Note: Descriptions are shown in the official language in which they were submitted.
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1
COMPOSITION AND METHOD FOR ENHANCING
TRANSDERMAL ELECTROTRANSPORT AGENT DELIVERY
TECHNICAL FIELD
This invention relates to the use of permeation enhancers for the
electrotransport delivery of agents through a body surface. More particularly,
this invention relates to permeation enhancers which reduce the electrical
resistance of the surface and facilitate the electrotransport of agents, such
as
i o drugs, therethrough.
BACKGROUND ART
The delivery of drugs and drug precursors by diffusion through the skin
is offers improvements over more traditional delivery methods, such as
subcutane-
ous injections and oral delivery. Transdermal drug delivery by passive
diffusion
avoids the hepatic first pass effect encountered with oral drug delivery.
Passive
transdermal drug delivery also reduces patient discomfort when compared to
subcutaneous injection, and provides more uniform drug blood concentrations
20 over time. The term "transdermal" delivery, broadly encompasses the
delivery of
an agent through a body surface, such as the skin, mucosa, or nails of an
animal
or the outer surface of a plant.
The skin functions as the primary barrier to the transdermal penetration of
external substances into the body and represents the body's major resistance
to
25 the delivery of agents. Up to the present time, most efforts have been
focussed
on reducing the physical resistance or enhancing the permeability of the skin
to
the delivery of the therapeutic agent being delivered. Various methods for
increasing the rate of transdermal drug diffusion have been used. For example,
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drug-impermeable backing layers made of metal, plastic and other materials
have been employed in skin patches in order to limit diffusion of drugs away
from the skin and, thereby. increase the diffusion of drugs into the skin. In
addition, an increase in the rate of absorption of agents into the skin was
_ produced by varying the temperature and the relative humidity of the
atmosphere adjacent to the skin Other efforts have been directed at abrading
or piercing the skin by mechanically disrupting its outermost stratum corneum
layer. Chemical absorption promoters or permeation enhancers have also been
utilized, both as integral components of therapeutic compositions or applied
prior
1 o to the therapeutic agent. These passive methods have generally proven
ineffective in significantly increasing the amount of agent delivered,
particularly
in the case of hydrophilic drugs (eg, in the form of water soluble salts) and
high
molecular weight agents (eg, polypeptides and proteins).
"Electrotransport" involves the delivery of a agent through a body surface
m with the assistance of an electrical field. Electrotransport, thus, refers
generally
to the passage of an agent through a substrate, such as the skin, mucous
membranes, or nails, which is at least partially induced by circulating an
electrical current through the substrate. Many agents, including therapeutic
drugs and precursors thereof, may be introduced into the human body by
2 o electrotransport. The electrotransport of an agent through a body surface
may
be attained by various methods. One widely used electrotransport method is
iontophoresis, which involves the electrically induced transport of charged
ions.
Electroosmosis. another type of electrotransport, involves the movement of a
liquid out of, or through, a biological membrane under the influence of an
electrical field. Electroporation, still another type of electrotransport.
involves
the movement of an agent through transiently-created pores formed in a
biological membrane under the influence of an electric field. When any given
agent is electrotransported, more than one of these methods may occur
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3
simultaneously to some extent. The term electrotransport, as used herein, is
given its broadest possible interpretation to include the electrically induced
or
enhanced transport of charged and uncharged agents or mixtures thereof,
regardless of the specific mechanisms) by which the agents) is(are) actually
s transported.
Electrotransport devices typically require at least two electrodes, both
being in electrical contact with some portion of the skin, nails, mucous
membrane, or other membrane surfaces of the body. One electrode, commonly
referred to as the "donor" or "active" electrode, is the electrode from which
an
to agent, such as a drug or drug precursor, is delivered into the body. The
other
electrode, typically termed the "counter" or "return" electrode, serves to
close the
electrical circuit through the body. For example, if the ionic agent to be
delivered is a cation, i.e. a positively charged ion, the anode will be the
active or
donor electrode while the cathode completes the circuit. Alternatively, if the
15 agent is an anion, ie, a negatively charged ion. the cathode will be the
donor
electrode while the anode completes the circuit. When anionic and cationic
drugs need to be delivered at the same time, both the anode and cathode may
be used for this purpose and the anionic drug placed in the cathode while the
cationic drug is placed in the anode. In addition, electrotransport delivery
2 o devices typically include an electrical power source in the form of one or
more
batteries, and an electrical control mechanism designed to regulate the flow
of
electric current through the electrodes and thereby the rate of drug delivery.
Alternatively, the power may be supplied, at least in part, by a galvanic
couple
formed by contacting two electrodes made of dissimilar materials. A complete
2 s electrical circuit is formed by electrically contacting one pale of the
power source
to the donor electrode, the donor electrode to the body, the body to the
counter
electrode, and the counter electrode to the opposite pole of the power source.
The donor electrode typically includes a reservoir or source of the agent or
drug
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to be delivered. The donor reservoir may take the form of a pouch, a cavity, a
porous sponge, a pad, and a pre-formed gel body, among others. The counter
electrolyte likewise typically includes a reservoir containing a biocompatible
electrolyte. Such reservoirs are electrically connected to the anode or
cathode
_ of the electrotransport device to provide either a fixed or a renewable
source of
one or more electrolytes, therapeutic agents or drugs.
It is known that electrotransport drug flux is roughly proportional to the
level of electric current applied by the device. However, there is a limit to
the
amount of current which may be comfortably tolerated by a patient. This
1 ~ problem becomes more acute as the size of the electrotransport system and,
therefore, the skin contact areas of the electrodes is reduced, as is the case
in
portable/wearable systems. As the skin contact area of an electrotransport
device decreases, the current density, (ie, the amount of current per unit of
skin
contact area) applied by the device increases. Thus, there is a limit to the
level
1 ~ of electric current which may be applied by any electrotransport device of
a
given size and, this current limit becomes lower as the size (ie, the skin
contact
area) of the device is reduced. In certain instances, electrotransport devices
operating at these current limits have been unable to deliver sufficient
amounts
of drug to effectively treat a disease. In those cases, the incorporation of a
o permeation enhancer into the electrotransport device may increase the amount
of the drug delivered, and help maintain a higher and therapeutically
effective
concentration of drug in the blood. In the context of this application, the
terms
"permeation enhancer" include absorption promoters and surtactants and
broadly describe a chemical species which either reduces the physical
resistance of a body surface to the passage of an agent therethrough or, as
electrotransport enhancers do, alters the ionic selectivity of the body
surface;
increases the electrical conductivity or the permeability of the body surface,
and/or the number of agent-transmitting pathways therethrough. The use of
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WO 96/02232 PCT/US95/08384
electrotransport enhancers may also help reduce the size of the
electrotransport
device by requiring a reduced total electric current and thereby a reduced
electrode skin-contact area for achieving a particular current density. A
reduction in the size of the device will also, most likely, improve patient
comfort
s and reduce manufacturing costs.
A limited number of electrotransport enhancers for the delivery of agents
have been disclosed in the literature. Ethanol, for instance, has been
utilized
as an electrotransport enhancer for polypeptides by Srinivasan et al.,
(Srinivasan et al, "lontophoresis of Polypeptides: Effect of Ethanol
Pretreatment
Zo of Human Skin", J Pharm Sci 79(7):588-91 (1990)). In US Pat. 4,722,726 to
Sanderson et al., the skin surface is pretreated with a surface active agent
prior
to the application of the drug to the skin to reduce competition with tissue
ions
migrating outwardly through the skin, with sodium lauryl sulfate being a
preferred
surface active agent. US Patent 5,023,085 to Francoeur et al. discloses the
use
is of unsaturated C,a-CZO acids, alcohols, amines, and esters, along with
ketones
for the iontophoretic delivery of certain drugs. Laid Open Patent Application
W091/16077 discloses the use of fatty acids, such as oleic acid, lauric acid,
capric acid, and caprylic acid, as penetration enhancers for the iontophoretic
delivery of drugs.
2 o Thus, there is a continuing need to provide transdermal electrotransport
enhancers that provide increased rates of delivery of agents, such as drugs or
precursors thereof, in the absence of detrimental effects, such as excessive
electric current, to the patient.
zs
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DISCLOSURE OF THE INVENTION
This invention relates to a composition for electrotransport agent delivery,
an electrotransport device containing the composition, and a method of
delivering an agent by electrotransport which utilizes the composition. The
composition comprises at least one agent to be transdermally delivered through
a body surface and at least one electrotransport enhancer of its delivery. The
transdermal electrotransport enhancer utilized herein comprises a hydrophobic
tail and a polar head, and has a hydrophile-lipophile balance (HLB) number
1 ~, greater than about 6, the polar head having a molecular weight (MW) of
less
than 150 Daltons and being either neutral or ionizable when placed in aqueous
solution.
This invention also relates to a transdermal electrotransport delivery
device that comprises a donor reservoir containing the agents) to be delivered
1 ~ through a body surtace and the electrotransport enhancer(s) of this
invention.
The electrotransport enhancer of this invention may be utilized to improve
the rate of electrotransport delivery of an agent through a body surface by
applying to the body surface a composition comprising the enhancer and the
agent, and applying an electrical current through the surface to induce the
z c electrotransport delivery of the agent therethrough, and reducing the
surface's
electrical resistance and increasing the flux of the agent therethrough when
compared with the flux obtained in the absence of enhancer.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a sectional view of one example of an electrotransport device
which may be used to deliver the composition of the present invention.
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Figure 2 is a sectional view of a two compartment cell used for in vitro
testing of transdermal electrotransport drug flux.
MODES FOR CARRYING OUT THE INVENTION
This invention improves on prior art technology suitable for the delivery of
agents, such as drugs and the like, through a body surtace, in order to make
available sufficiently high blood levels of the agents, eg, to treat
previously
untreatable diseases, in the substantial absence of detrimental effects to the
Zo patient. The rate at which an agent, such as a drug or drug precursor, is
delivered to the body may be improved by modifying the design of the delivery
device andlor the contents of the delivery composition. Gne way of increasing
the rate of delivery of an agent by electrotransport, is to reduce the
electrical
resistance of the body surface (eg, skin). This, in turn, reduces the power
requirements of the system and permits a reduction in the size of the device.
In
the present invention, the delivery of the agent (eg, drug) in conjunction
with the
electrotransport enhancer of the invention increases the electrotransport flux
of
the agent through the body surface and/or decreases the electrical potential
(voltage) required to electrotransport the agent through the body surface.
2o Thus, the electrotransport enhancer utilized in the present invention
increases the electrotransport flux of the agent through the surface andlor
decreases the electrical resistance of the body surface and, thereby, reduces
the voltage across the surface at a select current level by altering the ionic
selectivity of the body surface, increasing its electrical conductivity or its
permeability to the agent, andlor increasing the number of pathways available
within the surface for the passage of the agent therethrough. Increased flux
of
various agents andlor reduced voltage was obtained with enhancer molecules
having a lipophilic tail and polar head group of less than about 150 Dalton
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molecular weight (MW) and preferably in the range of about 16 to 150 Dalton
MW. When the polar head group becomes larger, the potentiating effect on the
transdermal electrotransport of the agent by the enhancer tends to diminish.
This may be caused by the large polar head groups physically impeding the
penetration of the enhancer into the body surface. On the other hand, within
the
specified size, the polar head groups may provide the electrotransport
enhancer
with increased aqueous solubility and help create a more hydrophilic pathway
for
the agent through the body surface. In some instances, the polar head group
may also interact with the agent to be delivered to increase the solubility of
the
1 ~~ latter. A "polar head group". as used herein, is a chemical residue,
having a
positive or negative charge, located at one end of the enhancer molecule, eg,
at
the end of a straight chain comprising saturated aliphatic residues. Examples
of
polar head groups for use in the present electrotransport enhancers include
alcohols (-OH), amines (-NHZ), mono- and di-substituted amines (-NRZ),
i ~ quaternary ammonium salts (-N+R4), sulfates (-S04 ~), sulfoxides (=SO),
esters (-
COO-R+), amides (-CONHZ), mono- and di-substituted amides (-CONRZ),
wherein R is selected from aliphatic, alicyclic and aromatic residues which
may
be substituted with N, O, S, or halogen, and alkali metal salts thereof such
as
sodium or potassium salts, among others.
~o In addition to the above characteristics relating to the polar head group,
the electrotransport enhancers of the invention were selected by their
hydrophile-lipophile balance (HLB) characteristics. The HLB is an empirical
value which was introduced by WC Griffin in 1949 and broadly reflects the
balance of size and strength of the hydrophilic and lipophilic groups present
in a
molecule. Molecules that are highly lipophilic have low HLB values, ie, below
about 5.0, and highly hydrophilic molecules have HLB values, above about 11Ø
Those with intermediate characteristics, accordingly, have intermediate HLB
values. An HLB number greater than about 7 indicates that the molecule is more
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9
hydrophilic than lipophilic. The chemical compounds providing the highest
increases in agent flux and/or decreases in cell voltage are those having an
HLB
number greater than about 6, and at times even greater than about 15, and as
high as about 40. The HLB number, thus, reflects a measure of the hydrophile-
s lipophile balance of the enhancer and is a relative proportion of its
hydrophilic
to hydrophobic character. Most surfactants have HLB numbers in the range of 0
.
to 20, although HLB values of up to 40, and higher are also possible. Thus,
most of the electrotransport enhancers utilized herein either possess a rather
balanced hydrophilic and lipophiliccharacter or are more hydrophilic than
io lipophilic as their HLB numbers increase. HLB numbers for a variety of
hydrophilic-lipophilic molecules have been calculated and are in the published
literature. A thorough discussion of HLB values and non-ionic surfactant HLB
numbers is provided for instance by Griffin, WC, "Calculation of HLB Values of
Non-ionic Surfactartts", J. Soc. Cos. Met. Chem. 5: 249-2S6 (1954); and Grin,
is WC, in Cosmetic Science and Technology, Vol. 3, Ch. XLIV, Balsam and
Saparin, Eds., ~. 583-607 (194).
The transdermal electrotransport enhancer suitable for use herein may be
charged or uncharged. If the enhancer is charged, the electrotransport
enhancer
2 o preferably has a charge opposite that of the agent. Enhanoers which are
uncharged or have a charge opposite the charge of the agent to be delivered
are
preferred for at least iwo reasons. First, an enhancer having a charge o~osite
that of the agent being delivered does not compete with the agent for canying
the electric current, which competition results in lower agent flux per unit
of
2s applied current. Second, once an enhancer having the same charge as that of
the agent is delivered into the skin, the skin becomes charged and, therefore,
in
most instahces, less permeable to ions (eg, agent ions) having the same charge
as the enhan~r.
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REPLACEMENT PAGE
In a still more preferred embodiment, the transdermal electrotransport
enhancer has a hydrophobic tail which comprises a C,o-C,2 saturated aliphatic
residue, and more preferably a linear one. This group of electrotransport
enhancers encompasses saturated alcohols, amines, mono- and di-substituted
s free amines, quaternary ammonium salts, sulfates, acid esters, di-
sulfoxides,
sulfoxides, free amides, mono- and di-substituted amides, esters and salts
thereof. The compositions of this invention may include one or more of these
enhancers as well as mixtures thereof with other enhancers such as unsaturated
derivatives thereof, organic acids, Cs-CZO unsaturated aliphatic acids, C$-C9
and
to C,3-CZO saturated analogues thereof, and esters thereof, and the like.
Examples
of electrotransport enhancers in accordance with the present invention include
lauryl amine, sodium laurate, decyl methyl sulfoxide, dodecyl pyrrolidone,
dimethyl lauramide, N, N-dimethyl-1-dodecaneamine (dimethyl lauramine) and
salts thereof, N, N-didodecyl-1-dodecaneamine (trilaurylamine), and sodium
i5 lauryl sulfate, mixtures thereof, and mixtures thereof with aliphatic acids
such as
lauric acid, among others.
AMEI~pEfl .
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According to one aspect of the present invention,
there is provided a composition for the transdermal
electrotransport delivery of an agent comprising: (a) at
least one agent for transdermal delivery; and (b) at least
one transdermal electrotransport enhancer having a
hydrophile-lipophile balance (HLB) number greater than
about 6 and comprising a hydrophobic tail and a polar head
of less than about 150 Dalton MW, the polar head group being
uncharged or having a charge opposite the charge of the
agent to be delivered if the agent is ionizable in solution;
wherein the electrotransport enhancer is selected from the
group consisting of saturated Clo-C12 aliphatic alcohols,
amines, mono- and di-substituted amines, quaternary ammonium
salts, sulfoxides, sulfates, amides mono- and di-substituted
amides, esters and salts thereof.
According to another aspect of the present
invention, there is provided uses of the compositions of the
invention as an analgesic or for treating diabetes.
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REPLACEMENT PAGE
In another embodiment, the electrotransport enhancer is uncharged or
neutral in aqueous solution. A "neutral electrotransport enhancer", as used
herein, is an enhancer having less than about 5% by weight ionization in
aqueous solution. Neutral electrotranspart enhancers are particularly suitable
s when the agent to be delivered is charged in aqueous solution but no
suitable
enhancer which is oppositely charged in solution can be found. Neutral
electrotransport enhancers are significantly better enhancers of agent flux
through a body surface than same-charged molecules when they are present in
the composition along with the ionizable agent. For example, in tests
conducted
io with the anti-asthmatic agent sodium cromolyn, dodecyl pyrrolidone
increases
anionic cromolyn flux by more than 50% and lowers skin resistivity to the drug
by
more than 30%. Another example of the suitability of the neutral
electrotransport
enhancers is provided by the increase in both flux and conductivity observed
when dimethyl lauramide is added to ketoprofen, a univalent anionic anti-
cs inflammatory agent. The group of neutral electrotransport enhancers
suitable for
use with this invention encompasses linear dialiphatic or aliphatic
sulfoxides,
pyrrolidones, esters, alcohols unsubstituted or mono- or di-substituted
amides,
and some di-substituted amines, among others. Specific neutral
electrotransport
enhancers include C,-C,o aliphatic esters of saturated C,o-C,z aliphatic
acids.
~D
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REPLACEMENT PAGE
Examples of electrotransport enhancers displaying a neutral or non-ionized
character in aqueous solution include n-decyl methyl sulfoxide, dodecyl
pyrrolidone, dimethyl lauramide, and mixtures thereaf. Neutral
electrotransport
enhancers are preferred in order to avoid transport competition between
s similarly charged ionized permeation enhancers and agents to be delivered.
The composition and electrotransport delivery device of this invention are
useful in the delivery of a broad class drugs that is deliverable through body
surfaces and membranes, including skin, mucosa and nails. As used herein, the
expressions "agent", "drug" or "drug precursor" are used interchangeably, and
to are intended to have their broadest interpretation as any therapeutically
active
substance which is delivered to a living organism to produce a desired,
usually
therapeutic, effect. This class of drugs includes therapeutic agents in all of
the
major therapeutic areas including, but not limited to, .anti-infectives such
as
antibiotics and antiviral agents; analgesics such as fentanyl, sufentanil, and
i5 buprenorphine, and analgesic combinations; anesthetics; anorexics; anti-
arthritics; antiasthmatic agents such as terbutaline; anticonvulsants;
antidepres-
sants; antidiabetics agents; antidiarrheals; antihistamines; anti-inflammatory
agents; antimigraine preparations; antimotion sickness preparations such as
scopolamine and ondansetron; antinauseants; antineoplastics; antiparkinsonism
2o drugs; antipruritics; antipsychotics; antipyretics; antispasmodics
including
gastrointestinal and urinary; anticholinergics; sympathomimetics; xanthine
derivatives; cardiovascular preparations including calcium channel blockers
such as nifedipine; beta-agonists such as dobutamine and ritodrine; beta
blockers; antiarrythmics; antihypertensives such as atenolol; ACE inhibitors
such
a5 as ranitidine; diuretics; vasodilators including general, coronary,
peripheral and
AMID SHAT
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cerebral; central nervous system stimulants; cough and cold preparations;
decongestants; diagnostics; hormones such as parathyroid hormones;
hypnotics; immunosuppressives; muscle relaxants; parasympatholytics;
parasympathomimetics; prostaglandins; proteins; peptides; psychostimulants;
s sedatives and tranquilizers.
More specifically, the composition and electrotransport delivery device of
this invention are useful in the controlled delivery of drugs such as
baclofen,
beciomethasone, betamethasone, buspirone, cromolyn sodium, diltiazem,
doxazosin, droperidol, encainide, fentanyl, hydrocortisone, indomethacin,
to ketoprofen, lidocaine, methotrexate, metoclopramide; miconazole, midazolam,
nicardipine, piroxicam, prazosin, scopolamine, sufentanil, terbutaline,
testosterone, tetracaine, and verapamil, among others. The invention is
particularly useful in the controlled delivery of peptides, polypeptides,
proteins,
or other macromolecules difficult to deliver transdermally or transmucosally
i s because of their size. These macromolecular substances typically have a
molecular weight of at least about 300 Daltons, and more typically, a
molecular
weight in the range of about 300 to 40,000 Daltons. Examples of peptides and
proteins which may be delivered using the composition, method and device of
the present invention include, without limitation, LHRH, LHRH analogs such as
ao buserelin, gonadorelin, naphrelin and leuprolide, GHRH, GHRF, insulin,
insulinotropin, heparin, calcitonin, octreotide, endorphin, TRH, NT-36 (N-
[[(s)-4-
oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary
hormones
(e.g., HGH, HMG, HCG, desmopressin acetate), follicle luteoids, a-ANF, growth
factor releasing factor (GFRF), (3-MSH, somatostatin, bradykinin,
somatotropin,
25 platelet-derived growth factor, asparaginase, bleomycin sulfate,
chymopapain,
cholecystokinin, chorionic gonadotropin, corticotropin (ACTH), erythropoietin,
epoprostenol (platelet aggregation inhibitor), glucagon, hirulog,
hyaiuronidase,
interferon, interleukin-2, menotropins (urofollitropin (FSH) and LH),
oxytocin,
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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, CSFs, 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.
1 o The electrotransport composition of the present invention may also
comprise other chemical additives which further increase body surface con-
ductivity or permeability. Suitable additives include buffers, solvents such
as
ethanol, propyleneglycol, glycerol, and water, which may increase drug or
enhancer solubility and/or increase charged ion concentrations, while others,
m such as fatty acids may, in addition increase agent flux. Examples of fatty
acids
suitable for use herein are oleic acid, lauric acid, capric acid, caprylic
acid, and
the like, among others. Other additives used in compositions suitable for
transdermal electrotransport of drugs may also be present in the composition.
These electrotransport enhancers must be pharmaceutically acceptable
ao and biocompatible since they are utilized in the transdermal delivery of a
drug or
agent through a body surface. The term "biocompatible", as used herein, means
that the enhancer does not produce significant detrimental side effects, such
as
irritation or sensitization, when contacted with the chosen body surface.
The composition of the invention typically comprises an amount of the
agent, such as a drug or a drug precursor, that upon transdermal
eiectrotransport delivery will provide a therapeutic amount of the agent and
maintain this level for a period of time. These amounts will vary with the
specific
agent to be delivered. The ingredients in the composition are typically added
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and mechanically mixed and incorporated into the donor reservoir of an
electrotransport delivery device prior to its use. The amount of
electrotransport
enhancer required for addition to the donor reservoir of an iontophoretic
delivery
device depends upon a multitude of factors. Far example, the properties of the
s chosen agent and enhancer, the applied voltage, and the desired delivery
rate
are a few of the variables to be taken into account to determine the electro-
transport enhancer concentration. Generally, the electrotransport enhancers of
the present invention are present in the composition in an amount of about
0.01
to 20 wt% based on the weight of the agent-enhancer solution, more preferably
io about 0.1 to 15 wt% of the agent-enhancer solution, and still more
preferably up
to about 5 wt% of the agent-enhancer solution.
The composition of the invention is typically provided to the patient in a
donor reservoir of a transdermal electrotransport device. Typical electro-
transport devices are comprised of an independent electrical power source (eg,
1 s one or more batteries), a donor or active electrode and a counter
electrode, and
an electrical control mechanism designed to regulate the level of applied
electric
current and, thereby, the rate of drug delivery.
One embodiment of an eiectrotransport delivery device of the present
invention is illustrated in Figure 1. The device 10 has two current conducting
2 o members, referred to herein as a donor electrode 12 and a counter
electrode 14.
The donor and counter electrodes 12 and 14 are positioned adjacent to the
donor reservoir 16 and the optional counter reservoir 18, respectively. The
donor reservoir 16 contains the agent to be delivered, while the optional
counter
reservoir 18 contains a biocompatible electrolytic salt. The donor electrode
12
and donor reservoir 16 are separated from the counter electrode 18 and
optional
counter reservoir 18 by an electrical insulator 20. The device 10 also has a
backing layer 22 composed of a water-proof, and preferably electrically
insulating material. Electric power is supplied by the power source, shown
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16
schematically as layer 24 in Figure 1, which may be a battery or a series of
batteries. The power source may optionally include current controlling
circuitry.
Power source 24 is in electrical contact with electrodes 12 and 14, such that
each electrode is in contact with the opposite pole of the power source 24.
The
device adheres to the body surface 100 by means of a peripheral adhesive layer
28. An optional passive flux control membrane 30 may be positioned between
the donor reservoir 16 and the body surface 100 for controlling passive agent
delivery (ie, flux occurring in the absence of any applied electrical
potential).
The device 10 of Figure 1 is merely one example of a suitable electrotransport
Zo delivery device to practice the present invention. In addition, the device
may
contain other features. such as a removable protective liner (not shown) on
the
skin-contacting face of the device. Furthermore, certain com-ponents in device
are optional according to the present invention, such as the counter reservoir
18 and the independent power source 24, if the electrodes 12 and 14 are
1 s chosen such that they form a galvanic couple.
The electrotransport enhancing composition of this invention can also be
used in electrotransport devices having a table-top electrical controller and
electrodes connected to the controller through long (eg, 1 to 3 m) electrical
cables. These "remote" electrodes may be attached to separate body surtace
locations while the patient remains immobile (eg, sitting or lying) near the
controller. There are numerous electrotransport device configurations known in
the art, ail of which are contemplated for use with the electrotransport
enhancing
composition of the invention. Thus, device 10 of Figure 1 is presented solely
for
illustrative purposes and represents only one example of a device which may be
used with the composition and method of the present invention.
The electrodes 12 and 14 may be composed of an electrically conductive
material such as a metal. For example, the electrodes 12 and 14 may be formed
from metal foil, metal screen, metal deposited or painted on a suitable
backing,
CA 02190370 2005-03-03
67696-225
17
such as by calendaring or film evaporation, or by embedding a metal powder in
a
binder matrix. Examples of suitable metals include silver, zinc, silver
chloride,
aluminum, platinum, stainless steel, gold, and titanium. In one prefen~d
embodiment the anodic electrode is comprised of silver while the catholic
s electrode is comprised of silver chloride. Silver is preferred, as an anode,
over
other metals because silver ions, produced by the oxidation of the silver
anode
(Ag -.~ Ag~ + e'), have relatively low toxicity to humans. Silver chloride is
preferred as a cathode because the reduction of silver chloride produces
chloride ions (AgCI + a -+ Ag + CI~ which are endogenous to the human body.
i o Alternatively, the electrodes 12 and 14 may be formed of a polymer matrix
containing a conductive filler such as a metal powder, powdered graphite;
carbon fibers, or other electrically conductive filler material. The polymer-
based
electrodes may be produced by mixing the conductive filler in a polymer
matrix.
The electrotransport delivery device of this invention can be powered in
is various forms. !f the donor and counter electrodes are of dissimilar metals
or
have different half cell reactions, the device may generate its own electrical
power. Typical materials which provide a galvanic couple include a zinc anodic
electrode and a silver chloride catholic electrode. Such a galvanic couple
powered system, absent some controlling means, activates automatically when
Zo body tissues and/or fluids complete the electrical circuit with the device.
Numerous other galvanic couple systems potentially useful in the present
invention are known in the art and need not be further described herein. (See
for example, CRC Handbook of Chemistry and Physics, pp D133-0138, 62"°
edition ('1981-1982),
2s for the disclosures of electrochemical halfi cell reactions which may be
combined to form a galvanic couple). In most cases, however, a separate
electrical power source 24, such as the one shown in Figure 2, will be
required
to power the electrotransport device. The power sourace 24 may include one ~or
CA 02190370 1996-11-14
WO 96102232 ~- ' ~ i'~ "~ ~ PCT/US95/08384
18
more batteries, connected in series or in parallel, and positioned between the
counter electrode 14 and donor electrode 12, such that the donor electrode 12
is
connected to one pole of the power source 24 and the counter electrode 14 is
connected to the opposite pole. One or more 3 V button cell batteries, eg,
PANASONIC~ Model CR 2025, are suitable to power electrotransport devices.
Power source 24 may also include electronic circuitry for controlling the
applied
electric current (eg, current level, pulsed or DC, frequency, duty cycle,
etc.) as
well as the operation of the electrotransport device, such that the patient
may
manually turn the system on and off, as in a device suitable for an on-demand
o medication regime, or to automatically turn the system on and off with some
desired periodicity, for example, to match the natural or circadian patterns
of the
body. A relatively simple controller or microprocessor may be provided as well
to control the current as a function of time or to generate complex current
wave
forms such as pulses or sinusoidal waves. The control circuitry may also
include
15 a biosensor and a feedback system to monitor biosignals, provide an
assessment of the progress of the therapy, and adjust the delivery of the drug
accordingly.
The donor reservoir 16 and the optional counter reservoir 18 may be
formed of any material adapted to hold a sufficient quantity of liquid therein
in
20 order to permit the transport of the agent therethrough by
electrotransport. For
example, gauzes, pads or sponges composed of cotton or other absorbent
fabric, both natural and synthetic, may be used. More preferably, the matrices
of
the reservoirs 1 S and 18 are composed, at least in part, of a hydrophilic
polymer
material. Hydrophilic polymers are typically preferred because water is a
25 preferred biocompatible solvent suitable for soiubilizing many drugs, and
hydrophilic polymers have a relatively high equilibrium water content. More
preferably, the matrices of the reservoirs 16 and 18 are solid polymer
matrices
composed, at least in part, of an insoluble hydrophilic polymer. Insoluble
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19
hydrophilic polymer matrices are preferred for structural reasons over soluble
hydrophilic polymers. The matrices may be cross-linked with the agent in place
such as in the case of a silastic matrix, or the polymers may be prefabricated
and sorbed with the components from solution as is the case with cellulose,
s woven fiber pads and sponges.
The agent reservoirs 16 and 18 may alternately be made of a hydrophilic .
polymeric gel which is swellable or soluble in water. The polymers may be
blended with the drug in any ratio, the dry weight drug loading being
preferably a
few percent up to about 50 wt°r6 of the reservoir. The polymers may be
linear or
io cross-linked. Suitable hydrophilic polymers include co-polyesters such as
HYTREL~ (DuPont De Nemours & Co., Wilmington; DE), polyvinyl pyrrolidones,
polyvinyl alcohol; polyethylene oxides such as POLYOX~ (Union Carbide
Corp.), CARBOPOL~ (BF Goodrich of Akron, OH); blends of polyoxy ethylene or
polyethylene glycol with polyacrylic acid such as POLYOX~ blended with
is CARBOPOL~, polyacrylamide, KLUCEL~, cross-linked dextran such as
SEPHADEX~ (Pharmacia Fine Chemicals, AB, Uppsala, Sweden), WATER
LOCK~ (Grain Processing Corp., Muscatine, Iowa) which is a starch-graft-
poly(sodium acrylate-co-acrylamide) polymer, cellulose derivatives such as
hydroxyethyl cellulose, hydroxypropyl methylcellulose, low-substituted
2 o hydroxypropyl cellulose, and cross-linked Na-carboxymethyl cellulose such
as
Ac-Di-Sol~ (FMC Corp., Philadelphia, PA), hydrogels such as polyhydroxyethyl
methacrylate (National Patent Development Corp.), natural gums, chitosan,
pectin, starch, guar gum, locust bean gum, and the like, along with blends
thereof. Of these, polyvinylpyrrolidones are preferred. This list is merely
2s exemplary of the materials suited for use in this invention. Other suitable
hydrophilic polymers have been listed by Scott and Ruff in (Scott, J.R., &
Roff,
W.J., in H>~ndbook of Common Polymers, CRC Press (1971 ).
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WO 96/02232 PCT/US95108384
The matrices of the reservoirs 16 and 18 may optionally contain a
hydrophobic polymer for enhanced structural rigidity. The hydrophobic polymer
is preferably heat fusible, in order to improve the lamination of the
reservoirs 16
and 18 to adjacent components, such as the insulator 20 shown in Figure 1.
Suitable hydrophobic polymers far use in the reservoir matrices include, but
are
not limited to, polyisobutylenes, polyethylene, polypropylene, polyisoprenes
and
polyalkenes, rubbers, copolymers such as KRATON~, polyvinylacetate,
ethylene vinyl acetate copolymers, polyamides such as nylons, polyurethanes,
polyvinylchloride, acrylic or methacrylic resins such as polymers of esters of
to acrylic or methacrylic acid with alcohols such as n-butanol, 1-methyl
pentanol, 2-
methyl pentanol, 3-methyl pentanol, 2-ethyl butanol, isooctanol, n-decanol,
alone or copolymerized with ethylenically unsaturated monomers such as acrylic
acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl
acrylamides,
N-alkoxymethyl methacrylamides, N-tert-butylacrylamide, itaconic acid, N-
1 ~ branched C,o-Cz4 alkyl maleamic acids, glycol diacrylates, and blends
thereof.
Most of the above-mentioned hydrophobic polymers are heat fusible. Of these,
polyisobutylenes are preferred.
The reservoir matrices may be a polymeric matrix structure formed by
blending the desired agent, drug, electrolyte, or other component(s), with the
2 o polymer by such processes as melt blending, solvent casting, or extrusion.
Typically, the donor reservoir 16 contains a drug to be delivered, while the
counter reservoir 18 contains an electrolyte, eg, a water soluble
biocompatible
salt. In addition to the drug and electrolyte, the reservoirs 16 and 18 may
also
contain other conventional materials such as dyes, pigments, inert fillers,
and
the like. The counter reservoir 18 may contain one or more biocompatible
electrolytic salts, such as sodium chloride. The insulator 20 prevents direct
ion
transport, ie, short circuiting, between the donor reservoir 16 or the donor
electrode 12 and the counter electrode 14 or optional counter reservoir 18,
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WO 96/02232 ~ ~ ~'' ~~ ~ ~~ PCT/US95/08384
21
Insulator 20 is made of material that is impermeable to the passage of water,
ions, and electrons. Preferably, the insulating material is a material capable
of
strong bonding with the reservoir polymers, thereby providing further overall
structural integrity for the device. Preferred insulating materials include
poiy(isobutyienes) and ethylene vinyl acetates (EVA). Similarly, the backing
layer 22 is composed of a material which is water-proof and preferably
electrically insulating. The primary function is to prevent electrical short-
circuiting. In addition, the backing layer 22 may provide some structural
integrity
to the device.
to The composition of the invention is intended far traps-surface
administration, and preferably transdermal administration. The amount of agent
to be delivered need not be specified herein, and will depend on the agent
itself
and the medical condition being treated.
Having thus generally described the invention, the following examples will
illustrate how variations of the above-described parameters provide
therapeutically effective electrotransport systems.
EXAMPLES
2 a Preparation of Skin Strips
Human cadaver skin strips were prepared by removing about 1 mm thick
samples with an electric dermatome. These skin strips were then placed in
polyethylene bags, which were sealed and temporarily stored at about
4°C.
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WO 96/02232 , PCT/US95/08384
22
Preparation of Skin Disks
Prior to their use in the electrotransport cell, the skin strips were placed
for about 90 seconds in one-liter beakers containing water at 60°C, and
gently
stirred. The skin strips were then removed and placed onto the absorbent side
of a piece of BENCHKOTE material with the dermis side down. The epidermis
was removed from each strip with a round-tip spatula while the dermis was
retained with the aid of flat tipped tweezers. Each epidermis, stratum corneum
side up, was transferred to a 2" deep Pyrex glass tray containing water. Each
io floating epidermis was stretched essentially flat. After removing each
epidermis
from the water, 2.22 cm (718 in. ) diameter disks were punched out of areas of
each epidermis having negligible surface damage. The punched disks were
stored with water droplets at 4°C in a sealed container to maintain
moisture and
subsequently mounted between the donor reservoir 44 and counter reservoir 46.
15 as shown in Figure 2, with the stratum corneum side facing the donor
compartment.
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WO 96/02232 PCT/US95/08384
23
Preparation of Electrotransport Delivery Device and Composition
Human cadaver epidermis disks 42 were mounted in a 2-compartment
polycarbonate electrotransport permeation cell illustrated in Figure 2. The
cell
s was comprised of a polycarbonate support structure 52, having rubber 0-ring
seals 54, held together with stainless steel bolt and nut 56. The human
epidermis disks 42 were mounted between the anodic compartment 44 and the
cathodic compartment 46. A silver anode 48 was placed adjacent the anodic
compartment 44 and a silver chloride cathode 50 was placed adjacent the
Zo cathodic compartment 46. The area of the human epidermis 42 exposed for
transport was about 1.26 cm2 and the volume of each of compartments 44 and
46 was about 2 ml. The electrodes 48, 50 were electrically connected to a
galvanostat (not shown in Figure 2), which can be set to apply the voltage
needed to achieve a constant predetermined level of electric current, ie, 126
N,A.
15 Solutions of the drug to be transported through the skin disks 42, and
each of the electrotransport enhancers to be tested were placed at different
times in the anodic donor compartment 44. Dulbecco's phosphate buffered
saline (approximately 0.15 N NaCI, with minor amounts of other ions, pH 7.0)
was placed in the cathodic receptor compartment 46. The skin resistance was
2o calculated from the voltages applied by the galvanostat according to Ohm's
law:
~'sk~~ = V / I ,
where V is the potential applied by the galvanostat and I is the electric
current,
126 microamps. The drug flux was determined by periodic
sampling of the solution in the receptor compartment 46.
CA 02190370 2005-03-03
67f 96-225
24
Example 1: Enhancement of Electrotransport Delivery of.
Metoclopramide HCI
s Aqueous metoclopramide HCI (an anti-emetic drug salt) solutions having a
concentration of about 100 mg/ml were placed in the donor compartment. The
pH in the donor compartment was not adjusted but remained naturally at about
5.0 to 5.5 throughout the experiments. In an aqueous solut'ron, metoclopramide
HCI forms a positively charged drug ion and the elec~rotransport enhancers
io utilized in this experiment were representative of the following different
.
categories of surfactants:
(a) ~ Anionic molecules, eg, sodium lauryl sulfate;
(b) Weak polar molecules, eg, polyethylene glycol monolaurate (ie,
PEG-4 monolaurate), polyethylene glycol di-laurate (ie, PfG-4 di~xate),
is polyoxyethylene(23) lauryl ether ~8rlj 35T*' solo by Signrna Chi Co., St.
Louis,
MO), and lauryl lactate;
(c) Hydrophilic molecules containing sugars, eg, sucrose laurate,
sorbitan monolaurate, and polysorbate-20;
(d) Hydrophilic molecules containing nitrogen, eg, dimethyl lauramide,
2o dodecyl pyrrolidone, urea, laurylamine, and dimethyl dodecylamine oxide;
(e) Miscellaneous group, eg, decyl methyl sulfoxide, and amphoteric
molecules, such as lauramphocarboxy propionate.
Each surfactant was added to a final concentration of 10 mM (except for
dodecylpyrrolidone which was added to a final concentration of 100 mM) to the
is donor solutions for comparative purposes. The system was maintained at
about
32°C by means of a HAAKE Model D1 heating blodcNvater bath. A constant
electric current of 126 pA, ie, 100 pAlan2, was applied with the galvanostat
across the anode 48 and cathode~50 throughout the entire prose-lure; and the
cell voltage was monitored over the entire time and then averaged.
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REPLACEMENT PAGE
Samples were automatically taken from the receptor compartment every
one to two hours, except for overnight periods, with an autosampler (ISCO
Model 2230 Lincoln City, NE) and a metering pump. The metoclopramide
concentration in the receptor compartment was determined by light absorption
at
s 310 nm wavelength, using a standard curve of concentration v. absorption.
The
absorption measurements were obtained with a 8452A UVlvis spectro-
photometer (Hewlett-Packard, Palo Alto, CA). Three cells were typically used
for
testing each of the electrotransport enhancer compositions to minimize error,
and tissue from the same donor was used in the three cells, two of the cells
io having the selected electrotransport enhancer in the donor compartment, and
the third cell being a control cell which contained no electrotransport
enhancer.
Generally, the flux and voltage measurements were taken at or after
about 5 hours, at which time these levels achieved a steady state.
The normalized mass flux and voltage values obtained in the presence of
is each one of the electrotransport enhancers for the steady state flux of
metoclopramide are shown in Table 1. That is each value obtained in the
presence of an enhancer is divided by the control value. Thus, the control
value
for the normalized flux and cell voltage are both 1, arid the normalized
values in
the presence of an enhancer deviate from this value as they influence the
ao resistivity of the skin and/or metoclopramide flux through the skin. For
instance,
a metoclopromide flux value of 1.87 indicates an almost doubling of the amount
of the drug delivered when dimethyl laurarnide was added to the donor
composition. Similarly, a cell voltage value of 0.45 indicates a cell voltage
and,
therefore, skin resistance of about one half that of the control, when
dimethyl
25 lauramide is added to the donor composition.
67696-225 '
CA 02190370 2005-03-03
26
TABLE 1
Normalized and
Mass Cell
Flux Voltage
for
Various
Electrotransport
Enhancers
Normalized Normalized
MetoGopramide Cell
Permeation HLB Polar Head Mass Flux ,
- Voltage
Enhancer No. (Daltons) n' {after 5 hrs) (after 5 hrs)
Control NIA NIA 3 ~ 1.00 1.00
4
(no enhancer)
Lauryl amine 11 17 ~ 2 0.136 .22
n-Decyl methyl32 83 3 1.59 .44
sulfoxide
Dodecyl 8 72 3 1.68 .35
pyirolidone
Dimethyllauramide8 72 3 1.87 .45
Sodium lauryl 40 96 3 1.84 .76
sulfate
Sorbitan 8.6 191 3 1.01 ~ .98
monolaurate
PEG-4 9.5 221 2 1.05 .74
monolaurate
Laurampho- 54 260 2 0.99 .93
carboxy
propionate
BRIJ 35r"" 17 1029 Z 1.04 .94
Potysorbate-ZO17 2783 2 0.92 .96
Laurylladate 4.7 89 3 0.97 .92
PEG-L 8 248 2 0.97 .76
Dilaurate
. ~HLB denotes hydrophile-lipophile balance.
n denotes number of samples tested.
As can be seen from Table 1, electrotransport enhanaers having polar
io head groups of less than about 150 Daltons and HLB values greater than
about
CA 02190370 2005-03-03
67696-225
27
6 evidenced drug flux increases greater than 50% above control. Amongst the
permeation enhancers tested, the ones showing superior characteristics include
sodium laurate, n-decyl methyl sulfoxide, dodecyl pyrrolidone, dimethyl
lauramide, and sodium lauryl sulfate. Some of these are anionic surtactants,
s such as sodium lauryl sulfate, which enhanced mass flux and decreased skin
resistance. Enhancers with weakly polar groups, such as PEG-4 mors~laurate,
PEG-4 dilaurate, Brij 35T"", and lauryl lactate; reduced skin resis#i~ty, none
of
these enhanced the mass flux of metaclopramide. Sorbitan monolaurate, and
polysorbate-20 have hydrophilic sugar moieties but fail to have a significant
io effect on either the electrotransport flux of metaclopramide or the skin
resistivity.
Dimethyl lauramide, dodecylpyrrolidone, urea, laurylamine, and dimethyl
dodecylamine oxide all contain nitrogen in their hydrophilic heads. Both
dimethyl lauramide and dodecylpyrrolidone were very effective enhancers.
Laurylamine, a positively charged molecule, not only did not enhance, but
is significantly decreased the flux of the cationic metoclopramide (ie, due to
competition between laurylamine and metoclopromide and due to charging of the
skin). Decyl methyl sulfoxide acted as a good enhancer, whereas the sole
amphoteric compound, lauramphocarboxy propionate, which has a polar head
that is too large, did not appear to affect either flux or skin resistivity.
Most
~ o surfactants with a polar head over the range established for the preferred
enhancers of this inventions showed little effect on metoclopramide flux,
although some had an effect on skin resistance.
Thus, preferred electrotrarisport enhancers of the invention are those
having a net charge in solution opposite that of the agent, when both the
agent
2s and the enhancer are present in ionized form in solution.
CA 02190370 1996-11-14
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WO 96/02232 PCT/US95/08384
28
Example 2: Measurement of Metoclopramide Flux with Ethanol as
Enhancer (Comparison with Prior Art)
The prior art teaches that ethanol can be used to enhance both passive
s and electrically-assisted transdermal drug delivery. This experiment was run
to
determine the effects of ethanol (10-30 wt %) on metoclopramide flux and cell
voltage under conditions similar to those described in Example 1. The agent
utilized, metoclopramide HCI, was placed in the donor compartment at about 100
mg metoclopramide/ml, and Dulbecco's phosphate buffered saline (pH 7) was
1 o placed in the receptor compartment. The system was maintained at
32°C and a
constant electric current of 100 ~A/cm2 was applied throughout the procedure.
All runs !gad the same concentration of metoclopramide and other
conditions, except for the following shown in Table 2 belovv.
15 TABLE 2
Content of Enhancer (Ethanol), Metoclopramide
Flux and Cell Voltage
Normalized
Enhancer Metoclopramide Normalized
Amount Mass Flux Cell Voltage
No. Type (wt%) n (after 5 hrs) (after 5 hrs)
1 None 0 1 1.00 1.00
2 Ethanol 10 3 0.86 0.82
3 Ethanol 20 3 0.73 0.70
4 Ethanol 30 3 0.93 0.78
The first line in Table 2 is a control wherein the electrically assisted
z o metoclopramide flux and cell voltage were measured in the absence of
ethanol,
and each assigned a value of 1.00. The remaining metoclopramide flux and cell
voltage values were normalized versus the control. Table 2 shows that the
CA 02190370 1996-11-14
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ARC 1798 ~ ~r '' ! tJ .~ / 1.) . : ; . .
29
REPLACEMENT PAGE
addition of 10 to 30 wt % ethanol to the donor solutions decreased the mass
flux
of metoclopramide and the skin conductivity.
Example 3: Enhancement of Electrotransport Delivery of Positively
s Charged Tetracaine
The electrotransport of tetracaine HCI, in the form of an aqueous solution
having a concentration of 100 mg/ml, was tested and found to behave similarly
to that of metoclopramide HCI. The average mass flux obtained was 100 ~,g/cm2
to hr, and there was a 1 to 2 hour time lag to reach steady state flux.
The electrotransport of tetracaine was also conducted with surtactant flux
enhancers, such as decyl methyl sulfoxide. Electrotransport pretreatment with
the enhancer was highly beneficial for increasing the mass flux of the agent
and
decreasing cell voltage.
i5 Tetracaine is a much less electrophilic molecule than metoclopramide
since it is positively charged at its tertiary amine group, but the rest of
the
molecule is very hydrophobic. Concentrations of tetracaine higher than 20 mg/
ml (75 mM) lead to the formation of micelles, due to the highly surfactant
nature
of the drug. Lower concentrations of tetracaine may lead to a better showing
of
Zo the effect of the enhancer.
AMENDED
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REPLACEMEfJT PAGE
Example 4: Enhancement of Electrotransport Delivery of Sodium
Cromolyn
Di-sodium cromolyn, when in aqueous solution, forms a divalent anion.
s The experimental conditions were as described in Example 1, except the
cromolyn donor solution was placed in the cathodic compartment 46 and the
Dulbecco's phosphate buffered saline receptor solution was placed in the
anodic
compartment 44; and the stratum corneum layer of skin disk 42 was mounted to
face the cathodic compartment 46.
io Dodecylpyrrolidone, when added to the donor solution, at a concentration
of 100 mM, increased cromolyn flux by 50 to 100% and lowered skin resistivity
by 30 to 70%.
ENDED St~iE~1'
CA 02190370 1996-11-14
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31
REPLACEMENT PAGE
Example 5: Enhancement of Electrotransport of Ketoprofen
Sodium ketoprofen in aqueous solution forms an univalent anionic anti-
inflammatory agent. The electrotransport delivery of 100 mM ketoprofen in the
presence of cationic and non-ionic surfactants was tested under the conditions
described in Example 1. The enhancers used were laurylamine and dimethyl
lauramide. Two sets of tests were conducted. The first in aqueous solution,
and
the second in 20 wt% ethanol/water solution. Both enhancers utilized increased
mass flux and skin conductivity when used in water alone. The addition of 20%
to ethanol as a solvent improved the performance of both enhancers.
Having thus generally described our invention and certain preferred
embodiments thereof, it will be readily apparent to a person of ordinary skill
in
the art that various modifications to the invention may be made without
departing
from the scope of this invention, which is limited only by the following
claims.
yip SHE
