Note: Descriptions are shown in the official language in which they were submitted.
~q~
This is a divisiollal a~pl:ication o-F Serial ~o. 395,6~1, Eilod
February 5th, 1982.
Technical Field
,
The invention is a dosage Eor aclministering drugs percutaneously.
It is particularly useful for administering estracliol percutalleollsly.
Background Art
The practicality of admin-ister:ing a givc;~n clrug percutaneously on
a continuous basis depends UpOII the concentrat:ion of drug in the bloocl that is
required to provide the desirecl therapy, how permeable the skin is to the
drug) and the amount of skin surface area that is available for administration.
The available skin surface area, while theoretically not being limited, is for
patient acceptance reasons typically confined to more than about 5 cm and
less than about 100 cm . With available area fixed in this range, the matter
narrows to whether sufficient drug will pass through that much area to provide
the desired therapy. If it will, it is simple to effectively administer the
drug percutaneously. If, however, the inherent permeability of the skin to
the drug is so high or so low that too much or too little drug will pass
through that area of skin, the rate of administration oE the drug to the skin
must be controlled or the permeability of the skin to the drug must be
increased, as the case may be, to make percutaneous administration practical.
The present invention involves a situation in which the permeability of the
skin to the drug is increased.
There is a great deal of literature concerning compounds that
enhance the percutaneous absorption of drugs. Typically a given amount of the
enhancer is applied to the skin together with a given amount of the drug in a
formulation that has no ability to control the rates at which the enhancer and
drug are administered to the skin surface. In such instances more drug and
more cnhai1ccr are prcsent at thc skin surEacc than the sk-in can ahsorb. I'hus
both drug and enhal1cer pass throug}- the skill at maximum rates wh-ich arc 1ikcly
to be in excess of that needed to providc the dcsired therapeutic rcsult.
United Statcs Patent No. ~,031,89~ sngges-ts prc- or coadminis-
tration of percutaneous absorpt:ion enhanccrs in conncction with thc controlled
percu-taneous administration oE scopolamine. Tl1e cnl~cLncer is applied to
eliminate the stratum corneum as a ratc-a-EEecting barric-r to scopolaminc
absorption. To do this the enhancer must elevate thc sk:in permeability to a
level at which scopolamine is capable oE moving through thc skin Easter than
it is being applied to the skin surface by the system described in -the patcnt.
Thus the scopolamine permeates through the skin surface. In this type of
application the scopolamine administration rate is said to be controlled by
the system rather than by the skin. Correlatively, the enhancer adminis-tration
rate (when coadministered with scopolamine) may be either system-controlled
or skin-controlled, but in either case is of such magnitude as to make the
scopolamine administration rate system~-controlled.
United States Patent No. 3,797,494 describes bandages for ad-
ministrating drugs percutal1eously in which the drug may be mixed with a
transport agent that enhances the penetration of the skin by the drug. The
main components of these bandages are a backing layer, a drug reservoir layer,
a microporous membrane layer, and a contact adhesive layer. The patent
indicates that the rate of drug administration is controlled by the rate at
which drug diffuses from the reservoir through the microporous membrane. These
bandages operate, therefore, in the same manner as those described in United
States Patent No. 4,031,894. The drug administration rate is controlled by
the bandage rather than by the rate at which drug is absorbed by the skin.
United States Patent No. 3,053,255 discloses a multilayer unit for
administering drugs percutaneously tllat is composod o:E thc folLowing layers
beginning with thc OtlC closest to the skin: a :Eibrous carrier laycr in which
the drug is absorbed; an impervious separator layer; a reservo:ir layer in W}liCil
a liquid transport agent that is a solvent ~For the drug :is ahsorbed; and ~m
impervious cover laycr. One or morc wicks rull between the rescrvoir layer and
the carrier layer and serve as a conduit ~for the flow of t-ranspolt agcrlt frorn
the :Eormer to the lattcr. Irl operati.on the t:ransport agcnt f:lows from t}lC
reservoir layer to the carrier layer via the wicks. The transport agent dis-
solves drug absorbed i.n the carr;.er layer as it passes therethrough alld then,
together with dissolved drug, is absorbed by the skin. The cross-sectional
area of the wicks '~mus-t be such that at least so much of the vehicle can flow
therethrough (including the active agent dissolved therein) as will be absorbed
by the skin from the active agent carrier". This quote indicates that the
amounts of drug and transport agent presented to the skin are equal to or
greater than the amounts that the skin can absorb.
Disclosure o_ Invention
The invention of Application 395,6~1 relates to a unit dosage
form and method that coadminister a drug and a percutaneous absorption enhancer
to a predetermined area of skin. The drug is administered to the skin at a
rate at least as great as the rate at which the skin is capable of absorbing
it while the percutaneous absorption enhancer is administered at a substantially
constant rate that increases thc permeability of the treated area of skin to
the drug to a magnitude such that sufficient drug is absorbed to provi.de a
therapeutically effective level of drug in the bloodstream. Accordingly the
rate of drug administration is controlled by the rate at which the skin absorbs
the drug whereas the rate o.E percutaneous absorption enhancer administration is
controlled by the rate at which the enhancer is released from the dosage form
to the s~in surface. riho rate oE drug adrn;.n-ist:rat:ion i.s, thereforo, cont-roilecl
indirectly by the controlled coroloase of the onhancer si.nce the Latter a:EEects
the rate at which the skin will absorb the cl:rug.
This invention provides a E)ercutaTIeous absor;)tio1l en}lancer
dispenser adapted to be suporposed upon the drl1g reservoir means o~ a trans-
dermal drug delive:ry clev:ice. rllis dispenser may be IlSOd in comb:inllt:ion either
with a transdermal delivory device nccordi.ng to App:licati.on 395~6~:1., or wi-th
other forms of transdermal delivery clevico. ~n a p-re-forrocl aspoct oE-this
i.nvention, the dispenser is used in cooperation with a transclermal delivery
device according to Appliction 395,641.
In its broadest aspect this invention provides a percutaneous
absorption enhancer dispenser adapted to be superposed upon the drug reservoir
rneans of a transdermal drug delivery device to control the rate by which the
drug within said reservoir means is absorbed through the skin, said enhancer
dispenser comprising iTI combination:
a) percutaneous absorption enhancer reservoir means; and
b) means for controlling the rate at which said percutaneous
a.bsorption enhancer is released from said enhancer reservoir means to said
drug reservoir means to maintain said rate substantially constant.
As used herein the term "substantial portion of the time period'
means at least about 60% of the time period, preferably at least about 90% of
the time period. Correlati.vely, the term "substantially constant" mea.ns a
variation of less than about -~ 20%, preferably less than about + 10%, over a
substantial portion oE the time period.
The dosage form of Application 395,6~il together with the dispenser
of this invention are especially useful for coadministering estradiol and
ethanol percutaneously to treat conditions associated with natural estradiol
cle-Eiciency, such as osteoporosis and headaches, nausea~ clepress:ion, hot :Elushes~
and other discom~Eorts that o-Eten occuring during mcnopause.
~rief Description of the Drawings
In thc drawings, whic}l are not to scale;
Figure l is an en.larged sectional schcmat:ic v:iow o:t` a -Elrst em-
bodiment of the inven-tion;
Figure 2 is an enlarged sect;.onal schema-t:ic view of a second
embodiment o:E the invelltlon;
Figure 3 is an enlarged schematic sectional view oE a third
embodiment of the invention;
Figure 4 is an enlarged sec-tional schematic view of a fourth
embodiment of the invention;
Figure 5 is a graph illustrating the relationship between -the drug
flux through slcin and the enhancer flux through skin that is typical for many
drug-enhancer combinations,
Figure 6 is a graph of estradiol fluxes versus time for the band-
age of Example 1 and for a gelled estradiol-ethanol mixture;
Figure 7 is a graph of ethanol fluxes versus time for the bandage
of Example 1 and :Eor a gelled estradiol-ethanol mixture;
Figure 8 is a graph showing the plasma estradiol concentration
resulting from estradiol administration via the invention and via a commercial
ointment; and
Figure 9 is a graph of estradiol fluxes versus ethanol fluxes
for the bandages of Example 2.
Modes for Carrying Out the Invention
Figure 1 illustrates a sel:f-adhering skin patch 11 that is
designed to be placed on unbroken skin 12. Patch 11 is a laminate that consists
of -Eour layers: a top backing layer 13; a drug-enhance-r reservoir laye-r 14;
a diffusion memb-rane ]ayer 15, and a contact adhesive laycr 16. Back.ing Layor
13 deEines the top oE the patch. It is rna(1e Erom a material or combin.ltior1 of
materials that is substa11tially impermeclble to the components of reservo:ir l4.
It serves as a protec-t:ive cover Eor the 1~atc1lJ keeps the cornponer1ts of reservo:ir
lamina 14 from escaping Erom the bandage, a11cl EulEi11s a structural suppo:rt
:Eunction. Examples oE ma-terials tha~ may be used to make Layer 13 are high and
low density polyethylene, polypropylene, polyvinylchloride, ancl polyethylene
terephthalate. In embodiments of the invention in which reservoir layer is
fluid, the outer edge of the backing layer will overlay the edge of the reser-
voir layer and be sealed by adhesion or fusion to the diffusion membrane layer.
In such structures the reservoir layer is contained wholly between the backing
layer and the membrane layer and does not have any exposed surfaces. The
backing and diffusion membrane layers will be inherently sealable to each other
or will include sealing means, such as an additional layer or adhesive, in such
embodiments.
Reservoir layer 14 is immediately below backing 13. It contains
supplies of both the percutaneous absorption enhancer and the clrug. The amount
cf drug in the reservoir will depend on the rate at which the drug is absorbed
by the skin Erom the bandage and the intended duration of therapy. Correlat-
ively, the amount of enhancer in the reservoir will depend upon the rate at
which the enhancer is administered -to the skin from the bandage to achieve the
desired degree of drug permeabili-ty enhancement over the treatment period.
Reservoir layer 14 may include diluents, stabilizers, vehicles, gelling agents,
and the like in addition to the clrug and enhancer.
In the embodiment of the invention that coadministers estradiol
and ethanol the principal components of lamina 14 are estradiol and ethanol.
~3~
The estradiol is present either wholly in so]ution or in both dissolved a~d
~rndissolved particulate form dispersed uniformly -through a continuous ethanol
phase. The continuous phase contains estradiol over the lifetimc of the band-
age and the minimum amount of estradiol in layer 14 will dopend on i-ts
solubility in the cont;nuous phase ancl the intellded lifetime of the bandage.
Typically about 0.2 to 12 rlK estradiol w:ill be contained in the reservoir layer.
Similarly, the minimum amount oE etllanol in layer 14 is that which :is suf-fi-
cient to provide a substantially constant flux of about 100 to ~00 mcg/cm2/hr,
preferably 100 to 400 mcg/cm2/hr, of ethanol to the area of skin being treated
over a substantial portion of the intended lifetime of the bandage. The con-
tinuous ethanol phase may also contain one or more covehicles, such as water,
along with ethanol to alter the solubility of estradiol in the continuous
phase. By reducing the solubility of estradiol in the lamina, -the quantity
o-f estradiol in the lamina may be reduced significantly. For instance by using
water as a covehicle at a 40% by weight level, the quantity of estradiol may
be reduced almost two orders of magnitude. Preferably the continuous phase is
in the form of a gel that contains 50% to 75% by weigh~ water so that it may
be handled easily in manufacturing the bandage. Known gelling agents such as
carboxypolymethylene, ethylene maleic anhydride, hydroxyethylcellulose, poly-
acrylamide, ethylhydroxyethylcellulose, hydroxypropylcellulose, and poly(methyl-
vinylether-maleic anhydride) may be included in the continuous phase to make it
gel. The viscosity of these gels are such that the estradiol-ethanol layer
should be wholly contained between the backing layer and the diffusion membrane
in the manner described above.
Diffusion membrane layer 15, the next layer of the laminate,
may be made of a dense or microporous polymer film that has the requisite
permeability to the drug and enhancer. It is the member of patch 11 that con-
trols the rate at which -the e~hcmcer :is adm:i.n;.stcrccl to -thc sk:in. ~[t doos
not, however, control the rate at which thc clrug i.s admi~:istered. :tn other
words, it is a principal pcrmeat:ion barrier to the enilancer bu~ not a s:igni.fi-
cant permeati.on barrier -to tlle drug. Ihe respect;.ve :Eluxes of the drug and
enhancer through layer 15 will depend U~OIl thc thiclcness o:f the l.ayer and its
di:Efusion coefficients relative to thc drug allCI the enhancer. I)i.E~Eusion co-
efficients may be determ:ined by standard -techn:i(l~les. Accorcling:iy, :Ei.:lms thclt
will permit the required :Eluxes o:E drug and enhancer may be selectecl based on
dif:Eusion coefficients and thickncss. Pre:Eerably the membrane layer 15 is
substantially impermeable to other components of the reservoir layer. Examples
of the types of polymer fi].ms that may be used to make layer 15 are disclosed
in United Stcates Patents ~os. 3,797,49~ and 4,031,89~.
Contact adhesive lamina 16 is directly below di-ffusion membrane
làyer 15. It is the means by which bandage 11 is affixed to the area of skin
to be treated. Its composition and thickness are such that it does not con
stitute a significant permeation barrier to the drug and the enhancer. In other
words it should be substantiallymorepermeable to the enhancer than layer 15
and at least as permeable to the drug as layer 15. During the time interval
between the manufacture and the use of bandage 11, layer 16 may absorb enhancer
and drug in amounts that will depend upon the composition and thickness of
layer 16 and the length of that time interval. If that interval is quite long,
layer 16 will absorb enhancer and drug until it is saturated therewith. The
release of such absorbed enhancer from layer 16 once the bandage is applied
to the skin may cause the release rate of enhancer from the bandage to exceed
the desired steady-state rate for a short period of time. That condition will
be transient and will not affect the functionality of the bandage in providing
controlled therapy. Contact adhesive compositions that may be used to make
: - 8 -
layer 16 are disclosecl in Uilitecl~States Paten-ts Nos. ~$,797,49~ and ~,031,89~.
Prior to use, bandage ll also :includes a protecti\/o undercoating
lamina (not shown). Jnst prior to use, thc undercoating lamina ;s ~ulled
away from ]amina 16 ancl discarded. It is made Erom mater:ials that are substall-
tially impermeable to the drug, the enhancer~ ancl any othe-r comporlonts oE l,IYOL
16. The same materials tha-t are used to make backing layer 13 may bo usecl to
make the undercoating laycr, proviclocl they are mado s-trlppablo suctl as by
siliconizing.
Bandage 11 is applied to a relatively no hairy area of skin 12
that is substantially free of wrinkles, creases, or folds. Various locations
on the torso, such as the flank or shoulder, provide suitable si-tes for the
bandage. As indicated above, once it is placed on the skin the bandage will
begin coadministering drug and enhancer to the wearer, with the enhancer being
released at a substantially constant rate (following an initial transient surge)
and drug being released at the rate at which the enhancer-treated skin is
capable of absorbing it. The rate at which the treated skin is capable o:E
absorbing the drug is affected by the enhancer Elux through it. ThereforeJ al-
though drug release is controlled principally by the skin, it is controlled
indirectly via the enhancer flux. In the embodiment that coadministers estra-
diol and ethanol the steady state release rate of ethanol from the bandage is
about lO0 to 800 mcg/cm2/hr, preferably about 100 to about 400 mcg/cm2lhr. Such
rates of ethanol release will permit percutaneous absorption of estradiol at a
therapeutically effective rate. In this regard the steady s-tate estradiol con-
centration in the plasma is incremented by about 15 to ~0 pg/ml for every 1 mcg
of estradiol administered per hour.
Figure 2 depicts another embodiment, generally designated 17, of
the invention in which the drug and enhancer are stored in separate reservoirs.
_ 9 _
Embodimellt 17 is n lamillate composed oE ~four layc-rs: a back;tlg layo-r l~, a
percutaneous enhallcer reservo:ir 19, a diEfllsion membrane layeY 227 a drug
reservoir-contact adhesive layer 23. L,aycr 1~ is :iden-tical in structure and
function to layer 13 o-f embocliment 11. Layer 1~ con-talns the supply of per-
cutaneous absorptiorl en11ancer. As in embocl:iment 11, the amount o-E enhancer -in
layer 19 will clepend on -the :rate of enilcmcer aclmin:ist-ration re~ irocl to achievo
the desired degree oE drug permeabillty enhallcemerlt. ~[t may inclucle cl:iluent,
stabilizers, vehicles, gelling agent, and other Eormulation aids :in acldition
to the enhancer. L,ayer 22 is the component of bandage 17 that controls the
release rate of enhancer to the skin. In this regard it is structurally com-
positionally and Eunct;onally similar to membrane 15 of embodiment 11. Since
the drug does not pass through layer 22, layer 22 need not be permeable to the
drug. Indeed it is preferred that it be substantially impermeable to the drug
to minimize upward migration of the drug from the drug reservoir layer 23.
Layer 23 contains the supply of drug admixed with a contact adhesive composition,
with the amount of drug depending on the rate at which the drug is absorbed
by the skin and the duration of the therapy. The contact adhesive composition
may be the same material as is used to make layer 16 of embodiment 11. Alter-
natively, layer 23 may be separated into a distinct drug reservoir layer com-
posed of the drug supply and a suitable matrix material and a distinct contact
adhesive layer underlying the drug reservoir layer.
Embodiments such as bandage 17 in which the drug and enhancer
supplies are separate may be advantageous or necessary in instances where for-
mulation or storage of the drug and enhancer in contact with each other is
impractical or lmdesirable or where separation of the drug and enhancer
facilitate selection of the diffusion membrane.
Figure 3 illustrates another embodiment, generally designated
- 10 -
25J irl wh1.c}l tbe supllics of d-rug and onlllrlccr are ;el)lr.Jte. iml~odimorlt 25 is
a lamlnate composocl o~ two layers: a h~cking layer 26 allCI a hotcrogeneous
microcapsule-containing basal layer 27. l3ackillg layer 26 is structurally
compositionally al~d f~mctionally identical -to layer 13 of embodirncnt l].
~leterogeneous basal layer 27 is composed of a continuous matrix phase 28 :in
which enhancer-containing microcapsules 29 and drug 32 (rcpresentcd by stip-
pling in Pigure 3) are dispersed. Continuous matrix phase 28 is a solid, sem:i-
solid or gel composition that is permeable to the enhancer ancl the drug. It
preferably adheres to skin. If it does not, an ad}lesivc overlay will have to
be used to keep embodiment 25 in con-~act with the sk:in. The con-tact adhesive
compositions that are used to make the contact aclhesive layers of embodiment 11
and 17 will usually be suitable for use as continuous matrix phase 28. Micro-
capsules 29 each consist of an inner core of percutaneous absorption enhancer
encapsulated by a diffusion membrane. The diffusion membrane functions as
diffusion membranes 15 and 22 and may be made of the same materials and be
selected based on the same criteria as membranes 15 and 22. Accordingly the
diffusion membrane of each microcapsule controls the rate at which -the enhancer
from all the microcapsule controls the rate at which the enhancer is released
$herefrom. The combined release of enhancer from all the microcapsules in turn
defines the rate of release of enhancer from embodiment 25. ~s in the case of
the other embodiments the amount of enhancer contained in layer 27 in micro-
capsule form will depend upon the required enhancer release rate and duration
of therapy. I~licrocapsules 29 may be made using conventional microcapsule
forming techniques. Drug 32 is present in continuous phase 28 in dissolved or
in both dissolved and undissolved forms. The amount of drug present in layer
27 is in excess of that required to provide a continuous source of drug at the
skin surface. The particular amount present in a given instance will depend
- 11 -
UpOIl the rate at wllich the drug is al)sorbcd hy tlle skin from Laycr 27 and tho
duration of therapy. The thicl~ness and composition o~ conti,nuou~-; phase 28
should be such tha-~ the phase does not constitute a pr;,nc;,pal perrnocltion bar-
rier to either the enhancer or the drug.
Figure 4 shows another embocllment oF the i,nvention, generally
designated 33. The componellts o~ embodiment 33 are backing l~lyer 34, a reser-
voir layer 35 that contains supplies of ~ercu-taneous absorption erl}lancer ancl
drug, a diffusion membralle layer 36, alld a peripheral ring 37 of contact acl-
hesive. Embodiment 33 is structurally, t'unctionally, cmd compositiorlally
identical to embodiment ll except in the following respects. First, the con-
tact adhesive component of embodiment 33 is in the form of a peripheral ring
rather than a continuous basal layer. Nei-ther drug nor enhancer passes through
ring 37 and it, therefore, need not to be permeable to those compositions.
Secondly, in embodiment 33 the basal surface from which drug and enhancer is
transferred to the skin is defined by diffusion membrane layer 36. Thirdly,
the backing layer is not flat but instead forms a pocket or cavity in which the
reservoir layer is held. Lastly, the outer edge of the backing layer is sealed
to the peripheral ring of contact adhesive.
The embodiments of Pigures 1~4 may be designed to administer drug
and enhancer at optimum rates to achieve the desired therapy. In order to
determine the optimum rate for a given drug-enhancer combination it is necessary
to determine the relationship between the drug flux through the skin and the
enhancer flux through the skin. Figure 5 shows a plot of enhancer flux versus
drug flux that is typical for many combinations. Drug flux increases substan-
tially linearly at enhancer fluxes between 0 and "a". At enhancer flux "a"
the drug flux levels off at "y" and is not increased by further increases in
the enhancer flux above "a". An optimum design for embodiment involving drug-
- 12 -
ellhallcer combinatiolls h.lvillg such a re]ationsllir) w-ill om~loy an enharlcer flux
slightly abovc "a". At that enhallcer flux, drug flux i,s at a maxi,mum .and is
unaffectecl by minor perturbations in the enhancer flux.
The following examples further illustrate the dosagc form of
the invention, its manufacture, and its operat:ion. Tllese exam~les are not in-
tended to ]imit the invention in any manner. Unless indicated otherwise
proportions are by weight.
xample l
_
Bandages that coadminister ethanol ancl estradiol were m.ade as
follows. A solution of estradiol in 95% ethanol was prepared by mixing 0.0315
part 17-~-estradiol in 1.000 part 95% ethanol. That mixture was gelled by
adding 0.0210 part hydroxypropyl-cellulose (mw lO00000, sold under the trademark
Klucel) with mixing,
Next, a contact adhesive composition was made by mixing poly-
isobutene (mw 1200000), polyisobutene (mw 35000), and light mineral oil in a
weight ratio of 1:1.25:2. A 50 micron thick layer of that contac-t adhesive was
cast onto a 75 micron thick film of siliconized polyethylene terephthalate.
Tlle contact adhesive side of the resulting two-layer subassembly was laminated
to a 50 micron-thick film of et]lylene-vinyl acetate (EVA) copolymer (9% vinyl
acetate). The resulting three-layer subassembly was cut into 15 cm x ll cm
pieces. Four 400 mg portions of the gelled estradiol-e-thanol mixture were
placed equally spaced on the EVA copolymer side of each piece and a 63.5 micron
thick backing film of aluminized polyethylene terephthalate with an EVA heat
sealable coating was laid over the gels. Tile backing film was heat sealed
to the EVA copolymer layer at the periphery of each piece at 130 C, 27 kg.
Finished bandages were punched from laminate with a 4 cm diameter puncll.
In vitro tests were carried out to determine the flux of estradiol
and ethanol -E:rom the al)ove described l-anclages us:inK thc has:i.c techn:i~lues
described by Chandrasekarall, et al, Am. :IIlst. Chcm. Eng J., 22, 828 (1.976).
Est:radiol concentration in the receptor Li~lu:id W.lS assayed ChrOillatOg:raphiCa11y.
For comparison -the same tests were carriecl out by applying a 2 m:L laycr o:E
the above described gellecl estradiol-cthclrlo:L m:ixture on the straturn corneum
side of the skin mo~m-ted in the difEusioncll cells. Figu:res 6 arlcl 7 ar~ plots
o.f the results of those tests, with l:igure 6 showirlg the estrad:i.ol ~luxes and
Figure 7 showing the ethanol fluxes. As shown the estracli.ol flux Erom the
gelled estradiol-ethanol mixture was nonl;.near despite a very high, substcmtial-
ly constant ethanol flux. In contrast both the estradiol and ethanol fluxes
were substantially constant from the bandages.
In vlvo tests were carried out by applying two of the above cles-
cribed bandages to the flank skin of 4 postmenopausal subjects. The results
were compared with those reported by Strecker, et al., ~laturitas, 1:183-190
(lg79). These reported tests were carried out by applying Oestrogel ointment
as prescribed to the abdominal skin (a portion containing 3000 mcg estradiol was
rubbed onto a ~00 cm2 area of skin). In -the tests on the invention bandages
plasma samples were taken from the subjects at regular time intervals and
analyzed by radioimmunoassay for estracliol content. Figure 8 is a plot of the
results of those analyses together with the reported values for the ointment.
As shown, estradiol administration via the bandages caused the concentration of
estradiol in the plasma to rise rapi.dly to about 70 pg/ml and hold at that level.
In contrast estradio]. administration via the ointment caused the concentration
of estradiol in the plasma to rise rapidly to about 80 pg/ml and then continu-
ously drop off over the succeeding 20 hr to about 25 pg/ml.
Example 2
The dependence of estradiol flux on ethanol flux in the bandage
- 1'~ -
was illustrated by the following tests.
~ our ban~lages were made as in Example 1 except that the ethanol
concentratioll was varied -to vary the ethanol -flux. Tll vitro ethanol and estra-
diol fluxes from these bandages werc cletermined by the procedure of example 1
These determinations are plotted in ~igure 9. As shown, cstradiol flux is
directly proportional to ethanol flux over the indicated ethanol flux range.
Example 3
_.
This example illustra-tes the use of water as a covehicle with
ethanol in the reservoir. Three sets of bandages were madc as irl Example ]
except that a 12% rather than a 9% vinyl acetate EVA film was used and 95%
ethanol was replaced with ca 75:25, 60:40, and 50:50 w/w ethanol-water mixes.
Estradiol con-tent per bandage was ~.5 mg, 3.6 mg, and 1.3 mg, respectively.
_ vitro tests were carried out as in Example 1 and the ethanol and estradiol
fluxes were comparable to those of the bandages of Example 1.
As described and shown above, the embodiments of the inven-tion may
be used to conveniently elevate the concentration o-f estradiol in the plasma
to constant levels. In this regard, it is believed that total plasma estradiol
levels in the range of about 25 to 60 pg/ml are most advantageous for treating
conditions associated with menopause and that levels in the range of about 25
to 40 pg/ml will be most advantageous for treating postmenopausal conditions
associated with the natural decrease in es-tradiol after the ovaries cease
functioning. Thus, to treat a given patient one first determines the extent
to which -the concentration must be eleva-ted to reach the above treatment levels.
One then administers a bandage having an effective surface area that will pro-
vide the estradiol flux that will achieve the required degree of elevation.
Based on the cstradiol flux per unit area of skin treated and the elevation of
estradiol in the plasma per 1 mcg estradiol administered per hour that are
described abovc, it is a~pparcllt that thc surfacc arca of skin trcatecl will
typically be in the rangc of 5 to 20 cm .
_ample _
Bandages that coadminis-ter ethanol and cstracli.ol wcrc made as
follows. A solution of estracliol in 95% ethanol was preparcd by mixing 2 g oF
estradiol in 100 ml in 95% etilanol. A gellcd solution of c-thanol was [)reparecl
by mixing 215.5 g of 95% ethanol with 353.5 g of watcr and add:illg 0.5 g hyclroxy-
propylcellulose (mw 1,000,000 sold under the tradcmark l~lucel) while m:ix:ing.
Next, a contact adhesive composition was made by mixing polyiso-
butene (mw 1200000), polyisobutene (mw 35000), and light mineral oil in a
weight ratio of 1:1.25:2. A 50 micron thick layer of that adhesive was cast
onto a 75 micron film of siliconized polyethylene -terephthalate. ~he contact
adhesive side of the resulting two-layer subassembly was laminated to a 38
micron-thick film of ethylene-vinyl acetate (EVA) copolymer (12% vinyl acetate).
The resulting three-layer subassembly was cut into 8 cm x 5 cm pieces. A 5S0
mg portion of the gelled ethanol mixture and a 20 mg portion of the estradiol
solution in ethanol were placed equally spaced on the EVA copolymer side of
each piece and 45.7 micron thick backing film of polyethylene terephthalate
with an EVA heat sealable coating was laid over the gels. The backing film was
heat sealed to the EVA copolymer layer at the periphery of each piece at 150 C,
23 kg. Finished bandages were punched from laminate with a 4 cm diameter cir-
cular punch.
Modifications of the above described invention that are within the
skill of those working in the pharmaceutical, chemical, and/or medical arts are
intended to be within the scope of the following claims.
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