Note: Descriptions are shown in the official language in which they were submitted.
~5~ S
BANDAGE FOR SUSTAINED DELIVERY OF DRUGS
_ _
Field of the Invention
This invention relates to bandages and
systems for controlled release of transdermally or
topically administered drugs and, more particularly,
to an improved bandage in which the patient's normal
skin moisture effects dissolution and delivery of
the drug.
Background of the Invention
As used in this application and the
appended claims, the word "drugs" is intended in its
broadest sense to apply to all medicaments of any
type, wnether topical or systemic, applied for
therapeutic purposes.
In recent years, there have been provided
numerous bandages designed for delivery of drugs to
the skin or mucosa of the wearer. One group of such
prior bandages is represented by U. S. Patent Nos.
3,632,7~0; 3,769,071; and 3,896,789, which teach the
2() incorporation oE specific active agents into a
pressure sensitive adhesive for direct contact with
skin lesions/ and the likeO Those bandages had no
means for control of the rate of delivery and were
objectionable for many applications because oE the
direct contact of the drug with the skin.
Another group of prior bandages employed
specially designed diffusion membranes and drug
reservoirs as represented by U. S. Patent Nos.
3,598,122 and 4,069,307. Those bandages were
complex, expensive, and involved difficult and
precise manufacturing techniques.
An offshoot or refinement of the drug
reservoir approach resulted in the
micro-encapsulation of fine particles of the drug
and the dispersion of the microcapsules within a
~5~
matrix comprising a discrete layer of a laminar
structure. Representative of such bandages are
U. S. Patent Nos. 3,996,934; and 3,598,123. Once
again, such bandages were complex, costly and
difficult to make.
U. S. Patent No. 4,286,592 teaches another
laminate bandage in which the drug is dispersed in a
dissolution carrier matrix, and discusses the use of
an adhesive to control the rate of dissolution and
administration of the drug. Here, too, the bandage
was complex and costly and required specific
manufacturing parameters.
A simpler bandage is shown in Patent No.
4,307,717, but it still required that the drug be
dispersed in a matrix and it did not address the
question of control of the rate of dissolution.
Summary of the Invention
___
The present invention grows out oE the
discovery that sustained, substantially constant
rate of release over long periods of time can be
ohtained using clrugs in solid Eorm. In its broadest
~orrn, the bandage of the invention comprises only a
l liquid-impermeable backing, a solid drug, ~ e-r~
in pellet form, and a moisture-permeable skin
contact adhesive. Controlled rate dissolution of
the solid drug results from contact therewith of
water or water vapor emanating from the skin of the
wearer.
The solid dru~ may be used in its pure form
and no added excipients, matrices, or dissolution
carriers are required. The salutary results
achieved derive from the correlation between the
body moisture and the solubility of the drug therein
and the fact that such moisture can pass through the
adhesive up to the drug and the dissolved drug is
s
able to pass back through the adhesive to the skin
of the patient.
Further control of the rate of dissolution
can be obtained in a number of ways. One method is
by varying the composition of the adhesive and/or
its thickness. Another method is to incorporate
into the adhesive a vehicle in which the drug is
soluble, but more or less soluble than in the body
moisture of the patient.
The bandage may also include a carrier web
for the adhesive. The carrier web material can also
be selected so ~hat it may have an effect on the
rate of dissolution. In all its forms, the
inventive bandage is simple, efficient, inexpensive
to make, and eliminates the objectionable features
of the prior art devices, such as, drug reservoirs,
matrices, microencapsulation, diffusion membranes,
and the like.
Vther features and advantages of the
2() inverltion will be apparent from the following
description and claims and are illustrated in the
accompanying drawings which show structure embodying
preferred features of the present invention and the
principles thereof.
Brief Description of the Drawin~s
FIG. 1 is a perspective view of a bandage
embodying the principles of the invention with
portions of the adhesive layer being broken away ~o
reveal internal structure;
FIG. 2 is an enlarged vertical sectional
view taken on the plane of line 2-2 in FIG. 1,
FIG. 3 is a similar view of a modified form
of the bandage;
FIG. 4 is a simllar view of another
modified form of the bandage; and
5~
FIG. 5 is a graph of the dissolution of two
representative drugs plotted against time, the drug
for the bandages of Examples 1, 2, and 3 being
timolol, and the drug for the bandage of Example 4
being phenylephrine hydrochloride.
Description oE the Preferred
Embodiments o. the Invention
Referring with greater particularlity to
the various figures of the drawings, there is
illustrated in FIGS. 1 and 2 the basic bandage
structure of the invention indicated generally by
the numeral 10. Bandage 10 comprises a flexible
liquid-impermeable backing layer or sheet 12. The
backing sheet 12 is chosen to prevent migration of
the drug therethrough and insure one-way diffusion
of the drug when applied. In this regard, the
backing sheet may be gas-impermeable as well as
li(luid--lmpermeable, it being necessary only that the
~arne be impermeable to the drug in its dissolved or
vaporized .state. ~or this purpose, a variety of
thin, sheet like materials are suitable, including
aluminum foil, polyester, polypropylene,
polyethylene, polyurethane film, and a laminate of
aluminum foil and polyester. Desirably, backing
sheet 12 is thin and flexible, having a thickness in
the range of 6 to 50 microns.
Positioned on the backing sheet 12 is a
thin pellet 14 made of a compressed, solid drug.
The solid drug pellet 14 may be substantially
circular in form and have an inner face 16 of
s~bstantially larger dimensions than the pellet's
thickness. l~In this regard, the pellet 14 may range
be~ween 0 5 and 10 cm in diameter, 5 and 1,000
~s;~
microns in thickness, and have a mass between 1 and
1,000 mg. The significance of the relatively large
surface area 16 will become apparen~ as the
description proceeds.
A layer of skin contact adhesive 18 covers
the pellet 14 and retains the same on the backing
sheet 12. The layer 18 may comprise any of the
conventional pressure sensitive adhesives, such as,
acrylic copolymer, styrene-butadiene-styrene,
styrene-isoprene-styrene and silicone polymer, and
may also contain tackifying resins.
The acrylic adhesives may be selected from
a variety of pressure-sensitive adhesive copolymers
as are well known in the art. Broadly, the useful
pressure-sensitive adhesives include the copolymers
o~ acrylic and/or methacrylic acids, alkyl acrylate
and methacrylate esters containing 1 to 10 carbon
atoms, such asl methyl methacrylate and
2-ethyl-hexyl acrylate, acrylamicles and
Tnethacrylam.ides, and addit.ional copolyrnerizable
monoettlylenically unsaturated monomers, such as,
vinyl acetate/ acrylonitrile and alkyl vinyl ethers
containing 1 to 10 carbon atoms/ such as, propyl
vinyl ether.
More specifically/ the pressure-sensitive
acrylic adhesives may comprise copolymers of
2-ethyl-hexyl acrylate, vinyl acetate and acrylic
acid sold under such trademarks or tradenames as
Gelva RA-788 made by Monsanto, AS-351 made by Avery
Chemical and Aeroset 1085 made by Ashland.
The pressure-sensitive rubber-based
adhesives may likewise be selected from a variety of
compounds of styrene-butadiene-styrene (SBS) and/or
styrene-isoprene-styrene (SIS) block copolymers, one
or more plasticizers and a stab.iliæer. Such
3~
, .
pressure-sensltive adhesives may include compounds of
rubber-based block copolymers sold under such trademarks
or tradenames as Kraton 1101 (SBS) or 1107 ~SIS) (Shell
Chemical Company), one or more tackifi.er resins sold under
such trademarks or tradenames as Hercolyn D, Piccolyte A-115,
Stabilite Ester 10 and Foral 85, and a sultable stabilizer.
More specifically, the pressure-sensitive
rubber-based adhesives may comprise from 10 to 3D%
block copolymers of styrene-butadiene-styrene or
styrene~isoprene-styrene, from 30 to 70~ tackifying
resins and 1 to 3~ of a stabilizer.
Silicone adhesives may comprige solvent
solutions of silicone gum and resin, partially
condensed, of the type sold under such trademarks or
tradenames as Dow Corning 355, and PSA 595 or PSA
6574 made by General Electric~
Thickness and composition oE the adhesive
layer 1.8 has been discovered to have an effect on
controlling the ra~e of dissolution of the drug
pellet 14 as will subsequently be described. It has
thu~ been ~ound that acrylic adhesives permit faster
rates of dissolution than a rubber-based adhesiv2,
and the adhesives may likewise contain tackifying
resins, or o~her additions or fillersO Adhesive
layers between 10 and 150 mlcrons in thickness have
been found to be effective depending upon the
particular dxug and application involved. The
adhesive layer lB may be urther modified by
addition of a drug dissolution vehicle as will be
seen from an example to be described.
Any solid drug which is compressible or
handleable in powder form may be employed in its
pllre foxm withou~ the addition of any addi~ives. In
general, the drug will have a rela~ively low melting
3S point, on the order of less than 150C and be
--7--
relatively soluble in water, in the range of 0.1 to
100 mg/ml. Successful results have been achieved
with adrenergics such as timolol and phenylephrine
hydrochloride.
In FIG. 3, there is illustrated a modified
form of the bandage 10 wherein the adhesive layer 18
comprises the outer coating of a carrier web 20. As
indicated, the carrier web is likewise coated with a
layer of adhesive 19 on the inner or pellet side
thereof. The adhesive layer 19 may vary in
thickness between 20 and 300 microns and may be the
same as layer 18, or comprise a different adhesive.
Preferably, carrier web 20 comprises a non-woven
fabric composed of nylon, polyethylene,
polypropylene, rayon, cellulose-rayon, or polyester
and having a fabric weight of from 1 to
100 gm/m . Woven fabrics of gauze or cellulosic
materials having a weight of from 0.5 to 100 gm/m2
may also be employed. Choice of carrier web
matericil can have an efEect on the rate of
dis.solution apparently relatecl to the polarity of
the material of construction. It has thus been
discovered, for example, that a carrier made of a
relatively polar molecule, such as nylon, tends to
retard the ra~e of dissolution.
In FIG. 4, there is illustrated another
modified form of the bandage 10. In this
embodiment, the impermeable backing sheet 12 is
covered by an outer layer 22 to give the bandage a
finished feel, look and wearability. The outer
layer 22 should be flexible, conformable,
lightweight and comfortably wearable. In this
regard the outer layer 22 may comprise occlusive
films of polyethylene, polypropylene, polyvinyl
chloride and polyurethane, or non occlusive woven or
3~
--8--
non-woven fabrics of the same composition as the
carrier web 18 or a perforated film of any of the
listed materials, and ranging in thickness from 10
to 200 microns.
As a final finish, khe bandage 10
preferably includes a protective liner (not shown),
for example, silicone or polyfluoroethylene coated
release liners as are well known in the art,
removably adhered to pressure sensitive layer 18.
Such a liner may be made of paper or film on the
order of 25 to 200 microns thickness and protects
the adhesive prior to use and prevents drug
migration through the adhesive during storageD
The examples which follow illustrate the
invention, but are not intended to limit the
invention in any way.
Example 1
A barldage for administering the
beta-adrenerylc h:Locker timolol transderma:lly Eor a
pe~ri.od in excess o:~ ~0 hours wa~, made in the
fol:Lowing manner. A 50 mg wafer~like pellet of
timolol was prepared in a standard potassium brornide
pellet press, the substantially circular pellet
having a diameter of about 1.25 cm and a thickness
of about 350 microns. The drug pelle~ was placed on
aluminum foil of 50 microns thickness and this was
overlaid with a layer of acrylic adhesive of 50
microns thickness, said adhesive being mass cast
from solution (toluene, heptane) at 40-50~ solids,
wherein the acrylic fraction comprises an acrylic
copolymer prepared through reaction of 2-ethyl-hexyl
acrylate, v:inyl acetate and acrylic acid. In vitro
release tests were carried out on the bandage using
standard apparatus and techniques~ narnely Standard
U.S.P. Type 2 dissolution apparatus with with a
~j3~
phosphate bufer solution of pH 7.4. Constant
release of the druy was sustained over a period in
excess of 80 hours, after which the release slowed
appreciably and the drug was substantially
exhausted. Between 4 and 72 hours, the drug release
approached a linear rate.
Example 2
A bandage for administering timolol was
made. As in Example 1, a 50 mg pellet of the drug
was prepared and placed on aluminum foil o 50
microns thickness. The pellet was then overlaid
with a tackified styrene-butadiene-styrene
pressure-sensitive adhesive containing 5~ mineral
oil, said adhesive being mass cast from solution
(toluene, heptane) at 40-50% solids, wherein the
rubber fraction comprises a compound of 18~
styrene-butadiene-styrene block copolymer, 15%
random styrene-butadiene copolymer, 61~ tackifying
resins, 5% mineral oi:L, and 1~ .stabiliæer. Eor
purposes of comparisorl, the solubility oE timolol is
ahout 8 mg/mL in water and about 4 mg/ml in mineral
oil. Ln the same standard in vitro release tests
substantially constant release of the drug was
sustained for a period in excess of 120 hours after
which the release slowed appreciably and the drug
was substantially exhausted. Between 8 and 100
hours, the drug release approached a linear rate.
Example 3
A bandage for the administration of timolol
was made by preparing a pellet of the drug and
placing the same on aluminum foil as in Examples 1
and 2. The pellet was then overlaid with an
adhesive carrier web made of non-woven polyester
having a fabric weight of 19.9 gm/m . The carrier
web had previously been coated on the pellet side
--10--
with acrylic adhesive, having the same composition
as in Example 1, of 25 microns thickness and on the
non-pellet, or skin-contact, side with the same
acrylic adhesive of 50 microns thickness. In the
same standard in vitro release tests substantially
constant release of the drug was sustained for a
period in excess of 120 hours after which the
release slowed appreciably and the drug was
substantially exhausted. Between about 15 and 960 hours, the drug release approached a linear rate.
Example 4
A bandage for the administration of the
drug phenylephrine hydrochloride was made in the
following manner. A 70 mg wafer-like pellet of the
drug was prepared in a standard potassium bromide
pellet press, the substantially circular pellet
having a diameter of about 1.25 cm and a thickness
of about 350 microns. The drug pellet was placed on
alurninurn foil of 50 microns thickness. This was
overLaid wJth an adhesive carrier web made of a
non-woven polyec;ter having a ~abric weight oE
l9~g cJrn/m2. The carrier web had previously been
coated on the pellet side with tackified
styrene butaaiene-styrene pressure~sensitive
adhesive, having the same composition as in Example
2~ of 25 microns thickness and on the non-pellet, or
skin-contact, side with acrylic adhesive, having the
same composition as in Example 1, of 50 microns
thickness. In the same standard in vitro release
tests, substantially constant release of the drug
was sustained for a period in excess of 35 hours,
after whic~ the drug release slowed appreciably and
the drug was substantially exhausted. Between abo~t
1 and 32 ho~rs, the drug release approached a linear
rate.
~5~
It should be apparent from the foregoing
that the invention provides a simple, efficient and
inexpensive bandage for the sustained transdermal or
topical administration of drugs over an extended
period of time. The use of solid drugs
advantageously eliminates all matrices,
encapsulations and dissolution media of the type
heretofore required in bandages of this type. It
should be appreciated that the term "bandage" is
used in its generic sense to apply to any skin
adhesive device whatever its form or shape. While
preferred embodiments have been illustrated and
described herein, changes and variations may be made
by those skilled in the art without departing from
the spirit and scope of the appended claims. The
invention is defined by the claims that follow.
