androgens only to th'e extent that they
can be converted in
vivo to testosterone and/or dihydrotestosterone. Two hormones produced by the
pituitary gland,
luteinizing hormone ("LH") and follicle stimulating hormone ("FSH"), are
required for the
development and maintenance of testicular function and negatively regulate
testosterone
production. Circulating testosterone is metabolized to various 17-keto
steroids through two
different pathways. Testosterone can be metabolized to dihydrotestosterone
("DHT") by the
enzyme Sa-reductase or to estradiol ("EZ") by an ammatase enzyme complex.
The gut metabolizes orally administered testosterone and the liver clears
about 44% in
the first pass. To achieve clinically effective blood levels of testosterone,
oral doses as high as
400 mg per day are required. The liver does not as extensively metabolize
synthetic androgens,
2
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such as methyltestosterone and fluoxymesterone, and thus the synthetic
androgens are more
suitable for oral administration.
The major metabolites of androgens in urine are physiologically inactive
either as free
steroids or as water-soluble conjugates. These metabolites are predominantly
etiocholanolone, a
S alpha -reduced metabolite of testosterone; and androsterone, a metabolite of
dihydrotestc~sterone. It is now also recognized that testosterone (but not
dihydrotestosterone) can
be aromatized into estradiol in a variety of extraglandular tissues, a pathway
that accounts for
most estrogen synthesis in men and posttnenopausal women. The role, if any, of
the
approximately 50 micrograms of estradiol synthesized each day in normal men
has never been
defined. Nevertheless, the production of estradiol is considered a normal
phenomenon.
Experimental evidence suggests that estradiol affects the proliferation of
male sex secotldary
organs, and that estradiol is necessary to induce prostate cancer in animal
models.
Testosterone circulates in the blood 98% bound to protein. In men,
approximately 40%
of the binding is to the high-affinity sex hormone binding globulin ("SHBG").
The remaining
60% is bound weakly to albumin. Thus, a number of measurements for
testosterone are
available from clinical laboratories. The term "free" testosterone as used
herein refers to the
fraction of testosterone in the blood that is not bound to protein. The term
"total testosterone" or
"testosterone" as used herein means the free testosterone plus protein-bound
testosterone. .The
term "bioavailable testosterone" as used herein refers to the non-sex hormone
binding globulin
bound testosterone and includes that weakly bound to albumin. Plasma
concentrations of sex
hormone binding globulin determine the ratio of free testosterone to bound
testosterone. Total
serum testosterone can be measured by assays such as a radioimmunoassay, see,
for example,
Furuyama ei al., ltadioimmunoassay for Plasma Testosterone, Steroids, 16:415-
428 (1970).
The following table from the UCLA-Harbor Medical Center summarizes the hormone
concentrations in normal adult men range:
3
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Table 1: Hormone
Levels in Normal
Me>r
Hormone Normal Range
Testosterone298 to 1043 ng/dL ,
Free testosterone3.5 to ,17.9 ng/dL
DHT 31 to 193 ng/dL
DHT/T Ratio 0.052 to 0.33 '
DHT + T 372 to 1349 ng/dL
SHBG 10.8 to 46.6 nmoUL
FSH 1.0 to 6.9 m1U%mL
LH 1.0 to 8.1 m1U/mL
E2 17.1 to 46.1 pg/mL
The normal range for total serum testosterone levels in healthy premenopausal
women
was reported to be 14 to 53.3 ngldL (Miller et al., Transdennal Testosterone
Administration in
Women with Acquired Immunodeficiencv Syndrome Wasting: A Pilot Study, J. of
Clinical
Endocrinology and Metabolism, Vol. 83(8): 2717-25 (199,8)). Using an ammonium
sulfate
precipitation method, the normal range of free testosterone levels in normal
premenopausal
women was reported to be between 1.6 to 12.7 ng/dL (Napkin et al., Daytime
Titers of
Testosterone, LI-i Estron~, Estradiol, and Testosterone-Bindinrz Protein:
Acute Effects of LH and
LH-Releasing Hormone in Men, J. Clinical Endocrinology Metabolism, Vol. 41:271-
81 (1975).
Using the equilibrium dialysis method, free testosterone levels measured in
healthy
premenopausal women was reported to be around 1.3 to 6.8 pg/ml, see, for
example, Mather, et
al., Free Plasma Testosterone Levels Durinu the Normal Menstrual Cycle. J
Endocrinol Invest.
1985 Oct;B(5):437-41.
There is considerable variation in the half life of testosterone reported in
the literature,
ranging from 10 to 100 minutes. Researchers do agree, however, that
circulating testosterone
has a diurnal variation in normal young men. Maximum levels occur at
approximately 6:00 a.m.
to 8:00 a.m. with levels declining throughout the day. Characteristic profiles
have a maximum
testosterone level of 720 ng/dL and a minimum level of 430 ng/dL. The
physiological
significance of this diurnal cycle, if any, however, is not clear.
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B. Testosterone Levels and Sexual Behavior/Performance
Because increasing testosterone concentrations has been shown to alter sexual
performance and libido, researchers have investigated methods of delivering
testosterone to men.
These methods include intramuscular injections (43%), oral replacement (24%),
pellet implants
(23%), and transdermal patches (10%). A summary of these methods is shown in
Table 2.
Table 2: Mode of Application and Dosage of Various Testosterone Preparations
Preparation Route Of ApplicationFull Substitution
Dose
In Clinical Use
Testosterone enanthateIntrarauscular injection200-25.0 g every
2-3 weeks
Testosterone cypionateIntramuscular m~ection2u0 mg every 2 weeks
Testosterone undecanoateOral 2-4 capsules at 40
mg per day
Transdermal testosteroneScrotal skin 1 membrane per day
patch Non-scrotal skin 1 or 2 systems per
day
Transdermal testosteroneImpl~~tion under 3-6 implants of 200
the mg every
patch abdominal skin 6 months
Testosterone implants
Under Development
Testosterone cyclodextrinSublingual 2.5-5.0 mg twice
daily
Testosterone undecanoateIntramuscular injection1000 mg every 8-10
weeks
Testosterone buciclateIntramuscular injection1000 mg every 12-16
weeks
Testosterone microspheresIntramuscular injection315 mg for 11 weeks
Obsolete
17a-MethyltestosteroneOral 25-5.0 g per day
Fluoxymesterone Sublingual 10.25 mg per day
Oral 10-20 mg per day
C. ~ Hypogonadal Men and Current Treatments for Hypogonadism
Male hypogonadism results from a variety of patho-physiological conditions in
which
testosterone concentration is diminished below the normal range. The
hypogonadic condition is
sometimes linked with a number of physiological changes, such as diminished
interest in sex,
impotence, reduced lean body mass, decreased bone density, lowered mood, and
energy levels.
Researchers generally classify hypogonadism into one of three types. Primary
hypogonadism
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includes the testicular failure due to congenital or acquired anorchia, 7~YY
Syndrome, XX males,
Noonan's Syndrome, gonads! dysgenesis, Leydig cell tumors, maldescended
testes, varicocele,
Sertoli-Cell-Only Syndrome, cryptorchidism, bilateral torsion, vanishing
testis syndrome,
orchiectomy, Klinefelter's Syndrome, chemotherapy, toxic damage from alcohol
or heavy
metals, and general disease (renal failure, liver cirrhosis, diabetes,
myotonia dystrophica).
Patients with primary hypogonadism show an intact feedback mechanism in that
the low serum
testosterone concentrations are associated with high FSH and LH
concentrations. However,
because of testicular~or other failures, the high LH concentrations are not
effective at stimulating
testosterone production.
Secondary hypogonadism involves an idiopathic gonadotropin or LH-releasing
hormone
def ~aenc~r. This type of hynogonadism includes Kalhnan's Syndrome, Prader-
Labhart-Willi's
Syndrome, Laurence-Moon-Biedl's Syndrome, pituitary .insuffciencyladenomas,
Pasqualini's
Syndrome, hemochromatosis, hyperprolactine~ia, or pituitary-hypothalamic
injury from tumors,
trauma, radiation, or obesity. Because patieilts with secondary hypogonadism
do not
demonstrate an intact feedback pathway, the lowei testosterone concentrations
are not associated
~ with increased LH or FSH levels. Thus, these men have low testosterone serum
levels but have
gonadotropins in the normat to low range.
Third, hypogonadism may be age-related. Men experience a slow but continuous
decline
in average serum testosterone~aRer approximately age 20 to 30 years.
Researchers estimate that
the decline is about 1-2% per year. Cross-sectional studies in men have found
that the mean
testosterone value at age 80 years is approximately 75% of that at age 30
years. Because the
serum concentration of SHBG increases as men age, the fall in bioavailable and
free testosterone
is even greater than the fall in total testosterone. Researchers have
estimated that approximately
50% of healthy men between the ages of 50 and 70 have levels of bioavailable
testosterone that
are below the lower normal limit. Moreover, as men age, the circadian rhythm
of testosterone
concentration is often muted, dampened, or completely lost. The major problem
with aging
appears to be within the hypothalamic-pituitary unit. For example, researchers
have found that
with aging, LH levels do not increase despite the low testosterone levels.
Regardless of the
cause, these untreated testosterone deficiencies in older men may lead to a
variety of
physiological changes, including sexual dysfunction, decreased libido, loss of
muscle mass,
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decreased bone density, depressed mood, and decreased cognitive function. The
net result is
.geriatric hypogonadism, or what is commonly referred to as "male menopause"
Today, hypogonadism is the most common hormone deficiency in men, affecting 5
in
every 1,000 men. At present, it is estimated that only five percent of the
estimated four to five
million erican men of all ages with hypogonadism currently receive
testosterone replacement
therapy. Thus, for years, researchers have investigated methods of delivering
testosterone to
men.' These methods include intramuscular injections (43%), oral replacement
(24%), pellet
implants (23%), and transdermal patches (10%). A surrunary of these methods is
shown in
Table 3.
Table 3: Mode of Application and Dosage of Various Testosterone Preparations
Preparation Route Of ApplicationFull Substitution'Dose
In Clinical Use
Testosterone enanthateIntramuscular injection200-25.0 g every
2-3 weeks
Testosterone cypionateIntramuscular'injection200 mg every 2 weeks
Testosterone undecanoateOral 2-4 capsules at 40
mg per day
Transdermal testosteroneScrotal skin 1 membrane per day
patch Non-scrotal skin 1 or 2 systems per
~ day
Transdermal testosterone~pl~~tion under 3-6 implants of 200
the mg every
Pad abdominal skin 6 months
Testosterone implants
Under Development
Testosterone cyclodextiinSublingual 2.5-5.0 mg twice
daily
Testosterone undecanoateIntramuswlar injection1000 mg every 8-10
weeks
Testosterone buciclateIntramuscular injection1000 mg every 12-16
weeks
Testosterone microspheresIntramuscular injection315 mg for 11 weeks
Obsolete
17a-MethyltestosteroneOral 25-5.0 g per day
Fluoxymesterone Sublingual 10-25 mg per day
Oral 10-20 mg per day
As discussed below, all of the testosterone replacement methods currently
employed
suffer from one or more drawbacks, such as undesirable pharmacokinetic
profiles or skin
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irritation. Thus, although the need for an effective testosterone replacement
methodology has
existed for decades, an alternative replacement therapy that overcomes these
problems has never
been developed.
Subdermal Pellet Implants
Subdermal implants have been used as a method of testosterone replacement
since the
1940s. The implant is produced by melting crystalline testosterone into a
cylindrical form.
Today, pellet implanxs are manufactured to contain either 100 mg (length 6 mm,
surface area
117 mmz) or 200 mg of testosterone (length 12 mm, surface area 202 mm2).
Patients receive
dosages ranging from 100 to 1,200 mg, depending on the individual's
requirements. The
implants are inserted subcutaneously either by using a trocar and cannula or
by open surgery into
1 S an area where the;e is relatively little movement. Frequently, ; ~ implant
a placed in t'rr, lower
abdominal wall or the buttock. Insertion is made under local anesthesia, and
the wound is closed
with an adhesive dressing or a fine suture.
Implants have several major drawbacks. First, implants require a surgical
procedure that
many hypogonadal men simply do not wish to endure. Second, implant therapy
includes a risk
of extrusion (8.5%), bleeding (2.3%), or infection (0.6%). Scarring is also a
risk. Perhaps most
important, the pharmacokinetic profile of testosterone pellet implant therapy
fails to provide men
with a suitable consistent testosterone level. In general, subdermal
testosterone implants produce
supra-physiologically high serum testosterone levels that'slowly decline so
that before the next
injection subriormally low levels of testosterone are reached. For example, in
one recent
pharmacokinetic study, hypogonadal patients who received six implants (1,200
mg testosterone)
showed an initial short-lived burst release of testosterone within the first
two days after
application. A stable plateau was then maintained over the next two months
(day 2: 1,015 ng/dL;
day 63: 990 ng/dL). Thereafter, the testosterone levels declined to baseline
by day 300. DHT
serum concentrations also rose significantly above the baseline, peaking at
about 63 days after
implementation and greatly exceeding the upper limit of the normal range. From
day 21 to day
189, the DHT/T ratio was significantly increased. The pharmacokinetic profiles
for testosterone,
DHT, and DHT/T in this study are shown in FIG. 1 of the study. See Jockenhovel
et al.,
Pharmacokinetics and Pharmacodynamics ofSubcutaneous Testosterone Implants in
s
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Hypogonadal Men, 45 CLINICAL ENDOCRINOLOGY 61-71 (1996). Other studies
involving
implants have reported similar undesirable pharmacokinetic profiles.
Injection of Testosterone Esters
Since the 1950s, researchers have experimented with the intramuscular depot
injection of
testostero a esters (such as enanthate, cypionate) to increase testosterone
serum levels in
hypogona~al men. More recent studies have involved injection of testosterone
buciclate or
testosterone undecanoate in an oil-based vehicle. Other researchers have
injected testosterone
microcapsule formulations.
Testosterone ester injection treatments suffer from many problems. Patients
receiving
injection therapy often complain that the delivery mechanism is painful and
causes local skin
reactions. In addition, testosterone microcapsule treatment requires two
simultaneous
intramuscular injections of a relatively large volume, which may be difficult
to administer due to
the high viscosity of the solution and the tendency to block the needle. Other
men generally find
testosterone injection therapy inconvenient because injection usually requires
the patient to visit
his physician every two to three weeks.
. Equally important, injection-based testosterone replacement treatments still
create an
undesirable pharmacokinetic profile. The profile generally shows a supra-
physiologic
testosterone concentration during the first 24 to 48 hours followed by a
gradual fall - often to
sub-physiologic levels - over then next few weeks. These high serum
testosterone levels,
paralleled by increases in E2, are also considered the reason for acne and
gynecomastia occurring
. in some patients, and for polycythaemia, occasionally encountered especially
in older patients
using injectable testosterone esters. In the case of testosterone buciclate
injections, the treatment
barely provides normal androgen serum levels and the maximal increase of serum
testosterone
over baseline does not exceed 172 ng/dL (6 nmolldL ) on average. Because
libido, potency,
wood, and energy are thought to fluctuate with the serum testosterone level,
testosterone
injections have largely been unsuccessful in influencing these variables.
Thus, testosterone
injection remains an undesirable testosterone replacement treatment method.
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Oral/SublinguaUBuccal Preparations of Androgens
1n the 1970s, researchers began using with oral, sublingual, or buccal
preparations of
androgens (such as fluoxymesterone, 17 alpha-methyl-testosterone or
testosterone undecanoate)
as a means for testosterone replacement. More recently, researchers have
experimented with the
sublingual,administration of testosterone-hydroxypropyl-beta-cyclodextrin
inclusion complexes.
Predictably both fluoxymesterone and methyl testosterone are I7-alkylated and
thus associated
with liver toxicity. Because these substances must first pass through the
liver, they also produce
an unfavorable effect on serum lipid profile, increasing LDL and decreasing
HDL, and
carbohydrate metabolism. While testosterone undecanoate has preferential
absorption through
the intestinal lymphatics, it has not been approved in the United States.
i~ The phannucokinetic profiles for oral, sublingual, and buccal delivery
mechanisms are
also undesirable because patients are subjected to supra-physiologic
testosterone levels followed
by a quick return to the baseline. For example, one recent testing of a buccal
preparation showed
that patients obtained a peak serum hormone levels within 30 minutes after
administration, with
a mean serum testosterone concentration of 2,688 +/- 147 ng/dL and a return to
baseline in 4 to 6
hours. See Dobs et al., Pharmacokinetic Characteristics, E~cacy and Safety of
Buccal
Testosterone in Hypogonadal Males: A Pilot Study, 83 J. CLINICAL ENDOCRINOLOGY
&
METABOLISM 33-39 (1998). To date, the ability of these testosterone delivery
mechanisms to
alter physiological parameters (such muscle mass, muscle strength, bone
resorption, urinary
calcium excretion, or bone formation) is inconclusive. Likewise, researchers
have postulated
that supra-physiologic testosterone levels inay not have any extra beneficial
impact on mood
parameters such anger, nervousness, and irntability.
Testosterone Transdermal Patches
The most recent testosterone delivery systems have involved transdermal
patches.
Currently, there are three patches used in the market: TESTODERIvI~,
TESTODERM~ TTS,
and ANDRODERM~.
TESTODERM~
TESTODERM~ (Alza Pharmaceuticals, Mountain View, CA) was the first
testosterone-
containing patch developed. The TESTODERM~ patch is currently available in two
sizes (40 or
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60 cm2). The patch contains 10 or 15 mg of testosterone and delivers 4.0 mg or
6.0 mg of
testosterone per day. TESTODERM~ is placed on shaved scrotal skin, aided by
application of
heat for a few seconds from a hair dryer.
Studies have also shown that after two to four weeks of continuous daily use,
the average
plasma concentration of DHT and DHTIT increased four to five times above
normal. The high
serum DHT levels are presumably caused by the increased metabolism of Sa-
reductase in the
scrotal skin.
Several problems are associated with the TESTODERM~ patch. Not surprisingly,
many
men simply do not like the unpleasant experience of dry-shaving the scrotal
hair for optimal
contact. In addition, patients may not be able to wear close-fitting underwear
when undergoing
r 5 treatment. Men frequently experience dislodgment of the patch, usually
with exercise or hot
weather. In many instances, mcn experience itching and/or swelling in the
scrotal area. Finally,
in a number of patients, there is an inability to achieve adequate serum
hormone levels.
TESTODERM~ TTS
The most recently developed non-scrotal patch is TESTODERM~ TTS (Alza
Pharmaceuticals, Mountain View, CA). It is an occlusive patch applied once
daily to the arm,
back, or upper buttocks. The system is comprised of a flexible backing of
transparent
polyester/ethylene-vinyl acetate copolymer film, a drug reservoir of
testosterone, and an
ethylene-vinyl acetate copolymer membrane coated with a layer of
polyisobutylene adhesive
formulation. A protective liner of silicone-coated polyester covers the
adhesive surface.
~ Upon application, serum testosterone concentrations rise to a maximum at two
to four
hours and return toward baseline within two hours after system removal. Many
men, however,
are unable to obtain and/or sustain testosterone levels within the normal
range. The
pharrnacokinetic parameters for testosterone concentrations are shown below in
Table 4:
1t
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Table 4: TESTODERM~TTS Testosterone Parameters
Parameters Day 1 Day 5
Cm~ (ng/dL)482 ~ 149 473 ~ 148
T"",~ (h) 3.9 3.0
Cmin (ng/dL)164 t 104 189 t 86
Tmin (h) 0 0
Because of TESTODERMa' patch is applied to the scrotal skin while the
TESTODERM
TTS~ patch is applied to non-scrotal skin, the two patches provide different
steady-state
concentrations of the two major testosterone metabolites, DTH and E2,see Table
5, below:
Table 5: Hormone Levels Using TES'rnl~ERlVh end TESTOnFRM~'~'1'S
Hormone Placebo TESTODERM TESTODERM TTS
DHT (ng/dL)11 134 38
EZ (pg/ml)3.8 10 21.4
Likewise, in contrast to the scrotal patch, TESTODERM TTS~ treatment creates a
DHT/T ratio that is not different from that of a placebo treatment. Both
systems, however, suffer
from similar problems. In clinical studies, TESTODERIvI~ TTS is associated
with transient
itching in 12% of patients, erythema in 3% of patients, and puritus in 2% of
patients. Moreover,
in one 14-day study, 42% of patients reported three or more detachments, 33%
of which
occurred during exercise.
ANDRODERM~
ANDRODERM~ (Watson Laboratories, Inc., Corona, CA) is a testosterone-
containing
patch applied to non-scrotal skin. The circular patch has a total surface area
of 37 cm? The
patch consists of a Iiquid reservoir containing 12.2 mg of testosterone and a
permeation-
enhanced vehicle containing ethanol, water, monoglycerides, fatty acid esters,
and gelling agents.
The suggested dose of two patches, applied each night in a rotating manner on
the back,
abdomen, upper arm, or thigh, delivers 4.1 to 6.8 mg of testosterone.
~2
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in general, upon repeated application of the ANDRODERM~ patch, serum
testosterone
levels increase gradually for eight hours after each application and then
remain at this plateau
level for about another eight hours before declining.
In clinical trials, ANDRODERM~ is as$ociated with skin irritation in about a
third of the
patients, and 10% to 15% of subjects have been reported to discontinue the
treatment because of
chronic skin irritation. Preapplication of corticosteroid cream at'the site of
application of
ANDRODERIVi~ has been reported to decrease the incidence and severity of the
skin irritation.
A recent study, however, found that the incidence of skin reactions
sufficiently noxious enough
to interrupt therapy was as high as 52%. See Parker et al., Experience with
Transdermal
Testosterone Replacement in Hypogonadal Men, 50 CLINICAL FrNDOCttINOLOGY
(Ox>:) 57-62
(1999). The study reported:
Two-thirds of respondents found the Andropatch unsatisfactory.
Patches were variously described as noisy, visually irldiscrete,
embarrassing, unpleasant to apply and remove, and generally to be
socially unacceptable. They fell off, in swimming pools and
showers, attracted ribald comments from sporting partners, and left
bald red marks over trunk and limbs. Dogs, wives, and children
were distracted by noise of the patches with body movements.
Those with poor mobility or manual dexterity (and several were
over 70 years of age) found it difficult to remove packaging an
apply patches dorsally.
Transdermal Pstch Summary
In sum, the transdermal patch generally offers an improved pharmacokinetic
profile
compared to other prior art testosterone delivery mechanisms. However, as
discussed above, the
clinical and survey data shows that all of these patches suffer from
significant drawbacks, such
as buritus, bum-like blisters, and erythema. Moreover, one recent study has
concluded that the
adverse effects associated with transdermal patch systems are "substantially
higher" than
reported in clinical trials. See Parker, supra. Thus, the transdermal patch
still remains an
inadequate testosterone replacement therapy alternative for most men.
D. Sexual Motivation and Libido
While the teens "sexual performance" and "impotence" describe physiological
effects,
the terms "sexual motivation" and "libido" describe psychological effects.
"Libido" or "sexual
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motivation" as used herein is a parameter measured by the duration, frequency
and extent of
sexual daydreams, anticipation of sex, flirting, and sexual interaction.
While doctors now believe that erectile dysfunction is primarily caused by a
physiological mechanism, some cases are still attributable to psychological
causes. Moreover,
decreased 1'bido may also be a reaction to the experience of impotence.
Unfortunately,
pharmaceuticals such as VIAGItA~ treat erectile dysfunction by focusing on the
physiological
mechanics of attaining and maintaining an erection and do little or nothing to
enhance the sexual
motivation or libido of men suffering from erectile dysfunction. Thus, there
remains a need to
treat sexual performance disorders such as impotence in a manner that
overcomes both the
physiological and psychological problems associated with the disorder.
A number of clinical studies involving testosterone replacement in hypogonadal
males
have provided convincing evidence that testosterone plays a role in both
sexual motivation libido
and sexual performance. For example, researchers have reported that
testosterone replacement
results in increased sexual fantasies, sexual arousal and desire, spontaneous
erections during
sleep and in the morning, ejaculation, sexual activities with and without a
partner, and orgasm
through coitus or masturbation. See generally Christiansen, Behavioral
Correlates of
Testosterone, TESTOSTERONE: ACTION, DEFICIENCY, SUBSTITUTIOn 109-111 (1998).
Additionally, testosterone has been shown to lower cholesterol and normalize
the
abnormal electrocardiograms of patients. Testosterone can also improve
diabetic retinopathy as
well as lower the insulin requirements of diabetic patients and decrease the
percentage of body
fat. Administration of testosterone to men has been reported to decrease risk
factors for heart
attack and low testosterone is also correlated :vah hyYertensio::, cbe~~ity,
,:,nd increased waist-to-
hip ratio.
E. Estradiol Synthesis, Metabolism, and Regulation
Estradiol (1,3,5(10)-Estratriene-3, 17 beta-diol) is secreted by the ovary and
placenta. It is
synthesized by the aromatization of androgens in the thecal and granulosa
cells of the ovary and
placenta. The aromatization is stimulated by follitropin (FSH). Estradiol
synthesis in turn
stimulates production of leutinizing hormone (Lutropin or LH) receptors
necessary for the
synthesis of androgen precursors. Estradiol is important for female sexual
differentiation during
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gestation, sexual development at the onset of puberty, and regulation oi'the
menstrual cycle. The
menstrual cycle is the result of a precise coordination of the functional
characteristics of the
central nervous system, the hypothalamus, the ,pituitary, the ovary, and the
endometrium which
regulate the cyclic release of Gonadotropin Releasing Hormone (GnRH), LH and
follitropin, and
ovarian steroids (estradiol and progesterone). Estradiol is involved in both
the stimulation and
inhibition of the release of the gonadotropins, exerting both a po$itive and a
negative feedback.
Early in the follicular phase, ovarian secretion of estradiol from the thecal
and granulosa cells is
modest. During the fbllicular phase, estradiol stimulates endometrial growth
(repairing the
endometrium after menses). Toward mid-cycle, LH production increases and
results in the
release of the ovum by the rupture of the developed follicle: After ovulation,
estradiol secretion
declines slightly. During the luteal phase, estradiol along with progesterone
are secreted by the
corpus luteum stimulating further endometrial growth. If the ovum is not
fertilized, there is a
further drop in estradiol and progesterone. This drop in estradiol and
progesterone initiates
menses. When the ovaries do not function properly due to age, menopause or
disease or have
been removed, the consequent lack of endogenous,estradiol may produce a number
of symptoms,
such as hot flushes, pain and increased hypocalcemia which may eventually lead
to osteoporosis.
Total serum estrogen can be measured by assays known in the art, such as a an
ammonium sulfate precipitation assay, see for exauple, Nankin et al.,
radioimmunoassay, see,
for example, Furuyama et al., (1975). Total serum estrogen refers to the sum
of the free estrogen
(that is, estrogen unattached to any protein), estrogen weakly bound to serum
proteins, such as
albumin-bound estrogen, and estrogen tightly bound to high, afFmity serum
proteins, such as sex
hormone binding globulin-bound estrogen.
The serum levels of estradiol required for clinical efficacy are in the range
of between 40-
60 pg/ml. This range of values is the physiologic serum level of the
premenopausal women
during the early follicular phase.
Estrogenic hormones are currently available in a number of formulations.
Transdermal
preparations containing estradiol include ERC ALORA~, CLIMARA~, DERMESTRIL~,
ESTRADERM~, ESTRADERM~ TTS, ESTR.ADERM MX~, EVOREL~, FEMATRIX~,
FEMPATCH~, FEMSEVEN~, MENOREST~, PROGYNOVA~ TS, and VIVELLE~.
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Estrogen gels containing estradiol include ESTROGEL~, and SANDRENA~. Oral
preparations of estrogen are also available in a capsule shaped, sugar coated
oral tablet,
containing 1.25 mg of esterified estrogen and 2.5 mg of methyltestosterone
marketed under the
brand ESTRATEST~ (Solvay Pharmaceuticals, Inc.). A half strength formulation
is also
available under the brand ESTRATEST~ HS (Solvay Pharmaceuticals, Inc.).
F. ~ Sexl Hormone Binding Globulin
The swcture and proposed function of sex hormone binding globulin have been
described and characterized, see, for example, Rosner et al., Sex Hormone-
Bindine Globulin
Mediates Steroid Hormone Sienal Transduction at the Plasma Membrane J. Steroid
Biochem:
Mol. Biol. Vol. 69:481-5 (1999). See also, for example, Petra, P. H., The
Plasma Sex Steroid
i ~ Binaine Protein (SBP or SHBG): A Critical Review of Recent i)eveiopments
of the Structure
Molecular Biolo~v_and Function. J. Steroid Biochem. Mol. Biol., Vol. 40:735-53
(1991). A
variety of methods have been used to quantify the serum concentrations of sex
hormone binding
globulin, including ammonium sulfate precipitation, gel filtration,
equilibrium dialysis, dextran-
coated charcoal, and radioimmunoassay (see, for example, Kahn et al.,
Radioimmunoassav for
Human Testerone-Estradiol Binding Globulin, J. Clinical Endocrinology and
Metabolism, Vol.
54:705-710 ( 1982). The mean serum sex hormone level in healthy premenopausal
women is
about 84 nmole/L and the normal range is about 36 nmole/L to about 185
nmole/L. Serum sex
hormone binding globulin levels are known to be elevated in women treated with
oral estrogens,
estrogen-containing oral contraceptives, clomiphene, tamoxifen, raloxifene,
phenytoin, and
sodium valproate, as well as in women who are pregnant, hyperthyroid, have
chronic liver
disease and HIV infection. See, for example, Bond et al., Sex Hormone Bindine
Globulin in
Clinical Pcrsp~:;tive,Actu. Obstet. Gynecol. Scand., Vol. 66:255-262 (1987).
See also, for
example, Miller et al., (1998).
G. Hormone Replacement Therapy
Various methods or dosage forms are in use or have been proposed for the
testosterone
and estradiol replacement therapy, for example, tablets, injectable, implants
and transdermal
devices (patches or gel), etc. Oral therapy, using tablets is well accepted by
the patient.
However, testosterone and estradiol is rapidly metabolized during the liver
first pass. Thus, a
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high dose of testosterone or estradiol is necessary to achieve clinical
appropriate serum levels.
Absorption via the gastrointestinal tract results in enhanced delivery of the
circulating
testosterone or estrogen to the liver, where much of it is metabolized to
inactive conjugates, and
only a fraction of the active hormone enter general circulation: The liver
responds to this
enhanced delivery with increased protein and lipid metabolism, and these
activities may carry
potential risks. Examples of these changes include enhanced hepatic synthesis
of renin
substrates, sex hormone binding globulin, and changes in cholesterol and lipid
lipoprotein
metabolism.
The use of parenteral injections and implants or pellets, while,they avoid
first pass
metabolization, are much less convenient for the patient, and are therefore
not popular:
Testosterone or estradiol transderrnal administration is culaneous deliv;;ry
final delivers
testosterone or estradiol into the systemic circulation via'the stratum
corneum at a constant rate.
Transdermal administration of drugs' offers several therapeutic and compliance
advantages over the more traditional routes of adrrlinistration. A major
drawback of this therapy
however, is the limitation of the amount of drug that can be transported
across the skin. This
limitation is due to several factors. Since the skin is a protective barrier
by nature, the rates of
transport of most compounds through the skin are quite slow. It is generally
accepted that a
surface of patch beyond 50-1 p0 cm2 would result in difficulty of application.
Therefore, the
application of a transdermal semisolid dosage form such as a gel, cream,
ointment, liquid, etc.,
augment the patient's compliance and the surface of application can be
extended.
One effect of estrogen supplementation is an increase in sex hormone binding
globulin.
Sex hormone binding globulin is a serum protein that binds both testosterone
and 17 beta-
estradiol, and this binding affects the biological availability of those
hormones. Therefore, the
increase in sex hormone binding globulin that occurs with estrogen and
progestin
supplementation results in lower levels of free androgens and estrogens, both
of which bind to
sex hormone binding globulin, and higher levels of estrogens must be
administered in order to
achieve the desired biological activity.
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All of the testosterone and estradiol replacement methods currently employed,
however,
suffer from one or more drawbacks: For example, subdermal pellet implants and
ester injections
are painful and require doctor visits. Many of these methods, such as
oral/sublingual/buccal
preparations, suffer from undesirable pharmacokinetic profile--creating supra-
physiologic
testosterone concentrations followed a return to baseline. Transdermal patches
provide less than
optimal phaymacokinetic characteristics, are embarrassing for many patients,
and are associated
with significant skin irritation. Thus, although the need for an effective
hormone replacement
methodology has existed for decades, an alternative replacement therapy that
overcomes these
problems has never been developed.
DETAILED DESCRIPTION OF THE INVENTION
While the present invention may be embodied in many different Ionns, several
specific
embodiments are discussed herein with the understanding that the present
disclosure is to be .
considered only as an exemplification of the principles of the invention, and
it is not intended to
limit the invention to the embodiments illustrated.
Where the invention is illustrated herein with particular reference to
methyltestosterone,
it will be understood that any other inhibitor of the synthesis of sex hormone
binding globulin
can, if desired, be substituted in whole or in part for methyltestosterone in
the methods,
combinations and compositions herein described. Where the invention is
illustrated herein with
particular reference to testosterone, it will be understood that any other
steroid in the testosterone
anabolic or catabolic pathway can, if desired, be substituted in whole or in
part for testosterone in
the methods, combinations and compositions herein described. Where the
invention is illustrated
herein with particular reference to estradiol, it will be understood tbat any
other estro~enic
hormone can, if desired, be substituted in whole or in part for estradiol in
the methods,
combinations and compositions herein described..
The present invention is directed to methods, combinations, and compositions
for
treating, preventing or reducing the risk of developing an androgenic or
estrogenic hormone
deficiency, or a male or female menopause disorder, or the symptoms associated
with, or related
to an androgenic or estrogenic hormone deficiency, or a male or female
menopause disorder, in a
male or female mammal in need thereof. The method comprises administering to
the mammal in
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a combination therapy an amount of a sex hormone binding globulin synthesis
inhibiting agent
and one or more steroids, including for example androgen and/or estrogen,
where the sex
hormone binding globulin synthesis inhibiting agent and the steroid together
make a menopause
disorder effective amount. The present invention includes methods of halting
or slowing the
progressio of'a menopausal disorder once it becomes clinically evident, or
treating the
symptoms ilelated to the menopausal disorder. The patient may already have a
menopausal
disorder at the time of administration, or be at risk for developing a
menopausal disorder. Also
included in the methods, combinations and compositions of the present
invention are
pharmaceutical compositions comprising a sex hormone binding globulin
synthesis inhibiting
agent and one or more steroids, including for example androgen and/or
estrogen, where the
individual agents together make a menopause disorder effective amount. The
present invention
also includes kits comprising a sex hormone binding globulin synthesis
inhibiting agent and one
or more steroids, including for example androgen and/or estrogen. The kits
also contain a set of
instructions for the patient. When administered as part of a combination
therapy, the sex
hormone binding globulin synthesis inhibiting agent together with the steroid
provide enhanced
treatment options for treating menopause in a mammal as compared to
administration of either a
sex hormone binding globulin synthesis inhibiting agent or a steroid alone.
. Besides being useful for human treatment, the present invention is also
useful for
veterinary treatment of companion mammals, exotic animals and farm animals,
including
mammals, rodents, and the like. In one embodiment, the mammals include horses,
dogs, and
cats.
Contemplated methods, combinations and compositions are useful to treat a
variety of
menopausal disorders, or the symptoms associated with, or related to a
menopausal disorder,
including but not limited to hypogonadism, sexual or erectile dysfunction,
decreased libido,
hyperglycemia, hyperglyceridemia, hypercholesterolemia, hypertension,
atherosclerosis,
cardiovascular disorders and diseases, vasomotor symptoms, obesity, diabetes,
osteoporosis,
osieopenia, vaginal dryness, thinning of the vaginal wall, relieving
menopausal symptoms and
hot flashes, improving cognitive dysfunction, Alzheimer's disease, dementia,
cataracts, cervical
cancer, uterine cancer, breast cancer, Klinefelter's syndrome, teratogenic
disorder, and cervical
dysplasia.
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The phrase "combination therapy" embraces the administration of a sex hormone
binding
globulin synthesis inhibiting agent and one or more steroids, including for
example, androgen
andlor estrogen, as part of a specific treatment regimen intended to provide a
beneficial effect
from the co-action of these therapeutic agents for the treatment of menopause.
The beneficial
effect of the combination includes, but is not limited to, pharmacokinetic or
pharmacodynamic
co=action resulting from the combination of therapeutic agents. ~
Administration of these
therapeutic agents in combination typically is carried out over a defined time
period (usually
minutes, hours, days; weeks; months or years depending upon the combination
selected).
"Combination therapy" generally is not intended to encompass the
administration of two or more
of these therapeutic agents as part of separate monotherapy regimens that
incidentally and
arbitrarily result in the combinations of the present invention. 'lCombination
therapy" is
intended to embrace administration of these therapeutic agents in a sequential
manner, that is,
where each therapeutic agent is administered at a different time, as well as
administration of
these therapeutic agents, or at least two of the therapeutic agents, in a
substantially simultaneous
manner. Substantially simultaneous administration can be accomplished, for
example, by
administering to tire subject a single capsule or tablet having a fixed ratio
of each therapeutic
agent or in multiple, single capsules, tablets, or gels for each of the
therapeutic agents.
Sequential or substantially simultaneous administration of each therapeutic
agent can be effected
by any appropriate route (including, but not limited to, oral routes,
percutaneous routes,
intravenous routes, intramuscular routes, and direct absorption through mucous
membrane
tissues. The therapeutic agents can be administered by the same route or by
different mutes. For
example, a first therapeutic agent of the combination selected may be
administered orally, while
the other therapeutic agents of the combination may be administered
percutaneously.
Alternatively, for example, all therapeutic agents may be administered orally,
or all therapeutic
agents may be administered percutaneously, or all therapeutic agents may be
administered
intravenously, or all therapeutic agents may be administered intramuscularly,
or all therapeutic
agents can be administered by direct absorption through mucous membrane
tissues. The
sequence in which the therapeutic agents are administered is not narrowly
critical. "Combination
therapy" also can embrace the administration of the therapeutic agents as
described above in
fuither combination with other biologically active ingredients, such as, but
not limited to, agents
for improving sexual performance or impotence, including agents to treat
erectile dysfunction,
CA 02501846 2002-06-26
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S such as V1AGR.A~, or increasing libido by increasing testosterone levels in
men, and non-drug
therapies, such as, but not limited to, surgery.
The phrase "menopause disorder" or "menopausal disorder" encompasses both male
"andropausaI" and female menopausal disorders, and includes either a peri-
menopausal
condition d~ a post-menopausal condition. "Peri-menopausal condition" refers
to a condition
that occurs'ether during menopausal onset, or prior thereto at a time when
menopausal onset
nornially occurs, and either is caused by menopausal onset or has a greater
than random
coincidence therewith. Peri-menopausal conditions include, for example, hot
flashes and
reduction of bone mass. "Post-menopausal condition" refers to a condition that
occurs after
menopausal onset, and either is caused by menopause or has a greater than
random coincidence
therewith. Post-menopausal wndiiious include, ror e~a~upie, vasomoim symptoms,
usteopenia,
osteoporosis, cardiovascular disease and cognitive dysfunction.
A "menopause disorder effect" or "menopause disorder effective amount" is
intended to
qualify the amount of a sex hormone binding globulin synthesis inhibiting
agent and a steroid,
including for example androgen and/or estrogen, required to treat or prevent a
menopause
disorder or relieve to some extent one or more of the symptoms of a menopause
disorder,
including, but not limited to, normalizing hypogonadism, improving sexual or
erectile
dysfunction, increasing libido, lowering blood cholesterol levels; normalizing
abnormal
electrocardiograms of patients and improving vasomotor symptoms; improving
diabetic
retinopathy as well as lowering the insulin requirements of diabetic patients;
decreasing the
percentage of body fat; decreasing the risk factors for heart attack,
hypertension, and obesity;
preventing osteoporosis, osteopenia, vaginal dryness, and thinning of the
vaginal wall; relieving
menopausal symptoms and hot flashes; improving cognitive dysfunction; treating
or reducing the
onset of cardiovascular disease, Alzheimer's disease, dementia, and cataracts;
and treating or
reducing the risk of cervical, uterine or breast cancer.
The phrase "non oral" or "non orally deliverable" refers to percutaneous,
transmucosal,
implantation, inhalation spray, rectal, vaginal, topical, buccal (for example,
sublingual), or
parenteral (for example, subcutaneous, intramuscular, intravenous,
intramedullary and
intradermal injections, or infusion techniques) formulations and
administrations.
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The use of the term' "about'' in the present disclosure means "approximately,"
and use of
the term "about" indicates that dosages slightly outside the cited ranges may
also be effective
and safe, and such dosages are also encompassed by the scope of the present
claims.
The phrase "pharmaceutically acceptable" is used adjectivally herein to mean
that the
modified noun is appropriate for use in a pharmaceutical product.
Pharmaceutically acceptable
cautions include metallic ions and organic ions. More preferred~metallic ions
include, but are not
limited to appropriate alkali metal salts, alkaline earth metal salts and
other physiological
acceptable metal ions. Exemplary ions include aluminum, calcium, lithium,
magnesiurg,
potassium, sodium and zinc in their usual valences. Preferred organic ions
include protonated
tertiary amines and quaternary ammonium cations, including impart,
trimethylamine,
diet.':;; :am:ae, N,:~d'-dibe~yl.,~y le~ediamia:,, ;,h:oroprocaine, choline,
diethanolamine,
ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary
pharmaceutically
acceptable acids include without limitation hydrochloric acid, hydrobromic
acid, phosphoric
acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric
acid, maleie acid,
malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic
acid, glucuronic acid,
pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartie acid,
glutamic acid, benzoic
acid, and the like. 1 '
The phrase "penetration enhancer" refers to an agent known to accelerate the
delivery of
the drug through the skin. These agents also have been rbferred to as
accelerants, adjuvants, and
sorption promoters, and are collectively referred to herein as "enhancers."
This class of agents
includes those with diverse mechanisms of action including those which have
the function of
improving the solubility and diffusibility of the drug, and those which
improve percutaneous
absorption by changing the ability of the stratum comeum to retain moisture,
softening the skin,
improving the skin's permeability, acting as penetration assistants or hair-
follicle openers or
changing the state of the skin such as the boundary layer. The penetration
enhancer of the
present invention is a functional derivative of a fatty acid, which includes
isosteric modifications
of fatty acids or non-acidic derivatives of the carboxylic functional gmup of
a fatty acid or
isosteric modifications thereof. In one embodiment, the functional derivative
of a fatty acid is an
unsaturated alkanoic acid in which the -COOH group is substituted with a
functional derivative
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thereof, such as alcohols, polyols, amides and substituted derivatives
thereof. The term "fatty.
acid" means a fatty acid that has four (4) to twenty-four (24) carbon atoms.
Non-limiting examples of penetration enhancers include Cg-C22 fatty acids such
as
isostearic acid; octanoic acid, and oleic acid; Cg-C22 fatty alcohols such as
oleyl alcohol and
lauryl alcohol; lower alkyl esters of Cg-C22 fatty acids such as ethyl oleate,
isopropyl myristate,
butyl stearate, and methyl laurate; di(lower)alkyl esters of C6-C22 diacids
such as diisopropyl
adipate; monoglycerides of Cg-C22 fatty acids such as glyceryl monolaurate;
tetrahydrofurfuryl
alcohol polyethylene glycol ether; polyethylene glycol, propylene glycol; 2-(2-
etla~xyethoxy)ethanol~ diethylene glycol monomethyl ether; alkylaryl ethers of
polyeth~lere
oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl
ethers; dimethyl
sulfoxide; glycerol; ethyl acetate; acetoacetic ester; N-alkylpyrrolidone; and
terpenes.
The thickeners used herein may include anionic polymers such as polyacrylic
acid
(CARBOPOL~ by B.F. Goodrich Specialty Polymers and Chemicals Division of
Cleveland,
Ohio), carboxymethylcellulose and the like. Additional thickeners, enhancers
and adjuvants may
generally be found in Remineton's The Science and Practice of Pharmacy, Meade
Publishing
Co.; United States Pharmacopeia/National Formulary.
As used herein, the term "lower alcohol," along or in combination, means a
straight-chain
or branched-chain alcohol moiety containing one to about six carbon atoms. In
one embodiment,
the lower alcohol contains one to about 4 carbon atoms, and in another
embodiment the lower
alcohol contains two to about 3 carbon atoms. Er~rnples of such alcohol
moieties include
methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-
butanol, and tert-butanol.
As used herein, the term "lower alkyl", alone or in combination, means a
straight-chain
or branched-chain alkyl radical containing one to about six carbon atoms. In
one embodiment,
the lower alkyl contains one to about four carbon atoms. Examples of such
radicals include
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tent-
butyl.
The compositions of the present invention are used in a "pharmacologically
effective
amount " T'his means that the concentration of the therapeutic agents of the
present invention are
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such that in the composition it results in a therapeutic level of drug
delivered over the term that
the drugs are to be used. Such delivery is dependent on a number of variables
including the time
period for which the individual dosage unit is to be used, the flux rate of
the therapeutic agent,
for example, testosterone or estradiol, from the gel, surface area of
application site, etc. The
amount of therapeutic agent, for example, testosterone or estradiol, necessary
can be
experimentally determined based on the flux rate of the drug.through the gel,
and through the
skin when used with and without enhancers. It is understood, however, that
specific dose levels
of the therapeutic agents of the present invention for any particular patient
depends upon a
variety of factors including the activity of the specific compound employed,
the age, body '
weight, general health, sex, and diet of the patient, the time of
administration, the rate of
excretion, the drug combination, and the severity of the particular disorder
being treated and
form or administration: Treatment dosages generally may be titrated to
optimize safety and
efficacy. Typically, dosage-effect relationships from in vitro andlor in vido
tests initially can
provide useful guidance on the proper doses,for patient administration.
Studies in animal models
generally may be used for guidance regarding effective dosages for treatment
of menopause in
accordance with the present invention. In terms of treatment protocols, it
should be appreciated
that the dosage to be administered will depend on several factors, including
the particular agent
that is administered, the route administered the condition of the particular
patient, etc. Generally
speaking, one will desire to administer an amount of the compound that is
effective to achieve a
serum level commensurate with the concentrations found to be effective in
vitro. Thus, where an
compound is found to demonstrate in vitro activity at, for example, 10 nglml,
one will desire to
administer an amount of the drug that is effective to provide about a 10 ng/ml
concentration in
vivo. Determination of these parameters is well within the skill of the art.
These considerations,
a~ well ~s eifC~ci~c formuia~ions and administration procedures are well known
in the art and are
described in standard textbooks.
Illustratively, for an adult human, a therapeutically effgctive amount of
methyltestosterone per daily dose for use in the present invention is
typically about 0.2 mg to
about 5.0 mg; a therapeutically effective amount of testosterone per daily
unit for use in the
present invention is typically about 0.1 mg to about 10 mg; and a
therapeutically effective
amount of estradiol per daily dose for use in the present invention is
typically about 0.1 mg to
about 10 mg.
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The present invention includes compounds that inhibit the synthesis of the sex
hormone
binding globulin. Sex hormone binding globulin is a serum protein, and is
known to bind to
testosterone and estradiol, effecting the biological activity of these
hormones. Specific
compounds of interest that inhibit the synthesis the sex hormone binding
globulin include but are
not limited to methyltestosterone and fluoxymesterone, and all salts, esters,
amides, enantiomers,
isomers, ta~tomers, prodrugs and derivatives of these compounds.
Methyltestosterone is
currently available in various formulations including those available orally,
for example
ANDROID~ and TESTRED~ ICN. Fluoxymesterone is also currently available in
various
formulations including those available orally, for example HALOSTESTIN~.
Corabinations of
the above mentioned compounds can be used.
:5 While not wishing to be bound by uzev~y, ii is believed chat
meciiylteszostemne necreases
hepatic synthesis of endogenous proteins like sex hormone binding globulin.
This decrease in
synthesis produces a decline in blood concentrations of sex hormone binding
globulin, which is
the primary means of endogenous hormone transport. The decrease in sex hormone
binding
globulin subsequently causes an increase in free-hormone concentration for
binding at the
receptor. Transdermal application of an androgen, for example, testosterone,
or an estrogen, for
example, estradiol, bypasses first-pass metabolism and can provide a means of
increasing
hormone concentrations in the bloodstream. Thus, in combination therapy,
methyltestosterone
and percutaneously administered testosterone andlor estradiol produce a
greater therapeutic
effect and provide a means of increasing hormone concentrations in the
bloodstream.
~ Methyltestosteroae and testosterone and/or estradiol produce a greater
therapeutic eff~t than
either entity alone because the decrease in hormone binding ability is coupled
with an increased
farm~ne bioavailability, producing higher free-hormone concentrations that
would be pioduced
by methyltestosterone alone, or testosterone alone, or estradiol alone.
Certain formulations of the invention will contain from about 0.2 mg to about
50.0 mg
methyltestosterone or the equivalent per dosage unit. The formulations may
contain for example,
about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1.0,1.1, 1.2, 1.3, 1.4,1.5, 2.0,
2.5, 3.0, 3.5, 4.0, 4.5, 5.0,
10.0, 20.0, 30.0, 40.0 or 50.0 mg methyltestosterone per dosage unit.
2s
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A class of androgens useful iti the methods, combinations and compositions of
the
present invention include steroids in the testosterone anabolic or catabolic
pathway. In a broad
aspect of the invention, the active ingredients employed in the composition
may include anabolic
steroids such as androisoxazole, bolasterone, clostebol, ethylestrenol,
formyldienolone, 4-
hydroxy-19-nortestosterone, methenolone, methyltrienolone, ~androlone,
oxymesterone,
quinbolone, stenbolone, trenbolone; androgenic steroids such as boldenone,
fluoxymesterone,
mestanolone, ~nesterolone, methandrostenolone,1?-methyltestosterone, 17 alpha-
methyl-
testosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone,
oxandrolone,
oxymetholone, prasterone, stanlolone, stanozoloI, dihydrotestosterone,
testosterone; and
progestogens such as anagestone, chlormadinone acetate, delmadinone acetate,
demegestone,
dimethisterone, dihydrogestemne, ethinylestrenol, ethisterone, ethynodiol,
ethynodiol diacetate,
flurogestone acetate, gestodene, gestonorone caproate, haioprogesterone, 17-
hydroxy-16-
methylene-progesterone, 17 alpha-hydroxyprogesterone, 17 alpha-
hydroxyprogesterone
caproate, medrogestone, medroxypiogesterone, megestrol acetate, melengestrol,
norethindrone,
norethindrone acetate, norethynodrel, norgesterone, norgestimate, norgestrel,
norgestrienone, 19-
norprogesterone, norvinisterone, pentagestrone, progesterone, promegestone,
quingestrone, and
trengestone; and all salts, esters, amides, enantiomers, isomers, tautomers,
prodrugs and
derivatives of these compounds. (Based upon the list provided in The Merck
Index. Merck &
Co. Rahway, N.J. (1998)).
Testosterone is currently available in various formulations including, but not
limited to
those available as an injectable, for example DEPO-TESTOSTERONE~ (testosterone
cypionate), and DELATESTRYL BTG~ (testosterone enanthate), as a transdermal,
for example
TESTODERM~ (testosterone), TESTODERM~ TTS testosterone), Curd Ai~IDROD'~r,RM~,
or
as a gel. One such testosterone gel that may be used in the methods,
combinations and
compositions of the present invention has only recently been made available in
the United States
under the trademark ANDROGELm by Unimed Pharmaceuticals, Inc., Deerfield,
Illinois, a
wholly owned subsidiary of Solway Pharmaceuticals, Inc.
Combinations of the above mentioned androgens can be used.
26
CA 02501846 2002-06-26
WO 03/002123 PCT/US02/20141
In one embodiment, the testosterone gel is comprised of the following
substances in
approximate amounts:
Table 6: Composition of ANDROGEL~
SUBSTANCE AMOUNT (w/w)
PER 100g OF
GEL
Testosterone 1.0 g
Carbopol 980 0.90 g
Isopropyl myristate0.50 g
0.1 N NaOH 4.72 g
Ethanol (95% 72.5 g*
w/w)
1 Fu~7 sed ~ 100 g
avatar yqsf)
*Corresponding to 67 g of ethanol.
One skilled in the art will appreciate that the constituents of this
formulation may be
varied in amounts yet continue to be within the spirit and scope of the
present invention. For
example, the composition may contain about 0.1 to about 10.0 g of
testosterone, about 0.1 to
about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl myristate, and about
30.0 to about
98.0 g ethanol.
A therapeutically effective amount of the gel is rubbed onto a given area of
skin by the
user. The combination of the lipophilic testosterone with the hydroalcoholic
gel helps drive the
' testosterone in to the outer layers of the skin where it is absorbed and
then slowly released into
the blood stream. As demonstrated by the data presented herein, the
administration of the gel of
the present invention has a sustained effect.
In another embodiment, the androgen is testosterone and is formulated for
percutaneous
administration comprising testosterone in a hydroalcoholic gel. The gel
comprises one or more
lower alcohols, a penetration enhancing agent, a thickener, and water.
Additionally, the present
invention may optionally include salts, emollients, stabilizers,
antimicrobials, fragrances, and
pmpellarns.
Certain formulations of the invention will contain from about 0.1 mg to about
100 mg
testosterone or the equivalent per dosage unit. The formulations may contain
for example, about
27
CA 02501846 2002-06-26
WO 03/002123 PCT/US07,/20141
0.1, 0.25, 0.5, 0.625, 1.0, 1.25,1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5,
b.0, 6.5, 7.0, 7.5, 8.0, 8.5,
9.0, 9.5,10.0, 20.0, 30.0, 40.0, 30.0 or 100.0 mg testosterone per dosage
unit.
Another class of agents useful in the methods, combinations and compositions
of the
present invention include estrogenic hormones. In one embodiment, the
estrogenic hormone is
the natwal~ occurring estrogen 17 beta-estradiol (beta-estradiol; 1, 3, 5(10)-
estratriene-3, 17
beta-diol). bther estrogenic steroid hormones can be used in partial or
complete replacement of
17 beta-estradiol, for example, an ester which is biologically compatible and
can be absorbed
effectively transdermally. The estradiol esters can be, illustratively
estradiol-3,17-diacetate;
estradiol-3-acetate; estradiol-17-acetate; estradiol-3,17-divalerate;
estradiol-3-valerate; estradiol-
17-valerate; 3-mono, 17-mono and 3,17-dipropionate esters, corresponding
cypionate,
heptanoate, benzoate and the like esters; ethynil ectrs~diol ~ warone and oher
~stro~eni~ .,temids
and salts, enantiomers, isomers, tautomers, prodrugs and derivatives thereof
that are possible to
administer by transdermal route. Other estrogen-related compounds that may be
used ~in the
methods, combinations and compositions of the present invention include, but
are not limited to
conjugated estrogens (including estrone sulfate, equilin, and 17-.alpha:
dihydroequilin), estradiol
valerate, estriol, estrone, estrone sulfate, estropipate, ethinyl estradiol,
mestranol, and all salts,
esters, amides, enantiomers, isomers, tautomers, prodrugs and derivatives of
these compounds.
Estrogenic hormones are currently available in various formulations including,
but not
limited to those available as a cream, pessary, vaginal ring, vaginal tablet,
transdermal
preparation, gel, and oral tablet. Examples of vaginal creams include
PREMARIN~ (conjugated
estrogen), ORTHO DIENOSTEROL~ (dienosterol), and OVESTIN~ (estriol). Available
pessary formulations include ORTHO-GYNEST~ (estriol), and TAMPOVAGAN~
(stilbestrol).
An example of a vaginal ring formulation is ESTRING~1 (estradiol), and an
example of a vaginal
tablet is VAGIFEM~ (estradiol). Available transdermal estrogen preparations
containing
estradiol include ERC ALORA~, CLIMARA~, DERMESTRIL~, ESTRADERM~,
ESTRADERM~ TTS, ESTRADERM~ MX, EVOREL~, FEMATRIX~, FEMPATCH~, .
FEMSEVEN~, MENOREST~, PROGYNOVA~ TS, and VIVELLE~. Available estrogen gels
containing estradiol include ESTROGEL~, and SANDRENA~. Estradiol is also
available
formulated as an implant pellet, for example, ESTRADIOL IMPLANT~. Tablet
formulations
include PREMARIN~ (conjugated estrogen), ESTRATAB~ (esterified estrogen),
28
CA 02501846 2002-06-26
WO 03/002123 PCT/US02/20141
ESTRATEST~ (esterified estrogen, methyltestosterone), MENEST~ (esterified
estrogen),
CLIMAGEST~, (estradiol), CLIMAVAL~ (estradiol), ELLESTE SOLO~ (estradiol),
ESTRACE~ (estradiol), PROGYNOVA~ (estradiol), ZUMENON~ (estradiol), HORMONINc9
(estradiol, estmne, estriol), HARMOEN~ (estrone), OGEN~ (estropipate), and
ORTHO-EST~
(estropipate).
Combinations of the above mentioned estrogenic hormones can be used.
In one embodiment, the estrogenic hormone is formulated for percutaneous
administration in a hydroalcoholic gel. The gel comprises one or wore lower
alcohols; a
penetration enhancing agent; a thickener; and water. Additionally, the present
invention may
optionally include salts, emollients. stabilizers, vn~,imic~mhial.s, ~gTance~.
and propellants.
1 S ~ In one embodiment, the estrogenic gel is comprised of the following
substances in approximate
amounts:
Table 7: Composition of Estradiol Gel
SUBSTANCE ~O~ (wow)
PER 100g OF
GEL
'17-beta-oestradiol0.06 g
Carbopol 980 1.0 g
Triethanolamine1.35 g
Ethanol (95% (59 rnl)
w/w)
Purified water100 g
(qsf)
One skilled in the art will appreciate that the constituents of this
formulation may be
varied in amounts yet continue to be within the spirit and scope of the
present invention. For
example, the composition may contain about 0.1 to about 10.0 g of estradiol,
about 0.1 to about
5.0 g CARBOPOL, about 0.1 to about 5.0 g triethanolamine, and about 30.0 to
about 98.0 g
ethanol.
A therapeutically effective amount of the gel is rubbed onto a given area of
skin by the
user. The combination of the lipophilic estradiol with the hydroalcoholic gel
helps drive the
29
CA 02501846 2002-06-26
WO 03/002123 PCT/US03120141
estradiol in to the outer layers of the skin where it is absorbed and then
slowly released into t$e
blood stream. It is contemplated that the administration of the gel of the
present invention has a
sustained effect.
Certain formulations of the invention will contain from about 0.1 mg to about
100mg
estradiol o~ the equivalent per dosage unit. The formulations may contain for
example, about 0.1,
0.25, 0.5, .625, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0,
6.5, 7.0, 7.5, 8.0, 8.5, 9.0,
9.5, 10.0, 20.0, 30.0, 40.0, 50.0 or 100.0 mg estradiol per dosage unit.
For additional examples of other compositions containing estrogen-related
compounds or
androgen-related compounds that may be used in the methods, combinations and
compositions
of the present invention, see for example, Sturdee, D. W., et al. Br. J.
Obstet. Gynecol.'(1997)
104:109-115.
Toxicity and therapeutic efficacy of the therapeutic agents of the present
invention can be
determined by standard pharmaceutical procedures, for example, for determining
LDso {the dose
lethal to 50% of the population) and the EDso {the dose therapeutically
effective in 50% of the
population). The dose ratio between toxic and therapeutic effects is the
therapeutic index and it
can be expressed as the ratio LDso/EDso. Compounds which exhibit large
therapeutic induces are
preferred. While compounds that exhibit toxic side effects may be used, care
should be taken to
design a delivery system that targets such compounds to the site of affected
tissue in order to
minimize potential damage to uninfected cells and, thereby, reduce side
effects.
As discussed above, combirxation therapy also can embrace the administration
of the
therapeutic agents as described above in further combination with ether
biologically active
ingredients, such as, but not limited to, agents for improving sexual
performance or impotence,
and include agents to treat erectile dysfunction, or increasing libido by
increasing testosterone
levels in men, such as VIAGRA~. Other pharmaceuticals useful for treating
erectile dysfunction
include any agent that is effective to inhibit the activity of a
phosphodiesterase. Suitable
phosphodiesterase inhibitors include, but are not limited to, inhibitors of
the type III
phosphodiesterase (CAMP-specific-cGMP inhibitable form), the type N
phospodiesterase (high
affinity-high specificity cAMP form) and the type V phosphodiesterase (the
cGMP specific
CA 02501846 2002-06-26
WO 0310;02123 PCTNS02/20141
form). Additional inhibitors that may be used in conjunction with the present
invention are
cGMP-specific phosphodiesteiase inhibitors other than type V inhibitors.
Examples of type III phospodiesterase inhibitors that may be administered
include, but
are not limited to, bypyridines such as milrinorie and amirinone,
innidazolones such as
piroximone and enoximone, dihydropyridazinones such as imazodan, 5-methyl-
imazodan,
indolidan and ICI1118233, quinolinone compounds such as cilostamide,
cilostazol and
vesnarinone, and other molecules such as bemoradan, anergrelide, siguazodan,
trequinsin,
pimobendan, SKF-94120, SICF-95654, lixazinone and isomazole.
Examples of type IV phosphodiesterase inhibitors suitable herein include, but
are not
limited to, rolipr~am and rolipram derivatives such as 8020-1724, nitraquazone
and ni~y~ISZ~ne
IS derivatives such as CP-77059 and RS-25344-00, xanthine derivatives,such as
denbufylline and
ICI63197, and other compound$ such as EMD54622, LAS-31025 and etazolate.
Examples of type V phosphodiesterase inhibitors include, but are not limited
to,
zaprinast, MY5445, dipyridamole, and sildenafil. Other tyke V
phosphodiesten3se inhibitors are
disclosed in PCT Publication Nos. WO 94/28902 and WO 96/16644. In the
preferred
embodiment, an inhibitor of phosphodiesterase type 5 ("PDES"), such as VIAGRA~
(sildenafil
citrate USP) is used.
Other compounds useful for treating erectile dysfunction may also be used.
These
include: (a) pentoxifylline {TRENTAL~; (b) yohimbine hydrocholoride
(ACTIBINE~,
YOCON~, YOHIMEX~; (c) apomorphine (tJPRIMA~); (d) alprostadil (the MUSE~
system,
TOPIGLAN~, CAVER~ECT~; (e) papavaerine (PA.VABID~, CERESPAN~; (fj phentolamine
(VASOMAX~, REGITINE~'), and combinations, salts, prodrugs, isomers, amides,
esters,
tautomers, derivatives and enantiomers of all of the above.
The compounds described in PCT Publication No. WO 94/28902 are
pyrazolopyrimidinones. Examples of the inhibitor compounds include 5-(2-ethoxy-
5
morpholinoacetylphenyl~l-methyl-3-n-propyl-1,6-dihydro-7H-p yrazolo[4,3-
dJpyrimidin-7-one,
5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7 -H-
pyrazolo[4,3-
d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]1-
methyl-3-n-propyl-
3l
CA 02501846 2002-06-26
WO 03/002123 PCTIUS02/20141
S 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-allyloxy-5-(4-methyl-1-
piperazinylsulfonyl)-phenylJ-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
dJpyrimidin-7-
one, 5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-
propyl-1,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, S-[2-ethoxy-5-[4-(2-hydroxyethyl}-I-
piperazinylsul~onyl)phenyl]-1-methyl-3 -n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-
14 one,,5-[5-[~-(2-hydroxyethyl)-I-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-
methy 1-3-n-propyl-
1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5[2-ethoxy-5-(4-methyl-1-
piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-
one, and 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-I-methyl-3-n-propyl-1,6-
dihyd ro-7H-
pyrazolo[4,3-d]pyrimidin-7-one.
I 5 The phosphodiesterase inhibitors described in PCT Purl~~;icrr_ N~_. 'aIQ
96;1 S~
include griseolic acid derivatives, 2-phenylpurinone derivatives,
phenylpyridone derivatives,
fused and condensed pyrimidines, pyrimidopyrimidine derivatives, purine
compounds;
quinazoline compounds, phenylpyrimidinone derivative, imidazoquinoxalinone
derivatives or
aza analogues thereof, phenylpyridone derivatives, and others. Specific
examples of the
20 phosphodiesterase inhibitors disclosed in WO 96/16644 include 1,3-dimethyl-
5-
benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2-propoxyphenyl)-6-purinone, 6-(2-
propoxyphenyl)-
1,2-dihydro-2-oxypyridine-3-carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-
d]pyrimid-4(3H)-
one, 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-
d]pyrimidi ne, 6-
hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide, 1-ethyl-3-
25 methylirnidazo[l,Sa]quinoxalin-4(SH)-one, 4-phenylmethylamino-6-chloro-2-(1-
imidazoloyl)quinazoline, 5-ethyl-8-[3-(N-cyclohexyl-N-methylcarbamoyl)-
propyloxy]-4,5-
dihydro-4-oxo-pyrida[3,2-a]-pyrrolo[1,2-aJpyrazine, 5'-methyl-3'-
(phenylmethyl)-
spiro[cyclopentane-1,7'(8'H)-(3'H)-imidazo[2;1b]purin]4'(5'H)-one, 1-[6-chloro-
4-(3,4-
methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine-4-carboxylic acid, (6R,
9S)-2-(4-
30 trifluoromethyl-phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydr
ocyclopent[4,5]-midazo[2,1-
b]-purin-4-one, lt-butyl-3-phenylmethyl-6-(4 pyridyl)pyrazolo[3,4-dJ-pyrimid-4-
one, 1-
cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-pyrazolo[3,4-dJpyrimid-4-
onc, 2-butyl-1-(2-
chlorobenzyl)6-ethoxy-carbonylbenzimidaole, and 2-(4-carboxypiperidino)-4-(3,4-
methylenedioxy-benzyl)amino-6-nitroquinazol ine, and 2-phenyl-8-
ethoxycycloheptimidazole.
32
CA 02501846 2002-06-26
WO 03/Q02123 PCT/US02/20141
Still other type V pl~osphodiesterase inhibitors useful in conjunction with
the present
invention include: IC-351 (ICOS); 4-bromo-5-(pyridyhnethylaminor6-[3-(4-
chlorophenyl)propoxy]-3(2H)pyridazi none; 1'-[4-[(1;3-benzodioxol-5-
ylmethyl)amiono]-6-
chloro-2-quinazolinyl]-4-piper idine-carboxylic acid, monosodium salt; (+~cis-
5,6a,7,9,9,9a-
hexahydro-2-[4-(trifluoromethyl)-phenymmethyl-5-meth yl-cyclopent-
4,5]imidazo[2,1-b]purin-
4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4;5,6a,7,8,9,9a-
octahydrocyclopent[4,5]imidazo[2,1- b]purin-4-one; 3-acetyl-1-(2-chlombenzyl)-
2-pmpylindole-
6-carboxylate; 4-bmmo-5-(3-pyridyhnethylamino)-6-(3-(4-ehlorophenyl)propoxy)-3-
(2H)pyridazinone; 1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-
1~,6-dihydro-
7 H-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-
chloro-2-
quinazolinyl]-4-piperi dinecarboxylic acid, monosodium salt; Pharmaprojects
No. 451f (Glaxo
Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa
Hakko; see
WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo
Wellcome); '
and Sch-51866.
Other phosphodiesterase inhibitors that may be used in the method of this
invention
include nonspecific phosphodiesterase inhibitors such as theophylline, IBMX,
pentoxifylline and
papaverine, and direct vasodilators such as hydralazine.
A testosterone containing gel, such as AndroGeltl~ is administered to increase
and
enhance the therapeutic effectiveness of drugs effective at inhibiting the
activity of a
phosphodiesterase, in either hypogonadal or eugonadal men having erectile
dysfunction. While
pharmaceuticals such as VIAGRA~ work principally by various physiological
mechanisms of
erection initiation and maintenance, the testosterone gel used in accordance
with the present
invention plays a beneficial role physiologically, and stimulates both sexual
motivation (that is,
libido) and sexual performance. Testosterone controls the expression of the
nitric oxide synthase
ge:ae. See Reilly et al., Androgenic Regulation of NO Availability in Rat
Penile Erection, 18 J.
3O ANDROLO(3Y 110 (1997); Park et al., Effects ofA~drogens on the Expression
of Nitric Oxide
Synthase mRNAs in Rat Corpous Cavernosum, 83 BJU INT'L. 327 (1999). Thus,
testosterone and
other androgens clearly play a role in erectile dysfunction. See Lugg et al.,
The Role of Nitric
Dxide in Erectile Function, 16 J. ANDROLOGY 2 (1995); Pennon et al., Androgen
and Pituitary
Control of Penile Nitric Oxide Synthase and Ereetile Function In the Rat, 55
B10LOGY of
33
CA 02501846 2002-06-26
WO 03/002123 PCT/U502/20141
REPRODUCTION 576 (1996); Traish et al., E,,~ects ojCastration and Androgen
Replacement on.
,E'rectile Function in a Rabbit Model, 140 ENDOCRINOLOGY 1861 (1999).
Moreover, testosterone
replacement restores nitric oxide activity. See Baba et a1 Delayed
Testosterone Replacement
Restores Nitric Oxide Synthase Containing Nerve Fibres and the Erectile
Response in Rat Penis,
BJU 1NT'L 953 (2000); Garban et al., Restoration ojNormal Adult Penile
Erectile Response in
.Aged Rats ~y Long-Term Treatment with Androgens, 53 BIOLOGY OF REPRODUCTION
1365
(1995); Mann et al., Androgen-dependent Nitric Oxide Release in Rat Penis
Correlates with
Levels ojConstitutive Nitric Oxide Synthase Isoenzymes, 61 BIOLOGY OF
REPRODUCTION 1012
(1999). . ,
As disclosed herein, adequate blood levels of testosterone are important to
erection. The
pharmaceuticals) f;~r erectile dysfunction a ~,l;~,r~ u: occ:;:::a..:,e avith
the prescription .
requirements. For example, VIAGRA~ is generally taken 20-40 minutes before
sexual
intercourse in SO mg doses. This combination of therapy is particularly useful
in hypogonadal
men who need increased testosterone levels in order to optimize the effects of
VIAGRA~ and
the sexual experience as a whole. In essence, a synergistic effect is
obtained. AndroGel~ is
preferably applied to the body for a sufficient number of days so that the
steady-state levels of
testosterone are achieved.
The active agents of the present invention may be administered, if desired, in
the form of
salts, esters, amides, enantiomers, isomers, tautomers, prodrugs, derivatives
and the like,
provided the salt, ester, amide, enantiomer, isomer, tautomer, prodrug, or
derivative is suitable
pharmacologically, that is, effective in the present methods, combinations and
compositions.
Salts, esters, amides, enantiomers, isomers, tautomers, prodrugs and other
derivatives of the
active agents may be prepared using standard procedures known to those skilled
in the art of
synthetic organic chemistry and described, for example, by J. March, Advanced
Or,~eanic
Chemistry: Reactions, Mechanisms and Structure: 4th Ed. (New York: Wiley-
Interscience,
1992). For example, acid addition salts are prepared from the free base using
conventional
methodology, and involves reaction with a suitable acid. Generally, the base
form of the drug is
dissolved in a polar organic solvent such as methanol or ethanol and the acid
is added thereto.
The resulting salt either precipitates or may be brought out of solution by
addition of a less polar
solvent. Suitable acids for preparing acid addition salts include both organic
acids, for example,
34
CA 02501846 2002-06-26
WO 03/002123 PCTlUS02/20141
acetic acid, propionic acid; glyoolic acid, pyruvic acid, oxalic acid, magic
acid, malonic acid,
succinic acid, malefic acid, fumaric acid; tartaric acid, citric acid, benzoic
acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid,
and the like, as well as inorganic acids, for example, hydrochloric acid,
hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition
salt may be reconverted
to the free base by treatment with a suitable base. Particularly preferred
acid addition salts of the
active agents herein are halide salts, such as may be prepared using
hydrochloric or hydrobromic
acids. Conversely, pieparatibn of basic salts of acid moieties which may be
present on a
phosphodiesterase inhibitor molecule are prepared in a similar manner using a
pharmaceutically
acceptable base such as sodium hydroxide, potassium hydroxide, ammonium
hydroxide, calcium
hydroxide, trimethylamine, or the like. Particularly preferred basic salts
herein are alkali metal
salts, for example, the sodium salt, and copper salts. Preparation of esters
involves
functionalization of hydroxyl and/or carboxyl groups which may be present
within the molecular
structure of the drug. The esters are typically acyl-substituted derivatives
of free alcohol groups,
that is, moieties that are derived from carboxylic acids of the formula RCOOH
where R is alkyl,
and preferably is lower alkyl. Esters can be reconverted td the free acids, if
desired, by using
conventional hydrogenolysis or hydrolysis procedures. Amides and prodrugs may
also be
prepared using techniques known to those skilled in the art ~or described in
the pertinent
literature. For example, amides may be prepared from esters, using suitable
amine reactants, or
they may be prepared from an anhydride or an acid chloride by reaction with
ammonia or a
lower~alkyl amine. Prodrugs are typically prepared by covalent attachment of a
moiety, which
results in a compound that is therapeutically inactive until modified by an
individual's metabolic
system.
The therapeutic agents of the present invention can be formulated as a single
pharmaceutical composition or as independent multiple pharmaceutical
compositions.
Pharmaceutical compositions according to the present invention include those
suitable for oral,
peFcutaneous, transmucosal, implantation, inhalation spray, rectal, vaginal,
topical, buccal (for
example, sublingual), or parenteral (for example, subcutaneous, intramuscular,
intravenous,
intramedullary and intradermal injections, or infusion techniques)
administration, although the
most suitable route in any given case will depend on the nature and severity
of the condition
being treated and on the nature of the particular compound which is being
used. Illustratively,
CA 02501846 2002-06-26
WO 03/002123 PCT/US02/20141
mdthyltestosterone is administration orally, and testosterone and estradiol
are administered
~percutaneously.
For oral administration, the pharmaceutical composition of methyltestosterone
may be in
the form of, for example, a tablet, capsule, cachet, lozenge, dispensable
powder, granule,
solution, suspension, emulsion or liquid. Capsules, tablets, etc., can be
prepared by conventional
methods wlell known in the art. Oral formulations can contain excipients such
as binders (for
example, hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic
materials and
starch), diluents (for example, lactose and other sugars, starch, dicalcium
phosphate and
cellulosic materials), disintegrating agents (for example, starch polymers and
cellulosic
materials) and lubricating agents (for example, stearates and talc).
Solutions, suspensions and
1 ~ powders for reconstitutable delivery systems include vehicles such as
suspending agents (for
example, gums, zanthans, cellulosics and sugars), humectants (for example,
sorbitol),
solubilizers (for example, ethanol, water, PEG and propylene glycol),
surfactants (for~example,
sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and
antioxidants (for
exsunple, parabens, vitamins E and C, and ascorbic acid), anti-caking agents,
coating agents, and
chelating agents (for example, EDTA).
Per~cutaneous administration includes transdermal delivery systems that
include patches,
gels, tapes and creams, and can contain excipients such as alcohols,
penetration enhancers, and
thickeners, as well as solubilizers (for example propylene glycol, bile salts,
and amino acids),
hydrophilic polymers (for example, polycarbophil and polyvinylpyrolidone), and
adhesives and
tackifiers (for example, polyisobutylenes, silicone-based adhesives, acrylates
and polybutene).
Transmucosal formulations or delivery systems include patches, tablets,
suppositories,
pessaries, gels and creams, and can contain excipients such as solubilizers
and permeation
enhancers (for example, propylene glycol, bile salts and amino acids), and
other vehicles (for
example, polyethylene glycol, fatty acid esters and derivatives, and
hydrophilic polymers such as
hydroxypropylmethylcellulose and hyaluronic acid).
InjectabIe drug formulations include solutions, suspensions, gels,
microspheres and
polymeric injectables, and can comprise excipients such as solubility-altering
agents (for
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example, ethanol, propylene glycol and sucrose) and polymers (for example,
polycaprylactones
and PLGA's).
Implantable formulations or systems include rods and discs, and can contain
excipients
such as PLGA and polycaprylactone.
The~therapeutic agents of the present invention can then be administered
orally,
percutaneously, transmucosally, by implantation, by inhalation spray,
rectally, vaginally,
topically, buccally or parenterally in dosage unit formulations containing
conventional nontoxic
pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The
compounds of the
present invention can be administered by any conventional means available for
use in
conjunction with pharmaceuticals, either as individual therapeutic compounds
or as a
combination of therapeutic compounds.
The compositions of the present invention can be administered for the
prophylaicis or
treatment of a menopause disorder by any means that produce contact of these
compounds with
their site of action in the body, for example in the ileum, the plasma, or the
liver of a mammal.
Additionally, the methods, combinations and compositions of the present
invention may
optionally include salts, emollients, stabilizers, antimicrobials, fragrances,
and propellants.
In another embodiment, the therapeutic agents come in the form of kits or
packages
containing a sex hormone binding globulin synthesis inhibiting agent, and one
or more steroids,
including for example, androgen andlor estrogen. Illustratively, the kits or
packages contain
methyltestosterone and testosterone, or methyltestosterone and estradiol, or
methyltestosterone
and testosterone and estradiol, or methyltestosterone and testosterone and a
piiarmaccutival
suitable for treating erectile dysfunction, or methyltestosterone and
estradiol and a
pharmaceutical suitable for treating erectile dysfunction, or
methyltestosterone and testosterone
and estradiol and a pharmaceutical suitable for treating erectile dysfunction,
in amounts
sufficient for the proper dosing of the drugs. In another embodiment, the kits
contain
methyltestosterone in a dosage form suitable for oral administration, for
example, a tablet, and
testosterone and/or estradiol in a dosage form suitable for percutaneous
administration, for
example, a gel or a patch. The therapeutic agents of the present invention can
be packaged in the
37
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form of kits or packages in which the daily (or other periodic) dosages are
arranged for proper
sequential or simultaneous administration. The present invention further
provides a kit or
package containing a plurality of dosage units, adapted for successive daily
administration, each
dosage unit comprising at least one of the therapeutic agents of the present
invention. This drug
delivery system can be used to facilitate administering any of the various
embodiments of the
therapeutic compositions. In one embodiment, the system contai#~s a plurality
of dosages to be
taken daily via oral administration (as commonly practiced in the oral
contraceptive art). In
another embodiment,' the system contains a plurality of dosages to be
administered weekly via
transdermal administration (as commonly practiced in the hormone replacement
art). In yet
another embodiment, the system contains a plurality of dosages to be
administered daily, or
weekly, or monthly, for example, with one or more therapeutic agents
administered orally, and
one or more therapeutic agents administered transdermally.
The present invention is fiuther illustrated by the following examples, which
should not
be construed as limiting in any way. For the below examples, it is understood
that
ANDROGEL~ administere3 at 5.0 g/day, delivers 50 mg/day of testosterone to the
skin of
which about 10%, or 5 mg, is absorbed; and ANDROGEL~ administered at 10.0
g/day,
delivers 100 mg/day of testosterone to the skin of which about 10%, or 5 mg,
is absorbed; and
estradiol gel (Table 7) administered at 5.0 g/day, delivers 3 mg/day of
estrogen to the skin of
which about 10%, or 0.3 mg, is absorbed; and estradiol gel administered at
10.0 g/day, delivers 6
mglday of estrogen to the skin of which about 10%, or 0.6 mg, is absorbed, for
30 days.
EXAMPLES
Example 1:
In one embodiment of the present invention, the therapeutic combination or kit
is
comprised of an orally deliverable methyltestosterone and a non-orally
deliverable testosterone.
In this example, methyltestosterone is formulated as a capsule for oral
administration and each
dosage unit contains 5 mg of methyltestosterone. Testosterone is formulated as
a gel for .
transdemlal administration as described above in Table 6 (ANDROGEL~).
In a prophetic example, 14 males and 10 females age 18 and older experiencing
a
menopausal disorder will be randomized to receive a daily dose of 5 mg or 20
mg
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metfiyltestosterone for 30 days, plus (a) 5.0 g/day ANDROGEL~, or (b) 10 glday
~ANDROGEL~. The testosterone gel is rubbed daily onto a given area of skin.
Menopausal
disorders will be studied prior to treatment, do=ing treatment and following
treatment, by
methods known in the art. Applicant expects the menopausal disorders will show
improvement
with the combination.
Example 2~:
In one embodiment of the present invention, the therapeutic combination or kit
is
comprised of an orally deliverable methyltestosterone and a non-orally
deliverable estrogen. In
this example, methyltestosterone is formulated as a capsule for oral
administration and each
dosage unit contains 5 mg of methyltestosterone. Estrogen is formulated as a
gel for transdermal
administration as described above in Table 7.
In a prophetic example,10 males and 10 females age 18 and older experiencing a
menopausal disorder will be randomized to receive a daily dose of 5 mg or 30
mg
methyltestosterone for 30 days, plus (a) 5.0 g/day estradiol gel or (b) 10
g/day estradiol gel. The
estrogen gel is rubbed daily onto a given area of skin. Menopausal disorders
will be studied
prior to treatment, during treatment and following treatment, by methods known
in the art.
Applicant expects the menopausal disorders will show improvement with the
combinations.
Example 3:
In one embodiment of the present invention, the therapeutic combination or kit
is
comprised of an orally deliverable methyltestosterone, a non-orally
deliverable testosterone, and
a non-orally deliverable estrogen. In this example, methyltestosterone is
formulated as a capsule
for oral administratian and each dosage unit contains 10 mg of
methyltestosterone. Testosterone
is formulated as a gel for transdermal administration as described above in
Table 6
(ANDROGEL~). Estrogen is formulated as a gel for transdermal administration as
described
above in Table 7.
In a prophetic example,10 males and 10 females age 18 and older experiencing a
menopausal disorder will be randomized to receive a daily dose of 10 mg or 50
mg
methyltestosterone for 30 days, plus (a) 5.0 glday ANDROGEL~ and 5.0 g/day
estradiol gel or
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(b) 5.0 g/day ANDROGEL~ and 10.0 g/day estradiol gel, or (c)' 10.0 g/day
ANDROGEL~ and
5 g/day estradiol gel, or (d) 10.0 g/day ANDROGEL~ and 10.0 g/day estradiol
gel. The gels are
rubbed daily onto a given area of skin. Menopausal disorders will be studied
prior to treatment,
during treatment and following treatment by methods known in the art.
Applicant expects the
menopausal disorders will show improvement with the combination.
Example 4:
In one embodiment of the present invention, the therapeutic combination or kit
is
comprised of an orally deliverable methyltestosterone, a non-orally
deliverable testosterone, and
a pharmaceutical agent for treating erectile dysfunction. In this example,
methyltestosterone is
formulated as a capsule for oral administration and each dosage unit contains
10 mg of
methyltestosterone. Testosterone is formulated as a gel for trarisdermal
administration as
described above in Table 6 (ANDROGEL~). The pharmaceutical agent for treating
esectile
.~
dysfunction is V1AGRA~ (citrate salt of sildenafil), an inhibitor of cyclic
guanosine
monophophate-specific phosphodiesterase type 5, and is formulated as a 50 mg
tablet for oral
administration.
In a prophetic example, 10 males age 18 and older will be randomized to
receive a daily
dose of 10 mg or 50 mg inethyltestosterone for 30~days, plus (a) 5.0 glday of
ANDROGEL~ for
days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least
1 day of
methyltestosterone and ANDROGEL~ therapy; or (b) 10.0 g/day of ANDROGEL~ for
30 days
plus 50 mg of sildenafil citrate 1 hour before intercourse after at least 1
day of
25 methyltestosterone and ANDORGEL~ therapy; or (c) 5.0 g/day of ANDROGEL~ for
30 days
and nothing brfors inte::oe:rse. The gel is rubbed daily onto a given area of
skin. Libido,
erections and sexual performance will be studied by methods known in the art.
Applicant
expects that all test parameters will show improvement with the combination.
Example 5:
30 In one embodiment of the present invention, the therapeutic combination or
kit is
comprised of an orally deliverable methyltestosterone, a non-orally
deliverable estrogen, and a
pharmaceutical agent for treating erectile dysfunction. In this example,
methyltestosterone is
formulated as a capsule for oral administration and each dosage unit contains
10 mg of
CA 02501846 2002-06-26
WO 03/002123 PCTlUS02720141
methyltestosterone. Estrogen is formulated as a gel for transdermal
administration as described
above in Table 7. The pharmaceutical agent for treating erectile dysfunction
is VIAGRA~
(citrate salt of sildenafil), an inhibitor of cyclic guanosine monophophate-
specific
phosphodiesterase type 5, and is formulated as a 50 mg tablet for oral
administration.
In a~rophetic example,10 males age 18 and older will be randomized to receive
a daily
dose of 10 mg or 50 mg methyltestostemne for 30 days, plus (a) 5.0 g/day of
estradiol gel for 30
days plus 50 mg of sildenafil citrate 1 hour before intercourse after at least
1 day of
methyltestosterone and estradiol gel therapy; or (b) 10.0 g/day of estradiol
gel for 30 days plus
50 mg of sildenaf 1 citrate 1 hour before intercourse after at least 1 day of
methyltestosterone and
,estiadiol gel therapy; or (c) 5.0 g/day of estradiol gel for 30 days and
nothing before intercourse.
The gel is rubbed daily onto a given area of skin. Libido, erections and
sexual performance will
be studied by methods Irnown in the art. Applicant expects that all test
parameters will show
improvement with the combination.
EaamDle 6:
In one embodiment of the present invention, the therapeutic combination or kit
is
comprised of an orally deliverable methyltestosterone, a non-orally
deliverable testosterone, a
non-orally deliverable estrogen and a pharmaceutical agent for treating
erectile dysfunction. In
this example, methyltestosterone is formulated as a capsule for oral
administration and each
dosage unit contains 10 mg of methyltestosterone. Testosterone is formulated
as a gel for
transdermal administration as described above in Table 6 (ANDROGEL~). Estrogen
is
formulated as a gel for transdermal administration as described above in Table
7. The
pizamaaceutical agent for treating erectile dysfunction is VIAGRA~ (citrate
sari of ~iidenafii j, ~sn
inhibitor of cyclic guanosine monophophate-specific phosphodiesterase type 5,
and is formulated
as a 50 mg tablet for oral administration.
In a prophetic example, 10 males age 18 and older will be randomized to rxeive
a daily
dose of 10 mg or 50 mg of methyltestosterone for 30 days, plus (a) 5.0 g/day
ANDROGEL~ and
5.0 glday estradiol gel for 30 days plus 50 mg of sildenafil citrate 1 hour
before intercourse after
at least 1 day of methyltestosterone, ANDROGEL~ and estradiol gel therapy; or
(b) 5.0 g/day
ANDROGEL~ and 10.0 g/day estradiol gel for 30 days plus 50 mg of sildenafil
citrate 1 hour
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WO 03/002123 . PCT/US02120141
before intercourse after at least 1 ~ day of methyltestosterpne and ANDORGEL~
therapy; or (c)
10.0 g/day ANDROGEL~ and 5.0 g/day estradiol gel for 30 days plus 50 mg of
sildenafil citrate
1 hour before intercourse after at least 1 day of'methyltestosterone,
ANDROGEL~ and esiradiol
gel therapy; (d) 10.0 g/day ANDROGEL~ and ,10.0 g/day estradiol gel far 30
days plus 50 mg
of sildenafil citrate 1 how before intercowse after at least 1 day of
methyltestosterone,
ANDROGEL~ and estradiol gel therapy; or (e) 5.0 g/day ANDROGEL~ and 5.0 g/day
estradiol
gel for 30 days and nothing before intercourse; or (~ 5.0 g/day ANDROGEL~ and
10.0 g/day
estradiol gel for 30 days and nothing before intercourse; or (g) 10.0 g/day
ANDROGEL~ and
5.0 g/day estradiol gel for 30 days and nothing before intercourse; or (h)
10.0 g/day
ANDROGEL~ and 10.0 g/day estradiol gel for 30 days and nothing before
intercourse. The gels'
are rubbed daily onto a øiven area of skin. Libido. erections and sexual
performance will be
studied by methods known in the art. Applicant expects that all test
parameters will show
improvement with the combination.
The practice of the present invention will eipploy, unless otherwise
indicated,
conventional techniques of pharmacology and pharmaceutics, which are within
the skill of the
art.
All cited literatwe and patent references are hereby incorporated herein by
reference.
Although the invention has been described with respect to specific embodiments
and examples, it
should be appreciated that other embodiments utilizing the concept of the
present invention are
possible without departing from the scope of the invention. The claimed
elements, and any and
all modifications, variations or equivalents that fall within the true spirit
and scope of the
underlying principles define the present invention.
42
