U.S. patent application number 11/051174 was filed with the patent office on 2005-06-16 for method and device for transdermal delivery of fentanyl and sufentanil.
Invention is credited to Bernstein, Keith J., Noorduin, Henk, Phipps, Joseph B., Southam, Mary.
Application Number | 20050131337 11/051174 |
Document ID | / |
Family ID | 23848034 |
Filed Date | 2005-06-16 |
United States Patent
Application |
20050131337 |
Kind Code |
A1 |
Phipps, Joseph B. ; et
al. |
June 16, 2005 |
Method and device for transdermal delivery of fentanyl and
sufentanil
Abstract
The invention provides an improved electrotransport drug
delivery system for analgesic drugs, namely fentanyl and
sufentanil. The fentanyl/sufentanil is provided as a water soluble
salt (eg, fentanyl hydrochloride) dispersed in a hydrogel
formulation for use in an electrotransport device (10). In
accordance with one aspect of the invention, the concentration of
fentanyl/sufentanil in the donor reservoir (26) solution is above a
predetermined minimum concentration, whereby the transdermal
electrotransport flux of fentanyl/sufentanil is maintained
independent of the concentration of fentanyl/sufentanil in
solution. In accordance with a second aspect of the present
invention, the donor reservoir (26) of the electrotransport
delivery device (10) is comprised of silver and the donor reservoir
(26) contains a predetermined "excess" loading of
fentanyl/sufentanil halide to prevent silver ion migration with
attendant skin discoloration. In accordance with a third aspect of
the present invention, a transdermal electrotransport delivered
dose of fentanyl/sufentanil is provided which is sufficient to
induce analgesia in (eg, adult) human patients suffering from
moderate-to-severe pain associated with major surgical
procedures.
Inventors: |
Phipps, Joseph B.; (Maple
Grove, MN) ; Southam, Mary; (Portola Valley, CA)
; Bernstein, Keith J.; (Somerville, NJ) ;
Noorduin, Henk; (Bergen op Zoom, NL) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
23848034 |
Appl. No.: |
11/051174 |
Filed: |
February 3, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11051174 |
Feb 3, 2005 |
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08465492 |
Jun 5, 1995 |
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6881208 |
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Current U.S.
Class: |
604/20 ; 424/449;
514/282 |
Current CPC
Class: |
A61N 1/0436 20130101;
A61N 1/0448 20130101; A61P 25/04 20180101 |
Class at
Publication: |
604/020 ;
514/282; 424/449 |
International
Class: |
A61N 001/30 |
Claims
1-23. (canceled)
24. A method for delivering an active agent through a body surface
by electrotransport comprising the steps of: a) providing an
electrotransport delivery device having a silver anodic donor
electrode, a cathodic counter electrode, and a donor reservoir
containing a loading amount of the analgesic drug in electrical
contact with the donor electrode, the device adapted to deliver up
to only a predetermined maximum total amount of analgesic drug over
a period of time, the loading amount prior to delivery being at
least two times greater than the predetermined maximum total amount
to prevent transient epidermal discoloration; and b) delivering
only up to the maximum total amount of the analgesic drug; wherein
the analgesic drug is selected from the group consisting of
fentanyl halide salts and sufentanil halide salts thereby avoiding
transient epidermal discoloration.
25. The method of claim 24, wherein the donor reservoir comprises a
hydrogel containing an aqueous fentanyl halide salt solution in a
loading that is at least 3 times greater than the predetermined
maximum total amount and wherein the donor reservoir is
substantially free of sources of halide other than the selected
analgesic drug halide salt.
26. The method of claim 24, wherein the donor reservoir comprises a
hydrogel containing an aqueous fentanyl salt solution in a loading
that is at least 3 times greater than the predetermined maximum
total amount, and during the delivery of the predetermined maximum
total amount maintaining the fentanyl concentration above 6 mg/mL
in the hydrogel, the body surface is skin.
27. The method of claim 24, wherein the donor reservoir comprises a
hydrogel containing an aqueous fentanyl salt solution or a
sufentanil salt solution and the body surface is intact human skin
and the period of time is at least 6 hours.
28. The method of claim 24, comprising enabling the delivery of the
analgesic drug through the body surface only up to the
predetermined maximum total amount of the analgesic drug and
wherein the drug delivery is substantially proportional to a level
of current applied by the delivery method during the iontophoretic
drug delivery.
29. The method of claim 24, wherein the drug is a salt of fentanyl
or salt of sufentanil and applying electrotransport current between
about 150 .mu.A to about 240 .mu.A.
30. The method of claim 28, wherein the drug is a salt of fentanyl
or salt of sufentanil and applying electrotransport current between
about 150 .mu.A to about 190 .mu.A.
31. The method of claim 28, wherein the drug is a salt of fentanyl
or salt of sufentanil and applying electrotransport current between
about 190 .mu.A to about 240 .mu.A.
32. The method of claim 24, comprising delivering only up to the
predetermined maximum total amount of the analgesic drug in
multiple predetermined dose amounts.
33. The method of claim 32, comprising applying electrotransport
current for delivery in multiple predetermined dose amounts with
delivery interval of up to about 20 minutes.
34. The method of claim 32, comprising applying electrotransport
current for delivery in multiple predetermined dose amounts with
delivery interval of about 8 to about 12 minutes.
35. The method of claim 32, comprising delivery in about 10 to
about 100 dose amounts.
36. The method of claim 32, comprising delivery in about 20 to
about 80 dose amounts.
37. The method of claim 36, wherein the predetermined dose amount
is about 20 to 60 .mu.g fentanyl halide.
38. The method of claim 37, wherein the predetermined dose amount
is about 40 .mu.g fentanyl halide.
39. The method of claim 32, comprising deliverying multiple
predetermined dose amounts over at least about 6 hours.
40. The method of claim 24, wherein the analgesic drug comprises
sufentanil hydrochloride and the loading amount is at least about 4
times greater than the predetermined maximum total amount.
41. The method of claim 24, wherein the donor reservoir has a
weight on a hydrated basis of about 0.5 g to 0.8 g and is loaded
with at least about 9 mg of fentanyl hydrochloride.
42. The method of claim 24, wherein the drug loading amount is such
that the analgesic drug amount remaining after the delivery of the
predetermined maximum total amount in the drug reservoir is at
least two times the predetermined maximum total amount of the
analgesic drug.
43. A method for transdermally delivering an active agent by
electrotransport comprising the steps of: a) providing an
electrotransport delivery device having a silver anodic donor
electrode, a cathodic counter electrode, and a donor reservoir
containing a loading amount of the analgesic drug in electrical
contact with the donor electrode, wherein the donor reservoir
comprises a hydrogel containing an aqueous fentanyl salt solution
that has a weight on a hydrated basis of about 0.5 g to 0.8 g, is
loaded with at least about 9 mg of fentanyl hydrochloride and is
substantially free of sources of halide other than fentanyl salt,
the device electronically adapted to deliver up to only a
predetermined maximum total amount of analgesic drug over a period
of time, the loading amount prior to delivery being at least two
times greater than the predetermined maximum total amount to
prevent transient epidermal discoloration by silver; b) delivering
only up to the predetermined maximum total amount of the analgesic
drug by delivering about 10 to about 100 predetermined dose
amounts, wherein the predetermined dose amount comprises about 20
to 60 .mu.g fentanyl halide delivered by applying a current of
about 150 .mu.A to about 240 .mu.A for a delivery interval of about
8 to about 12 minutes; c) maintaining the solution fentanyl
concentration above 6 mg/mL in the hydrogel.
44. A method for transdermally delivering an active agent by
electrotransport comprising the steps of: a) providing an
electrotransport delivery device having a silver anodic donor
electrode, a cathodic counter electrode, and a donor reservoir
containing a loading amount of the analgesic drug in electrical
contact with the donor electrode, wherein the donor reservoir
comprises a hydrogel containing an aqueous sufentanil halide
solution, the device electronically adapted to deliver up to only a
predetermined maximum total amount of analgesic drug over a period
of time, the loading amount prior to delivery being at least about
four times greater than the predetermined maximum total amount; and
b) delivering only up to the predetermined maximum total amount of
the analgesic drug by delivering about 10 to about 100
predetermined dose amounts, wherein the predetermined dose amount
comprises about 4 to 5.5 .mu.g sufentanil halide delivered by
applying a current of about 150 .mu.A to about 240 .mu.A for a
delivery interval of up to about 20 minutes; wherein the drug
reservoir prior to delivery has a loading amount of the analgesic
drug that is at least about four times greater than the maximum
total amount to prevent transient epidermal discoloration.
Description
TECHNICAL FIELD
[0001] The invention relates generally to improved electrotransport
drug delivery. Specifically, the invention relates to a device,
composition and method for improved electrotransport delivery of
analgesic drugs, particularly fentanyl and analogs of fentanyl. A
composition is provided in the form of a hydrogel formulation for
use in an electrotransport device.
BACKGROUND ART
[0002] The transdermal delivery of drugs, by diffusion through the
epidermis, offers improvements over more traditional delivery
methods, such as subcutaneous injections and oral delivery.
Transdermal drug delivery avoids the hepatic first pass effect
encountered with oral drug delivery. Transdermal drug delivery also
eliminates patient discomfort associated with subcutaneous
injections. In addition, transdermal delivery can provide more
uniform concentrations of drug in the bloodstream of the patient
over time due to the extended controlled delivery profiles of
certain types of transdermal delivery devices. 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.
[0003] The skin functions as the primary barrier to the transdermal
penetration of materials into the body and represents the body's
major resistance to the transdermal delivery of therapeutic agents
such as drugs. To date, efforts have been focussed on reducing the
physical resistance or enhancing the permeability of the skin for
the delivery of drugs by passive diffusion. Various methods for
increasing the rate of transdermal drug flux have been attempted,
most notably using chemical flux enhancers.
[0004] Other approaches to increase the rates of transdermal drug
delivery include use of alternative energy sources such as
electrical energy and ultrasonic energy. Electrically assisted
transdermal delivery is also referred to as electrotransport. The
term "electrotransport" as used herein refers generally to the
delivery of an agent (eg, a drug) through a membrane, such as skin,
mucous membrane, or nails. The delivery is induced or aided by
application of an electrical potential. For example, a beneficial
therapeutic agent may be introduced into the systemic circulation
of a human body by electrotransport delivery through the skin. A
widely used electrotransport process, electromigration (also called
iontophoresis), involves the electrically induced transport of
charged ions. Another type of electrotransport, electroosmosis,
involves the flow of a liquid, which liquid contains the agent to
be delivered, under the influence of an electric field. Still
another type of electrotransport process, electroporation, involves
the formation of transiently-existing pores in a biological
membrane by the application of an electric field. An agent can be
delivered through the pores either passively (ie, without
electrical assistance) or actively (ie, under the influence of an
electric potential). However, in any given electrotransport
process, more than one of these processes, including at least some
"passive" diffusion, may be occurring simultaneously to a certain
extent. Accordingly, the term "electrotransport", as used herein,
should be given its broadest possible interpretation so that it
includes the electrically induced or enhanced transport of at least
one agent, which may be charged, uncharged, or a mixture thereof,
whatever the specific mechanism or mechanisms by which the agent
actually is transported.
[0005] Electrotransport devices use at least two electrodes that
are in electrical contact with some portion of the skin, nails,
mucous membrane, or other surface of the body. One electrode,
commonly called the "donor" electrode, is the electrode from which
the agent is delivered into the body. The other electrode,
typically termed the "counter" electrode, serves to close the
electrical circuit through the body. For example, if the agent to
be delivered is positively charged, ie, a cation, then the anode is
the donor electrode, while the cathode is the counter electrode
which serves to complete the circuit. Alternatively, if an agent is
negatively charged, ie, an anion, the cathode is the donor
electrode and the anode is the counter electrode. Additionally,
both the anode and cathode may be considered donor electrodes if
both anionic and cationic agent ions, or if uncharged dissolved
agents, are to be delivered.
[0006] Furthermore, electrotransport delivery systems generally
require at least one reservoir or source of the agent to be
delivered to the body. Examples of such donor reservoirs include a
pouch or cavity, a porous sponge or pad, and a hydrophilic polymer
or a gel matrix. Such donor reservoirs are electrically connected
to, and positioned between, the anode or cathode and the body
surface, to provide a fixed or renewable source of one or more
agents or drugs. Electrotransport devices also have an electrical
power source such as one or more batteries. Typically at any one
time, one pole of the power source is electrically connected to the
donor electrode, while the opposite pole is electrically connected
to the counter electrode. Since it has been shown that the rate of
electrotransport drug delivery is approximately proportional to the
electric current applied by the device, many electrotransport
devices typically have an electrical controller that controls the
voltage and/or current applied through the electrodes, thereby
regulating the rate of drug delivery. These control circuits use a
variety of electrical components to control the amplitude,
polarity, timing, waveform shape, etc. of the electric current
and/or voltage supplied by the power source. See, for example,
McNichols et al., U.S. Pat. No. 5,047,007.
[0007] To date, commercial transdermal electrotransport drug
delivery devices (eg, the Phoresor, sold by Iomed, Inc. of Salt
Lake City, Utah; the Dupel Iontophoresis System sold by Empi, Inc.
of St. Paul, Minn.; the Webster Sweat Inducer, model 3600, sold by
Wescor, Inc. of Logan, Utah) have generally utilized a desk-top
electrical power supply unit and a pair of skin contacting
electrodes. The donor electrode contains a drug solution while the
counter electrode contains a solution of a biocompatible
electrolyte salt. The power supply unit has electrical controls for
adjusting the amount of electrical current applied through the
electrodes. The "satellite" electrodes are connected to the
electrical power supply unit by long (eg, 1-2 meters) electrically
conductive wires or cables. The wire connections are subject to
disconnection and limit the patient's movement and mobility. Wires
between electrodes and controls may also be annoying or
uncomfortable to the patient. Other examples of desk-top electrical
power supply units which use "satellite" electrode assemblies are
disclosed in Jacobsen et al., U.S. Pat. No. 4,141,359 (see FIGS. 3
and 4); LaPrade, U.S. Pat. No. 5,006,108 (see FIG. 9); and Maurer
et al., U.S. Pat. No. 5,254,081.
[0008] More recently, small self-contained electrotransport
delivery devices have been proposed to be worn on the skin,
sometimes unobtrusively under clothing, for extended periods of
time. Such small self-contained electrotransport delivery devices
are disclosed for example in Tapper, U.S. Pat. No. 5,224,927;
Sibalis, et al., U.S. Pat. No. 5,224,928; and Haynes et al., U.S.
Pat. No. 5,246,418.
[0009] There have recently been suggestions to utilize
electrotransport devices having a reusable controller which is
adapted for use with multiple drug-containing units. The
drug-containing units are simply disconnected from the controller
when the drug becomes depleted and a fresh drug-containing unit is
thereafter connected to the controller. In this way, the relatively
more expensive hardware components of the device (eg, batteries,
LED's, circuit hardware, etc.) can be contained within the reusable
controller, and the relatively less expensive donor reservoir and
counter reservoir matrices can be contained in the single
use/disposable drug-containing unit, thereby bringing down the
overall cost of electrotransport drug delivery. Examples of
electrotransport devices comprised of a reusable controller,
removably connected to a drug-containing unit are disclosed in
Sage, Jr. et al., U.S. Pat. No. 5,320,597; Sibalis, U.S. Pat. No.
5,358,483; Sibalis et al., U.S. Pat. No. 5,135,479 (FIG. 12); and
Devane et al., UK Patent Application 2 239 803.
[0010] In further development of electrotransport devices,
hydrogels have become particularly favored for use as the drug and
electrolyte reservoir matrices, in part, due to the fact that water
is the preferred liquid solvent for use in electrotransport drug
delivery due to its excellent biocompatiblity compared with other
liquid solvents such as alcohols and glycols. Hydrogels have a high
equilibrium water content and can quickly absorb water. In
addition, hydrogels tend to have good biocompatibility with the
skin and with mucosal membranes.
[0011] Of particular interest in transdermal delivery is the
delivery of analgesic drugs for the management of moderate to
severe pain. Control of the rate and duration of drug delivery is
particularly important for transdermal delivery of analgesic drugs
to avoid the potential risk of overdose and the discomfort of an
insufficient dosage.
[0012] One class of analgesics that has found application in a
transdermal delivery route is the synthetic opiates, a group of
4-aniline piperidines. The synthetic opiates, eg, fentanyl and
certain of its derivatives such as sufentanil, are particularly
well-suited for transdermal administration. These synthetic opiates
are characterized by their rapid onset of analgesia, high potency,
and short duration of action. They are estimated to be 80 and 800
times, respectively, more potent than morphine. These drugs are
weak bases, ie, amines, whose major fraction is cationic in acidic
media.
[0013] In an in vivo study to determine plasma concentration,
Thysman and Preat (Anesth. Analg. 77 (1993) pp. 61-66) compared
simple diffusion of fentanyl and sufentanil to electrotransport
delivery in citrate buffer at pH 5. Simple diffusion did not
produce any detectable plasma concentration. The plasma levels
attainable depended on the maximum flux of the drug that can cross
the skin and the drug's pharmacokinetic properties, such as
clearance and volume of distribution. Electrotransport delivery was
reported to have significantly reduced lag time (ie, time required
to achieve peak plasma levels) as compared to passive transdermal
patches (1.5 h versus 14 h). The researchers' conclusions were that
electrotransport of these analgesic drugs can provide more rapid
control of pain than classical patches, and a pulsed release of
drug (by controlling electrical current) was comparable to the
constant delivery of classical patches. See, also, eg, Thysman et
al. Int. J. Pharma., 101 (1994) pp. 105-113; V. Prat et al. Int. J.
Pharm., 96 (1993) pp. 189-196 (sufentanil); Gourlav et al. Pain, 37
(1989) pp. 193-202 (fentanyl); Sebel et al. Eur. J. Clin.
Pharmacol. 32 (1987) pp. 529-531 (fentanyl and sufentanil).
Passive, ie, by diffusion, and electrically-assisted transdermal
delivery of narcotic analgesic drugs, such as fentanyl, to induce
analgesia, have also both been described in the patent literature.
See, for example, Gale et al., U.S. Pat. No. 4,588,580, and
Theeuwes et al., U.S. Pat. No. 5,232,438.
[0014] In the last several years, management of post-operative pain
has looked to delivery systems other than electrotransport
delivery. Particular attention has been given to devices and
systems which permit, within predetermined limits, the patient to
control the amount of analgesic the patient receives. The
experience with these types of devices has generally been that
patient control of the administration of analgesic has resulted in
the administration of less analgesic to the patient than would have
been administered were the dosage prescribed by a physician.
Self-administered or patient controlled self-administration has
become known (and will be referred to herein) as patient-controlled
analgesia (PCA).
[0015] Known PCA devices are typically electromechanical pumps
which require large capacity electrical power sources, eg,
alternating current or multiple large capacity battery packs which
are bulky. Due to their bulk and complexity, commercially available
PCA devices generally require the patient to be confined to a bed,
or some other essentially fixed location. Known PCA devices deliver
drug to the patient by means of an intravenous line or a catheter
which must be inserted into the intended vein, artery or other
organ by a qualified medical technician. This technique requires
that the skin barrier be breached in order to administer the
analgesic. (See, Zdeb U.S. Pat. No. 5,232,448). Thus, as practiced
using commercially available PCA devices, PCA requires the presence
of highly skilled medical technicians to initiate and supervise the
operation of the PCA device along with its attendant risk of
infection. Further, commercially available PCA devices themselves
are somewhat painful to use by virtue of their percutaneous (ie,
intravenous or subcutaneous) access.
[0016] The art has produced little in the way of transdermal
electrotransport devices that can compete with the conventional
PCAs in terms of the amount of drug delivered to achieve adequate
analgesia and in a patient controlled manner. Further, little
progress has been made to provide a hydrogel formulation for
analgesic electrotransport, particularly fentanyl transdermal
electrotransport delivery, that has long term stability and has
performance characteristics comparable to the patient controlled
electromechanical pumps for, eg, intravenous delivery of analgesic.
There is need to provide an analgesic formulation in a suitable
device to take advantage of the convenience of electrotransport
delivery in a small, self-contained, patient-controlled device.
DESCRIPTION OF THE INVENTION
[0017] The present invention provides a method for improved
transdermal electrotransport delivery of fentanyl and analogs of
fentanyl, particularly sufentanil. As such, the method of the
present invention provides a greater degree of efficiency in
electrotransport delivery of analgesic fentanyl or sufentanil,
concomitantly providing a greater measure of patient safety and
comfort in pain management. The foregoing, and other advantages of
the present invention, are provided by a method of delivering
fentanyl or sufentanil through a body surface (eg, intact skin) by
electrotransport from an electrotransport delivery device having a
anodic donor reservoir containing an at least partially aqueous
solution of a fentanyl/sufentanil salt.
[0018] In one aspect, the invention concerns maintaining the
concentration of fentanyl or sufentanil salt in the donor reservoir
solution at or above a level at which the transdermal fentanyl or
sufentanil flux begins to become dependent on the concentration of
the drug in solution. For fentanyl, the transdermal
electrotransport flux remains independent of fentanyl concentration
at or above about 11 to 16 mM substantially throughout the fentanyl
electrotransport delivery period. By maintaining the concentration
of fentanyl salt solution at or above about 11 to 16 mM in the
donor reservoir, the electrotransport flux of the drug remains
substantially independent of the drug concentration in the donor
reservoir solution and substantially proportional to the level of
electrotransport current applied by the delivery device during the
electrotransport drug delivery. Maintaining the fentanyl salt
solution concentration above about 11 mM, and preferably above
about 16 mM ensures a predictable fentanyl flux with a particular
applied electrotransport current.
[0019] For sufentanil, the transdermal electrotransport flux
remains independent of sufentanil concentration at or above about
1.7 mM substantially throughout the sufentanil electrotransport
delivery period. By maintaining the concentration of sufentanill
salt solution at or above about 1.7 mM in the donor reservoir, the
electrotransport flux of the drug remains substantially independent
of the drug concentration in the donor reservoir solution and
substantially proportional to the level of electrotransport current
applied by the delivery device during the electrotransport drug
delivery. Maintaining the sufentanil salt solution concentration
above about 1.7 mM ensures a predictable sufentanil flux with a
particular applied electrotransport current.
[0020] In another aspect, the invention provides a donor reservoir
formulation for a transdermal electrotransport fentanyl/sufentanil
delivery device having an anodic donor electrode comprised of
silver, which donor reservoir formulation substantially prevents
migration of silver ions into, and discoloration of, the skin of
the patient. While the prior art has taught the advantage of using
a halide drug salt to prevent the migration of electrochemically
generated silver ions (see Untereker et al U.S. Pat. No.
5,135,477), it has now been discovered that for halide salts of
fentanyl or sufentanil which are delivered either continuously or
intermittently over longer electrotransport delivery periods (eg,
periods of at least several hours), the amount of
fentanyl/sufentanil halide needed in the donor reservoir in order
to prevent this silver migration must be well in excess of the
amount of fentanyl/sufentanil which is needed for therapeutic
purposes. For fentanyl hydrochloride, the amount of drug needed to
prevent silver ion migration has been determined to be at least
about 3 times the amount needed for delivery into the patient at
least under the specific electrotransport delivery conditions (ie,
applied electrotransport current, reservoir
size/weight/composition, and time of electrotransport current
application) which are described in more detail hereinafter.
[0021] In yet another aspect, the present invention concerns a
method of administering fentanyl or sufenanil by transdermal
electrotransport in order to treat moderate-to-severe pain
associated with major surgical procedures. We have determined that
a transdermal electrotransport dose of about 20 .mu.g to about 60
.mu.g of fentanyl, delivered over a delivery interval of up to
about 20 minutes, is therapeutically effective in treating
moderate-to-severe post-operative pain in human patients having
body weights above about 35 kg. Preferably, the amount of fentanyl
delivered is about 35 .mu.g to about 45 .mu.g over a delivery
interval of about 5 to 15 minutes, and most preferably the amount
of fentanyl delivered is about 40 .mu.g over a delivery interval of
about 10 minutes. Since fentanyl has a relatively short
distribution half life once delivered into a human body (ie, about
3 hours), the method of inducing analgesia preferably includes a
method for maintaining the analgesia so induced. Thus the method of
transdermally delivering fentanyl by electrotransport preferably
includes delivering at least 1 additional, more preferably about 10
to 100 additional, and most preferably about 20 to 80 additional,
like dose(s) of fentanyl over subsequent like delivery interval(s)
over a 24 hour period. The ability to deliver multiple identical
doses from a transdermal electrotransport fentanyl delivery device
also provides the capability of pain management to a wider patient
population, in which different patients require different amounts
of fentanyl to control their pain. By providing the capability of
administering multiple small transdermal electrotransport fentanyl
doses, the patients can titrate themselves to administer only that
amount of fentanyl which is needed to contol their pain, and no
more.
[0022] Other advantages and a fuller appreciation of specific
adaptations, compositional variations, and physical attributes of
the present invention can be learned from an examination of the
following drawings, detailed description, examples, and appended
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The present invention is hereinafter described in
conjunction with the appended drawings, in which like designations
refer to like elements throughout, and in which:
[0024] FIG. 1 is a perspective exploded view of an electrotransport
drug delivery device in accordance with the present invention;
[0025] FIG. 2 is a graph of normalized transdermal electrotransport
flux versus concentration of fentanyl HCl in aqueous solution;
[0026] FIG. 3 is a graph illustrating quality of analgesia in
patients administered with transdermal electrotransport fentanyl as
a function of time; and
[0027] FIG. 4 is a graph illustrating pain intensity experienced by
patients administered transdermal electrotransport fentanyl as a
function of time.
MODES FOR CARRYING OUT THE INVENTION
[0028] The present invention relates broadly to improved methods
for the transdermal electrotransport delivery of fentanyl or
sufentanil, in water soluble salt form, in formulations to achieve
a systemic analgesic effect.
Minimum Fentanyl/Sufentanil Concentration to Maintain Predictable
Electrotransport Flux
[0029] In one aspect, the present invention is characterized by
maintaining the transdermal electrotransport fentanyl/sufentanil
flux independent of drug concentration in the donor reservoir
during the electrotransport drug delivery period. In another
aspect, the present invention concerns a fentanyl or sufentanil
halide donor reservoir composition, which is adapted to be used in
an electrotransport delivery device having a silver anodic donor
electrode, which formulation is effective to prevent skin
discoloration from silver ions formed during oxidation of the
silver anode. In yet another aspect, the present invention provides
a fentanyl or sufentanil salt electrotransport delivery device, and
a method of using same, to achieve an analgesic effect which is
comparable to the effect achieved in known IV accessed patient
controlled analgesic pumps.
[0030] Concerning the first aspect of the present invention,
transdermal electrotransport fentanyl flux begins to become
dependent upon the concentration of the fentanyl salt in aqueous
solution as the fentanyl salt concentration falls below about 11 to
16 mM. The 11 to 16 mM concentration is calculated based only on
the volume of liquid solvent used in the donor reservoir, not on
the total volume of the reservoir. In other words, the 11 to 16 mM
concentration does not include the volume of the reservoir which is
represented by the reservoir matrix (eg, hydrogel or other matrix)
material. Furthermore, the 11 to 16 mM concentration is based upon
the number of moles of fentanyl salt, not the equivalent number of
moles of fentanyl free base, which is contained in the donor
reservoir solution.
[0031] For fentanyl HCl, the 11 to 16 mM concentration is
equivalent to about 4 to 6 mg/mL. Other fentanyl salts (eg,
fentanyl citrate) will have slightly differing weight based
concentration ranges based on the difference in the molecular
weight of the counter ion of the particular fentanyl salt in
question.
[0032] As the fentanyl salt concentration falls to about 11 to 16
mM, the fentanyl transdermal electrotransport flux begins to
significantly decline, even if the applied electrotransport current
remains constant. Thus, to ensure a predictable fentanyl flux with
a particular level of applied electrotransport current, the
fentanyl salt concentration in the solution contained in the donor
reservoir should be maintained above about 11 mM, and preferably
above about 16 mM. This aspect of the present invention maintains
the fentanyl salt concentration in solution above a minimum level
to ensure a predictable transdermal electrotransport flux at any
particular applied electrotransport current level.
[0033] In addition to fentanyl, water soluble salts of sufentanil
also have minimum aqueous solution concentrations below which the
transdermal electrotransport flux becomes dependent on
concentration of the sufentanil salt in solution. The minimum
concentration for sufentanil is about 1.7 mM, which for sufentanil
citrate is equivalent to about 1 mg/mL.
[0034] As long as there is no binding of the fentanyl/sufentanil to
the reservoir matrix material, the particular matrix material
chosen as the donor reservoir matrix has little if any effect on
the minimum concentration needed to assure predictable transdermal
electrotransport fentanyl/sufentanil flux. Hydrogel matrices in
particular exhibit no tendency to bind fentanyl or sufentanil and
so hydrogels are a preferred class of matrix materials for use with
this aspect of the present invention.
Prevention of Siver Migration During Fentanyl/Sufentanil
Electrotransport
[0035] The second aspect of the invention concerns the delivery of
fentanyl or sufentanil from an electrotransport device having a
silver donor electrode. Since fentanyl and sufentanil are both
bases, the salts of fentanyl and sufentanil are typically acid
addition salts, eg, citrate salts, hydrochloride salts, etc. The
acid addition salts of fentanyl typically have water solubilities
of about 25 to 30 mg/mL. The acid addition salts of sufentanil
typically have water solubilities of about 45 to 50 mg/mL. When
these salts are placed in solution (eg, aqueous solution), the
salts dissolve and form protonated fentanyl or sufentanil cations
and counter (eg, citrate or chloride) anions. As such, the
fentanyl/sufentanil cations are delivered from the anodic electrode
of an electrotransport delivery device. Silver anodic electrodes
have been proposed for transdermal electrotransport delivery as a
way to maintain pH stability in the anodic reservoir. See for
example, Untereker et al U.S. Pat. No. 5,135,477 and Petelenz et al
U.S. Pat. No. 4,752,285. These patents also recognize one of the
shortcomings of using a silver anodic electrode in an
electrotransport delivery device, namely that the application of
current through the silver anode causes the silver to become
oxidized (Ag.fwdarw.Ag.sup.++e.sup.-) thereby forming silver
cations which compete with the cationic drug for delivery into the
skin by electrotransport. Silver ion migration into the skin
results in a transient epidermal discoloration (TED) of the skin.
In addition to these patents, Phipps et al PCT/US95/04497 filed on
Apr. 7, 1995 teaches the use of supplementary chloride ion sources
in the form of high molecular weight chloride resins in the donor
reservoir of a transdermal electrotransport delivery device. While
these resins are highly effective at providing sufficient chloride
for preventing silver ion migration, and the attendant skin
discoloration, these resins can also have adverse reactions with
either the drug being delivered (ie, binding of drug to the resin)
and/or with the skin of the patient (ie, contributing to skin
irritation reactions). Thus, for the purposes of the following
discussion, the donor reservoir formulations of the present
invention will be assumed to be substantially free of such
secondary chloride ion source resins. While the Untereker and
Petelenz patents teach that providing a cationic drug in the form
of a halide salt prevents the migration of silver ions (ie, by
reacting the silver ions with the halide counter ion of the drug to
form a water insoluble silver halide precipitate;
Ag.sup.++X.sup.-.fwdarw.AgX), we have surprisingly discovered that
a significant excess (ie, an amount well in excess of the fentanyl
halide salt needed to be delivered to the patient for purposes of
achieving analgesia) of fentanyl halide must be provided in a donor
reservoir of an electrotransport fentanyl delivery device in order
to prevent silver ion migration. This is especially true for those
transdermal electrotransport delivery devices which are adapted to
apply electrotransport current for extended periods of time, eg,
longer than about 6 hours.
[0036] In general, the "excess" amount of fentanyl halide needed to
prevent silver ion migration will be highly dependent upon a number
of factors including the particular halide salt used (eg, chloride,
fluoride, bromide or iodide salt of the drug), the level of applied
electrotransport current, the size/weight/composition of the donor
reservoir, the applied current density level and the length of time
over which the electrotranport current is applied. We have
determined delivering fentanyl hydrochloride from polyvinyl alcohol
based donor reservoirs which are used to deliver fentanyl for
periods of up to about 15 hours, that the amount of fentanyl HCl
needed to prevent silver ion migration during electrotransport
delivery is about 2 to 3 times the amount of fentanyl HCl needed
for delivery into the patient over that same period of time for
purposes of inducing and maintaining analgesia.
[0037] In the specific case of an electrotransport delivery device
having a polyvinyl alcohol based donor reservoir containing
fentanyl hydrochloride and having a total weight (on a hydrated
basis) of about 0.3 to 0.8 g, which device (1) has an anodic donor
electrode comprised of silver (eg, silver foil or silver
powder-loaded polymer film) which is in electrical contact with the
donor reservoir, (2) has an electrical power source which applies a
DC current of about 190 .mu.A to 230 .mu.A to the donor and counter
electrodes, (3) applies a current density, measured as the total
applied current divided by the skin contact area of the donor
reservoir, of less than about 0.3 mA/cm.sup.2, and (4) is capable
of applying such current for up to about eighty separate delivery
intervals of about 8 to about 12 minutes duration, the fentanyl HCl
loading needed to induce and maintain analgesia is about 2.5 to 3.5
mg, yet the fentanyl HCl loading needed to prevent TED is at least
about 8 to 10 mg, and preferably at least about 11 to 13 mg. More
specifically in the case of an electrotransport delivery device
having a polyvinyl alcohol based donor reservoir containing
fentanyl hydrochloride and having a total weight (on a hydrated
basis) of about 0.5 to 0.8 g, which device applies a DC current of
about 210 .mu.A to the electrodes, and is capable of applying such
current for up to about eighty separate delivery intervals of about
10 minutes duration, the fentanyl HCl loading needed to induce and
maintain analgesia is about 3 mg, yet the fentanyl HCl loading
needed to prevent TED is at least about 9 mg, and preferably at
least about 12 mg.
[0038] In order to determine the loading of a halide salt of
fentanyl other than fentanyl HCl, it is only necessary to supply an
equivalent molar amount of halide ions to the reservoir since the
silver halide salts have fairly uniformly low water solubility. For
example, the loading of 8 to 10 mg of fentanyl HCl corresponds to a
molar loading of about 20 to 25 .mu.moles. Thus, about 20 to 25
.mu.moles of any of the other fentanyl halides (ie, fentanyl
fluoride, fentanyl bromide or fentanyl iodide) will provide an
equivalent degree of silver migration prevention as fentanyl
HCl.
[0039] In addition to fentanyl, "excess" amounts of sufentanil
halide salts also can be used to prevent silver ion migration.
Because sufentanil is about 7 to 10 times more potent than
fentanyl, only about 0.1 to 0.14 times the fentanyl dose is needed
to achieve an equivalent level of analgesia. However, because the
transdermal electrotransport delivery efficiency of sufentanil (ie,
the rate of sufentanil delivered per unit of applied
electrotransport current) is only about one-third that of fentanyl,
the applied electrotransport current needed to achieve the same
level of analgesia with sufentanil is about 0.3 to 0.4 times that
needed for fentanyl. Thus, the "excess" amount of sufentanil
chloride needed to prevent silver ion migration during
electrotransport delivery of sufentanil is correspondingly reduced
to about 6 to 10 .mu.moles or about 2.4 to 4 mg. The amount of
sufentanil HCl loading needed to prevent silver ion migration,
relative to the loading needed to achieve an analgesic effect in a
patient, is at least about 4 times the analgesically effective
loading.
[0040] As long as the reservoir matrix material has substantially
no silver ion binding capacity (ie, by means of a fixed anionic
(eg, COO.sup.-) moiety as is found in cation exchange membranes),
the particular matrix material chosen as the donor reservoir matrix
has little if any effect on the minimum loading of halide salts of
fentanyl and sufentanil which is effective to prevent silver ion
migration into the patient's skin. Hydrogel matrices in particular
exhibit little or no tendency to bind silver ions and so are a
preferred matrix material for use with this aspect of the present
invention.
Transdermal Electrotransport Fentanyl/Sufentanil Dosing for
Inducing and Maintaining Analgesia
[0041] In another aspect, the present invention provides a method
and electrotransport delivery device for delivering fentanyl or
sulfentinil through a body surface, eg, skin, to achieve an
analgesic effect. The fentanyl or sufentanil salt is provided in a
donor reservoir of an electrotransport delivery device as an
aqueous salt solution.
[0042] The dose of fentanyl delivered by transdermal
electrotransport is about 20 .mu.g to about 60 .mu.g over a
delivery time of up to about 20 minutes in human patients having
body weights of 35 kg or greater. Preferred is a dosage of about 35
.mu.g to about 45 .mu.g, and most preferred is a dosage of about 40
.mu.g for the delivery period. The method of the invention further
preferably includes delivery of about 10 to 100, and more
preferably about 20 to 80 additional like doses over a period of 24
hours in order to achieve and maintain the analgesic effect.
[0043] The dose of sufentanil delivered by transdermal
electrotransport is about 2.3 .mu.g to about 7.0 .mu.g over a
delivery time of up to about 20 minutes in human patients having a
body weights of 35 kg or greater. Preferred is a dosage of about 4
.mu.g to about 5.5 .mu.g, and most preferred is a dosage of about
4.7 .mu.g for the delivery period. The method of the invention
further preferably includes delivery of about 10 to 100, and more
preferably about 20 to 80 additional like doses over a period of 24
hours in order to achieve and maintain the analgesic effect.
[0044] The fentanyl/sufentanil salt-containing anodic reservoir
formulation for transdermally delivering the above mentioned doses
of fentanyl/sufentanil by electrotransport is preferably comprised
of an aqueous solution of a water soluble fentanyl/sufentanil salt
such as HCl or citrate salts. Most preferably, the aqueous solution
is contained within a hydrophilic polymer matrix such as a hydrogel
matrix. The fentanyl/sufentanil salt is present in an amount
sufficient to deliver the above mentioned doses transdermally by
electrotransport over a delivery period of up to about 20 minutes,
to achieve a systemic analgesic effect. The fentanyl/sufentanil
salt typically comprises about 1 to 10 wt % of the donor resevoir
formulation (including the weight of the polymeric matix) on a
fully hydrated basis, and more preferably about 1 to 5 wt % of the
donor reservoir formulation on a fully hydrated basis. Although not
critical to this aspect of the present invention, the applied
electrotransport current density is typically in the range of about
50 to 150 .mu.A/cm.sup.2 and the applied electrotransport current
is typically in the range of about 150 to 240 .mu.A.
[0045] The anodic fentanyl/sufentanil salt-containing hydrogel can
suitably be made of a any number of materials but preferably is
comprised of a hydrophilic polymeric material, preferably one that
is polar in nature so as to enhance the drug stability. Suitable
polar polymers for the hydrogel matrix comprise a variety of
synthetic and naturally occurring polymeric materials. A preferred
hydrogel formulation contains a suitable hydrophilic polymer, a
buffer, a humectant, a thickener, water and a water soluble
fentanyl or sufentanil salt (eg, HCl salt). A preferred hydrophilic
polymer matrix is polyvinyl alcohol such as a washed and fully
hydrolyzed polyvinyl alcohol (PVOH), eg, Mowiol 66-100 commercially
available from Hoechst Aktiengesellschraft. A suitable buffer is an
ion exchange resin which is a copolymer of methacrylic acid and
divinylbenzene in both an acid and salt form. One example of such a
buffer is a mixture of Polacrilin (the copolymer of methacrylic
acid and divinyl benzene available from Rohm & Haas,
Philadelphia, Pa.) and the potassium salt thereof. A mixture of the
acid and potassium salt forms of Polacrilin functions as a
polymeric buffer to adjust the pH of the hydrogel to about pH 6.
Use of a humectant in the hydrogel formulation is beneficial to
inhibit the loss of moisture from the hydrogel. An example of a
suitable humectant is guar gum. Thickeners are also beneficial in a
hydrogel formulation. For example, a polyvinyl alcohol thickener
such as hydroxypropyl methylcellulose (eg, Methocel K100MP
available from Dow Chemical, Midland, Mich.) aids in modifying the
rheology of a hot polymer solution as it is dispensed into a mold
or cavity. The hydroxypropyl methylcellulose increases in viscosity
on cooling and significantly reduces the propensity of a cooled
polymer solution to overfill the mold or cavity.
[0046] In one preferred embodiment, the anodic fentanyl/ufentanil
salt-containing hydrogel formulation comprises about 10 to 15 wt %
polyvinyl alcohol, 0.1 to 0.4 wt % resin buffer, and about 1 to 2
wt % fentanyl or sufentanil salt, preferably the hydrochloride
salt. The remainder is water and ingredients such as humectants,
thickeners, etc. The polyvinyl alcohol (PVOH)-based hydrogel
formulation is prepared by mixing all materials, including the
fentanyl or sufentanil salt, in a single vessel at elevated
temperatures of about 90.degree. C. to 95.degree. C. for at least
about 0.5 hr. The hot mix is then poured into foam molds and stored
at freezing temperature of about -35.degree. C. overnight to
cross-link the PVOH. Upon warming to ambient temperature, a tough
elastomeric gel is obtained suitable for fentanyl
electrotransport.
[0047] The hydrogel formulations are used in an electrotransport
device such as described hereinafter. A suitable electrotransport
device includes an anodic donor electrode, preferably comprised of
silver, and a cathodic counter electrode, preferably comprised of
silver chloride. The donor electrode is in electrical contact with
the donor reservoir containing the aqueous solution of a
fentanyl/sufentanil salt. As described above, the donor reservoir
is preferably a hydrogel formulation. The counter reservoir also
preferably comprises a hydrogel formulation containing a (eg,
aqueous) solution of a biocompatible electrolyte, such as citrate
buffered saline. The anodic and cathodic hydrogel reservoirs
preferably each have a skin contact area of about 1 to 5 cm.sup.2
and more preferably about 2 to 3 cm.sup.2. The anodic and cathodic
hydrogel reservoirs preferably have a thickness of about 0.05 to
0.25 cm, and more preferably about 0.15 cm. The applied
electrotransport current is about 150 .mu.A to about 240 .mu.A,
depending on the analgesic effect desired. Most preferably, the
applied electrotransport current is substantially constant DC
current during the dosing interval.
[0048] Reference is now made to FIG. 1 which depicts an exemplary
electrotransport device which can be used in accordance with the
present invention. FIG. 1 shows a perspective exploded view of an
electrotransport device 10 having an activation switch in the form
of a push button switch 12 and a display in the form of a light
emitting diode (LED) 14. Device 10 comprises an upper housing 16, a
circuit board assembly 18, a lower housing 20, anode electrode 22,
cathode electrode 24, anode reservoir 26, cathode reservoir 28 and
skin-compatible adhesive 30. Upper housing 16 has lateral wings 15
which assist in holding device 10 on a patient's skin. Upper
housing 16 is preferably composed of an injection moldable
elastomer (eg, ethylene vinyl acetate). Printed circuit board
assembly 18 comprises an integrated circuit 19 coupled to discrete
electrical components 40 and battery 32. Circuit board assembly 18
is attached to housing 16 by posts (not shown in FIG. 1) passing
through openings 13a and 13b, the ends of the posts being
heated/melted in order to heat stake the circuit board assembly 18
to the housing 16. Lower housing 20 is attached to the upper
housing 16 by means of adhesive 30, the upper surface 34 of
adhesive 30 being adhered to both lower housing 20 and upper
housing 16 including the bottom surfaces of wings 15.
[0049] Shown (partially) on the underside of circuit board assembly
18 is a battery 32, which is preferably a button cell battery and
most preferably a lithium cell. Other types of batteries may also
be employed to power device 10.
[0050] The circuit outputs (not shown in FIG. 1) of the circuit
board assembly 18 make electrical contact with the electrodes 24
and 22 through openings 23,23' in the depressions 25,25' formed in
lower housing, by means of electrically conductive adhesive strips
42,42'. Electrodes 22 and 24, in turn, are in direct mechanical and
electrical contact with the top sides 44',44 of drug reservoirs 26
and 28. The bottom sides 46',46 of drug reservoirs 26,28 contact
the patient's skin through the openings 29',29 in adhesive 30. Upon
depression of push button switch 12, the electronic circuitry on
circuit board assembly 18 delivers a predetermined DC current to
the electrodes/reservoirs 22,26 and 24,28 for a delivery interval
of predetermined length, eg, about 10 minutes. Preferably, the
device transmits to the user a visual and/or audible confirmation
of the onset of the drug delivery, or bolus, interval by means of
LED 14 becoming lit and/or an audible sound signal from, eg, a
"beeper". Analgesic drug, eg fentanyl, is then delivered through
the patient's skin, eg, on the arm, for the predetermined (eg, 10
minute) delivery interval. In practice, a user receives feedback as
to the onset of the drug delivery interval by visual (LED 14
becomes lit) and/or audible signals (a beep from the "beeper").
[0051] Anodic electrode 22 is preferably comprised of silver and
cathodic electrode 24 is preferably comprised of silver chloride.
Both reservoirs 26 and 28 are preferably comprised of polymer
hydrogel materials as described herein. Electrodes 22, 24 and
reservoirs 26, 28 are retained by lower housing 20. For fentanyl
and sufentanil salts, the anodic reservoir 26 is the "donor"
reservoir which contains the drug and the cathodic reservoir 28
contains a biocompatible electrolyte.
[0052] The push button switch 12, the electronic circuitry on
circuit board assembly 18 and the battery 32 are adhesively
"sealed" between upper housing 16 and lower housing 20. Upper
housing 16 is preferably composed of rubber or other elastomeric
material. Lower housing 20 is preferably composed of a plastic or
elastomeric sheet material (eg, polyethylene) which can be easily
molded to form depressions 25,25' and cut to form openings 23,23'.
The assembled device 10 is preferably water resistant (ie, splash
proof and is most preferably waterproof. The system has a low
profile that easily conforms to the body thereby allowing freedom
of movement at, and around, the wearing site. The anode/drug
reservoir 26 and the cathode/salt reservoir 28 are located on the
skin-contacting side of device 10 and are sufficiently separated to
prevent accidental electrical shorting during normal handling and
use.
[0053] The device 10 adheres to the patient's body surface (eg,
skin) by means of a peripheral adhesive 30 which has upper side 34
and body-contacting side 36. The adhesive side 36 has adhesive
properties which assures that the device 10 remains in place on the
body during normal user activity, and yet permits reasonable
removal after the predetermined (eg, 24-hour) wear period. Upper
adhesive side 34 adheres to lower housing 20 and retains the
electrodes and drug reservoirs within housing depressions 25,25' as
well as retains lower housing 20 attached to upper housing 16.
[0054] The push button switch 12 is located on the top side of
device 10 and is easily actuated through clothing. A double press
of the push button switch 12 within a short period of time, eg,
three seconds, is preferably used to activate the device 10 for
delivery of drug, thereby minimizing the likelihood of inadvertent
actuation of the device 10.
[0055] Upon switch activation an audible alarm signals the start of
drug delivery, at which time the circuit supplies a predetermined
level of DC current to the electrodes/reservoirs for a
predetermined (eg, 10 minute) delivery interval. The LED 14 remains
"on" throughout the delivery interval indicating that the device 10
is in an active drug delivery mode. The battery preferably has
sufficient capacity to continuously power the device 10 at the
predetermined level of DC current for the entire (eg, 24 hour)
wearing period.
[0056] The present invention is further explained by the following
examples which are illustrative of, but do not limit the scope of,
the present invention.
EXAMPLE 1
[0057] The following experiment was conducted in order to determine
the necessary minimum concentration of fentanyl salt in a donor
reservoir of a transdermal electrotransport delivery device in
order to ensure that the transdermal electrotransport fentanyl flux
remains approximately proportional to the level of applied
electrotransport current.
[0058] Anodic donor reservoir gels, having varying loadings of
fentanyl HCl, were prepared having the following composition:
1 Material (wt %) Water 81.3 PVOH 15.0 Fentanyl HCl 1.7 Polacrilin
0.1 0.5 N NaOH 1.9
[0059] The combination of Polacrilin and NaOH acted as a buffer to
maintain the pH of the gels around 5.5. Polacrilin (also known as
Amberlite IRP-64) is sold by Rohm & Haas of Philadelphia, Pa.
The materials were mixed in a beaker at elevated temperature of
90.degree. C. to 95.degree. C., poured into foam molds and stored
overnight at -35.degree. C. to cross-link the PVOH. The gels had a
skin contact area of 2 cm.sup.2 and a thickness of 1.6 mm. The gels
had a fentanyl HCl concentration of 21 mg/mL of water. A silver
foil anodic electrode was laminated to one surface of the gels.
[0060] The transdermal electrotransport fentanyl flux from these
gels was measured by in vitro flux studies using a two-compartment
diffusion cell and human cadaver skin. The gels were mounted on the
stratum corneum side of heat stripped human cadaver epidermis taken
from back skin samples. The other side of the epidermis was exposed
to a receptor compartment, having a volume of 4 cm.sup.2, and
filled with one tenth strength Dulbecco's phosphate buffered saline
(pH 7.4). A counter electrode comprised of a polyisobutylene film
loaded with silver chloride powder was placed in the receptor
compartment.
[0061] The donor and counter electrodes were electrically connected
to a galvanostat which was set to apply a constant DC current of
200 .mu.A (ie, 100 .mu.A/cm.sup.2). The current was applied
continuously for 16 hours and the receptor compartment was sampled
every hour over the 16 hour period.
[0062] Six identical flux experiments were run with different skin
samples and the transdermal flux was averaged over the 6 runs. The
transdermal fentanyl flux increased over the first 8 hours of
current application, after which the flux remained approximately
constant (ie, steady state flux was reached after 8 hours). The
fentanyl concentration was estimated by subtracting the amount of
fentanyl delivered through the skin into the receptor solution from
the original fentanyl content in the donor gel, and dividing by the
weight of water in the gel.
[0063] The normalized transdermal fentanyl flux, calculated as a
percentage of the steady state transdermal flux, was plotted versus
fentanyl concentration in the gel, and is shown in FIG. 2. As can
be seen from FIG. 2, the normalized flux remains at or near 100% at
fentanyl HCl concentrations above about 6 mg/mL. The normalized
flux begins to drop off as the fentanyl HCl concentration falls
below 6 mg/mL and particularly below about 4 mg/mL. These results
show that as the fentanyl HCl concentration falls below about 6
mg/mL, a more significant portion of the applied electrotransport
current is carried by ions other than fentanyl ions and the
fentanyl flux is more dependent on the fentanyl HCl concentration.
Thus, to ensure a predictable fentanyl flux with a particular level
of applied electrotransport current, the fentanyl HCl concentration
in the donor reservoir is preferably maintained above about 6
mg/mL.
EXAMPLE 2
[0064] The following study was conducted to determine the amount of
fentanyl hydrochloride drug loading which is necessary to prevent
silver migration, resulting in transient epidermal discoloration,
from a transdermal fentanyl electrotransport delivery device having
a donor reservoir gel weighing about 0.6 g and having a skin
contact area of about 2.8 cm.sup.2, which device is worn for a
period of up to 24 hours and which applies an electrotransport
current of 240 .mu.A (ie, a current density of 87 .mu.A/cm.sup.2)
over a delivery interval of about 10 minutes to deliver a 40 .mu.g
dose, and which can deliver up to 80 of such doses over the 24 hour
wearing period. Thus, the device has the ability to deliver up to
3.2 mg of fentanyl (80.times.40 .mu.g=3.2 mg) for therapeutic
purposes.
[0065] Fentanyl HCl-containing polyvinyl alcohol (PVOH)
hydrogel-based donor reservoirs, each reservoir having a total
weight of about 0.15 g, were made with the following
composition:
2 Material (wt %) Water 80.8 PVOH 15.0 Fentanyl HCl 2.0 Polacrilin
0.1 0.5 N NaOH 2.1
[0066] The materials were mixed in a jacketed beaker at 90.degree.
C. and then 0.15 g aliquots of the liquid gel were dispensed into
foam molds and frozen overnight at temperatures ranging from -15 to
-50.degree. C. The gels had a disk shape with an area of 1.0
cm.sup.2 and a thickness of 1.6 mm.
[0067] A silver foil was laminated to one surface of each of the
gels to form an anodic donor electrode assembly comprised of the
silver foil anode and the fentanyl containing gel reservoir.
Counter electrode assemblies were made using similarly sized PVOH
gels which contained citrate buffered saline (pH 4). A silver
chloride cathodic electrode (ie, silver chloride powder-loaded
polyisobutylene film) was laminated to one surface of the counter
gels. The electrodes were electrically connected to custom made
power sources which applied a constant DC current of 240 .mu.A (87
.mu.A/cm.sup.2).
[0068] The electrotransport systems were applied to the upper outer
arms of six male volunteers and worn for a period of 15 hours,
which is about 10% longer than the maximum time of current
application from this system (ie, 80.times.10 minutes=13.3 hrs).
Over the 15 hour wearing period, the systems applied current
continuously, after which the systems were removed and the arm of
each subject was closely examined to determine if transient
epidermal discoloration (TED), caused by migration of silver ions
formed in the anodic electrode assembly, had occurred. The subjects
were again examined one hour and again at 24 hours after system
removal to confirm the initial TED reading. In all six subjects, no
TED occurred at the site of attachment of the anodic electrode
assembly. This indicates that a fentanyl HCl loading of about 1.8
to 2 wt %, or about 3 mg in these gels, provides a sufficient
quantity of chloride ions to prevent migration of silver ions,
formed by oxidation of the silver anode, into the skin of the
patient over the 15 hour wearing period. Thus, an electrotransport
system which applies the same level of electrotransport current
over a maximum dosing period of 13.3 hours will likewise exhibit no
TED, even under conditions of maximum usage. The 2 wt % fentanyl
HCl loading in these PVOH-based donor gel reservoirs can be
scaled-up to larger reservoirs. Thus, for a fentanyl HCl-containing
PVOH-based donor reservoir having a total weight of about 0.6 g,
the reservoir containing substantially no other source of chloride
ions other than the drug counter ions, the fentanyl HCl loading
should be at least about 11 mg (ie, 1.8 wt %.times.0.6 g=11 mg)
even though the maximum amount of fentanyl which can be delivered
from the device over the 24 hour wearing period is only about 3.2
mg fentanyl. Thus, in order to prevent silver migration in this
device under conditions of maximum usage, an excess amount of
fentanyl HCl must be loaded into the anodic donor reservoir, which
excess loading is about 3 to 4 times the amount of fentanyl needed
for therapeutic purposes.
EXAMPLE 3
[0069] The following studies were conducted to determine the
transdermal electrotransport dosing level required to achieve an
acceptable level of analgesia in human patients suffering from
moderate to severe post-operative pain. The study was conducted in
132 post-operative male and female patients who were expected to
have moderate to severe pain after surgery, including orthopedic
(shoulder, knee, long bone) and abdominal (urological,
gynecological) surgeries. The patients wore one of two different
electrotransport fentanyl HCl delivery devices on the upper arm for
24 hours following surgery. Both devices applied electrotransport
current for a delivery interval of 10 minutes upon activating a
push button switch on the device. The first device, worn by 79 of
the 132 patients, applied an electrotransport current of 150 .mu.A
which delivered an average fentanyl dose of 25 .mu.g over the 10
minute delivery interval. The second device, worn by 53 of the 132
patients, applied an electrotransport current of 240 .mu.A which
delivered an average fentanyl dose of 40 .mu.g over the 10 minute
delivery interval.
[0070] In both devices, the patients could self-administer up to 6
doses every hour. Patients using the first (ie, 25 .mu.g dose)
device could apply a maximum of 144 doses. Patients using the
second (ie, 40 .mu.g dose) device were allowed to apply up to a
maximum number of 80 doses.
[0071] Both devices were two-part systems which included a reusable
electronic controller and a single use/disposable drug-containing
unit. Each drug unit contained an anodic fentanyl HCl-containing
donor gel and a cathodic saline-containing counter gel. All gels
had a skin contact area of 2 cm.sup.2 and a thickness of 0.16 cm.
The approximate weight of the donor gels was 350 mg. The anodic
donor gels in the 25 .mu.g dose and 40 .mu.g dose systems were the
same size and composition, only the applied electrotransport
current level was different. The cathodic counter electrode
assemblies each had a PVOH based gel which contained citrate
buffered saline. A silver chloride cathodic electrode was laminated
to one surface of the counter gel. The 25 .mu.g and 40 .mu.g dose
anodic gels had the following composition:
3 Material (wt %) Water 73.2 PVOH 10.0 Fentanyl HCl 1.4 Polacrilin
0.3 Polacrilin potassium 0.1 Glycerin 5.0 Cholestyramine resin
10.0
[0072] All patients were initially titrated to an acceptable level
of analgesia with intravenous (IV) fentanyl in the recovery room
immediately following surgery. Within 3 hours after surgery when
the patients had met the usual institutional standards for
discharge from the recovery room and were able to operate their
worn electrotransport delivery device, the patients were moved to a
ward where they could self administer fentanyl by transdermal
electrotransport for the management of their pain. In the event the
electrotransport fentanyl delivery regimen was insufficient to
control pain, the patients were retitrated with supplemental
fentanyl through IV administration to achieve adequate
analgesia.
[0073] In the 25 .mu.g dose group, 38 of 79 patients (ie, 48%)
required no supplemental IV fentanyl after leaving the recovery
room. In the 40 .mu.g dose group, 47 of 53 patients (ie, 89%)
required no supplemental IV fentanyl after leaving the recovery
room. Based on these percentages, it was determined that the 25
.mu.g dose regimen was insufficient, and the 40 .mu.g dose regimen
was sufficient, to treat the pain associated with these types of
surgical procedures in a majority of the patients tested. Based on
the fact that the 25 .mu.g dose regimen was analgesically effective
for about half the patients, it is likely that this lower dose
would be effective in treating less severe acute pain such as that
experienced with hernia repair, kidney stones, arthritis pain,
laparascopic procedures, and other conditions involving less severe
pain than that associated with major surgeries.
[0074] Pain intensity was assessed at baseline immediately before
activation of the first on-demand dose and again at times 0.5, 1,
2, 3, 4, 6, 8, 12, 16, 20 and 24 hours after the devices were first
activated. The patients were asked to assess pain intensity by
marking on a 10 cm long strip, containing a scale of 1 to 100, with
1 being associated with no pain and 100 being associated with the
most severe intensity pain. The quality of analgesia was evaluated
by a categorical rating of excellent, good, fair or unsatisfactory
according to the same time schedule as that for the pain intensity
measurements.
[0075] The quality of analgesia and pain intensity data for the 53
patients using the 40 .mu.g dose electrotransport devices are shown
in FIGS. 3 and 4, respectively.
[0076] Skin sites beneath the anode and cathode gels were assessed
at 1, 6 and 24 hours following removal of the devices and evaluated
for topical (eg, irritation) effects. The topical effects data are
shown in Table 1.
4TABLE 1 Hours ETS Extent of Post Skin Edema Erythema Erythema
Itching Papules Pustules Removal Site Score (%) (%) (%) (%) (%) (%)
1 Anode 0 74 15 19 91 92 100 1 8 49 32 6 6 0 2 19 36 49 4 2 0
Cathode 0 92 72 74 94 94 100 1 6 19 13 4 6 0 2 2 9 13 2 0 0 6 Anode
0 74 15 17 89 92 100 1 11 43 34 8 8 0 2 15 40 49 4 0 0 3 0 2 0 0 0
0 Cathode 0 92 68 68 91 91 100 1 4 19 13 9 6 0 2 4 9 19 0 4 0 3 0 4
0 0 0 0 24 Anode 0 83 34 36 91 96 98 1 9 40 38 8 4 2 2 8 26 36 2 0
0 3 0 0 0 0 0 0 Cathode 0 91 70 70 91 89 98 1 6 19 15 8 8 0 2 4 8
15 2 4 2 3 0 4 0 0 0 0 Erythema: 0 = None 1 = Barely perceptible
redness 2 = Definite redness 3 = "Beer" redness Itching: 0 = None 1
= Mild 2 = Moderate 3 = Severe Edema, Papules, Pustules. Extent of
Erythema: 0 = None 1 = <50% of occluded area 2 = >50% of
occluded area
EXAMPLE 4
[0077] Two fentanyl hydrochrloide-containing anodic donor reservoir
PVOH-based gels were made having the following compositions:
Donor Gel Formulations
[0078]
5 Material wt % wt % Purified Water 86.3 85.3 Washed PVOH 12.0 12.0
Fentanyl HCL 1.7 1.7 Hydroxy Methylcellulose -- 1.0
[0079] With both formulations, the water and PVOH are mixed at a
temperature between 92.degree. C. and 98.degree. C. followed by the
addition of fentanyl hydrochloride and subsequent further mixing.
The liquid gel was then pumped into foam molds having a disc-shaped
cavity. The molds were placed in a freezer overnight at -35.degree.
C. to cross-link the PVOH. The gels can be used as anodic donor
reservoirs suitable for transdermal electrotransport fentanyl
delivery.
[0080] In summary, the present invention provides a method for
improving the transdermal electrotransport of water soluble salts
of fentanyl, and sufentanil which are preferably delivered from an
electrotransport device having a silver anodic donor electrode and
a hydrogel based donor reservoir. The electrotransport device is
preferably a patient-controlled device. The hydrogel formulation
contains a drug concentration which is sufficient to maintain
transdermal electrotransport drug flux for a predetermined current
level, to inhibit silver ion migration to the skin of a wearer of
the electrotransport device and thus, prevent transient epidermal
discoloration, and to provide an acceptable level of analgesia.
* * * * *