U.S. patent application number 10/795584 was filed with the patent office on 2005-09-15 for transdermal systems containing multilayer adhesive matrices to modify drug delivery.
This patent application is currently assigned to Mylan Technologies, Inc.. Invention is credited to Jackson, Kristin, Miller, Kenneth James II.
Application Number | 20050202073 10/795584 |
Document ID | / |
Family ID | 34919791 |
Filed Date | 2005-09-15 |
United States Patent
Application |
20050202073 |
Kind Code |
A1 |
Jackson, Kristin ; et
al. |
September 15, 2005 |
Transdermal systems containing multilayer adhesive matrices to
modify drug delivery
Abstract
A transdermal drug-containing dosage unit comprises: a backing
layer substantially impervious to the drug to be delivered
transdermally; a first polymeric adhesive matrix, in contact with
the backing layer, having dispersed therein the drug and having a
first delivery profile of the drug; a second polymeric adhesive
matrix, in contact with said first polymeric adhesive matrix,
having dispersed therein the drug and having a second delivery
profile of the drug, wherein said second delivery profile is
different from said first delivery profile; and a release liner in
contact with the second polymeric adhesive matrix. The first
polymeric adhesive matrix can release the drug more quickly or more
slowly than the second polymeric adhesive matrix. Through the
selection of the two matrices, the delivery profile of the drug
through the skin can be selectively modified and controlled.
Inventors: |
Jackson, Kristin; (Enosburg
Falls, VT) ; Miller, Kenneth James II; (St. Albans,
VT) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W.
SUITE 800
WASHINGTON
DC
20005
US
|
Assignee: |
Mylan Technologies, Inc.
St. Albans
VT
|
Family ID: |
34919791 |
Appl. No.: |
10/795584 |
Filed: |
March 9, 2004 |
Current U.S.
Class: |
424/449 |
Current CPC
Class: |
A61F 13/00 20130101;
A61F 2013/0071 20130101; A61K 9/7092 20130101; Y10T 156/10
20150115; A61M 37/00 20130101; A61F 2013/00906 20130101; A61P 5/24
20180101; A61F 2013/00655 20130101; A61K 31/567 20130101; A61F
2013/00646 20130101; A61K 31/565 20130101; A61P 5/34 20180101; A61K
9/0014 20130101; A61P 5/30 20180101; A61K 9/7053 20130101; A61K
9/7061 20130101 |
Class at
Publication: |
424/449 |
International
Class: |
A61K 009/70 |
Claims
1. A transdermal drug-containing dosage unit which comprises: a) a
backing layer substantially impervious to the drug to be delivered
transdermally; b) a first polymeric adhesive matrix, in at least
partial contact with the backing layer, having dispersed therein
the drug and having a first initial rate of delivery of the drug;
c) a second polymeric adhesive matrix, in at least partial contact
with said first polymeric adhesive matrix, having dispersed therein
the drug and having a second initial rate of delivery of the drug,
wherein said second initial rate of delivery is different from said
first initial rate of delivery; and d) a release liner in at least
partial contact with the second polymeric adhesive matrix.
2. The transdermal drug-containing dosage unit of claim 1, wherein
said first polymeric adhesive matrix delivers said drug more slowly
than said second polymeric adhesive matrix.
3. The transdermal drug-containing dosage unit of claim 1, wherein
said second polymeric adhesive matrix delivers said drug more
slowly than said first polymeric adhesive matrix.
4. The transdermal drug-containing dosage unit of claim 1, wherein
one of said first and second adhesive matrices has an initial
delivery rate of a given amount of said drug that is at least about
10% faster than that of the other of said adhesive matrices.
5. The transdermal drug-containing dosage unit of claim 1, wherein
either said first or said second polymeric adhesive matrix
comprises an acrylic adhesive.
6. The transdermal drug-containing dosage unit of claim 1, wherein
said first adhesive matrix comprises an acrylic adhesive and said
second adhesive matrix comprises a silicone adhesive.
7. The transdermal drug-containing dosage unit of claim 1, wherein
said first adhesive matrix comprises an acrylic adhesive and said
second adhesive matrix comprises a polyisobutylene adhesive.
8. The transdermal drug-containing dosage unit of claim 6, wherein
said silicone adhesive comprises a standard silicone adhesive or an
amine compatible silicone adhesive.
9. The transdermal drug-containing dosage unit of claim 7, wherein
said polyisobutylene adhesive comprises a mixture of a high
molecular weight polyisobutylene having a molecular weight of at
least 1,000,000 and a low molecular weight polyisobutylene having a
molecular weight of at least about 100 but less than 1,000,000.
10. The transdermal drug-containing dosage unit of claim 9, wherein
said high molecular weight polyisobutylene comprises between about
20% and 80% by weight of the total polyisobutylene and said low
molecular weight polyisobutylene comprises between about 20% and
80% by weight of the total polyisobutylene.
11. The transdermal drug-containing dosage unit of claim 6 or 7,
wherein said acrylic adhesive comprises polymers of acrylic acid,
methacrylic acid, N-butyl acrylate, n-butyl methacrylate, hexyl
acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl
acrylate, 2-ethylhexyl methacrylate, decyl acrylate,
decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl
acrylate, or tridecyl methacrylate.
12. The transdermal drug-containing dosage unit of claim 6 or 7,
wherein said acrylic adhesive comprises a crosslinked carboxyl
functional acrylic adhesive, non-crosslinked carboxyl functional
acrylic adhesive, a crosslinked hydroxyl functional adhesive, a
non-crosslinked hydroxyl functional adhesive, a grafted adhesive or
a non-functional adhesive.
13. The transdermal drug-containing dosage unit of claim 1, which
further comprises at least one additional drug-containing polymeric
adhesive matrix in between said first and second polymeric adhesive
matrices.
14. A transdermal drug-containing dosage unit which comprises: a) a
backing layer substantially impervious to the drug to be delivered
transdermally; b) a first polymeric adhesive matrix, in at least
partial contact with the backing layer, having dispersed therein
the drug and having a first initial rate of delivery of the drug;
c) a second polymeric adhesive matrix, in at least partial contact
with the first adhesive matrix, having dispersed therein the drug
and having a second initial rate of delivery of the drug; d) a
third polymeric adhesive matrix, in at least partial contact with
the second adhesive matrix, having dispersed therein the drug and
having a third initial rate of delivery of the drug; and e) a
release liner in at least partial contact with the third polymeric
adhesive matrix; wherein said initial rates of delivery of at least
two of said matrices are different from one another.
15. The transdermal drug-containing dosage unit of claim 14, which
further comprises at least one additional drug-containing polymeric
adhesive matrix in between said first and second polymeric adhesive
matrices.
16. The transdermal drug-containing dosage unit of claim 14,
wherein each of said first, second and third initial rates of
delivery is different from said other initial rates of
delivery.
17. The transdermal drug-containing dosage unit of claim 14,
wherein either said first and third adhesive matrices or said
second adhesive matrix comprises an acrylic adhesive.
18. The transdermal drug-containing dosage unit of claim 17,
wherein said matrix or matrices which does (do) not comprise an
acrylic adhesive comprise(s) a silicone adhesive or a
polyisobutylene adhesive.
19. The transdermal drug-containing dosage unit of claim 16,
wherein one matrix comprises an acrylic adhesive, one matrix
comprises a polyisobutylene adhesive and one matrix comprises a
silicone adhesive.
20. The transdermal drug-containing dosage unit of claim 1, 13 or
14, wherein said drug comprises a cardiovascular drug, an
androgenic steroid, an estrogen, a progestational agent, a drug
which acts on the central nervous system, a nutritional agent, an
anti-inflammatory agent, an antihistamine, a miotic, a
dermatological agent, an anti-spasmodic, an anti-depressant, an
anti-cancer drug, an anti-diabetic, an anti-estrogen, an
anti-psychotic, an anti-infective agent, an anti-allergenic, an
anti-pyretic, an anti-migraine agent or a tranquilizer.
21. The transdermal drug-containing dosage unit of claim 1 or 14,
wherein said drug comprises an estrogen or a combination of an
estrogen and a progestin.
22. The transdermal drug-containing dosage unit of claim 21,
wherein said estrogen comprises estradiol or mono- or di-esters
thereof which are transdermally absorbable.
23. The transdermal drug-containing dosage unit of claim 21,
wherein said progestin comprises norethindrone acetate or
levonorgestrel.
24. A transdermal drug-containing dosage unit which comprises: a) a
backing layer substantially impervious to the drug to be delivered
transdermally; b) a first polymeric adhesive matrix, in at least
partial contact with the backing layer; c) a second polymeric
adhesive matrix, in at least partial contact with said first
polymeric adhesive matrix; and d) a release liner in at least
partial contact with the second polymeric adhesive matrix, wherein
a drug to be delivered transdermally is initially suspended or
dispersed within at least one of said first and second adhesive
matrices and wherein if said drug is suspended or dispersed within
both of said first and second adhesive matrices, said drug is
initially delivered from said first adhesive matrix at a rate which
is different from the initial rate of delivery of said second
adhesive matrix.
25. The transdermal drug-containing dosage unit of claim 1, 13 or
14 which comprises from about 0.05% to about 40% w/w of drug.
26. The transdermal drug-containing dosage unit of claim 25, which
comprises from about 0.1% to about 4.0% w/w of drug.
27. The transdermal drug-containing dosage unit of claim 21, which
comprises from about 0.1% to about 4.0% of said estrogen.
28. The transdermal drug-containing dosage unit of claim 27, which
further comprises from about 0.1% to about 20% of a progestin.
29. A method for administering a drug transdermally to an
individual in need of such administration, comprising applying to
skin of the individual a transdermal dosage unit comprising: a) a
backing layer substantially impervious to the drug to be delivered
transdermally; b) a first polymeric adhesive matrix, in at least
partial contact with the backing layer, having dispersed therein
the drug and having a first initial rate of delivery of the drug;
and c) a second polymeric adhesive matrix, in at least partial
contact with said first polymeric adhesive matrix, having dispersed
therein the drug and having a second initial rate of delivery of
the drug, wherein said second rate of delivery is different from
said first rate of delivery.
30. The method of claim 27, wherein the dosage unit further
comprises at least one additional drug-containing polymeric
adhesive matrix in between said first and second polymeric adhesive
matrices.
31. A method for administering a drug transdermally to an
individual in need of such administration, comprising applying to
skin of the individual a transdermal dosage unit comprising: a) a
backing layer substantially impervious to the drug to be delivered
transdermally; b) a first polymeric adhesive matrix, in at least
partial contact with the backing layer, having dispersed therein
the drug and having a first initial rate of delivery of the drug;
c) a second polymeric adhesive matrix, in at least partial contact
with the first adhesive matrix, having dispersed therein the drug
and having a second initial rate of delivery of the drug; and d) a
third polymeric adhesive matrix, in at least partial contact with
the second adhesive matrix, having dispersed therein the drug and
having a third initial rate of delivery of the drug.
32. The method of claim 31, wherein at least two of said initial
rates of delivery are different from one another.
33. The method of claim 31, wherein each of said initial rates of
delivery is different from the others.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to transdermal, pressure sensitive,
adhesive delivery systems for the delivery of an agent, such as a
drug, through the skin. More specifically, this invention is
directed to such systems which comprise multilayer adhesive
matrices.
[0002] A well-known method of delivering certain drugs in a
controlled manner over time is through the use of a transdermal
composition, such as a pressure sensitive adhesive containing the
drug. Known delivery systems involve the incorporation of the
desired drug into a carrier, such as a polymeric matrix and/or
pressure sensitive adhesive formulation. Problems encountered with
such delivery systems have included insufficient control over the
rate and duration of the transdermal absorption, and a variety of
compositions have been developed in efforts to maximize control of
the release of a desired drug and the efficacy of the delivery
unit.
[0003] Although a number of commercially useful transdermal
delivery systems have been produced, further improvements are
sought.
SUMMARY OF THE INVENTION
[0004] In accordance with the present invention, a transdermal
drug-containing dosage unit comprises:
[0005] a) a backing layer substantially impervious to the drug to
be delivered transdermally;
[0006] b) a first polymeric adhesive matrix, in contact with at
least a portion of the backing layer, having dispersed therein the
drug and having a first initial delivery profile of the drug;
[0007] c) a second polymeric adhesive matrix, in contact with at
least a portion of said first polymeric adhesive matrix, having
dispersed therein the drug and having a second delivery profile of
the drug, wherein said second delivery profile is different from
said first delivery profile; and
[0008] d) a removable release liner in contact with at least a
portion of the second polymeric adhesive matrix.
[0009] The invention further comprises a method for administering a
drug transdermally to an individual in need of such administration,
comprising applying to the skin of the individual a transdermal
dosage unit comprising:
[0010] a) a backing layer substantially impervious to the drug to
be delivered transdermally;
[0011] b) a first polymeric adhesive matrix, in contact with at
least a portion of the backing layer, having dispersed therein the
drug and having a first initial delivery profile of the drug;
and
[0012] c) a second polymeric adhesive matrix, in contact with at
least a portion of said first polymeric adhesive matrix, having
dispersed therein the drug and having a second delivery profile of
the drug, wherein said second delivery profile is different from
said first delivery profile.
[0013] The first polymeric adhesive matrix can release the drug
more quickly or more slowly than the second polymeric adhesive
matrix. Through the selection of the two matrices, the delivery
profile of the drug through the skin can be selectively modified
and controlled to an extent not possible with delivery devices
which comprise only a single adhesive matrix.
[0014] If desired, the compositions further can contain or employ
other ingredients known for use in pressure sensitive adhesives,
including crosslinking agents, plasticizers, tackifiers, fillers,
anti-oxidants and excipients or penetration enhancers.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 is a graph showing the transdermal flux (rate of
delivery) of three matrices, including a bi-layer matrix in
accordance with this invention.
[0016] FIG. 2 is a graph showing the cumulative delivery of the
three matrices of FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
[0017] This invention is directed to dermal compositions suitable
for the delivery of a drug through the skin. The compositions allow
for very controlled delivery of the drug through the unique
combination of two or more different adhesive matrices which can be
selected and layered to provide a desired drug delivery
profile.
[0018] Specifically, compositions of the present invention
comprise:
[0019] a) a backing layer substantially impervious to the drug to
be delivered transdermally;
[0020] b) a first polymeric adhesive matrix, in contact with at
least a portion of the backing layer, having dispersed therein the
drug and having a first delivery profile of the drug;
[0021] c) a second polymeric adhesive matrix, in contact with a
portion of said first polymeric adhesive matrix, having dispersed
therein the drug and having a second delivery profile of the drug;
and
[0022] d) a removable release liner in contact with at least a
portion of the second polymeric adhesive matrix.
[0023] The first and second polymeric adhesive matrices in a two
matric composition also will be referred to as the anchor adhesive
layer and the skin contact adhesive layer, respectively. They are
selected such that there is a significant difference in the rate of
drug delivery from each layer. In addition, the two adhesives also
can be selected such that there is a significant difference in one
or more other physical characteristics, such as the solubility,
miscibility or stability of the drug or desired excipients, in each
of the two layers, which can further affect the delivery of the
drug from the composition and through the skin of the person
wearing the composition. As used herein, "significant difference"
means a difference in drug delivery of at least about 10%-100%,
preferably at least about 15%-60%, between the two adhesive
matrices or layers. The desired difference in drug delivery rates
between the two layers can be achieved simply through the selection
of the two adhesive matrices or through the selection of the
adhesive for each matrix in combination with the choice of relative
thickness of each layer.
[0024] The first and second adhesive matrices can be selected such
that the rate of drug delivery initially is faster from the second
matrix, or skin contact layer, than it is from the first matrix, or
anchor layer. In such instances, there will be an initial burst, or
spike, of drug delivered through the skin of the wearer, followed
by a slower and more steady release of the drug. Alternatively, the
adhesive matrices can be selected such that the rate of drug
delivery initially is faster from the first matrix, or anchor
layer, than it is from the second matrix, or skin contact layer.
Such a system allows for the tuning of the delivery profile
depending upon the thickness of the two layers. Specifically, the
slower delivering adhesive layer contacting the skin controls the
delivery through the skin and modulates the faster delivering
adhesive layer's tendency to deliver the drug rapidly. In such
instances, there will be a continuous drug delivery, perhaps with a
"burst" in delivery at a specific time post-application, depending
upon the thickness and composition of the matrices and the drug
concentration. For instance, the burst could be accounted for by a
release of drug and components by the anchor layer having a driving
force so great as to overcome any rate limiting properties that the
skin contact layer may have. Such a release pattern is useful, for
example, in delivering drugs to the body to mimic a circadian
rhythm (e.g., testosterone).
[0025] The rate of release from an adhesive matrix can change over
the course of its functional lifespan. Often, this is caused by the
absorption of water or other components from the surface of the
skin of the wearer. Alternatively, one can incorporate into the
skin contact matrix an exhaustible penetration retardant or load
the skin contact matrix with solid drug crystals to impair initial
delivery of the drug through the skin.
[0026] In one embodiment of this invention, the composition
comprises more than two adhesive matrices, such as three or four or
five adhesive matrices. For example, a composition could comprise
one or more additional adhesive matrices sandwiched in between the
adhesive matrix which is in contact with the backing layer, and the
adhesive matrix which is in contact with the release liner. An
advantage to including three or more matrices is having increased
ability to control the rate of delivery either through the use of
the different layers or by adding different excipients to the
different layers to change or control the rate of delivery. Other
advantages include increased chemical stability, processing,
cosmetic or physical (improved wear) advantages. If there are more
than two adhesive matrixes in a composition, the initial rate of
delivery of the drug from one of the matrices is different from
that from at least one of the other matrices. In one embodiment,
the initial rate of drug delivery in each matrix is different from
that of each other matrix.
[0027] The adhesives used in the compositions, or unit dosage
forms, of the present invention are those which are tacky or sticky
to the touch and which typically adhere to a substrate, such as the
skin, upon the application of mild pressure. They therefore often
are referred to as pressure sensitive adhesives.
[0028] The choice for each adhesive matrix layer can be made from
any pressure sensitive adhesives conventionally used in transdermal
delivery devices, provided that the two materials chosen have
significantly different drug delivery rates. In one preferred
embodiment, one matrix comprises an acrylic adhesive and the other
matrix comprises a silicone adhesive. In this combination, the
acrylic adhesive has the relatively slow delivery characteristics;
the silicone adhesive has the more rapid delivery characteristics.
In a second preferred embodiment, one matrix comprises an acrylic
adhesive and the other comprises a polyisobutylene adhesive. In
this embodiment, the acrylic adhesive again has the relatively slow
delivery characteristics; the polyisobutylene adhesive delivers the
drug more rapidly.
[0029] If the composition comprises three adhesive matrices, it can
comprise, for example, an acrylic adhesive layer sandwiched between
two silicone adhesive layers, or a silicone adhesive layer in
between two acrylic adhesive layers. Alternatively, each layer
could have a different polymer, such as a silicone,
polyisobutylene, and acrylate adhesive multilayer system. The
choice of adhesive for each layer will be determined by the
delivery profile desired for the final composition.
[0030] Suitable silicone adhesives include pressure sensitive
adhesives made from silicone polymer and resin. The polymer to
resin ratio can be varied to achieve different levels of tack.
Specific examples of useful silicone adhesives which are
commercially available include the standard BIOPSA.RTM. series
(7-4400, 7-4500 and 7-4600 series) and the amine compatible
(endcapped) BIOPSA.RTM. series (7-4100, 7-4200 and 7-4300 series)
manufactured by Dow Corning. Preferred adhesives include
BIO-PSA.RTM. 7-4202, BIOPSA.RTM. 7-4301, BIO-PSA.RTM. 7-4302,
BIO-PSA.RTM. 7-4501, BIO-PSA.RTM. 7-4502 and BIO-PSA.RTM.
7-4602.
[0031] Suitable polyisobutylene adhesives are those which are
pressure sensitive and have suitable tack. The polyisobutylene can
comprise a mixture of high and low molecular weight
polyisobutylenes. Specifically, high molecular weight
polyisobutylenes are those with a molecular weight of at least
1,000,000. Low molecular weight polyisobutylenes are those with a
molecular weight of at least 100 but less than 1,000,000.
Desirably, the high molecular weight polyisobutylene comprise
between about 20 and 80% by weight of the total polyisobutylene,
preferably between about 40% and 50%, most preferably about 45%,
and the low molecular weight polyisobutylene comprises between
about 80% and 20% by weight of the total polyisobutylene,
preferably between about 50% and 60%, most preferably about 55%. A
specific example of a useful polyisobutylene is one which comprises
45% high molecular weight polymer (.about.1,250,000) and 55% low
molecular weight polymer (.about.44,000) at approximately 25%
solids in n-heptane.
[0032] Useful acrylic polymers include various homopolymers,
copolymers, terpolymers and the like of acrylic acids. They include
copolymers of alkyl acrylates or methacrylates. Polyacrylates
include acrylic acid, methacrylic acid, N-butyl acrylate, n-butyl
methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl
acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl
acrylate, decylmethacrylate, dodecyl acrylate, dodecyl
methacrylate, tridecyl acrylate, and tridecyl methacrylate. Useful
acrylic adhesives include crosslinked carboxyl functional adhesives
such as DURO-TAK.RTM.87-2194, non-crosslinked carboxyl functional
adhesives such as DURO-TAK.RTM.87-2051, crosslinked hydroxyl
functional adhesives such as DURO-TAK.RTM.87-2516, non-crosslinked
hydroxyl functional adhesives such as DURO-TAK.RTM.87-2287, grafted
adhesives such as DURO-TAK.RTM.87-5298 and non-functional adhesives
such as DURO-TAK.RTM.87-4098. Preferred acrylic adhesives include
crosslinked carboxyl functional acrylic adhesives, such as
DURO-TAK.RTM. 87-2194 manufactured by National Starch and Chemical
Co.
[0033] In addition to the aforementioned adhesives, other adhesives
useful in compositions in accordance with this invention include
other acrylate, rubber or silicone pressure adhesives, whether
hotmelt, waterborne or solvent based.
[0034] In addition to the two or more adhesive layers, compositions
in accordance with this invention comprise a backing and a release
liner, each of which can comprise materials conventionally used in
transdermal patch compositions. The material chosen for the backing
is one which is flexible, impermeable to the drug, and, if desired,
can be colored or labeled. The backing provides support and a
protective covering for the dosage unit. Suitable backing materials
include those known in the art for use with pressure sensitive
adhesives. For example, the backing can comprise a polyolefin,
polyester, multi-layer EVA film and polyester, polyurethane or
combination thereof. A preferred backing material is MEDIFLEX.RTM.
1000, a polyolefin manufactured by Mylan Technologies, Inc.
[0035] The release liner is removed and discarded from the
composition to expose the skin contact adhesive layer which
functions as the means of applying the composition to the patient
and through which the drug passes as it is delivered to the
patient. Suitable release liners include those known in the art for
use with pressure sensitive adhesive compositions. For example, the
release liner can comprise a fluorosilicone coated polyester or
silicone coated polyester. A preferred release liner is
MEDIRELEASE.RTM. 2500, MEDIRELEASE.RTM. 2249 and MEDIRELEASE.RTM.
MR2226, each manufactured by Mylan Technologies, Inc., or
Scotchpak.RTM. 1022, manufactured by 3M Pharmaceuticals/D.D.S. The
release liner can, however, comprise other materials, including
paper or paper-containing layers or laminates, various
thermoplastics, polyester films, foil liners, and the like.
[0036] Once the dosage unit forms have been prepared, they are
placed in appropriate packaging for storage until they are to be
applied in transdermal treatment.
[0037] The compositions of this invention possess sufficient
adhesive properties that once the release liner is removed and the
composition is applied to the skin the composition can remain in
place for a period of time sufficient to distribute the desired
amount of the drug contained therein with a low incidence of
debonding.
[0038] The compositions of this invention can be made by first
preparing separate adhesive blends for each layer of the dosage
unit, then dissolving or suspending the drug of choice in at least
one of the blends, each of which has been made by mixing a suitable
solvent with the pressure sensitive adhesive of choice. The anchor
layer is coated first on a release liner, dried and then laminated
to the desired backing film, according to predetermined parameters,
such as temperature and dwell time (line speed), which yield
minimal residual solvent levels. The skin contact layer then is
coated on a separate release liner and dried. The release liner is
removed from the anchor layer and the adhesive side of the skin
contact layer is laminated onto the adhesive side of the anchor
layer so that the anchor layer is between the backing and the skin
contact layer. If the drug initially is suspended or dissolved in
only one of the two adhesive layers, it will, over time,
equilibrate into the other adhesive layer until a common
equilibrium is achieved. It may be desirable to prepare the
composition with the drug initially suspended or dispersed in only
one of the two adhesive layers if, for example, the other adhesive
layer is prepared with a solvent which would be deleterious to the
drug but which evaporates during processing (coating and
drying).
[0039] If more than two layers are to be provided, the third
(middle) layer is coated as a liquid onto a release liner, dried,
laminated to either the adhesive side of the dried skin contact
layer or the adhesive side of the dried anchor layer once the
release liner has been removed from the latter, then the two parts
of the dosage unit are laminated to one another as above.
[0040] Suitable solvents for use in preparing the adhesive blends
include acetone, heptane, ethyl acetate, isopropanol, ethanol,
hexane, toluene, xylene, 2,4-pentanedione, methanol and water.
[0041] Alternative methods for producing or achieving a transdermal
delivery dosage unit in accordance with this invention may be
apparent to persons skilled in the art, and such alternative
methods also fall within the scope of the present invention. For
example, an adhesive blend can be coated onto the backing film
rather than the release liner. Alternatively, an adhesive coating
can be created without using a solvent, such by heating the
adhesive to its melting temperature (hot-melt adhesive). With this
technique, no drying of the adhesive is required, only cooling.
[0042] There are many coating techniques for applying a continuous
liquid coating onto a substrate, including using a gravure roll,
reverse roll, falling film, inkjet, etc. All of these are
well-known to persons of ordinary skill in the art and can be used
to create pressure-sensitive adhesive layers from a solvated blend.
Alternatively, a thin adhesive coating can be achieved by
extrusion, in which the adhesive blend is forced through a die
under pressure onto the substrate either as a continuous coating or
as a printed (intermittent) pattern.
[0043] The thickness of the anchor and skin contact layers of the
compositions of this invention can vary, depending upon such
factors as the amount of drug to be delivered from the composition
and the desired wear period. Generally, however, the skin contact
layer has a thickness of between about 5 and 150 gsm, preferably
between about 25 and 50 gsm. The anchor layer generally has a
thickness of between about 5 and 150 gsm, preferably between about
25 and 100 gsm. Variations can be determined as a matter of routine
experimentation by those of ordinary skill in the art.
[0044] The compositions of the present invention are suitable for
the transdermal delivery of a wide range of drugs. The term "drugs"
is intended to have its broadest interpretation as including any
therapeutically, prophylactically and/or pharmacologically or
physiologically beneficial active substance, or a mixture thereof,
which is delivered to a living being to produce a desired,
beneficial effect. More specifically, any drug which can produce a
pharmacological response, localized or systemic, whether
therapeutic, diagnostic, or prophylactic in nature, is within the
contemplation of the present invention. Also included within the
scope of the invention are bioactive agents, such as insect
repellants, sun screens, cosmetic agents, etc. The drug can be
provided in an amount sufficient to cure, diagnose, or treat a
disease or other condition. This definition includes, but is not
limited to:
[0045] 1. cardiovascular drugs, such as nitroglycerin, propranolol,
isosorbide dinitrate, isosorbide mononitrates, diltiazem,
nifedipine, procainamide, clonidine and others,
[0046] 2. androgenic steroids, such as testosterone,
methyltestosterone and fluoxymesterone,
[0047] 3. estrogens, such as conjugated estrogens, esterified
estrogens, etropipate, 17-.beta. estradiol, 17-.beta. estradiol
valerate, equilin, mestranol, estrone, estriol and
diethylstilbestrol,
[0048] 4. progestational agents, such as progesterone,
19-norprogesterone, norethindrone, norethindrone acetate,
melengestrol chloradinone, ethisterone, medroxyprogesterone
acetate, hydroxyprogesterone caproate, norethynodrel,
dimethisterone, ethinylestrenol, norgestrel, megestrolacetate, and
ethinodiol diacetate,
[0049] 5. drugs which act on the central nervous system, including
sedatives, hypnotics, analgesics, anesthetics, and antianxiety
agents; such as salicylic acid derivatives, opiates, opioids and
the like; including chloral hydrate, benzodiazepines, naloxone,
haloperidol, pentobarbitol, phenobarbitol, secobarbital, codeine,
lidocaine, dibucaine, benzocaine, fentanyl, fentanyl analogs and
nicotine,
[0050] 6. nutritional agents, including vitamins, essential amino
acids and essential fats,
[0051] 7. anti-inflammatory agents, including hydrocortisone,
cortisone, dexamethasone, prednisolone, prednisone, halcinonide,
methylprednisolone, flurocortisone, corticosterone, paramethasone,
ibuprofen, naproxen, fenoprofen, fenbufen, indoprofen, salicylic
acid, methyl salicylate, sulindac, mefenamic acid, piroxicam,
indonisilone and tolmetin,
[0052] 8. antihistamines, such as diphenhydramine, triprolidine,
chlorcyclizine, promethazine, cyclizine, chlorprenaline,
terrenadine, phenylpropanolamine and chlorpheniramine,
[0053] 9. miotics, such as pilocarpine,
[0054] 10. dermatological agents, such as vitamins A and E,
[0055] 11. anti-spamodics, including atropine, methantheline,
papverine, cinnmedrine and methscopolamine,
[0056] 12. anti-depressants, such as isocaboxazid, phenelzine,
imipramine, amitrptyline, trimepramine, dozepin, desipramine,
nortriptyline, protriptyline, amoxapine and maprotiline,
[0057] 13. anti-cancer drugs,
[0058] 14. anti-diabetics, such as insulin,
[0059] 15. anti-estrogens or hormone agents, including tamoxifen or
HCG,
[0060] 16. anti-infectives, including antibiotics, antibacterials
and anti-virals, such as tetracycline, chloramphenicol,
sulfacetamide, sulfadiazine, sulfamerazine, sulfoxazole,
idoxuridine, and erythromycin,
[0061] 17. anti-allergenics, such as antazoline, metapyrilene, and
pyrilamine,
[0062] 18. anti-pyretics, including aspirin and salicylamide,
[0063] 19. anti-migraine agents, including dihydroergotamine and
pizotyline,
[0064] 20. tranquilizers, including reserpine, chlorpromazine, and
antianxiety benzodiazepines, and
[0065] 21. anti-psychotic agents, including haloperidol loxapine,
molindone, thiothixene, pimozide, risperidone, quetiapine fumarate,
olanzapine, and/phenothiazine derivatives.
[0066] Other drugs suitable for delivery using a transdermal system
can be readily determined by persons of ordinary skill in the art.
In addition, pharmacologically acceptable derivatives of the drugs,
such as ethers, esters, amides, acetals, salts and the like, which
are suitable for transdermal administration can be used.
[0067] In a preferred embodiment, a composition of this invention
comprises estradiol, a combination of estradiol and norethindrone
acetate or a combination of estradiol and levonorgestrel or other
progestin. Such patches are indicated for post-menopausal women as
hormone replacement therapy. One or more bioactive and
biocompatible derivatives of estradiol capable of being absorbed
transdermally can be used in place of, or in combination with,
estradiol. Derivatives of estradiol include 13- or 7-mono-esters
and di-esters of estradiol, including estradiol-3,17-diacetate;
estradiol-17-acetate; estradiol-3,17-valerate;
estradiol-3-valerate; estradiol-17-valerate; 3-mono-17-mono- and
3,17-dipilivate esters; 3-mono-, 17-mono-, and 3,17-dipropionate
esters; corresponding heptanoate and benzoate esters; ethanol
estradiol; estrone; and other estrogenic steroids and derivatives
which are transdermally absorbable.
[0068] Other suitable progestins include progesterone,
medroxyprogesterone acetate, ethynodiol diacetate, and the
like.
[0069] When estradiol is used as the sole active drug in the dosage
unit, each unit typically comprises from about 0.1% to about 4.0%
(w/w) estradiol. When estradiol is provided in combination with
either norethindrone or levonorgestrel or other progestin, each
dosage unit typically comprises about 0.1% to about 4.0% (w/w)
estradiol and about 0.1% to about 20% of the progestin. These
ranges are intended only as guidelines; the actual amount of drug
provided depends upon the choice of adhesive for the skin contact
and anchor layers, the amount of drug desired to be delivered
transdermally to the patient within a certain period of time, and
the rate at which the drug can permeate through the skin of the
person wearing the dosage unit or patch.
[0070] In one specific embodiment of this invention, a transdermal
dosage unit comprises a silicone skin contact layer of about 25 gsm
(grams/m.sup.2) and an acrylate anchor layer of about 75 gsm and
contains about 1.4% (w/w) estradiol. In a second specific
embodiment, a transdermal dosage unit comprises a silicone skin
contact layer of about 50 gsm and an acrylate anchor layer of about
75 gsm and contains about 1.4% estradiol. In a third specific
embodiment, a transdermal dosage unit comprises a silicone skin
contact layer of about 25 gsm and an acrylate anchor layer of about
100 gsm, each containing about 1.4% estradiol.
[0071] In a fourth specific embodiment, a transdermal dosage unit
comprises a polyisobutylene skin contact layer of about 50 gsm
which contains 1.0% (w/w) estradiol and a 50 gsm anchor layer which
contains about 1.4% (w/w) estradiol in an acrylate adhesive.
[0072] The amount of drug to be incorporated into the compositions
of this invention vary, depending upon the drug or combination of
drugs of interest, the desired therapeutic effect and the time span
over which the composition will release the drug and provide
therapy. As the passage of drugs through the skin often is the rate
limiting step, the amount of drug chosen and the rate of release
from the adhesives typically are selected so as to provide for
delivery of the drug for a prolonged period of time, wherein the
minimum amount of the drug in the system is based upon the rate at
which it will pass through the skin in the time period for which
the composition is to provide therapy. The amount of drug in the
composition typically can vary from about 0.05% to about 40% by
weight of the delivery device and preferably is within the range of
about 0.1% to about 20% by weight, most preferably within the range
of about 0.1% to about 4.0% by weight.
[0073] The drug(s) of interest can be provided in admixture with
other ingredients which are compatible with the transdermal
administration of the desired drug to patients. Such other
ingredients include crosslinking agents, plasticizers, tackifiers,
fillers, anti-oxidants, dispersing agents and excipients, such as
propylene glycol.
[0074] The invention is further illustrated by the following
examples, which are not to be construed as limiting.
EXAMPLES
Example 1
Preparation of a Two-Layer Delivery Device
[0075] Separate adhesive blends are made for each layer of the
finished system, with the drug dissolved or suspended in at least
one blend. The blends are made by suspending or dissolving the drug
in a combination of solvent, adhesive, and, optionally, excipient.
Desired remaining components for each blend can be dispersed in a
premix or added directly to the adhesive blends along with the
drug. Once all the components are added together in their
respective blend, the blends are mixed separately with an air
driven mixer until uniform. See Table 1 below for example amounts
of each component blend:
1TABLE 1 Component % (w/w) Wet Weight (g) Anchor Layer Blend Ethyl
Alcohol Dehydrated 4.56 9.50 Alcohol USP-200 Proof punctilious
(Ethyl Alcohol) Estradiol Hemihydrate, USP, micronized 0.63 1.32
Povidone USP (Plasdone K-29/32) 1.55 3.23 DURO-TAK .RTM. 87-2194
93.25 194.14 Skin Contact Layer Blend Ethyl Alcohol Dehydrated 5.89
6.00 Alcohol USP-200 Proof punctilious (Ethyl Alcohol) Estradiol
Hemihydrate, USP, micronized 0.81 0.83 Povidone USP (Plasdone
K-29/32) 2.00 2.04 360 Medical Fluid (100 cSt.) 2.94 3.00 BIO-PSA
.RTM. 7-4502 88.36 90.08
[0076] Following thorough mixing, the anchor layer blend is coated
onto an appropriate release liner at the specified thickness to
obtain the desired gsm. The laminate is dried for 4 minutes at
41.degree. C. followed by 4 minutes at 77.degree. C. in forced air
ovens, then laminated to the desired backing film. The skin contact
layer blend is coated onto a separate release liner and dried,
using the same conditions as were used to prepare the anchor layer
laminate.
[0077] To assemble the finished product, the anchor layer release
liner is removed and the adhesive side of the dried skin contact
layer is laminated to the adhesive side of the anchor layer.
Example 2
[0078] Transdermal delivery devices were made in accordance with
the teachings of Example 1. Each device contained a total of
0.1-4.0% (w/w) drug. The anchor adhesive matrix of each delivery
device was an acrylic pressure-sensitive adhesive and initially
contained 0.1%4.0% drug and between 0-5.0% (w/w) povidone. The skin
contact matrix of each delivery device comprised a silicone
pressure-sensitive adhesive and initially contained 0.1% to 4.0% of
the drug, 0-5% (w/w) povidone and 0-5% of a tackifier/plasticizer.
The silicone contact layer of each device had a thickness of 5-100
gsm and the anchor layer had a thickness of 5-150 gsm. In one
embodiment, the device comprised 1.4% estradiol in each of the
acrylic adhesive layer and the skin contact layer, 3.4% povidone in
each of the acrylic adhesive layer and the skin contact layer, and
the skin contact layer comprised 5% of 360 Medical Fluid (100 cSt)
as the tackifier/plasticizer.
Example 3
[0079] Transdermal delivery devices were made in accordance with
the teachings of Example 1. Each device contained a total of
0.1-4.0% (w/w) drug. The anchor adhesive matrix of each delivery
device was an acrylic pressure-sensitive adhesive and initially
contained 1.4% drug and between 0-5.0% (w/w) povidone. The anchor
layer also contained 0-10% (w/w) propylene glycol. The skin contact
matrix of each delivery device comprised a polyisobutylene
pressure-sensitive adhesive and initially contained 1.0% drug, 0-5%
(w/w) povidone and 10-50% of a tackifier/plasticizer. In each
device, the skin contact layer had a thickness of 5-100 gsm and the
anchor layer had a thickness of 5-100 gsm. In one embodiment, the
device comprised 3.4% povidone in each of the acrylic adhesive
layer and the skin contact layer, and the skin contact layer
comprised 30% mineral oil as the tackifier/plasticizer.
Example 4
[0080] A transdermal device was made in accordance with the
teachings of Example 2. The silicone skin contact layer had a
thickness of 25 gsm and the anchor layer had a thickness of 75
gsm.
Example 5
[0081] A transdermal device was made in accordance with the
teachings of Example 2. The silicone skin contact layer had a
thickness of 50 gsm and the anchor layer had a thickness of 75
gsm.
Example 6
[0082] A transdermal delivery device was made in accordance with
the teachings of Example 3. The polyisobutylene skin contact layer
had a thickness of 50 gsm and the acrylate anchor layer had a
thickness of 50 gsm.
Example 7
[0083] Transdermal delivery devices were made in accordance with
the teachings of each of Examples 2 and 3. In each device, the drug
was estradiol, a combination of estradiol and norethindrone acetate
or a combination of estradiol and levonorgestrel.
Example 8
[0084] Transdermal delivery devices were made in accordance with
the teachings of Example 2. In each device, the silicon adhesive
was BIO-PSA.RTM. 7-4202, 7-4301, 7-4302, 7-4501, 7-4502 or
7-4602.
Example 9
[0085] Transdermal delivery devices were made in accordance with
the teachings of Example 3. In each device, the polyisobutylene
adhesive comprised from 20-80% of polyisobutylene with a molecular
weight of at least 1,000,000 and 80-20% of polyisobutylene with a
molecular weight of between 100 and 1,000,000.
Example 10
[0086] Transdermal delivery devices were made in accordance with
the teachings of Example 9. In each device, the polyisobutylene
adhesive comprised 45% polyisobutylene with a molecular weight of
at least 1,000,000 and 55% polyisobutylene with a molecular weight
of between 100 and 1,000,000.
Example 11
[0087] A transdermal delivery device was made in accordance with
the teachings of Example 2. The 50 gsm skin contact layer contained
1.4% estradiol hemihydrate, 3.4% povidone and 5% 360 Medical Fluid
(100 cSt) in a medical grade, silicone pressure sensitive adhesive
BIO-PSA.RTM. 7-4502. The 75 gsm anchor layer contained 1.4%
estradiol hemihydrate and 3.4% povidone in DURO-TAK.RTM. 87-2194, a
medical grade acrylate pressure sensitive adhesive. The backing
consisted of polyolefin (MEDIFLEX.RTM. 1000). The release liner was
fluorosilicone coated polyester (MEDIRELEASE.RTM. 2500 or
Scotchpak.RTM. 1022). All percentages are w/w.
[0088] The delivery system had a size of 30 cm.sup.2, produced a
delivery spike of estradiol and delivered approximately 0.1 mg/day
in vitro.
Example 12
[0089] A transdermal delivery device was made in accordance with
the teachings of Example 3. The 50 gsm skin contact layer contained
1.0% estradiol hemihydrate, 3.4% povidone and 30% mineral oil in
medical grade polyisobutylene pressure sensitive adhesive. The 50
gsm anchor layer contained 1.37% estradiol hemihydrate, 8.0%
propylene glycol and 3.4% povidone in DURO-TAK.RTM. 87-2194, a
medical grade acrylate pressure sensitive adhesive. The backing
consisted of polyolefin (MEDIFLEX.RTM. 1000). The release liner was
siliconized polyester (MEDIRELEASE.RTM. 2249). All percentages are
given on a w/w basis.
[0090] The delivery device had a size of 30 cm.sup.2, produced a
delivery spike of estradiol and delivered 0.1 mg/day in vitro.
Example 13
[0091] A transdermal delivery device was made in accordance with
the teachings of Example 1. The anchor layer matrix comprised 50
gsm DURO-TAK.RTM. 87-2194 to which was laminated a 50 gsm
polyisobutylene skin contact layer matrix. The anchor layer matrix
contained 1.37% estradiol hemihydrate, 4.0% propylene glycol, 3.4%
povidone and 1.13% colloidal silicon dioxide. The skin contact
layer matrix contained 1.37% estradiol hemihydrate, 3.4% povidone,
4.0% propylene glycol, 1.13% colloidal silicon dioxide, and 30%
mineral oil in a polyisobutylene adhesive. The backing was
MEDIFLEX.RTM. 1000 and the release liner was MEDIRELEASE.RTM.
2226.
Example 14
[0092] A transdermal delivery device was made in accordance with
the teachings of Example 1. The anchor layer matrix comprised 75
gsm DURO-TAK.RTM. 87-2194 to which was laminated a 50 gsm skin
contact layer matrix of BIO-PSA.RTM. 7-4502. The anchor layer
matrix contained 1.37% estradiol hemihydrate and 3.4% povidone. The
skin contact layer matrix contained 1.37% estradiol hemihydrate,
3.4% povidone and 5% 360 Medical Fluid (100 cSt). The backing was
MEDIFLEX.RTM. 1000 and the release liner was MEDIRELEASE.RTM.
2500.
Example 15
[0093] A delivery device was made in which the rate of delivery of
drug from the skin contact layer was slower than the rate of
release from the anchor layer. The transdermal delivery profiles of
the bilayer and constitutive monolayers show that the bi-layer
delivers drug through the skin at the same normalized rate as the
rapidly delivering (silicone) matric, but at a steady rate
characteristic of the slow-delivery (acrylic) matrix.
[0094] Rapidly delivering adhesive films were prepared by coating a
silicone adhesive blend so as to create a homogeneous dry adhesive
layer containing 1.25% estradiol, 5% polyvinyl pyrrolidone, 4%
oleic acid, and BIO-PSA.RTM. 7-4502 silicone adhesive. The blend
was coated onto 3M ScotchPak.RTM. 1022 release liner and dried for
4 minutes at 41.degree. C. and 4 minutes at 77.degree. C. to create
adhesive films of approximately 100 grams per square meter
(gsm).
[0095] Slowly delivering adhesive films were prepared by coating an
acrylic adhesive blend so as to create a homogeneous dry adhesive
layer containing 1.25% estradiol, 5% polyvinyl pyrolidone, 4% oleic
acid and DURO-TAK.RTM. 87-2516 acrylic adhesive from National
Starch and Chemical Co. The blend was coated onto MEDIRELEASE.RTM.
2249 release liner and dried for 4 minutes at 40.degree. C. and 4
minutes at 77.degree. C. to create two dry adhesive films of
approximately 25 and 100 gsm, respectively.
[0096] Two drug delivery systems were prepared by laminating either
the 100 gsm rapidly delivering silicone adhesive film or the 100
gsm slowly delivering acrylic adhesive film to 3M CoTran 9722
backing film.
[0097] A third drug delivery system was prepared by first
transferring the rapidly delivering silicone adhesive film from the
release liner to 3M CoTran 9722 backing film. The 25 gsm slowly
delivering acrylic adhesive film was laminated on top of the
rapidly delivering silicone adhesive film. The finished system
consisted of a backing film, 100 gsm silicone adhesive layer, 25
gsm acrylic adhesive layer and release liner. After allowing all
systems to equilibrate, they were tested for in vitro delivery of
drug through human skin. The table below summarizes the three
systems tested:
2 System 3 (Bi-Layer System 1 (Rapidly System 2 (Slowly with Slowly
Delivering Delivering Silicone Delivering Acrylic Acrylic Matrix in
Adhesive Matrix) Matrix) Contact with Skin) GSM: 100 GSM: 100
Acrylic GSM: 25 Silicone GSM: 100 Estradiol 1.25% Estradiol 1.25%
Estradiol 1.25% PVP 5% PVP 5% PVP 5% Oleic Acid 4% Oleic Acid 4%
Oleic Acid 4%
[0098] By laminating the two layers together, the resulting
transdermal system delivered the medication through the skin at the
same normalized rate as the rapidly-delivering matrix, but at a
steady continuous rate more characteristic of the slowly-delivering
matrix. See FIGS. 1 and 2.
* * * * *