Transdermal device having decreased delamination

A device for the transdermal administration of a drug comprising a microporous tie layer located between the drug reservoir and the contact adhesive. The tie layer eliminates blooming and delamination and has no appreciable adverse effect on either the drug flux or release rate from the device.

FIELD OF INVENTION 
This invention relates to medical devices for delivering drugs to the body 
through intact skin and more particularly to decreasing blooming and 
delamination at the interface of contact adhesive and drug reservoir layer 
of the medical device without affecting the drug flux and release rate 
from the therapeutic transdermal system. 
BACKGROUND OF THE INVENTION 
Devices that deliver drugs through skin for absorption into the body are 
known in the art. For example, U.S. Pat. No. 4,915,950 to Miranda et al, 
describes a transdermal drug delivery device including an absorbent source 
layer laminated to a pressure sensitive pharmaceutically acceptable 
contact adhesive. The source layer has an anchor adhesive layer laminated 
to its opposing side and a drug-impermeable backing layer applied to the 
anchor adhesive. 
U.S. Pat. No. 4,817,594 to Juhasz, describes an integral anti-bacterial 
wound dressing containing the following five layers: the first layer of a 
permeable material; a layer of semipermeable material; a layer of 
electrically-conducted material in the form of an open mesh; a layer of 
charcoal fabric; and a non-adherent wound facing second layer of a 
permeable material. 
U.S. Pat. No. 4,687,476 to Pailin, describes a continuous multi-layer strip 
used as a topical dressing, wherein the strip has a continuous layer of a 
first foil and on one side thereof a laminated material comprising a layer 
of skin adhesive protected with a release film. 
U.S. Pat. No. 4,542,013 to Keith, describes a trinitroglycerol-containing 
substantially disaccharide-free polymeric diffusion matrix for transdermal 
systemic delivery of trinitroglycerol. The bandage may also include a 
facestock layer with skin adhesive, which comprises a foam, film-type, 
non-woven or vinyl tape with an acrylic, silicon or rubber adhesive. 
U.S. Pat. No. 5,217,718 to Colley et al, describes a therapeutic system for 
the transdermal administration of dexmedetomidine that is a laminated 
composite of a backing layer, an optional anchor adhesive layer, a contact 
adhesive layer; and one or more additional layers. The composite also 
preferably contains an optional porous intermediate layer between the 
anchor and contact adhesive layer, wherein, when an anchor is included, it 
is typically an absorbent, non-woven fabric. 
U.S. Pat. No. 5,298,258 to Akemi et al, describes an acrylic oily gel 
bioadhesive material comprising a substrate having on one surface thereof, 
a crosslinked gel layer. 
U.S. Pat. No. 4,938,964 to Sakai et al, describes a formulation which may 
be applied using a conventional support. A cotton or non-woven fabric may 
be used for the support. (All of the aforementioned U.S. Patents are 
incorporated herein in their entirety by reference.) 
U.S. Pat. No. 4,904,475 describes a porous support structure for use in a 
device for delivering ionized drugs from an aqueous reservoir. 
In addition, Black "Transdermal Drug Delivery Systems", U.S. Pharmacist, 
November 1982, pp 49-78, provides additional background information 
regarding commercially available transdermal drug delivery systems. A 
reasonably complete summary of the factors involved in percutaneous 
absorbtion of drugs may be found in Arita, et al, "Studies on Percutaneous 
Absorption of Drugs", Chem. Phar. Bull., Vol. 18, 1970, pp 1045-1049; 
Idson, "Percutaneous Absorption", J. Phar. Sci., Vol. 64, No. 6, pp 
910-922; and Clooney, Advances in Biomedical Engineering, Part I, Chapter 
6, "Drug Permeation Through Skin: Controlled Delivery For Topical or 
Systemic Therapy", Marcel Dekker, Inc., New York and Basel, 1980, pp 
305-318. 
Although the transdermal drug delivery route is rapidly becoming a 
preferred delivery route for a wide variety of drugs, transdermal delivery 
is not without its problems. In general, direct contact of an adhesive 
with a drug reservoir which contains an amphipathic molecule, eg, a 
non-ionic surfactant such as a permeation enhancer, eg, a monoglyceride, 
ie, glycerol monolaurate or glycerol monooleate, has a problem of blooming 
at the interface of the contact adhesive/drug reservoir. The occurrence of 
blooming is caused by the surfactant migrating to the relatively lower 
energy interface generated by laminating an adhesive to the reservoir. 
It is accordingly an objective of this invention to provide a drug delivery 
system adapted for use with drug reservoirs containing amphipathic 
molecules having reduced blooming and delamination at the interface of the 
contact adhesive and drug reservoir. 
It is another object of the invention to provide a transdermal drug 
delivery device for use with an amphipathic molecule such as a non-ionic 
surfactant having a microporous tie layer interconnecting the drug 
reservoir and contact adhesive. 
It is yet another object of the invention to provide a transdermal drug 
delivery device having a microporous tie layer interconnecting the drug 
reservoir and contact adhesive which does not affect the flux or the drug 
release profiles of the therapeutic transdermal system and which reduces 
the occurrence of blooming and delamination at the interface. 
These and other objects and advantages of this invention will be readily 
apparent from the following description with reference to the accompanying 
figures.

DETAILED DESCRIPTION OF THE INVENTION 
The specific drugs used herein are not critical to the invention. As used 
herein, the term "drug" is to be construed in its broadest sense as 
material which is intended to produce some beneficial effect on the 
organism to which it is applied. 
As used herein, the term "transdermal" delivery or application refers to 
the delivery or application of agents by passage of skin, mucosa, and/or 
other body surfaces by topical application or by iontophoresis. 
As used herein, the term "therapeutically effective" amount or rate refers 
to the amount or rate of drug or active agent needed to effect the desired 
therapeutic result. 
As used herein "amphipathic" molecule refers to an unsymmetrical molecule 
having one end being hydrophilic and the other end hydrophobic, including, 
for example, non-ionic surfactants. 
As used herein, the term "non-ionic surfactant" refers to a non-ionic agent 
which has the effect of altering the interfacial tension of water and 
other liquids or solids, for example, a monoglyceride. Surfactants may be 
used as a permeation enhancer for drug transport across skin. 
As used herein, the term "monoglyceride" refers to glycerol monooleate, 
glycerol monolaurate, and glycerol monolinoleate, or a mixture thereof. 
Monoglycerides are generally available as a mixture of monoglycerides, 
with the mixture deriving its name from the monoglyceride present in the 
greatest amount. 
As used herein, the term "glycerol monooleate" refers to glycerol 
monooleate itself or a mixture of glycerides wherein glycerol monooleate 
is present in the greatest amount. 
As used herein, the term "glycerol monolaurate" refers to glycerol 
monolaurate itself or a mixture of glycerides wherein glycerol monolaurate 
is present in the greatest amount. 
As used herein, the term "glycerol monolinoleate" refers to glycerol 
monolinoleate itself or a mixture of glycerides wherein glycerol 
monolinoleate is present in the greatest amount. 
As used herein, the term "lactate ester" or "lactic ester of an alcohol" 
refers to ethyl lactate, lauryl lactate, myristyl lactate, cetyl lactate, 
or a mixture thereof. 
Referring now to FIG. 1, a preferred embodiment of a transdermal delivery 
device 1, according to this invention is shown. The system is specifically 
adapted to reduce the problem of blooming and delamination of the contact 
adhesive from the drug reservoir layer when the drug reservoir contains a 
non-ionic surfactant. The inventors solved the problem by including a 
microporous tie layer between the drug reservoir layer and the contact 
adhesive. In FIG. 1, transdermal delivery device 10, comprises a reservoir 
containing a drug and the permeation enhancing mixture. Reservoir 12 is 
preferably in the form of a matrix containing the drug and permeation 
enhancer mixture dispersed therein. Reservoir 12 is sandwiched between a 
backing layer 14 and a microporous tie layer 15. On the other side of the 
tie layer 15 is the in-line contact adhesive layer 16. The device 10 
adheres to the surface of the skin 18, by means of the adhesive layer 16. 
The adhesive layer 16 may optionally contain the permeation enhancing 
mixture and/or drug. A strippable release liner (not shown in FIG. 1) is 
normally provided along the exposed surface of the adhesive layer 16 as 
removed prior to application of device 10 to skin 18. 
In FIG. 2, transdermal delivery device 20, comprises a drug- and permeation 
enhancing mixture-containing reservoir ("drug reservoir") 12 substantially 
as described with respect to FIG. 1. Permeation enhancer reservoir 
("enhancer reservoir") 26 comprises the permeation enhancing mixture 
dispersed throughout and contains the drug at or below saturation. 
Enhancer reservoir 26 is made from substantially the same matrix as is 
used to form drug reservoir 12. Rate-controlling membrane 28 for 
controlling the release rate of the permeation enhancer from enhancer 26 
to drug reservoir 12 is placed between the two reservoirs. 
Superimposed over the permeation enhancer mixture 26 of device 20 is a 
backing 14. On the skin proximal side of reservoir 12 are a microporous 
tie layer 15; an adhesive layer 16, and a strippable liner 24 which would 
be removed prior to application of the device to the skin. 
The purpose of the tie layer is to reduce blooming and delamination at the 
drug reservoir and contact adhesive but not to affect the flux or the 
release rate profiles of the drug from therapeutic transdermal systems. 
Potential tie layers should be formed from materials that have a low or 
negligible solubility of the amphipathic molecule and the drug and should 
have a porous or open structure so that the drug flux, as well as drug 
release rates, are not affected by the tie layer. Useful tie layers 
include but are not limited to microporous polypropylene membranes, 
microporous polyethylene membranes, porous polycarbonate, and spun bonded 
filamentous materials. The main defining characteristic of the tie layer 
is that it be formed of a material that does not absorb either the 
amphipathic molecule or the drug and is sufficiently open to allow 
transport of the drug and permeation enhancer. 
The device is constructed so that the drug reservoir and/or adhesive layer 
when laminated on either side of the tie layer fills in the space defined 
by the open spaces in the tie layer. 
In the embodiments of FIGS. 1 and 2, the carrier or matrix material of the 
reservoirs has sufficient viscosity to maintain its shape without oozing 
or flowing. If, however, the matrix or carrier is a low-viscosity flowable 
material such as a liquid or gel, the composition may be fully enclosed in 
a pouch or pocket as known to the art from U.S. Pat. No. 4,379,454, for 
example, and is illustrated in FIG. 3. 
Device 30 in FIG. 3 comprises a backing member 14 which serves a protective 
cover for the device, in part structural support, and substantially keeps 
components in device 30 from escaping from the device. Device 30 also 
includes a reservoir 12 which contains the drug and permeation enhancer 
mixture and bears on its surface distant from the backing member 14, a 
rate-controlling membrane 28, for controlling the release of the drug 
and/or permeation enhancer mixture from device 30. The outer edges of the 
backing member overlay the edges of reservoir 12 and are joined along the 
parameter over the outer edges of the rate-controlling membrane 28 in a 
fluid-tight arrangement. This sealed reservoir may be effected by 
pressure, fusion, adhesion, and adhesive applied to the edges, or other 
methods known in the art. In this manner, reservoir 12 is contained only 
between backing member 14 and rate-controlling membrane 28. On the 
skin-proximal side of rate-controlling membrane 28 are a microporous tie 
layer 15; an adhesive layer 16; and a strippable liner 24, respectively. 
The strippable liner 24 would be removed prior to application of the 
device 30 to the skin. 
In an alternative embodiment of device 30 of FIG. 3, reservoir 12, contains 
the permeation enhancing mixture and the drug at or below saturation. The 
drug at or above saturation and an additional amount of permeation 
enhancer mixture are present in the adhesive layer 16 which acts as a 
separate reservoir. 
The formulation to be contained in a drug reservoir is non-aqueous based 
and designed to deliver the drug and permeation enhancer mixture at 
necessary fluxes. Typical non-aqueous gels are comprised of silicon fluid 
or mineral oil. Mineral oil-based gels also typically contain 1-2 wt % of 
a gelling agent such as colloidal silicon dioxide. The suitability of a 
particular gel depends upon the compatibility of its constituents with 
both the drug and permeation enhancing mixture and any other components in 
the formulation. The reservoir matrix should be compatible with the drug, 
permeation enhancer mixture, and any carrier therefore. The term "matrix" 
as used here refers to well-mixed composite ingredients fixed into shape. 
When using a non-aqueous-based formulation, the reservoir matrix is 
preferably composed of a hydrophobic polymer. Suitable polymeric matrices 
are well known in the transdermal drug delivery art, and examples are 
listed in the above-named patents previously incorporated herein by 
reference. A typical laminated system would comprise a polymeric membrane 
and/or matrix such as ethylene vinyl acetate (EVA) copolymers, such as 
those described in U.S. Pat. No. 4,144,317, incorporated herein by 
reference preferably having a vinyl acetate (VA) content in the range of 
from about 9% up to about 60% and more preferably from about 9% to 40% VA. 
Polyisobutylene/oil polymers containing from 4-25% high molecular weight 
polyisobutylene and 20-81% low molecular weight polyisobutylene with the 
balance being an oil such as mineral oil or polyisobutenes may also be 
used in the matrix material. 
The amount of drug present in the therapeutic device and required to 
achieve an effective therapeutic result depends on many factors, such as 
the minimum necessary dosage of the drug of the particular indication 
being treated; the solubility and permeability of the matrix, of the 
adhesive layer, and the rate-controlling membrane, if present; and the 
period of time for which the device will be fixed to the skin. The minimum 
amount of drug is determined by the requirement that sufficient quantities 
of drug must be present in the device to maintain the desired rate of 
release over the given period of application. The maximum amount for 
safety purposes is determined by the requirement that the quantity of drug 
present cannot exceed a rate of release that reaches toxic levels. 
The drug is normally present in the matrix or carrier at a concentration in 
excess of saturation, the amount of excess being a function of the desired 
length of the drug delivery period of the system. The drug may, however, 
be present at a level below saturation without departing from this 
invention as long as the drug is continuously administered to the skin or 
mucosal site in an amount and for a period of time sufficient to provide 
the desired therapeutic rate. 
The permeation enhancing mixture is dispersed throughout the matrix or 
carrier, preferably at a concentration sufficient to provide 
permeation-enhancing amounts of enhancer in the reservoir throughout the 
anticipated administration period. Where there is an additional, separate 
permeation enhancer matrix layer as well, as in FIG. 3, the permeation 
enhancer normally is present in the separate reservoir in excess of 
saturation. 
In addition to the drug and permeation enhancer mixture, which are 
essential to the invention, the matrix or carrier may also contain dies, 
pigments, inert fillers, excipients, and other conventional components of 
pharmaceutical products for transdermal devices known in the art. 
Because of the wide variation in skin permeability from individual to 
individual and from site to site on the same body, it may be preferable 
that the drug and permeation enhancer mixture be administered from a 
rate-controlled transdermal delivery device. Rate control can be obtained 
through either an adhesive or through other means. A certain amount of 
drug will bind reversibly to the skin, and is accordingly preferred that 
the skin-contacting layer of the device include this amount of the agent 
as a loading dose. 
The surface area of the device of this invention can vary from less than 1 
cm.sup.2 to greater than 200 cm.sup.2. A typical device, however, will 
have a surface area within the range of about 5-50 cm.sup.2. 
The devices of this invention can be designed to effectively deliver drug 
for an extended period of time from several hours up to seven days or 
longer. Seven days is generally the maximum time limit for application of 
a single device because the adverse effect of inclusion of a skin site 
increases with time and a normal cycle of sloughing and replacement of the 
skin cells occurs in about seven days. 
It is believed that this invention has utility in connection with the 
delivery of drugs within the broad class normally delivered through body 
surfaces and membranes, including skin. As used herein, the expressions 
"drug" and "agent" are used interchangeably and are intended to have their 
broadest interpretation as to any therapeutically active substance which 
is delivered to a living organism to produce a desired, usually 
beneficial, effect. In general, this includes therapeutic agents in all of 
the major therapeutic areas, including, but not limited to, ACE 
inhibitors, adenohypophyseal hormones, adrenergic neuron blocking agents, 
adrenocortical steroids, inhibitors of the biosynthesis of adrenocortical 
steroids, alpha-adrenergic agonists, alpha-adrenergic antagonists, 
selective alpha-two-adrenergic agonists, analgesics, antipyretics and 
anti-inflammatory agents, androgens, local anesthetics, general 
anesthetics, antiaddictive agents, antiandrogens, antiarrhythmic agents, 
antiasthmatic agents, anticholinergic agents, anticholinesterase agents, 
anticoagulants, antidiabetic agents, antidiarrheal agents, antidiuretic, 
antiemetic and prokinetic agents, antiepileptic agents, antiestrogens, 
antifungal agents, antihypertensive agents, antimicrobial agents, 
antimigraine agents, antimuscarinic agents, antineoplastic agents, 
antiparasitic agents, antiparkinson's agents, antiplatelet agents, 
antiprogestins, antithyroid agents, antitussives, antiviral agents, 
atypical antidepressants, azaspirodecanediones, barbiturates, 
benzodiazepines, benzothiadiazides, beta-adrenergic agonists, 
beta-adrenergic antagonists, selective beta-one-adrenergic antagonists, 
selective beta-two-adrenergic agonists, bile salts, agents affecting 
volume and composition of body fluids, butyrophenones, agents affecting 
calcification, calcium channel blockers, cardiovascular drugs, 
catecholamines and sympathomimetic drugs, cholinergic agonists, 
cholinesterase reactivators, dermatological agents, 
diphenylbutylpiperidines, diuretics, ergot alkaloids, estrogens, 
ganglionic blocking agents, ganglionic stimulating agents, hydantoins, 
agents for control of gastric acidity and treatment of peptic ulcers, 
hematopoietic agents, histamines, histamine antagonists, 
5-hydroxytryptamine antagonists, drugs for the treatment of 
hyperlipoproteinemia, hypnotics and sedatives, immunosuppressive agents, 
laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular 
blocking agents, organic nitrates, opioid analgesics and antagonists, 
pancreatic enzymes, phenothiazines, progestins, prostaglandins, agents for 
the treatment of psychiatric disorders, retinoids, sodium channel 
blockers, agents for spasticity and acute muscle spasms, succinimides, 
thioxanthenes, thrombolytic agents, thyroid agents, tricyclic 
antidepressants, inhibitors of tubular transport of organic compounds, 
drugs affecting uterine motility, vasodilators, vitamins and the like. 
Representative drugs include, by way of example and not for purposes of 
limitation, bepridil, diltiazem, felodipine, isradipine, nicardipine, 
nifedipine, nimodipine, nitredipine, verapamil, dobutamine, isoproterenol, 
carteolol, labetalol, levobunolol, nadolol, penbutolol, pindolol, 
propranolol, sotalol, timolol, acebutolol, atenolol, betaxolol, esmolol, 
metoprolol, albuterol, bitolterol, isoetharine, metaproterenol, 
pirbuterol, ritodrine, terbutaline, alclometasone, aldosterone, 
amcinonide, beclomethasone dipropionate, betamethasone, clobetasol, 
clocortolone, cortisol, cortisone, corticosterone, desonide, 
desoximetasone, 11-desoxycorticosterone, 11-desoxycortisol, dexamethasone, 
diflorasone, fludrocortisone, flunisolide, fluocinolone, fluocinonide, 
fluorometholone, flurandrenolide, halcinonide, hydrocortisone, medrysone, 
6.alpha.-methylprednisolone, mometasone, paramethasone, prednisolone, 
prednisone, tetrahydrocortisol, triamcinolone, benoxinate, benzocaine, 
bupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine, etidocaine, 
lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, 
tetracaine, alfentanil, chloroform, clonidine, cyclopropane, desflurane, 
diethyl ether, droperidol, enflurane, etomidate, fentanyl, halothane, 
isoflurane, ketamine hydrochloride, meperidine, methohexital, 
methoxyflurane, morphine, propofol, sevoflurane, sufentanil, thiamylal, 
thiopental, acetaminophen, allopurinol, apazone, aspirin, auranofin, 
aurothioglucose, colchicine, diclofenac, diflunisal, etodolac, fenoprofen, 
flurbiprofen, gold sodium thiomalate, ibuprofen, indomethacin, ketoprofen, 
meclofenamate, mefenamic acid, mesalamine, methyl salicylate, nabumetone, 
naproxen, oxyphenbutazone, phenacetin, phenylbutazone, piroxicam, 
salicylamide, salicylate, salicylic acid, salsalate, sulfasalazine, 
sulindac, tolmetin, acetophenazine, chlorpromazine, fluphenazine, 
mesoridazine, perphenazine, thioridazine, trifluoperazine, 
triflupromazine, disopyramide, encainide, flecainide, indecainide, 
mexiletine, moricizine, phenytoin, procainamide, propafenone, quinidine, 
tocainide, cisapride, domperidone, dronabinol, haloperidol, 
metoclopramide, nabilone, prochlorperazine, promethazine, 
thiethylperazine, trimethobenzamide, buprenorphine, butorphanol, codeine, 
dezocine, diphenoxylate, drocode, hydrocodone, hydromorphone, 
levallorphan, levorphanol, loperamide, meptazinol, methadone, nalbuphine, 
nalmefene, nalorphine, naloxone, naltrexone, oxybutynin, oxycodone, 
oxymorphone, pentazocine, propoxyphene, isosorbide dinitrate, 
nitroglycerin, theophylline, phenylephrine, ephedrine, pilocarpine, 
furosemide, tetracycline, chlorpheniramine, ketorolac, bromocriptine, 
guanabenz, prazosin, doxazosin, and flufenamic acid. 
Other representative drugs include benzodiazepines, such as alprazolam, 
brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, 
demoxepam, diazepam, flumazenil, flurazepam, halazepam, lorazepam, 
midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, 
temazepam, triazolam, and the like; an antimuscarinic agents, such as 
anisotropine, atropine, clidinium, cyclopentolate, dicyclomine, flavoxate, 
glycopyrrolate, hexocyclium, homatropine, ipratropium, isopropamide, 
mepenzolate, methantheline, oxyphencyclimine, pirenzepine, propantheline, 
scopolamine, telenzepine, tridihexethyl, tropicamide, and the like; an 
estrogen such as chlorotrianisene, diethylstilbestrol, estradiol, 
estradiol cypionate, estradiol valerate, estrone, estrone sodium sulfate, 
estropipate, ethinyl estradiol, mestranol, quinestrol, sodium equilin 
sulfate and the like; an androgen, such as danazol, fluoxymesterone, 
methandrostenolone, methyltestosterone, nandrolone decanoate, nandrolone 
phenpropionate, oxandrolone, oxymetholone, stanozolol, testolactone, 
testosterone, testosterone cypionate, testosterone enanthate, testosterone 
propionate, and the like; or a progestin such as ethynodiol diacetate, 
gestodene, hydroxyprogesterone caproate, levonorgestrel, 
medroxyprogesterone acetate, megestrol acetate, norethindrone, 
norethindrone acetate, norethynodrel, norgestrel, progesterone, and the 
like. 
Preferably, the transdermal drug delivery device contains a sufficient 
amount of permeation enhancer mixture to provide systemic administration 
of the drug through the skin for a predetermined period of time for the 
drug to provide an effective therapeutic result. 
The aforementioned patents describe a wide variety of materials which can 
be used for fabricating the various layers and components of the 
transdermal drug delivery devices according to this invention. This 
invention, therefore, contemplates the use of materials other than those 
specifically disclosed herein, including those which may hereafter become 
known to the art and to be capable of performing the necessary functions. 
The following example is offered to illustrate the practice of the present 
invention and is not intended to limit the invention in any manner. 
EXAMPLE 1 
The drug/permeation enhancer reservoir was prepared by mixing ethylene 
vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 
40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type 
mixer) until the EVA 40 pellets fused. Testosterone, glycerol monolaurate, 
lactic acid, myristyl lactate, lauroyl lactylic acid, and lauryl lactate 
were then added as required. The mixture was blended, cooled and 
calendered to a 5 mil thick film. The compositions of the reservoirs are 
given in Table 1. 
TABLE 1 
______________________________________ 
Drug/Permeation Enhancer Reservoir Composition 
(weight percent) 
FIG. 4 
______________________________________ 
GML/lauryl lactate/lactic acid/testosterone/EVA 40 
20/12/3/10/55 
GML/myristyl lactate/lactic acid/testosterone/EVA 40 
20/12/3/10/55 
GML/lauroyl lactylic acid/testosterone/EVA 40 
20/5/10/65 
GML/lauryl lactate/lauroyl lactylic acid/testosterone/EVA 40 
20/12/5/10/53 
______________________________________ 
This film was then laminated to an acrylic contact adhesive (MSP041991 P, 
3M) on one side and Medpar.RTM. backing (3M) on the opposite side. All 
systems were tested with and without a Celgard.RTM. (Hoechst Celanese) 
microporous polypropylene membrane which, when present, was laminated 
between the reservoir and adhesive. The laminate was then cut into 1.98 
cm.sup.2 circles using a stainless steel punch. 
Circular pieces of human-epidermis were mounted on horizontal permeation 
cells with the stratum corneum facing the donor compartment of the cell. 
The release liner of the system was then removed and the system was 
centered over the stratum corneum side of the epidermis. The cells were 
then masked. A known volume of the receptor solution (0.10% phenol/H.sub.2 
O) that had been equilibrated at 35.degree. C. was placed in the receptor 
compartment. Air bubbles were removed; the cell was capped and placed in a 
water bath-shaker at 35.degree. C. 
At given time intervals, the entire receptor solution was removed from the 
cells and replaced with an equal volume of fresh receptor solutions 
previously equilibrated at 35.degree. C. The receptor solutions were 
stored in capped vials at 4.degree. C. until assayed for testosterone 
content by HPLC. 
The fluxes achieved for the different systems are shown in FIG. 4. As shown 
in FIG. 4, the fluxes for the devices that contained the Celgard.RTM. were 
equivalent on average to those fluxes obtained from the devices that did 
not contain the Celgard.RTM. membrane. 
No blooming or delamination was observed. 
The invention has been described in detail with particular reference to 
certain preferred embodiments thereof, but it will be understood that 
variations and modifications can be affected within the scope and spirit 
of the invention.