CA1183085A - Percutaneous absorption enhancer dispenser - Google Patents

Abstract

Abstract A dosage form that coadministers a drug and a percutaneous absorption enhancer to a defined area of the skin. The dosage form comprises a body that contains supplies of drug and enhancer and has a basal surface that contacts the area of skin and transmits the drug and enhancer to the area for absorption thereby. The drug is provided to the basal surface at a rate at least as great as the rate at which the skin is able to absorb the drug whereas the enhancer is via a rate controlling means at a substantially constant rate that increases the permeability of the treated area of skin to the drug to a level at which the drug is absorbed at a therapeutically effective rate. A
preferred embodiment delivers estradiol and employs ethanol as an enhancer, the ethanol delivery rate being about 100-800 mcg/hr/cm2 of skin surface.

Description

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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.

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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 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 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-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.

Claims (11)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A percutaneous absorption enhancer dispenser adapted to be super-posed upon the drug reservoir means of a transdermal drug delivery device to control the rate by which the drug within said reservoir moans is absorbed through the skin, said enhancer dispenser comprising in combination:
a) percutaneous absorption enhancer reservoir means; and b) means for controlling the rate at which said percutaneous absorption enhancer is released from said enhancer reservoir means to said drug reservoir means to maintain said rate substantially constant.

2. The dispenser of claim 1 further comprising means for maintaining said enhancer reservoir in enhancer transferring relationship to said drug reservoir means.

3. The dispenser of claim 1 comprising a laminate of:
a) an enhancer impermeable backing;
b) said percutaneous enhancer reservoir means; and c) said enhancer release rate controlling means.

4. The dispenser of claim 3, wherein said enhancer reservoir means comprises a dispersion of said enhancer in a matrix, said means for controlling the release of said enhancer is a release rate controlling membrane and said enhancer reservoir means is sandwiched between said impermeable backing and said membrane.

5. The dispenser of claim 4 comprising means for maintaining said dispenser in enhancer transferring relationship to said drug reservoir.

6. The dispenser of claim 5 wherein said means for maintaining said enhancer reservoir in enhancer transferring relationship to said drug reser-voir means is an adhesive property of said transdermal drug delivery device.

7. The dispenser of claim 5 wherein the transdermal drug delivery device upon which said enhancer dispenser is to be superposed is adapted to deliver said drug to the skin at a rate in excess of the rate that is absorb-able through a predetermined area of untreated skin and said enhancer release rate controlling means is adapted to deliver said percutaneous absorption enhancer at a predetermined substantially constant rate selected to permit absorption of said drug at a rate higher than the rate of absorption through untreated skin and lower than the rate said transdermal drug delivery device is capable of delivering said drug to the predetermined area of the skin.

8. The dispenser of claim 7 wherein said permeation enhancer is ethanol.

9. The dispenser of claim 1 wherein the transdermal drug delivery device upon which said enhancer dispenser is to be superposed is adapted to deliver said drug to the skin at a rate in excess of the rate that is absorb-able through a predetermined area of untreated skin and said enhancer release rate controlling means is adapted to deliver said percutaneous absorption enhancer at a predetermined substantially constant rate selected to permit absorption of said drug at a rate higher than the rate of absorption through untreated skin and lower than the rate said transdermal drug delivery device is capable of delivering said drug to the predetermined areaof the skin.

10. The dispenser of claim 3 wherein the transdermal drug delivery device upon which said dispenser is to be superposed is adapted to deliver said drug to the skin at a rate in excess of the rate that is absorbable through a predetermined area of untreated skin and said enhancer release rate controlling means is adapted to deliver said percutaneous absorption enhancer at a predeter-mined substantially constant rate selected to permit absorption of said drug at a rate higher than the rate of absorption through untreated skin and lower than the rate said transdermal drug delivery device is capable or delivering said drug to the predetermined area of the skin.

11. The dispenser of claim 4, wherein the transdermal drug delivery device upon which said dispenser is to be superposed is adapted to deliver said drug to the skin at a rate in excess of the rate that is absorbable through a predetermined area of untreated skin and said enhancer release rate controlling means is adapted to deliver said percutaneous absorption enhancer at a predetermined substantially constant rate selected to permit absorption of said drug at a rate higher than the rate of absorption through untreated skin and lower than the rate said transdermal drug delivery device is capable of deliver-ing said drug to the predetermined area of the skin.