CA2218873C - Electrotransport agent delivery method and apparatus - Google Patents

Abstract

An electrotransport agent delivery device (10) for delivering a therapeutic agent through intact skin, and a method of operating same, is provided. The device applies a pulsing electrotransport current wherein the length of the applied current pulses is at least 5 msec and preferably at least 10 msec. Most preferably, the current pulses have a magnitude above a critical level (I c) at which the skin is transformed into a higher electrotransport delivery efficiency (E) state.

Description

6 The present invention generally concerns a method and apparatus for 7 the electrically assisted delivery of a therapeutic agent (e.g., a drug) through a 8 body surface (e.g., skin) at increased efficiency. This invention is particularly 9 applicable to the electrotransport of highly potent therapeutic agents which are to be delivered at small dosage levels.

14 The present invention concerns in vivo methods and apparatuses for electrotransport delivery of therapeutic agents, typically drugs, 16 into a patient. Herein the terms "electrotransport", "iontophoresis" and 17 "iontophoretic" are used to refer to methods and apparatus for transdermal 18 delivery of therapeutic agents, whether charged or uncharged, by 19 means of an applied electromotive force to an agent-containing reservoir.
The particular therapeutic agent to be delivered may be completely charged 21 (i.e., 100% ionized), completely uncharged, or partly charged and partly 22 neutral. The therapeutic agent or species may be delivered by 23 electromigration, electroosmosis or a combination of these processes.
24 Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically-induced osmosis. In general, electroosmosis 26 of a therapeutic species into a tissue results from the migration of solvent, 27 in which the species is contained, as a result of the application of 28 electromotive force to a reservoir containing the therapeutic species.
29 As used herein, the terms "electrotransport", "iontophoresis" and "iontophoretic" refer to (1) the delivery of charged drugs or agents by 31 electromigration, (2) the delivery of uncharged drugs or agents by the 1 process of electroosmosis, (3) the delivery of species by transport 2 processes which include an electroporation step (See, e.g., Weaver et al 3 US Patent 5,019,034), (4) the delivery of charged drugs or agents by the 4 combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs or agents by the 6 combined processes of electromigration and electroosmosis, combinations 7 of the above processes to deliver either or both of charged or uncharged 8 species.

9 lontophoretic devices for delivering ionized drugs through the skin have been known since the early 1900's. See for example Deutsch 11 US Patent 410,009. In presently known electrotransport devices, at least 12 two electrodes or electrode assemblies are used. Both electrodes/electrode 13 assemblies are disposed so as to be in intimate electrical contact with some 14 portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, 16 medicament, drug precursor or drug is delivered into the body through 17 the skin by iontophoresis. The other electrode, called the counter or 18 return electrode, serves to close the electrical circuit through the body.
19 In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, 21 e.g., a battery. For example, if the ionic substance to be delivered into the 22 body is positively charged, then the positive electrode (the anode) will be the 23 active electrode and the negative electrode (the cathode) will serve to 24 complete the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the 26 anodic electrode will be the counter electrode.

27 As is discussed above, electrotransport delivery devices can be used 28 to deliver uncharged drugs or agents into the body, e.g., transdermally. This 29 is accomplished by a process called electroosmosis. Electroosmosis is the (e.g., transdermal) flux of a liquid solvent (e.g., the liquid solvent containing 1 the uncharged drug or agent) which is induced by the presence of an electric 2 field imposed across the skin by the donor electrode.
3 Electrotransport electrode assemblies/devices generally include a 4 reservoir or source of the beneficial agent or drug (preferably an ionized or ionizable species or a precursor of such species), which is to be delivered into 6 the body by electrotransport. Examples of such reservoirs or sources include 7 a pouch as described in Jacobsen US Patent 4,250,878, a pre-formed gel 8 body as disclosed in Webster US Patent 4,383,529 and Ariura, et al 9 US Patent 4,474,570 and a receptacle containing a liquid solution as disclosed in Sanderson, et al US Patent 4,722,726. Such drug reservoirs 11 are connected to the anode or the cathode of an electrotransport device to 12 provide a fixed or renewable source of one or more desired species or 13 agents. Electrical current is typically applied to the reservoir by means of a 14 current distributing member, which may take the form of a metal plate, a foil layer, a conductive screen, or a polymer film loaded with an electrically 16 conductive filler such as silver or carbon particles. The current distributing 17 member, including any appropriate connectors and associated connective 18 conductors such as leads, and the reservoir comprise an electrode assembly 19 herein.
The prior art has recognized that "competitive" ionic species having the 21 same charge (i.e., the same sign) as the drug ions being delivered by 22 electrotransport have a negative impact on electrotransport drug delivery 23 efficiency. The efficiency (E) of electrotransport delivery of a particular 24 species is defined herein as the rate of electrotransport delivery of that species per unit of applied electrotransport current (mg/mA-h). The prior art 26 further recognized that competitive ionic species were inherently produced 27 during operation of these devices. The competitive species produced are 28 dependent upon the type of electrode material which is in contact with the 29 drug solution. For example, if the electrode is composed of an electrochemically inert material (e.g., platinum or stainless steel), the 1 electrochemical charge transfer reaction occurring at the electrode surface 2 tended to be water electrolysis since water is the overwhelmingly preferred 3 liquid solvent used in electrotransport drug solutions. Water electrolysis 4 produces competing hydronium ions at the anode (in the case of cationic electrotransport drug delivery) and competing hydroxyl ions at the cathode 6 (in the case of anionic electrotransport drug delivery). On the other hand, 7 if the electrode is composed of an electrochemically oxidizable or reducible 8 species, then the electrode itself is oxidized or reduced to form a competitive s ionic species. For example, Untereker et al US Patent 5,135,477 and Petelenz et al US Patent 4,752,285 recognize that competitive ionic species 11 are electrochemically generated at both the anode and cathode of an 12 electrotransport delivery device. In the case of an electrotransport delivery 13 device having a silver anodic donor electrode, application of current through 14 the silver anode causes the silver to become oxidized (Ag --+ Ag+ + e") thereby forming silver cations which compete with the cationic drug for 16 delivery into the skin by electrotransport. The Untereker and Petelenz 17 patents teach that providing a cationic drug in the form of a halide salt causes 18 a chemical reaction which removes the "competing" silver ions from the donor 19 solution (i.e., by reacting the silver ions with the halide counter ion of the drug to form a water insoluble silver halide precipitate; Ag+ + X- -> AgX), thereby 21 achieving higher drug delivery efficiency. In addition to these patents, 22 Phipps et al PCT/US95/04497 filed on April 7, 1995 teaches the use of 23 supplementary chloride ion sources in the form of high molecular weight 24 chloride resins in the donor reservoir of a transdermal electrotransport delivery device. These resins are highly effective at providing sufficient 26 chloride for preventing silver ion migration, yet because of the high molecular 27 weight of the resin cation, the resin cation is effectively immobile and hence 28 cannot compete with the drug cation for delivery into the body.

1 The prior art has long recognized that the application of electric 2 current through skin causes the electrical resistance of the skin to decrease.
3 See, for example, Haak et al US Patent 5,374,242 (Figure 3). Thus, as the 4 electrical resistance of the skin drops, lower voltages are needed to drive a 5 particular level of electrotransport current through the skin. This same 6 phenomenon is observed in a technique referred to as "electroporation"
7 of the skin. See Weaver et al US Patent 5,019,034. Electroporation 8 involves the application of short, high voltage electrical pulses to produce 9 what is characterized as a transient (e.g., decreasing to normal levels in 10 to 120 sec. for excised frog skin) increase in tissue permeability.

11 Electroporation is also characterized by the creation of pores in lipid 12 membranes due to reversible electrical breakdown. Electroporation does not, 13 itself, deliver any drug but merely prepares the tissue thereby treated for 14 delivery of drug by any of a number of techniques, one of which is iontophoresis.

19 The present invention arises from the discovery that when delivering a therapeutic agent (eg, a drug) via electrotransport through a living body 21 surface (eg, skin) of an animal (eg, a human) using a pulsing electrotransport 22 current, the efficiency of electrotransport agent delivery is increased by 23 maintaining the width of the applied current pulses above a minimum period 24 of time. For certain drugs delivered transdermally to humans via electrotransport, this minimum period has been found to be about 5 msec, 26 and preferably about 10 msec. In general, this discovery means that lower . 27 frequency pulsing electrotransport currents tend to provide more efficient 28 agent delivery than higher frequency pulsing electrotransport currents, since 29 the longer the pulse width, the fewer the number of pulses which can be applied in any unit of time. Thus, when using pulsing currents having pulse 1 widths of at least about 5 msec, and preferably at least about 10 msec, the 2 pulsing frequencies tend to be less than about 100 Hz and more preferably 3 less than about 10 Hz. 4 As used herein, the term "electrotransport agent delivery efficiency (E)"

means the rate of transdermal electrotransport delivery (mg/h) per unit of 6 applied electrotransport current (mA) and expressed in units of micrograms of 7 agent (i.e., drug) delivered per milliamp-hour of applied electric current 8 ( g/mAh). Electrotransport delivery efficiency, in some aspects of its 9 meaning, is analogous to transport number. Transport number is a unitless quantity, less than one, indicating the fractional charge carried by a particular 11 ionic species, e.g., a drug or agent, during e(ectrotransport delivery.
12 Electrotransport delivery efficiency, as defined herein, is more broadly 13 applicable to include the transport of uncharged species and is more 14 reflective of the scope of the invention.
The terms "pulsing current" and "pulsed current" as used herein refer 16 to an applied electrotransport current having a periodic (i.e., the waveform 17 repeats over time and has a wave length and a frequency) waveform shape 18 comprised of a first segment of applied electrotransport current having a first 19 average current magnitude, and a second segment of applied electrotransport current having a second average current magnitude, the second average 21 current magnitude being less than the first average current magnitude. In 22 general, the second average current magnitude is less than about 70% of the 23 first average current magnitude, more typically less than about 50% of the 24 first average current magnitude and most typically less than about 25% of the first average current magnitude. The second average current magnitude can 26 be zero or substantially zero, but in any event is substantially less than the 27 first average current magnitude. 28 The present invention is not limited to any particular periodic pulsed 29 waveform shape and may take the form of any of various types of periodic waveforms including sinusoidal, trapezoidal, square or rectangular current 1 waveforms. A square pulsed current waveform shape is particularly suitable 2 for practicing this invention.
3 In a preferred embodiment of the present invention, the first average 4 current magnitude is sufficient to produce a current density which is equal to or greater than a critical current density, I, Applied electrotransport current 6 densities (generally expressed in units of microamperes per square 7 centimeter ( A/cm2) herein) above this critcal level result in even further 8 enhancement of electrotransport transdermal agent delivery efficiency. This 9 "further" enhancement of the skin's electrotransport delivery efficiency has been found to be non-transitory, i.e., to last for at least several minutes to 11 several hours or longer after application of current densities and over periods 12 of time in accordance with this preferred embodiment of the invention. This 13 preferred embodiment of the invention induces (e.g., through a pre-treatment 14 or pre-application step in which species are delivered) a high efficiency drug-transmissive state in the skin to which an electrotransport drug delivery 16 device is applied. The induced, high efficiency state continues and can be 17 utilized to deliver drug or other therapeutic agent transdermally with increased 18 efficiency. In usual circumstances, this will permit delivery of drug with more 19 precise control and at a lower current. This phenomenon has only been found in the transdermal delivery of drug or agent through intact living skin or tissue 21 (i.e., in vivo) and is not exhibited in dead skin (i.e., excised skin through which 22 species are electrotransported in vitro). In this manner, the treated skin 23 exhibits a statistically significant, non-transitory increase in drug delivery 24 efficiency relative to skin which has not been so treated. Generally speaking, utilization of this preferred embodiment of the invention significantly increases 26 the drug/agent delivery efficiency and reduces or eliminates variability in the 27 drug delivery efficiency of the skin site which is so treated. Since 28 electrotransport delivery efficiency remains elevated and less variable after 29 utilization of this embodiment (relative to untreated skin), utilization of this ii embodiment of the invention permits the delivery of drug or agent through intact skin by electrotransport with increased control and efficiency.

Thus, in one aspect of the present invention there is provided a method of electrotransport drug or agent delivery through a body surface involving the steps of delivering a therapeutic agent by a pulsing electrotransport current, the current pulses being sufficiently long (i.e., at least about 5 msec and preferably at least about 10 msec), to reduce or avoid capacitive loss and thereby deliver the agent at an enhanced electrotransport delivery efficiency (E). In a preferred aspect, the current pulses have a sufficient magnitude to produce a current density greater than or equal to Ic, to convert the electrotransport delivery efficiency of the body surface (i.e., the skin) through which the agent is delivered to a non-transitory state of higher electrotransport delivery efficiency. Thereafter, the drug or agent is delivered through the body surface while the body surface is in the higher efficiency transfer state.

In another aspect of the present invention, there is provided a device for delivering a therapeutic agent through a body surface by electrotransport, the device having a donor reservoir containing the therapeutic agent, wherein the donor reservoir is placed in therapeutic agent transmitting relation with the body surface, the device also having a delivery area, a source of electrical power and a current controller for applying a pulsing current to the reservoir and the body surface, the pulsing current having a periodic waveform including a wave length, a frequency, and first and second segment with corresponding average magnitudes, the device also having a current density defined by the pulsing current divided by the delivery area, the 5204.4-4 8a device being characterized by: the first segment being at least about 5 msec and the frequency being less than or equal to about 100 Hz.

In another aspect of the present invention, there is provided a method of operating an electrotransport device, the device for delivering a therapeutic agent through a body surface, and the device having a donor reservoir containing the therapeutic agent and placed in therapeutic agent transmitting relation with the body surface, the device also having a delivery area, a source of electrical power and a current controller for applying a pulsing current to the reservoir and the body surface, the pulsing current having a periodic waveform including a wave length, a frequency, and first and second segment with corresponding average magnitudes, the device also having a current density defined by the pulsing current divided by the delivery area, the method being characterized by the steps of: controlling the first segment to at least about 5 msec; and, controlling the frequency to less than or equal to about 100 Hz.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the present invention, as well as other objects and advantages thereof, will become apparent upon consideration of the following modes for carrying out the invention especially when taken with the accompanying drawings, wherein:

FIG. 1 is a graph of transdermal electrotransport drug delivery efficiency (E) versus applied electrotransport current density (Id) for in vivo electrotransport transdermal delivery of fentanyl;

il.

8b FIG. 2 is a graph of electrotransport current versus time, showing three pulsed current waveforms having the same pulsing frequency but differing pulse widths and duty cycles;

1 FIG. 3 is an exploded perspective view of a transdermal 2 electrotransport drug delivery device which can be used in accordance with 3 the method of the present invention;
4 FIG. 4 is a graph of electrotransport current versus time, showing two pulsed waveforms having the same peak current and pulse width but different 6 pulsing frequencies;
7 FIG. 5 is a graph of mean serum fentanyl concentration versus time, 8 showing how initial electrotransport administered doses increase subsequent 9 fentanyl delivery through a 24 hour period;
FIG. 6 is average serum fentanyl concentration, as a function of time, 11 for applied electrotransport current densities of 10, 20 and 40 A/cm2;
12 FIG. 7 is a graph of serum fentanyl concentration versus time for 13 delivery of fentanyl at pulsing frequencies of 1, 10 and 625 Hz; and 14 FIG. 8 is a graph of serum goserelin concentration versus time, for applied electrotransport current densities of 50 and 100 A/cm2.

19 The present invention is based upon the discovery that when delivering an agent (e.g., a drug) transdermally through intact skin via electrotransport 21 using a pulsing electrotransport current, the efficiency (E) of transdermal 22 electrotransport agent (e.g., drug) delivery is increased by maintaining the 23 width of the current pulses greater than 5 msec and preferably greater than 24 10 msec. Since pulse width is inherently related to pulsing frequency, the discovery means that the efficiency of electrotransport delivery, when using a 26 pulsing current, is greater at lower pulsing frequencies. Preferably, the 27 pulsing frequency is maintained below about 100 Hz, and more preferably 28 less than about 10 Hz. By maintaining longer pulse widths (and 29 correspondingly lower pulsing frequencies), the inefficiencies associated with "charging up" the electrical capacitance of the skin are minimized. These 1 inefficiencies, termed "capacitive loss", are described in McNichols et al US
2 Patent 5,047,007. Capacitive loss results because a portion of each pulse is 3 consumed by the process of charging the skin without delivering drug. The 4 shorter the pulse width (and hence the higher the pulsing frequency), the 5 relatively greater is the capacitive loss for each pulse.
6 In a preferred practice, the electrotransport current density during the 7 first segment and the length of the first segment are selected to maintain the 8 higher efficiency species delivery state of the body surface (e.g., skin).
This 9 invention also includes the preferred practice of intentionally renewing the 10 highly efficient species delivery state so as to optimize drug delivery efficiency 11 if drug or agent delivery conditions are used which do not periodically renew 12 it. In another preferred practice, the present invention is utilized to deliver 13 drug or agent transdermally, i.e., through intact skin. In yet a further preferred 14 practice, the present invention is used to deliver drug or agent through intact, live, human skin.
16 In this preferred practice of this invention, the precise current density 17 and treatment time period needed to convert untreated skin to a highly 18 transmissive state have been found to be fairly specific to the drug or 19 therapeutic agent to be delivered. However, for the electrotransport delivery of analgesics using a pulsing electrotransport current, a pulse width of at least 21 10 msec at a current density of about 40 A/cm2, preferably at least about 22 50 A/cm2 and most preferably at least about 70 A/cm2 appears to convert 23 the body site so treated to a highly efficient drug transmissive state.
This 24 preferred embodiment of the invention arises out of the discovery that electrotransport delivery efficiency is highly dependent (i.e., it is non-constant) 26 at current densities in the range of about 0 to about 30 A/cm2, is moderately 27 dependent upon current density in the range of about 40 to about 70 A/cm2 28 and is relatively independent of current density at current densities in excess 29 of about 70 A/cm2. This unexpected change in efficiency (in theory, efficiency is not predicted to change with increasing current density) permits 1 electrotransport transdermal delivery of drug with significantly enhanced 2 electrotransport delivery efficiency.
3 A second unexpected result is achieved in this preferred practice of the 4 present invention, i.e., the change of the skin to the higher efficiency transmissive state is non-transitory with the skin remaining in the higher, 6 and more stable, efficiency state for minutes to hours after the initial 7 transformation, even in cases where the subsequently applied 8 electrotransport current density is lowered to a level below Ic or turned off, 9 completely. In other words, when the skin site has been converted to a highly efficient agent transmissive state by applying a pulsing electric current over 11 pulse widths of at least 5 msec, and at or above current density I, reduction 12 in applied electrotransport current (and therefore current density) does not 13 cause the skin to immediately return to its initial, lower electrotransport 14 delivery efficiency state. This observation respecting in vivo drug delivery is critically important to electrotransport system design.
16 The term "non-transitory" as used herein, when referring to the high 17 efficiency electrotransport agent delivery state, means of sufficient length to 18 permit drug to be delivered to achieve a therapeutic effect, generally at 19 least several minutes and preferably at least an hour. Thus, for example, a relatively inexpensive ionic species may be used to trigger conversion of, 21 e.g., a skin site, to a highly efficient and more stable ionic species delivery 22 state, and thereafter relatively more expensive drug or agent may be 23 delivered at greater efficiency and stability by electrotransport. Where the 24 drug or agent is inexpensive, it may be used to convert the body delivery site to the highly efficient and more stable state, and thereafter may be delivered 26 with greater efficiency, i.e., at lower current density and at greater stability.
27 The term "high/higher efficiency state" as used herein means 28 conversion of any particular body or skin site to a state in which drug or agent 29 delivery is at least 10% (preferably at least 20%) more efficient than the same skin site prior to conversion in accordance with this invention. Generally, the 1 parameter which will be most reflective of this efficiency increase will be the 2 electrotransport delivery efficiency measured in micrograms of drug delivered 3 per milliamp-hour of applied electrotransport current.
4 The term "more stable efficiency" as used herein means conversion from a state of more variable electrotransport agent delivery efficiency to one 6 of less variability by exposure of the body site to a current density above the 7 critical current density , I, for a time period longer than the critical time, t,.
8 Critical current density for purposes of increased stability, has been found to 9 be as low as about 40 A/cm2.
The transdermal drug flux achieved by delivering drug at higher 11 electrotransport delivery efficiency (i.e., at electrotransport current densities 12 above the critical level I.
,) may in some cases be higher than the flux needed 13 to achieve the desired therapeutic effect. In such cases, it is desirable to 14 reduce the transdermal drug flux, without reducing the electrotransport current density below the critical level I, so as to maintain the skin in the high 16 efficiency and high stability transfer state. This problem may be overcome by 17 one or more of the following three methods.
18 The flrst method of reducing the drug flux without reducing the applied 19 level of electrotransport current, and hence current density, is to deliver the drug using a pulsing electrotransport current, the pulses of current producing 21 a current density above Ic, and adjusting the pulse width of the current pulses 22 (i.e., adjusting the duty cycle) in order to control the drug delivery rate. The 23 term "duty cycle" as used herein is the ratio of the first period length (in msec) 24 to the sum of the lengths of the first and second periods and is usually expressed as a percent. In other words, the duty cycle is the ratio of pulse 26 width to cycle length. For example, if a device applies current pulses of 27 msec duration at a pulsing frequency of 1 pulse per second (i.e., 1 Hz), then 28 the device is operating in a 50% duty cycle. In general, pulsing 29 electrotransport currents typically have duty cycles of 10 to 95%, more typically 20 to 90%, and most typically 30 to 90%. In this practice of the 1 invention, the magnitude of the current pulses is selected in view of the 2 known area of the surface from which drug is delivered, thereby defining a 3 fixed and known current density (i.e., the ratio of current to the area from 4 which current flows). Thus, if it is decided, based upon application of the above principles, that a specific maximum current for a given anode surface 6 area e.g., Ima, will provide the enhanced efficiency drug delivery discussed 7 above, then by increasing or decreasing the duty cycle, the amount of drug 8 delivered at the high efficiency state can be increased or decreased without 9 causing the applied current density to change. In choosing the parameters of drug delivery if using this approach, the magnitude of the current pulses is 11 selected so that the resulting current density transforms the skin into the high 12 efficiency state and the duty cycle of the current pulses is altered to adjust the 13 drug delivery rate (i.e., a low dose of drug is administered by a high density 14 (i.e., greater than Ic) pulsing current having a shorter pulse width, and hence a low duty cycle and a high dose of drug is administered by the same 16 magnitude current density but being pulsed at a longer pulse width 17 corresponding to a higher duty cycle.
18 This aspect of the invention is more specifically illustrated in Fig. 2 19 where waveforms for three different pulsing electrotransport currents of the same frequency are shown. In FIG. 2 time is illustrated on the horizontal axis, 21 while current amplitude is illustrated on the vertical axis. The three current 22 waveforms shown in FIG. 2 all have the same magnitude, and hence the 23 same maximum applied current density Imax for an electrotransport delivery 24 device of any one size. This particular current density Imax is greater than the critical current density level I,. The three current waveforms have differing 26 duty cycles, which is the percentage of time during which the current is 27 applied. The three waveforms have duty cycles of 75% (top waveform), 28 50% (middle waveform) and 25% (bottom waveform). Thus, the 25% duty 29 cycle waveform delivers drug transdermally by electrotransport at about 1 one-half the dosing level of the 50% duty cycle waveform and about one-third 2 the dosing level of the 75% duty cycle waveform. All three waveforms 3 administer drug transdermally by electrotransport through skin which is 4 transformed into the high efficiency transfer state by reason of ImaX being greater than I, 6 The second method of reducing the drug flux without reducing the 7 applied level of electrotransport current, and hence current density, is to 8 deliver the drug using a pulsing electrotransport current, the pulses of current 9 producing a current density above Ic, and maintaining the pulse amptitude and pulse width constant while adjusting the pulsing frequency in order to 11 control the drug delivery rate. In this manner, current density is maintained at 12 or above the level which transforms the skin into the high efficiency state.
13 Exemplary of this, a device employing a pulsed current waveform having 14 current pulses with a magnitude of 0.2 mA, a pulse width of 10 msec, and a frequency of 10 Hz will deliver roughly half as much drug as the same device 16 run at a frequency of 20 Hz. Given a constant drug delivery area, e.g., of an 17 electrode assembly, the applied current densities of these two devices is the 18 same and is above the high efficiency critical level I, so that both devices 19 deliver drug transdermally by electrotransport with higher efficiency and lower variability compared to devices which apply electrotransport current at current 21 densities below the critical level I. From these two examples of the invention, 22 one skilled in this art will appreciate that a combination of frequency and duty 23 cycle may be used to alter the rate of drug delivery while maintaining the first 24 average magnitude sufficient high to produce a current density above Ic.
FIG.
4 shows the waveforms for a device operated to have a constant 9 msec 26 pulse width, the frequency for a device operated according to the lower 27 waveform being one-half that of a device operated according to the upper 28 waveform (i.e., 50 Hz versus 100 Hz).
29 The third method of reducing the drug flux without reducing the applied level of electrotransport current, and hence current density, is to intentionally 1 deliver competitive co-ions (i.e., ionic species having a charge like that of the 2 therapeutic agent, but which species do not induce a therapeutic effect when 3 delivered into a patient) together with the desired drug so that some portion 4 of the applied electrotransport current is carried by the co-ions rather than the 5 drug ions. Delivery of competitive co-ions, for a given current, in addition to 6 the drug or agent ions, provides adequate current density but reduces the 7 quantity of therapeutic agent delivered. Delivery of competitive co-ions from, 8 e.g., the drug reservoir, also reduces potentially expensive and potent total 9 drug or agent delivered. This approach, under the specific conditions 10 described, permits drug dosage control as well as providing enhanced 11 stability of electrotransport therapeutic agent delivery efficiency. This 12 approach is generally discouraged in the patent literature because it 13 otherwise tends to reduce drug delivery efficiency. This aspect of this 14 invention is particularly applicable to electrotransport delivery of those drugs 15 or therapeutic agents which are therapeutically effective when (i) delivered at 16 low transdermal fluxes and/or (ii) when present in low concentrations in the 17 blood. Generally speaking, this aspect of the present invention is particularly 18 applicable to the electrotransport delivery of highly potent drugs or other 19 therapeutic agents.
The competitive ionic species can be loaded into the donor reservoir 21 (e.g., a biocompatible salt is added to the donor reservoir) before 22 electrotransport agent delivery and/or can be generated in situ during 23 the operation of the electrotransport device. Generation of competitive 24 ionic species in situ may be accomplished using a secondary electrode and appropriate electrical control circuitry as described in Phipps et al 26 US Patent 5,443,442 for example.
27 The amount of the competitive species intentionally added to the donor 28 reservoir will be specific to the drug or agents to be delivered and the relative 29 electrophoretic mobilities of the drug ions and the competing ionic species.
Generally, the competitive species will be ionic and should have delivery 1 characteristics similar to those of the drug being delivered. The quantity of 2 co-delivered species to be added is selected so that the total current density 3 is raised above the critical current density, I, where the ionic species 4 efficiency is normalized or stabilized so that variation of delivery efficiency is no longer experienced.
6 The teachings in Theeuwes et al US Patent 5,080,646 may be utilized 7 in determining the proper amount of competitive co-ion species to be added 8 to the donor reservoir of an electrotransport delivery device. The patent 9 discusses the processes involved in the transport of species through a biological surface such as skin, mucosa, or tissue. The Theeuwes et al 11 Patent provides a mathematical analysis which permits one skilled in this art, 12 when unacceptable random variability of electrically-assisted drug flux is 13 experienced, to select a suitable quantity and species of competitive co-ion to 14 be delivered along with the drug or agent.
Another way to use an inexpensive ionic species to transform the skin 16 into the higher efficiency transfer state is to utilize a reverse polarity system 17 wherein the electric current is initially applied at a level sufficient to produce a 18 current density at or above I, but which current carries the opposite polarity 19 used to deliver the drug. In this way, the skin can be transferred into the higher/more stable efficiency state with application of current with little or no 21 associated delivery of drug. Once the skin is transformed, the polarity of the 22 applied electrotransport is then returned to the normal polarity used for drug 23 delivery. One example of such a system has an anodic donor reservoir 24 containing a cationic drug (D+) with an anionic counter ion (X-) such as chloride. The applied electrotransport current polarity is initially set to drive 26 the counter ion X- from the donor reservoir for at least the critical time, t., 27 required to transform the skin to the high efficiency/stability state. Once the 28 skin is transformed, the polarity of the applied current is reversed to deliver 29 the drug cation D+ from the donor reservoir into the skin.

1 As is noted above, agent delivery efficiency is preferably increased by 2 exposure of the site to a current density at or above Ic and for a time period 3 equal to or greater than a critical time, tc. Generally speaking, for a pulsing 4 electrotransport device, the pulse width (i.e., the length of the first segment of the waveform) must equal or exceed tc. Thus, tc, in a practice of this invention 6 using pulsed current electrotransport devices and for delivery of fentanyl, falls 7 between about 0.5 msec and 30 msec. It is believed that the minimum pulse 8 width to cause transformation to the higher efficiency state is about 10 msec 9 for fentanyl.
Table I shows data which support the above observation. Table 1 11 shows drug delivery efficiency data for a device programmed to run at 12 frequencies of 1 Hz, 10 Hz and 625 Hz. A 31 % duty cycle was employed.

Rate of Fentanyl Delivery ( g/hr) Frequency Pulse Width (Hz) (msec) Without After Bolus Treatment Bolus Treatment*
625 0.5 7 34 10 31 52** 52**
1 310 48** 48**

17 * "Bolus Treatment" means a direct current bolus delivery of fentanyl for 18 a period of 30 minutes at a current density of 0.1 mA/cm2.

** The numbers in these two columns are the same because even at a 21 pulse width as short as 31 msec, the skin site had already transformed 22 to its highly efficient state.

Table 1 also indicates that fentanyl delivery is significantly lower at a 26 high pulsing frequency of 625 Hz compared to the lower pulsing frequencies 1 of 1 and 10 Hz. This phenomenon is called capacitive loss, which loss 2 becomes greater as pulsing frequency is increased at a given duty cycle.
3 Table 1 also shows that until a critical pulse width is achieved, regardless of 4 frequency, no transformation of the body site agent delivery efficiency occurs.
Pulsed current electrotransport devices are well known in the art.
6 Such devices are described in numerous technical articles and the patent 7 literature including Bagniefski et al "A Comparison of Pulsed and Continuous 8 Current lontophoresis", Journal of Controlled Release. 113-122, (1090);
9 McNichols et al, US patent 5,047,007; Sibalis US Patent 5,135,478; R.
Burnette et al "Influence of Constant Current lontophoresis on the Impedance 11 and Passive Na} Permeability of Excised Nude Mouse Skin", 77 12 J.Pharmaceutical Sciences 492 (1988); Pikal et al, "Study of the Mechanisms 13 of Flux Enhancement Through Hairless Mouse Skin by Pulsed DC
14 lontophoresis," 8 Pharmaceutical Research 365 (1991).
In a preferred aspect of the present invention, the efficiency (E) of 16 transdermal electrotransport drug delivery is, at least at lower applied 17 electrotransport current densities, dependent on the applied electrotransport 18 current density (Id). This phenomenon is illustrated graphically in FIG. 1.
19 Specifically, when electrotransport current densities above a critical current density level, lc, are applied to the skin of living animals for sufficient periods 21 of time longer than a critical period of time, tc, on the order of several 22 milliseconds, the drug delivery efficiency (E) increases to a plateau level and 23 is no longer dependent upon the level of applied current density. It is 24 important to note that the variable electrotransport delivery efficiency effect is a limited exception to the widely reported principle that transdermal 26 electrotransport drug flux is linearly dependent upon the level of applied 27 electrotransport current. Our discovery is that this principle is only true at 28 current densities above a critical current density level I, Thus, we have 29 discovered that, at applied current densities below the critical current density level Ic, the rate of electrotransport drug delivery per unit of applied 1 electrotransport current is not constant as has been previously assumed. Not 2 only is the electrotransport drug delivery efficiency (E) lower at current 3 densities below Ic, E also exhibits greater variability at current densities below 4 Ic than at current densities above the critical level I. Thus, at applied current densities below IC, the electrotransport delivery is less efficient in that more 6 electrotransport current must be applied to deliver a predetermined amount of 7 drug. A still further aspect of our discovery is that the interpatient variability in 8 transdermal electrotransport efficiency is lower at applied current densities 9 above the critical level Ic and higher at applied current density levels below the critical level Ic.
11 In general, the critical current density level I, for human skin is in the 12 range of about 40 to 100 A/cm2, although the critical level Ic will vary 13 somewhat depending upon (i) the particular drug being delivered, 14 (ii) the particular patient being treated, and (iii) the particular skin location of the patient wearing the electrotransport device. Typically, a current density at 16 or above the critical level Ic need only be applied for several milliseconds to 17 several seconds before the skin enters the high efficiency drug transfer state.
18 However, applied current densities below the critical level Ic are unable to 19 transform the skin into the high efficiency transfer state, even when these low level current densities are applied for extended periods of time (e.g., up to 21 several hours application). This transformation of the skin to a higher 22 efficiency delivery state occurs only in living animals and does not occur with 23 excised skin taken from living or dead animals, i.e., 24 the skin transformation has not been found to occur when in vitro flux studies were run.
26 Once the skin has been transformed into the high efficiency 27 transfer state, it tends to remain in that state for an extended period of time 28 (e.g., up to 24 hours) even if no further electrotransport current is thereafter 29 applied to the skin or if only low level current densities (i.e., current densities less than the critical level Ic) are thereafter applied to the skin. This result is 1 illustrated in FIG. 5 and is discussed below. The "transformed" skin is in 2 general only those skin sites which are in contact with the donor and counter 3 electrodes/reservoirs of the electrotransport delivery device and through 4 which skin sites the applied current has been passed. Thus, if a skin site on 5 the upper arm of a patient has been transformed by application of 6 electrotransport current densities above the critical level IC, the skin on the 7 lower (same) arm, the legs, torso or other arm of the patient does not 8 become transformed. The skin transformation of this invention is a 9 localized phenomenon which is limited to those portions of the skin to 10 which the donor and counter electrodes/reservoirs are attached. Since the 11 skin at the counter electrode site also is converted to the high efficiency 12 delivery state, methods and devices for delivering agents from the "donor"
13 and "counter" electrodes, or both (e.g., by alternating current polarity) 14 are within the scope of this invention.
15 Our discovery is particularly critical in those transdermal 16 electrotransport drug delivery regimens wherein the drug is delivered at two 17 (or more) different dosing levels, one dosing level being administered at a 18 current density below the critical level l, and another dosing level being 19 administered at a current density above the critical level. For example, 20 many drugs are adapted to be administered at a low dose baseline rate for 21 extended periods, the baseline rate being interrupted periodically by periods 22 of higher dosing. Examples of drugs which are administered in this fashion 23 include (1) analgesics, such as fentanyl and sufentanil, which are 24 administered at a low baseline level to treat (e.g., chronic) pain and which are periodically delivered at higher doses to treat more severe episodes of pain;
26 (2) anti-emetics, such as the 5HT3 receptor antagonists ondansetron and 27 granisetron, which are administered continuously at low levels (e.g., during 28 weeks over which a patient is undergoing chemotherapy) and which are 29 periodically administered at higher dosing levels (i.e., during the actual chemotherapeutic administration); (3) anti-epileptics, such as phenytoin, 1 which are delivered continuously at low baseline levels and periodically at 2 higher levels when the patient is undergoing an epileptic seizure; and 3 (4) anti-diabetic drugs, such as insulins, which can be delivered continuously 4 at low baseline levels and periodically (e.g., just before, during or after meals) at higher levels. The problem encountered with this type of transdermal 6 electrotransport drug administration is that after the drug is administered at 7 the higher dosing rate (with the applied current density above the critical level, ,), when the applied electrotransport current is readjusted to apply the 8 Ie 9 original lower baseline level, the transdermal electrotransport drug flux does not return to the same baseline level. The drug flux instead falls to a level 11 somewhere between the original baseline rate and the high dosing rate, 12 because the skin has been transformed into a higher efficiency drug delivery 13 state. For example, if the efficiency is enhanced by a factor of two, after the 14 skin has experienced a current density above the critical current density, and then the current is lowered to the original base line current, the drug 16 delivery rate would be twice that experienced before the transformation.
17 The higher baseline rate could result in a drug overdose if the electrotransport 18 system does not compensate for this shift in efficiency. To eliminate this 19 problem, the electrotransport system should reduce the current applied (e.g., by approximately a factor of two) after the skin has experienced a current 21 density greater than Ic. With reference to FIG. 1, data point 2 is a likely 22 efficiency that would be experienced at the drug delivery site were current 23 (and therefore current density) reduced after exposure of the body site to 24 current density at or above I, for at least a period of time t,. At data point "2"
electrotransport agent delivery efficiency is higher than the agent delivery 26 efficiency which was initially experienced at a current density of about 20 27 A/cm2 (i.e., at a time before exposure of the skin to a current density above 28 I~).
29 Reference is now made to FIG. 3 which depicts an exemplary electrotransport device which can be used in accordance with the present 1 invention. FIG. 3 shows a perspective exploded view of an electrotransport 2 device 10 having an activation switch in the form of a push button switch 12 3 and a display in the form of a light emitEing diode (LED) 14. Device 10 4 comprises an upper housing 16, a circuit board assembly 18, a lower housing 20, anode electrode 22, cathode electrode 24, anode reservoir 26, cathode 6 reservoir 28 and skin-compatible adhesive 30. Upper housing 16 has lateral 7 wings 15 which assist in holding device 10 on a patient's skin. Upper 8 housing 16 is preferably composed of an injection moldable elastomer 9 (e.g., ethylene vinyl acetate). Printed circuit board assembly 18 comprises an integrated circuit 19 coupled to discrete electrical components 40 and 11 battery 32. Circuit board assembly 18 is attached to housing 16 by posts 12 (not shown in FIG. 3) passing through openings 13a and 13b, the ends 13 of the posts being heated/melted in order to heat stake the circuit board 14 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 16 being adhered to both lower housing 20 and upper housing 16 including the 17 bottom surfaces of wings 15.
18 Shown (partially) on the underside of circuit board assembly 18 is a 19 battery 32, which is preferably a button cell battery and most preferably a lithium cell. Other types of batteries, such as sizes AAA and AAAA may also 21 be employed to power device 10.
22 The circuit outputs (not shown in FIG. 3) of the circuit board assembly 23 18 make electrical contact with the electrodes 24 and 22 through openings 24 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, 26 are in direct mechanical and electrical contact with the top sides 44',44 of 27 drug reservoirs 26 and 28. The bottom sides 46',46 of drug reservoirs 26,28 28 contact the patient's skin through the openings 29',29 in adhesive 30. Upon 29 depression of push button switch 12, the electronic circuitry on circuit board assembly 18 delivers a predetermined DC current to the electrodes/reservoirs 1 22,26 and 24,28 for a delivery interval of predetermined length, e.g., about 2 minutes. Preferably, the device transmits to the user a visual and/or audible 3 confirmation of the onset of the drug delivery, or bolus, interval by means of 4 LED 14 becoming lit and/or an audible sound signal from, e.g., a "beeper".
Drug (e.g., an analgesic drug such as fentanyl) is then delivered through the 6 patient's skin, e.g., on the arm, for the predetermined delivery interval.
In 7 practice, a user receives feedback as to the onset of the drug delivery interval 8 by visual (LED 14 becomes lit) and/or audible signals (a beep from the 9 "beeper"). A preferred device is described in commonly owned, pending patent application entitled "Display for an Electrotransport Device", US
Patent 11 Application Serial Number 08/410,112, filed March 24, 1995.
12 Anodic electrode 22 is preferably comprised of silver and cathodic 13 electrode 24 is preferably comprised of silver chloride. Both reservoirs 26 14 and 28 are preferably comprised of polymer hydrogel materials as described herein. Electrodes 22, 24 and reservoirs 26, 28 are retained by lower housing 16 20. When the drug being delivered by electrotransport is cationic, the anodic 17 reservoir 26 is the "donor" reservoir which contains the drug and the cathodic 18 reservoir 28 contains a biocompatible electrolyte. When the drug being 19 delivered by electrotransport is anionic, the cathodic reservoir 28 is the "donor" reservoir which contains the drug and the anodic reservoir 26 21 contains a biocompatible electrolyte.
22 The push button switch 12, the electronic circuitry on circuit board 23 assembly 18 and the battery 32 are adhesively "sealed" between upper 24 housing 16 and lower housing 20. Upper housing 16 is preferably composed of rubber or other elastomeric material. Lower housing 20 is preferably 26 composed of a plastic or elastomeric sheet material (e.g., polyethylene) 27 which can be easily molded to form depressions 25,25' and cut to form 28 openings 23,23'. The assembled device 10 is preferably water resistant 29 (i.e., splash proof) and is most preferably waterproof. The system has a low profile that easily conforms to the body thereby allowing freedom of 1 movement at, and around, the wearing site. The anode reservoir 26 and the 2 cathode reservoir 28 are located on the skin-contacting side of device 10 and 3 are sufficiently separated to prevent accidental electrical shorting during 4 normal handling and use.
The device 10 adheres to the patient's body surface (e.g., skin) by 6 means of a peripheral adhesive 30 which has upper side 34 and body-7 contacting side 36. The adhesive side 36 has adhesive properties which 8 assures that the device 10 remains in place on the body during normal user 9 activity, and yet permits reasonable removal after the predetermined (e.g., 24-hour) wear period. Upper adhesive side 34 adheres to lower 11 housing 20 and retains the electrodes and drug reservoirs within housing 12 depressions 25,25' as well as retains lower housing 20 attached to upper 13 housing 16.
14 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 16 12 within a short period of time, e.g., three seconds, is preferably used to 17 activate the device 10 for delivery of drug, thereby minimizing the likelihood of 18 inadvertent actuation of the device 10.
19 Upon switch activation an audible alarm signals the start of drug delivery, at which time the circuit supplies a predetermined level of 21 DC current to the electrodes/reservoirs for a predetermined delivery interval.
22 The LED 14 remains "on" throughout the delivery interval indicating that the 23 device 10 is in an active drug delivery mode. The battery preferably has 24 sufficient capacity to continuously power the device 10 at the predetermined level of DC current for the entire wearing period.
26 The present invention is particularly useful in the transformation of 27 human skin in the transdermal electrotransport delivery of drugs to humans.
28 However, the invention also has utility in delivering drugs to other animals and 29 is not limited to humans.

1 The terms "agent" and "drug" are used interchangeably herein and are 2 intended to have their broadest interpretation as any therapeutically active 3 substance which is delivered to a living organism to produce a desired, 4 usually beneficial, effect. In general, this includes therapeutic agents in all of 5 the major therapeutic areas including, but not limited to, anti-infectives such 6 as antibiotics and antiviral agents, analgesics and analgesic combinations, 7 anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, 8 anti-depressants, antidiabetic agents, antidiarrheals, antihistamines, anti-9 inflammatory agents, antimigraine preparations, antimotion sickness 10 preparations, antinauseants, antineoplastics, antiparkinsonism drugs, 11 antipruritics, antipsychotics, antipyretics, antispasmodics including 12 gastrointestinal and urinary antispasmodics, anticholinergics, 13 sympathomimetrics, xanthine derivatives, cardiovascular preparations 14 including calcium channel blockers, beta-blockers, antiarrythmics, 15 antihypertensives, diuretics, vasodilators including general, coronary, 16 peripheral and cerebral vasodilators, central nervous system stimulants, 17 cough and cold preparations, decongestants, diagnostics, hormones, 1s hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, 19 parasympathomimetrics, proteins, peptides, polypeptides and other 20 macromolecules, psychostimulants, sedatives and tranquilizers.
21 The present invention can be used to deliver transdermally by 22 electrotransport the following drugs: interferons, alfentanyl, amphotericin B, 23 angiopeptin, baclofen, beclomethasone, betamethasone, bisphosphonates, 24 bromocriptine, buserelin, buspirone, calcitonin, ciclopirox, olamine, copper, 25 cromolyn sodium, desmopressin, diclofenac diflorasone, diltiazem, 26 dobutamine, dopamine agonists, dopamine agonists, doxazosin, droperidol, 27 enalaprii, enalaprilat, fentanyl, encainide, G-CSF, GM-CSF, M-CSF, GHRF, 28 GHRH, gonadorelin, goserelin, granisetron, haloperidol, hydrocortisone, 29 indomethacin, insulin, insulinotropin, interieukins, isosorbide dinitrate, ketoprofen, ketorolac, leuprolide, LHRH, lidocaine, lisinopril, LMW heparin, 1 melatonin, methotrexate, metoclopramide, miconazole, midazolam, nafarelin, 2 nicardipine, NMDA antagonists, octreotide, ondansetron, oxybutynin, PGE1, 3 piroxicam, pramipexole, prazosin, prednisolone, prostagiandins, scopolamine, 4 seglitide, sufentanil, terbutaline, testosterone, tetracaine, tropisetron, vapreotide, vasopressin, verapamil, warfarin, zacopride, zinc, and zotasetron.
6 This invention is also believed to be useful in the transdermal 7 electrotransport delivery of peptides, polypeptides and other macromolecules 8 typically having a molecular weight of at least about 300 daltons, and typically s a molecular weight in the range of about 300 to 40,000 daltons. Specific examples of peptides and proteins in this size range include, without 11 limitation, LHRH, LHRH analogs such as buserelin, gonadorelin, nafarelin and 12 leuprolide, GHRH, insulin, heparin, calcitonin, endorphin, TRH, NT-36 13 (chemical name: N=[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-14 protinamide), liprecin, pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate, etc.,), follicle luteoids, aANF, growth hormone 16 releasing factor (GHRF), (3MSH, TGF-(3, somatostatin, atrial natriuretic 17 peptide, bradykinin, somatotropin, platelet-derived growth factor, 1s asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic 19 gonadotropin, corticotropin (ACTH), epidermal growth factor, erythropoietin, epoprostenol (platelet aggregation inhibitor), follicle stimulating hormone, 21 glucagon, hirulogs, hyaluronidase, interferons, insulin-like growth factors, 22 interieukins, menotropins (urofollitropin (FSH) and LH), oxytocin, 23 streptokinase, tissue plasminogen activator, urokinase, vasopressin, ACTH
24 analogs, ANP, ANP clearance inhibitors, angiotensin I1 antagonists, antidiuretic hormone agonists, antidiuretic hormone antagonists, bradykinin 26 antagonists, CD4, ceredase, CSF's, enkephalins, FAB fragments, IgE peptide 27 suppressors, IGF-1, neuropeptide Y, neurotrophic factors, opiate peptides, 28 parathyroid hormone and agonists, parathyroid hormone antagonists, 29 prostagiandin antagonists, pentigetide, protein C, protein S, ramoplanin, renin 1 inhibitors, thymosin alpha-1, thrombolytics, TNF, vaccines, vasopressin 2 antagonist analogs, alpha-1 anti-trypsin (recombinant).
3 Generally speaking, it is most preferable to use a water soluble form of 4 the drug or agent to be delivered. Drug or agent precursors, i.e., species which generate the selected species by physical or chemical processes such 6 as ionization, dissociation, dissolution or covalent chemical modification 7 (i.e., prodrugs), are within the definition of "agent" or "drug" herein.
"Drug" or 8 "agent" is to be understood to include charged and uncharged species as 9 described above.
While the disclosure has focused upon the electrotransport delivery of 11 ionic species, the present invention is also applicable to the electrotransport 12 delivery of uncharged species, e.g., by electroosmosis. Thus, the 13 transformation of the skin into the high efficiency transport state is not limited 14 to electrically assisted transport of ionic species but also to electroosmotic 1s delivery of uncharged (i.e., non-ionized) species.
16 The following examples illustrate some of the advantages of the 17 present invention.
18 ÃXAMPLE1 Pulsing Frequency and Fentanyl Flux 22 This study assessed the effect of pulsing frequency on the 23 electrotransport delivery of fentanyl using pulsed current waveforms.
24 The frequencies evaluated in this study were 1, 10, and 625 Hz.
The electrotransport devices were configured to deliver a 200 A
26 square wave current pulse, having a 31 % duty cycle. At the frequency of 27 1 Hz, the 31 % duty cycle square wave current achieved a current pulse width 28 of 310 msec. At the frequency of 10 Hz, the 31 % duty cycle square wave 29 current achieved a current pulse width of 31 msec. At the frequency of 625 Hz, the 31 % duty cycle square wave current achieved a current pulse 1 width of 0.5 msec. The electrotransport devices delivered fentanyl through 2 the skin from a donor hydrogel having a skin contact surface area of 2 cm2.
3 Thus, the applied maximum current density, Imax, was 100 A/cm2 4 (200 A = 2 cm2 = 100 A/cm2). The gels were imbibed with an aqueous solution of fentanyl HCI. After treatment periods of varying duration, 6 the electrotransport devices were removed. The skin site was then washed 7 to remove any residual fentanyl.
8 For each treatment, blood samples were taken commencing with the 9 application of current from the electrotransport devices. Serum fentanyl levels from each patient were used to calculate mean drug flux.
11 FIG. 7 shows that the use of a square-wave frequency of 625 Hz 12 resulted in minimal fentanyl flux. This is shown in the lower most nearly 13 horizontal curve in FIG. 7. The use of the lower pulsing frequencies, 1 and 14 Hz, resulted in increased fentanyl flux. This is shown in the upper two curves 1s of FIG. 7. No statistically significant difference in fentanyl flux was observed 16 between 1 and 10 Hz. These results suggest that the use of lower pulsing 17 frequencies results in higher electrotransport delivery efficiency of fentanyl.
18 The remaining Examples do not utilize a pulsing electrotransport 19 current, and are therefore relevant only to the preferred aspect of the present invention wherein the applied current density (of each of the pulses) is 21 maintained above Ic.

Current Density and Increased Efficiency 27 This study evaluated the effect of applied current density on 28 electrotransport drug delivery efficiency. Drug delivery efficiency is expressed 29 in terms of the rate of drug delivery per unit of applied current. The study 1 involved the application of electrotransport devices to eighteen healthy male 2 volunteers for a duration of about one day.
3 The two electrotransport treatments involved the delivery of fentanyl, 4 from a donor reservoir containing an aqueous solution of fentanyl HCI and having a skin-contact area of 5 cm2, at a baseline current of 100 A. Thus, 6 the applied electrotransport current density was 20 A/cm2 (= 100 A = 5 7 cm2). Six of the eighteen volunteers were administered 4 bolus doses during 8 the first hour of treatment by applying current levels of 1300 A (i.e., an 9 applied electrotransport current density of 260 A/cm2) for a duration of 2.5 minutes at 15 minute intervals. Following the administration of the four 11 boluses in the first hour of treatment, these six volunteers received 12 continuous transdermal electrotransport fentanyl administration at a current 13 density of 20 A/cm2 from hour 2 through 24 hours. The remaining twelve 14 volunteers received continuous transdermal electrotransport fentanyl administration at a current density of 20 A/cm2 over the entire 24 hour 16 delivery period. After the treatment period, the electrotransport devices were 17 removed. The skin site was then washed to remove any residual fentanyl.
18 Blood samples were taken over the entire 24 hour period commencing 19 with the application of current from the electrotransport devices. Serum fentanyl concentrations were used to calculate mean transdermal fentanyl 21 fluxes using subject specific pharmacokinetic parameters and conventional 22 methods.
23 FIG. 5 shows that once a skin site receives a minimum level of current 24 (for a fixed electrode area) for a sufficient duration, a high electrotransport efficiency state is achieved. FIG. 5 shows the mean serum fentanyl 26 concentration in the blood of the subjects over the 24 hour testing period.
27 As is shown in the uppermost curve (0===0===0) in FIG. 5, the six volunteers 28 which received the four 260 A/cm2, 2.5 minute bolus administrations in the 29 first hour of treatment exhibited higher efficiency fentanyl transdermal delivery than the group of twelve subjects shown as three groups of four in the three 1 lower curves (to emphasize inherent variability) who received only the 20 2 A/cm2 constant DC current. Once this high-efficiency transport state is 3 achieved, more drug is delivered through the skin per unit of applied current.
4 Further, the effect lasted the entire 24 hours of the treatment. This is 5 indicated by the vertical separation between the upper curve and the 6 three lower curves in FIG. 5.
7 Specifically, the six volunteers who received the four 260 A/cm2 8 doses in the first hour of treatment exhibited a mean transdermal fentanyl flux 9 of 113 g/h while the twelve volunteers who received only the 20 A/cm2 10 baseline current exhibited a mean transdermal fentanyl flux of 57 g/h.
This 11 indicates that the efficiency was enhanced by about a factor of two as a result 12 of the initial high current density applications.

16 Current Density and Fentanyl Flux 18 This study was undertaken to evaluate the relationship of current 19 density and drug flux in the transdermal electrotransport delivery of fentanyl.
Electrotransport devices, delivering constant DC currents, were applied to 21 8 healthy male volunteers for a duration of 24 hours. The three 22 electrotransport treatment regimens in this study differed only in the applied 23 electrotransport current (and therefore current density) levels. The 24 electrotransport devices delivered fentanyl through the skin from a donor hydrogel having a skin contact surface area of 5 cm2. The gels were imbibed 26 with an aqueous solution of fentanyl HCI. The current density levels used in 27 this study were 10, 20, and 40 A/cm2. After a 24 hour treatment period, 28 the electrotransport devices were removed. The skin site was then washed to 29 remove any residual fentanyl. All 8 volunteers received each treatment approximately 1 week apart.

1 For each treatment, blood samples were taken over a 24 hour period 2 commencing with the application of current from the electrotransport devices.
3 Serum fentanyl concentrations over the 24 hours are shown in FIG. 6.
4 The top curve (--~--0--0--) in FIG. 6 was the 200 A treatment (i.e., 40 A/cm2), the middle curve (-~-~-~-) the 100 A treatment (i.e., 20 A/cm2) 6 and the bottom curve (--O--O--O--) the 50 A treatment (i.e., 10 A/cm2).
7 As in Example 2, the serum fentanyl concentrations from each patient were 8 used to calculate mean transdermal fentanyl flux and the mean total amount 9 of fentanyl delivered. A drug delivery efficiency level for each treatment was derived by dividing the mean fentanyl delivery rate by the current density 11 applied to the skin.
12 The average transdermal fentanyl fluxes were 19, 73 and 173 g/h at 13 the applied current densities 10, 20 and 40 A/cm2, respectively. This data 14 shows a non-linear relationship between applied current and transdermal electrotransport fentanyl flux within the electrotransport current density range 16 of 10 to 40 A/cm2. An almost ten-fold increase in drug delivery rate was 17 observed as the current was increased four-fold from 50 A to 200 A. This 18 unexpected result indicates that the efficiency of fentanyl delivery was 19 enhanced by a factor of about 2.5-fold due to the change in current density from 10 to 40 A/cm2.

24 This study was undertaken to evaluate the relationship between current density and drug flux in the transdermal electrotransport delivery of 26 goserelin. The study involved the application of electrotransport devices, 27 applying constant current, to 12 normal male volunteers for a duration of 28 8 hours.

1 The two electrotransport treatment regimens in this study differed 2 only in applied current density levels. The electrotransport devices delivered 3 goserelin through the skin from polyvinyl alcohol (PVOH)-based donor 4 hydrogels having a skin-contact surface area of 4 cm2. The gels contained an aqueous goserelin solution. The current density levels used in this study 6 were 50 and 100 A/cm2. After an 8 hour treatment period, the 7 electrotransport devices were removed. The skin site was then washed to 8 remove any residual goserelin. All 12 volunteers received each treatment 9 seven days apart.
For each treatment, seven blood samples were taken over a 24 hour 11 period commencing with the application of current from the electrotransport 12 devices. Serum goserelin concentrations from each patient were used to 13 calculate mean drug flux and the mean total amount of drug delivered.
14 FIG. 8 shows the goserelin blood plasma concentrations for the 8 hour duration of electrotransport administration for the two current densities (i.e., 16 50 and 100 A/cm2). The 100 A/cm2 curve is the upper curve in FIG. 8 while 17 the lower curve in FIG. 8 is the 50 A/cm2 data. From this concentration data, 18 transdermal goserelin fluxes were calculated. The average transdermal 19 goserelin flux was 5.8 g/h at an applied current density of 50 A/cm2 while the average transdermal flux of goserelin was 21.6 g/h at an applied current 21 density of 100 A/cm2. Thus, a non-linear relationship between applied 22 current density and drug flux was shown by the data. An almost four-fold 23 increase in drug flux is observed as the current density rises from 50 to 24 100 A/cm2. This data also suggests the existence of a critical current density, I, ., which for transdermal electrotransport delivery of goserelin falls 26 between 50 and 100 A/cm2, above which more drug is delivered through the 27 skin per unit of applied current.
28 The above disclosure will suggest many alternatives, permutations, 29 and variations of the invention to one skilled in this art without departing from the scope of the invention. The above disclosure is intended to be illustrative 1 and not exhaustive. All such, permutations, variations, and alternatives 2 suggested by the above disclosure are to be included within the scope of the 3 attached claims.

Claims (28)

CLAIMS:

1. A device for delivering a therapeutic agent through a body surface by electrotransport, the device having a donor reservoir containing the therapeutic agent, wherein the donor reservoir is placed in therapeutic agent transmitting relation with the body surface, the device also having a delivery area, a source of electrical power and a current controller for applying a pulsing current to the reservoir and the body surface, the pulsing current having a periodic waveform including a wave length, a frequency, and first and second segment with corresponding average magnitudes, the device also having a current density defined by the pulsing current divided by the delivery area, the device being characterized by:

the first segment being at least about 5 msec and the frequency being less than or equal to about 100 Hz.

2. The device of claim 1, wherein the first segment is about 10 msec and the frequency is less than about 10 Hz.

3. The device of claim 1, wherein the second average magnitude is less than about 70% of the first average magnitude.

4. The device of claim 1, wherein the second average magnitude is less than about 50% of the first average magnitude.

5. The device of claim 1, wherein the second average magnitude is less than about 25% of the first average magnitude.

6. The device of claim 1, wherein the second average magnitude is substantially zero.

7. The device of claim 1, wherein the periodic waveform is in the shape of a member selected from the group consisting of sinusoidal, trapezoidal, square and rectangular.

8. The device of claim 1, wherein the first segment has a maximum current magnitude providing a maximum current density I max.

9. The device of claim 8, wherein I max is greater than or equal to about 40 µA/cm2.

10. The device of claim 1, wherein the current density is greater than or equal to about 40 µA/cm2 during the first average magnitude.

11. The device of claim 1, wherein the therapeutic agent is fentanyl, the controller controls the first average magnitude to provide an average current density of at least about 40 µA/cm2 during the first segment, and wherein the controller controls the length of the first segment to at least about 10 msec.

12. The device of claim 1, wherein the therapeutic agent is goserelin, wherein the controller controls the first average magnitude to provide an average current density of at least about 50 µA/cm2 during the first segment, and wherein the controller controls the length of the first segment to at least about 10 msec.

13. The device of claim 1, wherein the controller adjusts the first and second segments and varies the therapeutic delivery rate.

14. The device of claim 1, wherein the donor reservoir includes at least one suitable competitive co-ion specie reducing the delivery rate of the agent.

15. A method of operating an electrotransport device, the device for delivering a therapeutic agent through a body surface, and the device having a donor reservoir containing the therapeutic agent and placed in therapeutic agent transmitting relation with the body surface, the device also having a delivery area, a source of electrical power and a current controller for applying a pulsing current to the reservoir and the body surface, the pulsing current having a periodic waveform including a wave length, a frequency, and first and second segment with corresponding average magnitudes, the device also having a current density defined by the pulsing current divided by the delivery area, the method being characterized by the steps of:

controlling the first segment to at least about 5 msec; and, controlling the frequency to less than or equal to about 100 Hz.

16. The method of claim 15, wherein the first segment is controlled to about 10 msec and the frequency is controlled to less than about 10 Hz.

17. The method of claim 15, further including the step of controlling the second average magnitude to less than about 70% of the first average magnitude.

18. The method of claim 15, further including the step of controlling the second average magnitude to less than about 50% of the first average magnitude.

19. The method of claim 15, further including the step of controlling the second average magnitude to less than about 25% of the first average magnitude.

20. The method of claim 15, further including the step of controlling the second average magnitude to substantially zero.

21. The method of claim 15, further including the step of controlling the periodic waveform in the shape of a member selected from the group consisting of sinusoidal, trapezoidal, square and rectangular.

22. The method of claim 15, further including the step of controlling the first segment to have a maximum current magnitude providing a maximum current density I max.

23. The method of claim 22, wherein I max is greater than or equal to about 40 µA/cm2.

24. The method of claim 15, further including the step of controlling the current density to greater than or equal to about 40 µA/cm 2 during the first average magnitude.

25. The method of claim 15, further including the steps of controlling the first average magnitude to provide an average current density of at least about 40 µA/cm2 during the first segment, and controlling the length of the first segment to at least about 10 msec, wherein the therapeutic agent is fentanyl.

26. The method of claim 15, further including the step of controlling the first average magnitude to provide an average current density of at least about 50 µA/cm2 during the first segment, and controlling the length of the first segment to at least about 10 msec, wherein the therapeutic agent is goserelin.

27. The method of claim 15, further including the step of adapting the controller to adjust the first and second segments and vary the therapeutic delivery rate.

28. The method of claim 15, further including the step of reducing the delivery rate of the agent by adding to the donor reservoir at least one suitable competitive co-ion specie.