Note: Descriptions are shown in the official language in which they were submitted.
CA 02497686 2001-08-29
:. w
METHOD OF INCREASING TESTOSTERONE AND RELATED STEROID
CONCENTRATIONS IN WOMEN
FIELD OF THE INVENTION
The prrseat invention is related to methods, kits, combinations, and
compositions for
transdermally delivering an effective amount of testosterone using a
hydroalcoholic gel
formulation.
DESCRIPTION OF THE RELATED ART
Transdcrmal preparations of testosterone have provided a useful delivery
system for
normalizing serum testosterone levels in hypogonadal mcn and preventing the
clinical
symptoms and long term eS'ects of androgen deficient mca. Available
transderxnal
preparations of testosterone include, for example, TESTODERM~, TESTODF.RM~
TTS,
and ANDRODERM~. Testosterone is also available in other formulations including
those
available as an injectable, for example, DEPO-TESTOSTERONE~ (testosterone
cypionate),
and DELATESTRYL HTG~ (testosterone enanthate), or as a gel, for example,
I S ANDROGEL~ marketed by Unimed Pharmaceuticals, lne., Deerfield, Illinois,
the assignee
of this application.
In men, transdermal patches are applied to the scrotal skin or other parts of
the body.
Recently, a one-percent testosterone gel has been approved for use in men, and
provides
dosing flexibility with minimal skin irritation. This gel is marketed undo the
name
ANDROGEL~. However, all currently available testosterone transdermal products
are
specifically contraindieatxd for use in women in the United States.
Furthermore, none of the
currently available androgen treatment modalities for women, for example, oral
methyltestosterone, intramuscular testosterone cater injections or
subcutaneous testosterone
implants can achieve reproducible testosterone serum levels on a consistent
daily basis.
I
ueoaias.= sno~ ~~mcomba~s
CA 02497686 2001-08-29
A. Testosterone Physiology in Women
The excretion of androgenic steroids in the urine of adult women was
demonstrated
more than 50 years ago. Since that time, physiologists and clinicians have
explored the
sources and biological functions of testosterone and other endogenous
androgtnic hormones
in the human female, sec, for example, Geist S.H., Androgen therapy in the
human female,_J.
Clfn. Endocrinol. 1941; 1:154-161. It is now known that androgens arc secreted
by both the
ovaries and adrenal glands in women. Each source contributes about 50%
(directly and
through precursors) (set, for example, Abraham G.E., Ovarian and adrenal
contribution to
peripheral androRtns during~the menstrual eycle, J. Clin. Endocrinol. Metab.
1974; 39:340-
346) to the approximately 300 ~g of testosterone produced daily in healthy
"cycling" women
(see, for example, Southren A. L., et al., Further study of factors affectintt
the metabolic
clearance rate of testosterone in man, J. Clin. Endocrinol. Metab. 1968;
28:1105-I 112).
While the adverse effects of excess androgen production, as occurs in the
polycystic ovary
syndrome and certain androgen producing tumors, have been well descn'bed (see,
far
example, Lobo R.A., Chapter 20: Androtten excess in Infertility, Contraception
and
Reyroductive Endocrinolojnr, Third Edition. DR Mishell, V. Davajan and R Lobo,
Editors.
Blackwell Scientific Publications, Boston. pp 422-446, 1991), the normal
physiological
effects of androgens in women have been much less appreciated. As inferred
from animal
studies, male physiology, and the symptoms of women with deficient androgen
production,
the major physiological effects of androgens in normal women include, but are
not limited to
anabolic effects on muscle, skirt, hair and bone; stimulatory effects on
erythropoiesis;
modulatory effects on immune function; and psychological e8'ects on mood, well-
being and
sexual function.
In addition, endogenous androgens are important for the development of pubic
hair
and are thought to modulate the action of cstrogens and progestins on a
variety of
IZ8082~5.2 52101 I~26C 01736615
CA 02497686 2001-08-29
reproductive target tissues. It is also believed that androgens play an
important role in
modulating the secretory function of the lacrimal gland. ,
Filly percent of circulating testosterone is derived from direct ovarian
secretion in the
thecal cells under the control of luteinizing hormone. The other half is
derived from
peripheral conversion of adrenal androgen precursors dchydrocpiandrosterone, '
androstenedione, and dehydroepiandrosterone sulfate. Testosterone can also be
converted to
dihydrotestosterone or estradiol. Thus, testosterone saves as both a hormone
and as a pro-
hormone.
Testosterone circulates in the blood 98% bound to protein. In women,
approximately
66% of the binding is to the high-affinity sex hormone binding globulin. The
remaining 34%
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 usod 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. The
order of affinity
for the steroids most strongly bound by sex hormone binding globulin is
dihydmtestosterone
> testosttrone > androstenedione > estrogen. Sex hormone binding globulin
weakly binds
dihydrotestosterone, but not dihydrotestosterone sulfate. Table 1 shows the
approximate
hormonal levels in normal pre-menopausal women.
izaosxvs.x sz~omexecomae~s
CA 02497686 2001-08-29
Table 1: Hormone Levels is Normal Pre-Menopausal Women
Hormone Mean ~ sd Median Range
Testosterone (amoUL)1.20 t 0.69 0.98 0.4 - 2.7
Free testosterone 12.80 ~ 5.59 12.53 4.1- 24.2
(pmol/L)
Free testosterone 1.4 t LI 1.1 0.4 - 6.3
of total
testosterone
Luteintzing hormone 7,2~ 3.3 6.7 3.0-18.7
()<U/L)
Follicle stimulating4_7 ~ 3,6 4.2 1.5 - 21.4
hormone ()<U/L)
Sex bormone binding 66.1 t 22.7 7l .0 17.8 -114.0
globulin (nmol/L)
However, there is no genital consensus on what constitutes "testosterone
deficiency"
in women because historically it has been impossible to develop assays capable
of measuring
such small hormonal levels. This is especially true when measuring free or
bioavailsblc
testostemne levels. Consequently, currently available laboratory evaluations,
including
measuring total, free, and bioavailablc serum testosterone levels, have not
been used
extensively to identify hypoaadrogenic women.
B. Androgen Administration is Women
In comparison to other hornione deficiency states, testosterone deficiency in
women
has been largely ignored as a clinical entity. Nevertheless, there exist well-
defined patient
populations where androgen production is clearly deficient and where
associated
symptomatology has been described, including, for example, young
oophorectomizedlhystcrectomized women, post-menopausal women on estrogen
ceplscement
therapy, women on oral contraceptives, women with adrenal dysfunction, women
with
corticosteroid-induced adrenal suppression, and human immunodeficiency virus-
positive
women.
12!08215.2 51101 il26C 017)6615
CA 02497686 2001-08-29
Despite the clear benefits of administering testosterone to both normal end
testosterone deficient women, almost all of the testosterone delivery
preparations for human
use ate designed for hypogonadal men who require significantly grcatrcr
amounts of
testosterone than a testosterone deficitnt women. As a result, these
formulations and devices
are unsuitable far women requiring low doses of testosterone. Intramuscular
injunction of
testosterone esters, for example, is the popular form of androgen replacement
for men but is
unsatisfactory for women because of the very high levels of testosterone in
the first 2-3 days
after injection. Moreover, many women report increased acne and occasional
cliteromegaly
with this type of testosterone administration. Patients receiving injection
therapy often
complain that the delivery mechanism is painful and causss local skin
reactions.
Because increasing testosterone concentrations has been shown to alto sexual
performance and libido, researchers have investigated methods of delivering
testosterone to
men. These methods include inrramuscular injections (43%), oral replacement
(24%), pellet
implants (23%), and tzansdemnal patches (10%). A summary of those mcthoda is
shown in
I S Table 2.
Ll
t Z8012~5.I 511D1 1126C 01736615
CA 02497686 2001-08-29
Table 2: Mode of Application
and Dosage of Various
Testosterone Preparations
Preparation Route Of ApplicationFuU Substitution Dose
In Clinical Use
Testosterone enanthat~Intramuscular 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
Transdcrmal testosteroneScrotal skin 1 membrane per day
patch Non-scrotal skin 1 or 2 systems per
day
Transdecmal testosteroneImplantation under 3-b 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
17x-MethyltestosteroneOral 25-5.0 g per day ",
Fluoxymestemne Sublingual 10-25 mg per day
Oral I 0-20 mg per day
However, none of the current testosterone replacement products available for
use in
women are approvod in the United States for chronic treatment of the female
testosterone
deficiency states dcscn'bed herein. Also, currently available
mcthyltestosttmne products,
which can be administered orally, are no longer recommended as a testosterone
replacement .
method for hypogonadal men, sae, for example, GoorenLJ. G. and Poldermaa K H.,
Safe
aspects of androgens. In Testosterone: Action. Deficiency, Substitution. E.
Nieschlag and
FiNi. Behre, editors, Springer-Verlag, Heidelberg, p. 136 (1990). The long
acting injectable
testost~emnc-esters, such as cnnnthate or cypionate an formulated for high
dose
administration to men (for example 200 -300 mg) and produce supra-
physiological hormone
levels, evrn when given at lower doers to women (for example 50 -100 mg) (see,
for
example, Sherwin H.B, and Gelfand M.M., Differential symptom rest~onse to
~arenttral
estrogen andlor androRCn administration in the surgical menovause. Arr~. J.
Obstet. Gynecol.
1985; 151:153-160). Testosterone implants, which have been used experimentally
in the
izsosa~s~ s=poi mscom3~~s (,
CA 02497686 2001-08-29
past, can likewise produce supra-physiological hormone levels in women, see,
for example,
Burger H.G. et al., The management of persistent menopausal sLrmytoms with
oestradiol-
testosterone implants: clinical, lipid and hormonal results, Maturitas 1984;
6:351-358. The
supra-physiological androgen levels associated with these products have
produced viriliz3ng
side effects in some patients, see for example, Burger H.~. et al., (1984).
Also see, for
example, Sherwin B.B, and Gelfand M. M., (1985). Also see, for example, Urmsn
B., et al.,
Elevated serum testosterone, hirsutism and virilism associated with combined
androtten-
estrogen hormone replacement thsranv. Obstet. Gynecot.,1991; 7:595-598.
Given the above, however, ESTR.ATEST~, which is a combination of
methyltestostcrone and esterified estrogcns in oral tablet formulations, is
the most commonly
used androgen product used to treat women in the United States. At present,
however, its only
approved indication is for the treatment of moderate to severe vasomotor
symptoms
associated With menopause is those patients not impmvod by cstrogens alone.
Pharmacological doses of methyltestosterone higher than those suggested for
hypogonadal
men have also been used to treat breast cancer in women. However, oral
administration
produces inappropriate testosterone levels and unpredictable absorption
patters between
patients (Buckler 1998). Moreover, because the liver metabolizes the
preparation, there is a
risk of hepatoxicity not to mention first pass metabolism.
Testosterone pellet implants (50 mg or 100 mg of testosterone) inserted under
local
anesthesia in the abdominal wall have been used in conjunction with atrogea
pellet implants
for many years. Testosterone levels peak about one month after implantation
and then return
to baseline by month five or six. The testosterone levels are high and
characterized by
substantial rises and falls over several months and marked individual
variation in this period.
In addition, implants require a surgical procedure that many men and women
siiaply do got
neoams.= sztot mbconm~s
CA 02497686 2001-08-29
wish to endure. In hypogonadal men, for example, implant therapy includes a
risk of
extrusion (8.5%), bleeding (2.3%), or infection (0.6%).
Given the problems associated with injected, orally administered and implant-
based
testosterone delivery methods, researchers have recently begun experimenting
with more
controlled release preparations that can deliver stable and physiological
testosterone levels to
women. In the past decade, the transdetmal delivery of estradiol has become
recognized as a
safe, physiological and patient-friendly method for estrogen replacement
therapy in women. ,
Second generation estradioI patches that use adhesive matrix technology have
recently
become available in the United StaLcs and Europe. Matrix technology now exists
to
transdermaDy administer physiological amounts of testosterone alone for the
treatment of
androgen deficiency states in women. As the patient populations defined above
are
approximately 50% deficient in their testosterone production, the transdermal
systems have
been designed to deliver approximately half of the normal daily testosterone
production rate
or about 150 ug per day. Matrix technology-based transdermal testosterone
administration
has been used successfully in women to treat acquired immunodeficiency
syndrome wasting
and female sexual dysfunction aRer oophorectomy.
Two testosterone patches for women have been tested in clinical studies.
Buckler and
his associates have investigated a testosterone patch (Ethical
Pharmaceuticals, IJK) delivering
either 840,1100, 3000 ~g testosterone per day applied twice weekly to the
anterior
abdominal wall, but did not disclose the composition of the patch (Buckler
1998). Another
patch, the TMTDS patch (Watson Laboratories, Salt Lake City, U'I~, is a
translucent patch
having a surface area of 18 cmZ which uses sorbitan monooleate as a permeation
enhancer
and s hypoallergenic acrylic adhesive nn an alcohol-fret matrix. The average
testosterone
content of each patch is 4.1 mg. Each patch is designed to deliver
testosterone at s nominal
naoems.z szio~ iazscomas6~s g
CA 02497686 2001-08-29
rate of 150 g of testosterone per day over an application period of three to
fow days. Thus,
the TMTDS patch is applied twice per week (Javanbakhl et al. 2000):
While clinical sNdies have reported that the testosterone-containing patch is
capable
of increasing testosterone concentrations in women via a controlled release
mechanism, the
patches db not provide dosing flexibility. Moreover, their visibility may be
esthetically
unappealing to some woman and may have a tendency to fall off, especially
during rigorous
physical exercise.
For these and other reasons, therefore, it would be a difficult but much
desired
advance in the art to provide an effective percutaneously administered
testosterone
formulation to be applied directly to the skin of a women in the form of, for
example, a gel,
ointment, or cream, to treat testosterone deficient disorders.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
While the present invention may be embodiod in many different forms, 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
testosterone, it
will be understood that any other steroid in the testosterone synthetic
pathway can, sf desired,
be Substituted in whole or in part for testosterone in the methods, kits,
combinations, and
compositions herein described. Where the invention is illustrated herein with
particular
reference to methyltestostaone, 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
methyltestostcrone in the methods, kits, combinations, and compositions herein
descn'bed.
Where the invention is illustrated herein with particular reference to
estradiol, it will be
neoaxvs.~ swot mibconams 9
CA 02497686 2001-08-29
understood that any other estrogenie hormone can, if desired, be substituted
in whole or in
part for estradiol in the methods, kits, combinations, and compositions herein
desen'bed.
The present invention is directed to methods, kits, combinations, and
compositions for
treating, preventing or reducing the risk of developing a testosterone
deficient disorder, or the
symptoms associated with, or related to a testosterone deficient disorder in a
female mammal
in need thereof. The method comprises percutaneously administering a
testosterone deficient
disorder-effective amount of steroid in the testosterone synthetic pathway,
for example,
testosterone, to a female mammal. The present invention includes methods of
reversing,
halting or slowing the progression of a testostremne deficient disorder once
it becomes
clinically evident, or treating the symptoms associated with, or related to
tire testosterone
deficient disorder. The patient may already have a testosterone deficient
disordet at the time ,
of administration, or be at risk of developing a testosterone deficient
disorder. Also included
in the present invention is a method of administering a steroid in the
testosterone synthetic
pathway, for example testosterone, to a mammal in need thereof. The method
comprises
1 S administering to the mammal a testosterone deficient disorder-effective
satount of a
perctttaneously deliverable composition comprised of a pharmaceutically-
acceptable steroid
in the testosterone synthetic pathway, for example testosterone, one or more
lower alcohols,
such as ethanol or isopropanol, a penetration enhancing agent, a thickener,
and water. Also
included in the methods, kits, combinations, and compositions of the present
invention are
pharmaceutical compositions comprising a testosterone deficient disorder-
effective amount of
testosterone. In one embodiment the testosterone composition is formulated as
a
hydroalcoholic gel. In another embodiment; the gel comprises testosterone, one
or more
lower alcohols, such as ethanol or isopropanol, a penetration enhancing agent,
a thickener,
and water. The present invention also includes kits comprising percutaneously
deliverable
testosterone. The kits also contain a set of instructions for the patient. In
another
neows.Z sz~omxecan36a~s 10
CA 02497686 2001-08-29
embodiment, the methods, kits, combinations, and compositions are used in
conjunction with
other steroids or pharmaceutical agents effective at treating, preventing, or
reducing the risk
of developing a testosterone deficient disorder. In one embodiment, the
present invention
employing testosterone is used in conjunction with a pharmacologically
effective amount of
an estrogcnic hormone, for example, estradiol either in the same dosage form
or as separate
dosage forms. In another embodiment, the methods, kits, combinations, and
compositions
an used with another steroid or pharmaceutical agent that increases
testosterone levels in a
mammal, for example, mcthyltcstostcrone. Additionally, the present invention
optionally
include salts, esters, amides, enantiomers, isomers, tautomers, prodrugs, or
derivatives of the
compounds of the present invention, as well as emollients, stabilizers,
antimicrobials,
fragrances, and propellants. ?he methods, kits, combinations, and compositions
of the
present invention provide enhanced treatment options for treating a
testosterone deficient
disorder in a female mammal, for example, a women, as compared to those
currently
available.
Besides being useful for human treatment, the present invention is also useful
for
veterinary treatment of companion mammals, exotic animals and farm including
mammals, rodents, and the like. In one embodiment, the mammals include hoiaes,
dogs, and
cats.
A class of steroids in the testosterone synthetic pathway useful in the
methods, kits,
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
androisoxawle,
bolastcrone, clostebol, ethylest<enol, forrnyldienolone, 4-hydroxy-19-
nortestostemne,
methenolone, methyltrieaolone, nandrolone, oxymesterone, quinbolone,
stenbolone,
trenbolone; androgenic steroids such as b~oldenone, fluoxymesterone,
mestanolone,
neosi4s.: s:~o> »bconabsu 11
CA 02497686 2001-08-29
mesterolone, methandrostenolone, 17 ~c methyltestosterone, 17 alpha-methyl-
testosterone 3-
cyclopentyl enol ether, norethandrolonc, normethandrone, oxandrolone,
oxymetholone,
prasterone, stanlolone, stanozolol, dihydrotestosterone, testosterone; and
progestogens such
as anagestone, chlormadinone acetate, delmadinone acetate, demegestone,
dimethisterone,
dihydrogestemne, ethinylestrenol, ethisterone, ethynodiol, ethynodiol
diacetate, flurogestone
acetate, ~estodene, gatonorone caproate, haloprogesteronc,17-hydroxy-16-
methylene-
progesterone, l7 alpha-hydmxyprogesterone,17 alpha-hydmxyprogesterone
caproate,
medrogcstone; medroxyprogcsterone, megestrol acetate, melengestrol,
norethindrone,
norethindrone acetate, norcthynodrcl, norgesterone, norgestimate, norgestrel,
norgesirienonc,
19-norprogesterone, norvinisterone, pcntagestrone, progesterone, promegesbone,
quingestrone, and trcngestone; and all salts, esters, amides, enantiomers,
isomers, tautomers,
prodntgs and derivatives of these compounds. {Based upon the list provided in
'The Merck
Index, Merck & Co. Rahway, N.1. {1998)). Combinations of the above mentioned
steroids
can be used.
In one embodiment, testosterone is formulated as a hydroalcoholic gel. In
another
embodiment, the gel comprises testosterone, one of more lower alcohols, such
as ethanol or
isopropanol, a ptnetratioa enhancing agent, a thickener, and water.
Additionally, the gel
optionally includes the salts, esters, amides, enantiomers, isomers,
tsutomers, ptodntgs, or
derivatives of testosterone, ss well as emollients, stabilizers,
antimictobials, fragrances, and
propellants.
Dlustratively, certain formulations of the present invention deliver about
0.01 g to
about 700.0 g testosterone, or the equivalent thereof, to a patient per dosage
unit. Ia another
embodiment of the prestnt invention, the formulations deliver from about 0.1 g
to about 10.0
g testosterone, oz the equivalent thezeof, to a patient per dosage unit. In
yet another
embodiment of the present invention, the fotanulations of the present
invention deliver from
1 ~808~15.2 51101 11160 01736615 12
CA 02497686 2001-08-29
about 0.17 g to about 0.5 g testosterone, or the equivalent thereof, to a
patient per dosage unit.
In still another embodiment of the present invention, the formulations of the
present invention
deliver about 0.25 g testosterone, or the equivalent thereof, to a patient per
dosage unit.
Thus, for example, a testosterone gel formulated as a single dosage unit for
once a day
administration contains about 0.17 g, or about 0.25 g, or about 0.5 g
testosterone, while'a gel
formulated as a single dosage unit for once a week administration contains
about 1.19 g, or
about 1.75 g, or about 3.50 g testosterone, respectfully.
In one embodiment, the formulation is a gel and is comprised of the following
substances in approximate amounts:
Table 3: Composition of Testosterone
Gel
AMOUNT (wtw)
SUBSTANCE PER IOOg OF
GEL
Testosterone 1.0 g
Carbapol 980 0.90 g
Isopropyl myristate0.50 g
0.1 N NaOH 4.72 g
Ethanol (95% 72.5 g'
wlw)
Purified water 100 g
(qsf)
~c:orreaponama cu o r ~ or emano~,
The gel is rubbed onto the clean dry skin of the upper outer thigh and hip
once daily.
Following application, the gel is allowed to air dry. The patient washes her
hands.
Application of the gel results in an increased testosterone level having a
desirable
pharmacokinetic profile similar to that in normal women. The gel is thus
useful for treating a
i
number of conditions of diseases in women. j
J 5 Achieving target delivery rates demonstrated by testosterone gel can be
estirnatcd
from the pharmacokinetics in testosterone gel in men. The mean serum
concentration (Cavg)
128081~5.2 51101 11160 01736613 1 3
CA 02497686 2001-08-29
values in rnen after applying of varying amounts of gel to the upper body is
given below in
Table 4.
Table 4
Mean Average Serums Testosterone Concentrations and Daily Delivery hate sites
Administration of Testosterone Gel 1% is Men
Dose (EtL) Mean Cavg Daily Delivery Rate
(B~) O~dL) 14~8~~Y)~
5.0 555 (t 225) 3330
7.5 601 (t 309) 3606
10.0 713 (t 209) 427$
' Metabolic Clearance Rate of Daily Testosterone = 600 L/day
Based on the results obtained in men, a testosterone gel dose of 0.5 grams
delivers
approximately 300 pg of testosterone per day.
Illustratively, for an adult woman, a testosterone deficient disorder-
effective amount
of testosterone per daily dose delivezs to the blood scrum typically about 100
~g to about 150
itg to about 300~g of testosterone per day. Thus, to achieve a serum blood
level of about 100
~g testosterone, RELIBRAI"' (applicant's trademark for gel product for women)
is
administered at about 0.17 g/day, which delivers about 1.7 mg/day of
testosterone to the skin
of which about 0.1 mg, is absorbed; or to achieve a serum blood level of about
150 Itg
testosterone, RELIHRA is administered at about 0.25 g/day, which delivers
about 2.5 mg/day
of testosterone to the skin of which about 0.15 mg, is absorbed; or to achieve
a scrum blood
level of about 300 pg testosterone, RELIBRA is administered at about 0.5
g/day, which
delivers 5.0 mg/day of testosterone to the skin of which about 0.3 mg, is
absorbed.
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 0.01 to about 100.0 g of
testostcroae, 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 g ethanol.
12808245.2 5~ 101 14160 0 ~ 73b615 14
CA 02497686 2001-08-29
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 "phamtaceuticaUy acceptable" is used adjccnvally herein to mean
that the
modified noun is appropriate for use in a pharmaceutical product.
Pharmaceutically '
acceptable canons include metallic ions and organic ions, More preferred
metallic ions
include, but are not limited ~ appropriate alkali metal salts, alkaline earth
met:l salts and
other physiological acceptable metal ions. Exemplary ions include aluminum,
calcium,
lithium, magnesium, potassium, sodium and zinc in their usual valences.
Preferred organic
ions include protonated tertiary amines and quaternary ammonium canons,
including in part,
trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chlomprocaine,
choline,
diethanolamine, ethylcnediamine, meglumine (N-methylglucamine) and procaine.
Exemplary pharrnaceuncally acceptable acids include without limitation
hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid, rnethanesulfonie acid,
acetic acid, formic
IS acid, tartaric acid, malefic acid, malic acid, citric acid, isocitric acid,
succinic acid, lactic acid,
gluconic acid, glucuronic acid, pyruvic acid oxalacenc acid, fumaric acid,
propionic acid,
aspartic acid, glutamic acid, benzoic acid, and the like.
The phrase'~enetration enhanccr" refers to an agent known to accelerate the
delivery
of the drug through the skin. These agents also have been referred to as
accelerants,
adjuvants, and absorption promoters, and arc collectively referred to herein
as "enhatscas:'
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 percutanoous 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.
izaosi~s.z smov ~ssocom36s~s 15
\~~
CA 02497686 2001-08-29
i
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 group 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 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 C8-C22 fatty acids such
as
isostearic acid, oetanoie acid, and oleic acid; C8-C22 fatty alcohols such as
oleyl alcohol and
lauryl alcohol; lower alkyl esters of C8-C22 fatty acids such as ethyl oleate,
isopropyl
myristate, butyl stearaLe, and methyl laurels; di(lower)alkyl esters of C6-C22
diacids such as
diisopropyl adipate; monoglyccrides of C8-C22 fatty acids such as glycetyl
monolaurate;
tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol,
propylene glycol;
2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether, alkylaryl
ethers of
polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide
dimethyl
ethers; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetic ester; N-
alkylpyrroliaone; and
terpenes.
The thickencra used herein may include anionic polymers such as polyserylie
acid
(CARBOPOL~ by B.F. Goodrich Specialty Polymers and Chemicals Divisioa of
Cleveland,
Ohio), carboxymethyleellulose and the like. Additional thickeners, enhances
and adjuvsnts
may generally be found in Reminstton's The Science and Practice of Pharmacy'
Mead
Publishing Co., United States PharmacopeialNational Formulary.
As used herein, the term "lower alcohol," alone 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
iaos~;s.i snot ~szbcomns 1~
CA 02497686 2001-08-29
embodiment the lower alcohol contains two to about 3 carbon atoms. Examples 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. Fatampks
of such
radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sac-
butyl, and tort butyl.,
The term "treat" or "treatment" as used herein refers to any treatment of a
mammalian
condition, disorder, or disease associated with an androgen deficiency or a
testosterone
deficiency, and includes, but is not limited to, preventing the condition,
disorder, or disease
from occurring in a mammal which may be predisposed to the condition,
disorder, or disease,
but has not yet been diagnosed as having the condition, disorder, or disease;
inhibiting the
condition, disorder, or disease, for example, arresting the development of the
condition,
disorder, or disease; relieving the condition, disorder, or disease, for
example, causing
regression of the condition, disorder, or disease; or relieving the condition
caused by the
disease or disorder, for example, stopping the symptoms of the disease or
disorder.
The term "prevent" or "prevention; ' in relation to a testosterone deficient
condition,
disorder, or disease, means no testosterone deficient condition, disorder, or
disease
development if none had occurrod, or no further testosterone deficient
condition, disorder, of
disease development if there had already been development of the teswsterone
deficient
condition, disorder, or dituce.
The phrase "testosterone de5cient disorder'' refers to a to a condition,
disorder, or
disease that occurs in a mammal due to lack of endogenous testosterone
production. In
I
women, such conditions, disorders, or diseases include, but are not li»sited
to, hypogon~dis:n,
sexual dysfunction, decreased h'bido, hypercholesterolemia, abnormal
electrocardiograms,
11808245.2 521U11a16C'0173b613 l~
L
CA 02497686 2001-08-29
vasomotor symptoms, diabetic retinopathy, hyperglycemia, hyperinsulinemia,
hypoinsulinemia, increased percentage of body fat, hypertension, obesity,
osteoporosis,
osteopenia, vaginal dryness, thinning of the vaginal wall, menopausal symptoms
and hot
flashes, cognitive dysfunction, cardiovascular disease, Alzheimer's disease,
dementia,
cataracts, and cervical cancer uterine cancer or breast cancer.
Decreased production of testosterone by a woman can be causod by several
factors,
including, but not limiLcd to, use of oral contraceptives; surgery, for
exataple, removal of the
uterus (hysterectomy), or removal of one of both ovaries (oophorecty/
ovariectomy); estrogen
replacement therapy in post-menopausal women; premature ovarian failure;
adrenal
dysfunction, for example primary adrenal insufficiency; corticosteroid-induced
adrenal
suppression; panhypopituitarism; and chronic illness, such as systemic lupus
erythematosis,
rheumatoid arthritis, human immunodefieiency virus (HIV) infection, chronic
obstructive
lung disease, and end stage renal disease.
Physiological and psychological disorders associated with testosterone
de5ciency in a
1S woman include, for example, decreased libido and sexual performance,
decreasal bone
mineral density and related markers, diminished body composition, human
immunodeficiency virus wasting syndrome, decreased cognition, diminished mood
and self
esteem, decreased muscle mass and performance, premenstrual syndrome, and
autoimmune
disease.
A "testosterone deficient disorder effect" or "testosterone deficient disorder-
effective
amount" is intended to qualify the amount of testosterone required to treat oz
prevent a
testosterone deficient disorder in a mammal, or relieve to some extent one or
snore of the
symptoms associated with, or related to, a testosterone deficient disorder in
a mammal. In a
woman, this includes, but is not limited W, normalizing hypogonadism;
improving SeXUaI
dysfunction; increasing libido; normalizing cholesterol levels; nortnaliziag
abnorn~al
Ili0EZ45_2 3Z10111~6C01736613 lg
CA 02497686 2001-08-29
~ i
electrocardiograms of patitnts and improving vasomotor symptoms; improving
diabetic
retinopathy as well as lowering the insulin requirements of diabetic patients;
decreasing the
percentage of body fat; normalizing glucose levels; decreasing the risk
factors for
cardiovascular disease, including normalizing hypertension, and treating
obesity; preventing
osteoporosis, osteopenia, vaginal dryness, and thinning of the vaginal wall;
relieving
menopausal symptoms and hot flashes; improving cognitive dysfunction;
treating, preventing .
or reducing the onset of cardiovascular disease, Alzheimer's disease,
dementia, and cataracts;
and treating, preventing or reducing the risk of cervical, uterine or breast
cancer.
The compositions of the present invention arc used in s "testosterone
deficient
disorder effective amount." 'Ibis means that the concentration of the
testosterone is such that
a therapeutic level of drug is delivered over the term that the percutaneously
delivered
formulation is 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, from the gel, surface area of application
site, etc. The
amount of therapeutic agent 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 of administration.
Treatment
dosages generally may be titrat~ed to optimize safety and efficacy. Typically,
dosage~Pf~t
relationships from in vitro and/or in vivo 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
tiso~u.~ szio~ to?~c'oi7~ms Ig
CA 02497686 2001-08-29
present invention. In terms of treatment protocols, it should be appreciated
that the dosage to
be adrninistercd 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 wilt desire to administer an amount of the compound that is
effective to
achieve a serum level commensurate with the concentrations found to be
elective in vitro.
Thus, where an compound is found to demonstrate in vitro activity at, for
example, 10 ng/ml, '
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, as well as effective formulations and
administration procedures are
well known in the art and arc described in standard textbooks.
In order to measure and determine the testosterone deficient-effective amount
of
testosterone to be delivered to a subject, serum testosterone concentrations
can be measured
using standard assay techniques. Free serum testosterone levels are measured
by the recently
validated and highly sensitive equilibrium dialysis method discussed in Sinha-
Hikirn et al.,
The Use of a Sensitive Eguilibrium Dial~rsis Method for the Measurement of Fm
Testosterone Levels in Healthy, Cyclin~ Women and in HIV-Infected Women. 83 J.
CLIMGL
ENDOCRINOLOGY d'c METiIBOIJSM 1312-18. (1998), and is herein fully
incorporated by
reference.
As used herein, the phrases "androgen deficiency" or "ZCStost~erone
deficiency" are
used interchangeably, and refer to lower serum levels of free testosterone in
a subject as
compared to the median serum levels for healthy women of the same age. Normal
cycling
women produce approximately 300 leg of testosterone per day. Their total serum
testosterone
levels generally range from about 20 ng/dL to about 80 ng/dL averaging about
40 ngldL. In
healthy young women, for example, mean free testosterone levels arc generally
about 3.6
pg/mL. However, several factors may influence both total and free testosterone
serum levels.
ma~,s.t sxiot mbcombsts 20 ~'L~
CA 02497686 2001-08-29
For example, in regularly owlating women, there is a small but significant
increase in plasma
testosterone levels during the middle third of the menstrual cycle. However,
mean
testosterone levels (1.2 nmollL or 33 ngldL) and mean free testosterone levels
(12.8 pmoUL
oz 3.6 pglmL) during the luteal and follicular phases are not significantly
different.
Additionally, testosterone production declines continuously after age 30 so
that serum
testosterone levels in a 60-year-old woman are only 50% of the levels in a
young 30-year-old
woman. Although the percentage of free testosterone generally does not vary
with age, an
absolute decline in free testosterone has been observed. This decline does not
occur abruptly
at menopause but instead occurs gradually and continuously as a result of the
age-related
decrease in both the adrenal and ovarian androgen production. Thus, women
begin to
experience symptoms associated with menopause in the immediate pre-menopausal
years.
The decline in testosterone following menopause results from the combination
of ovarian
failure, decreasing renal secretion, and peripheral conversion. Also, for
example, after
ovariectomy, testosterone concentrations decrease by about SO%. Diagnosis of a
I 5 testosterone deficiency is known to the average physician practicihg in
the relevant field of
medicine.
Nevertheless, there exist well-defined patient populations where testosterone
production is clearly deficient and where associated symptornatology has been
described, and
such populations are contemplated as falling within the scope of the present
invention.
Patients to be treated with the present invention include those at risk of
developing a
testosterone deficient disorder, or patients currently experiencing a
zestostemne deficient
disorder event. Standard testosterone deficient disorder risk factors sre
known to the average
physician practicing in the relevant field of medicine. Patients who are
identified as having
one or more risk factors known in the art to be at risk of developing a
testosterone deficient
disorder, as well as people who already have a testosterone deficient
disorder, are intended to
f tE0E243.2 32101 1426(' U 17!°613 21
CA 02497686 2001-08-29
be included within the group of people considered to be at risk for having a
testosterone
deficient disorder event
In addition, contemplated methods, kits, combinations, and compositions of the
present invention are useful to treat testosterone deficiency in a woman,
which includes a
S woman where testosterone production is deficient, or where the associated
symptomatology
related to deficient testosterone production is clinically evident. This
includes, for example, a
oophorectomized/hysterectomized woman, a post-menopausal woman on estrogen
replacement therapy, a woman on oral contraceptives, a woman with an
ovariectomy, a
woman with premature ovarian failure, a woman with adrenal dysfunction, a
woman with
corticosteroid-induced adrenal suppression, a woman with panhypopituitarism, a
woman with
primary adrenal insufficiency, and a woman experiencing chronic illness, such
as systemic
lupus erythematosis, rheumatoid arthritis, human immunodeficiency virus (HIS
infection,
chmnic obstructive lung disease, and end stage renal disease.
In one embodiment of the present invention, the methods, kits, combinations,
and
composition are useful in treating a woman who have undergone surgery,
including, for
example, bilateral oophorectomy with hysterectomy, and particularly a woman
whose surgery
was performed at a younger age, prior to her natural menopause. In the U.S.
alone, more than
250,000 women undergo combined oophorectomy/hysterectomy procedures annually
and are
clearly deficient in testosterone production. Serum testosterone levels
typically decrease by
50% in a oophorectomizcd woman compared to their pre-operative levels,
however, in some
cases the levels may still remain within the normal reference range
(approximately 20 - 80
ng~dL). Estrogen and progesterone levels, which are primarily dependent on
ovarian
secretion, are also markedly reduced after oophorectomy. The resulting
multiple hormone
deficiency state is associated with vasomotor symptoms, high-turnover
osteoporosis, and
female sexual dysfunction. While estrogen replacement therapy is standard for
the treatment
nsosz~s.z szioi azxomeeis 22
CA 02497686 2001-08-29
of vasomotor symptoms and osteoporosis in the oophorectomized/hysterectomizcd
female,
concomitant testosterone therapy has not been indicated for treatment of
female sexual
dysfunction or for its effects with estrogen replacement therapy on bone
metabolism. Such
women are contemplated as falling within the scope of the present invention.
In another embodiment of the present invention, the methods, kits,
combinations, and
composition are useful in treating a post-menopausal woman. In contrast to the
oophorectomized state, the post-menopausal ovary may continue to synthesize
testosteroncs
in the stmmal tissue at rates that are not necessarily lower than the
premenopausal period. In
sonic post-menopausal women, testosterone levels increase as a consequence of
the stromal
response to elevated luteinizing hormone levels, while in others testosterone
levels decrease
or remain the same. Since estrogen replacement therapy lowers luteinizing
hormone levels,
ovarian testosterone secretion would be expected to decrease in post-
menopausal womtn who
receive estrogen replacement therapy. With oral estrogen replacement therapy
preparations,
the fall in testosterone levels may be obscured by the concomitant rise in sex
hormone
IS binding globulin levels, which reduces testosterone clearance. However,
free and/or
bioavailable testosterone levels are found to be lower in a post-menopausal
woman receiving
oral estrogen replacement therapy. While the effects of transdermal estrogen
replacement
therapy on the androgen/luteinizing hormone status of post-menopausal women
has not been
studied, a reduction in total and free testosterone levels, associated with a
decrease in
luteinizing hormone levels, would also be cxpocted. As many post-menopau5at
women
experience symptoms of female sexual dysfunction that are not ameliorated by
estrogen
replacement therapy, it is believed that testosterone deficiency is a
contributing factor, and
this group of women would fall within the scope of the present invention.
In yet another embodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating a woman who uses oral contracepiaon.
Oral
usoa~~s.z sno~ mecomms 23
CA 02497686 2001-08-29
contraception is the most common method of contraception among adolescents,
and overall
about 46% of the sexually active population use oral contraception. The most
common type
of oral contraceptive contains both estrogen and progestin and has proven to
be about 99%
effective. Thus, almost half of all premenopausal women (<44 years old) ste
potentially
S taking oral contraceptives. In comparison to healthy "cycling" women, the
testosterone
levels in women treated with estrogen-containing oral contraceptives are
markedly lower,
particularly when compared at the pre-owlatory phase of the no:mal cycle, when
testosterone
levels are highest This effect result from the luteinizing hormone suppression
produced by
oral contraceptives and is analogous to the effect of estrogen replacement
therapy described
above. Psychosexual aspects of perception are afl:ect~d by the lower
testosterone levels and
may be related to the clinical observation of decreased libido is some woman
using oral
contraceptives.
In yet another embodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating a woman who have an undergone an
ovariectomy by,
1 S for example, surgery, chemical means, irradiation, or gonadotropin-
releasing hormone
antagonists. Such surgery Icads to decreased ovarian androgen product.
In another embodiment of the present invention, the methods, kits,
combinations, and
composition are useful in treating a woman with premature ovarian failure.
Premature
ovarian failure, such as that associated with Turner's Syndrome or the
autoimmune or
idiopathic destruction of the ovary, is associated with impaired testosterone
production.
In still another embodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating a woman who has decreased adrenal
function.
Decrease adrenal function, which may result from a variety of causes,
repnsent~ another
category of patients where testosterone production may be reduced by
appmxinnatcly 50%.
primary adrenocortical deficiency, or Addison's disease, is a rare endocrine
disorder with
ueosZU.i szio> >4zbeomee~s 24
\3''~
CA 02497686 2001-08-29
multiple etiologies, including tuberculosis and fungal infections. The
estimated prevalence in
women is approximately 5 per 100,000. Due to the lack of gluco- and mineral
corticoid
secretion, Addison's disease can be Life threatening. While some researchers
have noted the
associated testosterone deficiency, replacement therapy is oRen ignored. As
the
adrenocorticotropie hormone appears to be the primary stimulator of adrenal
androgen
production, deficient adrenoeorticotrapic hormone secretion can also lead to
testosterone
deficiency in women. This can result from pituitary disease or surgery, for
example,
secondary adrenocottical deficiency, or as a pharmacological effect of
wcogenoua
corticosteroid administration that can suppress adrenocorticotropic hormone
secretion.
In one embodiment of the present invention, the methods, kits, combinations,
and
composition are useful in treating a woman when chronic coriicosteroid thtrapy
is
administered. Chronic corticosteroid therapy is used for a variety of
conditions, which
include rheumatoid arthritis, systemic lupus erythematosus, Sjogren's
syndrome,
immunosupprcssion for transplants, asthma, ctc. Corticosteroid-induced adrenal
suppression
may thus represent the largest group of patients with deficient adrenal
androgen production.
Androgen deficiency is recognized as a contn'butory factor to corticosteroid-
induced
osteoporosis. By stimulating bone formation (osteoblast activity),
testosterone replacement is
beneficial in the treatment of corticostemid-induced osteoporosis in
premenopausal woman,
and is beneficial in estrogen replacement therapy where treating past-
menopausal women. In
a woman with autoimmune disorders, such as rheumatoid arthritis and systemic
lupus
erythematosus, testosterone deficiency can contribute to the underlying
tendency to produce
autoantzbodics, as has been seen in a variety of animal models of autoimmutle
disease.
Testosterone replacement can thus help to ameliorate the autoimmune disease
process, itself.
Despite these considerations, the potential therapeutic benefits of
testosiemne replacement in
treating corticosteroid suppressed women have largely been ignored.
neost~ss s:ror »aco»~eb~s
CA 02497686 2001-08-29
In another embodiment of the present invention, the methods, kits,
combinations, and
composition are useful in treating a panhypopituitarism woman.
Panhypopituitarism from,
any cause is attended by a severe testosterone deficiency because of
derangement of
androgen secretion by both the ovaries and the adrenal glands.
In yet another embodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating a woman with primary adrenal
insufficiency. Primary
adrenal insufficiency is associated with testosterone deficiency.
1n one embodiment of the present invention, the methods, kits, combinations,
and
composition are useful in treating a woman with chronic illnesses. Chronic
illnesses in a
woman are attended by decreased circulating testosterone concentrations.
Glueocorticoid
administration inhibits adrenal androgen production by their inhibitory
effects on
adrenocorticotropic hormone secretion. In addition, glucocorticoids also have
inhibitory
effects at all levels of the hypothalamic-pituitary-ovarian axis.
In still another embodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating a human immunodcficiency virus-positive
woman. In
contrast to human immunodeficiency virus-positive men, where testosterone
deficiency is
common, it is not known whether human immunodeficiency virus-positive women
are
deficient in testosterone. Amenoahea, which appears to be increased in woman
with acquired
immunodeficiency syndrome (AIDS), may be an indication that ovarian stemid
production is
diminished. Adrenal function can also be deficient in acquired immunode5ciency
syrtdmme
patients due to cytomegalovirus infection, tuberculosis and/or fungal
infections. Megestrol
acetate, a progestational agent used to stimulate appetite in human
immunode5ciency virus
infected persons, suppresses gonadotropins and is it believed to lower
testosterone levels in
women, similar to its effects in men. In addition, the use of oral
contraceptives by a human
immunodeficieacy virus-positive woman also reduces testosterone levels, as
descnbed above
neos~4s.x sz~oi t~zscon3ms 26
CA 02497686 2001-08-29
in normal women. Physiological testosterone replacement can be used as an
anabolic agent
for treating/preventing the wasting syndrome and for enhancing quality of life
in a woman.
1"~e methods, kits, combinations, and compositions of the present invention
are also
useful to treat a number of physiological and psychological parameters
associated with
testosterone deficiency in a woman, and include, for example, increasing
libido anti
improving sexual performance and dysfuntion, increasing bone mineral density
and related
markers, improving body composition, preventing human i~nmunodcficiency virus
wasting
syndrome, improving cognition, improving mood and self-cst~em, improving
muscle mass
and performance, treating premenstrual syndrome, and treating autoimmune
diseases.
In one embodiment of the present invention, the methods, kits, combinations,
and
composition are useful in treating the libido of a woman. Testosterone
concentrations clearly
affect female libido. Over the past few decades, several correlational studies
found that
higher testosterone levels were associated with less sexual avoidance, more
sexual
gratification, more sexual thoughts, more initiation of sexual activity,
higher levels of sexual
interest and desire, and mote anticipation of sexual activity. More recently,
found a
correlation between sexual desire and testosterone in a subset of women, those
who wen
human immunodeficieucy virus-positive.
In one embodiment of the present invention, the methods, kits, combinations,
and
composition are useful in treating sexual performance in a woman. Studies have
shows that
testosterone influences sexual performance in women. Correlational studies
have found that
testosterone is associated with higher sexual arousability as measured by
vasocongestive
responses to erotic films, increased frequency of masturbation, increased
frequency of coitus,
and a higher number of sexual partntrs. Another correlational study also
showed that
testosterone is associated with decressed vaginal atrophy.
izsast~ss szvoi me ut~abs~s 27 '
~3
CA 02497686 2001-08-29
In another embodiment of the present invention, the methods, kits,
combinations, and
composition are useful in treating female sexual dysfunction in a woman.
Surgical '
menopause, that is, total abdominal hysterectomy and bilateral salpingo-
oophorectomy,
performed prior to the natural menopause causes a syndrome of female sexual
dysfunction in
a significant number of women that is unrelieved by conventional estrogen
replacement
therapy. The sexual components of this syndrome include decreased h'bido,
decreased
arousal and a diminished ability to attain orgasm. The psychological
components include
decreased energy, depressed mood, and a general decrease in well-being. These
are
generally distinguishable from the classic estrogen deficiency symptoms of
vaginal atrophy,
diminished lubrication, hot flushes and emotional liability that can adversely
affect sexual
funcrion and psychological well-being in menopausal women who do nat receive
adequate
estrogen replacement therapy. Rather than estrogen deficiency, the hormonal
basis for this
syndrome is attributed to a testosterone deficiency state resulting from the
absent ovarian
production of testosterone and its precursors.
In one study, the effects of testosterone in women with impaired sexual
function aRer
surgically induced menopause were evaluated using a transdcrmal patch. Seventy-
five
women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy
received
conjugated equine estrogens (at least 0.625 mg per day orally) and, in random
order, 150 Ng
of testosterone, and 300 ~tg of trstosterone per day transdermally for 12
woeks each. Outcome
measures included scores on the Brief Index of Sexual Functioning far Women
(HISF), the
Psychological Wetl-Being Index (PGVVI], and a sexual function diary completed
ova the
telephone. The mean (tSD) serum free testosterone concentration increased from
1.2 t 0.8
pg/mL during placebo treatment to 3.9 t 2.4 pglmL and 4.9 t 4.8 pg/mL during
treatment
with 160 and 300 pg of testosterone per day, respectively (normal range, 1.3
to 6.8 pg/mL.
Despite an appreciable placebo response, the higher testosterone dose resulted
in further
neosms.~ smv iascom3ssu 28
i
i
CA 02497686 2001-08-29
increases in scores for frequency of sexual activity and pleasure-orgasm in
the Brief Index of
Sexual Functioning for Women (P = 0.03 for both comparisons with placebo). At
the higher
dose, the percentages of women who had sexual fantasies, masturbated, or
engaged in sexual
intercourse at least once a week increased two to three times from base line.
'The positive-
s well-being, depressed-mood, and composite scores of the Psychological Well-
Being Index
also improved at the higher dose (P = 0.04, P = 0.04, respectively, for the
comparison with
placebo), but the scores on the telephone-based diary did not increase
significantly.
In another embodiment of the present invention, testosterone therapy is used
in
conjunction with estrogen therapy. Studies have shown that testosterone and
estrogen
replacement resulted in increased sexual desire, frequency of sexual
fantasies, sexual arousal,
and coital or orgasmic frequency compared to those given estrogen alone or a
placebo
reported that women receiving estrogen plus testosterone experienced more
increased libido,
activity, satisfaction, pleasure, fantasy, orgasm, and rc'.cvancy as compared
to women
receiving estrogen alone. Treatment with premarin and methyltestost~erone
resultod in
significantly increased reports of pleasure from masturbation. Treatment with
estrogen and
methyltestosterone similarly results in increased sexual interest. Most
recently, it has been
found that transdermal testostezone tireatment in women after oophorectomy
improved sexual
function and psychological well-being. It is conteruplated that testosterone
administration
alone will have therapeutic benefits if given without estrogen. For example,
women with
hypothalamic amenorrhea show increased vaginal vasocongestion with
testosterone treatment
compared to a placebo.
In still another erabodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating decreased bone density in a woman.
Another
physiologic parameter linked to testosterone administration in women is
decreased bone
mineral density. Several con:elational studies have shown that increased
tesDostarone
1280E2~3.2 321011126001736615 2g
CA 02497686 2001-08-29
concentrations are associated with increased bone mineral density. It has been
found that
higher bioavailable testosterone levels were associated with higher bone
mineral density in
the ultradistal radius in women. Women having polycystic ovary syndrome had
neck bone
mineral density positively correlated to free testosterone levcis. Upper body
bone mineral
density had significant correlation with testosttronc. A cross-sectional
analysis of sex
hormone concentrations and bone mineral density in women recruited for a
prospective study
of risk factors for osteoporosis and found a significant positive correlation
between
testosterone and bone mineral density. Another study involved an age-
stratified sample of
304 women and found a corrcladon coefficient between bone mineral density and
testosterone as shown below in Table 5:
Table 5: Correlatioasl Coeft'icieats between
Testosterone and Bvne Mineral Density*
Total Biosrvailable
TestosteroneTestosterone
Total body 0.22 0.22
Lateral spine0.27 0.29
Prozimal 0.25 0.30
femur
Radius 0.27 0.28
'15.f10lla O. CI at., J l.ttn Gn~GItnW mctuu. t7ao ~m,o~y).uvv-
74.
As with libido and sexual performance, testosterone is often given in
conjunction with
estrogen in order to prevent bone loss or increase bone mineral density. For
example, in a
cross sectional study, it was found that subcutaneous estradiol (75 mg) and
testosterone (100
mg) prevented osteoporosis and maintained normal bone mineral density in post-
menopausal
women. In another study the effects of estrogen given alone to those of
esirogea plus
androgen therapy in post-menopausal women. While the estrogen-only group had a
reduction in serum markers of bone formation, women treated with combined
estrogen and
testosterone had increased bone formation markers. Similarly, it has been
shown tbat
i~noams.i smoi isacomms 30
1~
CA 02497686 2001-08-29
estrogen and testosterone replacement with implant pellets increases bone mass
more than
estrogen implants alone, increased bone mineral density by 5.7% in the spine
and 5.2% in the
neck femur region. Treatment with estrogen and methyltestosterone similarly
results in
increased spine and hip bone mineral density. Also, it has been reported that
orally given
estrogens and methyltestostemne prevented bone loss and increased bone mineral
density in
the spine and hip.
In another embodiment of the present invention, the methods, kits,
combinations, and
composition are useful in treating body composition of a woman. Testosterone
has been
linked to improved body composition in women. Testosterone is positively
correlated to
body mass index and exogenous androgens influenced body composition and
regional body
fat distribution in obese post-menopausal worncn. Other researchers have found
an increase
in fat-free mass and a reduced fat mass to fat free mass ratio in
postmenopausal women
treated with concurrent estrogen-testosterone therapy. Thus, administration of
testosterone to
normal women or those having testosterone deficiencies may have a therapeutic
improvement
in body composition.
In still another embodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating or preventing human immunodcficiency
virus wasting
syndrome in a woman. In recent years, researchers have found that testosterone
administration to women infected with human immunodeficiency virus may treat
or prevent
human immunodeficiency virus wasting syndrome. It has been found that lower
free
testosterone levels in human immunodeficiency virus-infected women using a
traca analog
method. For example, testosterone replacement in a patch delivering 150 ug/day
of
testosterone to human immunodeficiency virus-infected women had a 4% increase
in body
weight over 12 weeks. In addition, the patients had an improved quality of
life. Thus,
12808?15.2 52101 142600176615 31
CA 02497686 2001-08-29
. a
testosterone administration can be used gas a method of preventing wasting in
women
suffering from acquired immunodeficiency syndrome or related disorders.
In yet another embodiment of the present invention, the methods, kits,
combinations,
and composition are useful in treating or preventing short-term and long-term
memory and
other higher-order cognitive fwnctions in a woman. Sex steroids arc important
for short-term
and long-term memory and other higher-order cognitive functions.
Postmenopausal women
receiving estrogen plus testosterone following oophorectomy had higher scores
on two tests
of short-term memory, a test of long-term memory, and a test of logical
reasoning. It has
been reported that the administration of testosterone is associated with
better visio-spacial
14 function and verbal skills. Women with high testosterone levels scored
higher on
spcciallmathematical tasks than women with low testosterone concentrations.
Women with
higher Mini-Mental State Examination scores had significantly higher mean
total and
bioavailable testosterone concentrations. Testosterone levels are also related
to verbal
fluency. Again,1he benefits of testosterone administration on cognitive
parameters may be
optimized by concurrent estrogen administration. For example, subcutaneous
implants of
oestradiol (40 mg) and testosterone (l00 mg) have shown increases in
concentration.
In one embodiment of the prtsrnt invention, the methods, kits, combinations,
and
compositions are useful in treating or preventing a mood or self-esteem
disorder in a woman.
Parameters associates with testosterone serum levels in women arc mood and
self-esteem.
Menopausal women who roccived both estrogen and testosterone felt more
composed, elated,
and energetic than those who were given estrogen alone. Sirailarly,
testosterone
concentrations are positively correlated tn self esteem. Thus, it is
contemplated that
testosterone therapy will improve mood when used alone or in conjunction with
estrogen.
In another emboditneot of the present invention, the methods, kits,
combinations, end
composition are useful in increasing muscle size and performance in a woman.
Aadrogens
ixeoeus.z smoi ~amcotrms 32
CA 02497686 2001-08-29
and anabolic steroids have long since been used to increase muscle size and
perfocrnance in
men. Researchers have recently also found that testosterone is an important
determinant of
greater muscle size in women with polycystic ovary syndrome. Thus,
administration of
testosterone to a normal or testosterone deficient woman may be useful for
improving muscle
mass and performance.
Many of the symptoms described above fall under the umbrella of what is
commonly
considered to be premenstrual syndrome (PMS). In general, lower levels of
testosterone .
throughout the menstrual cycle have been reported in women who suffer from
premenstrual
syndrome compared with controls. Testosterone replacement is currently used s:
a
management of premenstrual syndrome in the United Kingdom and Austalia.
Marneging
premenstrual syndrome with oestradiol/testosterone implants resulted in
improvements in
libido, enjoyment of sex, and tiredness. Thus, it is contemplated that the
rirethods, kits,
combinations, and compositions of the present invention can be useful in
treating
premenstrual syndrome in a woman, especially in conjunction with estrogen
administration.
In one embodiment of the present invention, the methods, kits, cornbinationa,
and
composition are useful in suppressing both cell-mediated and humoral immune
responses in a
woman. Androgens appear to suppress both cell-mediated and humoral immune
responses.
Many researchers have advocated increasing testosterone levels in women as
protective
against autoimmune disease, such as rheumatoid arthritis. ?estostemne
administration
therefore is contemplated to be effective in treating a woman with such
disatdets.
Toxicity and therapeutic efficacy of the therapeutic agents of the present
invention
can be determined by standard pharmaceutical procedures, fos example, for
determining LDso
(the dose lethal to 50% of the population) and the EDso (the dose
therapeutically e8'ective in
50°~ of the population). The dose ratio between toxic and ttrerapeutic
effects is the
therapeutic index and it can be expressed as the ratio l.DSO/F.Dso. Compounds
which exhibit
izaoBZ~s.z smog mbcombs~s 33
CA 02497686 2001-08-29
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.
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, kits,
combinations, and
compositions. Salts, esters, amides, enantiomers, isomers, tautomers, pmdrugs
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 Organic 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, acetic acid, propionic acid, glycolic
acid, pyntvic
acid, oxalic acid, matte 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 flee base
by tTeatrnent with
a suitable base. Particularly prefemd acid addition salts of the active agents
herein are halide
salts, such as may be prtparod using hydrochloric or hydrobromie acids.
Particularly
II8082451 SI101 14360 01736615 34
I
CA 02497686 2001-08-29
preferred basic salts here 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 to 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 caters, 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 fotmulaced as a single
pharmaceutical composition containing at least one therapeutic agent; or as
independent
multiple pharmaceutical compositions where each composition contains at least
one
therapeutic agent. Pharmaceutical compositions according to the present
invention include
those compositions with at least one therapeutic agent formulated for
percutaneous
administration. Pereutsneous administration includes transdermal delivery
systems that
include patches, gels, tapes and creams, and can contain excipients such as
alcohols,
penetration enhaneers, and thickeners, as well as solubilizer~s (for example
propylene glycol,
bile salts,.and amino acids), hydrophilic polymers (for example, polycarbophil
sad
polyvinylpyrolidone), and adhesives and tackifiers (far example,
polyisobutylenes, ailicone-
based adhesives, acrylstes and polybutenc).
The therapeutic agents of the present invention can then be administered
percutaneously in dosage unit formulations containing conventional nontoxic
szafluss.x sz~oi i~zeeo»abaes 35
CA 02497686 2001-08-29
pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The
compounds of
the present invention can he administered by any conventional means available
for use in
conjunction with pharmaceuticals, either as individual therapeutic compounds
of as a
combination of therapeutic compounds.
The compositions of the present invention can be administered for treating,
preventing; or reducing the risk of developing a testosterone deficiency in a
mammal 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, kits, combinations, and compositions of the present
invention may optionally include salts, emollients, stabilizers,
antimicrobials, fragrances, and
ptopeliants.
In another embodiment of the present invention, the therapeutic agents come in
the
form of kits or packages containing testosterone- Illustratively, the kits or
packages contain
testosterone in a dosage form suitable for percutaneous administration, for
example, a gel or a
patch, in amounts for the proper dosing of the drugs. The therapeutic agents
of the present
invention can be packaged in the 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 tht presaat 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 contains a plurality of dosages to be to be
administered daily or
weekly via percutanoous administration. The kits or packages also contain a
set of
instructions for the patient.
12608143.2 52101 14Z6C 01736613
i
CA 02497686 2001-08-29
s
The present methods, kits, combinations, and compositions can also be used in
"combination therapy" with another steroid of pharmaceutical agent that
increases
testosterone levels in a mammal, or, as mentioned above, with an estrogenic
hormone.
A class of steroids or pharmaceutical agents that increases testosterone
levels in a
mammal useful in the methods, kits, combinations, and compositions of the
present invention
include compounds that inhibit the synthesis of the sex hormone bindiag
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
methyltestosteronc and fluoxymestemne, and all salts, esters, amides,
enantiomers, isomers,
tautomers, prodrugs and derivatives of these compounds. Methyltestostemne is
currently
available in various formulations including those available orally, for
example ANDROID~
and TESTItED~. Fluoxymesterone is also currently available in various
formulations
including those available orally, for example HALOS"fESTIN~. Combinations of
the above
mentioned compounds can be used.
While not wishing to be bound by theory, it is believed that
methyltestosterone
decreases 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. TYansdermal 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, when used
in
combination, methyltestostccone and percutaneously administered testosterone
(and
optionally estradiol) produce a greater therapeutic eflact and provide a means
of incteaSing
ueoams.z snot nzecornms 3~
i
i
CA 02497686 2001-08-29
hormone concentrations in the bloodstream. Methyltestosterone and testosterone
(and
optionally estradiol) produce a greater therapeutic effect than either entity
alone because the
decrease in hormone binding ability is coupled with an increased hormone
bioavailability,
producing higher free-hormone concentrations that would be produced by
testosterone alone.
In another embodiment of the present invention, the estrogenic hormone that
can be
used in conjunction with the methods, lilts, combinations, and composition is
the naturally
occurring estrogen 17 beta-estradiol (beta-estradiol; 1, 3, 5(10)-estratriene-
3, I7 bets-diol).
Other estrogenic steroid hormones can be used in partial or complete
replacement of 17 beta-
estradiol, for example, an ester which is biologically compatl'ble and can be
absorbed
effectively transdermally. The estradiol esters can be, illustratively
estradiol 3,17-diacetstc;
cstradiol-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
cypionatc, heptanoate, benzoate and the like esters; ethynil estradiol;
estrone and other
estrogenic steroids and salts, cnantiomers, 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, kits, combinations, and
compositions of the
present invention include, but an not limited to conjugated cstrogens
(including estrone
sulfate, equilin, and 17-.alpha.-d~ydroequilin), estradiol valerate, eattiol,
estrone, estrone
sulfate, estmpipate, ethinyl cstradiol, mestranol, and all salts, esttrs,
amides, enantiomers,
isomers, tautomers, prodrugs and derivatives of these compounds_
Esvogenic 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 OVES'TIN~
(estriol).
Available pessary formulations include ORTHO-GYNEST~ (cstriol), and
~:aoatas.i smov is~eromee~s 3g
',(l
CA 02497686 2001-08-29
TAMPOVAGAN~ (stilbestrol). An example of a vaginal ring formulation is
ESTRING~
(estradiol), and an example of a vaginal tablet is VAGIFEM~ (cstradiol).
Available
transdermal estrogen preparations containing estradiol include ERC A,LORAt~,
CLIMARA~, DERMESTRIL~, ESTRADERM~, ESTRADE1Z.M~ TTS, ESTRADERM~
MX, EVOREL~, FEMATRIX~, FEMPATCH~, FEMSEVEN~?, MENOREST~,
PROGYNOVA~ TS, and VIVELLE~. Estrogen gels containing estradiol include
ESTRAGEL (under development by Applicant), and SANDRENA~. Estradiol is also
available formulated as an implant pellet, for example, ESTRADIOL IMPLAN'h~.
Tablet
formulations include PRFMARIN~ (conjugated estrogen), ESTRATAB~ (e;sterified
estrogen), ESTRATEST~ (esterified estrogen, methyltestostemne), MENEST~1
(esterified
estrogen), CLIMAGEST~, (estradiol), CLITZAVAL~ (estradiol), ELLESTE SOLO~
(estradiol), ESTRACE~ (estradiol), PROGY'NOVA~ (estradiol), ZUMENON~
(estradiol),
HORMOIvTIN~ (estradiol, estronc, estriol), I~iARMOEN~ (estrona), 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 more lower
alcohols, a
penetration enhancing agent, a thickener, and water. Additionally, the
estrogenie gel
optionally includes salts, emollients, stabilizers, antimicrobials,
fragrances, and propellants.
Illustratively, the estrogenic gel is comprised of the following substances as
shown
below in Table 6, in approximate amounts.
~:eou45s szioi mbcoir~s~s 3g
i
t
i
vl
CA 02497686 2001-08-29
Table 6: Composition
of ESTRAGEL
SUBSTANCE AMOUNT (w/w)
PER 100g OF GEL
17-beta-oestradiol0_06 g
Carbopol 980 1.0 g
Triethanolamino1.35 g
Ethanol (95% (59 ml)
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 estradivl,
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.
The phrase "combination therapy" embraces the administration of a steroid in
the
testosterone synthesis pathway in conjunction with another steroid or
pharmaceutical agent
that increases testosterone levels in a mammal, or with an estrogenic hormone,
as part of a
specific treatment regimen intended to pmvide a beneficial effect fmm the eo-
action of these
therapeutic agents for the treatment of a testosterone deficient disorder in a
mammal The
beneficial effect of the combination includes, but is not limitod to,
pharmacokinetic or
pharmacodynamic co-action resulting from the combination of therapeutic
agents.
Administration of these therapeutic agents in combination typically is canted
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.
"Combination therapy" is intended to embrace administration of these
therapeutic agents in a
l2l08245.Z SZ101 1~126C O 173661 S 40
i\
CA 02497686 2001-08-29
sequential manna, that is, whore 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 the subject a single gel having
a fixed ratio of
each therapeutic agent or in multiple, single capsules, tablets, or gels for
oath 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 routes. 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 percutancously. Alternatively, for example, 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 descn'bed above in
further
combination with other biologically active ingredients, such as, but not
limit~cd to, agents for
improving sexual performance or increasing, and non-drug therapies, such as,
but not linuted
to, surgezy.
The therapeutic compounds which make up the combination therapy may be a
combined dosage form or in separate dosage forms intended for substantially
simultaneous
oral administration. The therapeutic compounds that make up the combination
therapy may
also be administered sequentially, with either therapeutic compound being
administered by a
regimen calling for two step administration. Thus, a regimen may call for
sequential
~xaosz4ss s:rot wax owaeis
1
CA 02497686 2001-08-29
administration of the therapeutic compounds with spaced-apart administration
of the separate,
active agents. The time period between the multiple administration steps may
range from, for
example, a few minutes to scvaal hours to days, depending upon the properties
of each
therapeutic compound such as potency, solubility, bioavailability, plasma half
life and kinetic
profile of the therapeutic compound, as well as depending upon the effect of
food ingestion
and the age and condition of the patient Circadian variation of the target
moieeule
concentration may also detezxnine the optimal dose interval. The therapeutic
compounds of
the combined therapy whether administered simultaneously, substantially
simultaneously, or
sequentially, rnay involve a regimen calling for administration of one
therapeutic compound
by oral route and another therapeutic compound by percutaneous route. Whether
the
therapeutic compounds of t'he combined therapy are administered orally, by
inhalation spray,
rectally, topically, buccally (e.g., sublingual), or parenterally (e.g.,
subcutanoous,
intramuscular, intravenous and intradermal injections, or infusion
techniques), separately or
together, each such therapeutic compound will be contained in a suitable
pharmaceutical
formulation of pharmaceutically-acceptable excipients, diluents or other
formulations
components. Examples of suitable pharmaceutically-acceptable formulations
containing the
therapeutic compounds are given above. Additionally, drug formulations are
discussed in,
for example, Hooves, John E., Reminstton's Pharmaceutical Sciences, Mack
Publishing Co.,
Easton, Pennsylvania 1975. Another discussion of drug formulations can be
found in
Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosarre Forms, Mancel
Decker, New
York, N.Y., 1980.
The present invention is further illustrated by the following examples, which
should
not be construed as limiting in any way. In the below example, it is assumed
that normal
cycling women produce approximately 30U Ng of testosterone per day, and their
seluln
testosterone levels generally range from about ZO ng/dL to about 80 ng/dL
averaging about
meoazas,x sZtoj tszbcomee~s 42
CA 02497686 2001-08-29
40 ngldL. Bilateral oophorectomy in pre-menopausal women reduces testosterone
production
by approximately 50%, resulting in an average total scrum level of
approximately 20 ng/dL.
From a physiological perspective, testosterone therapy in surgically
menopausal women who,
for example, experience female sexual dysfunction, is to replace the missing
ovarian
testosterone production of approximately 150 Ng per day and restore the levels
of testosterone
and its active androgenic metabolite dihydrotestosterone (DHT) to their
previous levels
within the normal physiological range.
The following examples are provided for exemplification of the present
invention and
arc not intended to be limiting in any way.
EXAMPLES
Example 1. Dosage olTestosterone in a Female after Bilateral Oophorectomy
In one embodiment of the present invention, the methods, kits, combinations,
and
compositions arc comprised of a percutancously deliverable testosterone
formulation. In this
example, testosterone is formulated as a gel for transdermal administration as
described
above in Table 3 (RELIHRA).
In a prophetic example, 24 pre-menopausal women who have undergone bilateral
oophorectomy are randomized to receive: (a) 0.17 g/day of RELIBRA, which
delivers 1.7
mg/day of testosterone to the skin of which about 0.1 mg, is absorbed, for 30
days; or (b) 0.25
glday of RELIHRA, which delivers 2.5 mg/day of testosterone to the skin of
which about
0.15 mg is absorbed, for 30 days; or (c) 0.5 glday of RELIBRA, which delivers
5.0 mg/day of
testosterone to the skin of which about 0.3 mg is absorbed, for 30 days; or
(d) a gel
containing a placebo for 30 days. The gel is rubbed onto the clean dry skin of
the upper outer
thigh and hip once daily. Following application, the gel is allowed to air
dry. The patient
washes her hands
~ZSOausa sZio~ ~sZxomeb~s st3
CA 02497686 2001-08-29
Applicants expect that from a physiological perspective, all test parameters
will show
an improvement in female sexual dysfunction over the placebo. Accordingly,
Applicant '
expects that RELIH1ZA can be applied to improve female sexual dysfunction as
compared to
placebo in pre-menopausal women who have undergone a bilateral oophoreetomy.
Example 2. Dosage of Testosterone and Methyltestosterone in a Female after
Bilateral
Oophorectomy
In one embodiment of the present invention, the methods, kits, combinations,
and
compositions are comprised of a pcrcutaneously deliverable testosterone
formulation, and an
orally deliverable methyltcstostaone formulation. In this example,
testosterone is formulated
as a gel for transdetmal administration as described above in Table 3
(RELIHRA), and
methyltestosterone is formulated as a capsule for oral administration and each
dosage unit --
contains 10 mg of methyltcstosterone.
In a prophetic example, 24 pre-menopausal women who have undergone bilateral
oophorectomy are randomized to receive a daily oral dose of 10 mg or 50 mg
methyltestosterone for 30 days, plus: (a) 0.17 g/day of RELIBItA, which
delivers 1.7 mg/day
of testosterone to the skin of which about 0.1 mg, is absorbed, for 30 days;
or (b) 0.25 g/day
of IZFL1BRA, which delivers 2.5 mg/day of testosterone to the skin of which
about 0.15 mg
is absorbed, for 30 days; or (c) 0.5 g/day of RELIHItA, which delivers 5.0
mg/day of
testosterone to the skin of which about 0.3 mg is absorbed, for 30 days; or
(d) a gel
containing a placebo for 30 days. The gel is rubbed onto the clean dry skin of
the uppex outer
thigh and hip once daily. Following application, the gel is allowed to air
dry. 'Ihe patient
washes her hands.
Applicants expect that from a physiological perspective, all test parameters
will show
an improvement in female sexual dysfunction over the placebo. Accordingly,
Applicant
expects that RELIBRA can be administered in conjunction with
methyltestosterone to
maoez~s.i smog uzsconaba~s
CA 02497686 2001-08-29
..
improve female sexual dysfunction as compared to placebo 1n pre-menopausal
women who
have undergone a bilateral oophorectomy.
Example 3. Dosage of Testosterone and Estrogen in a Female after Bilateral
Oophorectotny
In one embodiment of the present invention, the methods, kits, combinations,
and
compositions are comprised of a percutaneously deliverable testosterone
formulation, and a
non-orally deliverable estrogen. In this example, testosterone is formulated
as a gel for
transdermal administration as descn'bed above in Table 3 (RELIHRA), and
estradiol is
formulated as a gel for transdcrmal administration as descnbcd above in Table
5
(ESTRAGEL).
In a prophetic example, 24 pre-menopausal women who have undergone bilateral
..
oophorectomy are randomized to receive a daily dose of 5 g or 10 g ESTRAGEL
for 30. days,
plus: (a) 0.17 g/day of RELIBItA, which delivers 1.7 m~Jday of testosterone to
the skin of
which about 0.1 mg, is absorbed, for 30 days; or (b) 0.25 g/day of RELIHRA,
which delivers
2.5 mgJday of testosterone to the skin of which about 0.15 mg is absorbed, for
30 days; or (c)
0.5 g/day of ItELIHItA, which delivers 5.0 mg/day of testosterone to the skin
of which about
0.3 mg is absorbed, for 30 days; or (d) a gel containing a placebo for 30
days. The gel is
rubbed onto the clean dry skin of the upper outer thigh and hip once daily.
Following
application, the gel is allowed to air dry. The patient washes her hands.
Applicants expect that from a physiological perspective, all test parameters
will show
an improvement in female sexual dysfunction over the placebo. Accordingly,
Applicant
expects that RELIBR.A can be administered in conjunction with estradiol to
improve female
sexual dysfunction as compared to placebo in pre-menopausal women who have
undergone a
bilateral oophorectomy.
12808215 5210114~6C01736613 45
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CA 02497686 2001-08-29
Example 4. Combination Testoateroae and Estrogen Gel
Substance Amount (wlw) per 100g of Gel
Testosterone 1.0g (or about O.Sg)
17-beta-oestradiol 0.06g (or about O.l Og)
Carbopol 980 1.0g
Triethanolamine 1.35g
Isopropyl myristate O.SOg
-.
0.1 N Na0I3 __
4.728
Ethanol (95% w/w) 72.Sg
Purified Water (qsf) 100g
The gel is rubbed onto the clean dry skin of the upper outer thigh and hip
once daily.
Following application, the gcl is allowed to air dry. The patient washes her
hands.
Application of the gel results in an increased testosterone level having a
desirable
pharmacokinetic profile similar to that in normal women. The gel is thus
useful for treating a
number of conditions or diseases in women.
The contents of all cited references throughout this application are hereby
expressly
incorporated by reference. The practice of the present invention will employ,
unless
otherwise indicated, conventional techniques of pharmacology and
pharmaceutics, which are
within the sivll of the art.
Although the invention has been described with respect to specific
erobodimtnts and
examples, it should be appreciated that other embodiments utilizing the
concept of the present
invention arc possible without departing from the scope of the invention The
present
l5 invention is definod by the claimed elements, and any and all
modifications, variations, or
equivalents that fall within the true spirit and scope of the underlying
principles.
i
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