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Patent 2280033 Summary

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(12) Patent Application: (11) CA 2280033
(54) English Title: COMPOSITION AND METHOD FOR SUPPLEMENTING TESTOSTERONE IN WOMEN WITH SYMPTOMS OF TESTOSTERONE DEFICIENCY
(54) French Title: COMPOSITION ET PROCEDE SERVANT A ADMINISTRER TESTOSTERONE A DES FEMMES PRESENTANT DES SYMPTOMES DE DEFICIENCE EN TESTOSTERONE
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61K 31/56 (2006.01)
  • A61K 9/00 (2006.01)
(72) Inventors :
  • RAKO, SUSAN (United States of America)
(73) Owners :
  • THERATECH, INC. (United States of America)
(71) Applicants :
  • THERATECH, INC. (United States of America)
(74) Agent: SMART & BIGGAR
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 1998-02-05
(87) Open to Public Inspection: 1998-08-13
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US1998/002089
(87) International Publication Number: WO1998/034621
(85) National Entry: 1999-08-06

(30) Application Priority Data:
Application No. Country/Territory Date
60/037,473 United States of America 1997-02-07
60/039,717 United States of America 1997-02-12
60/046,642 United States of America 1997-05-16

Abstracts

English Abstract




The present invention provides compositions and methods for providing
androgenic steroids, such as testosterone, in effective amounts to women who
are in need of androgenic steroid supplementation.


French Abstract

L'invention concerne des compositions et des procédés servant à administrer des stéroïdes androgènes, tels que testostérone, en quantité efficace à des femmes nécessitant un apport de stéroïdes androgènes.

Claims

Note: Claims are shown in the official language in which they were submitted.



26


CLAIMS


1. A formulation for topical application
comprising from about 0.01% to about 2.5% of an
androgenic steroid uniformly contained in a
pharmaceutically acceptable carrier.
2. A formulation according to Claim 1 wherein
said pharmaceutically acceptable carrier is a member
selected from the group consisting of solutions,
suspensions, emulsions, gels, ointments, creams and
pastes.
3. A formulation according to Claim 2
additionally containing at least one member selected
from the group consisting of enhancers and solvents.
4. A formulation according to Claim 3 containing
both an enhancer and a solvent.
5. A formulation according to Claim 4 wherein
said solvent is a member selected from the group
consisting of C2 to C7 alcohols, C3 or C4 diols,
ethoxydiglycol, DMSO, DMF, DMA, 1-n-dodecyl-
cyclazacycloheptan-2-one, N-methyl-pyrrolidone,
N-(2-hydroxyethyl)pyrrolidone and mixtures thereof.


27



6. A formulation according to Claim 5 wherein the
enhancer is a member selected from the group consisting
of C8 C18 fatty acids, C1 to C8 esters of fatty acids, C8
C18 fatty alcohols, sorbate esters and salts, glycerol
esters of fatty acids, C7 to C22 fatty acid esters of
.alpha.-hydroxy acids and mixtures thereof.
7. A formulation according to Claim 5 wherein the
androgenic steroid is a member selected from the group
consisting of natural testosterone, testosterone esters,
methyltestosterone, androstenedione, andrenosterone,
dehydroepiandrosterone, fluoxymesterone,
methandrostenolone, 17.alpha.-methylnortestosterone,
norethandrolone, dehydrotestosterone, oxymetholone,
stanozolol, ethylestrenol, oxandrolone, bolasterone and
mesterolone.
8. A formulation according to Claim 7 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone, methyltestosterone and
esters thereof.
9. A formulation according to Claim 8 wherein the
androgenic steroid is methyltestosterone.
10. A formulation according to Claim 8 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone and testosterone esters.
11. A method of providing an androgenic steroid to
a woman in need of testosterone supplementation,
comprising topically administering a formulation
comprising from about 0.01 to about 2.5% of the
androgenic steroid in a pharmaceutically acceptable
carrier to the genital mucosa of the woman.


28
12. A method according to Claim 11 wherein said
pharmaceutically acceptable carrier is a member selected
from the group consisting of solutions, suspensions,
emulsions, gels, ointments, creams and pastes.
13. A method according to Claim 12 wherein the
androgenic steroid is a member selected from the group
consisting of natural testosterone, testosterone esters,
methyltestosterone, androstenedione, andrenosterone,
dehydroepiandrosterone, fluoxymesterone,
methandrostenolone, 17.alpha.-methylnortestosterone,
norethandrolone, dehydrotestosterone, oxymetholone,
stanozolol, ethylestrenol, oxandrolone, bolasterone and
mesterolone.
14. A method according to Claim 13 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone, methyltestosterone and
esters thereof.
15. A method according to Claim 14 wherein the
androgenic steroid is methyltestosterone.
16. A method according to Claim 14 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone and testosterone esters.
17. A method of reducing genital atrophy in a
woman, comprising applying to the genital mucosa of the
woman a formulation comprising from about 0.01% to about
2.5% of an androgenic steroid in a cream base.
18. A method according to Claim 17 wherein the
androgenic steroid is methyltestosterone.


29
19. A method according to Claim 18 wherein
methyltestosterone is present at a concentration of from
about 0.1% to about 0.25%.
20. A method for improving the cardiovascular
health of a woman comprising topically administering a
formulation comprising from about 0.01% to about 2.5% of
an androgenic steroid in a pharmaceutically acceptable
carrier to the genital mucosa of the woman.
21. A method of providing an androgenic steroid to
a woman in need of testosterone supplementation, which
comprises the steps of:
(1) determining the need for testosterone
supplementation in said woman as evidenced by the
monitoring by a health care professional of one
more parameters selected from the group consisting
of
(a) serum testosterone levels,
(b) serum free testosterone unbound to
globulin
(c) loss of sexual desire,
(d) decreased sensitivity to sexual
stimulation of the breasts and
genitalia,
(e) decreased ability to achieve orgasm
(f) diminished vital energy and sense
of well-being,
(g) loss of muscle tone,
(h) thinning or loss of pubic hair,
(i) genital atrophy not responsive to
estrogen supplementation,
(j) presence of dry skin and dry and
brittle scalp hair;
(2) providing a composition for topical
application containing an effective amount of an





30



androgenic steroid uniformly contained in a
pharmaceutically acceptable carrier, and
(3) topically administering to the genital
mucosa of said woman an effective amount of said
composition for a period of time sufficient return
one or more of the monitored parameters to its
desired physiological state.
22. A method according to Claim 21 wherein a
monitored parameter is the serum testosterone level.
23. A method according to Claim 22 wherein said
desired physiological state is a serum testosterone
level of between 15 and 80 ng/dl.
24. A method according to Claim 21 wherein a
monitored parameter is the serum free testosterone
unbound to globulin.
25. A method according to Claim 24 wherein said
desired physiological state is a free testosterone
unbound to globulin of between 0.7 and 2.0 pg/ml.
26. A method according to Claim 21 wherein the
androgenic steroid is a member selected from the group
consisting of natural testosterone, testosterone esters,
methyltestosterone, androstenedione, andrenosterone,
dehydroepiandrosterone, fluoxymesterone,
methandrostenolone, 17.alpha.-methylnortestosterone,
norethandrolone, dehydrotestosterone, oxymetholone,
stanozolol, ethylestrenol, oxandrolone, bolasterone and
mesterolone.
27. A method according to Claim 26 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone, methyltestosterone and
esters thereof.


31
28. A method according to Claim 27 wherein the
androgenic steroid is methyltestosterone.
29. A method according to Claim 27 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone and testosterone esters.
30. A method according to Claim 29 wherein the
androgenic steroid is testosterone.
31. A method of progressively providing an
androgenic steroid to a woman in need of testosterone
supplementation, which comprises the steps of:
(1) topically administering to the genital
mucosa of said woman a composition comprising an
effective amount of a an androgenic steroid
uniformly contained in a pharmaceutically
acceptable carrier for a period of time sufficient
to provide a testosterone level suitable to the
needs of the woman;
(2) discontinuing said topical genital
administration; and
(3) orally, transdermally or parenterally
administering to said woman an effective amount of
an androgenic steroid sufficient to maintain said
testosterone level.
32. A method according to Claim 31 wherein said
testosterone level is the serum testosterone level.
33. A method according to Claim 32 wherein said
serum testosterone level is between 15 and 80 ng/dl.
34. A method according to Claim 31 wherein said
testosterone level is serum free testosterone unbound to
globulin.


32
35. A method according to Claim 33 wherein said
serum free testosterone unbound to globulin is between
0.7 and 2.0 pg/ml.
36. A method according to Claim 31 wherein the
androgenic steroid is a member selected from the group
consisting of natural testosterone, testosterone esters,
methyltestosterone, androstenedione, andrenosterone,
dehydroepiandrosterone, fluoxymesterone,
methandrostenolone, 17.alpha.-methylnortestosterone,
norethandrolone, dehydrotestosterone, oxymetholone,
stanozolol, ethylestrenol, oxandrolone, bolasterone and
mesterolone.
37. A method according to Claim 36 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone, methyltestosterone and
esters thereof.
38. A method according to Claim 37 wherein the
androgenic steroid is methyltestosterone.
39. A method according to Claim 37 wherein the
androgenic steroid is a member selected from the group
consisting of testosterone and testosterone esters.
40. A method according to Claim 39 wherein the
androgenic steroid is testosterone.
41. A method according to Claim 36 wherein the
androgenic steroid in step (1) is present in said
carrier for topical application at a concentration of
between about 0.01 and 2.5% and is administered in step
(3) as a dosage of between about 0.25 and 0.8 mg/day.
42. A method according to Claim 41 wherein the
androgenic steroid is methyltestosterone.


33
43. A method according to Claim 42 wherein the
carrier for topical application is a cream.
44. A method according to Claim 43 wherein the
methyltestosterone dosage in step (3) is administered
orally.
45. A method according to Claim 41 wherein the
androgenic steroid is testosterone or an ester thereof.
46. A method according to Claim 45 wherein the
dosage in step (3) is administered parenterally.
47. A method according to Claim 45 wherein the
dosage in step (3) is administered transdermally.

Description

Note: Descriptions are shown in the official language in which they were submitted.



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COMPOSITION AND METHOD FOR SUPPLEMENTING TESTOSTERONE
IN WOMEN WITH SYMPTOMS OF TESTOSTERONE DEFICIENCY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of US
Provisional Application No. 60/037,473, filed on
February 7, 1997; US Provisional Application No.
60/039,717, filed February 12, 1997; and US Provisional
Application No. 60/046,642, filed May 16, 1997.
BACKGROUND
Women who are menopausal, either naturally or as a
result of ovarian failure or loss (e.g., secondary to
hysterectomy, surgical oophorectomy or chemotherapy)
frequently develop testosterone deficiency, with its
attendant undesirable effects.
Because of the above, it would be desirable to
provide compositions and methods for their
administration that would enable women exhibiting
symptoms of testosterone deficiency to take supplemental
amounts of and androgenic steroid in such a manner as to
restore physiological testosterone levels and promote
the return of sexual health and activity, promote
feelings of well-being, promote cardiovascular and
coronary health, maximize muscle tone and inhibit bone
loss. The present invention is.drawn to the attaining of
these desires.
SUMMARY OF THE INVENTION
The present invention relates to compositions and
methods for providing androgenic steroids in effective
amounts to women who are in need of supplementation,
such as women whose total serum testosterone or free
testosterone levels are less than optimal or
significantly below normal physiological levels due to
menopause and/or natural aging or as a result of
hysterectomy or ovarian failure (e.g., consequent to
chemotherapy), or adrenal insufficiency.


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2
In one embodiment a topical formulation, comprising
effective amounts of androgenic steroids in a
pharmaceutically acceptable carrier, is applied to the
genital mucosa for a period of time sufficient to
overcome or ameliorate symptoms of testosterone
deficiency.
The invention also relates to a method of
progressively providing androgenic steroids in effective
amounts to women who are in need of testosterone
supplementation, by means of first applying to the
genital mucosa effective amounts of androgenic steroids
in a pharmaceutically acceptable carrier for a time
sufficient to bring the testosterone level to within
physiological ranges as determined by serum blood levels
("total testosterone") or serum free testosterone
unbound to sex hormone binding globulin ("free
testosterone"). Once the testosterone levels are within
physiological ranges, the topical application to the
genital mucosa is replaced by the oral, transdermal or
parenteral administration of lower amounts of androgenic
steroids to maintain the testosterone levels within the
desired physiological ranges.
Obviously, the need for supplementing androgenic
steroids should be determined by a physician or other
health care professional based on monitoring symptoms of
testosterone deficiency. Not every female will exhibit
the same symptoms and it is possible that testosterone
levels might even be within physiological ranges but,
based on other factors, testosterone deficiency may
still be diagnosed. Such symptoms might include, but not
be limited to, global loss of sexual desire, decreased
sensitivity to sexual stimulation in the nipples and in
the clitoris, decreased arousability and capacity for
orgasm, diminished vital energy and sense of well-being,
and, loss of muscle tone. Some women also notice other
symptoms such as thinning and loss of pubic hair,
genital atrophy not responsive to estrogen, dry and
r


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3
brittle scalp hair, and, dry skin. Other symptoms, while
less documented, include cardiovascular and coronary
heart disease and dry eye in patients suffering from
Sjogren's syndrome.
It is therefore highly desirable, if not
imperative, that testosterone supplementation for a
female patient be based on a diagnosis by a physician
who prescribes the mode of application, dosage and
duration of treatment.
As noted in U.S. Patent 5,460,820, the transdermal
administration of between about 50 to 500 ug of
testosterone per day is usually sufficient to maintain
serum blood levels of between about 15 to 80 ng/dl. On
the other hand, the daily dosage of methyltestosterone,
administered orally, is suggested to be between about
100 to 800 ug (i.e. 0.10 to 0.80 mg/day).
V~hen used within the context of this invention, the
terms "androgenic steroid", "testosterone agent" or
"testosterone" ( when used generically), must be taken
in context and are generally meant to encompass any
androgenic steroid that is functional in reducing
symptoms of testosterone deficiency in females. Members
selected from the group consisting of natural
testosterone, testosterone esters, methyltestosterone,
methyl testosterone esters, androstenedione,
andrenosterone, dehydroepiandrosterone, fluoxymesterone,
methandrostenolone, 17a-methylnortestosterone,
norethandrolone, dehydrotestosterone, oxymetholone,
stanozolol, ethylestrenol, oxandrolone, bolasterone and
mesterolone are representative of androgenic steroids.
Of this group testosterone, methyltestosterone and
esters thereof are preferred. Representative esters
include the propionate, phenylacetate, enanthate and
cypionate esters of testosterone and methyltestosterone.
Serum, or total, testosterone or free testosterone
determined by analysis of blood or other body fluids
will generally refer to natural testosterone. Based on


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4
the above dosages and knowledge of physiological
testosterone ranges, one skilled in the art can readily
determine what amount of each androgenic steroid or
testosterone agent to administer. What is important is
that the dosage of the testosterone agent must be
sufficient to overcome the deficiency being monitored or
treated without administering too great a dosage.
However, it is the object of this invention to provide
a method of treating testosterone deficiencies to bring
the testosterone level in any given female within that
female's normal physiological range and the exact dosage
is not as critical as is the obtaining of the resultant
physiological norm for that patient.'''
Too high a dosage of testosterone, or application
of a dosage for too long a period of time may be
manifest by symptoms of testosterone excess, i.e.
irritability, clitoral enlargement, increased facial
hair and lowering of the voice. By following the
guidelines contained in the present invention, such
indications will not be manifest and the patient and
prescribing physician should not be unduly concerned
over undesirable side effects.
Since the genital mucosa readily absorbs androgenic
steroids, the initiating of testosterone supplementation
in that area quickly provides vitalization of the
genitalia as well as providing systemic delivery of
testosterone to other areas.~As the genital tissues
become healthier following topical testosterone
application, the blood circulation is improved and
testosterone receptors become well supplied with the
concomitant increase in sexual sensation and
gratification. A sense of well-being and self awareness
usually results.
The compounding of a formulation for topical
application to the genital mucosa may be in various
forms, e.g. a solution, emulsion, cream, gel, ointment)
paste and the like. Generally, the concentration of


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testosterone or other androgenic steroid will be between
about 0.01 and 2.5~ by weight of the formulation with
concentrations of between about 0.1 and 1.0o being
preferred. The carrier used may be a solvent for
5 testosterone or a vehicle in which the testosterone may
be uniformly dissolved or suspended.
By "pharmaceutically acceptable carrier" is meant
a vehicle or carrier in which the androgenic steroid,
and any other ingredients such as enhancers and/or
solvents, along with any other additives, are contained
in a single or phase separated fluid state. By "fluid"
is meant a composition that is not solid but may be
present in varying degrees or states of viscosity. The
carrier per se may serve as a solvent or a solvent or
co-solvent may be added. Carriers can be water or
organic based and may contain a mixture of liquids or
solvents appropriately gelled or thickened. In other
words, such carriers may comprise, but are not limited
to, solutions, suspensions, emulsions, gels, ointments,
creams, pastes or any other similar state which permits
the outward diffusion of testosterone or other
androgenic steroid and any enhancer, solvent or other
additives as desired. The continuous phase forming such
carriers can vary from hydrophilic to hydrophobic
depending upon the desired combination. Representative
inert ingredients other than water include, but are not
limited to, polypropylene glycol, polyethylene glycol,
polyvinyl alcohols, petrolatum, polyvinylpyrrolidone,
mineral oil, silicone oil, ethylene-vinyl acetate
polymers or other low molecular weight polymers soluble
in water, CZ-CB lower alcohols or suitable solvents.
In addition to the carrier, the formulation may
contain a solvent (or solvents) and an absorption
enhancer (or enhancers). Optionally, the formulation
can also comprise preservatives, fragrances and/or
stabilizers. Typically, the androgenic steroid is in the
form of natural testosterone, methyltestosterone, and


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6
esters thereof such as testosterone or
methyltestosterone propionate, cypionate, or enanthate.
Suitable enhancers include those conventionally
used in the art . Representative of these are CB to Cle
fatty acids, C1 to C8 esters of CR to C18 fatty acids, C~
to C18 fatty alcohols, sorbate esters and salts, glycerol
esters of fatty acids, C~ to C22 fatty acid esters of a-
hydroxy acids and mixtures of any of the above.
Enhancers may be present in any functional amount and
will generally be present in amounts of between about
0.01 and 30~ by weight.
Also, certain solvents can serve as both solvents
and enhancers. Representative of these are CZ to C~
alcohols, C3 or C4 diols, ethoxydiglycol, DMSO, DMF, DMA,
1-n-dodecyl-cyclazacycloheptan-2-one, N-methyl-
pyrrolidone, N-(2-hydroxyethyl)pyrrolidone and the like.
As with enhancers, solvents may be present in any
functional amount. Since some solvents may actually
function as the carrier vehicle, it is not practical to
restrict the amount of solvent to any numerical range
except to state that "effective amounts" may be
utilized.
Other additives such as thickening agents, gums,
fragrances, stabilizers, agents to increase the
solubility of androgenic steroids (e. g. cyclodextrins,
etc . ) , and the like can also be incorporated into the
formulation.
The absorption enhancer or enhancers render the
androgenic steroid more readily available by enabling or
enhancing its uptake into genital mucosal cells or the
surrounding skin. This facilitates delivery to the
genital mucosa or the skin and absorption of the
androgenic steroid utilized.
Typically, topical formulations comprise from about
0.010 to about 2.5~ testosterone and can comprise any
concentration within this range which is appropriate to


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7
produce the desired effects. The lowest concentration
that can bring about the desired effects is preferred.
In that regard formulations comprising from about 0.050
to about 1o testosterone are preferred.
While the invention encompasses the utilization
of testosterone, methyltestosterone and esters thereof
it may be beneficial to utilize methyltestosterone when
administered concurrently with estrogens or when it is
preferred estradiol levels be maintained as low as
possible. Methyltestosterone does not tend aromatize in
situ into estradiol whereas small amounts of
testosterone may be converted to estradiol. Use of
methyltestosterone is of particular value, for example,
in women who develop testosterone deficiency as a result
of ovarian failure following chemotherapy for breast
cancer and who need to keep their estrogen levels as low
as possible. However, while the following examples
primarily illustrate the use of methyltestosterone, that
is not intended to be a limitation on the invention as
other androgenic steroids may also be utilized to bring
about the desired results but may need to be monitored
more carefully.
In the embodiments exemplified in the following
Examples 1-15, a dosage of between 0.25 and 0.5 mg
methyltestosterone/0.1 ml transmucosal cream is used. In
other words, the concentration of methyltestosterone in
the topical preparation is between 0.25 and 0.5o by
weight. The concentration most appropriate for a
particular woman can be determined empirically (e.g., by
varying the concentration and assessing the resulting
effects on genital atrophy and sexual sensitivity).
In carrying out the present invention upon
determining the presence of one or more symptoms of
testosterone deficiency, a formulation comprising an
androgenic steroid, such as methyltestosterone, at an
appropriate concentration is applied to the genital
mucosa in sufficient quantity and for sufficient time,


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8
as the patient is monitored by her physician, to reduce
genital atrophy and bring about a reduction in the
symptoms of testosterone deficiency. Typically this will
vary from about one week to three months and, most
typically from about three to nine weeks. Subsequently,
to keep testosterone blood levels within physiological
ranges, topical genital administration is reduced and
supplemented by oral, transdermal or parenteral
administration of low doses of the androgenic steroid,
such as methyltestosterone, in sufficient quantity to
maintain the benefits obtained from the use of the
topical genital formulation. Preferably, the oral dose
of methyltestosterone is in the range of .1 mg to .8 mg
per day and the transdermal dose of testosterone, as
noted in U.S. Patent 5,460,820, is in the range of 0.05
to 0.5 mg per day for testosterone.
The transdermal or parenteral dose for
methyltestosterone or oral or parenteral dosages
testosterone may require minor adjustments. However, it
is to be noted that the overall ranges for testosterone
and methyltestosterone given above overlap considerably
such that a general dosage range of testosterone or
methyltestosterone, in any administered form, of from
about 0.01 to 1.0 mg/day should be suitable. However,
this range may vary for any given androgenic steroid
according to its relative potency and bioavailability.
Therefore the key to the exact amount is that of
functionality. Any androgenic dosage that is equivalent
to 0.01 to 1.0 mg/day of testosterone or
methyltestosterone should be effective.
As described herein, the formulation of the present
invention provides a means by which the health of the
genital mucosa and sexual sensitivity of the clitoris
and vagina can be improved and other systemic benefits
of improved testosterone levels can also be achieved.
t ii


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9
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE
INVENTION
The following compositions described are for topical
application to the genitals, particularly the genital
mucosa, and to the adjacent skin. The formulation
comprises an androgenic steroid suitable for
testosterone supplementation as noted above in
combination with a pharmaceutically acceptable carrier.
More than one androgenic steroid or form of testosterone
can be included in a single formulation (e.g., to
provide forms which can vary in their availability).
Testosterone, methyl testosterone and their esters, as
noted above, are preferred androgenic steroid agents.
Commercially available carriers can be used to
produce the formulation of the present invention or
carriers specifically designed for delivery of
testosterone to the genital mucosa or skin can be used.
For example, a cream base, such as that available from
Professional Compounding Centers of American, Inc.
("PCCA") and referred to as PLO gel or Pluronic Lecithin
Organogel can be used. The PCCA base includes: Soya
granular lecithin; Poloxamar 407, NF: isopropyl
palmitate, NF; purified water, USP; alcohol, USP; sorbic
acid, NF and potassium sorbate, NF.
Alternatively, a cream base, referred to as
"Pharmavan cream" and available from The Apotherecary,
(Keene, NH), is used in Examples 1-14 below. Pharmavan
cream includes; cetyl alcohol NF (1.0~); stearic acid
NF (15.00 ; isopropyl myristate (5.0~); polyoxyl 40
stearate NF (1.0~); stearyl alcohol NF (1.0~); potassium
sorbate (0.1~) and distilled water (qs 100.00 . The
cream base is made by combining the cetyl alcohol NF,
stearic acid NF, isopropyl myristate, polyoxyl 40
stearate NF and stearyl alcohol NF and heating the
resulting combination to 75°C. The potassium sorbate is
dissolved in 75~ of the distilled water, heated to 75°C
and the xanthene gum is dispersed in this potassium


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sorbate/distilled water mixture. The two combinations
of components are combined, preferably by adding the
potassium sorbate/water/xanthene gum combination to the
cetyl alcohol-containing combination. The resulting
5 combination (which contains all of the components
described above) is homogenized and mixed at slow speed
until it is of uniform consistency and makeup. The pH
is adjusted, if needed, to be within a range of 4.0 to
5.5 and, preferably, between pH about 4.5 and about 5Ø
10 Sufficient additional distilled water is added (qs to
volume) and mixing is carried out to produce a uniform
consistency. The resulting combination is allowed to
set up (e. g., for 24 hours or sufficient time to produce
a cream of the desired consistency). A
methyltestosterone topical cream is produced by
combining methyltestosterone, ethoxydiglycol and the
Pharmavan cream described above. For example, a
methyltestosterone topical cream containing 0.5 mg
methyltestosterone/0.1 ml cream can be produced by
combining 0.150 gm methyltestosterone, 10.0 ml
ethoxydiglycol and Pharmavan cream qs 30.0 ml.
In the method of the present invention, the
androgenic steroid-containing formulation is applied
topically to the genital mucosa, in an effective
quantity (a sufficient quantity to improve the health of
the genital mucosa and supply testosterone to local
testosterone receptors). Testosterone, such as
methyltestosterone) in the formulation is absorbed,
resulting in increased systemic levels and attendant
benefits (e. g., restoration of vital energy, sexual
libido, capacity for orgasm and intensity of orgasm,
sensitivity to sexual stimulation in the nipples,
improvement of muscle tone, improved moisture in skin
and hair, increased deposition of bone, stimulation of
red blood cell production and improvements in mood and
sense of well-being). The topical formulation is
applied one or more times a day for a sufficient number


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11
of days (e.g., 1 week to 3 months and, generally 3-9
weeks) to produce the desired effect. When sufficient
benefit has been achieved through topical genital
application, topical genital application is reduced or
discontinued and oral or transdermal supplementation
with an appropriate low dosage of the same or different
androgenic steroid is begun, in order to maintain blood
levels of testosterone sufficient to maintain the
effects achieved as a result of topical application.
For example) application to the genital mucosa can be
discontinued and a low dose of testosterone can be
administered orally, transdermally or parenterally, in
an amount sufficient to maintain the desired blood
levels. Alternatively, application to the genital
mucosa can be continued but at a reduced level or
frequency (e. g., using a formulation containing less
androgenic steroid than the formulation initially used
or applying the formulation on a less frequent basis) in
combination with oral, transdermal or parenteral
administration of one or more of the forms of
testosterone. In general, methyltestosterone will be
administered orally at a dose of from about 0.10 mg to
about 0.80 mg per day; the dose will be adjusted
according to an individual woman's needs. In a
particular embodiments of Examples 1-14, the dose will
be from about 0.3 mg to about 0.6 mg per day.
Methyltestosterone capsules (e. g., capsules containing
0.05 mg, 0.10 mg, 0.25 mg or 0.50 mg methyltestosterone)
can be administered. The dose of oral
methyltestosterone can be taken in a single daily dose
or in two or more smaller quantities.
The following case studies based on a physician
determination of testosterone deficiency are exemplary
of the results obtained using testosterone
supplementation according to the invention. The
formulation applied was compounded as described above,


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12
i.e. methyltestosterone, ethyoxydiglycol and Pharmvan
cream.
EXAMPLE 1
Patient A is a 41 year old woman who had a
hysterectomy three years prior. She had huge fibroid
tumors of the uterus weighing up to five pounds. Her
ovaries were not removed. She described herself prior
to the surgery as a very sexually active woman in a
satisfying relationship with a wonderful man. Following
her surgery, she lamented that she "feels nothing"
sexually. She has noticed some loss of scalp hair but
not much change in pubic hair. She complained that she
has a loss of general vital energy and is very
distressed about lack of sexual feeling, pleasure and
libido.
Tests showed that her total serum testosterone was
virtually unmeasurable at 3.0 ng/dl (normal range 15-80
ng/dl) and serum free testosterone was also negligible
at 0.16 pg/ml (normal range 1.0-2.0 pg/ml). Serum
estradiol was within normal limits at 125 pg/ml.
Thyroid hormone studies were within normal limits.
Patient A was treated with topical
methyltestosterone cream 0.250, .1 ml applied to the
genital mucosa each night after bathing and, after 4
days, she noted an appreciable improvement in genital
sexual sensitivity and pleasure on stimulation. After
three weeks she stated that her sexual vitality had been
restored and that she "feels like herself again."
EXAMPLE 2
Patient B is a 53 year old woman whose menstrual
periods stopped three years ago, when she was age 50.
She complained of changes in her personality, having
rageful feelings, being forgetful, unable to
concentrate, having no energy and was most troubled
because she had no sexual feelings at all. Her sexual
r T


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13
feelings had been waning somewhat for several years.
She reported she last felt fully well and sexually alive
when she was about 40. She had previously enjoyed a
very good sexual relationship with her husband but now
had no sexual interest at all. She stated that she took
estrogen for 3-4 months about a year ago but stopped
because she got nervous about potential breast cancer
risks. On a mammogram, some calcifications showed up,
but were negative for cancer on needle biopsy. Patient
B complained of having hot flashes and disrupted sleep.
Patient B's total serum testosterone was low at
14.8 ng/dl; as was serum free testosterone, at 0.38
pg/ml. Her serum estradiol was 6.28 pg/ml, which is in
the menopausal range. Thyroid hormone levels were
within normal limits.
She was started on methyltestosterone topical cream
0.25, 0.1 ml per day applied to the genital mucosa.
After six weeks on this regimen, Patient B was sleeping
much better, having fewer hot flashes, more comfortable
in mood and with distinctly improved sex drive and
capacity for sexual pleasure.
EXAMPLE 3
Patient C is a 39 year old woman complaining of
decreases clitoral and vaginal sensitivity, low libido
and dyspareunia. For the past year, she also had a
depressed mood, and her energy level was quite low.
Menarche began at age 13, and her periods had never been
regular.
Serum testosterone was low at 14.0 ng/dl, and serum
free testosterone was low at .3 pg/ml. Thyroid hormone
levels were within normal limits.
She was started on Premarin 0.9 mg q.d., and
micronized progesterone 200 mg q.d. for the first ten
days of each month to insure that she had proper
shedding of her endometrium. After six weeks, she felt
somewhat better, but noticed no improvement in her sex


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14
drive. She was started on topical methyltestosterone
0.250, using .1 ml daily applied to her genital mucosa.
At her next visit, six weeks later, she reported that
her mood was fine, her energy was good, and her sex
drive was markedly improved. She was having no pain on
sexual intercourse, and was very pleased with her
present state.
EXAMPLE 4
Patient D is a 60 year-old-woman who has never been
treated with estrogen, and sought professional advice
complaining of the decline in her energy and her sex
drive. Her last menstrual flow was at about age 50.
She had not had sexual intercourse since she was about
age 51. She had vaginal dryness.
On laboratory evaluation, she was found to have an
elevated serum FSH of 66.6 MIU/ml, compatible with her
menopausal status. Serum estradiol was <20 pg/ml.
Serum testosterone was 12 ng/dl. A free testosterone
level was .74 pg/ml.
Because of her low serum estradiol level, she was
started on Premarin 0.9 mg daily, to be cycled with
micronized progesterone 200 mg daily for the first ten
days of each month. After 6 weeks she was tolerating
this regimen well but having no improvement in sexual
energy. She was started on topical methyltestosterone
0.25, using .1 ml daily applied to her genital mucosa.
Six weeks later, she reported increased sexual
sensitivity and pleasure, and improved sexual libido.
EXAMPLE 5
Patent E is a 46 year old woman who, at age 38, had
a total hysterectomy and bilateral salpingo-oophorectomy
for ovarian cyst and severe endometriosis. She was
subsequently placed on the Climara patch 0.1 mg. On the
estrogen treatment, she developed migraine headaches
once weekly which were severe and associated with


CA 02280033 1999-08-06
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vomiting. These were treated with Imitrex 25 mg. She
came in complaining of markedly decreased sex drive.
On hormonal evaluation, her serum estradiol was 44
pg/ml, serum total testosterone was low at 10.3 ng/dl,
5 and free testosterone was very low at <.15 pg/ml. DHEA
S was within normal limits for her age at 109 mcg/dl, as
were thyroid function studies.
She was started on topical methyltestosterone
0.25, using .1 ml daily applied to her genital mucosa.
10 Six weeks later, she reported that her libido was
better, she was sleeping better and having fewer
migraine headaches. Her libido improved further on
slight increase in the testosterone to 1.5 ml
alternating with 1.0 ml per day.
EXAMPLE 6
Patient F is a 40 year old woman who had a
hysterectomy and bilateral salpingo-oophorectomy five
years ago for bad menstrual periods, severe
endometriosis, and painful intercourse. She had enjoyed
an active sex life and had a good sex drive prior to the
surgery, although intercourse had been painful due to
the endometriosis. Following the surgery, she was
placed on Premarin .625 mg per day. During the 2 year
period previous to her visit, she had suffered a
complete loss of sexual libido and activity. During the
previous year, she has had Increasing problems with
insomnia and frequent headaches. Her weight has
increased 30-40 lbs in the past five years, and she was
much less active than she had been previously.
A serum estradiol was 186 pg/ml, a total
testosterone was low normal at 18 ng/dl, and the free
testosterone was the low end of the normal range at 1.05
pg/ml. Thyroid function studies were within normal
limits.
The patient was started on methyltestosterone .25~
cream, .1 ml applied to the genital mucosa daily. On


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16
her return in 8 weeks, she was pleased to report
increased sexual sensitivity and desire, better energy
and sleep. She has begun to exercise, and reports
improved muscle tone and a weight loss of 4 pounds.
EXAMPLE 7
Patient G is a 41 year old woman who was still
menstruating regularly, with periods every 28 days, but
who reported loss of sexual libido and was very
distressed that she had lost most of her pubic hair.
Migraine headaches, which she has had since she was a
teenager, had become more problematic. She noted muscle
weakness, and had also gained 20-25 pounds and had noted
a marked decline in her energy level. She had also been
having some problems with concentration.
On hormonal evaluation, she had a slight elevation
of her FSH and a serum estradiol of 69.9 pg/ml and 46.2
pg/ml on separate occasions, both somewhat low but not
quite menopausal levels. Her serum testosterone was
quite low at 1.9 ng/dl, and a free testosterone was low
at 0.79 pm/ml.
To stabilize her perimenopausal status, she was
started on Premarin 0.9 mg daily, with the subsequent
addition of .25~ methyltestosterone cream, 0.1 ml
applied to the genital mucosa daily. After 8 weeks, she
reported improvement in her sexual libido, fewer
migraine headaches and better~general energy.
EXAMPLE 8
Patient H is a 43 year old woman suffering severe
depression and loss of sexual libido and pleasure since
a hysterectomy and bilateral salpingo-oophorectomy four
years ago for large uterine myomata. She had been
treated with a variety of estrogen preparations,
including Ogen and Estraderm. She had a trial of an
androgen implant at one time to determine if it would be
beneficial. She did not notice improvement in mood or


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17
libido and felt agitated (possibly from too high a blood
level of testosterone). She had been treated for major
depressive disorder with multiple antidepressants
including Zoloft, Desyrel, Parnate, Wellbutrin,
Anafranil, Prozac, lithium, Ritalin, Risperidone, and
ETC.
Serum estradiol was 38.6 pg/ml, total testosterone
level was low at 4.9 ng/dl and free testosterone was
0.24 pg/ml. Thyroid hormone levels were within normal
limits. Increasing her estradiol by prescribing
Estraderm 0.1 mg resulted in some improvement in her
depression. Six weeks later, she was started on
methyltestosterone topical cream 0.25 at .1 ml applied
to the genital mucosa daily. After 6 weeks, the patient
reported better energy and improvement in sexual
sensitivity and libido.
EXAMPLE 9
Patient I is a 48 year old woman with a history of
carcinoma of the breast diagnosed when she was 40 and
treated with chemotherapy. The carcinoma was found to
be estradiol receptor negative, progesterone positive.
Following the chemotherapy, she became menopausal and
her libido declined. She also noted a decline in her
energy and increase in symptoms of depression. She was
taking Zoloft 50 mg daily and was using Estrace vaginal
cream once weekly.
Serum estradiol was very low at 29 pg/ml.
Interestingly enough, serum and free testosterone levels
were within normal limits at 33 ng/dl and 1.7 pg/ml,
respectively. Thyroid hormone levels, prolactin and
DHEA-S evaluations were within normal limits.
On the chance that her testosterone receptors were
deficient because of the low estradiol levels (estrogen
stimulates production of testosterone receptors) and
that a higher level of testosterone might partially
overcome this deficiency, she was given


CA 02280033 1999-08-06
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18
methyltestosterone cream 0.25, to use 0.1 ml per day on
the genital mucosa. After 6 weeks, she reported a
return of sexual sensation and libido and a significant
improvement in her mood.
EXAMPLE 10
Patient J is a 50 year old perimenopausal woman who
had been taking a contraceptive (Norinyl), containing
ethinyl estradiol and norethindrone. Prior to starting
the oral contraceptive, she had been experiencing some
hot flashes. While taking the oral contraceptive, her
sex drive had decreased. She was having painful
intercourse, and she had also noted some loss of pubic
hair.
Laboratory evaluation showed that she had no
measurable total testosterone, and virtually no serum
free testosterone (.25 pg/ml).
The oral contraceptive was discontinued and she was
placed on Premarin 0.9 mg per day and topical
methyltestosterone .25~ cream, 0.1 ml per day to be
applied to her genital mucosa. Return visit 8 weeks
later found her pleased to be enjoying pain-free
intercourse, greater sexual pleasure and significant
improvement in sexual libido. Return visit in three
months found the return of normal amount and texture of
pubic hair.
EXAMPLE 11
Patient K is a 55 year old woman who has been on
hormone replacement therapy since age 42, when she began
suffering from night sweats and vaginal dryness. At the
time of consultation, she was using Estraderm 0.05 mg
twice weekly. She had had problems with mild depression
for many years, but it had been worse since she had been
menopausal. She had been taking Prozac 20 mg daily for
the past seven years. She had had poor libido for more
than 8 years.


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19
Serum estradiol was 47.3 pg/ml, serum total
testosterone was less than 20 ng/dl and free
testosterone was very low at 0.48 pg/ml. Serum T3, T4,
free T4 and TSH levels were within the normal range.
S Estraderm dosage was increased to 0.1 mg twice
weekly. After 6 weeks, she noted mild improvement in
the vaginal dryness, but no improvement in sexual libido
or sensitivity. She was started on methyltestosterone
0.250 cream, 0.1 m1 per day applied to the genital
mucosa. After 6 weeks, she reported improvement in
sexual sensitivity and return of libido. She also noted
markedly improved vaginal lubrication on intercourse.
EXAMPLE 1Z
Patient L is a 50 year oid woman complaining of low
energy, mood problems, and depression. She had been
taking Wellbutrin 300 mg daily for the past 3-4 years.
Her sex drive was low and she was unable to have an
orgasm. Her sexual activity had declined gradually over
the past 10 years. When she was younger she enjoyed a.
very active sex life. She still had slight menstrual
periods about every three weeks.
Laboratory values showed an elevated FSH at 33.0
m1U/ml, serum estradiol at 139.0 pg/ml. Serum total
testosterone was 27 ng/dl, but free testosterone was
very low at 0.34 pg/ml. .
She was started on topical methyltestosterone 0.5~,
0.1 ml per day applied to the genital mucosa. After
three weeks, she had only a mild increase in libido.
Premarin 0.9 mg was added, and within 6 weeks, her sex
drive was much better, and her mood was improved.
EXAMPLE 13
Patient M is a 48 year old woman who, two years
previous, had a total hysterectomy with bilateral
salpingo-oophorectomy because of fibroids. Following


CA 02280033 1999-08-06
WO 98/34621 PCT/US98/02089
the surgery, she was placed on Premarin 0.625 mg.
Complaining of lethargy and depression, the dosage was
increased to .9 mg daily. Subsequently, about one year
previous, the dosage was decreased to 0.625 mg because
5 of her concerns regarding the risk of breast cancer.
Immediately following the surgery, she noted a decrease
in her sex drive and sexual function. She is unable to
have an orgasm.
On hormonal evaluation, her serum estradiol was 75
10 pg/ml, serum total testosterone was low at 11.6 ng/dl,
and serum free testosterone was virtually absent at 0.2
pg/ml.
The patient was started on methyltestosterone .25~
cream 0.1 ml applied daily to the genital mucosa.
15 Returning after 6 weeks, she reported the return of
sexual sensitivity, markedly improved sexual libido and
capacity for orgasm. She also noted a marked
improvement in general energy.
20 EXAMPLE 14
Patient N is a 57 year old woman who, at age 45,
began to notice mood changes and decline in energy. At
that time, she was also having the onset of heavy
menstrual bleeding, was told that she had myomata and
needed a hysterectomy. When she was 47, a bilateral
salpingo-oophorectomy and total hysterectomy was
performed. Following the surgery, her moods worsened
and she had a marked decline in her sex drive. She is
unable to have an orgasm. She was sent to a
psychiatrist and was treated with tricyclics, Nardil,
Zoloft and Prozac, with no significant improvement in
her mood or sexual function. For a six month period she
was treated with Premarin 0.625 mg daily, which was then
increased to 1.25 mg daily. She developed fluid
retention, headaches, and continued depression, so she
discontinued estrogen therapy. She complained of having
r i


CA 02280033 1999-08-06
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21
very low energy, insomnia, difficulty falling asleep and
early morning awakening.
Laboratory testing revealed serum estradiol of <20
pg/ml, total serum testosterone of 21 ng/ml and serum
free testosterone at 0.77 pg/ml. Thyroid function
studies were all within normal limits. Serum
cholesterol was elevated at 329 mg/dl, and triglycerides
were 394 mg/dl.
She was started on Estrace 1.0 mg daily, tolerated
it well and it was subsequently increased to 2.0 mg
daily. She noted some improvement in mood and general
energy, but no improvement in sexual function. She then
was given methyltestosterone 0.25 cream, 0.1 ml daily
applied to the genital mucosa. On return six weeks
later, she felt markedly better, had the return of
sexual sensitivity and pleasure, improved libido and
capacity for orgasm. Her mood and energy was
substantially better.
Example I5
Patient O is a 51 year old woman who had her last
menstrual period one year previous. She reported that
when she was 47, having irregular menstrual periods with
light flow. She experienced a loss of sexual libido and
general energy over a period of several months. She
noted a significant loss of pubic hair and flaccidity of
her labia. Scalp hair was dry and breaking. For the
previous 18 months she had been taking Premarin .625 mg.
and cycling with Provera 10 mg for ten days each month.
She reported a feeling of "flatness" and lack of zest
and experienced no sexual sensation in nipples or
genitals.
Laboratory tests showed total testosterone below
the limits of detection and free testosterone was low at
0.1 pg/ml. She had tried using Estratest H.S. which made
her feel agitated and disrupted her sleep.


CA 02280033 1999-08-06
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22
She was treated with testosterone propionate 2o in
petrolatum, a small amount applied to the genital mucosa
once per day. After two months, she began to experience
sexual sensitivity and pleasure and the return of sexual
libido and general vital energy. After four months, her
pubic hair had regrown to normal amount and texture.
Serum testosterone was elevated significantly above
physiological levels at this point. The topical
preparation was discontinued in favor of oral
methyltestosterone 0.25 mg. per day, which sustained her
libido, capacity for sexual pleasure and feeling of well
being.
The following examples are representative of
various formulations and treatment regimens that
illustrate the invention.
Three pharmaceutical carriers are illustrated as
representative. Carrier A is the Pharmvan cream carrier
given above as used in Examples 1-14. Carrier B is a
gelled base comprising ethanol/water/glycerin (50:20:30
volume) gelled with 1.5~ w hydroxypropyl cellulose and
containing about 2.5~ w of an oleic acid ester of
glycerol as an enhancer. Carrier C is a petrolatum base
containing 2~ isopropyl palmitate as an enhancer.
Oral Tablet A is a sugar coated tablet containing
the specified amount of methyl testosterone in an inert
lactose/magnesium stearate/microcrystalline cellulose
carrier. Oral Tablet B is a pressed tablet containing
the specified amount of fluoxymesterone in a calcium
stearate/corn starch carrier. Injectable solution A is
a testosterone cypionate ester uniformly contained in a
cottonseed oil/benzyl alcohol solution stabilized by
benzyl benzoate. Transdermal patch A is a matrix patch
as described in U.S. Patent 5,460,820 formulated to
deliver 100 ug/day of testosterone.
Following diagnoses of one or more symptoms of
testosterone deficiency in a woman the designated
topical formulation is applied one or more times daily
T T


CA 02280033 1999-08-06
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23
to the genital mucosa for a time sufficient to alleviate
the symptoms of testosterone deficiency. When indicated,
the topical treatment is replaced by an oral,
transdermal or parenteral maintenance formulation
administered using the formulation and/or dosage
indicated.
Example 16
Topical formulation: 0.2~ w. natural testosterone
in Carrier B
Maintenance: Transdermal Patch A
Example 17
Topical formulation: 0 . 15 ~ w . microni zed
testosterone propionate in
Carrier C
Maintenance: 0.5 mg testosterone cypionate
in Injection Solution A
administered weekly
Example 18
Topical formulation: 0.3~ w. testosterone in
Carrier A
Maintenance: .2 mg fluoxymesterone as Oral
Tablet B administered daily
Example 19
Topical formulation: 0.15 w. testosterone
enanthate in Carrier C
Example 20
Topical formulation: 0.05 w. testosterone
enanthate in Carrier A
Maintenance: Transdermal Patch A


CA 02280033 1999-08-06
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24
Example 21
Topical formulation: 0.150 w.
dehydroepiandrosterone in
Carrier B
Maintenance: 0.1 mg dehydroepiandrosterone
as Oral Tablet B administered
daily
Example 22
Topical formulation: 0.2~ w. testosterone in
Carrier C
Maintenance: .2 mg methyltestosterone as
Oral Tablet A administered
daily
Examsale 23
Topical formulation: 0.1~ w. methyltestosterone
propionate in Carrier A
Maintenance: Transdermal Patch A
Examt~le 24
Topical formulation: 0.12 50/50 ratio of
testosterone and testosterone
propionate in Carrier B
Maintenance: .2 mg fluoxymesterone as Oral
Tablet B administered daily
These examples are intended to be indicative only
of regimens that can be utilized. Each regimen will
preferably be customized to meet the needs of the
patient. While the examples have been directed primarily
to the delivery of an androgenic steroid to provide
needed supplementation based on determination of a need
for such, it is likely that such administration will be
concurrent with the administration of estrogen and/or
estrogen and progestin formulations.


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In addition to the above, it is believed, the
supplementation of testosterone by means of genital
application of an effective amount of testosterone in a
pharmaceutically acceptable carrier may enhance coronary
5 vasodilation, and has effects on carbohydrate metabolism
beneficial to blood vessel endothelium. Genital topical
application of testosterone to women to bring
testosterone levels to within normal limits may have a
cardiovascular protective effects.
10 Those skilled in the art will recognize, or be able
to ascertain using no more than routine experimentation,
many equivalents to the specific embodiments of the
invention described herein. Such equivalents are
intended to be encompassed by the following claims.

Representative Drawing

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Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 1998-02-05
(87) PCT Publication Date 1998-08-13
(85) National Entry 1999-08-06
Dead Application 2004-02-05

Abandonment History

Abandonment Date Reason Reinstatement Date
2003-02-05 FAILURE TO REQUEST EXAMINATION
2003-02-05 FAILURE TO PAY APPLICATION MAINTENANCE FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $300.00 1999-08-06
Registration of a document - section 124 $100.00 1999-10-15
Maintenance Fee - Application - New Act 2 2000-02-07 $100.00 2000-02-02
Maintenance Fee - Application - New Act 3 2001-02-05 $100.00 2001-01-19
Maintenance Fee - Application - New Act 4 2002-02-05 $100.00 2002-01-21
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
THERATECH, INC.
Past Owners on Record
RAKO, SUSAN
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Description 1999-08-06 25 1,222
Abstract 1999-08-06 1 43
Claims 1999-08-06 8 289
Cover Page 1999-10-13 1 27
Correspondence 1999-09-13 1 2
Correspondence 1999-09-20 1 2
Assignment 1999-08-06 3 90
PCT 1999-08-06 7 294
Assignment 1999-10-15 4 169