U.S. patent application number 15/072802 was filed with the patent office on 2016-11-17 for transdermal testosterone device and delivery.
This patent application is currently assigned to Noven Pharmaceuticals, Inc.. The applicant listed for this patent is Noven Pharmaceuticals, Inc.. Invention is credited to Juan A. Mantelle.
Application Number | 20160331762 15/072802 |
Document ID | / |
Family ID | 43770596 |
Filed Date | 2016-11-17 |
United States Patent
Application |
20160331762 |
Kind Code |
A1 |
Mantelle; Juan A. |
November 17, 2016 |
TRANSDERMAL TESTOSTERONE DEVICE AND DELIVERY
Abstract
Described are transdermal drug delivery systems for the
transdermal administration of testosterone, comprising a polymer
matrix and testosterone. Methods of making and using such systems
also are described.
Inventors: |
Mantelle; Juan A.; (Miami,
FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Noven Pharmaceuticals, Inc. |
Miami |
FL |
US |
|
|
Assignee: |
Noven Pharmaceuticals, Inc.
Miami
FL
|
Family ID: |
43770596 |
Appl. No.: |
15/072802 |
Filed: |
March 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12953019 |
Nov 23, 2010 |
9320742 |
|
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15072802 |
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61265411 |
Dec 1, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/7053 20130101;
A61P 9/00 20180101; A61K 31/568 20130101; A61K 9/7061 20130101;
A61K 9/7069 20130101; A61K 47/10 20130101; A61P 5/26 20180101; A61P
15/00 20180101 |
International
Class: |
A61K 31/568 20060101
A61K031/568; A61K 9/70 20060101 A61K009/70; A61K 47/10 20060101
A61K047/10 |
Claims
1. A transdermal drug delivery system comprising a drug-containing
layer defining an active surface area and comprising a polymer
matrix comprising 2-25% by weight acrylic adhesive, 45-70% by
weight silicone adhesive, about 2-25% by weight soluble
polyvinylpyrrolidone (PVP), about 5-15% penetration enhancer, and
about 0.1-10% by weight testosterone, all based on the total dry
weight of the polymer matrix, wherein the system includes less than
0.3 mg/cm.sup.2 testosterone, and achieves a testosterone flux that
is at least 0.7 .mu.g/cm.sup.2/hour, based on the active surface
area.
2. The transdermal drug delivery system of claim 1, wherein the
system achieves a testosterone flux that is at least 0.89
.mu.g/cm.sup.2/hour, based on the active surface area.
3-4. (canceled)
5. The transdermal drug delivery system of claim 1, wherein the
penetration enhancer comprises oleyl alcohol.
6. The transdermal drug delivery system of claim 1, wherein the
composition further comprises an antioxidant selected from the
group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole
(BHA), ascorbyl palmitate, alpha-tocopherol and its esters, citric
acid and propyl gallate, and mixtures thereof.
7. The transdermal drug delivery system of claim 6, wherein the
antioxidant comprises BHT.
8. The transdermal drug delivery system of claim 1, wherein the
acrylic adhesive and silicone adhesive are present in a ratio of
from about 1:2 to about 1:6, based on the total weight of the
acrylic and silicone adhesives.
9. The transdermal drug delivery system of claim 1, wherein the
polymer matrix comprises an amount of testosterone effective to
deliver a therapeutically effective amount of testosterone over a
period of time selected from the group consisting of at least 1
day, at least 2 days, at least 3 days, at least 4 days, at least 5
days, at least 6 days and at least 7 days.
10. The transdermal drug delivery system of claim 1, wherein the
polymer matrix comprises an amount of testosterone effective to
deliver an amount of testosterone of from about 100 to about 500
.mu.g/day.
11. The transdermal drug delivery system of claim 1, wherein the
polymer matrix comprises an amount of testosterone effective to
deliver an amount of testosterone of from about 100 to about 450
.mu.g/day.
12. The transdermal drug delivery system of claim 1, wherein the
polymer matrix comprises an amount of testosterone effective to
deliver an amount of testosterone of from about 300 .mu.g/day to
about 500 .mu.g/day.
13-14. (canceled)
15. The transdermal drug delivery system of claim 1, wherein the
polymer matrix has a coat weight of greater than about 10
mg/cm.sup.2.
16. The transdermal drug delivery system of claim 1, wherein the
polymer matrix has a coat weight of about 12.5 mg/cm.sup.2.
17. A transdermal drug delivery system comprising a polymer matrix
comprising 2-25% by weight acrylic adhesive, 45-70% by weight
silicone adhesive, about 2-25% by weight soluble PVP, about 5-15%
penetration enhancer, and about 0.1-10% by weight testosterone, all
based on the total dry weight of the polymer matrix, wherein the
system has an active surface area of 14.0 cm.sup.2 and is effective
to deliver an amount of testosterone per day of from about 300
.mu.g to about 500 .mu.g.
18. A method for administering testosterone, comprising applying to
the skin or mucosa of a subject in need thereof a transdermal drug
delivery system comprising a drug-containing layer defining an
active surface area and comprising a polymer matrix comprising
2-25% by weight acrylic adhesive, 45-70% by weight silicone
adhesive, about 2-25% by weight soluble PVP, about 5-15%
penetration enhancer, and about 0.1-10% by weight testosterone, all
based on the total dry weight of the polymer matrix, wherein the
system includes less than 0.3 mg/cm.sup.2 testosterone, and
achieves an testosterone flux that is at least 0.7
.mu.g/cm.sup.2/hour, based on the active surface area.
19. The method of claim 18, wherein the system achieves a
testosterone flux that is at least 0.89 .mu.g/cm.sup.2/hour, based
on the active surface area.
20. The method of claim 18, wherein the system has an active
surface area that is about 14.0 cm.sup.2 and is effective to
deliver an amount of testosterone per day of from about 300 .mu.g
to about 500 .mu.g.
21. A method of making a transdermal drug delivery system for
administering testosterone, comprising forming a polymer matrix
comprising about 0.1-10% by weight testosterone and a polymer blend
comprising 2-25% by weight of an acrylic adhesive, 45-70% by weight
of a silicone adhesive, about 5-15% by weight of a penetration
enhancer, and about 2-25% by weight soluble PVP, all based on the
total dry weight of the polymer matrix, and applying the polymer
matrix to a support layer such that the system includes less than
0.3 mg/cm.sup.2 testosterone.
22. The method of claim 21, wherein the system has an active
surface area that is about 14.0 cm.sup.2.
23. (canceled)
24. The method of claim 21, wherein the polymer matrix further
comprises about 0.01% by weight BHT, based on the total dry weight
of the polymer matrix.
25. The method of claim 21, wherein the polymer matrix is applied
to the support layer at a coat weight of greater than about 10
mg/cm.sup.2.
26. The method of claim 21, wherein the polymer matrix coat weight
is about 12.5 cm.sup.2.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. 61/265,411, filed
Dec. 1, 2009, the entire contents of which are incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] Described herein are compositions and methods for the
transdermal delivery of testosterone.
BACKGROUND
[0003] This invention relates generally to transdermal drug
delivery systems, and more particularly, to transdermal drug
delivery systems for the delivery of testosterone. The use of a
transdermal system, for example, a patch comprising a
pressure-sensitive adhesive containing a drug, as a means of
delivering drug through the skin is well known. However, there
remains a need for transdermal drug delivery systems designed for
the delivery of specific drugs, such as testosterone, and there
remains a particular need for smaller transdermal drug delivery
systems that exhibit desired pharmacokinetic properties.
[0004] Transdermal delivery systems (adhesive patches) as dosage
forms have been the subject of a vast number of patent applications
over the last 25 years, yielding many patents but few commercial
products in comparison. To those working in the field, the
relatively small number of commercial products is not surprising.
Although regulatory, economic, and market hurdles play a role in
limiting the number of products on the market, the task of
developing a transdermal delivery system that achieves desired
physical and pharmacokinetic parameters to satisfy physician and
patient demand is more daunting. Parameters to be considered during
commercial product development may include drug solubility, drug
stability (e.g., as may arise from interaction with other component
materials and/or the environment), delivery of a therapeutic amount
of drug at a desired delivery rate over the intended duration of
use, adequate adhesion at the anatomical site of application,
integrity (e.g., minimal curling, wrinkling, delaminating and
slippage) with minimal discomfort, irritation and sensitization
both during use and during and after removal, and minimal residual
adhesive (or other components) after removal. Size also may be
important from a manufacturing and patient viewpoint, and
appearance may be important from a patient viewpoint. The physical
manufacturing and production aspects of commercial product
development (e.g., the identity and costs of materials, equipment,
and labor) and supporting analytical methods required for
regulatory compliance also can be significant.
[0005] Of the physical parameters that are considered when
developing a commercial transdermal drug delivery system, size,
e.g., surface area at the site of application, is often dictated
and limited by other physical and pharmacokinetic requirements,
such as desired drug delivery rates and daily dosages. In general,
it is easier to develop a relatively "large" transdermal drug
delivery system that will achieve drug delivery at target
therapeutic levels over an intended duration of therapy, than it is
to develop a smaller transdermal drug delivery system that still
exhibits acceptable pharmacokinetic properties. Still, because size
directly impacts costs (e.g., costs of component materials, costs
of packaging materials, costs for production and manufacturing
equipment, labor costs relative to product yield per run time,
etc.) and patients generally prefer smaller systems to larger ones
(both for aesthetic reasons and comfort, since a smaller surface
may permit the use of less aggressive adhesives), there is a need
for smaller transdermal drug delivery systems.
SUMMARY
[0006] In accordance with one embodiment, there is provided a
transdermal drug delivery system comprising a drug containing layer
defining an active surface area and comprising a polymer matrix
comprising testosterone, wherein the system includes less than 0.3
mg/cm.sup.2 testosterone and achieves a testosterone flux that is
at least about 0.7 .mu.g/cm.sup.2/hour, such as at least about 0.89
.mu.g/cm.sup.2/hour, based on the active surface area. In some
embodiments, the polymer matrix comprises a polymer blend
comprising an acrylic adhesive, a silicone adhesive, and soluble
PVP. In some embodiments, the polymer matrix comprises about 2-25%
by weight acrylic adhesive, about 45-70% by weight silicone
adhesive, about 2-25% by weight soluble PVP, about 0-15%
penetration enhancer, about 0.1-10% by weight testosterone, and,
optionally, about 0.001-0.1% by weight antioxidant, all based on
the total dry weight of the polymer matrix. In some embodiments,
the polymer matrix comprises about 20% by weight acrylic adhesive,
about 59% by weight silicone adhesive, about 12% by weight soluble
PVP, about 6.0% by weight oleyl alcohol, about 2-3% by weight
testosterone, and, optionally about 0.01% by weight
butylhydroxytoluene, all based on the total dry weight of the
polymer matrix. In some embodiments, the acrylic adhesive and
silicone adhesive are present in a ratio of from about 1:2 to about
1:6, based on the total weight of the acrylic and silicone
adhesives.
[0007] In some embodiments, the penetration enhancer comprises
oleyl alcohol or dipropylene glycol, or both.
[0008] In some embodiments, the polymer matrix comprises an amount
of testosterone effective to deliver a therapeutically effective
amount of testosterone over a period of time selected from the
group consisting of at least 1 day, at least 2 days, at least 3
days, at least 4 days, at least 5 days, at least 6 days and at
least 7 days. In some embodiments, the polymer matrix comprises an
amount of testosterone effective to deliver an amount of
testosterone of at least 300 .mu.g/day, over a period of at least 3
days.
[0009] In some embodiments, the polymer matrix has a coat weight of
greater than about 10 mg/cm.sup.2. In some embodiments, the polymer
matrix has a coat weight selected from the group consisting of
about 12.0, about 12.5, about 13.0 and about 15 mg/cm.sup.2.
[0010] In accordance with some embodiments, there is provided a
transdermal drug delivery system comprising a polymer matrix
comprising testosterone, wherein the system has an active surface
area that is about 50% of 28.0 cm.sup.2, including about 14
cm.sup.2, and is effective to deliver an amount of testosterone per
day of at least 300 .mu.g/day.
[0011] In accordance with some embodiments, there is provided a
method for administering testosterone, comprising applying to the
skin or mucosa of a subject in need thereof a transdermal drug
delivery system comprising a drug-containing layer defining an
active surface area and comprising a polymer matrix comprising
testosterone, wherein the system includes less than 0.3 mg/cm.sup.2
testosterone and achieves an testosterone flux that is at least
about 0.7 .mu.g/cm.sup.2/hour, such as at least about 0.89
.mu.g/cm.sup.2/hour, based on the active surface area. In some
embodiments, the system has an active surface area that is about
50% of 28.0 cm.sup.2, including about 14 cm.sup.2, and is effective
to deliver an amount of testosterone per day of at least 300
.mu.g/day.
[0012] In accordance with some embodiments, there is provided a
method of making a transdermal drug delivery system for
administering testosterone, comprising forming a polymer matrix
comprising testosterone and a polymer blend comprising an acrylic
adhesive, a silicone adhesive, and soluble PVP, and applying the
polymer matrix to a support layer such that the system includes
less than 0.3 mg/cm.sup.2 testosterone. In some embodiments, the
system has an active surface area that is about 50% of 28.0
cm.sup.2, including about 14 cm.sup.2. In some embodiments, the
polymer matrix comprises about 20% by weight acrylic adhesive,
about 59% by weight silicone adhesive, about 12% by weight soluble
PVP, about 6.0% by weight oleyl alcohol, about 2-3% by weight
testosterone and, optionally about 0.01% by weight
butylhydroxytoluene, all based on the total dry weight of the
polymer matrix. In some embodiments, the polymer matrix is applied
to the support layer at a coat weight of greater than about 10
mg/cm.sup.2. In some embodiments, the polymer matrix coat weight is
selected from the group consisting of 12.0, about 12.5, about 13.0
and about 15 mg/cm.sup.2.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 illustrates the testosterone flux (.mu.g/cm.sup.2/hr)
over time (0-96 hours) from a transdermal delivery system according
to the invention ( ), as compared to Intrinsa.RTM.
(.diamond-solid.).
[0014] FIG. 2 illustrates the cumulative amount of drug delivered
per unit area (.mu.g/cm.sup.2) over time (0-96 hours) from a
transdermal delivery system according to the invention ( ), as
compared to Intrinsa.RTM. (.diamond-solid.).
DETAILED DESCRIPTION
[0015] The field of transdermal delivery systems suffers from the
problem of needing to balance many different competing factors to
develop a commercial product that exhibits, for example both
clinical efficacy and satisfactory wear properties while remaining
acceptable to patients. For example, when selecting the size of a
transdermal delivery system, it is necessary to balance factors
that favor a smaller size (such as lower cost, better adhesive
performance and improved aesthetics) against factors that favor a
larger size (such as the target delivery rate (flux) and daily
dose). The Intrinsa.RTM. transdermal testosterone product
(manufactured by Watson Pharmaceuticals Inc.) is 28 cm.sup.2 and
contains 8.4 mg of testosterone. Thus, the Intrinsa.RTM. product
includes 0.3 mg/cm.sup.2 testosterone. The Intrinsa.RTM. product is
said to deliver 300 .mu.g testosterone per day.
[0016] In accordance with some embodiments, the present invention
provides transdermal drug delivery systems for the transdermal
delivery of testosterone that have a smaller active surface area
than Intrinsa.RTM. but achieve daily dosages that are about equal
to or greater than the Intrinsa.RTM. products. For example, the
present invention includes transdermal drug delivery systems that
achieve daily dosages that are about equal to an Intrinsa.RTM.
product, in a smaller sized system. The ability to provide a
smaller system without sacrificing daily dosage represents a
significant advance.
[0017] Applicant surprisingly discovered that adjusting the coat
weight of the drug-containing adhesive layer could be used to
adjust the flux per unit area, and thus permitted the development
of smaller transdermal drug delivery systems that achieve
comparable daily dosages. This result is surprising because coat
weight is typically selected to control the duration of delivery,
but is not generally understood to impact delivery rate. Thus,
while it is known in the art to increase coat weight to provide
delivery over a longer period of time, it was not known that
increasing coat weight could increase delivery rate or flux, and
thus permit the development of a smaller system while maintaining
daily dosage.
[0018] Moreover, Applicant surprisingly discovered that the
drug-containing adhesive layers described herein achieve a flux per
unit area that is greater than that of the Intrinsa.RTM. product,
but with a similar amount drug per unit area. This permitted the
development of smaller transdermal drug delivery systems that
achieve comparable daily dosages. This result is surprising because
Applicant is able to achieve comparable drug delivery with less
drug.
[0019] In accordance with some aspects, there are provided
transdermal drug delivery systems and methods for the transdermal
delivery of testosterone. In specific embodiments, the systems
exhibit increased flux than other known testosterone devices (such
as Intrinsa.RTM., manufactured by Watson Pharmaceuticals Inc.) and,
therefore, exhibit increased drug delivery per unit area. For
example, in some embodiments, the systems exhibit a flux greater
than the about 0.45 .mu.g/cm.sup.2/hour exhibited by the
Intrinsa.RTM. product, such as a flux that is at least about 0.70
.mu.g/cm.sup.2/hour, including a flux that is at least 0.70
.mu.g/cm.sup.2/hour, including a flux that is at least about 0.89
.mu.g/cm.sup.2/hour, at least 0.89 .mu.g/cm.sup.2/hour, at least
about 1.0 .mu.g/cm.sup.2/hour, at least 1.0 .mu.g/cm.sup.2/hour, at
least about 1.5 .mu.g/cm.sup.2/hour, and at least 1.5
.mu.g/cm.sup.2/hour. In some embodiments, the systems described
herein achieve a flux that at least is about 0.70
.mu.g/cm.sup.2/hour, including at least 0.70 .mu.g/cm.sup.2/hour,
at least about 0.89 .mu.g/cm.sup.2/hour, at least 0.89
.mu.g/cm.sup.2/hour, at least about 1.0 .mu.g/cm.sup.2/hour, at
least 1.0 .mu.g/cm.sup.2/hour, at least about 1.5
.mu.g/cm.sup.2/hour, or at least 1.5 .mu.g/cm.sup.2/hour, over a
period of time of a least 3 days, including a period of time of 3
days, or a period of time of 4 days or longer.
[0020] In some embodiments, the systems have a lower amount of drug
per unit area than other known testosterone devices, but still
achieve effective drug delivery. For example, in some embodiments,
the systems have a coat weight such that the amount of testosterone
per unit area is less than the 0.3 mg/cm.sup.2 testosterone of the
Intrinsa.RTM. product, such as an amount of drug per unit area of
about 0.28 mg/cm.sup.2.
[0021] Thus, in accordance with some aspects, the invention permits
the use of smaller devices to achieve comparable drug delivery.
DEFINITIONS
[0022] Technical and scientific terms used herein have the meanings
commonly understood by one of ordinary skill in the art to which
the present invention pertains, unless otherwise defined. Reference
is made herein to various methodologies known to those of ordinary
skill in the art. Publications and other materials setting forth
such known methodologies to which reference is made are
incorporated herein by reference in their entireties as though set
forth in full. Any suitable materials and/or methods known to those
of ordinary skill in the art can be utilized in carrying out the
present invention. However, specific materials and methods are
described. Materials, reagents and the like to which reference is
made in the following description and examples are obtainable from
commercial sources, unless otherwise noted.
[0023] As used herein, the singular forms "a," "an," and "the"
designate both the singular and the plural, unless expressly stated
to designate the singular only.
[0024] The term "about" and the use of ranges in general, whether
or not qualified by the term about, means that the number
comprehended is not limited to the exact number set forth herein,
and is intended to refer to ranges substantially within the quoted
range while not departing from the scope of the invention. As used
herein, "about" will be understood by persons of ordinary skill in
the art and will vary to some extent on the context in which it is
used. If there are uses of the term which are not clear to persons
of ordinary skill in the art given the context in which it is used,
"about" will mean up to plus or minus 10% of the particular
term.
[0025] The phrase "substantially free" as used herein generally
means that the described composition (e.g., transdermal drug
delivery system, polymer matrix, etc.) comprises less than about
5%, less than about 3%, or less than about 1% by weight, based on
the total weight of the composition at issue, of the excluded
component.
[0026] As used herein "subject" denotes any animal in need of drug
therapy, including humans. For example, a subject may be suffering
from or at risk of developing a condition that can be treated or
prevented with testosterone, or may be taking testosterone for
health maintenance purposes.
[0027] As used herein, the phrases "therapeutically effective
amount" and "therapeutic level" mean that drug dosage or plasma
concentration in a subject, respectively, that provides the
specific pharmacological response for which the drug is
administered in a subject in need of such treatment. It is
emphasized that a therapeutically effective amount or therapeutic
level of a drug will not always be effective in treating the
conditions/diseases described herein, even though such dosage is
deemed to be a therapeutically effective amount by those of skill
in the art. For convenience only, exemplary dosages, drug delivery
amounts, therapeutically effective amounts and therapeutic levels
are provided below with reference to adult human subjects. Those
skilled in the art can adjust such amounts in accordance with
standard practices as needed to treat a specific subject and/or
condition/disease.
[0028] As used herein, "active surface area" means the surface area
of the drug-containing layer of the transdermal drug delivery
system.
[0029] As used herein, "coat weight" refers to the weight of the
drug-containing layer per unit area of the active surface area of
the transdermal drug delivery system.
[0030] As used herein, "testosterone" includes androgenic steroids
such as testosterone, testosterone acetate, testosterone enanthate,
testosterone proprionate, 17-beta-cypionate, testosterone
nicotinate, testosterone phenylacetate, and non-esters that have
groups on the 17 position, such as testosterone 17-chloral
hemiacetal.
[0031] As used herein, "flux" (also called "permeation rate") is
defined as the absorption of a drug through skin or mucosal tissue,
and is described by Fick's first law of diffusion:
J=-D(dCm/dx)
where J is the flux in g/cm.sup.2/sec, D is the diffusion
coefficient of the drug through the skin or mucosa in cm.sup.2/sec
and dCm/dx is the concentration gradient of the drug across the
skin or mucosa.
[0032] As used herein, the term "transdermal" refers to delivery,
administration or application of a drug by means of direct contact
with skin or mucosa. Such delivery, administration or application
is also known as dermal, percutaneous, transmucosal and buccal. As
used herein, "dermal" includes skin and mucosa, which includes
oral, buccal, nasal, rectal and vaginal mucosa.
[0033] As used herein, "transdermal drug delivery system" refers to
a system (e.g., a device) comprising a composition that releases
testosterone upon application to the skin (or any other surface
noted above). A transdermal drug delivery system may comprise a
drug-containing layer, and, optionally, a backing layer and/or a
release liner layer. In some embodiments, the transdermal drug
delivery system is a substantially non-aqueous, solid form, capable
of conforming to the surface with which it comes into contact, and
capable of maintaining such contact so as to facilitate topical
application without adverse physiological response, and without
being appreciably decomposed by aqueous contact during topical
application to a subject. Many such systems are known in the art
and commercially available, such as transdermal drug delivery
patches. As described below, in one embodiment, the transdermal
drug delivery system comprises a drug-containing polymer matrix
that comprises a pressure-sensitive adhesive or bioadhesive, and is
adopted for direct application to a user's (e.g., a subject's)
skin. In other embodiments, the polymer matrix is non-adhesive and
may be provided with separate adhesion means (such as a separate
adhesive layer) for application and adherence to the user's
skin.
[0034] As used herein, "polymer matrix" refers to a polymer
composition which contains one or more drugs. In some embodiments,
the matrix comprises a pressure-sensitive adhesive polymer or a
bioadhesive polymer. In other embodiments, the matrix does not
comprise a pressure-sensitive adhesive or bioadhesive. As used
herein, a polymer is an "adhesive" if it has the properties of an
adhesive per se, or if it functions as an adhesive by the addition
of tackifiers, plasticizers, crosslinking agents or other
additives. Thus, in some embodiments, the polymer matrix comprises
a pressure-sensitive adhesive polymer or a bioadhesive polymer,
with testosterone dissolved or dispersed therein. The polymer
matrix also may comprise tackifiers, plasticizers, crosslinking
agents, enhancers, co-solvents, fillers, antioxidants,
solubilizers, crystallization inhibitors, or other additives
described herein. U.S. Pat. No. 6,024,976 describes polymer blends
that are useful in accordance with the transdermal systems
described herein. The entire contents of U.S. Pat. No. 6,024,976 is
incorporated herein by reference.
[0035] As used herein, the term "pressure-sensitive adhesive"
refers to a viscoelastic material which adheres instantaneously to
most substrates with the application of very slight pressure and
remains permanently tacky. A polymer is a pressure-sensitive
adhesive within the meaning of the term as used herein if it has
the properties of a pressure-sensitive adhesive per se or functions
as a pressure-sensitive adhesive by admixture with tackifiers,
plasticizers or other additives.
[0036] The term pressure-sensitive adhesive also includes mixtures
of different polymers and mixtures of polymers, such as
polyisobutylenes (PIB), of different molecular weights, wherein
each resultant mixture is a pressure-sensitive adhesive. In the
last case, the polymers of lower molecular weight in the mixture
are not considered to be "tackifiers," said term being reserved for
additives which differ other than in molecular weight from the
polymers to which they are added.
[0037] In some embodiments, the polymer matrix is a
pressure-sensitive adhesive at room temperature and has other
desirable characteristics for adhesives used in the transdermal
drug delivery art. Such characteristics include good adherence to
skin, ability to be peeled or otherwise removed without substantial
trauma to the skin, retention of tack with aging, etc. In some
embodiments, the polymer matrix has a glass transition temperature
(T.sub.g), measured using a differential scanning calorimeter, of
between about -70.degree. C. and 0.degree. C.
[0038] As used herein, the term "rubber-based pressure-sensitive
adhesive" refers to a viscoelastic material which has the
properties of a pressure-sensitive adhesive and which contains at
least one natural or synthetic elastomeric polymer.
[0039] In some embodiments, the transdermal drug delivery system
includes one or more additional layers, such as one or more
additional polymer matrix layers, or one or more adhesive layers
that adhere the transdermal drug delivery system to the user's
skin. In other embodiments, the transdermal drug delivery system is
monolithic, meaning that it comprises a single polymer matrix layer
comprising a pressure-sensitive adhesive or bioadhesive with drug
dissolved or dispersed therein, and no rate-controlling
membrane.
[0040] The transdermal drug delivery system also may include a drug
impermeable backing layer or film. In some embodiments, the backing
layer is adjacent one face of the polymer matrix layer. When
present, the backing layer protects the polymer matrix layer (and
any other layers present) from the environment and prevents loss of
the drug and/or release of other components to the environment
during use. Materials suitable for use as backing layers are
well-known known in the art and can comprise films of polyester,
polyethylene, vinyl acetate resins, ethylene/vinyl acetate
copolymers, polyvinyl chloride, polyurethane, and the like, metal
foils, non-woven fabric, cloth and commercially available
laminates. A typical backing material has a thickness in the range
of 2 to 1000 micrometers. For example, 3M's Scotch Pak.TM. 1012 or
9732 backing material (a polyester film with an ethylene vinyl
acetate copolymer heat seal layer) is useful in the transdermal
drug delivery systems described herein.
[0041] The transdermal drug delivery system also may include a
release liner, typically located adjacent the opposite face of the
system as compared to the backing layer. When present, the release
liner is removed from the system prior to use to expose the polymer
matrix layer and/or an adhesive layer prior to topical application.
Materials suitable for use as release liners are well-known known
in the art and include the commercially available products of Dow
Corning Corporation designated Bio-Release.RTM. liner and
Syl-off.RTM. 7610 (both silicone-based) and 3M's 1020, 1022, 9744,
9748 and 9749 Scotchpak.TM. (fluoropolymer coated polyester
films).
[0042] The transdermal drug delivery system may be packaged or
provided in a package, such as a pouchstock material used in the
prior art for transdermal drug delivery systems in general or for
transdermal testosterone drug delivery systems in particular. For
example, DuPont's Surlyn.RTM. can be used in a pouchstock
material.
[0043] A used herein, a "monolithic" transdermal drug delivery
system may include a backing layer and/or release liner, and may be
provided in a package.
[0044] In accordance with some embodiments, the transdermal dug
delivery system comprises a drug-containing polymer matrix layer
that comprises a pressure-sensitive adhesive blend comprising an
acrylic polymer, a silicone polymer, and a soluble PVP.
[0045] Acrylic Polymers
[0046] The term "acrylic polymer" is used here as in the art
interchangeably with "polyacrylate," "polyacrylic polymer," and
"acrylic adhesive." The acrylic-based polymers can be any of the
homopolymers, copolymers, terpolymers, and the like of various
acrylic acids or esters. In some embodiments, the acrylic-based
polymers are adhesive polymers. In other embodiments, the
acrylic-based polymers function as an adhesive by the addition of
tackifiers, plasticizers, crosslinking agents or other
additives.
[0047] The acrylic polymer can include copolymers, terpolymers and
multipolymers. For example, the acrylic polymer can be any of the
homopolymers, copolymers, terpolymers, and the like of various
acrylic acids. In some embodiments, the acrylic polymer constitutes
from about 2% to about 95% by weight of the polymer content of the
polymer matrix, including about 3% to about 90% and about 5% to
about 85%, such as 2% to 95%, 3% to 90% and 5% to 85%. In some
embodiments, the amount and type of acrylic polymer is dependent on
the type and amount of testosterone used.
[0048] Acrylic polymers useful in practicing the invention include
polymers of one or more monomers of acrylic acids and other
copolymerizable monomers. The acrylic polymers also include
copolymers of alkyl acrylates and/or methacrylates and/or
copolymerizable secondary monomers or monomers with functional
groups. Combinations of acrylic-based polymers based on their
functional groups is also contemplated. Acrylic-based polymers
having functional groups include copolymers and terpolymers which
contain, in addition to nonfunctional monomer units, further
monomer units having free functional groups. The monomers can be
monofunctional or polyfunctional. By varying the amount of each
type of monomer added, the cohesive properties of the resulting
acrylic polymer can be changed as is known in the art. In some
embodiments, the acrylic polymer is composed of at least 50% by
weight of an acrylate or alkyl acrylate monomer, from 0 to 20% of a
functional monomer copolymerizable with the acrylate, and from 0 to
40% of other monomers.
[0049] Acrylate monomers which can be used include acrylic acid and
methacrylic acid and alkyl acrylic or methacrylic esters such as
methyl acrylate, ethyl acrylate, propyl acrylate, amyl acrylate,
butyl acrylate, butyl methacrylate, hexyl acrylate, methyl
methacrylate, hexyl methacrylate, heptyl acrylate, octyl acrylate,
nonyl acrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate,
isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate,
2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate,
dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl
methacrylate, glycidyl acrylate, and corresponding methacrylic
esters.
[0050] Non-functional acrylic-based polymers can include any
acrylic based polymer having no or substantially no free functional
groups.
[0051] Functional monomers, copolymerizable with the above alkyl
acrylates or methacrylates, which can be used include acrylic acid,
methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl
acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide,
acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl
methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl
methacrylate, methoxyethyl acrylate and methoxyethyl
methacrylate.
[0052] As used herein, "functional monomers or groups," are monomer
units typically in acrylic-based polymers which have reactive
chemical groups which modify the acrylic-based polymers directly or
which provide sites for further reactions. Examples of functional
groups include carboxyl, epoxy, hydroxyl, sulfoxyl, and amino
groups. Acrylic-based polymers having functional groups contain, in
addition to the nonfunctional monomer units described above,
further monomer units having free functional groups. The monomers
can be monofunctional or polyfunctional. These functional groups
include carboxyl groups, hydroxy groups, amino groups, amido
groups, epoxy groups, etc. Typical carboxyl functional monomers
include acrylic acid, methacrylic acid, itaconic acid, maleic acid,
and crotonic acid. Typical hydroxy functional monomers include
2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl
acrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate,
hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl
methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate,
hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl
acrylate, hydroxyhexyl methacrylate. As noted above, in some
embodiments, the acrylic polymer does not include such functional
groups.
[0053] Further details and examples of acrylic adhesives which are
suitable in the practice of the invention are described in Satas,
"Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive
Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand
Reinhold, New York (1989); "Acrylic and Methacrylic Ester
Polymers," Polymer Science and Engineering, Vol. 1, 2nd ed., pp
234-268, John Wiley & Sons, (1984); U.S. Pat. No. 4,390,520;
and U.S. Pat. No. 4,994,267, all of which are expressly
incorporated by reference in their entireties.
[0054] Suitable acrylic polymers also include pressure-sensitive
adhesives which are commercially available, such as the
acrylic-based adhesives sold under the trademarks DURO-TAK.RTM. by
National Starch and Chemical Corporation, Bridgewater, N.J. (such
as DURO-TAK.RTM. 87-2287, -4098, -2852, -2196, -2296, -2194, -2516,
-2070, -2353, -2154, -2510, -9085, -9088 and 73-9301). Other
suitable acrylic adhesives include those sold under the trademark
EUDRAGIT.RTM. by Roehm Pharma GmbH, Darmstadt, Germany, those sold
by Cytec Surface Specialties, St. Louis, Mo., under the trademarks
GELVA.RTM. Multipolymer Solution (such as GELVA.RTM. 2480, 788,
737, 263, 1430, 1753, 1151, 2450, 2495, 3067, 3071, 3087 and 3235).
For example, hydroxy functional adhesives with a reactive
functional OH group in the polymeric chain, can be used.
Non-limiting commercial examples of this type of adhesives include
both GELVA.RTM. 737, 788, and 1151, and DURO-TAK.RTM. 87-2287,
-4287, -2510 and -2516.
[0055] Silicon Polymers
[0056] The term "silicone-based" polymer is used interchangeably
with the terms silicon polymers, siloxane, polysiloxane, and
silicones as used herein and as known in the art. A suitable
silicone-based polymer may also be a pressure-sensitive adhesive.
Thus, in some embodiments, the silicone-based polymer is an
adhesive polymer. In other embodiments, the silicone-based polymer
functions as an adhesive by the addition of tackifiers,
plasticizers, crosslinking agents, or other additives.
[0057] Suitable polysiloxanes include silicone pressure-sensitive
adhesives which are based on two major components: (i) a polymer or
gum and (ii) a tackifying resin. A polysiloxane adhesive can be
prepared by cross-linking a gum, typically a high molecular weight
polydiorganosiloxane, with a resin, to produce a three-dimensional
silicate structure, via a condensation reaction in an appropriate
organic, volatile solvent, such as ethyl acetate or heptane. The
ratio of resin to polymer can be adjusted in order to modify the
physical properties of polysiloxane adhesives. Sobieski, et al.,
"Silicone Pressure Sensitive Adhesives," Handbook of
Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 508-517 (D.
Satas, ed.), Van Nostrand Reinhold, New York (1989).
[0058] Exemplary silicone-based polymers are adhesives (e.g.,
capable of sticking to the site of topical application), including
pressure-sensitive adhesives. Illustrative examples of
silicone-based polymers having reduced silanol concentrations
include silicone-based adhesives (and capped polysiloxane
adhesives) such as those described in U.S. Pat. No. Re. 35,474 and
U.S. Pat. No. 6,337,086, which are incorporated herein by reference
in their entireties, and which are commercially available from Dow
Corning Corporation (Dow Corning Corporation, Medical Products,
Midland, Mich.) as BIO-PSA.RTM. 7-4100, -4200 and -4300 product
series, and non-sensitizing, pressure-sensitive adhesives produced
with compatible organic volatile solvents (such as ethyl acetate or
heptane) and available commercially under their BIO-PSA.RTM. 7-4400
series, -4500 series, such as -4502, and -4600 series.
[0059] Further details and examples of silicone pressure-sensitive
adhesives which are useful in the polymer matrices and compositions
and methods described herein are mentioned in the following U.S.
Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767, which are
all expressly incorporated by reference herein in their entireties.
It should also be understood that silicone fluids are also
contemplated for use in the polymer matrices and methods described
herein.
[0060] In some embodiments, the polysiloxane constitutes from about
9% to about 97% of the polymer content of the polymer matrix,
including about 8% to about 97% and about 14% to about 94%, such as
9% to 97%, 8% to 97%, and 14% to 94%.
[0061] Soluble PVP
[0062] In some embodiments, the polymer matrix includes soluble
PVP. Soluble PVP has been found to be highly effective in
preventing crystallization of drugs, such as testosterone, in
adhesive-type transdermal drug delivery system. Soluble PVP also
may modulate the transdermal permeation rate of the drug.
[0063] The term "PVP" or "polyvinylpyrrolidone" refers to a
polymer, either a homopolymer or copolymer, containing
N-vinylpyrrolidone as the monomeric unit. Typical PVP polymers are
homopolymeric PVPs and the copolymer vinyl acetate
vinylpyrrolidone. The homopolymeric PVPs are known to the
pharmaceutical industry under a variety of designations including
Povidone, Polyvidone, Polyvidonum, Polyvidonum soluble, and
Poly(l-vinyl-2-pyrrolidone). The copolymer vinyl acetate
vinylpyrrolidone is known to the pharmaceutical industry as
Copolyvidon, Copolyvidone, and Copolyvidonum. The term "soluble"
when used with reference to PVP means that the polymer is soluble
in water and generally is not substantially cross-linked, and has a
molecular weight of less than about 2,000,000. See, generally,
Buhler, KOLLIDON.RTM.: POLYVINYLPRYRROLIDONE FOR THE PHARMACEUTICAL
INDUSTRY, BASF Aktiengesellschaft (1992).
[0064] The amount and type of soluble PVP used may depend on the
quantity and type of testosterone present, as well as the type of
adhesive, but can be readily determined through routine
experimentation. Typically, the PVP is present in an amount from
about 1% to about 20% by weight, preferably from about 5% to about
15% by weight, based on the total weight of the polymer matrix.
However, the amount of PVP can be higher than 20% for example, up
to 40%, depending on the particular drug used and on the desired
properties of the blend. The soluble PVP may have a molecular
weight of about 2,000 to 1,100,000, including 5,000 to 100,000, and
7,000 to 54,000. In some embodiments, the soluble PVP has a
molecular weight of from about 17,000 to about 90,000, such as from
about 17,000 to about 60,000, including from 17,000 to 90,000 and
from 17,000 to 60,000.
[0065] In some embodiments, the polymer matrix comprises a soluble
PVP with a rubber-based pressure-sensitive adhesive and a
polyacrylate polymer, such as a blend of an acrylic polymer, a
polysiloxane and a soluble PVP. In some embodiments, the blend is
chosen to affect the rate of drug delivery. More specifically, a
plurality of polymers including a soluble polyvinylpyrrolidone,
which may have different solubility parameters for the drug and
which may be immiscible with each other, may be selected to adjust
the solubility of the drug in the polymer matrix, thereby
controlling the maximum concentration of the drug in the system,
and modulating drug delivery through the dermis.
[0066] The amount of acrylic-based polymer and silicone-based
polymer can be adjusted so as to modify the saturation
concentration of the drug in the polymer matrix in order to affect
the rate of delivery of the drug from the system and through the
skin. In some embodiments, the acrylic-based polymer and
silicone-based polymer are used in a weight ratio of from about
2:98 to about 96:4, including about 2:98 to about 90:10 and 2:98 to
about 86:14, such as 2:98 to 96:4, 2:98 to 90:10 and 2:98 to
86:14.
[0067] The concentration by weight of the testosterone in the
transdermal drug delivery system is typically about 0.1 to about
50%, including about 0.1 to about 40% and about 0.3 to about 30%,
such as 0.1 to 50%, 0.1 to 40% and 0.3 to 30%, all based on the
total weight of the polymer matrix. In some embodiments, the
testosterone is testosterone, and is present at an amount of from
about 0.1 to 10%, including from about 0.1 to about 5%, such as
from 0.1 to 10% and 0.1 to 5%, all based on the total dry weight of
the polymer matrix. Irrespective of whether there is high-loading
or low-loading of the testosterone into the transdermal drug
delivery system, the pressure-sensitive adhesive composition can be
formulated to maintain acceptable shear, tack, and peel adhesive
properties.
[0068] Stabilizers
[0069] In some embodiments, the polymer matrix comprises a
stabilizer that stabilizes the testosterone. For example,
testosterone can be formulated with an antioxidant such as
butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbyl
palmitate, alpha-tocopherol and its esters, citric acid and propyl
gallate, and mixtures thereof. In some embodiments, a stabilizer
may be used in an amount of about 0.001 to about 0.1% by weight,
including about 0.01% by weight, such as 0.01% by weight, based on
the dry weight of the polymer matrix.
[0070] Other Components
[0071] In one embodiment, the polymer matrix comprises a
penetration enhancer. A "penetration enhancer" is an agent known to
accelerate the delivery of the drug through the skin. These agents
also have been referred to as accelerants, adjuvants, and sorption
promoters, and are collectively referred to herein as "enhancers."
This class of agents includes those with diverse mechanisms of
action, including those which have the function of improving
percutaneous absorption, for example, by changing the ability of
the stratum corneum to retain moisture, softening the skin,
improving the skin's permeability, acting as penetration assistants
or hair-follicle openers or changing the state of the skin
including the boundary layer.
[0072] Illustrative penetration enhancers include but are not
limited to polyhydric alcohols such as dipropylene glycol,
propylene glycol, and polyethylene glycol; oils such as olive oil,
squalene, and lanolin; fatty ethers such as cetyl ether and oleyl
ether; fatty acid esters such as isopropyl myristate; urea and urea
derivatives such as allantoin which affect the ability of keratin
to retain moisture; polar solvents such as
dimethyidecylphosphoxide, methyloctylsulfoxide,
dimethyllaurylamide, dodecylpyrrolidone, isosorbitol,
dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, and
dimethylformamide which affect keratin permeability; salicylic acid
which softens the keratin; amino acids which are penetration
assistants; benzyl nicotinate which is a hair follicle opener; and
higher molecular weight aliphatic surfactants such as lauryl
sulfate salts which change the surface state of the skin and drugs
administered. Other agents include oleic and linoleic acids,
ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol,
tocopheryl acetate, tocopheryl linoleate, propyl oleate, and
isopropyl palmitate.
[0073] In one embodiment, the penetration enhancer is oleyl
alcohol. In another embodiment, the penetration enhancer is a
glycol, such as dipropylene glycol, propylene glycol, butylene
glycol or polyethylene glycol. In other embodiments, the
penetration enhancer comprises a mixture of at least two
penetration enhancers. For example, a penetration enhancer may
comprise oleyl alcohol and one or more polyhydric alcohols, such as
glycerine, dipropylene glycol, butylene glycol, propylene glycol.
For instance, the penetration enhancer may include oleyl alcohol
and dipropylene glycol.
[0074] In some embodiments, a penetration enhancer is used in an
amount up to about 30% by dry weight of the polymer matrix,
including up to 30% by weight, up to about 20% by weight, including
20% by weight, or up to about 10% by weight, up to 10% by weight,
or up to 5% by weight, including up to 5% by weight, based on the
dry weight of the polymer matrix. In some embodiments, a
penetration enhancer is used in an amount of from about 5% to about
15%, such as from 5% to 15%. In specific embodiments, the
penetration enhancer comprises a mixture of oleyl alcohol and
dipropylene glycol which together amount to about 14% by weight of
the polymer matrix. The polymer matrix may further comprise various
thickeners, fillers, and other additives or components known for
use in transdermal drug delivery systems.
[0075] The amount of testosterone to be incorporated in the polymer
matrix varies depending on the particular drug, the desired
therapeutic effect, and the time span for which the system is to
provide therapy. For most drugs, the passage of the drugs through
the skin will be the rate-limiting step in delivery. A minimum
amount of drug in the system is selected based on the amount of
drug which passes through the skin in the time span for which the
system is to provide therapy. In some embodiments, a system for the
transdermal delivery of testosterone is used over a period of about
1 day, about 3 days, about 7 days, or longer. Thus, in one
embodiment, the systems comprise an amount of drug (e.g.,
testosterone) sufficient to deliver therapeutically effective
amounts of drug over a period of from 1 day to 3 days, 7 days, or
longer, including for 1 day, for 2 days, for 3 days, for 4 days,
for 5 days, for 6 days, for 7 days, or for longer.
[0076] In some embodiments, a therapeutically effective amount of
testosterone delivered by the composition is from about 100 to
about 500 .mu.g/day, including 100-500 .mu.g/day and 100-450
.mu.g/day, and further including at least about 300 .mu.g/day,
including 300 .mu.g/day. Thus, in some embodiments, the transdermal
drug delivery system comprises an amount of testosterone effective
to achieve a delivery of from about 100 to about 500 .mu.g/day,
including 100-500 .mu.g/day or 100-450 .mu.g/day, or at least about
300 .mu.g/day, including 300 .mu.g/day. As noted above, in some
embodiments, these rates are achieved over a duration of
application of at least about 1 day, including at least about 3
days and at least about 7 days, such as at least 1 day, at least 2
days, at least 3 days, at least 4 days, at least 5 days, at least 6
days, and at least 7 days.
[0077] In some embodiments, the transdermal drug delivery system
comprises a smaller amount of testosterone than an Intrinsa.RTM.
product, but achieves comparable drug delivery. For example, in
some embodiments a transdermal drug delivery system according to
the invention may contain about 4 mg, including 3.94 mg,
testosterone in a 14 cm.sup.2 device, and achieve drug delivery
comparable to an Intrinsa.RTM. product that contains about 8 mg,
including 8.4 mg, testosterone in a 28 cm.sup.2 device.
[0078] In some embodiments, the system comprises a polymer matrix
comprising an amount of acrylic-based polymer of about 1 to about
70% by weight, including about 2 to about 25% by weight, based on
the dry weight of the polymer matrix, such as 2-25% by weight
acrylic-based polymer.
[0079] In some embodiments, the system comprises a polymer matrix
comprising an amount of silicone polymer of about 5 to about 70% by
weight, including about 45 to about 70% by weight, based on the dry
weight of the polymer matrix, such as 45-70% by weight silicone
polymer.
[0080] In some embodiments, the system comprises a polymer matrix
comprising an amount of soluble PVP of about 1 to about 30% by
weight, including about 2 to about 25% by weight, based on the dry
weight of the polymer matrix, such as 2-25% by weight soluble
PVP.
[0081] In some embodiments, the system comprises a polymer matrix
comprising an amount of oleyl alcohol of about 1 to about 10% by
weight, including about 4 to about 8% by weight, based on the dry
weight of the polymer matrix, such as 4-8% by weight oleyl
alcohol.
[0082] In some embodiments, the system comprises a polymer matrix
comprising an amount of dipropylene glycol of about 1 to about 10%
by weight, including about 5 to about 10% by weight, based on the
dry weight of the polymer matrix, such as 5-10% by weight
dipropylene glycol.
[0083] In some embodiments, the system comprises a polymer matrix
comprising an amount of an antioxidant, such as butylhydroxytoluene
(BHT), of about 0.001 to about 0.1% by weight, including about
0.01% by weight, based on the dry weight of the polymer matrix,
such as 0.01% by weight butylhydroxytoluene (BHT).
[0084] In some embodiments, the polymer matrix comprises about
2-25% by weight acrylic adhesive, about 45-70% by weight silicone
adhesive, about 2-25% by weight soluble PVP, about 0-15%
penetration enhancer, and about 0.1-10% by weight testosterone,
and, optionally, about 0.001 to about 0.1% by weight
butylhydroxytoluene (BHT), all based on the dry weight of the
polymer matrix. In specific embodiments, the polymer matrix
comprises about 20% by weight acrylic adhesive, about 59% by weight
silicone adhesive, about 12% by weight soluble PVP, about 6% by
weight oleyl alcohol, about 2-3% by weight testosterone and,
optionally, about 0.01% by weight butylhydroxytoluene (BHT).
[0085] In some embodiments, the acrylic adhesive and silicone
adhesive are present in a ratio of from about 1:2 up to less than
about 1:7, such as up to about 1:6, based on the weight of the
acrylic and silicone adhesives. For example, in some embodiments,
the acrylic adhesive and silicone adhesive are present in a ratio
of about 1:2, 1:3, 1:4, 1:5 or 1:6, based on the weight of the
acrylic and silicone adhesives. In specific embodiments, the
acrylic adhesive and silicone adhesive are present in a ratio of
1:2.8, based on the weight of the acrylic and silicone
adhesives.
[0086] As noted above, in embodiments where the polymer matrix
comprises a pressure-sensitive adhesive or bioadhesive, the polymer
matrix can serve as an adhesive portion of the system (e.g., a
reservoir device), or can serve as one or more layers of a
multi-layer system. Alternatively, a polymer matrix comprising a
pressure-sensitive adhesive or bioadhesive with drug dissolved or
dispersed therein can constitute a monolithic device. In
embodiments where the polymer matrix does not comprise an adhesive,
but instead, for example, comprises a polymeric drug reservoir, it
can be used in combination with one or more adhesive layers, or
with a surrounding adhesive portion, as is well known to those
skilled in the art.
[0087] In some embodiments, the system consists essentially of the
polymer matrix layer. By "consists essentially of the polymer
matrix layer" means that the system does not contain any other
layers that affect drug delivery, such as an additional
rate-controlling polymer layer, rate-controlling membrane, or drug
reservoir layer. It will be understood, however, that the system
that consists essentially of the polymer matrix layer may comprise
a backing layer and/or release liner.
[0088] As discussed above, in some embodiments, the systems have a
greater flux than other known testosterone devices for use by
females (such as Intrinsa.RTM., manufactured by Watson
Pharmaceuticals Inc.), and, therefore, exhibit increased drug
delivery per unit area of the active surface area. For example, in
some embodiments, the systems exhibit a flux greater than the about
0.45 .mu.g/cm.sup.2/hour exhibited by the Intrinsa.RTM. product,
such as a flux that is about double, such as a flux of about 0.89
.mu.g/cm.sup.2/hour. In some embodiments, the systems described
herein achieve a flux that is at least about 0.7
.mu.g/cm.sup.2/hour, including at least 0.7 .mu.g/cm.sup.2/hour,
including at least about 0.89 .mu.g/cm.sup.2/hour and at least 0.89
.mu.g/cm.sup.2/hour, or at least about 1.0 .mu.g/cm.sup.2/hour,
including at least 1.0 .mu.g/cm.sup.2/hour, over a period of time
of at least about 1 day, including at least about 3 days and at
least about 7 days, such as at least 1 day, at least 2 days, at
least 3 days, at least 4 days, at least 5 days, at least 6 days,
and at least 7 days.
[0089] In some embodiments, the systems have a different coat
weight than other known testosterone devices. In some embodiments,
the polymer matrix has a coat weight of greater than about 10
mg/cm.sup.2. In some embodiments, the polymer matrix has a coat
weight selected from the group consisting of about 12.0, about
12.5, about 13.0 and about 15 mg/cm.sup.2.
[0090] In some embodiments, the systems have an amount of
testosterone per unit area of the active surface area that is less
than the 0.3 mg/cm.sup.2 testosterone of the Intrinsa.RTM. product,
such as an amount of testosterone of about 0.28 mg/cm.sup.2.
[0091] The system may be of any shape or size suitable for
transdermal application. In some embodiments, the systems are
smaller than the Intrinsa.RTM. product, but achieve comparable
daily dosages. For example, the systems may have an active surface
area of 50% of the active surface area of an Intrinsa product, such
as about 50% of 28 cm.sup.2, and deliver a daily dosage of
testosterone comparable to that of the Intrinsa.RTM. product, such
as an amount of testosterone of at least about 300 .mu.g/day. In
one embodiment, the system has an active surface area of about 14
cm.sup.2 and delivers a daily dosage of testosterone comparable to
that of the 28 cm.sup.2 Intrinsa.RTM. product, e.g., about 300
.mu.g/day.
[0092] The polymer matrices described herein may be prepared by
methods known in the art. The polymer matrices can be formed into
systems by methods known in the art. For example, the polymer
matrix material can be applied to a backing layer and release liner
by methods known in the art, and formed into sizes and shapes
suitable for use.
[0093] For example, after the polymer matrix is formed, it may be
brought into contact with a support layer, such a releaser liner
layer or backing layer, in any manner known to those of skill in
the art. Such techniques include calender coating, hot melt
coating, solution coating, etc.
[0094] For example, a polymer matrix can be prepared by blending
the components of the polymer matrix, applying the matrix material
to a support layer such as a backing layer or release liner, and
removing any remaining solvents. The testosterone can be added at
any stage. In one embodiment, all polymer matrix components,
including testosterone, are blended together. In another
embodiment, the polymer matrix components other than testosterone
are blended together, and then the testosterone is dissolved or
dispersed therein. The order of steps, amount of ingredients, and
the amount and time of agitation or mixing can be determined and
optimized by the skilled practitioner. An exemplary general method
is as follows:
[0095] Appropriate amounts of soluble PVP, solvent(s), enhancer(s),
and organic solvent(s) (for example toluene, or ethyl acetate an/or
isopropyl alcohol) are combined and thoroughly mixed together in a
vessel.
[0096] Testosterone and any antioxidant being used (such as BHT)
are added to the mixture and agitation is carried out until the
drug is uniformly mixed in.
[0097] Appropriate amounts of polysiloxane and acrylic polymer are
then added to the drug mixture, and thoroughly mixed.
[0098] The formulation is then transferred to a coating operation
where it is coated onto a protective release liner at a controlled
specified thickness. The coated product is then passed through an
oven in order to drive off all volatile processing solvents.
[0099] The dried product on the release liner is then joined to the
backing material and wound into rolls for storage.
[0100] Appropriate size and shape "systems" are die-cut from the
roll material and then pouched.
[0101] Other manufacturing methods are known in the art that are
suitable for making the systems described herein.
[0102] In some embodiments, there is provided a method of effecting
transdermal drug delivery of testosterone, such as testosterone, by
applying a system as described herein to the skin or mucosa of a
subject in need thereof. In some embodiments, the system comprises
testosterone, and the system is applied over a period of at least
about 1 day, at least about 2 days, at least about 3 days, at least
about 4 days, at least about 5 days, at least about 6 days, or at
least about 7 days, such as for 1, 2, 3, 4, 5, 6 or 7 days. In some
embodiments, the method is effective to achieve therapeutic levels
of testosterone in the subject during the application period. As
noted above, a typical testosterone dosage ranges from at least
about 100 to about 500 .mu.g/day, including 100-500 .mu.g/day and
100-450 .mu.g/day, including at least about 300 .mu.g/day,
including 300 .mu.g/day.
[0103] In some embodiments, the systems described herein are
designed for use by female patients, including female patients
undergoing testosterone therapy for congestive heart failure. In
other embodiments, the systems described herein are designed for
use by female patients undergoing hormone replacement therapy or
therapy to improve their libido. In some embodiments, the systems
described herein may be designed are adapted for use by male
patients.
[0104] The following specific examples are included as illustrative
of the transdermal drug delivery systems and polymer matrices
described herein. These example are in no way intended to limit the
scope of the invention. Other aspects of the invention will be
apparent to those skilled in the art to which the invention
pertains.
Example 1
[0105] A polymer matrix with the following composition is
prepared:
TABLE-US-00001 % w/w in Finished Ingredient Dry Product Silicone
polymer 59.74 (BIO PSA 4502) Acrylic polymer (Gelva 788) 20.00 PVP
(Povidone 30) 12.00 Oleyl Alcohol 6.00 Butylated Hydroxytoluene
0.01 Testosterone USP, CIII 2.25 Total 100.00
[0106] The polymer matrix is applied with a coat weight of 12.5
mg/cm.sup.2 to a Scotch Pak.TM. 1022 release liner, and Scotch
Pak.TM. 9732 (polyethylene) backing material is applied. Individual
systems with an active surface area of 14 cm.sup.2 are prepared.
The systems are packaged in Surlyn.RTM. 0.0007 pouchstock
material.
[0107] Human cadaver skin permeation studies are performed to
quantitatively determine the effective permeation through the
stratum corneum. The stratum corneum is obtained from split
thickness, cryo-preserved cadaver skin by the heat separation
technique. Samples of 5/16'' diameter are cut from the laminate, in
quadruplicate, and mounted onto 1/2'' cut pieces of the stratum
corneum. These samples are place on modified Franz diffusion cells.
The receptor is filled with 7.5 mL of 0.9% NaCl and 0.01% NaN.sub.3
in deionized water. The cells are maintained at a constant
32.degree. C. and magnetically stirred at approximately 300 rpm. At
specified time points, samples of the receptor phase are taken with
complete replacement of the receptor phase. These samples are
quantified by high-performance liquid chromatography (HPLC)
utilizing Waters HPLC instrumentation. C-8 (15 cm.times.4.6 mm) 5
.mu.m particle size columns (HYPERSIL made by MetaChem
Technologies, Inc., Torrance, Calif.) are used at 50.degree. C.
(column temperature).
[0108] FIG. 1 illustrates the testosterone flux (.mu.g/cm.sup.2/hr)
over time (0-96 hours) from a transdermal delivery system according
to the invention ( , top line), as compared to Intrinsa.RTM.
(.diamond-solid., bottom line).
[0109] FIG. 2 illustrates the cumulative amount of drug delivered
per unit area (.mu.g/cm.sup.2) over time (0-96 hours) from a
transdermal delivery system according to the invention ( , top
line), as compared to Intrinsa.RTM. (.diamond-solid., bottom
line).
[0110] The results show that the system according to the invention
achieves a greater flux than the Intrinsa.RTM. product and is able
to achieve therapeutic daily dosages (such as at least 300
.mu.g/day over three to four days) despite its significantly
smaller size.
* * * * *