U.S. patent application number 14/875947 was filed with the patent office on 2016-09-01 for method and composition for transdermal drug delivery.
This patent application is currently assigned to Acrux DDS Pty Ltd. The applicant listed for this patent is Acrux DDS Pty Ltd. Invention is credited to Tony DIPIETRO, Igor GONDA, Andrew HUMBERSTONE, Kerrie SETIAWAN, Adam WATKINSON, Nina WILKINS.
Application Number | 20160250227 14/875947 |
Document ID | / |
Family ID | 39612458 |
Filed Date | 2016-09-01 |
United States Patent
Application |
20160250227 |
Kind Code |
A1 |
DIPIETRO; Tony ; et
al. |
September 1, 2016 |
METHOD AND COMPOSITION FOR TRANSDERMAL DRUG DELIVERY
Abstract
The invention is directed to a transdermal drug delivery
composition which includes at least one physiologically active
agent; and at least one volatile solvent; and at least one
viscosity modulating agent. The invention extends to methods of
administering such a composition to a subject and treatment of
subjects using the composition.
Inventors: |
DIPIETRO; Tony; (Templestowe
Lower, AU) ; HUMBERSTONE; Andrew; (Vaud, CH) ;
GONDA; Igor; (San Francisco, CA) ; WATKINSON;
Adam; (Lympne, GB) ; SETIAWAN; Kerrie; (South
Yarra, AU) ; WILKINS; Nina; (Kensington, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Acrux DDS Pty Ltd |
West Melbourne |
|
AU |
|
|
Assignee: |
Acrux DDS Pty Ltd
West Melbourne
AU
|
Family ID: |
39612458 |
Appl. No.: |
14/875947 |
Filed: |
October 6, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14509404 |
Oct 8, 2014 |
9180194 |
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14875947 |
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12823448 |
Jun 25, 2010 |
8993520 |
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14509404 |
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11445463 |
Jun 2, 2006 |
8435944 |
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12823448 |
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60752884 |
Dec 23, 2005 |
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Current U.S.
Class: |
424/60 |
Current CPC
Class: |
A61P 15/00 20180101;
A61P 17/00 20180101; A61K 47/10 20130101; A61K 47/14 20130101; A61K
9/0014 20130101; A61K 47/32 20130101; A61K 8/37 20130101; A61P 5/24
20180101; A61K 47/12 20130101; A61Q 17/04 20130101; A61P 5/26
20180101; A61K 31/568 20130101 |
International
Class: |
A61K 31/568 20060101
A61K031/568; A61K 47/32 20060101 A61K047/32; A61Q 17/04 20060101
A61Q017/04; A61K 47/14 20060101 A61K047/14; A61K 8/37 20060101
A61K008/37; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 3, 2005 |
AU |
2005902902 |
Claims
1.-20. (canceled)
21. A method of treatment of androgen deficiency in an adult male
subject, comprising topically administering to at least one axilla
of the subject a composition comprising: (a) testosterone; (b) from
40 to 99% v/v of a volatile solvent carrier selected from ethanol,
ethyl acetate, isopropanol and mixtures thereof; and (c) from 0.1%
to 15% w/v of at least one sunscreen ester penetration
enhancer.
22. A method according to claim 21, wherein the sunscreen ester
penetration enhancer is selected from the group consisting of octyl
dimethyl-para-aminobenzoate, octyl paramethoxycinnamate, octyl
salicylate and mixtures thereof.
23. A method according to claim 21, wherein the sunscreen ester
penetration enhancer is octyl salicylate
24. A method according to claim 21, wherein the composition is
administered without covering the composition with a physical
barrier bonded to the administration area.
25. A method according to claim 21, wherein the volatile solvent
carrier is ethanol, isopropanol or a mixture thereof.
26. A method according to claim 21, wherein the composition is
administered in an amount to provide a serum testosterone level of
300-1000 ng/dL.
27. A method according to claim 21, wherein the composition further
comprises from 1-5% w/v of a thickener.
28. A method according to claim 27, wherein the thickener is
polyvinylpyrrolidone.
29. A method according to claim 21, wherein the composition has an
in vitro drying time of less than three minutes.
30. A method of treatment of androgen deficiency in an adult male
subject comprising topically administering to at least one axilla
of the subject a composition comprising: (a) testosterone; (b) from
40 to 99% v/v of a volatile solvent carrier selected from ethanol,
ethyl acetate, isopropanol and mixtures thereof; (c) from 0.1% to
15% w/v of at least one sunscreen ester penetration enhancer; and
(d) from 1-5% w/v polyvinylpyrrolidone.
31. A method according to claim 30, wherein the sunscreen ester
penetration enhancer is selected from the group consisting of octyl
dimethyl-para-aminobenzoate, octyl paramethoxycinnamate, octyl
salicylate and mixtures thereof.
32. A method according to claim 31, the wherein the sunscreen ester
penetration enhancer is octylsalicylate.
33. A composition for transdermal delivery of testosterone to at
least one axilla of a subject comprising: (a) testosterone; (b)
from 40% to 99% v/v of a volatile solvent carrier selected from
ethanol, ethyl acetate, isoproponol and mixtures thereof; and (c)
from 0.1% to 15% w/v of at least one sunscreen ester penetration
enhancer; and (d) from 1-5% w/v polyvinylpyrrolidone.
34. A composition according to claim 33, wherein the sunscreen
ester penetration enhancer is selected from the group consisting of
octyl dimethyl-para-aminobenzoate, octyl paramethoxycinnamate,
octyl salicylate and mixtures thereof.
35. A composition according to claim 33, wherein the sunscreen
ester penetration enhancer is octyl salicylate
36. A composition according to claim 34, wherein the volatile
solvent carrier is ethanol, isopropanol or a mixture thereof.
37. A composition according to claim 33, wherein the composition
has an in vitro drying time of less than three minutes.
38. A composition according to claim 33, wherein the volatile
solvent carrier is selected from ethanol, isoproponol and a mixture
thereof, and the sunscreen ester penetration enhancer is octyl
salicylate.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a method and composition
for transdermal delivery of a physiologically active agent. It has
particular but not exclusive application to the delivery of an
agent in areas prone to perspiration.
BACKGROUND OF THE INVENTION
[0002] Efficient transdermal delivery of a physiologically active
agent offers several clinical and patient advantages in treatment
of disease.
[0003] Drug delivery by injection is traditionally the quickest
route of administration to the systemic circulation, however the
duration of action of is often short lived and the mode of delivery
is invasive and painful. Transdermal drug delivery is receiving
increased attention due to the ability of the administration regime
to provide a controlled route for the release of an active agent to
the systemic circulation.
[0004] However, transdermal drug delivery is complicated by the
fact that the skin behaves as a natural barrier. As a result, the
success of transdermal delivery system often relies on the ability
of a composition to be able to penetrate the stratum corneum of the
skin and thereby transport an active agent across the skin.
[0005] Problems with transdermal delivery arise particularly in
cases where a drug is slow to be absorbed through the skin or where
a relative high dose of drug needs to be absorbed. In these
circumstances it is often necessary to apply a transdermal
composition to a large area of skin in order to achieve the
required dose.
[0006] One example of this problem is encountered in the
administration of androgens such as testosterone. Recent estimates
show that approximately 13 million men in the United States
experience testosterone deficiency and less than 10% receive
treatment for the condition. The daily dose required to maintain
testosterone levels within the normal range is relatively high
(typically 5-10 mg/day), thus it provides a challenge for
transdermal delivery. Similar problems occur with progesterone. The
previously used topical administration of testosterone, for example
in treatment of hypogonadism, requires application of gel or cream
to a wide area of the body and that the area of application remains
covered. Application of composition over a wide area severely
increases the risk of transfer from patient to partner or child,
thus persons such as family members may be subjected to accidental
dosing of the drug. This can have serious consequences.
[0007] Transdermal administration of some drugs may also be
accompanied by undesirable side effects. For example, testosterone
is responsible for increasing perspiration and producing
perspiration related odour in the presence of the enzyme
5-alpha-reductase which converts testosterone to
dihydrotestosterone (DHT). Scrotal skin has a relatively high level
of 5-alpha-reductase and continuous trans-scrotal delivery of
testosterone produces levels of DHT and DHT/testosterone ratios 4
to 5 fold greater than normal. Such abnormal levels and ratios may
give rise to undesirable side effects.
[0008] Problems also arise with the location of application, and
side effects associated with the location. Ahmed, S. R., et al. (J
Clin Endocrinol Metab (1988) 66:546-557) and Findlay, J. C. (J Clin
Endocrinol Metab (1989) 68:369-373) report that the 60 cm.sup.2
ALZA trans-scrotal system delivers about 3.7 mg/day and produces
low-normal testosterone levels in hypogonadal men. Such dosages are
believed to be somewhat less than the amount needed to mimic
endogenous production (5-10 mg/day).
[0009] Trans-scrotal delivery of testosterone is also associated
with high dihydrotestosterone (DHT) and DHT/testasterone ratio
levels and does not provide a level of testosterone delivery that
mimics endogenous production. Further, scrotal skin is sensitive
and as noted above, limited in area, which may result in discomfort
and poor patient acceptance of this modality of delivery.
[0010] Many transdermal compositions utilise penetration enhancers
to assist delivery of the pharmaceutical active across the skin.
Increased cutaneous blood flow and subsequent heat production is
also reported to assist. U.S. Pat. No. 6,743,448 describes a
topical testosterone formulation comprising arginine which is said
to facilitate the production of nitrous oxide and enhance
vasodilation.
[0011] However locally induced vasodilation and subsequent heating,
particularly in areas having increased cutaneous blood flow such as
the axilla is likely to cause excess perspiration and discomfort,
due to the increased number of sweat glands present in such areas.
This can be problematic for the subject on the basis that
transdermal delivery of some pharmaceutical actives may be hindered
by the use of antiperspirants and/or deodorants. This is
undesirable because delivery may be compromised because of
perspiration, resulting in inconsistent delivery and/or patient
acceptability and compliance is hindered by instructions not to use
antiperspirant or deodorant with drug delivery that promotes
perspiration.
[0012] There is therefore a need for a method and composition for
transdermal administration which provides rapid, consistent
delivery and allows the area of application to be minimised, as
well as being convenient for subjects to use desirably with reduced
side effects to subjects and others with whom they come in
contact.
SUMMARY OF THE INVENTION
[0013] In accordance with one aspect, the invention provides a
transdermal drug delivery composition which includes (i) at least
one physiologically active agent; and (ii) at least one volatile
solvent; and (iii) at least one viscosity modulating agent. In some
embodiments, the composition further comprises a penetration
enhancer. In some embodiments, the viscosity modulating agent is a
gelling or thickening agent. In some embodiments, the solvent is a
lower alkyl alcohol or a mixture of such alcohols. In some
embodiments, the penetration enhancer is one or a mixture of octyl
dimethyl-para-aminobenzoate, octyl para-methoxycinnamate and
octisalate. In some embodiments, the composition further comprises
an antiperspirant and/or a deodorant.
[0014] In accordance with another aspect, the invention provides a
method of delivering an active agent systemically to a patient by
application of the active agent to one or more axilla. In some
embodiments, administration is essentially only to the axilla. In
some embodiments, an antiperspirant and/or a deodorant is applied
at about the same time as a composition comprising the active
agent.
[0015] In accordance with another aspect, the invention provides a
method of treatment of testosterone deficiency of a subject
comprising delivery of an androgenic compound according to the
method describe above, in which the active agent is the androgenic
compound.
[0016] In accordance with another aspect, the invention provides a
method of delivering an agent systemically to a patient by
application of the active agent with a volatile solvent to one or
more axilla. In some embodiments, the active agent is in a
transdermal drug delivery composition as described above.
[0017] In accordance with another aspect, the invention provides a
method of transdermal testosterone delivery to a subject comprising
topically applying to an area of skin of a subject a transdermal
composition comprising (i) an androgenic compound; and (ii) a
volatile carrier; and (iii) at least one dermal penetration
enhancer; and (iv) at least one viscosity modulating agent. In some
embodiments, the androgenic compound is testosterone or a
derivative thereof. In some embodiments, the area of skin is the
axilla and testosterone is delivered resulting in a blood level of
at least a predetermined amount.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] In the drawings:
[0019] FIG. 1 is a graph showing the variation in blood level of
testosterone with time after transdermal application;
[0020] FIG. 2 is a graph of testosterone permeation profiles
obtained after application of a deodorant spray to a composition
according to one embodiment of the invention;
[0021] FIG. 3 is a graph of testosterone permeation profiles
obtained after application of ethanol (3 .mu.L) to the same
embodiment of the invention as in FIG. 2;
[0022] FIG. 4 is a graph of the testosterone permeation profiles
obtained from the application of a different embodiment of the
invention compared with application of a control.
[0023] FIG. 5 is a graph of the estradiol permeation profile
obtained from the application of another embodiment of the
invention compared with application of a control.
DETAILED DESCRIPTION
[0024] The applicant has developed a method and a composition for
transdermal administration which allows rapid delivery of active
agents and reduces the risk of undesirable side effects in a
patient. The delivery is "rapid" in the sense that little time of
the patient is required. For example, in one embodiment, the
transdermal composition is dry within 3 minutes.
Pharmacodynamically, delivery of the active is substantially
"steady-state", once a reservoir of the active is established in
the skin. The reservoir is maintained (ie, "topped-up") by daily
doses of the composition. Steady-state is the practical description
of the delivery profile--there is some, but surprisingly minor,
variation in delivery rates between doses. The invention therefore
provides a method of administration which allows rapid delivery of
active agents and minimises the risk of side effects in a
patient.
[0025] The applicant has surprisingly observed that the transdermal
composition of the current invention has antiperspirant and/or
deodorant properties. The composition therefore allows the active
agent to be rapidly delivered whilst also enabling perspiration
and/or odour to be reduced. The use of the invention thus permits
use of areas such as the axilla for transdermal drug delivery
without patient inconvenience of not using normal
antiperspirant/deodorant products (important for patient
compliance) which may otherwise interfere with delivery of the
active.
[0026] As such, there is provided a transdermal drug delivery
composition which includes at least one physiologically active
agent; and at least one volatile solvent; and at least one
viscosity modulating agent. Preferably the viscosity modulating
agent is a gelling or thickening agent. The viscosity modulating
agent may be a thickening agent and suitable thickening agents
include polyvinyl pyrrolidone. In some embodiments, the thickening
agent is an antiperspirant or the composition further includes an
antiperspirant and/or a deodorant.
[0027] In this specification and the claims, the term "viscosity
modulating agent" is used to refer to a component of the
composition which alters the viscosity of the overall resulting
composition. The nature of the viscosity modulating agent depends
not only on the agent itself, but also the proportion in which it
is present and the presence or absence of other components. For
example, a gelling agent may act as a viscosity modulating agent
providing that an activator for that gelling agent is present. For
example, hydroxypropylmethylcellulose (HPMC) may be used in a
composition with an activator, in which the volatile solvent is a
lower alkyl alcohol at a concentration of around 2% w/w. A suitable
activator would be sodium chloride. Concentration may be important
as, in this example, at 0.1% w/w HPMC has different effects. A
thickening agent is one which increases viscosity, and is often
anhydrous. Viscosity modulating agents are further described
below.
[0028] Further, the term "transdermal" is used co-terminously with
"topical" in describing the application of agents to the skin. Both
terms "topical" and "transdermal" are used herein in the broadest
sense to refer to administration of a drug to the skin surface of
an animal, including humans, so that the drug passes through the
skin tissue. Unless otherwise stated or implied, the terms topical
drug delivery and transdermal drug delivery are used
interchangeably. From a strict drug-delivery perspective,
"transdermal" is sometimes used to refer only to systemic delivery
through the skin whereas "topical" requires only delivery into or
on the skin for local effect. The invention described in this
specification is equally applicable to both transdermal and topical
modes of delivery, and is described here as "transdermal" only for
convenience. For avoidance of doubt, the invention provides in
various embodiments compositions and methods suitable for topical
application corresponding to those described in the specification
as transdermal applications.
[0029] Typically, the composition appears like a lotion. In this
context, "lotion" is used in its broad descriptive sense, rather
than the more specific formulatory sense which refers to a mixed
phase or suspension of active. The composition of the invention is
often a true solution, but with increased viscosity so that its
viscosity is more similar to that usually associated with a lotion.
The viscosity of the composition is preferably greater than that of
water but less than about 300 centipoise. The viscosity in
different embodiments is in the range of 10 to 200, 20 to 100 or 30
to 50 centipoise.
[0030] In another embodiment, there is provided a transdermal drug
delivery composition which includes at least one physiologically
active, at least one volatile solvent, and at least one viscosity
modulating agent and without a penetration enhancer.
[0031] In a different embodiment, there is provided a transdermal
drug delivery composition which includes at least one
physiologically active agent, at least one volatile solvent, at
least one viscosity modulating agent, and at least one penetration
enhancer. The penetration enhancer assists in the uptake of the
physiologically active agent at least through the outer layers of
the skin, typically to form a reservoir of active within the skin.
Typical penetration enhancers suitable for use in the invention are
further described below.
[0032] The volatile solvent (also sometimes called a "volatile
carrier" or "vehicle") will typically be present in a higher
concentration, such as 80% or more w/w. The volatile solvent may be
any such solvent that is pharmacologically suitable and many such
solvents are known in the art. One of the advantages of the
inclusion of a volatile solvent or volatile carrier is that it
facilitates the composition to dry rapidly, allow the absorption of
the active agent, and avoid the problems of accidentally dosing
others by confining administration to a small area of skin,
preferably the axilla. Preferably the volatile solvent has a vapour
pressure above 35 mm Hg at atmospheric pressure and normal skin
temperature of 32 degrees Celsius.
[0033] Preferably, the solvent is a lower alkyl alcohol or a
mixture of such alcohols. Suitable solvents include ethanol, ethyl
acetate, isopropanol, acetone, ethyl formate, methyl acetate,
methyl ethyl ketone, pentane and chloroform or mixture thereof in
the range of about 40 to 99% v/v of the composition, preferably
more than 50%, 60%, 70% or 80%. An aerosol propellant, such as
dimethyl ether or R134a, may also constitute a volatile solvent for
the purpose of the present invention.
[0034] Preferably the compositions of the invention are
non-occlusive, in that in the broadest sense, the composition is
not trapped to the skin, or the skin is not closed to the
atmosphere, by means of a patch device, fixed reservoir,
application chamber, tape, bandage, sticking plaster, or the like,
which remains on the skin a the site of application for a prolonged
length of term. Such devices tend to be uncomfortable for the
wearer or can be embarrassing or unsightly.
[0035] The viscosity modulating agent will commonly be a thickening
agent or a gelling agent. It will often be used to increase the
viscosity of the composition containing a solution of the
physiologically active agent in the volatile solvent. Given the
nature of the volatile solvents, the solution will typically have
very low viscosity. The purpose of the viscosity modulating agent
is to increase the viscosity of the solution such that the
composition is retained in the vicinity of the area of application
for a brief period of time so as to permit increased uptake of the
physiologically active agent at that site. The viscosity modulating
agent will typically increase the viscosity to about that of a
typical lotion (eg, sunscreen), but not to the point where the
composition becomes a gel. Typically, the viscosity of a
transdermal drug delivery composition according to the invention
will be less than 300 centipoise and often about 150
centipoise.
[0036] The viscosity modulating agent must retain its activity in
the context of the other components of the composition of the
invention. In particular, the thickening agent must remain active
and stable in this environment. For example, where the composition
has a high alcohol content (for example, where the volatile solvent
comprises primarily alcohol at greater than 80% v/v), the
thickening agent must be effective in a high alcoholic environment.
Having these requirements in mind, a skilled person can select
several thickening agents from those known in the art. Desirably, a
thickening agent also inhibits the solvent evaporation rate so as
to enhance the so-called "solvent burst" of active agent into the
skin at the site of application.
[0037] It will be appreciated by one skilled in the art that the
amount of thickening agent required is a question of degree and
compromise with other parameters. It is also known that many
thickening agents have peak activity at a particular concentration,
and that activity may drop off substantially with slightly higher
and slightly lower percentage concentrations. For example, in one
preferred embodiment where the composition comprises over 80%
alcohol and the thickening agent used is PVP, the desirable
concentration of PVP is between 1 and 3%, and its activity is
substantially reduced outside that range.
[0038] Gelling agents are matrix-forming agents which, once
activated, act by forming a matrix within and around the
composition they are in. Thickening agents are usually anhydrous
agents which increase the viscosity of the composition. In one
embodiment, a thickening agent is used. The thickening agent may be
an antiperspirant and/or an occlusive agent for the drug delivery
composition. In another embodiment, both a deodorant and an
antiperspirant are in a composition with the at least one active
agent and dermal penetration enhancer. Suitable thickening agents
include polyvinyl pyrrolidone or PVP (Povidone.TM.). The
antiperspirant may be an occlusive agent also, and a thickening,
occlusive agent may have antiperspirant effects.
[0039] Despite the inherent antiperspirant and/or deodorant
properties of the compositions of the invention, the composition
may be optionally administered with deodorant and antiperspirant
additives that do not interfere with the active. In another form,
there is provided a transdermal drug delivery composition which
includes at least one physiologically active agent; and at least
one volatile solvent; and at least one antiperspirant or
deodorant.
[0040] The antiperspirant agent may be any suitable substance that
reduces or inhibits the production of perspiration. In some
instances, an antiperspirant agent can also provide deodorant
benefits. Preferably, the antiperspirant agent is selected from the
group consisting of inorganic or organic salts of aluminium,
zirconium, zinc or mixtures thereof.
[0041] In one embodiment, the antiperspirant agent is an aluminium
salt having the general formula:
Al.sub.2(OH).sub.xQ.sub.y.wH.sub.2O [0042] where Q is chlorine,
bromine or iodine; [0043] x is 2 to 5; [0044] x+y=6, where x and y
do not need to be integers; and [0045] wH.sub.2O represents a
variable amount of hydration.
[0046] In another embodiment, the antiperspirant agent is a
zirconium salt of the following general formula:
ZrO(OH).sub.2n-nzB.sub.z.wH.sub.2O
where [0047] z is a variable in the range of from 0.9 to 2.0 so
that the value of 2n-nz is zero or a positive; [0048] n is the
valency of B; [0049] B is selected from the group consisting of
chloride, other halide, sulphamate, sulphate and mixtures thereof;
and [0050] wH.sub.2O represents a variable amount of hydration.
[0051] In a preferred embodiment, the antiperspirant agent is
selected from the group consisting of aluminium chloride, aluminium
chlorohydrate, aluminium chlorohydrex polyethylene glycol,
aluminium chlorohydrex propylene glycol, aluminium dichlorohydrate,
aluminium dichlorohydrex polyethylene glycol, aluminium
dichlorohydrex propylene glycol, aluminium sesquichlorohydrate,
aluminium sesquichlorohydrex polyethylene glycol, aluminium
sesquichlorohydrex propylene glycol, aluminium zirconium
octachlorohydrate, aluminium zirconium octachlorohydrex gly,
aluminium zirconium pentachlorohydrate, aluminium zirconium
pentachlorohydrex gly, aluminium zirconium tetrachlorohydrate,
aluminium zirconium tetrachlorohydrex gly, aluminium zirconium
trichlorohydrate and aluminium zirconium trichlorohydrex gly. These
antiperspirant agents have approved listings under the United
States Food & Drug Administration Federal Register.
[0052] The present invention also contemplates that other
antiperspirant agents may also be used. Examples of these
antiperspirant agents include aluminium bromohydrate, aluminium
chloride, aluminium citrate, aluminium sulfate, ammonium alum,
cobalt acetylmethionate, potassium alum, sodium alum and sodium
aluminium chlorohydroxy lactate.
[0053] In another embodiment, the composition of the invention
comprises a deodorant agent. The deodorant agent may be any
suitable substance that provides deodorancy benefits in masking or
neutralising odours that are produced by the action of bacteria.
Generally, deodorant agents do not interfere with the production of
perspiration. Representative examples of deodorant agents include,
but are not limited to, one or more of cetyl-trimethylammonium
bromide, cetyl pyridinium chloride, benzethonium chloride,
diisobutyl phenoxy ethoxy ethyl dimethyl benzyl ammonium chloride,
sodium N-lauryl sarcosine, sodium N-palmithyl sarcosine, lauroyl
satcosine, N-myristoyl glycine, potassium N-lauryl sarcosine,
stearyl, trimethyl ammonium chloride, sodium aluminium
chlorohydroxy lactate, tricetylmethyl ammonium chloride,
2,4,4'-trichloro-2'-hydroxy diphenyl ether, diaminoalkyl amides
such as L-lysine hexadecyl amide, heavy metal salts of citrate,
salicylate, and piroctose, especially zinc salts, and acids
thereof, heavy metal salts of pyrithione, especially zinc
pyrithione and zinc phenolsulfate. Other deodorant agents include,
without limitation, odour absorbing materials such as carbonate and
bicarbonate salts, e.g. as the alkali metal carbonates and
bicarbonates, ammonium and tetraalkylammonium carbonates and
bicarbonates, especially the sodium and potassium salts, or any
combination of the above.
[0054] In a preferred embodiment, the composition comprises a
combination of antiperspirant and deodorant agents.
[0055] The antiperspirant and deodorant agents may be present in
the composition in any amount that provides beneficial
antiperspirant and/or deodorancy effects. The antiperspirant agent
or deodorant agent may be present in an amount of from about 0.05
to 60%, and is preferably from about 1 to 40%, more preferably from
about 5 to 30% and even more preferably from about 8 to 15% by
weight of the composition. Where the composition of the invention
comprises a combination of antiperspirant and deodorant agents, the
combined amounts of these agents is preferably within the preferred
range stated above.
[0056] The composition may be applied to any area of skin.
Preferably it is applied to areas of skin having increased
cutaneous blood flow, such as the axilla, scrotum, between toes,
groin, plantar arch of the foot or palm of the hand. Other suitable
areas include where there is suitably permeable skin. In
particularly, it is desirable to apply it to only one or more of
these areas while still effectively delivering the required dose of
active agent. It is also known that some areas of the skin are
relatively more permeable to active agents than others. The
invention is usefully employed to deliver active agent through
these areas only, thus limiting the total area of skin to which the
composition must be applied in order to deliver an effective dose
of the active agent.
[0057] Moreover, the invention provides a method for transdermal
delivery of an active agent to areas of the skin prone to
perspiration, particularly higher rates of perspiration relative to
other areas. Such areas of skin have typically not been preferred
for transdermal delivery because of the desirability for patients
to be able to maintain use of antiperspirants and deodorants. In a
preferred form, the method provides for administration of a
composition including the active agent to those areas of skin which
provide maximal systemic absorption. It is believed that this is
due, at least in part, to increased cutaneous blood flow and heat.
These areas may be one of more of the axilla, scrotum, groin,
planter arch of foot, palm of hand or forehead. Preferably the area
is at least one axilla. These areas in particular may benefit
greatly from the antiperspirant and/or deodorant effects of the
composition when it is applied.
[0058] In another form, the invention comprises a method of
delivering an active agent systemically to a patient by application
of the active agent to one or more axilla. The active agent is
preferably in a transdermal drug delivery composition as described
in this specification. Preferably, administration is essentially
only to the axilla. In another form, administration is to areas
selected from the group consisting of the axilla, scrotum, groin,
planter arch of foot, palm of hand and forehead. In one form, the
method avoids application or administration of the composition to
the upper arms, shoulders or abdomen of a subject. The transdermal
drug delivery composition of the present invention is capable, upon
application to an area of skin, of delivering a therapeutically
effective amount of active agent to the systemic circulation.
[0059] The composition may be applied to any area of skin on a
subject, selected from one or more of planter foot arch, lateral
ankle, palm, upper arm, ventral forearm, dorsal forearm, back,
chest, thigh, abdomen, groin, scalp, axilla, forehead, lower back,
buttocks or scrotum. The composition is preferably applied to those
areas of skin which provide maximal systemic absorption due to
increased cutaneous blood flow and heat. These areas may be one of
more of the axilla, scrotum, planter arch of foot, palm of hand or
forehead. Preferably the area is at least one axilla. These areas
in particular may benefit greatly from the antiperspirant and/or
deodorant effects of the composition when it is applied.
[0060] A further advantage of the compositions according to the
invention is that a therapeutically effective amount may be applied
to a minimal surface area, therefore minimising the unpleasant side
effects and patient inconvenience associated with applying large
amounts of a composition to a large surface area. Preferably the
area of skin to which the composition is applied is less than 500
cm.sup.2. Desirably, the area is less than 300 cm.sup.2, 100
cm.sup.2, 50 cm.sup.2, 20 cm.sup.2 10 cm.sup.2, and 5 cm.sup.2.
[0061] A key advantage achievable with some embodiments of the
invention is increased flux of the active, thereby enabling a
greater proportion of active in a dose to be delivered to the
patient and utilising a smaller area of skin. In some cases, a much
smaller area than used to date is required, consequently improving
patient acceptability and compliance. This is particularly
applicable where the active otherwise has poor or low flux, a large
systemic dose is desired and/or a faster onset of action is
desired.
[0062] The penetration enhancer is also sometimes called an
"absorption" enhancer. A number of penetration enhancers may be
utilised including fatty acids, fatty acid esters, fatty alcohols,
glycols and glycol esters, 1,3-dioxolanes and 1,3-dioxanes,
macrocyclic ketones containing at least 12 carbon atoms,
oxazolidinones and oxazolidinone derivatives,
alkyl-2-(N,N-disubstituted amino)-alkanoate esters,
(N,N-disubstituted amino)-alkanol alkanoates, sunscreen esters and
mixtures thereof. Most preferably the dermal penetration enhancer
is selected from the list including oleic acid, oleyl alcohol,
cyclopentadecanone (CPE-218.TM.), sorbitan monooleate, glycerol
monooleate, propylene glycol monolaurate, polyethylene glycol
monolaurate, 2-n-nonyl 1,3-dioxolane (SEPA.TM.), dodecyl
2-(N,N-dimethylamino)-propionate (DDAIP) or its salt derivatives,
2-ethylhexyl 2-ethylhexanoate, isopropyl myristate, dimethyl
isosorbide, 4-decyloxazolidinon-2-one (SR-38.TM., TCPI, Inc.),
3-methyl-4-decyloxazolidinon-2-one, octyl
dimethyl-para-aminobenzoate, octyl para-methoxycinnamate,
octisalate and mixtures thereof.
[0063] Preferred penetration enhancers are sunscreen esters such as
the compounds disclosed in our U.S. Pat. No. 6,299,900 the contents
of which are herein incorporated by reference. These include the
compounds being safe skin-tolerant ester sunscreens of formula:
##STR00001## [0064] wherein R.sup.1 is hydrogen, lower alkyl, lower
alkoxy, halide, hydroxy or NR.sup.3R.sup.4; [0065] R.sup.2 is long
chain alkyl; [0066] R.sup.3 and R.sup.4 are each independently
hydrogen, lower alkyl or R.sup.3 and R.sup.4 together with the
nitrogen atom to which they are attached form a 5- or 6-membered
heterocyclic ring; [0067] n is 0 or 1; and [0068] q is 1 or 2.
[0069] Preferred penetration enhancers are esters having a long
chain alkyl para-aminobenzoate, long chain alkyl
dimethyl-para-aminobenzoate, long chain alkyl cinnamate, long chain
alkyl methoxycinnamate or long chain alkyl salicylate; most
preferably the penetration enhancer is one or a mixture of octyl
dimethyl-para-aminobenzoate ("Padimate O"), octyl
para-methoxycinnamate and octyl salicylate ("octisalate" per
USP).
[0070] The concentration of absorption/penetration enhancer may be
in the range from 10-10,000 weight percent of
absorption/penetration enhancer based upon the weight of active
ingredient. The ratio of penetration enhancer to active ingredient
may vary considerably and will be governed as much as anything, by
the pharmacological results that are required to be achieved. In
principle, it is desirable that as little absorption enhancer as
possible is used. However, usually the penetration enhancer is in
the range from 0.01-15% of the total composition.
[0071] Heat can also act to enhance penetration of an active agent,
together with or independently of such a penetration enhancer. Heat
is not itself regarded as a "penetration enhancer". Without being
bound by the theory or mode of action, it is believed that heat can
disrupt and/or fluidise the lipid structures in the skin to enhance
penetration. Accordingly, in one embodiment, the invention provides
at least one physiologically active agent and at least one
viscosity modulating agent which is applied in the presence of
heat. Preferably, the composition also includes a dermal
penetration enhancer.
[0072] Heat may result from utilising the patient's own body heat
to warm the skin to the core body temperature (the outer layers of
skin often being below that temperature) and/or the heat may be
from an external source. Such external sources include conventional
heat packs (eg, for therapeutic or physiotherapeutic uses),
radiation heat (eg, heat lamps), exothermic chemical reactions or
in situ generation of heat.
[0073] Heat is suggested to enhance the transdermal delivery of
various drugs by increasing skin permeability, body fluid
circulation, blood vessel wall permeability, rate-limiting membrane
permeability, and drug solubility. Accordingly, whether or not heat
is applied around the time of application of the composition,
application of a transdermal composition is preferably to areas of
skin having increased cutaneous blood flow, and therefore warmer.
Such areas include but are not limited to, the planter arch of the
foot, palm of the hand, axilla and scrotum. However associated with
areas of increased heat is increased perspiration and perspiration
related body odour. Therefore, it is desirable if the transdermal
composition is also an antiperspirant and/or a deodorant. An
antiperspirant reduces the amount of perspiration produced by
blocking the sweat glands. A deodorant masks or covers the odour
associated with perspiration, using either fragrance or an
anti-bacterial ingredient to reduce odour-causing bacteria on the
skin. Antiperspirants can have an indirect deodorant effect in the
underarm area, but a deodorant cannot act as an antiperspirant. It
is further desirable if known antiperspirants and/or deodorants can
be added to the composition without inhibiting drug delivery.
[0074] Without being bound by any theory, the applicant believes
that the viscosity modulating agent and/or penetration enhancer in
the composition function to minimise perspiration, and that the
volatile carrier functions to inhibit bacteria and therefore odour
by a bactericidal activity of the carrier.
[0075] In one embodiment, the composition consists essentially of
one physiologically active agent; one volatile solvent; and one
viscosity modulating agent, each as described above. Preferably, it
further includes a penetration enhancer as described above. In one
embodiment, the viscosity modulating agent is an antiperspirant,
and the composition optionally also includes a deodorant. Each of
these embodiments may or may not also include water.
[0076] The invention also provides a use of at least one
physiologically active agent; and at least one volatile solvent;
and at least one viscosity modulating agent in the manufacture of a
medicament for transdermal delivery of the active agent to a
subject. The medicament is preferably for treatment or prevention
of a condition treatable or preventable by the active.
[0077] In another embodiment of the invention, the composition may
include at least one additional active agent and/or at least one
additional inactive agent. In a different embodiment, the
composition does not include a herbal extract (or like component),
whether as a physiologically active agent or otherwise.
[0078] The transdermal drug delivery composition of the present
invention is capable, upon application to an area of skin, of
delivering a therapeutically effective amount of active agent to
the systemic circulation. Accordingly, in one aspect, there is
provided a method of transdermal delivery of an active agent
comprising applying to an area of skin of a subject the transdermal
composition described above. In particular, the method can be used
to deliver a predetermined amount of active and/or sufficient
active to achieve a predetermined bloodstream level or
concentration of the active. For some actives (eg, those with a
short half-life) other measures of the amount of active delivered
will be appropriate.
[0079] The composition may also be administered by other known
topical techniques including a lotion, gel, spray etc. These can be
formulated by adding suitable carriers, excipients and thixotropic
agents which are inert to the active to facilitate retaining the
composition on the skin sufficiently for delivery of the active
agent as contemplated by the invention.
[0080] The transdermal composition of the invention and the
composition used in the method of the invention may be applied,
including but not limited to axilla, of a subject in any of a range
of forms. Suitable forms include for example lotions, gels, foams,
pastes, soft solids, firm sticks, solutions, sprays, aerosols,
roll-ons and the like, each of which represent different forms of
the invention. The composition may be applied in an occlusive or
non-occlusive manner. It is preferred that the composition is
applied in a non-occlusive manner and in the most preferred
embodiment the composition is applied as a lotion, aerosol or
spray.
[0081] The transdermal composition of the invention and the
composition used in the method of the invention may further
comprise additional components that will facilitate its preparation
into forms suitable for application to the axilla of a subject.
Examples of additional components include but are not limited to
surfactants, buffers, solvents and propellants.
[0082] It is particularly preferred that the composition of the
invention and the composition used in the method of the invention
is applied without being covered by adhesives, adhered patches,
adhered bandages or films. Such devices tend to be uncomfortable
for the wearer or can be embarrassing or unsightly. The invention
allows non-occlusive administration of physiologically active
agents by the transdermal compositions in the axilla under the
subjects clothing.
[0083] In applying the composition of the invention, an
antiperspirant and/or a deodorant may be applied at about the same
time as the composition. Preferably, the antiperspirant and/or
deodorant is applied after application of the composition of the
invention. As noted above, in some embodiments of the invention, an
antiperspirant and/or a deodorant may be incorporated within the
composition, thus requiring only one substance to be applied by a
patient. The antiperspirant and/or deodorant will be selected from
those which do not interfere with the drug delivery mechanism.
Preferably, the antiperspirant and deodorant added complement the
natural antiperspirant and deodorising properties of the
transdermal drug delivery composition itself as described
above.
[0084] The invention also provides a method of transdermal drug
delivery comprising applying a predetermined dose of a transdermal
drug delivery composition as described above to a patient. As
described below, a preferred form of the invention involves
applying the composition to at least one axilla. In the composition
of the invention, the invention extends to a method in which an
antiperspirant and/or a deodorant is applied to the axilla region
at about the same time as the transdermal drug delivery composition
is applied. Preferably, the antiperspirant and/or deodorant is
applied after the transdermal drug delivery composition is applied
to at least one axilla region.
[0085] In the methods of the invention the compositions are
preferably administered without being covered by an adhesive
bandage, patch or other physical barrier bonded to the
administration area. Preferably the transdermal composition becomes
touch dry within three minutes of application to the area of skin,
more preferably within about one minute.
[0086] The antiperspirant and/or deodorant properties of the
composition are particularly advantageous when the physiologically
active agent is testosterone or derivatives thereof for treating
testosterone deficiency in a subject. Testosterone is responsible
for increasing perspiration and producing perspiration and
perspiration related odour in the presence of 5-alpha-reductase,
due to the conversion of testosterone to dihydrotestosterone (DHT).
Accordingly there is provided a composition as described above in
which the physiologically active agent is selected from at least
one or more of androgenic compound, such as testosterone or
derivatives thereof. The physiologically active agent may therefore
be selected from androgenic compounds which are synthetically
derivatized from testosterone and are known to provide the same or
a similar physiological activity. Such compounds include without
limitation, testosterone salts, such as acetate, enanthate,
cypionate, isobutyrate, dehydro-epiandrosterone, propionate,
undecanoate esters and cyproterone acetate. In other embodiments,
one or more of the following are included: 5-alpha-reductase
inhibitors (such as finasteride, turosteride, LY-191704 and
MK-386). Other suitable compounds include methyltestosterone,
clostebol acetate, drostanolone, furazabol, nandrolone oxandrolone,
stanozolol, trenbolone acetate, dihydro-testosterone,
17-.alpha.-methyl-19-nortestosterone and fluoxymesterone.
[0087] Contrary to what might be expected from the activity of
testosterone, the applicant has found that testosterone may be
administered in accordance with the invention to provide rapid
delivery without inducing sweating and odour that distress a
subject. The unacceptable levels of these side effects identified
in the art have been attributed to the presence of elevated
testosterone.
[0088] In a preferred embodiment of this aspect of the invention,
the invention provides a method of treatment of testosterone
deficiency in a subject comprising topically applying to an area of
skin of a subject a transdermal composition comprising: [0089] a
physiologically active agent selected from at least one of
testosterone or derivatives thereof; [0090] a volatile carrier;
[0091] at least one dermal penetration enhancer; and [0092] at
least one viscosity modulating agent.
[0093] In one embodiment, the carrier is isopropyl alcohol, the
penetration enhancer is octisalate, the active agent is
testosterone and the thickening agent is polyvinylpyrrolidone.
These may be in the following percentages: [0094] 30% v/v carrier;
[0095] 8% w/v enhancer; [0096] 1% w/v active; [0097] 2% w/v
thickener; [0098] 10% v/v sterile water; and [0099] the balance
ethanol.
[0100] In another embodiment, there is provided a transdermal drug
delivery composition consisting essentially of the above 6
components in those proportions. In another form of the invention,
these 6 components in these proportions are used in the manufacture
of a medicament for the treatment of a subject, particular a
subject in need of treatment with the active. For example, a
subject suffering from decreased testosterone blood levels is
treated with a composition where the active is testosterone or a
related androgenic agent or testosterone derivative as set out
above.
[0101] In further embodiments, the invention provides a method of
treatment of oestrogen and/or progestin deficiency, a method of
treatment of chronic pain, and a method of treatment of anxiety
related disorders. Other actives as set-out below are also
contemplated for use with the invention.
[0102] In one embodiment, a composition containing testosterone as
the active agent is applied to the axilla of a patient to deliver
testosterone resulting in a blood level of at least a predetermined
amount. In one embodiment, the predetermined amount is the normal
range. In the case of testosterone, the blood level achieved is at
least 200 ng/dL, preferably 300-1000 ng/dL. Preferably, the
composition is only applied to the axilla.
[0103] Physiologically active agents that may be used in the
transdermal drug delivery compositions of the present invention
include any locally or systemically active agents which are
compatible with the penetration enhancers of the present invention
and which can be delivered through the skin, particularly with the
assistance of the dermal penetration enhancer to achieve a desired
effect. These active agents are preferably therapeutics, and
include (grouped by therapeutic class): [0104] (a) Alimentary
System agents including antidiarrhoeals such as diphenoxylate,
loperamide and hyoscyamine. [0105] (b) Cardiovascular System agents
including: [0106] (i) antihypertensives such as hydralazine,
minoxidil, captopril, enalapril, clonidine, prazosin, debrisoquine,
diazoxide, guanethidine, methyldopa, reserpine, trimetaphan; [0107]
(ii) Calcium channel blockers such as diltiazem, felodopine,
amlodipine, nitrendipine, nifedipine and verapamil; [0108] (iii)
antiarrhythmics such as amiodarone, flecainide, disopyramide,
procainamide, mexiletene and quinidine; [0109] (iv) antiangina
agents such as glyceryl trinitrate, erythritol tetranitrate,
pentaerythritol tetranitrate, mannitol hexanitrate, perhexilene,
isosorbide dinitrate and nicorandil; [0110] (v) beta-adrenergic
blocking agents such as alprenolol, atenolol, bupranolol,
carteolol, labetalol, metoprolol, nadolol, nadoxolol, oxprenolol,
pindolol, propranolol, sotalol, timolol and timolol maleate; [0111]
(vi) cardiotonic glycosides such as digoxin and other cardiac
glycosides and theophylline derivatives; [0112] (vii) adrenergic
stimulants such as adrenaline, ephedrine, fenoterol, isoprenaline,
orciprenaline, rimeterol, salbutamol, salmeterol, terbutaline,
dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and
dopamine; [0113] (viii) vasodilators such as cyclandelate,
isoxsuprine, papaverine, dipyrimadole, isosorbide dinitrate,
phentolamine, nicotinyl alcohol, co-dergocrine, nicotinic acid,
glyceryl trinitrate, pentaerythritol tetranitrate and xanthinol;
and [0114] (ix) antimigraine preparations such as ergotamine,
dihydroergotamine, methysergide, pizotifen and sumatriptan. [0115]
(c) Drugs Affecting Blood and Haemopoietic Tissues including:
[0116] (i) Anticoagulants and thrombolytic agents such as warfarin,
dicoumarol, low molecular weight heparins such as enoxaparin;
streptokinase and its active derivatives; and [0117] (ii)
haemostatic agents such as aprotinin, tranexamic acid and
protamine. [0118] (d) Drugs Affecting the Central Nervous System
including: [0119] (i) Analgesics; [0120] (ii) antipyretics
including the opioid analgesics such as buprenorphine,
dextromoramide, dextropropoxyphene, fentanyl, alfentanil,
sufentanil, hydromorphone, methadone, morphine, oxycodone,
papaveretum, pentazocine, pethidine, phenoperidine, codeine and
dihydrocodeine; and [0121] (iii) Others include acetylsalicylic
acid (aspirin), paracetamol, and phenazone. [0122] (e) Hypnotics
and sedatives such as the barbiturates, amylobarbitone,
butobarbitone and pentobarbitone and other hypnotics and sedatives
such as choral hydrate, chiormethiazole, hydroxyzine and
meprobamate. [0123] (f) Antianxiety agents such as the
benzodiazepines, alprazolam, bromazepam, chlordiazepoxide,
clobazam, chiorazepate, diazepam, flunitrazepam, flurazepam,
lorazepam, nitrazepam, oxazepam, temazepam and triazolam. [0124]
(g) Neuroleptic and antipsychotic drugs such as the phenothiazines,
chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine,
thiopropazate, thioridazine and trifluoperazine and the
butyrophenones, droperidol and haloperidol and the other
antipsychotic drugs such as pimozide, thiothixene and lithium.
[0125] (h) Antidepressants such as the tricyclic antidepressants
amitryptyline, clomipramine, desipramine, dothiepin, doxepin,
imipramine, nortriptyline, opipramol, protriptyline and
trimipramine and the tetracyclic antidepressants such as mianserin
and the monoamine oxidase inhibitors such as isocarboxazid,
phenelizine, tranylcypromine and moclobemide and selective
serotonin re-uptake inhibitors such as fluoxetine, paroxetine,
citalopram, fluvoxamine and sertraline. [0126] (i) CNS stimulants
such as caffeine. [0127] (j) Anti-alzheimer's agents such as
tacrine. [0128] (k) Anti-parkinson agents such as amantadine,
benserazide, carbidopa, levodopa, benztropine, biperiden,
benzhexol, procyclidine and dopamine-2 agonists such as
S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923).
[0129] (l) Anticonvulsants such as phenytoin, valproic acid,
primidone, phenobarbitone, methyiphenobarbitone and carbamazepine,
ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam.
[0130] (m) Antiemetics, antinauseants such as the phenothiazines,
prochloperazine, thiethylperazine and 5HT-3 receptor antagonists
such as ondansetron and granisetron and others such as
dimenhydrinate, diphenhydramine, metoclopramide, domperidone,
hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride
and brompride. [0131] (n) Musculoskeletal System including: [0132]
(i) Non-steroidal anti-inflammatory agents including their racemic
mixtures or individual enantiomers where applicable, such as
ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac,
aloxiprin, aproxen, aspirin, diflunisal, fenoprofen, indomethacin,
mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide,
salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol and
ketoralac; [0133] (ii) Additional non-steroidal antiinflammatory
agents which can be formulated in combination with the dermal
penetration enhancers include salicylamide, salicylic acid,
flufenisal, salsalate, triethanolamine salicylate, aminopyrine,
antipyrine, oxyphenbutazone, apazone, cintazone, flufenamic acid,
clonixeril, clonixin, meclofenamic acid, flunixin, coichicine,
demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride,
dimefadane, indoxole, intrazole, mimbane hydrochloride, paranylene
hydrochloride, tetrydamine, benzindopyrine hydrochloride,
fluprofen, ibufenac, naproxol, fenbufen, cinchophen, diflumidone
sodium, fenamole, flutiazin, metazamide, letimide hydrochloride,
nexeridine hydrochloride, octazamide, molinazole, neocinchophen,
nimazole, proxazole citrate, tesicam, tesimide, tolmetin, and
triflumidate; [0134] (iii) Antirheumatoid agents such as
penicillamine, aurothioglucose, sodium aurothiomalate, methotrexate
and auranofin; [0135] (iv) Muscle relaxants such as baclofen,
diazepam, cyclobenzaprine hydrochloride, dantrolene, methocarbamol,
orphenadrine and quinine; and [0136] (v) Agents used in gout and
hyperuricaemia such as allopurinol, colchicine, probenecid and
sulphinpyrazone. [0137] (o) Hormones and Steroids including: [0138]
(i) Oestrogens such as oestradiol, oestriol, oestrone,
ethinyloestradiol, mestranol, stilboestrol, dienoestrol,
epioestriol, estropipate and zeranol; [0139] (ii) Progesterone and
other progestagens such as allyloestrenol, dydrgesterone,
lynoestrenol, norgestrel, norethyndrel, eclometrine,
norethisterone, norethisterone acetate, gestodene, levonorgestrel,
medroxyprogesterone and megestrol; [0140] (iii) Antiandrogens such
as cyproterone acetate and danazol; [0141] (iv) Antioestrogens such
as tamoxifen and epitiostanol and the aromatase inhibitors,
exemestane and 4-hydroxy-androstenedione and its derivatives.
Androgens and anabolic agents such as testosterone,
methyltestosterone, clostebol acetate, drostanolone, furazabol,
nandrolone oxandrolone, stanozolol, trenbolone acetate,
dihydro-testosterone, 17-.alpha.-methyl-19-nortestosterone and
fluoxymesterone; [0142] (v) 5-alpha reductase inhibitors such as
finasteride, turosteride, LY-191704 and MK-386; [0143] (vi)
Corticosteroids such as betamethasone, betamethasone valerate,
cortisone, dexamethasone, dexamethasone 21-phosphate,
fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide,
fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide,
halopredone, hydrocortisone, hydrocortisone 17-valerate,
hydrocortisone 17-butyrate, hydrocortisone 21-acetate
methylprednisolone, prednisolone, prednisolone 21-phosphate,
prednisone, triamcinolone, triamcinolone acetonide; [0144] (vii)
Further steroidal antiinflammatory agents such as cortodoxone,
fluoracetonide, fludrocortisone, difluorsone diacetate,
flurandrenolone acetonide, medrysone, amcinafel, amcinafide,
betamethasone and its other esters, chloroprednisone,
clorcortelone, descinolone, desonide, dichlorisone, difluprednate,
flucloronide, flumethasone, flucortolone, fluoromethalone,
fluperolone, fluprednisolone, meprednisone, methylmeprednisolone,
paramethasone, cortisone acetate, hydrocortisone
cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone
acetate, flurandrenolone acetonide, medrysone, amcinafal,
amcinafide, betamethasone, betamethasone benzoate, chloroprednisone
acetate, clocortolone acetate, descinolone acetonide,
desoximetasone, dichlorisone acetate, difluprednate, flucloronide,
flumethasone pivalate, flunisolide acetate, fluperolone acetate,
fluprednisolone valerate, paramethasone acetate, prednisolamate,
prednival, triamcinolone hexacetonide, cortivazol, formocortal and
nivazol; [0145] (viii) Pituitary hormones and their active
derivatives or analogs such as corticotrophin, thyrotropin,
follicle stimulating hormone (FSH), luteinising hormone (LH) and
gonadotrophin releasing hormone (GnRH); [0146] (ix) Thyroid
hormones such as calcitonin, thyroxine and liothyronine and
antithyroid agents such as carbimazole and propylthiouracil; and
[0147] (x) Other miscellaneous hormone agents such as octreotide.
[0148] (q) Pituitary inhibitors such as bromocriptine. [0149] (r)
Ovulation inducers such as clomiphene. [0150] (s) Hypoglycaemic
agents such as insulin, chlorpropamide, glibenclamide, gliclazide,
glipizide, tolazamide, tolbutamide, rosiglitazone and metformin.
[0151] (t) Genitourinary System agents. [0152] (u) Diuretics such
as the thiazides, related diuretics and loop diuretics,
bendrofluazide, chlorothiazide, chlorthalidone, dopamine,
cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside,
methycholthiazide, metolazone, quinethazone, bumetanide, ethacrynic
acid and frusemide and potassium sparing diuretics, spironolactone,
amiloride and triamterene. [0153] (v) Antidiuretics such as
desmopressin, lypressin and vasopressin including their active
derivatives or analogs. [0154] (w) Obstetric drugs including agents
acting on the uterus such as ergometrine, oxytocin and gemeprost.
[0155] (x) Prostaglandins such as alprostadil (PGE1), prostacyclin
(PGI2), dinoprost (prostaglandin F2-alpha) and misoprostol. [0156]
(y) Antimicrobials including: [0157] (i) cephalosporins such as
cephalexin, cefoxytin and cephalothin; [0158] (ii) penicillins such
as amoxycillin, amoxycillin with clavulanic acid, ampicillin,
bacampicillin, benzathine penicillin, benzylpenicillin,
carbenicillin, cloxacillin, methicillin, phenethicillin,
phenoxymethylpenicillin, flucloxacillin, mezlocillin, piperacillin,
ticarcillin and azlocillin; [0159] (iii) tetracyclines such as
minocycline, chlortetracycline, tetracycline, demeclocycline,
doxycycline, methacycline and oxytetracycline and other
tetracycline-type antibiotics; [0160] (iv) minoglycosides such as
amikacin, gentamicin, kanamycin, neomycin, netilmicin and
tobramycin. Antifungals such as amorolfine, isoconazole,
clotrimazole, econazole, miconazole, nystatin, terbinafine,
bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole
and flucytosine, salicylic acid, fezatione, tictatone, tolnaftate,
triacetin, zinc, pyrithione and sodium pyrithione; [0161] (v)
Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin,
enoxacin and norfloxacin. Sulphonamides such as
phthalylsulphthiazole, sulfadoxine, sulphadiazine, sulphamethizole
and sulphamethoxazole; [0162] (vi) Sulphones such as dapsone; and
[0163] (vii) Other miscellaneous antibiotics such as
chloramphenicol, clindamycin, erythromycin, erythromycin ethyl
carbonate, erythromycin estolate, erythromycin glucepate,
erythromycin ethylsuccinate, erythromycin lactobionate,
roxithromycin, lincomycin, natamycin, nitrofurantoin,
spectinomycin, vancomycin, aztreonam, colistin IV, metronidazole,
tinidazole, fusidic acid and trimethoprim; 2-thiopyridine N-oxide;
halogen compounds, particularly iodine and iodine compounds such as
iodine-PVP complex and diiodohydroxyquin; hexachlorophene;
chlorhexidine; chloroamine compounds; benzoylperoxide [0164] (z)
Anti-tuberculosis drugs such as ethambutol, isoniazid,
pyrazinamide, rifampicin and clofazimine. Antimalarials such as
primaquine, pyrimethamine, chloroquine, hydroxychloroquine,
quinine, mefloquine and halofantrine. [0165] (aa) Antiviral agents
such as acyclovir and acyclovir prodrugs, famciclovir, zidovudine,
didanosine, stavudine, lamivudine, zalcitabine, saquinavir,
indinavir, ritonavir, n-docosanol, tromantadine and idoxuridine.
[0166] (ab) Anthelmintics such as mebendazole, thiabendazole,
niclosamide, praziquantel, pyrantel embonate and
diethyicarbamazine. [0167] (ac) Cytotoxic agents such as
plicamycin, cyclophosphamide, dacarbazine, fluorouracil and its
prodrugs [described, for example, in International Journal of
Pharmaceutics 111, 223-233 (1994)], methotrexate, procarbazine,
6-mercaptopurine and mucophenolic acid. [0168] (ad) Metabolism
agents including anorectic and weight reducing agents such as
dexfenfluramine, fenfluramine, diethylpropion, mazindol and
phentermine. [0169] (ae) Agents used in hypercalcaemia such as
calcitriol, dihydrotachysterol and their active derivatives or
analogs. [0170] (af) Respiratory System agents including: [0171]
(i) antitussives such as ethylmorphine, dextromethorphan and
pholcodine; [0172] (ii) expectorants such as acetylcysteine,
bromhexine, emetine, guaiphenesin, ipecacuanha and saponins; [0173]
(iii) decongestants such as phenylephrine, phenylpropanolamine and
pseudoephedrine; and [0174] (iv) bronchospasm relaxants such as
ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol,
tulobuterol, sodium cromoglycate, cromoglycic acid and its prodrugs
[described, for example, in International Journal of Pharmaceutics
7, 63-75 (1980)], terbutaline, ipratropium bromide, salmeterol and
theophylline and theophylline derivatives. [0175] (ag) Allergy and
Immune System agents including: [0176] (i) antihistamines such as
meclozine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine,
chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine,
diphenhydramine, diphenylamine, doxylamine, mebhydrolin,
pheniramine, tripolidine, azatadine, diphenylpyraline,
methdilazine, terfenadine, astemizole, loratidine and cetirizine.
[0177] (ah) Local anaesthetics such as bupivacaine, amethocaine,
lignocaine, cinchocaine, dibucaine, mepivacaine, prilocaine and
etidocaine. [0178] (ai) Stratum corneum lipids, such as ceramides,
cholesterol and free fatty acids, for improved skin barrier repair
[Man, et al. J. Invest. Dermatol., 106(5), 1096, 1996].
[0179] (aj) Neuromuscular blocking agents such as suxamethonium,
alcuronium, pancuronium, atracurium, gallamine, tubocurarine and
vecuronium. [0180] (ak) Smoking cessation agents such as nicotine,
bupropion and ibogaine. [0181] (al) Insecticides and other
pesticides which are suitable for local or systemic application.
[0182] (am) Dermatological agents, such as vitamins A and E,
vitamin E acetate and vitamin E sorbate. [0183] (an) Allergens for
desensitisation such as house dust mite allergen. [0184] (ao)
Nutritional agents, such as vitamins, essential amino acids and
essential fats. [0185] (ap) Keratolytics such as the alpha-hydroxy
acids, glycollic acid and salicylic acid. [0186] (aq)
Psychicenergisers, such as 3-(2-aminopropyl)indole,
3-(2-aminobutyl)indole, and the like. [0187] (ar) Anti-acne agents
such as containing isotretinoin, tretinoin and benzoyl peroxide.
[0188] (as) Anti-psoriasis agents such as containing etretinate,
cyclosporin and calcipotriol. [0189] (at) Anti-itch agents such as
capsaicin and its derivatives such as nonivamide [Tsai, et al.
Drug. Dev. Ind. Pharm., 20(4), 719, 1994]. [0190] (au)
Anticholinergic agents, which are effective for the inhibition of
axillary sweating and for the control of prickly heat. The
antiperspirant activity of agents such as methatropine nitrate,
propantheline bromide, scopolamine, methscopolamine bromide, and
the new class of soft antiperspirants, quaternary acyloxymethyl
ammonium salts [described, for example, by Bodor et al, J. Med.
chem. 23, 474 (1980) and also in United. Kingdom Specification No.
2010270, published Jun. 27, 1979]. [0191] (av) Other
physiologically active peptides and proteins, small to medium-sized
peptides, e.g., vasopressin and human growth hormone.
[0192] Preferably the active agents are androgens, preferably
testosterone; oestrogens, preferably estradiol; progesterone and
other progestagens; broncho-dilators; antianxiety agents,
preferably buspirone; and central nervous system agents, preferably
fentanyl.
[0193] In another embodiment, the composition may further include a
second active agent to provide the composition with additional
usage benefits. The second active agent may be any one of those
listed above, or herbal extracts and/or cosmetic agents (such as,
age spot and keratose removing agents, anti-aging agents,
antioxidants, and hydroxy acids).
[0194] Preferably the second active agent is an antifungal agent.
Fungal infections are common in areas of the body having higher
production of heat and perspiration.
[0195] In yet another embodiment, the composition may further
comprise one or more inactive agents. Such inactive ingredients may
be referred to as "additives". Examples of such additives include
but are not limited to, humectants, deodorant agents,
antiperspirants, pH adjusting agents, preservatives, emulsifiers,
occlusive agents (including without limitation patches and film
formers), solubilizing agents, colorants, and surfactants
(including without limitation anionic surfactants).
[0196] The method of the invention is particularly suited to
treatment of testosterone insufficiency and the conditions and
diseases associated therewith.
[0197] The invention may be applied to a range of active agents and
in the treatment of a range of conditions. These include the
delivery of oestradiol, progestin, ADHD agents and fentanyl, which
may be used to treat various indications as already known by
treatment through other routes of administration.
[0198] The preferred method of the invention wherein the active
agent is testosterone or a derivative thereof, may be used to treat
testosterone deficiency in men and women and the conditions and
diseases resulting therefrom. The composition may comprise
testosterone or a derivative thereof. There are number of closely
related androgenic compounds which are synthetically derivatized
from testosterone are known to provide the same or a similar
physiologic activity, as discussed above.
[0199] Testosterone production in both men and women declines
naturally with age. Testosterone deficiency may result from disease
or damage to the hypothalamus, pituitary gland, or testicles that
inhibits hormone secretion and testosterone production, and is also
known as hypogonadism. Depending on age, insufficient testosterone
production can lead to abnormalities in muscle and bone
development, underdeveloped genitalia, and diminished virility,
libido and/or desire.
[0200] Testosterone deficiency in men (hypogonadism) may be present
at birth (congenital) or may develop later (acquired). It is
classified by the location of its cause along the
hypothalamic-pituitary-gonadal axis: [0201] Primary, disruption in
the testicles [0202] Secondary, disruption in the pituitary [0203]
Tertiary, disruption in the hypothalamus.
[0204] The most common congenital cause is Klinefelter's syndrome.
This condition, which is caused by an extra X chromosome, results
in infertility, sparse facial and body hair, abnormal breast
enlargement (gynecomastia), and small testes.
[0205] Congenital hormonal disorders such as leutenizing
hormone-releasing hormone (LHRH) deficiency and
gonadotropin-releasing hormone (GnRH) deficiency (e.g., Kallmann's
syndrome) also may cause testosterone deficiency.
[0206] Other congenital causes include absence of the testes
(anorchism; also may be acquired) and failure of the testicles to
descend into the scrotum (cryptorchidism).
[0207] Acquired causes of testosterone deficiency include
chemotherapy; damage occurring during surgery involving the
pituitary gland, hypothalamus, or testes; glandular malformation;
head trauma that affects the hypothalamus; infection (e.g.,
meningitis, syphilis, mumps); isolated LH deficiency (e.g., fertile
eunuch syndrome); radiation; testicular trauma; and tumours of the
pituitary gland, hypothalamus, or testicles.
[0208] Androgen deficiency in women has been associated with an
increased rate of sexual problems or complaints in a number of
studies. These problems are frequently encountered in
oophorectomized women and those with androgen deficiency from other
causes. Hypoactive sexual desire disorder (HSDD) in women is the
persistent or recurring deficiency (or absence) of sexual
fantasies, thoughts and/or desire for, or receptivity to, sexual
activity, which causes personal distress. The cause may be either
physiological or psychological or a combination of both. Common
physiological etiologies include hormone deficiencies, medications,
and surgical interventions. Any disruption of the female hormonal
milieu caused by these etiologies can result in decreased sexual
desire. The lack of, or a decrease in, sexual desire may also be
secondary to poor sexual arousal and response, or to pain
associated with sexual activity. Another factor may be difficulty
with inability to attain or maintain sufficient sexual excitement,
a condition known as female sexual arousal disorder (FSAD).
[0209] The method of the invention may also be used in treatment of
sexual dysfunction in men and women.
[0210] Normal daily production of testosterone in normal young men
ranges from 3-10 mg per day with diurnal variation (maximum
.about.7 am declining throughout the day). The aim of testosterone
therapy in men is to deliver physiologic amounts of testosterone to
the systemic circulation producing serum testosterone levels within
the normal range for healthy men (e.g. 300-1000 ng/dL or 10-35
nM).
[0211] Several clinical studies have demonstrated that in
conditions such as female sexual dysfunction, testosterone
administration, which is aimed at restoring testosterone levels to
normal reproductive levels, is effective in improving sexual
function. The studies to date suggest that systemic administration
of doses ranging from 150 .mu.g to 300 .mu.g a day would be
sufficient to return testosterone levels to mid- to high
premenopausal levels in androgen deficient women.
[0212] The invention may be used in treating a wide variety of
conditions responsive to testosterone therapy such as hypogonadism
(primary and secondary), AIDS Wasting Syndrome, micropenis,
somatopause, andropause, viropause, or androgen deficiency in adult
males (ADAM), anaemia from renal dialysis or chronic kidney
disease, benign prostatic hyperplasia, acne, diabetes, infertility,
libido, periodontal disease, post-anabolic steroid abuse, dry eyes,
diabetic retinopathy, retinopathy, and Lupus Erythematosis
decreased bone density (i.e. osteoporosis), hyperlipemia,
predisposition toward prostrate cancer, heart disease, angina, and
hypertension.
[0213] When the composition of the invention and the composition
used in the method of the invention includes a volatile solvent,
one of the significant advantages of the preferred embodiment of
the invention is that it dries rapidly, allows absorption of the
active agent (particularly testosterone), and avoids the problems
of accidentally dosing others by confining administration to
axilla. The transdermal composition of the invention and the
composition used in accordance with the method of the invention do
not interfere with the application and use of other substances or
products on the skin of a subject.
[0214] In the most preferred embodiment, the transdermal
composition of the invention and the composition used in the method
of the invention is applied as a lotion, spray or aerosol which is
formulated to dry on the skin within three minutes of application.
In this way we have found that the composition is driven into the
skin and the testosterone composition forms a reservoir in the skin
which we have found is particularly active in enhancing blood
levels via the axilla without the undesirable effects associated
with high localised subcutaneous testosterone levels in this
region.
[0215] The compositions used in the method of the invention
preferably have a drying time of less than three minutes. Drying
time may be determined by in vitro or in vivo tests. A suitable in
vitro test involves placing a 10 .mu.L sample on a clean glass
slide at room temperature (approx 20.degree. C.) and using a four
decimal place analytical balance the time take for the vehicle to
stop evaporating is measured. The resulting drying times from three
repetitions of the test may be averaged.
[0216] For in vivo drying time measurement 10 .mu.Ls applied to
volar forearms (32.degree. C.) of three subjects and the drying
time is measured by touch and visual verification (no visible
surface vehicle or shine).
[0217] The invention wilt now be described with reference to the
following examples. It is to be understood that the examples are
provided by way of illustration of the invention and that they are
in no way limiting to the scope of the invention.
EXAMPLES
[0218] The examples are described with reference to the
drawings.
Example 1
[0219] This example compares the single dose pharmacokinetics of
testosterone following application of a single dose of a metered
dose of a testosterone lotion to (a) the inner arm and (b) axilla,
in healthy women.
[0220] In this example, the composition (referred to here as
"Composition 1") contained the following components in the amounts
by weight specified.
TABLE-US-00001 TABLE 1 Component Use Concentration Testosterone USP
Active 1% w/v % Octisalate USP Penetration enhancer 8% w/v Povidone
USP Thickener 1-5 w/v % Purified water USP Vehicle 10% v/v
Isopropyl alcohol USP Vehicle 30% v/v Alcohol USP Vehicle
balance
[0221] An open label, two period study was conducted in 12 healthy
premenopausal women.
[0222] In each period, 1 mL of a metered dose testosterone lotion
was applied as a single dose to either the inner arm or the axilla
according to the randomisation schedule. Samples were collected
over 72 hours for each subject and subsequently analysed for
testosterone content.
[0223] Two women were withdrawn from the study prior to the first
dosing period. Ten women completed the study and the results are
presented in the graph shown in FIG. 1. The baseline corrected data
comparing testosterone uptake from the axilla and the inner arm
shows that the axilla has roughly a two fold increased uptake over
the inner arm (AUC.sub.0-72 was 5610.34 ng/dL/hr for the axilla
compared to 2975.08 ng/dL/hr for the inner arm). No adverse
sweating or odour was reported.
Example 2
[0224] This example investigated the cumulative testosterone
permeation through human skin in vitro following deodorant spray
application.
[0225] Finite-dose in vitro diffusion studies were undertaken using
excised human, male abdominal skin whereby the deodorant was
applied to the skin surface at pre-determined times after the
topical application of a 5 .mu.L dose of a testosterone lotion,
formulated according to example 1. These experiments were performed
over 24 hours using stainless steel, flow through diffusion cells
based on those described previously (Cooper, E. R. J. Pharm. Sci.
1984, 73, 1153-1156) except that the cell was modified to increase
the diffusion area to 1.0 cm.sup.2. The formulations were applied
using a finite dose technique (Franz, T. J. Curr. Probl. Dermatol.,
1978, 7, 58-68) to mimic clinical dosing conditions at an applied
dose volume of 5 .mu.L/cm.sup.2. A piece of stainless steel wire
mesh was placed directly below the skin in the receptor chamber of
the of the diffusion cell to maintain a turbulent flow of receptor
solution below the skin. The diffusion cells were maintained at a
flow rate of approximately 1.0 mL/cm.sup.2/hr by a microcassette
peristaltic pump (Watson Marlow 505S UK). The cells were kept at
32.+-.0.5.degree. C. by a heater bar and the samples were collected
into appropriately sized plastic vials on an automated fraction
collector (Isco Retriever II, Lincoln, Nebr.) at specified
intervals. The receptor solution (20% v/v EtOH in 0.002% w/v
NaN.sub.3) maintained sink conditions below the skin.
[0226] At designated, pre-determined time points following the
application of the testosterone lotion, the following were
applied:-- [0227] one spray of a deodorant (containing isobutane,
denatured alcohol, propane, triethyl citrate, parfum, butane, and
water) was applied to the skin surface for approximately 1 sec from
a constant distance of .about.10 cm from the top of the donor
compartment of the cell; or [0228] 3 .mu.L of ethanol (the
estimated amount of ethanol present in a 1 sec spray of
deodorant).
[0229] The amount of testosterone that permeated the skin was
quantified using a validated HPLC method.
[0230] The application of a spray of deodorant at different time
points after the topical application of the testosterone lotion did
not have a significant effect (enhancing or inhibitory) on the
permeation of testosterone through human epidermis in vitro.
Application of neat ethanol (EtOH) after testosterone lotion dosing
also revealed no significant effect on the permeation of
testosterone lotion through human epidermis in vitro.
[0231] FIG. 2 shows the testosterone permeation profiles obtained
after application of deodorant spray to the formulation. FIG. 3
shows testosterone permeation profiles obtained after application
of ethanol (3 .mu.L) to the Composition 1 formulation. In both
cases, it can be seen that the control line does not differ
significantly along the time period examined.
[0232] The application of either a spray of deodorant or a
finite-dose of neat EtOH did not appear to have an effect on the
skin permeation of testosterone from a 5 .mu.L dose of the lotion.
Therefore it was concluded that the application of deodorant to the
skin after application of the testosterone lotion will not impede
transdermal penetration of testosterone.
Example 3
[0233] This example investigated the cumulative testosterone and
estradiol permeation through human skin in vitro when included in a
commercial deodorant
[0234] Finite-dose in vitro diffusion studies were undertaken using
heat-separated human, female abdominal epidermis. These experiments
were performed over 24 hours using stainless steel, flow through
diffusion cells based on those described previously (Cooper, E. R.
J. Pharm. Sci. 1984, 73, 1153-1156) except that the cell was
modified to increase the diffusion area to 1.0 cm.sup.2. The
formulations were applied using a finite dose technique (Franz, T.
J. Curr. Probl. Dermatol., 1978, 7, 58-68) to mimic clinical dosing
conditions at an applied dose volume of 5 .mu.L/cm.sup.2. A piece
of stainless steel wire mesh was placed directly below the skin in
the receptor chamber of the of the diffusion cell to maintain a
turbulent flow of receptor solution below the skin. The diffusion
cells were maintained at a flow rate of approximately 1.0
mL/cm.sup.2/hr by a microcassette peristaltic pump (Watson Marlow
505S UK). The cells were kept at 32.+-.0.5.degree. C. by a heater
bar and the samples were collected into appropriately sized plastic
vials on an automated fraction collector (Isco Retriever II,
Lincoln, Nebr.) at specified intervals. The receptor solution (20%
v/v EtOH in 0.002% w/v NaN.sub.3) maintained sink conditions below
the skin. [0235] Two formulations were used that consisted of:--
[0236] Composition 2: 1% w/v testosterone, 5% w/v octisalate, 32%
v/v EtOH to 100% v/v Deodorant (Rexona Essentials for Men `Dry`
Antiperspirant Deodorant Spray, Unilever, Australia, BN: 6030
10793) [0237] Composition 3: 0.5% w/v E2 estradiol, 5% w/v
octisalate, 52% v/v EtOH to 100% v/v Deodorant (Rexona Activreserve
`Classic Silk` Antiperspirant Deodorant Spray, Unilever, Australia,
BN: 6054 11280) [0238] Note: extra ethanol was required in each of
the formulations in order for the octisalate to remain miscible.
The amount of ethanol differed between formulations as the
deodorants used differed.
[0239] The amount of testosterone (TES) and estradiol (E2) that
permeated the skin was quantified using a HPLC method.
[0240] The permeation of TES through human epidermis in vitro was
unaltered when the drug was added, with octisalate (OS) in an EtOH
solution, to a commercial deodorant compared to its permeation from
an ethanolic solution without the penetration enhancer. FIG. 4
shows the TES permeation profiles obtained from the application of
Composition 2 compared with application of a control. There is no
significant difference in the curves produced. With composition 3,
the permeation of E2 through human epidermis in vitro was
significantly improved, when the drug was added, with OS in an EtOH
solution, to a commercial deodorant compared to its permeation from
an ethanolic solution without the penetration enhancer. FIG. 5
shows the E2 permeation profiles obtained from the application of
Composition 3, compared with application of a control. The improved
permeation is apparent after only 4 hours, and the difference
becomes more significant with time particularly after 16 hours from
dose.
[0241] The in vitro skin permeation of TES or E2 from an ethanolic
solution comprised of OS and a commercial deodorant was therefore
comparable to, if not higher than, its permeation from the
ethanolic solutions comprised of the drug alone. This demonstrates
that the addition of ingredients typically found in commercial
deodorants to the formulations did not inhibit transdermal
permeation of testosterone or estradiol.
Example 4
[0242] A study was conducted to assess the antiperspirant and
deodorant characteristics of Composition 1 without added
antiperspirant or deodorants. In this study, 16 male volunteers
were asked to apply Composition 1 to their axilla(s) in a similar
manner as in Example 1, and also to refrain from the use of other
deodorants or antiperspirants on the axilla (armpits) that received
Composition 1. The subjects were, however, instructed to apply
deodorant if they were distressed with symptoms of sweating and to
report such application. Interestingly, none of the subjects
reported a need to use deodorant or antiperspirant when Composition
1 had been applied to the axilla.
[0243] Finally, various other modifications and/or alterations may
be made without departing from the spirit of the present invention
as outlined herein. The invention disclosed and defined in this
specification extends to all alternative combinations of two or
more of the individual features mentioned or evident from the text
or drawings. All of these different combinations constitute various
different aspects of the invention.
* * * * *