Note: Descriptions are shown in the official language in which they were submitted.
lOS9~09
There are soveral patents that relato to bandages for administering
systcmic drugs transdermally. In thi~ regard, United States Patent No.
3,797,4~4 is believod to be the most relevant to the prese~t invention.
Figure 2 of that patent shows a bandage that includes the basic elements of
the invontion bandage. Indeed, tho invontion bantage is considered to be a
patentable ombodiment of the bandage depicted in said Figure 2. Both bandages
are la~inates that inclute a backing, a drug reserYoir, a microporous membrane
ant a contact adhcsive layer. Howovor, scopolamino is present in the inven-
tion bantage in specific proportions in the contact adhesive layer as well as
in the reservoir. Also, tho matrix of the reservoir layer of the invention
bandage is a gel.
The antiemetic and antinausoant properties of scopolamine and re-
latod compounds aro known. Those propertios have been investigated by admi-
nisterlng scopolamine ant related compounds intra~uscularly ant orally.
tC~. Woot and A. Graybiel, '~hoory of Antimotion Sickness Drug Mechanisms",
Aerosp. Met. 43: 249-52, 1972; ant C.D. Wood ant A. Graybiol, "A Theory of
Motion Sicknos~ Based on Pharmacological Roactions", Clin. Pharm. 11: 621-9,
1970; J.J. Brand and P. Whittingham, "Intramuscular Hyoscino in Control of
Motion Sicknoss", Lancet 2: 232-4, 1970.)
Scopolamine acid salts and the C4-C12 esters of scopolamine have
beon applied topically as antiperspirants. tF.S.K. MacMillan, H.H. Reller ant
P.H. Snyter, "Tho Antiperspirant Action of Topically Applied Anticholinergics",
J. Invest. Der~,43: 363-7, 1964,) The C4-C12 scopolamine esters are roported
to be morc offective antlperspirants than scopolamino itself because they
penetrate bettor. These osters arc the subject of United Statcs Patent No.
3,767,786. They were tested as antiperspirants by applying them as solutions
or creams to the forearm and axilla at a dose of 2 mg. Minor systemic respon-
sos were obser~ed. Such respor.ses wera correlated with systomic responses
obtained by administoring ~he esters subcutaneously and it was estimatet there-
from that only 5~ to 10~ of the dermally applied esters was absorbed.
-- 1 --
lOS9909
The abo~e ~entionet patont suggests using ~inoral oil as a vehicle
for antiperspîrant co positions containing the osters, provited there is suf-
ficiont water iscible vohiclo also present to provide a modium for absorption
by the skin Various surfactants are reportod as absorption onhancers for the
scopola ine esters
The invontion provides a therapeutic system in the for~ of a bantage
for ad inistering scopola ino base through unbroken skin to inhibit e esis and
nausea comprising a la inate of a backing la ina that is substantially imper-
eable to scopola ino base, ono face of which for~s the top of the bandage, a
scopola ine base roservoir lamina adjacent the opposite face of the backing
laoina, a icroporous e brane la ina adjacent and below the scopolamino reser-
voir la ina through which scopolamine base is released from the roservoir la-
ina aftor the bandage is affixod to the skin, a contact adhesive la ina adja-
cont and below the microporous me brane lamina by which the bandage is affixed
to the skin, and optionally a strippable coating la ina that is substantially
i por~oablo to the co pononts of tho contact adhesive la ina and is adapted to
bo strippod off tho bandage bofore the bandage is affixed to the skin charac-
terizod by tho reservoir la ina being co prised of about 0 2 to about 3 g
scopolamine base disporsed in a gellot mixturo of aineral oil of about 10 to
about 100 cp at 25 C and polyisobutono; the tortuosity, porosity and thickness
of tho e brane lad na, the concontration gradiont of scopola~ino base across
tho embrano, and the diffusion coefficient of scopolamine base in the ineral
oil are such that scopola ine baso is released through the membrane la ina at
a substantially constant rate in the range of about 0 3 to about 10 cg por
~ 9
L ~ hour; and the contact la ina being comprised of about 10 to about 200 ~y~ scopo-
la ine base per cm2 effective surface area dispensed in sait gelled ixture
The invention also provites a process for Daking the above doscribed
therapeutic system characterized by casting the scopola ine base roservoir
la ina onto the backing lamina; casting the con~act adhesive la ina onto the
strippable coating la ina; interposing the microporous e brane lamina betwoen
1059909
the two castings; and laminating the two castings and interposed microporous
membrane lamina together.
As used herein the term"effective surface area" means the surface
area of the bandage that contacts the skin and through which scopolamine is
administeret to the skin. As used herein in connection with describing the
constant rate portion of the administration and the rate at which scopolmaine
is released from said reservoir layer, the term "substantially" indicates
that the rate may vary _20%. Such variation may be inherent in the manufac-
turing procedure, or be caused by temperature fluctuation, poor affixation of
the bandage to the skin, and the like.
The therapeutic system administers scopolamine transdermally to
effectively inhibit nausea and emesis without eliciting intolerable parasym-
patholytic side effects. It does this by delivering scopolamine base to the
plasma in a controlled manner according to a precise dosage program consisting
of an initial pulse administration followed by administration at a substan-
tially constant rate until a desired total quantity of scopolamine has been
administered.
Emesis and nausea may be induced by pregnancy, vestibular disturban-
ces (e.g., those caused by motion), radiation treatment,drug treatment or
treatment with anesthetics. Such illness may be inhibited by the method of
this invention.
The purpose of the pulse portion ~f the dosage program is to shorten
the time it takes for the scopolamine concentration in the plasma to reach the
level required for preventive therapy. It partially does this by "saturating"
the skin with scopolamine. In this respect the skin initially acts as a
"sink" rather than as a "conduit", with most of the scopolamine being bound
within the skin and not passing through to circulation. However, once the
skin is "saturated", that is the binding sites are occupied, it permits addi-
tional scopolamine to pass through circulation. Thus the amount of scopola-
mine administered in the pulse is a function of the area of skin being treated.
1059909
A pulse of 10 to 2G0 mcg scopolamine per cm of skin being treated will usual-
ly allow the therapeutic level in the plasma to be reached within about 3 hr.
AccordinglyJ an adequate time margin of safety is provided if administration
is begun at least about 3 hr before illness is expected. In most instances
the pulse will be in the range of lO0 to 175 mcg scopolamine per cm2 of skin
being treated. The concentration of scopolamine in the plasma can be related
to the concentration of free scopolamine in the urine if the glomerular filt-
ration rate of the subject is known, and it is convenient to express the quan-
tity of scopola~ine in the plasma in terms of a urinary excretion rate. An
average urinary excretion rate of about 0.3 mcg free scopolamine per hr was
found to generally correspond to a therapeutic plasma level. However, it was
also found that this rate is subject to about a ~5-fold biological variation.
Therefore, ~he rate ranges between about 0.05 and about 1.5 mcg per hr depen-
ding on the individual.
The purpose of the substantially constant rate administration por-
tion of the dosage program is to supplement, if necessary, the pulse administ-
ration in delivering e ugh scopolamine to reach the~ above mentionet therapeu-
tic level and to hold that level for as long as is necessary. It follows that
the constant rate atministration portion will proceed for as long as therapy is
required. In this regard a total (including the pulse) of 0.1 to 2.5 mg sco-
polamine administered in accordance with the above described dosage program
will provide a therapeutic effect for about 3 hours to 7 days. It also fol-
lows that the level of constant rate administration may vary depending on the
body weight (plasma volume) of the patient. In this regard in most instances
the rate will be in the range of 3 to 4 mcg per hr for adults and 1 to 2 mcg
per hr for children.
The skin location at which the therapeutic system is applied is im-
portant because the histology, thickness and vascularization of skin varies
from individual ts individual as well as from body site to b~dy site on a given
individual, and such variance affects the efficacy with which scopolamine may
~ 059909
be delivered to the plasma Applicants have found that the effect of this
variance may be substantially eliminatet in either of two ways The first
way is to apply the system to a skin site, namely the mastoidal area, where
scopola ine permeation does not vary significantly from individual to indivi-
dual and thus the quantity of scopolamine delivered to the plasma or the rate
at which such delivery is made is not significantly different between indivi-
duals The second way is to eliminate the stratum cornoum as a quantity-
affecting or rate-affecting element by treating the skin at the administration
site with a skin per~eation enhancing agont Such treatment will allow the
system to be appliet to body sites, such as the arms, legs or torso, other
than the mastoital area Depending on the particular agent involved, the
treataent aay occur prior to or simultaneously with the ad~inistration of
scopolamine base fro the system Likewise, the quantity of agent needed
will depend on the particular agent used In any event, the agent plays the
dual role of increasing the per~eability of the stratum corneua to scopolanine
and decreasing the tendency of the stratum corneum to bind scopolamine Ex-
a ples of known agents which may be used are dodecyl pyrrolitone, dimethyl
lauramide and di ethyl sulfoxide All three of these agents ay be used in
pre-treat ent applications The pyrrolidone and lauraaide aar be applied to
the atministration site at about 4 to 8 ag/cm2 for approxiaately an hour and
then washed off They ay be incorporatet into the system and ad inistered
si ultaneously with the scopol oine at approxi ately the same dosago as the
scopola ine The suIfoxite is preferably used only as a pre-treatment at
doses in the range of 5 to 100 mg/cm2 for approximately one hour, and then
washet off
The trawing is an enlarget, schematic, cross-sectional view of the
preferred embotiment of the bandage of the invention The trawing depicts a
bandage, generally designated 10, that when applied to skin administers sco-
plamine base according to the prescribed tosage program Bandage 10 is a five-
layer laainate The top layer 11 is a backing that is substantially imperme-
-- 5 --
1059909
able to scopolamine base. Its face 12 forms the top surface of the bandage.
Backing 11 serves as a protective covering, keeps the volatile components of
the bandage from escaping, and fulfills a support function. Preferably,
backing layer 11 is itself a laminate of films of polymer and metal foil such
as aluminu~ foil. Polymers that may be used in tho layer are high and low
density polyethylcne, polypropylene, polyvinylchlorite and polyethylene
torephthalate.
Below and adjacent to layer 11 is a scopolamine reservoir layer 13.
Layer 13 contains about 1 to about 6 mg scopolamine base, the undissolved
portion of which is tepicted as troplets 14. The scopolamine base contsined
in layer 13 is teli~ered to the plasma during the constant administration por-
tion of the dosage program. Droplets 14 are dispersed homogeneously in a
gellet mixture of mineral oil of about 10 to about 100 cp at 25C and a blend
of polyisobutene. The oil will usually constituto 35~ to 65% by weight of
tho mixture ant the polyisobutene will correspondingly usually constitute 35
to 6S% by weight of the mixture. The polyisobutene blend co prises a low
lecular weight polyisobutene (35,000-50,000 viscosity average molecular
weight) and a high molecular weight polyisobutene (1,000,000-1,500,000 visco-
sity average molecular weight). Preferret mixtures co prise 35S to 65% mine-
ral oil, lOS to 40% low molecular weight polyisobutene, and 20% to 40% high
lecular weight polyisobutene. These oil-polyisobutene mixtures are excel-
lent adhesives ant help to holt the bandage together. If they were not good
adhesives, other means, such as heat soaling, would have to be used to keep
the bandage together.
The mineral oil in layer 13 functions as a carrier for the scopola-
mine base. Scopolamine base has limited solubility in the mineral oil (approxi-
mately 2 mg/ml) and the relative amounts of each in layer 13 are such that the
mineral oil is saturated with the base for essentially the entire dispensing
lifetime of the bandage.
The next lamina in the bandage is a microporous m~mbrane 15 whose
~059909
pores are filled with the above described mineral oil. Membrane 15 is the
element of the bandage that controls the rate at which the base is released
from layer 13. The flux of scopolamine through membrane 15 and the area of
membrane 15 must be such that scopolamine is released from reservoir layer 13
to the skin at a substantially constant rate in the range of 0.3 to 10 mcg/hr
after the bandage has been put in use. The flux follows Ficks' law. It is a
function of the tortuosity, porosity and thickness of the membrane, the oon-
centration gradient of scopolamine base across the membrane and the diffusion
coefficient of scopolamine base in the mineral oil. The concentration gradi-
ent depends on the scopolamine concentrations in the mineral oil at the oppo-
site sides of the membrane. The diffusion coefficient depends on the mineral
oil viscosity and decreases with increasing viscosity. The three properties
of the membrane are, of course, constant for any given membrane. Membranes
that have porosities from about 0.1 to 0.85, tortuosities from 1 to 10, and
thicknesses from 10 3 to 10 2 cm may be used. The membrane may be formed
from polymers such as polypropylene, polycarbonates, polyvinylchloride,
cellulose acetate, cellulose nitrate, and polyacrylonitrile.
Below and adjacent membrane 15 is a contact adhesiYe lamina 16.
Lamina 16 contains 10 to 200 mcg scopolamine base per cm effective surface
area. The undissolved portion of the scopolamine is depicted as droplets 17.
The scoplamine base in lamina 16 is the pulse dosage of the invention method.
The scoplamine is dispersed in the same mineral oil-polyisobutene mixture that
is used in layer 13. Lamina 16 is the means by which the bandage is attached
to the skin. In this regard the mineral oil-polyisobutene mixture adheres less
strongly to skin than it does to the other laminas of the bandage; therefore,
the bandage tends to remain intact when it is pulled off the skin.
Prior to use, the bandage also includes a strippable, protective
coating 18 that covers lamina 16. Just prior to use, coating 18 is peeled away
from lamina 16 and discarded. It may be made from scopolamine-mineral oil im-
105991~9
pormeable materials such as tho poly ers from which backing 11 may be made,
with the provision that these atorials are mate strippablo, such as by sili-
conizing
Bandago 10 may be applied to either mastoidal rogion and it will
administer scopola~ine according to the described dosago program without re-
quiring any prior or si ultaneous treat ent of the rogion with a skin per-
moation enhancing agent As indicatet abovo, if the b~ndage is applied to a
body site other than a astoidal aroa, the site should bo treated with one or
re of the describod skin per~eation enhancing agents If si~ultaneous
treatment is dosired, the agent ay be incorporated into bandage 10 In that
instance, layers 13 and 16 will contain effectivo quantities of such agents
Tho sizo of the bandage is not critical The bandage will usually
be si~ed to ad inister scopola ine to an area of skin in the range of 0 5 to
4 cm2 Corrolativoly, tho effective surfaco area of the bandage will also
usually be in the range of 0 5 to 4 cm2
Tho following oxamples illustrato the in~ontion Thoy are not in-
tendot to li it tho scopc of the invention in any way Unless indicated
otherwise, parts are by weight
Exa ple 1
A solution of 29 2 parts high molecular weight polyisobutene tsold
undor the designation Vistanex MML-100, 1,200,000 viscosity average olecular
weight), 36 5 parts low olecular weight polyisobutene (sold under the desig^
nation Vistanex LM-MS, 35,000 ~iscosity average locular weight), 58 4 parts
mineral oil (10 cp ~ 25C), 15 7 parts scopolamine base and 860 2 parts chlo-
roform is solvent cast onto an approxi ately 65 icron thickbackingfila of
alu inizet polyethylone teraphthalate (sold under the designation MEDPAR) to
for~ a scopolamine base reservoir layer approxiaately 50 microns thick A
contact adhesive layer-strippable coating co bination is similarly prepared
by solvent casting onto a 200 micron thick siliconizod, alu~inized, polyethy-
leno backod polyethylene terephthalate film a solution of 31 8 parts of said
~de ll1aM~
8 --
1059909
high molecular weight polyisobutene, 39 8 parts of sait low molecular weight
polyisobutene, 63 6 parts of said d neral oil, 4 6 parts of scopola~ine base
ant 860 2 parts chloroform The rosulting contact athesive layer is approxi-
~ately 50 microns thick
The above toscribet backing_roservoir layor combination is then lami-
natet to one face of a 25 ~icron thick microporous polypropylene membrane
(sold under the tesignation Celgart 2400) saturatet with sait mineral oil ant
the above described contact athesive layer-strippable coating combination is
la inatet to the opposite faco of the me~brane Ono cm2 circular, tisc-shapet
bantages are punch cut from the resulting S-layer laminate Each bantage is
dosignet to release an initial 130-150 cg/cm2 pulse of scopola ine followet
by an ossontially constant tosage of 3-3 5 mcg/c~2/hr
Exa ple 2
A solution of 22 3 parts of the high molecular weight polyisobutene
described in Ex~rple 1, 28 0 parts of the low olocular woight polyisobutene
toscribet in Exa~plo 1, 44 9 parts mineral oil (66 cp e 25C), 12 8 parts
scopola ino baso, 8 8 parts dimethyl laura ide and 883 2 parts of chlorofor~
is solvent cast onto tho backing film tescribod in Exa ple 1 to form a scopola-
ine base resorvoir layor approximately 50 icrons thick A contact athesive
layer-strippable coating combination is similarly preparod by solvent casting
onto the siliconi~ed polyethylene terophthalate film described in Example 1 a
solution of 23 5 parts of said high molecular weight polyisobutene, 29 5 parts
of sait low molocular weight polyisobutene, 47 6 parts mineral oil (66 cp 0
25C), 7 8 parts scopola ine base, 9 0 parts dimethyl lauramide and 882 6 parts
chloroform The resulting contact layer is approxi~ately SO ~icrons thick
The abovo describet backing-reservoir layer combination is then la-
minated to one face of a 25 micron thick icroporous polypropylene me brane
(sold under the designation Celgard 2400) saturated with said mineral oil and
the above described contact adhesive layer-strippable coating combination is
- 30 laminated to the opposite face of the me~brane Four cm2 circular, disc-shaped
~ ~r~ rl~
_ 9 _
1059909
bandages are punch cut from the resulting 5-layer la~inate. ~ach bandage is
designed to release an initial 125 mcg/cm2 pulse of scopolamine followed by
an essentially constant dosage of 2 mcg/cm2/hr.
The bandages of Example 2 were tested on a double blind basis as
follows. A bandage was applied to the skin behind the ear of 17 subjects
prior to exposure to motion at sea. Placebo bandages (no scopolamine present)
were similarly applied to 18 subjects. All subjects had a prior history of
experiencing tion-induced nausea. Only one of the 17 subjects wearing the
bandages of 8xa~ple 2 beca~e ill to the extent that additional antinauseant
medication has to be administered while at sea. In contrast, 9 of the sub-
jects wearing the placebo bandages had to receive additional antinauseant
metication while at sea.
_ 10 -
