Method for enhanced electrotransport agent delivery

An electrotransport composition comprises at least one C.sub.2 -C.sub.4 lower alcohol, unsaturated derivatives thereof, or mixtures thereof, and at least one C.sub.8 -C.sub.14 higher alcohol, unsaturated derivatives thereof, or mixtures thereof. An electrotransport device and a method of increasing transdermal electrotransport flux utilize the composition of the invention for delivering pharmaceutically-acceptable agents across a body surface such as skin.

BACKGROUND OF THE INVENTION 
1. Technical Field 
This invention relates generally to permeation enhancers for 
electrotransport agent delivery. More particularly, this invention relates 
to compositions comprising different alcohols as permeation enhancers. 
These compositions may be incorporated into electrotransport devices for 
the delivery of agents, such as drugs and prodrugs, through a body 
surface. 
2. Background Art 
Drugs are most conventionally administered either orally or by injection. 
Unfortunately, many medicaments are completely ineffective or of radically 
reduced efficacy when orally administered since they either are not 
absorbed or are adversely affected before entering the blood stream and 
thus do not possess the desired activity. On the other hand, the direct 
injection of the medicament into the blood stream, while assuring no 
modification of the medicament in administration, is a difficult, 
inconvenient and uncomfortable procedure, sometimes resulting in poor 
patient compliance. Transdermal drug delivery offers improvements in these 
areas. The term "transdermal" is used herein in its broadest sense as the 
delivery of an agent through a body surface, such as the skin, mucosa, or 
nails. There are two major types of transdermal agent delivery, one driven 
by a concentration-gradient force (passive transdermal delivery), and the 
other driven, in addition, by a force created by applying an electrical 
potential (electrotransport delivery). 
The term "passive" transdermal delivery, is used herein to describe the 
passage of an agent through a body surface, eg, skin, in the absence of an 
applied electrical current. Typically, passive delivery devices have a 
drug reservoir which contains a high concentration of a drug. The device 
is placed in contact with a body surface for an extended period of time, 
and is allowed to diffuse from the reservoir and into the body of the 
patient, which has a much lower concentration of drug. The primary driving 
force for passive drug delivery is the concentration gradient of the drug 
across the skin. In this type of delivery, the drug reaches the 
bloodstream by diffusion through the dermal layers of the body. The 
preferred agents for passive delivery are hydrophobic non-ionic agents, 
given that the drug must diffuse through the lipid layers of the skin. 
The term "electrotransport" is used herein to describe the passage of a 
substance, eg, a drug or prodrug, through a body surface or membrane, such 
as the skin, mucous membranes, or nails, induced at least partially by the 
application of an electric field across the body surface (eg, skin). A 
widely used electrotransport process, iontophoresis, involves the 
electrically induced transport of therapeutic agents in the form of 
charged ions. Ionizable therapeutic agents, eg, in the form of a salt 
which when dissolved forms charged agent ions, are preferred for 
iontophoretic delivery because the charged agent ions move by 
electromigration within the applied electric field. Electroosmosis, 
another type of electrotransport process, involves the movement of a 
liquid, which liquid contains a charged and/or uncharged therapeutic agent 
dissolved therein, through a biological membrane under the influence of an 
electric field. Another type of electrotransport, electroporation, 
involves the formation of transiently-existing pores in a living 
biological membrane under the influence of an electric field and delivery 
of a therapeutic agent therethrough. However, in any given 
electrotransport process, more than one of these processes may be 
occurring simultaneously to some extent. Accordingly, the term 
"electrotransport" is used herein in its broadest possible interpretation 
to include the electrically induced or enhanced transport of at least one 
agent, which may be charged, ie, in the form of ions, or uncharged, or of 
mixtures thereof, regardless of the specific mechanisms by which the agent 
is actually transported. 
A common goal in both passive and electrotransport delivery is to enhance 
the rate of delivery of the agent. A further goal in electrotransport 
delivery is to reduce the electrical resistance of the skin or other body 
surfaces, so that the power requirements for a given level of applied 
electric current or drug flux will be lowered. The term "permeation 
enhancer" is used herein to describe additives which cause an increase in 
drug delivery rates both in passive and electrotransport delivery, 
regardless of whether the enhancement occurs by reduction of electrical or 
diffusional resistance. 
Although there are similarities between electrotransport and passive 
transdermal delivery, there are also substantial differences. One 
difference relates to the different pathways utilized for delivery through 
the skin by the passive and electrotransport induced processes. 
Transdermal electrotransport delivery of an agent occurs within the 
hydrophilic pathways through the skin, ie, the sweat ducts, around hair 
follicles, and/or through pores, because these are the paths of least 
electrical resistance. On the other hand, passive transdermal delivery 
occurs primarily by direct diffusion through the lipid layers of the skin. 
Accordingly, an ideal passive permeation enhancer will disrupt the lipid 
layers of the skin, while an ideal electrotransport enhancer will 
preferably decrease the electrical resistance of the existing hydrophilic 
pathways in the skin. (See, Rolf, D., "Chemical and Physical Methods of 
Enhancing Transdermal Drug Delivery," Pharmaceutical Technology, pp 
130-140 (September 1988); Cullander, C., "What are the Pathways of 
lontophoretic Current Flow through Mammalian Skin?", Advanced Drug 
Delivery Reviews, 9:119-135 (1992)). 
Thus, it is not surprising that many passive permeation enhancers do not 
enhance electrotransport delivery rates. For instance, Hirvonen et al 
indicate that N, N-dimethylamino acetate (DDAA) and azone increase the 
rate of passive permeation of the agent sotalol relative to that obtained 
with sotalol alone (control). (Hirvonen et al, "Transdermal Permeation of 
Model Anions and Cations: Effect of Skin Charge, lontophoresis and 
Permeation Enhancers", Proceed. Intern. Symp. Control. Rel. Bioact. 
Mater., 19:452 (1992)). And the passage of an electric current was also 
shown to increase the rate of delivery of sotalol compared to that of its 
passive rate (control). However, the addition to solatol of either DDM or 
azone reduced the rate of electrotransport of solatol compared to its rate 
of electrotransport without DDAA or azone (control). Clearly, DDAA and 
azone, both known passive permeation enhancers, were not only inoperative 
in electrotransport, but they actually reduced the rate of 
electrotransport delivery of the agent. Kontturi et al indicated that the 
aforementioned passive enhancers, in fact, increase skin resistivity, and 
advanced that passive enhancers such as those are inappropriate for use in 
electrotransport drug delivery. (Kontturi et al, "Electrochemical 
Characterization of Human Skin by Impedance Spectroscopy: The Effect of 
Penetration Enhancers", Pharmaceutical Research 10(3):381-385 (1993)). 
Other permeation enhancers have been disclosed to be useful in passive 
transdermal delivery. For example, WIPO Laid Open Patent Application WO 
91/16930 to Ferber et al discloses that an aqueous solution of up to 40 
v/v% lower alcohol and higher alcohol in a saturating amount is suitable 
for enhancing passive transdermal delivery. Suitable passive transdermal 
delivery enhancers disclosed therein are lower C.sub.2 -C.sub.4 alcohols 
such as ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol, and 
higher alcohols such as C.sub.6 -C.sub.14 alcohols including 1-hexanol, 
1-octanol, 1-nonanol, 1-decanol, 1-undecanol, 1-dodecanol, 1-tridecanol, 
1-tetradecanol, 4-methyl-1-pentanol, 5-methyl-1-heptanol, 
3,3-dimethyl-1-octanol, 3-cyclopentyl-1-propanol, cis-3-hexen-1-ol, 
trans-3-hexen-1-ol, 9-decen-1-ol and 2-octanol. 
The number of permeation enhancers disclosed as useful in electrotransport 
delivery is considerably more limited. Ethanol, for instance, has been 
used as a permeation enhancer for the electrotransport delivery of 
polypeptides is discussed by Srinivasan et al (Srinivasan et al, 
"lontophoresis of Polypeptides: Effect of Ethanol Pretreatment of Human 
Skin," J. Pharm. Sci. 79(7):588 (July 1990)). Surfactant (eg, sodium 
lauryl sulfate) permeation enhancers for electrotransport drug delivery 
are disclosed in Sanderson et al, U.S. Pat. No. 4,722,726 and fatty acid 
(eg, oleic acid) permeation enhancers for electrotransport drug delivery 
are disclosed in Francoeur et al, U.S. Pat. No. 5,023,085. 
Thus, in general, there is still a need for compositions which reduce the 
electrical resistance of the skin and, thus, increase agent 
electrotransport therethrough, producing an enhancement of the delivery 
rate of the agent while reducing the power requirements of the 
electrotransport device and/or the area of contact between the device and 
the body surface. 
DISCLOSURE OF THE INVENTION 
This invention arose from a desire to improve on prior art technology in 
the field of transdermal electrotransport delivery. This invention 
provides a composition that enhances the electrotransport flux of a drug 
or prodrug through a body surface such as skin. The permeation enhancing 
composition comprises in combination (1) at least one lower alcohol and 
(2) at least one higher alcohol, both of which may be linear branched, 
aromatic, and/or cyclic. The lower alcohol is preferably a C.sub.2 
-C.sub.4 alkanol or unsaturated derivatives thereof, and more preferably 
ethanol. The higher alcohol is preferably a C.sub.8 -C.sub.14 alkanol or 
unsaturated derivatives thereof, more preferably a C.sub.10 -C.sub.12 
alkanol or unsaturated derivatives thereof. Of these higher alcohols, 
dodecanol and 1-dodecanol are most preferred. 
The composition of the invention reduces the electrical resistance of body 
surfaces, such as the skin, mucosa, and nails, during electrotransport 
agent delivery, and permits a reduction in the size of the delivery device 
and/or the power (ie, voltage) required to maintain a particular level of 
electrotransport current and rate of electrotransport agent delivery. 
The present composition is suitable for use in reducing the electrical 
resistance of the body surface (eg, skin) site adjacent the donor 
electrode of an electrotransport delivery device, the skin site adjacent 
the counter electrode of the device, or both body surface sites. The 
permeation enhancer composition may be applied to the body surface prior 
to or during agent delivery, but the composition is preferably placed in 
the donor and/or counter reservoir of an electrotransport delivery device 
and is delivered to the body surface simultaneously with the agent. 
Also provided herein is an electrotransport delivery device comprising 
donor and counter electrodes, at least one of the electrodes having a 
reservoir comprising the lower/higher alcohol composition, an electrical 
power source which is electrically connected to the donor and counter 
electrodes, and optionally electronic control circuitry. 
The composition of the present invention may be used with different 
electrotransport devices for the delivery of a variety of pharmaceutically 
acceptable agents, including those specifically disclosed herein. One 
particular application for which the composition is most suitable is the 
electrotransport delivery of amine and amino acid containing agents. 
This invention will now be described in further detail with reference to 
the accompanying drawing.

MODES FOR CARRYING OUT THE INVENTION 
This invention arose form a desire to improve on prior art technology for 
the transdermal delivery of pharmaceutically-acceptable agents, such as 
drugs or prodrugs, suitable for the prevention or treatment of disease in 
humans. The present technology has particular application in the field of 
electrotransport delivery of pharmaceutically-acceptable agents (eg, 
drugs) and particularly agents containing amine groups and/or peptide 
groups. 
This present invention, thus, provides a transdermal electrotransport 
permeation enhancing composition, comprising at least one lower alcohol, 
preferably a C.sub.2 -C.sub.4 alkanol or unsaturated derivatives thereof, 
or mixtures thereof, and at least one higher alcohol, preferably a C.sub.8 
-C.sub.14 alkanol or unsaturated derivative thereof, or mixtures thereof. 
An alcohol, as used herein, is defined as an alkyl compound having at 
least one hydroxyl (--OH) group, which may be saturated or unsaturated, 
linear, branched, cyclic and/or aromatic. This definition also includes 
polyhydric alcohols having more than one hydroxyl group, such as glycols 
or diols. A "higher alcohol", as used herein, refers to a straight or 
branched chain or cyclic C.sub.8 -C.sub.14 alcohol. The higher alcohol may 
be a primary, secondary or tertiary alcohol. Examples of higher alcohols 
include, without limitation, 1-dodecanol, 3-dodecanol, 1-decanol, 
1-undecanol, 3-butyl-1-octanol, 4-pentyl-1-hexanol, and 
5-propyl-2-decanol. The higher alcohol is preferably a straight chain 
alcohol having 10 to 12, and more preferably 12, carbon atoms. Preferred 
as a higher alcohol is dodecanol, and still more preferred is 1-dodecanol. 
A "lower alcohol", as used herein, encompasses an alcohol preferably 
having 2 to 4 carbon atoms. The lower alcohol may be a primary, secondary 
or tertiary alcohol including, without limitation, ethanol, 1-propanol, 
2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, and unsaturated 
derivatives thereof. More preferably, the lower alcohol is ethanol or 
propanol, and still more preferably it is ethanol. The alcohols of the 
composition of this invention may have other substituents which do not 
interfere with the electrotransport delivery enhancing characteristics of 
the composition. The combination of the lower and higher alcohols in an 
electrotransport composition produces an unexpected enhancement of the 
transdermal electrotransport drug flux, which is accompanied by an 
unexpected reduction in skin resistance during electrotransport drug 
delivery, when compared with the drug flux and skin resistance when 
electrotransporting drug in the presence of either the lower alcohol or 
the higher alcohol alone. 
An increase in the delivery rate of the agent and a decrease in the 
electrical resistance of the body surface are achieved by contacting the 
agent (eg, drug) to be delivered and the composition with the body surface 
while applying an electrical current through the composition, the agent, 
and the body surface. More preferably, the composition of the invention is 
added directly to the donor reservoir, counter reservoir, or both 
reservoirs of an electrotransport delivery device. However, the body 
surface may also be treated with the lower/higher alcohol composition 
prior to the electrotransport delivery of the drug. In addition, it is 
possible to apply the lower/higher alcohol composition to the body surface 
after electrotransport delivery of the agent has been initiated. 
The concentration of the higher alcohol in the fully hydrated donor 
reservoir, ie, under reservoir conditions immediately prior to use, is 
preferably about 0.01 to 100 millimolar (mM). More preferably, the higher 
alcohol concentration is about 1 to about 50 mM, and still more preferably 
greater than 10 mM. The concentration of the lower alcohol in the donor 
reservoir is preferably about 0.5 to 30% (v/v), more preferably less than 
about 25% (v/v), and still more preferably, 10 to 25% (v/v). In one 
particularly preferred form of the device, the composition present in the 
donor reservoir preferably contains sufficient water to achieve greater 
than 50% ionization of the agent to be delivered. The concentration of the 
pharmaceutically-acceptable agent to be delivered may vary substantially, 
depending on the type of drug, its potency, and the like. The 
concentration of the agent in the fully hydrated donor reservoir is 
generally about 1 microgram/mL (.mu.g/mL) to 100,000 .mu.g/mL, and more 
preferably about 1000 .mu.g/mL to about 50,000 .mu.g/mL. Furthermore, the 
donor reservoir may contain other chemical species such as buffering 
agents, antioxidants, antimicrobial agents and agents that further 
increase the conductivity of the body surface or its permeability, and the 
like. Other suitable additives may be chosen to increase drug solubility 
and/or increase charged ion concentration. The donor reservoir may also 
contain additives which inhibit microbial growth or perform other 
functions unrelated to the delivery of the agent. 
This invention is useful in the delivery of drugs or prodrugs within a 
broad class that are deliverable through body surfaces and membranes, 
including the skin, mucosa and nails. As used herein, the expressions 
"agent", "drug" and "prodrug" are used interchangeably, and are intended 
in their broadest interpretation as any pharmaceutically-acceptable 
substance which may be delivered to a living organism to produce a 
desired, usually beneficial, effect. In general, this includes therapeutic 
agents in all of the major therapeutic fields including, but not limited 
to, anti-infectives such as antibiotics and antiviral agents; analgesics 
such as fentanyl, sufentanil, and buprenorphine, and analgesic 
combinations; anesthetics; anorexics; antiarthritics; antiasthmatic agents 
such as terbutaline; anticonvulsants; antidepressants; antidiabetics 
agents; antidiarrheals; antihistamines; antiinflammatory agents; 
antimigraine preparations; antimotion sickness preparations such as 
scopolamine and ondansetron; antinauseants; antineoplastics; 
antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; 
antispasmodics including gastrointestinal and urinary; anticholinergics; 
sympathomimetrics; xanthine derivatives; cardiovascular preparations 
including calcium channel blockers such as nifedipine; betaagonists such 
as dobutamine and ritodrine; beta blockers; antiarrythmics; 
antihypertensives such as atenolol; ACE inhibitors such as ranitidine; 
diuretics; vasodilators including general, coronary, peripheral and 
cerebral; central nervous systems stimulants; cough and cold preparations; 
decongestants; diagnostics; hormones such as parathyroid hormones; 
hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; 
parasympathomimetrics; prostaglandins; proteins; peptides; 
psychostimulants; sedatives and tranquilizers. 
More specifically, this invention is useful for the controlled delivery of 
baclofen, beclomethasone, betamethasone, buspirone, cromolyn sodium, 
diltiazem, doxazosin, droperidol, encainide, fentanyl, hydrocortisone, 
indomethacin, ketoprofen, lidocaine, methotrexate, metoclopramide, 
miconazole, midazolam, nicardipine, piroxicam, prazosin, scopolamine, 
sufentanil, terbutaline, testosterone, tetracaine, and verapamil, among 
other drugs. 
The invention is particularly useful in the controlled delivery of 
peptides, polypeptides, proteins, or other macromolecules difficult to 
deliver transdermally or transmucosally because of their size. These 
macromolecular substances typically have a molecular weight of at least 
about 300 Daltons, and more typically, in the range of about 300 to 40,000 
Daltons. Examples of peptides and proteins which may be delivered in 
accordance with the present invention include, without limitation, LHRH, 
LHRH analogs such as buserelin, gonadorelin, naphrelin and leuprolide, 
GHRH, GHRF, insulin, insulinotropin, heparin, calcitonin, octreotide, 
endorphin, TRH, NT-36 (chemical name: 
N-(s)-4-oxo-2-azetidinyl!carbonyl!-L-histidyl-L-prolinamide!, liprecin, 
pituitary hormones (eg, HGH, HMG, HCG, desmopressin acetate), follicle 
luteoids, .alpha.-ANF, growth factor releasing factor (GFRF), .beta.-MSH, 
somatostatin, bradykinin, somatotropin, platelet-derived growth factor, 
asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic 
gonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (platelet 
aggregation inhibitor), glucagon, hirudin and hirudin analogs such as 
hirulog, hyaluronidase, interferon, interleukin-2, menotropins 
(urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen 
activator, urokinase, vasopressin, desmopressin, ACTH analogs, ANP, ANP 
clearance inhibitors, angiotensin II antagonists, antidiuretic hormone 
agonists, antidiuretic hormone antagonists, bradykinin antagonists, CD4, 
ceredase, CSF's, enkephalins, FAB fragments, IgE peptide suppressors, 
IGF-1, neurotrophic factors, colony stimulating factors, parathyroid 
hormone and agonists, parathyroid hormone antagonists, prostaglandin 
antagonists, pentigetide, protein C, protein S, renin inhibitors, thymosin 
alpha-1, thrombolytics, TNF, vaccines, vasopressin antagonist analogs, 
alpha-1 antitrypsin (recombinant), and TGF-beta. 
One example of an electrotransport device suitable for use with the present 
invention is illustrated in FIG. 1. Device 10 has two current distributing 
members or electrodes, comprised of electrically conductive materials, 
referred to herein as donor electrode 12 and counter electrode 14. The 
electrodes may be composed of any materials which are sufficiently 
electrically conductive, including without limitation, silver, silver 
chloride, zinc, carbon, and stainless steel. The electrodes may be present 
in a variety of forms including a metal foil or screen, a polymer film 
having an electrically conductive coating or a polymer matrix containing 
an electrically conductive filler, eg, powdered carbon or metal, formed by 
conventional processes such as extruding, calendering, film evaporation, 
or spray coating. In FIG. 1, the donor and counter electrodes 12 and 14 
are positioned adjacent to, and in electrical contact with, donor 
reservoir 16 and counter reservoir 18, respectively. The donor reservoir 
16 contains a solution of the beneficial agent (eg, a drug) to be 
delivered, while the counter reservoir 18 contains a solution of a 
biocompatible electrolytic salt such as sodium chloride or optionally 
another beneficial agent to be delivered. The reservoirs 16 and 18 are 
formed of any material adapted to absorb and hold a sufficient quantity of 
liquid therein in order to permit the passage of the agent therethrough by 
electrotransport. Since water is the preferred liquid solvent for forming 
the solutions contained in reservoirs 16 and 18, the reservoirs preferably 
contain one or more hydrophilic polymers such as polyvinylpyrrolidone, 
polyvinyl alcohol, or polyethylene glycols, optionally mixed with a 
hydrophobic polymer such as polyisobutylene, polyethylene, and/or 
polypropylene. An electrical insulator 20 is positioned between (i) the 
donor electrode 12 and the donor reservoir 16, and (ii) the counter 
electrode 14 and the counter reservoir 18. The insulator 20, may be an air 
gap or a material which conducts neither electrons nor ions to a 
substantial extent, and prevents the device 10 from short-circuiting 
through a path which does not include the body surface 40, to which the 
device 10 is applied. The device 10 optionally includes a backing layer 22 
composed of a liquid-impermeable non-conducting material. The device 10 
has an electronic circuit, illustrated schematically in FIG. 1 as layer 
24, having an electric power source, eg, one or more batteries, therein. 
Typically, the electronic circuit layer 24 is relatively thin and is 
preferably comprised of electronically conductive pathways, which are 
printed, painted or otherwise deposited on a thin, flexible substrate such 
as, for example, a film or polymeric web. The electronic circuit layer 24 
is, for example, a printed flexible circuit. In addition to the power 
source, the electronic circuit layer 24 may also include one or more 
electronic components which control the level, waveform shape, polarity, 
timing, etc, of the electric current applied by the device 10. For 
example, the circuit layer 24 may contain one or more elements of control 
circuitry such as a current controller, eg, a resistor or a 
transistor-based current control circuit, an on/off switch, and/or a 
microprocessor adapted to control the current output of the power source 
over time. The outputs of the circuit layer 24 are electrically connected 
to the electrodes 12 and 14, so that at any one time each electrode is in 
electrical contact with an opposite pole of the power source within the 
circuit layer 24. 
In this embodiment, the device 10 adheres to the body surface by means of a 
peripheral adhesive layer 28. The device may optionally contain an in-line 
adhesive layer, ie an ion-conducting adhesive layer positioned between 
reservoirs 16, 18 and the body surface, eg, the skin surface. An in-line 
adhesive must be composed of an ion-transmitting material, ie beneficial 
agent ions must be capable of passing through the adhesive layer to reach 
the body surface. Optional flux control membranes 30 and 32, such as those 
disclosed in Theeuwes et al, U.S. Pat. Nos. 5,080,646; 5,147,296; and 
5,169,382, are positioned between the donor reservoir 16 and the body 
surface 40 and between the counter reservoir 18 and the body surface 40, 
respectively, in order to limit or control the amount of passive, ie 
non-electrically assisted, flux of agent to the body surface 40. 
The invention will be further described by reference to the following 
examples, wherein human cadaver skin electrical resistivity and drug flux 
were measured for various permeation enhancer compositions. 
EXAMPLES 
Preparation of Human Cadaver Skin 
Skin strips having a thickness of 1 mm were removed from a human cadaver 
with an electric dermatome. These skin strips were placed in polyethylene 
bags, sealed and placed in a refrigerator at 4.degree. C. for temporary 
storage. Prior to use in an electrotransport cell, the skin strips were 
placed in 1 liter beakers containing water at 60.degree. C. for about 90 
seconds, and gently stirred. The skin strips were then removed, and placed 
onto the absorbent side of a piece of BENCHKOTE fabric with their dermis 
side down. The epidermis was removed from each strip with a round-tip 
spatula, and flat tipped tweezers to retain the dermis. Each epidermis, 
stratum corneum side up, was then transferred to a 5 cm deep PYREX glass 
tray filled with water. Each floating epidermis was stretched essentially 
flat, and then removed from the water, and 2.2 cm diameter disks of each 
epidermis were punched out of areas having no observable surface damage. 
The disks were stored at 4.degree. C. in a sealed container with water 
droplets to maintain their moisture. 
Experimental Set-up for Electrotransport 
The disks were mounted between the donor and receptor compartments, with 
the stratum corneum side facing the donor compartment, of a 2-compartment 
polycarbonate electrotransport permeation cell. The volume of each 
compartment was about 2 mL and the area between the two compartments, ie, 
the exposed area for transport, was about 1.26 cm.sup.2. 
An aqueous solution of the drug being transdermally delivered and the 
selected permeation enhancer composition, if any, was placed in the donor 
compartment. Dulbecco's phosphate buffered saline (approximately 0.15N 
NaCl, pH 7.0) was placed in the receptor compartment. 
The rate of transport of drug and the electrical resistance of the skin 
were monitored throughout the experiments while applying an electric 
current. 
The cell was maintained at 32.degree. C. by a Haake Model D1 heating 
block/water bath. The electrodes were connected to a galvanostat, which 
applied a constant current of 126 .mu.A (current density of 100 
.mu.A/cm.sup.2) and monitored the voltage drop across the skin by placing 
two Ag/AgCl junction reference electrodes, one each in the donor and 
receptor solutions, and measuring the voltage difference (AV) between the 
electrodes. 
The resistance of the skin (R) was obtained from Ohm's law: 
R=.DELTA.V/i 
where i equals the applied current (ie, 126 .mu.A). 
Example 1 
Enhanced Effect of Composition of the Invention Over Either Component Alone 
on Agent Flux and Skin Resistance 
The following experiments were conducted to assess the effect of one 
composition of the invention, containing ethanol and dodecanol, on the 
transdermal delivery of sodium ketoprofen (ketoprofen anions) by 
electrotransport from a cathodic electrode. The electrotransport delivery 
of ketoprofen in the presence of various enhancers was assessed 
side-by-side for comparative purposes. The enhancers used were as follows: 
(i) ethanol alone; (ii) dodecanol alone; (iii) no enhancer; (iv) ethanol 
and dodecanol. The initial concentration of ketoprofen in the donor 
compartment was 100 mg/mL, and the donor solution had a pH (unbuffered) of 
5.0 to 5.5. A silver chloride composite polymer electrode (cathode) was 
placed in the donor compartment, and a silver foil electrode (anode) was 
placed in the receptor compartment. 
Each experiment was started by connecting the power source to the 
electrodes, and samples were automatically taken from the receptor 
compartment every one to two hours, except for overnight experimentation, 
using an Isco Model 2230 autosampler and a metering pump. The 
concentration of ketoprofen in the samples was determined by high 
performance liquid chromatography (HPLC) using a Shimadzu Model SCL-6B 
chromatograph. Each run was conducted in triplicate, including the 
control, to minimize errors. All cells were set-up with tissue from the 
same cadaver. The selected permeation enhancer composition was placed in 
the donor compartment, while the control cell's donor compartment 
contained no enhancer. 
Flux and voltage measurements generally reached steady state after about 4 
hours of cell operation. The steady state flux values and calculated skin 
resistances are shown in Table 1 in normalized form, ie, all values are 
divided by their respective control value. 
TABLE 1 
______________________________________ 
Comparison of Effect on Agent Flux and Skin Resistance 
of Lower or Higher Alcohol Alone, and 
Composition of Invention 
Normalized 
Ketoprofen 
Normalized Skin 
Permeation Enhancer(s) 
Flux Resistance 
______________________________________ 
Control (No Enhancer) 
1.00 1.00 
Ethanol (25% v/v) 
1.24 0.47 
Dodecanol (&lt;100 mM) 
1.93 0.39 
Dodecanol (&lt;100 mM) 
10.15 0.06 
and Ethanol (20% v/v) 
______________________________________ 
As Table 1 above illustrates, the addition of ethanol alone produced a 
reduction in skin resistance to 0.47 with respect to 1 for the control 
(more than a 50% reduction in skin resistance), while the addition of 
dodecanol alone produced a reduction in skin resistance to 0.39 with 
respect to the value of 1 for the control (almost a 60% reduction in skin 
resistance). 
The composition containing both dodecanol and ethanol, however, produced an 
unexpectedly greater reduction in skin resistance to only 0.06 with 
respect to the value of 1 for the control (a reduction in skin resistance 
of greater than 94%). In addition, ethanol alone increased the rate of 
delivery of ketoprofen by only 24%, and dodecanol alone increased it by 
93%. The ethanol/dodecanol composition, representative of the invention, 
produced an unexpected enhancement of ketoprofen electrotransport flux, 
which was more than 10 times greater than the control. 
Although ethanol is present in slightly different amounts when tested alone 
(25% v/v) and with dodecanol (ethanol 20% v/v) as an enhancer, this 
difference in its concentration does not significantly alter its effect. 
This is confirmed in Example 2. 
Example 2 
Measurement of Metoclopramide Flux With Ethanol/Dodecanol as Enhancer in 
Comparison With Ethanol Alone as Enhancer (Comparison of Invention With 
Prior Art) 
The experimental conditions were identical to those described in Example 1, 
except an aqueous solution of metoclopramide HCl, instead of sodium 
ketoprofen, was placed in the donor compartment. In addition, the silver 
chloride cathode was placed in the receptor compartment and the silver 
foil anode was placed in the donor compartment since metoclopramide ions 
are cationic as opposed to ketoprofen ions which are anionic. The 
concentration of metoclopramide in the donor solution was about 100 mg 
metoclopramide/mL, and saline pH 7 was placed in the receptor compartment. 
The system was maintained at 32.degree. C. and a constant electric current 
of 100 .mu.A/cm.sup.2 was applied throughout the procedure. 
All runs had the same concentration of agent and other conditions, except 
for the following shown in Table 2. 
TABLE 2 
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Content of Enhancer (Ethanol), Metoclopramide 
Flux and Cell Voltage 
Normalized 
Enhancer Metoclopramide 
Normalized 
Amt Mass Flux Skin Resistance 
# Type (wt %) n (after 5 hrs) 
(after 5 hrs) 
______________________________________ 
1 None 0 1 1.00 1.00 
2 Ethanol 10 3 0.86 1.32 
3 Ethanol 20 3 0.73 1.13 
4 Ethanol 30 3 0.93 1.26 
5 Dodecanol 
2 
Ethanol 30 3 1.55 0.50 
______________________________________ 
The mass flux and skin resistance values were normalized versus the 
control. The second column from the right shows the normalized values 
versus the electrotransport flux of metoclopramide in the absence of any 
permeation enhancer (first line). The skin resistance (which was 
calculated from the measured cell voltage .DELTA.V using Ohm's law, 
R=i/.DELTA.V) was also normalized with respect to the value obtained by 
electrotransport of metoclopramide in the absence of any permeation 
enhancer (rightmost column). These values have been provided to permit a 
comparison with the values for the permeation enhancing compositions shown 
in Table 1. For example, when dodecanol was utilized in the presence of 30 
wt% ethanol, the electrotransport mass flux of metoclopramide was enhanced 
by over 50% and the skin resistance was lowered to one-half the resistance 
of the control. However, the use of ethanol alone as a flux enhancer is 
shown in Table 2 not to enhance, but to actually decrease, the mass flux 
of metoclopramide and increase the resistance of the skin during 
electrotransport delivery of metoclopramide. 
Having thus generally described the invention, and described in detail 
certain preferred embodiments thereof, it will be readily apparent that 
various modifications to the invention may be made by those skilled in the 
art without departing from the scope of this invention, which is limited 
only by the following claims.