U.S. patent application number 14/731978 was filed with the patent office on 2015-09-24 for dermal delivery device.
This patent application is currently assigned to AGILE THERAPEUTICS, INC.. The applicant listed for this patent is Agile Therapeutics, Inc.. Invention is credited to Robert G. CONWAY, Agis KYDONIEUS, Thomas M. ROSSI.
Application Number | 20150265547 14/731978 |
Document ID | / |
Family ID | 42319255 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150265547 |
Kind Code |
A1 |
KYDONIEUS; Agis ; et
al. |
September 24, 2015 |
DERMAL DELIVERY DEVICE
Abstract
A transdermal drug delivery device is disclosed. Over an
extended wear period, the device causes cumulative moderate
irritation plus significant irritation of less than 5% and/or
achieves a meaningful degree of detachment over a seven day period
of less than 20%.
Inventors: |
KYDONIEUS; Agis; (Kendall
Park, NJ) ; CONWAY; Robert G.; (Whitehouse Station,
NJ) ; ROSSI; Thomas M.; (Stockton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Agile Therapeutics, Inc. |
Princeton |
NJ |
US |
|
|
Assignee: |
AGILE THERAPEUTICS, INC.
Princeton
NJ
|
Family ID: |
42319255 |
Appl. No.: |
14/731978 |
Filed: |
June 5, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13463494 |
May 3, 2012 |
9050348 |
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14731978 |
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12687489 |
Jan 14, 2010 |
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13463494 |
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PCT/US2008/069618 |
Jul 10, 2008 |
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12687489 |
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PCT/US2008/069622 |
Jul 10, 2008 |
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12687489 |
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60948757 |
Jul 10, 2007 |
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60948759 |
Jul 10, 2007 |
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Current U.S.
Class: |
604/290 ;
604/307 |
Current CPC
Class: |
A61P 5/24 20180101; A61K
9/7061 20130101; A61K 31/56 20130101; A61K 31/57 20130101; A61P
15/18 20180101; A61K 9/7084 20130101; A61K 31/56 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 31/57 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/57 20060101 A61K031/57 |
Claims
1. A transdermal drug delivery patch comprising: A) an active
ingredient (AI) layer having a skin contacting surface and a
non-skin contacting surface and comprising a pressure sensitive
adhesive and the drug and B) an overlay adjacent the non-skin
contacting surface of the AI layer, said overlay comprising: (i) a
pressure sensitive adhesive (PSA) layer that is applied directly or
indirectly to the AI layer and (ii) an elastomeric and permeable
overlay covering, whereby: (i) at the end of an extended wear
period, the patch causes cumulative moderate irritation plus
significant irritation of less than 5%; or (ii) at the end of a
seven day wear period, the patch exhibits meaningful degree of
detachment over a seven day period of less than 20%.
2. The patch of claim 1 in which the AI layer is a polymeric matrix
that comprises a humectant.
3. The patch of claim 2 in which the humectant is polyvinyl
pyrrolidone (PVP).
4. The patch of claim 2 which further comprises an internal backing
layer between the AI layer and the overlay, said internal backing
layer being impermeable to moisture and to the components of the
polymeric matrix.
5. The patch of claim 4 in which the overlay additionally comprises
an intermediate layer between the PSA layer and the overlay
covering, said intermediate layer being permeable to moisture but
impermeable to the PSA in the PSA layer.
6. The patch of claim 5 in which the PSA layer comprises a
hydrophobic PSA and a humectant.
7. The patch of claim 6 in which the PSA layer in the overlay
comprises a polyisobutylene (PIB) PSA and a humectant, the
intermediate layer in the overlay is a polyacrylate PSA, and the
overlay covering is non-tacky, flexible and permeable.
8. The patch of claim 1 in which the AI layer comprises a skin
permeation enhancer that is dimethyl sulfoxide (DMSO) or a
C.sub.8-C.sub.20 saturated or unsaturated fatty acid or an ester or
alcohol thereof.
9. The patch of claim 5 in which the AI layer comprises a skin
permeation enhancer that is DMSO or a C.sub.8-C.sub.20 saturated or
unsaturated fatty acid or an ester or alcohol thereof.
10. The patch of claim 7 in which the AI layer comprises a skin
permeation enhancer that is DMSO or a C.sub.8-C.sub.20 saturated or
unsaturated fatty acid or an ester or alcohol thereof.
11. The patch of claim 1 in which the overlay covering is a foam or
a woven or nonwoven fabric that allows water vapor permeation
through it at a rate that is greater than the transepidermal water
loss.
12. The patch of claim 1 in which the AI layer comprises a
progestin, an estrogen, or both a progestin and an estrogen.
13. A method of delivering a drug to a patient in need thereof that
comprises applying to the skin of the patient a transdermal drug
delivery patch of claim 1, wherein the AI layer comprises an
effective amount of the drug.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] Continuation of U.S. application Ser. No. 13/463,494, filed
May 3, 2012 and issued as U.S. Pat. No. 9,050,348, which is a
continuation of U.S. application Ser. No. 12/687,489, filed Jan.
14, 2010 (abandoned), which is a continuation-in-part of U.S.
Application No. PCT/US2008/069618, filed Jul. 10, 2008, which
claims benefit of U.S. Provisional Application No. 60/948,757,
filed Jul. 10, 2007, and also a continuation-in-part of U.S.
Application No. PCT/US2008/069622, filed Jul. 10, 2008, which
claims benefit of U.S. Provisional Application No. 60/948,759,
filed Jul. 10, 2007, the entire contents of all of the preceding
being incorporated by reference herein.
FIELD OF THE INVENTION
[0002] This invention is in the field of delivery of
pharmacologically or cosmetically active agents to the skin for
systemic, local, or topical administration.
BACKGROUND OF THE INVENTION
[0003] A dermal delivery device is an adhesive "patch" for
application to the skin that is used to deliver a wide variety of
pharmacologically and cosmetically active agents. Such patches can
be used to deliver an agent transdermally, i.e., through the skin
and into the bloodstream for systemic treatment or into or through
the skin for local treatment. Such patches can also be used to
administer topical treatments, including cosmetically active
agents.
[0004] Transdermal drug delivery devices intended for extended
wear, i.e., 3 or more days, are susceptible to problems of
inadequate adhesion and/or skin irritation. Irritation can be
caused or exacerbated by a number of factors, including the nature
of the active. Certain skin permeation enhancers are also known to
contribute to irritation. These include dimethyl sulfoxide (DMSO)
and long chain aliphatic compounds including fatty acids, such as
laurates and oleates and derivatives thereof, e.g., lauryl
alcohol.
[0005] Various attempts have been made to address the skin
irritation problem. These include controlling the rate of
transdermal delivery of irritating drugs through use of a rate
controlling membrane, inclusion of irritation inhibitors such as a
lysozymal uptake inhibitor, a complexing agent, a second active
agent that reduces irritation/sensitization, a sucrose fatty acid,
aluminum hydroxide and/or titanium oxide. In some cases, a
particular salt of an irritating active may be found to be less
irritating.
SUMMARY OF THE INVENTION
[0006] This invention relates to extended wear dermal delivery
devices, or patches, that cause cumulative moderate irritation plus
significant irritation of less than 5%.
[0007] This invention also relates to extended wear dermal delivery
devices, or patches, that achieve a meaningful degree of detachment
of less than 20%.
[0008] In illustrative embodiments, the device of the invention,
over a seven day wear period, causes cumulative moderate irritation
plus significant irritation of less than 5% and additionally
achieves a meaningful degree of detachment over a seven day period
of less than 20%.
[0009] Thus, in general terms, the inventions relates to a
transdermal drug delivery patch comprising (A) an active ingredient
(AI) layer having a skin contacting surface and a non-skin
contacting surface and comprising a pressure sensitive adhesive and
the drug and (B) an elastic and porous backing material whereby at
the end of an extended wear period, the patch causes cumulative
moderate irritation plus significant irritation of less than 5% or
causes cumulative moderate irritation plus significant irritation
of less than 5% and a meaningful degree of detachment over a seven
day period of less than 20%, or both.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 illustrates an exploded cross-section of an
illustrative dermal delivery system of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The inventors have discovered that skin irritation, which
can be a problem with extended wear patches (e.g., 3 or more days),
can be minimized, and adhesion can be enhanced, by careful patch
design and formulation. Through such design, use of a rate
controlling membrane is unnecessary, particularly when the AI layer
comprises a polymeric matrix comprising a PSA, e.g., as described
below. It may also not be necessary to employ irritation inhibitors
or to employ particular salt forms selected on the basis of reduced
irritancy.
[0012] It may also be possible to employ skin permeation enhancers
that are known to be skin irritants because removal of other
sources of irritation, e.g., physical stress on the skin, are
minimized. Such permeation enhancers include, e.g., dimethyl
sulfoxide (DMSO) and long chain aliphatic compounds such as fatty
acids or esters or derivative of fatty acids, e.g.,
C.sub.8-C.sub.20 saturated or unsaturated fatty acids such as
lauryl lactate and isopropyl myristate. These include, e.g.,
C.sub.8-C.sub.20 saturated or unsaturated fatty alcohols, such as
myristyl, palmityl or oleyl alcohols.
[0013] Thus, in illustrative embodiments of the invention, patches
do not comprise a skin irritation inhibitor, do not employ a
rate-controlling membrane, do not employ a non-irritating salt of
an irritating active, and/or do not require a supporting layer for
the AI layer that is flexible and porous. It is also not necessary
to employ an adhesion adjusting agent, such as polydiorganosiloxane
polymer in order to reduce tissue damage upon removal of the
patch.
[0014] In an illustrative embodiment of the invention, the patch is
intended for application to normal healthy skin, such as on the
arm, chest, back, buttocks or leg, although other embodiments can
be designed for use on inflamed or irritated skin tissue. In
illustrative embodiments, the release and transdermal
administration are dependent on drug concentration in the AI
layer.
[0015] For example, designing and formulating a patch that adheres
well can reduce irritation from physical stresses on the skin such
as by minimizing friction caused by movement of the patch against
the skin; use of materials that are elastic such that they conform
by stretching and re-forming (i.e., recovering more or less its
original dimensions after being stretched during wear) can improve
adhesion and minimize irritation by improving adhesion and/or by
minimizing the friction between the patch and the skin; use of
materials that are soft such that they do not have "hard" edges can
minimize irritation such as by reducing friction between the edges
of the patch or of its components, e.g., an overlay, and the skin;
use of a humectant such as PVP can improve adhesion and reduce
irritation such as by minimizing buildup of moisture between the
patch or its components and the skin; use of a backing material
that is porous (i.e., water vapor-permeable to the extent that
moisture that does build up in the AI layer or in the extended
perimeter of an overlay can escape) can improve adhesion by
preventing buildup of moisture and also thereby reduce
irritation.
[0016] A covering that is attached directly or indirectly to the AI
layer, e.g., an overlay can comprise an elastic and porous material
adjacent the non-skin-contacting surface of the AI layer. By
"elastic" is meant that the material is capable of stretching with
skin movement during normal activities and of re-forming
substantially to its original shape and size. By "porous" is meant
that the material is permeable, i.e., permeable to moisture, more
specifically, permeable to water vapor. The elasticity and porosity
of such backing material are such that, at the end of an extended,
e.g., seven day, wear period, the patch causes cumulative moderate
irritation plus significant irritation of less than 5%, including
4% or less, 3% or less, and 2% or less and/or such that there is a
meaningful degree of detachment over a seven day period of less
than 20%.
[0017] Preferably, such elastomeric and permeable layer is part of
an overlay that extends beyond the perimeter of the AI layer. In
this case, an internal backing layer that comprises a non-porous
material covering all or a portion of the non-skin contacting
surface of the active ingredient layer can be used to prevent or
minimize passage of the components of the polymer matrix in the AI
layer through the non-skin-contacting surface of the device. In
this embodiment, the elastic and porous backing material in the
overlay provides sufficient elasticity and permeability to the
device to confer adequate adhesion and acceptable irritation, i.e.,
moderate irritation plus significant irritation of <5% including
4% or less, 3% or less, and 2% or less.
[0018] In a particular illustrative embodiment, an impermeable
internal backing layer is adhered to the entire surface area of the
non-skin contacting face of the active ingredient layer. In such
embodiment, a peripheral adhesive system such as an overlay is
employed to improve adhesion and reduce irritation, particularly by
proper choice of a PSA and overlay material. Polyisobutylene (PIB)
PSAs, such as are described below, are particularly useful in the
PSA layer of the overlay. Other useful materials for the overlay
include materials that are flexible, including multidimensionally
elastically stretchable films or fabrics. Such elastomeric and soft
materials include porous foams and woven or nonwoven fabrics, which
will stretch and reform with movement of the skin, retain their
shape and reduce buildup of moisture between the peripheral
adhesive layer and the skin. The porosity of the material can be
chosen such that the water vapor permeation rate through the
material is higher than the transepidermal water loss.
[0019] When PSAs that are of low molecular weight such that they
would pass through the permeable, i.e., porous, overlay covering,
e.g., a PIB, are employed in the overlay, it can be useful also to
employ an intermediate layer that permits moisture, but not the
PSA, to reach and penetrate the porous material. Such intermediate
layer, which need not detract from the elasticity of the backing
layer, can be, e.g., a polyacrylate PSA or a polyurethane. In
addition, if the PSA is hydrophobic, such as a PIB PSA, it is
advantageous to employ a humectant, such as PVP, in the PSA layer
of the overlay.
[0020] As noted above and discussed below, the overlay can extend
beyond the perimeter of the AI layer in all directions, typically
by a margin of about 0.1 to about 1.5 cm, more specifically about
0.3 to about 1.2 cm and more specifically about 0.8 cm beyond the
perimeter of the AI layer. The precise surface area of extension is
selected to provide a peripheral adhesive surface area that is
adequate to ensure good adhesion throughout the contemplated wear
period but that is not larger than necessary. Use of an overlay
that is larger than necessary has several disadvantages, e.g., a
larger skin contact surface area can increase irritation and is
generally more noticeable and therefore less aesthetically
pleasing; in some embodiments, a patch surface area, including a
peripheral adhesive, can be less than about 50 cm.sup.2, less than
about 30 cm.sup.2, or less than about 25 cm.sup.2.
[0021] Such patch design also preferably incorporates a humectant
into the polymeric matrix of the AI layer. As mentioned above and
further described below, the humectant absorbs moisture from the
surface of the skin and thereby reduces irritation and enhances
adhesion.
[0022] Patches designed as described above and as illustrated
hereinbelow, at the end of an extended, e.g., seven day, wear
period, can cause cumulative moderate irritation plus significant
irritation of less than 5%, including 4% or less, 3% or less, and
2% and/or can achieve a meaningful degree of detachment over a
seven day period of less than 20%, including less than 18%, less
than 15%, less than 12%, and less than 10%.
[0023] By "moderate irritation plus significant irritation" is
meant that the patch causes erythema, papules, definite edema,
vesicular eruption, with the reaction spreading beyond test (i.e.,
application) site. With reference to the FDA's draft Guidance on
Ethinyl Estradiol; Norelgestromin extended release/transdermal
film, July 2009 ("FDA Guidance"), a copy of which is incorporated
herein as though fully set forth, "moderate irritation plus
significant irritation" corresponds to a Dermal Response/Skin
Appearance score of 7.
[0024] A cumulative moderate irritation plus significant irritation
of less than 5% means that moderate irritation plus significant
irritation was observed in fewer than 5% of skin application sites
on patients in a study population of, e.g., about 50 to about 1000
patients, e.g., about 100 to about 300 patients, including 200
patients which is the number of patients recommended in the FDA
Guidance.
[0025] By "meaningful degree of detachment" is meant that a patch
is less than 50% adhered, i.e., more than half of the patch has
become detached from the skin. With reference to the FDA Guidance,
"meaningful degree of detachment" corresponds to an Adhesion score
of 3 or 4.
[0026] A meaningful degree of detachment over a seven day period of
less than 20%, means that there was a meaningful degree of
detachment in fewer than 20% of patients in a study population of,
e.g., 10 to 1000 patients.
[0027] A mean adhesion score means the mean (p<.05) adhesion
score in a population of patients (n=100 to 500) using the
following adhesion scoring patch:
[0028] 0=>/=90% adhered (essentially no lift off the skin)
[0029] 1=>/=75% to <90% adhered (some edges only lifting off
the skin)
[0030] 2=>/=50% to 75% adhered (less than half of the patch
lifting off the skin)
[0031] 3=>0% to <50% adhered but not detached (more than half
of the patch lifting off the skin without falling off)
[0032] 4=0% adhered--patch detached (patch completelly off the
skin).
[0033] In illustrative embodiments of the invention, the patch
achieves both, a cumulative moderate irritation plus significant
irritation of less than 5% and a meaningful degree of detachment
over a seven day period of less than 20%.
[0034] In certain illustrative embodiments, the overlay can be
packaged separately from the AI layer. An internal backing layer
can be integrated with the AI layer or with the overlay. In either
case, the user would apply the overlay on top of the AI layer,
rather than applying an integrated patch that comprises both the
overlay and the AI layer.
[0035] The description that follows is of an illustrative
embodiment of the invention for dermal delivery of a composition
comprising contraceptive hormones and that comprises one or more
volatile components. Of course, the active can be any drug that is
active when administered by transdermal delivery, passive or
otherwise. Furthermore, while use of a seal between an overlay and
a release liner to minimize or prevent loss of volatile components,
as described hereinbelow, can be advantageous, such seal is not an
essential feature of the current invention which is more broadly
directed at achieving adequate adhesion and acceptable skin
irritation.
[0036] With reference to FIG. 1, this illustrative device of the
invention comprises 4 layers. One is the AI layer (6). The second
is a release liner (4). The third is an internal backing layer (5).
The fourth is an overlay, which in this illustrative device, itself
comprises three component layers (1,2,3), referred to herein below
as, respectively, a PSA layer (3), an intermediate layer (2), and
an overlay covering or overlay coating (1). The overlay can also be
described as comprising, in this illustrative embodiment, a PSA
layer (3) and an overlay covering (1 and 2). In any event, one
feature of this illustrative embodiment of the invention is
formation of a seal between the PSA layer (3) of the overlay
(1,2,3) and the release liner (4).
[0037] A feature of a related aspect of this illustrative
embodiment of the invention is use of a PIB PSA in the PSA layer
(3) of the overlay (1,2,3).
[0038] A feature of another related aspect of this illustrative
embodiment of the invention is use of an overlay (1,2,3) comprising
a PIB PSA layer (3) and a material (1,2) that covers the PIB PSA
layer , so that the PIB PSA does not come into contact with fingers
or clothing, but that permits water vapor transmission outward from
the skin. As illustrated in FIG. 1, the material comprises Layers 1
and 2, Layer 2 being a PSA that prevents migration of the PIB PSA
into the overlay coating (1).
[0039] A feature of another aspect of this illustrative embodiment
of the invention is use of an intermediate layer (2) between the
PIB PSA layer (3) and a porous overlay covering (1).
[0040] In illustrative embodiments, the entire patch is flexible so
that it will adhere effectively and comfortably to the contours of
the site of application and so that it will withstand the flexions
associated with normal living activities.
[0041] These and other aspects of the invention are more fully
described hereinbelow or otherwise will be apparent to a person of
ordinary skill in the art based on such description.
[0042] An illustrative, non-limiting, embodiment of the invention
that comprises an entire transdermal delivery system of the
invention is as follows.
[0043] The AI Layer
[0044] Layer 6 comprises the AI and a volatile component, typically
in a PSA matrix. The volatile component is typically at least
partially dissolved in the AI layer. So, for example, in an
illustrative embodiment of the invention, Layer 6 comprises one or
more hormones as AIs, an acrylic PSA, and a volatile skin
permeation enhancer. The volatile component, however, can also be,
for example, the AI itself or a solvent or carrier. Illustrative
formulations of transdermal hormone compositions useful in delivery
devices of the present invention are described, for example, in
U.S. Pat. No. 7,045,145 and in US 20070065495.
[0045] In an illustrative embodiment, the AI is an active
pharmaceutical ingredient (API) that is one or more hormones such
as a progestin, e.g., levonorgestrel, and an estrogen, e.g.,
ethinyl estradiol or 17-.beta. estradiol, dispersed in an adhesive
polymer matrix. In another aspect of the invention for delivery of
a hormone, the API is limited only to a progestin. In other such
aspects, the API comprises a progestin, an estrogen and a
testosterone, or a testosterone alone.
[0046] Other APIs that can also be delivered in accordance with
this invention include "small molecules", i.e., low molecular
weight (e.g., <2000 Daltons) synthetic organic compounds such as
but not limited to fentanyl, nicotine, scopolamine, nitroglycerine,
clonidine, methylphenidate, lidocaine, prilocaine, oxybutynin,
antipsychotics such as fluphenazine, alprazolam, risperidone, and
olanzapine, Parkinsons drugs such as rotigotine and selegilene
Alzheimer's drugs such as rivastigmine and donepezil,
anti-hypertensives such as enalapril, BPH drugs such as tamsulosin
and terazosin, and anti-asthma drugs such as albuterol and
montelukast.
[0047] The AI can also be a cosmetic agent such as keratolytic
agents such as alpha- and beta-hydroxycarboxylic acids and
beta-ketocarboxylic acids; alpha-hydroxy acids such as glycolic
acid, lactic acid, tartaric acid, malic acid, citric acid, mandelic
acid and, in general, fruit acids; beta-hydroxy acids such as
salicylic acid and its derivatives; antibacterials such as
clindamicyn or erythromycin phosphate, or antibiotics of the
tetracycline type; ascorbic acid and its biologically compatible
salts and esters; enzymes; tautening agents such as protein, soya
and wheat powders; hydroxylated polyacids; sucroses and their
derivatives; urea; amino acids; plant and yeast extracts; protein
hydrolysates such as collagen and elastin hydrolysates; hyaluronic
acid; mucopolysaccharides; vitamins; panthenol; folic acid;
acetylsalicylic acid; allantoin; kojic acid; hydroquinone; retinoic
acid and derivatives thereof; fatty acids; etc.
[0048] As described in US 20070065495, an illustrative Layer 6 is
prepared as described in Example 1, below. This example describes
formulations that use a combination of skin permeation enhancers,
including DMSO and a lower (C1-C4) alkyl ester of lactic acid such
as ethyl lactate, both of which are volatile components and are
examples of volatile components that may be included in a
transdermal drug delivery device of the invention. By "volatile,"
is meant that the agent has a vapor pressure above 0.1 mm Hg at 20
C. Other illustrative volatile components useful in the present
invention are known to those skilled in the art and include other
volatile organic solvents, for example, sulfoxides such as decyl
methyl sulfoxide; alcohols such as ethanol, propanols, hexanols,
and benzyl alcohol, fatty acids such as valeric acid, isovaleric
acid, isopropyl butyrate, ethyl acetate, and butyl acetate; polyols
such as butanediol and ethylene glycol; amides such as
dimethylacetamide, diethyl toluamide, dimethylformamide,
pyrrolidone, and methyl pyrrolidone; terpenes such as limonene,
pinene, terpinone, mentone, eucalyptus, and menthol; alkanes such
as hexane and heptane, and organic acids such as citric acid.
[0049] Skin permeation enhancers and solvents additional to DMSO
and similar organic solvents include but are not limited to those
described in Example 1.
[0050] The following description relates to a preferred formulation
of Layer 6 for delivery of a hormone, said layer, or patch,
comprising one or more hormones, skin permeation enhancers, and a
PSA matrix comprising an adhesive polymer and a
humectant/plasticizer.
[0051] Skin Permeation Enhancers: Drug molecules released from a
transdermal delivery system must be capable of penetrating each
layer of skin. In order to increase the rate of permeation of drug
molecules, a transdermal drug delivery system, desirably, is able
to increase the permeability of the outermost layer of skin, the
stratum corneum, which provides the most resistance to the
penetration of molecules. In this regard, the present invention
allows for a transdermal drug delivery system that employs one or
more skin permeation enhancers in specific amounts.
[0052] A combination of skin permeation enhancing agents is
preferably employed in the practice of the present invention for
delivery of levonorgestrel and ethinyl estradiol (EE) or 17
beta-estradiol. The combination comprises a mixture of (1) a
pharmaceutically acceptable organic solvent, such as dimethyl
sulfoxide (DMSO), (2) a fatty (C8-C20) alcohol ester of a hydroxy
acid, such as lauryl lactate, (3) a lower (C1-C4) alkyl ester of a
hydroxy acid, e.g., ethyl lactate, and (4) a C6-C18 fatty acid,
such as capric acid. In specific embodiments, the fatty alcohol
ester of lactic acid is lauryl lactate and the lower alkyl ester of
lactic acid is ethyl lactate. A medium- to long-chain fatty acid in
the skin permeation enhancer formulation can be employed among the
skin permeation enhancers. Capric acid is preferred for use but
other C6-C 18 saturated or unsaturated fatty acids may be used,
including but not limited to caproic acid, caprytic acid, lauric
acid and myristic acid, to name a few.
[0053] These skin permeation enhancers can be present in amounts as
described below. In certain embodiments, one or more of the skin
permeation enhancers may be eliminated from the polymer matrix.
[0054] In a particular such embodiment, the pharmaceutically
acceptable organic solvent is DMSO. Other organic solvents suitable
for use in the present invention include, but are not limited to,
C1-C8 branched or unbranched alcohols, such as ethanol, propanol,
isopropanol, butanol, isobutanol, and the like, as well as azone
(laurocapram: 1-dodecylhexahydro-2H-azepin-2-one) and
methylsulfonylmethane, to name a few.
[0055] The fatty alcohol ester of a hydroxy acid can be a fatty
alcohol ester of lactic acid, such as lauryl lactate. However,
other hydroxy acids and fatty alcohols may be utilized. Alternative
hydroxy acids include, but are not limited to, alpha-hydroxy acids
such as glycolic acid, tartaric acid, citric acid, malic acid and
mandelic acid, as well as the beta-hydroxy acid, salicylic acid.
Alternative fatty alcohols include any C8-C20 saturated or
unsaturated fatty alcohols, such as myristyl, palmityl or oleyl
alcohols, to name a few.
[0056] The lower alkyl ester of hydroxy acid can also utilize
lactic acid, and can be, e.g., ethyl lactate. However, other
hydroxy acids, such as glycolic acid, tartaric acid, citric acid,
malic acid, mandelic acid and salicylic acid, may also be utilized.
In addition isopropylmyristic acid (IPM) may be used as a
substitute for the lower alkyl ester of hydroxy acid.
[0057] The aforementioned combination of skin permeation enhancers
may be used to enhance transdermal delivery of steroid hormones
from any type of transdermal delivery device. An adhesive polymer
matrix-type system as described in detail herein is preferred for
use; however, the enhancer combination may also be utilized in
non-adhesive polymers, as well as in multi-layer or reservoir-type
transdermal delivery systems, to name a few.
[0058] Hormones: A transdermal drug delivery device utilizing the
aforementioned skin permeation enhancers can be used to deliver
various types of API, including a hormone, capable of transdermal
delivery. In one embodiment, a combination of a progestin and an
estrogen is utilized for one or more of the following purposes: (1)
control of fertility, (2) control of acne, (3) treatment of
endometriosis, (4) treatment of premenstrual dysphoric disorder
(PMDD), and (5) induction of amennorhea. In another embodiment, a
progestin alone is utilized for one or more of the following
purposes: (1) control of fertility, (2) supporting pregnancy, (3)
as an alternative hormonal therapy for individuals for whom
estrogen is contra-indicated (e.g., lactating females), and (4)
preventing galactorrhea. In still another embodiment, a combination
of progestin, estrogen and testosterone is utilized as a hormone
replacement therapy for the treatment of deficiency of these
hormones in females. Yet another embodiment is directed to a THDS
formulated for delivery of testosterone alone, which is useful for
the treatment of decreased libido resulting from testosterone
deficiency in both males and females.
[0059] Levonorgestrel is a potent progestin on a weight-dose basis,
which is an important factor since the progestins often exhibit a
much lesser degree of transdermal absorption than do the estrogens.
Other progestins that could be used in part or total are
norgestrel, norgestimate, desogestrel, gestodene, norethindrone,
nore-thynodrel, hydrogesterone, ethynodiol dicetate,
hydroxyprogesterone caproate, medroxyprogesterone acetate,
norethindrone acetate, progesterone, megestrol acetate, gestogen
and certain others which are biocompatible and absorbable
transdermally. These include biocompatible derivatives of
progestins that are transdermally absorbed, some of which,
advantageously, are bioconvertible after transdermal absorption to
the original progestin. The progestin and other hormones selected
preferably have high compatibility with each other.
[0060] For combinations of progestin with estrogen, the synthetic
hormone ethinyl estradiol is particularly suitable, although
natural estrogen or other analogs can be used. This hormone may be
transdermally delivered in conjunction with the particularly
suitable progestin, levonorgestrel, by a TDHS of the present
invention at desirable daily rates for both hormones. Ethinyl
estradiol and levonorgestrel are compatible and can be dispersed in
the adhesive polymer formulation. Typically, a transdermal dosage
unit designed for one-week therapy should deliver at least about 20
.mu.g/day of levonorgestrel, e.g., about 50 to about 100 .mu.g/day
(or an equivalent effective amount of another progestin) and 10-50
.mu.g/day of ethinyl estradiol (or an equivalent effective amount
of another estrogen). Those respective amounts of progestin and
estrogen are believed to be necessary to inhibit ovulation and to
maintain normal female physiology and characteristics. In the
present invention, the amount of levonorgestrel transdermally
delivered is preferably 30 .mu.g per day for more than one day to
about one week with a 15 cm.sup.2 transdermal delivery device.
Derivatives of 17.beta.-estradiol that are biocompatible, capable
of being absorbed transdermally and preferably bioconvertible to 17
.beta.-estradiol may also be used, if the amount of absorption
meets the required daily dose of the estrogen component and if the
hormone components are compatible. Such derivatives of estradiol
include esters, either mono- or di-esters. The monoesters can be
either 3- or 17-esters. The estradiol esters can be, illustratively
speaking, estradiol-3, 17-diacetate; estradiol-3-acetate; estradiol
17-acetate; estradiol-3, 17-divalerate; estradiol-3-valerate;
estradiol-17-valerate; 3-mono-, 17-mono- and 3, 17-dipivilate
esters; 3-mono-, 17-mono- and 3,17-dipropionate esters; 3-mono-,
17-mono- and 3, 17-dicyclo pentyl-propionate esters; corresponding
cypionate, heptanoate, benzoate and the like esters; ethinyl
estradiol; estrone; and other estrogenic steroids and derivatives
thereof that are transdermally absorbable.
[0061] Combinations of the above with estradiol itself (for
example, a combination of estradiol and estradiol-17-valerate or
further a combination of estradiol-17-valerate and estradiol-3,
17-divalerate) can be used with beneficial results. For example,
15-80% of each compound based on the total weight of the estrogenic
steroid component can be used to obtain the desired result. Other
combinations can also be used to obtain desired absorption and
levels of 17 .beta.-estradiol in the body of the subject being
treated.
[0062] Formulations comprising testosterone may utilize natural
testosterone or synthetic testosterones that are absorbed
transdermally. For instance, methyl testosterone is suitable for
use in the present invention. A transdermal device for testosterone
delivery in premenopausal women should be formulated for delivery
of up to about 300 .mu.g daily. For treatment of testosterone
deficiency in males, transdermal hormone delivery systems should be
formulated to deliver up to about 3-6 mg daily.
[0063] It will be appreciated that the hormones may be employed not
only in the form of the pure chemical compounds, but also in a
mixture with other pharmaceuticals that may be transdermally
applied or with other ingredients which are not incompatible with
the desired objective as listed above. Thus, simple
pharmacologically acceptable derivatives of the hormones such as
ethers, esters, amides, acetals, salts and the like, if
appropriate, may be used. In some cases, such derivatives may be
preferred. The progestin compound and the estrogenic steroid are
ordinarily dispersed or dissolved concurrently in fabricating the
hormone-containing adhesive polymer matrix or they may be dispersed
or dissolved separately.
[0064] As noted above, this invention is not limited to transdermal
delivery of an estrogen or a progestin or even to transdermal
delivery of a steroidal hormone. Instead, the invention can be
practiced using a wide range of actives.
[0065] Polymers Used as Active Patch Components: The AI-containing
layer can be a polymer matrix comprising the pharmaceutically or
cosmetically active ingredient. The polymer can be a PSA to form a
biologically acceptable adhesive polymer matrix, preferably capable
of forming thin films or coatings through which the AI can pass at
a controlled rate. Suitable polymers are biologically and
pharmaceutically compatible, nonallergenic, insoluble in and
compatible with body fluids or tissues with which the device is
contacted. The use of water soluble polymers is generally less
preferred since dissolution or erosion of the matrix would affect
the release rate of the AI as well as the capability of the dosage
unit to remain in place on the skin. So, in certain embodiments,
the polymer is non-water soluble.
[0066] Preferably, polymers used to form a polymer matrix in the
AI-containing layer have glass transition temperatures below room
temperature. The polymers are preferably non-crystalline but may
have some crystallinity if necessary for the development of other
desired properties. Cross-linking monomeric units or sites can be
incorporated into such polymers. For example, cross-linking
monomers that can be incorporated into polyacrylate polymers
include polymethacrylic esters of polyols such as butylene
diacrylate and dimethacrylate, trimethylol propane trimethacrylate
and the like. Other monomers that provide such sites include allyl
acrylate, allyl methacrylate, diallyl maleate and the like.
[0067] A useful adhesive polymer formulation comprises a
polyacrylate adhesive polymer of the general formula (I):
##STR00001##
[0068] wherein X represents the number of repeating units
sufficient to provide the desired properties in the adhesive
polymer and R is H or a lower (C1-C10) alkyl, such as ethyl, butyl,
2-ethylhexyl, octyl, decyl and the like. More specifically, it is
preferred that the adhesive polymer matrix comprises a polyacrylate
adhesive copolymer having a 2-ethylhexyl acrylate monomer and
approximately 50-60% w/w of vinyl acetate as a co-monomer. An
example of a suitable polyacrylate adhesive copolymer for use in
the present invention includes, but is not limited to, that sold
under the tradename of Duro Tak.RTM. 87-4098 by National Starch and
Chemical Co., Bridgewater, N.J., which comprises a certain
percentage of vinyl acetate co-monomer.
[0069] Humectant/plasticizer: Preferably, a plasticizer/humectant
is dispersed within the adhesive polymer formulation. Incorporation
of a humectant in the formulation allows the dosage unit to absorb
moisture from the surface of skin which in turn helps to reduce
skin irritation and to prevent the adhesive polymer matrix of the
delivery system from failing. The plasticizer/humectant may be a
conventional plasticizer used in the pharmaceutical industry, for
example, polyvinyl pyrrolidone (PVP). In particular, PVP/vinyl
acetate (PVPNA) co-polymers, such as those having a molecular
weight of from about 50,000, are suitable for use in the present
invention. The PVPNA acts as both a plasticizer, acting to control
the rigidity of the polymer matrix, as well as a humectant, acting
to regulate moisture content of the matrix. The PVPNA can be, for
example, PVPNA S-630 which is a 60:40 PVP:VA co-polymer that has a
molecular weight of 51,000 and a glass transition temperature of
110 C. The amount of humectant/plasticizer is directly related to
the duration of adhesion of the overlay. Preferably, the PVP/vinyl
acetate is PVPNA S-630 supplied by International Specialty
Products, Inc. (ISP) of Wayne, N. J., wherein the PVP and the vinyl
acetate are each present in approximately equal weight percent.
[0070] The shape of the device of the invention is not critical.
For example, it can be circular, i.e., a disc, or it can be
polygonal, e.g., rectangular, or elliptical. The surface area of
the AI layer generally should not exceed about 60 cm.sup.2 in area.
Preferably, it will be about 5 to 50 cm.sup.2, more preferably,
about 8 to about 40 cm.sup.2. Most preferably, the discs will be
about 10 to about 20 cm.sup.2. A disc of 15 cm.sup.2 is preferred
because of its relatively small size, yet being capable of
dispersing high levels of hormones. Specific embodiments of the
invention feature patches having an AI layer with a surface area of
10, 12.5, 15, 17.5 or 20 cm.sup.2. However, other sizes may be
utilized.
[0071] In illustrative embodiments, the AI layer is disposed
directly between the internal backing layer and the release liner.
There is not a "reservoir" or pre-formed pocket, as such; rather,
the AI layer and internal backing layer are hermetically sealed
between the overlay and the release liner.
[0072] With such polymeric matrix, the active ingredient does not
need to be contained, e.g., in microcapsules or other
containment/release means.
[0073] The Internal Backing Layer
[0074] When the PSA comprises a polyacrylate matrix, as described
above, the organic component can escape through the skin and
non-skin contacting surface of the system. In order to minimize
such escape through non-skin contacting surface, an internal
backing layer can be employed. This layer, which inhibits
absorption of components of the AI layer into the overlay, is
illustrated as Layer 5 in FIG. 1.
[0075] Such internal backing layer can be made of any suitable
material that is impermeable or substantially impermeable to the AI
and to excipients of the adhesive polymer matrix. The internal
backing layer serves as a protective cover for the AI layer and
provides a support function. The backing layer can be formed so
that it is essentially the same size as the hormone-containing
adhesive polymer matrix or it can be of larger dimension so that it
can extend beyond the edges of the AI-containing patch outwardly.
The backing layer can be any appropriate thickness that will
provide the desired protective and support functions. A suitable
thickness is from about 10 to about 300 microns. More specifically,
the thickness is less than about 150 microns, yet more
specifically, it is less than about 100 microns, and most
specifically, the thickness is less than about 50 microns.
[0076] Examples of materials suitable for making the internal
backing layer are films of polypropylene, polyesters such as
poly(ethylene terephthalate), metal foils, metal foil laminates of
such suitable polymer films, and the like. Polyester films, such as
Mylar.RTM. (DuPont Teijin) and Scotchpak.RTM. 9732 (3M Company),
are particularly suitable for use in the present invention.
[0077] The internal backing layer is, in general, a separate layer
from the overlay or any component layer of the overlay, e.g., it is
not co-extruded or co-molded with the overlay. In illustrative
embodiments, the internal backing layer can be coated on the
surface adjacent the AI layer with a "tie-coat," e.g., a polyvinyl
acetate-polyethylene vinyl acetate copolymer or other soft polymer
or copolymer.
[0078] The Release Liner
[0079] The surface area of the release liner is greater than that
of the AI layer. This can be seen in FIG. 1, where the diameter (in
the case of a round device) or width and length (in the case of a
polygonal device) of Layer 3 is greater than that of Layers 5 and
6, such that it extends beyond the AI layer in some or all
directions.
[0080] The release liner is made of any material (1) that is
impermeable or substantially impermeable to the components of the
AI layer, (2) to which the PSA in the overlay will adhere, as
discussed further hereinbelow, and (3) that is readily removable by
peeling from the AI layer and overlay PSA just prior to applying to
the skin. "Impermeable" and "substantially impermeable," will be
understood to mean that the components of the AI layer, in
particular, the volatile components, do not become absorbed by or
otherwise pass into or through the release liner such as to alter
the performance of the device, in particular, the skin permeability
or efficacy of the active ingredients.
[0081] The release liner can have the same dimensions as the
overlay, discussed below, or it can extend totally or partially
beyond the edge of the patch. In one illustrative embodiment, the
release liner extends partially beyond the overlay so as to form
"tabs" of release liner material that extend beyond the edges of
the overlay for easy separation of the release liner from the rest
of the system.
[0082] Preferably, it comprises a fluorinated or siliconized
polyester film or another fluorinated or siliconized polymer such
as a polyacrylonitrile copolymer, or a foil lined with a
siliconized or fluorinated polymer. The release liner is preferably
not polystyrene because it has been shown that polystyrene will
absorb DMSO. A preferred material for the release liner when the
layer 4a of the overlay comprises a PIB PSA is a Scotchpak.RTM.
liner (3M Company), such as Scotchpak.RTM. 1022 or Scotchpak.RTM.
9744 fluorinated polyester release liners.
[0083] In this illustrative embodiment, a drug-permeable membrane,
rate-control membrane, porous membrane, seal peel, peelable disk or
other layer, covering or coating between the polymeric matrix and
the release liner is not required. Instead, in illustrative
embodiments, owing to the viscosity of the polymeric matrix, the
release liner is in direct contact with the AI layer and, outside
the perimeter of the AI layer, with the overlay.
[0084] The Overlay
[0085] The overlay in this illustrative embodiment comprises three
component layers, referred to in FIG. 1 as layers 1, 2, and 3. The
overlay comprises a PSA in which the solubility of the volatile
components is less, preferably significantly less, than the
solubility of those same components in the AI matrix. So, e.g.,
when the volatile component is DMSO or ethyl lactate, a PIB PSA may
be chosen. With reference to FIG. 1, the PIB PSA layer is Layer 3.
Generally, such PIB PSA comprises a mix of a low to medium
molecular weight and a high molecular weight PIB, a plasticizer
such as polybutene, and a hydrocolloid such as a cross-linked
polyvinylpyrrolidine. Useful PIBs include, e.g., Oppanol.RTM. PIBs
(BASF), which have average molecular weights of between 40,000 and
4,000,000.
[0086] A useful PIB PSA comprises crospovidone such as
Kollidon.RTM. CLM crospovidone (BASF) (e.g., 5-45 wt %, preferably
15-30 wt %, and more preferably 20-25 wt %); a low viscosity PIB
such as Oppanol.RTM. B12 (molecular weight: 51000, viscosity at 150
C: 150 Pascal-seconds) (e.g., 10-60 wt %, preferably 30-50 wt %); a
high viscosity PIB such as Oppanol.RTM. B100 (viscosity:
[0087] approximately 1100 Pascal-seconds) (e.g., 2-15 wt %,
preferably 5-15 wt %); a polybutene such as Indopol.RTM. 1900
(Innovene LLC) (molecular weight: 2500, viscosity at 100 C:
3900-4200 centistokes) (e.g., 10-60 wt %, preferably 20-40 wt %);
and a mineral oil (0-20 wt %). For example, an illustrative
formulation comprises about 20 wt % crospovidone, about 40 wt % of
a low viscosity PIB, about 8 wt % of a high viscosity PIB and about
32 wt % of polybutene. (The term, "about," as used in this
specification, means plus or minus 10%. By "low viscosity" is meant
less than about 300 Pascal-seconds and by "high viscosity" is meant
more than about 800 Pascal-seconds, when the viscosity is measured
at 150 C.) Cross-linking of the PVP is useful because such
cross-linked polymers tend to be water-swellable but water
insoluble. Such PIB PSA can provide good wear stability, e.g.,
attachment under normal living conditions for at least 7 days.
[0088] Other rubber-based polymers that can be used in place of PIB
PSA in the overlay include silicone-based PSAs, such as
BIO-PSA.RTM. (Dow Corning); copolymers and terpolymers of
styrene/butadiene/styrene, styrene/isoprene/styrene, and
styrene-ethylene/butylenes-styrene, such as Kraton D
styrene/butadiene and Kraton G styrene-ethylene/butylene-styrene or
styrene-ethylene/propylene-styrene. Isoprene rubbers, such as
Kraton IR linear polyisoprene homopolymers, can also be used.
[0089] As shown in FIG. 1, and like the release liner, the overlay
can extend beyond the perimeter of the AI layer in all directions,
typically by a margin of about 0.1 to about 1.5 cm, more
specifically about 0.3 to about 1.2 cm, and yet more specifically
about 0.8 cm beyond the perimeter of the AI layer.
[0090] The overlay, if it comprises a PSA layer, improves adherence
to the skin by supplementing the adhesion provided by the PSA in
the AI layer, if present, or, in the case of an AI layer that does
not comprise a PSA, it provides adherence to the skin.
[0091] In addition, in one illustrative embodiment of the
invention, the overlay adheres to the release liner around the
perimeter of both layers, thereby sealing in the components of the
AI layer. By properly selecting the materials that comprise the
overlay and the release liner, this seal between them prevents, or
substantially prevents, escape of the volatile component in the AI
layer but still allows the release liner to be peeled away easily
by the user prior to topical application.
[0092] The seal is formed in situ by mechanically pressing together
the edges of the overlay that extend beyond the perimeter of the AI
layer and the edges of the release liner that extend beyond the
perimeter of the AI layer. When the first overlay layer is a PIB
PSA and the release liner is a fluorinated or siliconized polyester
film, a suitable seal can be made by applying pressure. The amount
of pressure required to form such seal is not critical. Finger
pressure is adequate. Of course, in an illustrative embodiment of
the invention, it is desirable that the seal can be broken by
peeling the release liner from the rest of the system by hand just
prior to application to the skin.
[0093] The seal between the overlay PSA and the release liner
prevents, or substantially prevents, loss of the components of the
AI layer through the seal between these two layers such as during
storage of the system.
[0094] The seal can also be formed by ultrasonically welding the
release liner to the overlay or to the internal backing layer such
as is described in the U.S. patent application based on
WO2009009651, which is incorporated in its entirety herein as
though fully set forth.
[0095] The overlay can also comprise a covering (1) that does not
comprise a PSA, i.e., that comprises a non-PSA layer, such that the
surface of the overlay that is exposed to fingers, clothing and
ambient dirt or dust is non-tacky, is flexible or malleable so as
to flex with skin and muscle movements, is of an unnoticeable or
attractive color and texture, and permits moisture from the skin to
pass through the device owing to its being porous or otherwise
permeable to water.
[0096] Thus, it may be desirable to utilize a multi-layered overlay
comprising a first layer of a PSA in which the volatile component
is insoluble, covered with an intermediate layer and an overlay
covering having the properties described above. Such illustrative
overlay is illustrated in FIG. 1 as Layers 1, 2, and 3.
[0097] While a PIB PSA is useful for containing DMSO or ethyl
lactate, or both, in the AI layer, the PIB PSA may flow through
most overlay coverings having the properties described above. Such
flow of the PIB PSA can cause the device to become tacky and
discolored. Therefore, it may be desirable to use an overlay
covering that itself comprises two layers, one of which is a
polymeric layer interposed between the PIB PSA (an intermediate
layer) and a backing layer. Such intermediate layer can be a
polyacrylate PSA as described above, because such PSA will
substantially prevent flow of the PIB PSA into and through the
overlay covering but will substantially not itself migrate into or
through the overlay covering.
[0098] Thus, in an illustrative embodiment of the invention, the AI
layer comprises a polyacrylate matrix further comprising a
humectant, e.g., PVP/VA, and skin permeation enhancers including
DMSO, ethyl lactate, or both, or another one or more volatile
organic solvents; the overlay is a laminate that comprises three
layers: a PIB PSA layer (3, in FIG. 1); an intermediate layer that
comprises a material that does not permit flow of the PIB PSA but
that does permit passage of moisture (2, in FIG. 1); and an overlay
covering (or backing layer) that is non-tacky, attractive,
flexible, and moisture permeable (1, in FIG. 1).
[0099] Materials useful in the intermediate layer include, e.g.,
polyacrylates, polyurethanes, plasticized polyvinyl chlorides, and
copolymers of polyethylene and ethyl vinyl acetate. Rubber-based
polymers that are of very high molecular weight, e.g., at least
about 150,000 Daltons can also be used, as can rubber-based
polymers that can be crosslinked. Examples include the Kraton D
styrene/butadiene, Kraton G styrene-ethylene/butylene-styrene or
styrene-ethylene/propylene-styrene and Kraton IR linear
polyisoprene homopolymers Butyl rubbers and silicone rubbers, which
are cross-linkable, can also be used. The intermediate layer can
comprise a PSA that binds the first overlay layer as well as the
overlay covering. High molecular weight, cross-linked polymers are
preferred. Preferably, such PSA is a polyacrylate such as is
described above with reference to the AI layer.
[0100] Materials used in the overlay covering are not PSAs. They
include, for example, a polyurethane film, foam or spun bonded
structure, a polyolefin foam, a PVC foam or a woven or non-woven
fabric. Illustrative wovens include KOB 051, 053 and 055 woven
polyesters (Karl Otto Braun.) Illustrative non-woven fabrics
include polyesters. An illustrative polyurethane material is
CoTran.TM. 9700 melt-blown polyurethane nonwoven backing (3M),
which can be colored in skin tones. Suitable materials are
described, e.g., as backing layers in U.S. Pat. No. 6,660,295.
[0101] If the overlay covering is not porous, then it can be used
without an intermediate layer. However, if the overlay covering is
not porous, adhesion problems can result from a build up of
moisture in the skin/PIB PSA interface. Use of a solid material,
i.e., one that is not porous, but that is otherwise permeable to
water, such as a thin, e.g., 1 mil (i.e., 0.001 inch), polyurethane
film, can be used. However, a porous material such as a foam or
fabric will, in general, better retain its shape and provide good
adhesion.
[0102] Thus, based on the above description of an integrated
transdermal delivery system, it can be seen that an aspect of this
embodiment of the invention pertains to containing a volatile
component in the AI layer by forming a seal between an overlay and
a release liner.
[0103] Another aspect of this embodiment of the invention pertains
to use of a PIB PSA in an overlay for an AI layer that comprises a
volatile solvent, especially, DMSO, because DMSO is poorly soluble
in PIB PSAs. See Table 1, below, which compares the solubility of
DMSO in a polyacrylate PSA (Duro Tak 87-4098, National Starch) and
in a PIB PSA such as is described above.
TABLE-US-00001 TABLE 1 SATURATION SOLUBILITIES (MG/G) PSA DMSO
Ethyl Lactate Lauryl Lactate Duro-Tak 87-4098 8 150 1000 PIB PSA
0.01 0.03 785
[0104] These data indicate that DMSO and ethyl lactate, which are
both volatile, cannot migrate into the PIB PSA because of
saturation considerations. Of course, it will be understood that
some amount of absorption into the overlay is acceptable and,
indeed, unavoidable, at least under certain conditions. It is
important, however, in this embodiment of the invention, that the
solubility of the volatile component in the AI containing layer be
higher than, preferably substantially higher than, the solubility
of the volatile component in the overlay PSA. References herein to
a PSA that does not absorb volatile components must be understood
in this context. In any event, the above data also indicate that
the lauryl lactate, which is relatively not volatile, can flow into
the PIB PSA by contact, which is why an internal backing layer is
preferred in the transdermal drug delivery system of the
invention.
[0105] Consistent with the above data, wear studies have shown that
the PIB PSA retains its adhesiveness better than the polyacrylate
PSA when stored in the presence of volatile enhancers owing to the
reduced tendency of the volatile enhancers to migrate into the PIB
PSA from an acrylic adhesive AI matrix, which migration would
adversely affect the PIB PSA adhesiveness.
[0106] Overlay PIB and polyacrylate PSAs were tested in wear
studies to determine their ability to adhere to skin for long
periods of time. Table 2 shows that when absorption of excipients
was minimized (25 C exposure) the acrylic adhesive gave better
results than the PIB. When absorption of excipients was allowed to
proceed in a more rapid rate (40 C exposure) the adhesion provided
by the PIB PSA was better than that of the acrylic PSA. It is
important to note that the adhesivity of the PIB PSA was the same
when exposed to higher (40 C) or lower (25 C) conditions, for
absorption of volatile excipients.
TABLE-US-00002 TABLE 2 ADHESIVITY OF INTEGRAL OVERLAY/ACTIVE
PATCHES Overlay Equilibration Equilibration Adhesive Time
Temperature Adhesivity (1) Acrylic 1 month 25 C. 16.2 Acrylic 1
month 40 C. 12.8 PIB 1 month 25 C. 15.1 PIB 1 month 40 C. 15.1 (1)
Note: These are relative values in which a higher number signifies
better adhesion.
[0107] Another aspect of this embodiment of the invention pertains
to use of an overlay covering to cover the PIB PSA, which layer
protects against contact with the PIB PSA and allows water vapor
transmission. Another aspect of this embodiment of the invention
pertains to use of a porous overlay covering and an intermediate
layer that is permeable to moisture but that inhibits or prevents
flow of the PIB PSA into and through the overlay covering.
[0108] The data in Table 3, below, illustrate that (1) use of a
urethane overlay with or without a PIB PSA layer (PIB PSA is
protecting the urethane on one side only) will result in
absorption, and therefore loss, of volatile components such as are
in the skin permeation enhancer composition illustrated in Examples
1 and 2 and (2) a polyester film does not absorb such components,
even when coated with a PIB PSA such as when the internal backing
layer is Mylar.RTM. and the overlay comprises a PIB PSA.
TABLE-US-00003 TABLE 3 ABSORPTION OF ENHANCERS BY PATCH COMPONENTS
(wt %) 1. Polyurethane spun bonded CoTran(TM) 9700 (3M) 10.6
nonwoven for overlay 2. Same as 1 but coated with Hi-Tack Nonwoven
9.65 acrylic adhesive Medical Tape 9904 (3M) 3. Same as 2 but
overcoated 7.6 with 2 mm of PIB PSA (similar to Table 1) Polyester
internal backing layer Mylar .RTM. 0.96 Polyester coated with 2 mm
PIB Mylar .RTM. 1.12 PSA(similar to Table 1)
[0109] The data in Table 3 were obtained by placing in a metal
dessicator the 4 enhancers in the same ratio as in the patch
described in the Examples, below. The different components of the
patch were placed in the same dessicator, making certain that the
liquid enhancers (which were placed in a beaker on the bottom of
the dessicator) were not in contact with the patch components.
Therefore, any absorption of the enhancers into the patch
components could only take place through vapor transfer. The
dessicator was placed in a 40 C oven and the absorption into the
patch components was measured by weighing the samples and
determining the weight gain after 3 months.
[0110] Polyester non-woven fabrics, e.g., KOB 053 and KOB 055, were
also shown not to absorb the volatile components to a significant
extent.
EXAMPLES
[0111] The following examples are set forth to describe this
embodiment of the invention in greater detail. They are intended to
illustrate, not to limit, the invention.
Example 1
Fabrication of Transdermal Drug Delivery System
[0112] Example 1 is a description of one of the ways to fabricate a
dermal delivery system of the invention. It will be appreciated
that other ways can also be used. In this example, Part A
illustrates preparation of Internal Backing/AI layer/Release Liner
Laminate. Part B illustrates fabrication of a foam/acrylic PSA/PIB
PSA overlay structure. Part C illustrates fabrication of an
integrated device, or system, of the invention utilizing the
laminates prepared in Parts A and B.
[0113] Part A. Fabrication of an Internal Backing/AI layer/Release
Liner Laminate: After deaeration, an adhesive polymer composition
comprising the AI and the volatile component(s) is applied to the
backing layer material, and subsequently dried for a set time at a
set temperature. In an alternative embodiment, the adhesive polymer
matrix may be applied to a release liner instead of to the backing
layer. Accordingly, reference herein to application of the adhesive
polymer matrix to the backing layer will be understood to include
this alternative embodiment. Application of the deaerated adhesive
polymer matrix to the backing layer may be accomplished using
commercially available laboratory coating/drying apparatus
routinely used for this purpose. For instance, the Werner Mathis
Model LTSV/LTH apparatus may be utilized, as well as other
laboratory coating devices available from Werner Mathis AG (Zurich,
Switzerland). Other suitable devices include, but are not limited
to, instruments produced by Chemsultants, Inc. (Mentor, Ohio).
[0114] The thickness of the adhesive polymer solution applied to
the backing layer, as well as the time and temperature of drying,
are all process parameters that can be varied to achieve the final
concentrations and ratios of hormones and permeation enhancing
agents within the patch. For instance, it has been found that a
change in the thickness of adhesive polymer matrix applied to the
backing layer (e.g., from 300 to 800 .mu.m) can result in an
overall greater retention of volatile skin permeation enhancers
when the other two process parameters, drying time and drying
temperature, are held constant. In contrast, changing the drying
time, e.g., from 5 to 25 minutes, or the drying temperature, e.g.,
from 40-100 C, can result in overall losses in retention of
volatile skin permeation enhancers, to a greater or lesser degree
depending on the enhancer.
[0115] Thus, it will be appreciated by those of skill in the art
that, in addition to selection of appropriate amounts of starting
materials in the adhesive polymer starting formulation, an
appropriate combination of (1) initial thickness of the deaerated
adhesive polymer solution spread on the backing layer, (2) drying
time and (3) drying temperature may be selected to achieve the
final composition of skin permeation enhancers and AIs in the
device.
[0116] The dried adhesive polymer matrix is next laminated with a
piece of release liner (such as Scotchpak.RTM. 1022 or 9744, 3M
Co., St. Paul Minn.) (or backing layer, if the alternative
embodiment is utilized), preferably of the same size to form a
sheet of the transdermal hormone delivery systems.
[0117] Part B. Fabrication of a non-woven/acrylic PSA/PIB PSA
Overlay Laminate: The fabrication of the overlay is performed in
two steps.
[0118] In the first step, a PET-silicone coated release liner is
unwound and a solution of an acrylic adhesive Duro-Tak 87-2852 is
coated on the silicone side of the release liner. The web proceeds
through heated ovens where the solvents are blown off and the
release liner/solid acrylic PSA laminate is formed. The laminate
proceeds toward a laminator unit where the 3M 9700 spun bonded
non-woven is unwound and the acrylic PSA and the 3M 9700 go through
the heated laminator rolls where a three layer laminate is formed
(3m 9700/acrylic PSA/silicone release liner).
[0119] In the second step a PET-silicone coated release liner is
unwound and a solution of a PIB PSA is coated on the silicone side
of the release liner. The web proceeds through heated rolls where
the solvents are blown off and the release liner/solid PIB PSA
laminate is formed. The laminate proceeds toward a laminator unit
where the 3M 9700/acrylic PSA/silicone release liner laminate is
positioned. The 3M 9700 laminate is unwound, its release liner is
removed and discarded and the rest of the laminate proceeds toward
the heated laminator rolls where it combines and gets laminated to
the release liner/solid PIB PSA laminate to form the finished
overlay composed of 3M 9700 spun bonded non-woven/acrylic PSA/PIB
PSA/silicone release liner.
[0120] Part C. Fabrication of an Integrated Device of the Invention
(Double Disc Conversion Process): The conversion of a double disc,
peripheral adhesive transdermal delivery device is fabricated on a
die cutting-laminating piece of equipment typical for the industry.
It has at least two payout stations, two die cutting stations, one
lamination station, and three rewind stations. A roll of overlay
laminate (Polyurethane, Polyacrylate PSA and PIB PSA) from Part B
and a roll of release liner/active patch/internal backing layer
laminate from Part A are mounted onto the payout spindles. The
active patch laminate is threaded through a die cutting station
where a partial or kiss cut is performed in the shape of the active
patch through the internal backing and AI layer, and not through
the release liner. The waste material around the patches is
delaminated from the protective liner and wound onto a rewind
spindle.
[0121] The overlay laminate is threaded through the conversion
machine, the release liner is removed and the exposed overlay
adhesive-urethane backing is laminated over the patch and onto the
release liner from the active patch laminate. The resultant
laminate with the active patch sandwiched between the overlay and
the release liner is die cut in a shape larger than the active
patch and collected for the next processing step. The resulting
liner with holes cut out in the shape of the overlay-patch is wound
on a rewind spindle.
Example 2
Control of Loss of Volatile Components
[0122] A transdermal hormone delivery device was prepared
comprising an internal backing layer, an AI layer, and a release
liner. The AI layer comprised, as a polymer matrix PSA: Duro Tak
87-4098; as a humectant: PVP/VA-S360; as skin permeation enhancers:
dimethylsulfoxide (DMSO), lauryl lactate (Ceraphyl.RTM. 31), ethyl
lactate, and capric acid; as the AI: levonorgestrel and ethinyl
estradiol.
[0123] The device also comprised an overlay comprising a
polyurethane spun bonded non-woven backing, which is able to absorb
large amounts of the volatile excipients, DMSO and ethyl lactate,
an acrylic PSA coated onto the polyurethane foam, and a PIB PSA
coated on top of the acrylic PSA. The internal backing layer was
composed of a Mylar polyester backing film onto which was coated an
acrylic PSA containing the AI as well as the volatile excipients,
DMSO and ethyl lactate at 8 wt % and 1.7 wt % nominal
concentrations, respectively, and a non-volatile excipient, lauryl
lactate at 8.4 wt % nominal concentration. The release liner was a
Mylar polyester film coated with a fluoropolymer release coating.
The patches were assembled so that the release liner was in direct
contact with the PIB PSA of the overlay, forming an in situ seal
around the active patch.
[0124] The devices were placed in a 25 C or 40 C oven. After 6
weeks and 12 weeks, devices were removed from the oven and the
active section of each device was separated from the overlay. The
amounts of DMSO, lauryl lactate, and ethyl lactate in the active
patch were determined using gas chromatography. (12 weeks exposure
to 40 C is intended to simulate 18 months exposure to room
temperature (25 C)). The results are shown in Table 4.
TABLE-US-00004 TABLE 4 Amounts of DMSO, Ethyl Lactate, and Lauryl
Lactate in the AI Patch DMSO Ethyl Lactate Lauryl Lactate
Conditions (wt %) (wt %) (wt %) 6 wks, 40 C. .sup. 9.02 1.66 9.02
12 wks, 40 C. .sup. 8.98 1.57 9.20 12 wks, room temp 9.08 1.79
9.10
[0125] These results demonstrate that the seal between the overlay
and the release liner and the use of an overlay, internal backing
layer, and release liner, are adequate to prevent loss of volatile
components (DMSO, ethyl lactate) and a non-volatile component
(lauryl lactate).
[0126] Dermal delivery devices of the invention can optionally be
packaged for distribution and sale to users. Standard packaging can
be used or, if desired, packaging that exerts pressure on the in
situ seal between the release liner and the PSA of the overlay can
be employed. The purpose for such packaging is to keep the release
liner and overlay in contact with each other and to minimize
slippage or gapping that might occur, e.g., during transportation.
Such packaging can comprise a closable packet (e.g., a clamshell
packet that is hinged to open but that can be snapped close) that
when closed fits snugly around the perimeter of the delivery
device, thereby exerting a small amount of pressure on the in situ
seal, but that is shaped so as not to squeeze the AI-containing
patch.
Example 3
Clinical Study
[0127] Devices of a type described in Example 2 were analyzed for
adhesion and irritation in a clinical study. Placebo patches or
patches containing actives were applied to the skin of women for
pre-determined time periods, among which were (1) one week, (2) two
monthly treatment cycles, and (3) three monthly treatment
cycles.
[0128] Adhesion Analyses:
[0129] A) Placebo patches applied for one week to 59 women: one out
of 59 patches (1.7%) exhibited meaningful degree of detachment;
[0130] B) Active patches applied for two treatment cycles to 38
women: 12 out of 149 patches (8.1%) exhibited meaningful degree of
detachment;
[0131] C) Placebo and active patches applied for three treatment
cycles to 59 women: 13 out of 208 patches (6.3%) exhibited
meaningful degree of detachment;
[0132] The mean cumulative total adhesion score (calculated per FDA
Guidance) was 0.9 with an upper limit of 1.38 (placebo patch, one
week, 59 women).
[0133] Irritation Analyses:
[0134] A) Placebo patches applied for one week to 54 women: 0 out
of 54 patches (0.0%) resulted in significant irritation and 1 out
of 54 patches (1.9%) resulted in moderate irritation.
[0135] B) Active patches applied for two treatment cycles to 38
women: 0 out of 143 patches (0.0%) resulted in significant
irritation and 6 out of 143 patches (4.2%) resulted in moderate
irritation.
[0136] C) Placebo and active patches applied for two treatment
cycles to 54 women: 0 out of 197 patches (0.0%) resulted in
significant irritation and 7 out of 197 patches (3.6%) resulted in
moderate irritation.
[0137] The mean cumulative total irritation score (calculated per
FDA Guidance) was 0.11 with an upper limit of 0.21 (placebo patch,
one week, 54 women).
[0138] The present invention is not limited to the embodiments
described and exemplified above, but is capable of variation and
modification within the scope of the appended claims. Published
patent applications and patents referenced in this specification
are incorporated herein by reference as though fully set forth.
* * * * *