Abstract:
An apparatus for the electrically assisted delivery of therapeutic agent is described. An apparatus of the invention has rigid zones or regions which are physically connected by flexible means such as a web. The flexible means permits the rigid zones to move independently with respect to each other while remaining physically connected or coupled. In a preferred embodiment, the rigid zones are physically and electronically coupled by the flexible means. In another preferred embodiment, the skin side of the rigid zones has a radius of curvature which approximates that of the body site to which the device is to be attached. 
     A method of increasing the body or surface conformability of a rigid electrotransport device is described. The method involves the step of intentionally placing rigid subcomponents of the device in physically separate zones within the device. The rigid zones are separate and are coupled by flexible connector means. In this manner, a conformable mosaic of rigid zones which comprises the device is created.

Description:
This Application is a continuation of Application Ser. No. 07/999,206 filed Dec. 31, 1992 now abandoned. 
    
    
     TECHNICAL FIELD 
     This invention generally concerns apparatuses for the electrically assisted delivery of a therapeutic agent. Such apparatuses are referred to broadly herein as electrotransport devices. 
     More specifically, this invention relates to electrotransport drug delivery devices in which active species or drugs are directly or indirectly delivered through the skin of a patient by application of electromotive force. Yet more specifically; this invention relates to electrotransport devices having physically coupled, substantially rigid zones or regions wherein the means of coupling permits the zones or regions to be planar or non-planar and thereby to conform to complex, curved and non-planar surfaces. 
     Yet even more specifically, this invention relates to electrotransport devices, such as iontophoresis devices, having physically and electrically coupled rigid zones or regions which are maintained in intimate contact with a patient&#39;s skin so as to deliver, transdermally, drug or therapeutic agent. 
     BACKGROUND OF THE INVENTION 
     The present invention concerns apparatuses for transdermal delivery or transport of therapeutic agents, typically through iontophoresis. Herein the terms “electrotransport”, “iontophoresis”, and “iontophoretic” are used to refer to methods and apparatus for transdermal delivery into the body of therapeutic agent, whether charged or uncharged, by means of an applied electromotive force to an agent-containing reservoir. The particular therapeutic agent to be delivered may be completely charged (i.e., 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, electroosmosis, electroporation or a combination of these. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically-induced osmosis. In general, electroosmosis of a therapeutic species into a tissue results from the migration of solvent, in which the species is contained, as a result of the application of electromotive force across the therapeutic species reservoir-tissue interface. 
     As used herein, the terms “iontophoresis” and “iontophoretic” refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of charged or uncharged drug(s) or agent(s) by the combined processes of electromigration, electroosmosis, and electroporation. 
     Iontophoretic devices for delivering ionized drugs through the skin have been known since the early 1900&#39;s. Deutsch U.S. Pat. No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices, namely that the patient needed to be immobilized near a source of electric current. The Deutsch device was powered by a galvanic cell formed from the electrodes and the material containing the drug to be transdermally delivered. The galvanic cell produced the current necessary for iontophoretically delivering the drug. This device allowed the patient to move around during iontophoretic drug delivery and thus imposed substantially less interference with the patient&#39;s daily activities. 
     In presently known iontophoresis devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, medicament, drug precursor or drug is delivered into the body via the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient&#39;s skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery; and usually to circuitry capable of controlling current passing through the device. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode. In some instances, the drug may be formulated such that in one formulation the drug ions are positively charged and in a second formulation the drug ions are negatively charged. In such situations, the positively charged drug ions may be delivered from the anode and/or the negatively charged drug ions may be delivered from the cathode. Hence, drug delivery may occur from one or both electrodes and may occur simultaneously as well as sequentially. 
     Furthermore, existing iontophoresis devices generally require a 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 iontophoretically delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species or agents. 
     Perhaps the most common use of iontophoresis today is in diagnosing cystic fibrosis by delivering pilocarpine transdermally. Iontophoretically delivered pilocarpine stimulates sweat production, the sweat is collected, and is analyzed for its chloride ion content. Chloride ion concentration in excess of certain limits suggests the possible presence of the disease. 
     Electrotransport devices generally contain an electronic circuit which controls the current output of the device. In more recent years, the size of electrotransport devices has been reduced to a point where the devices can be mounted and worn on the skin. In order to protect, adequately, the electronic circuitry in such skin-mounted devices and for a variety of other reasons, these devices have generally utilized a substantially rigid container or assembly. See for example Lattin et al. U.S. Pat. No. 4,406,658 (FIGS. 2 and 3) and Lattin et al. U.S. Pat. No. 4,457,748 (FIGS. 1, 3 and 4). While these rigid devices were acceptable in those applications (e.g., cystic fibrosis diagnosis) which required the patient to wear the device for only a short period of time, i.e., on the order of 30 minutes or less, these devices have been found to be somewhat uncomfortable in those applications where the patient must wear the device for periods longer than an hour. Particularly in applications where the patient must wear the device for an extended period of time (e.g., days, weeks or months) comfort is a significant issue. 
     In response to these difficulties, the advantages of developing a flexible electrotransport delivery device were recognized. For example, Ariura et al. U.S. Pat. No. 4,474,570, discloses one example of a flexible iontophoresis device. This device utilizes electrode assemblies comprised of a current distributing conductive layer, a drug, or electrolyte salt-containing gel layer and a thin backing layer, all laminated together. The Ariura device utilizes minimal electronic circuitry, specifically only a single button cell battery which is connected though a flexible lead wire to an electrode assembly. In order to make the device completely flexible, Ariura utilizes thin “sheet” batteries which have a thickness of only about 0.5 to 2 mm. Because the Ariura et al device is completely flexible, it is able to conform to many irregular body surfaces and can be worn comfortably for longer periods of time. While flexible iontophoretic delivery devices, such as that disclosed by Ariura et al. represent a significant advantage over rigid devices, in terms of comfort for the wearer, they present other disadvantages. For example, the Ariura et al. device is very limited in terms of the electronic circuitry which may be utilized in the device and yet still retain its flexible characteristics. Furthermore, there are many iontophoretic drug delivery applications which the current requirements are too high for the single small battery disclosed in the Ariura et al device. If multiple batteries are placed in the Ariura et al device, the device becomes substantially nonflexible and thereby loses its comfort advantage. 
     In addition to batteries, electrotransport delivery devices may have other components which are themselves relatively rigid and inflexible (i.e., one or more electrical components) or which require a relatively rigid housing in order to adequately protect the component during shipping and handling of the device. For example, “dry” electrotransport delivery devices which are hydrated immediately before use sometimes carry on-board water pouches. In order to adequately safeguard against premature hydration caused by inadvertent rupture of the on-board water pouches, it may be necessary to provide structural rigidity to the device at least in the vicinity of the water pouches. Other device components, e.g., delicate electronics, may require at least portions of the electrotransport device to be relatively rigid to provide protection, electrical continuity or other function. 
     Unfortunately, devices having rigid regions generally do not conform well to the body site to which the device is attached, particularly when the means of attachment is a releasable contact adhesive. This can cause an electrotransport system to peel away from the body site, or to alternatively cause internal layers of the device itself to detach or delaminate and thereby fail. This invention allows an electrotransport drug delivery device having rigid regions to conform to the body su face (e.g., to skin) to which it is adhesively held with a reduced tendency to peel away. 
     U.S. Pat. No. 4,752,285 to Petelenz discloses a wrist-disposed iontophoresis device held in place by a bracelet comprising an iontophoresis apparatus including a remote electrode. The iontophoresis apparatus and electrode of Petelenz &#39;285 are connected by wires to a separate current source. 
     The present invention overcomes the problems encountered in the prior art and is not suggested or disclosed in the references alone or in combination. 
     SUMMARY OF THE INVENTION 
     Briefly, in one aspect, the present invention is an assembly or device for delivering an agent by electrotransport through a body surface. A device of this invention has at least two rigid regions which are adapted to be maintained in ion-transmitting relationship with the body surface at spaced apart locations, and which are held in their spaced apart locations preferably by means of biocompatible adhesive. Despite substantial rigidity, at least a drug delivery component of the assembly of this invention is maintained in intimate, drug-transmitting relation with the body surface. A device of this invention further includes a flexible connector means which physically connects the rigid regions but which permits the rigid regions to move with respect to each other during agent electrotransport without loss of intimate contact with the surface of the patient&#39;s body. Specific embodiments of flexible connector means of this invention include hinges and flexible polymeric webs. 
     In a preferred practice of this invention, the flexible connector means both (1) physically connects or couples the rigid zones; to one another and (2) electronically connects a component in one of the rigid zones to a component in the other rigid zone. Generally, this means that a flexible electronic conductor comprises a part of the flexible connector means. 
     In a preferred practice, the rigid components or zones of the assembly of this invention are held in intimate, ion-transmitting relation to a portion of a patient&#39;s body by means of a biocompatible adhesive. 
     In yet another preferred practice, a device of this invention has a plurality of rigid zones and a plurality of flexible connector means physically or physically and electronically coupling the rigid zones. 
     In a further preferred practice of this invention, the rigid regions are contoured to the body surface to which they are applied. 
     Preferably, the rigid regions have a flexural rigidity, EI, greater than about 1.5×10 −3  kg-m 2 /rad and the flexible connector means has a flexural rigidity of less than about 0.75×10 −3  kg-m 2 /rad. More preferably, the rigid regions have a flexural rigidity of greater than about 5.0×10 −3  kg-m 2 /rad and the flexible connector means has a flexural rigidity of less than about 0.45×10 −3  kg-m 2 /rad. Most preferably, the rigid regions have a flexural rigidity of greater than about 15×10 −3  kg-m 2 /rad and the flexible connector means has a flexural rigidity of less than about 0.15×10 −3  kg-m 2 /rad. In addition, the difference between the flexural rigidity of a rigid region and the flexural rigidity of the flexible connector means (ΔEI) is preferably greater than about 0.3×10  −3  kg-M 2 /rad, more preferably greater than about 1.5×10 −3  kg-m 2 /rad, and most preferably greater than about 5.0×10 −3  kg-m 2 /rad. 
     The flexural rigidity of a rigid zone and/or a flexible connector means is measured in accordance with the test method described in connection with FIG. 12, hereinafter. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The present invention may be better understood with reference to the detailed description below and the attached drawings in which like numerals are used to refer to like features throughout and in which: 
     FIG. 1 is a perspective view of one embodiment of the present invention; 
     FIG. 1A is an enlarged side view of the flexible connector means  16  shown in FIG. 1; 
     FIG. 1B is a side view of an alternate connector means  16 ′ which can be used in place of flexible connector means  16  shown in FIG.  1 A. 
     FIG. 2 is an exploded view of a second embodiment of the present invention similar to that of FIG. 1 
     FIG. 2A is an enlarged partial section side view of its flexible connector means  16 ″ shown in FIG.  2 . 
     FIG. 3 is a perspective view of another embodiment of the present invention; 
     FIG. 4 is an exploded view of the components of the device shown in FIG. 3; 
     FIG. 5 is an exploded, perspective view of another embodiment of this invention; 
     FIG. 6 is a perspective, partial phantom view of another embodiment of the present invention; 
     FIG. 7 is a perspective, partial phantom view of the embodiment of the invention shown in FIG. 6 but rotated approximately 45° from the orientation shown in FIG. 6; 
     FIG. 8 is a top view of yet another embodiment of the present invention; 
     FIG. 9 is another top view of the device shown in FIG. 8 in which the rigid components  204  and  206  have been physically separated; 
     FIGS.  10  and FIG. 11 are further embodiments of the present invention; 
     FIG. 12 is a side view of an apparatus for measuring the flexibility and/or rigidity of an electrotransport device or any component thereof; and 
     FIG. 13 is yet a further embodiment of the present invention. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Thus there is shown, in FIG. 1, a perspective view of an electrotransport device or assembly  10  of this invention. Electrotransport device  10  comprises two rigid (as defined herein) housings or subassemblies  12 ,  14  connected by flexible connector means  16 . Housings  12  and  14  each comprise rigid zones or region, which rigid zones or regions are physically connected to one another by flexible connector means  16 . Device  10  includes a flexible, biocompatible or skin compatible adhesive sheet  18  which preferably extends beyond the outer perimeter of housings  12 ,  14 . By making the area of adhesive sheet  18  larger than the area of housings  12 ,  14  there is greater area of contact between sheet  18  and a patient&#39;s skin resulting in more secure attachment of the device  10  thereto. The extension of the peripheral edges of flexible sheets  18  beyond the peripheral edges of rigid housings  12 ,  14  also permits a more gentle transition between the patient&#39;s skin and rigid housings  12 ,  14 , thereby making device  10  more comfortable to wear. 
     The rigid housings  12 ,  14  may contain, for example, electrical circuit components which are coupled through e.g., flexible hinge  16 . The circuit components are mounted (and protected) in the two rigid housings  12 ,  14 . These housings are preferably comprised of a substantially thermoplastic, rigid material. The housings  12 ,  14 , themselves, are substantially incapable of conforming to the contour of the underlying skin surface and, but for hinge  16 , would eventually cause the underlying adhesive sheet  18 , (which contains a typical skin contact adhesive) either to peel away from the skin, or pull on the skin and thereby cause discomfort for the wearer as a result of normal body movement. 
     In FIG. 1A there is shown a detail of the flexible connector  16  which physically (and preferably) electronically couples or connects rigid housings  12 ,  14 . Connector  16  comprises a base  17  on which adhesive  18  is located. Base  17  and adhesive  18  have a zone, line, or means of flex which in this example is simply a “necked down” region or portion  25  of the support member. The necked down segment  25  is more flexible than the rest of the support structure. Alternatively a cross-sectioned “V” segment could be used in place of the “necked down” region shown to provide the increased flexibility or flex zone, region or line. Segment  25  permits rigid zones  12 ,  14  to move independently with respect to each other while maintaining their physical proximity. Base  17  may further comprise flexible electronic coupler means. This embodiment of the invention is discussed below. Base  17  may or may not contain flexible circuitry depending upon the rest of the device construction. In the embodiment shown base  17  contains flexible electrical connector or circuitry (not shown). 
     Another example of a flexible connector means which can be used flexibly to connect rigid housings  12 ,  14  is hinge  16 ′ shown in FIG.  1 B. Hinge  16 ′ is formed by inserting flexible fin  17  into recess  19  in housing  12 . Fin  17  is slidably received in recess  19 , allowing fin  17  to slide in and out of recess  19  as housings  12 ,  14  are flexed about hinge  16 ′. Thin, flexible zone  31  provides a region or area which permits housings  12 ,  14  to bend or flex with respect to each other. Those skilled in the flexible hinge art will readily appreciate that any number of hinge designs may be used in place of the specific designs illustrated in FIGS. 1A,  1 B and  2 A. 
     The terms “rigid” and “flexible” are used to describe not only housings  12 ,  14 , and hinge  16 , respectively, but are also used extensively elsewhere herein. The term “rigid” when used in describing a portion or zone of an electrotransport system means that the portion or zone has sufficient stiffness so as to be incapable of adhering to a body surface (e.g., to skin) of a patient using a biocompatible and pharmaceutically acceptable contact adhesive without injury to the body surface or identifiable patient discomfort, throughout the normal range of body motion. In other words, a “rigid” zone of an electrotransport system is prone to peel from the skin, or alternatively to undergo delamination of adjacent layers within the rigid zone of the system, thereby interfering with the desired agent or drug delivery protocol. 
     The term “flexible” when used to describe the flexible means which connects the rigid zones of an electrotransport system means having sufficient flexibility so as to enable the “rigid” portions or zones of the system to be capable of adhering to the body surface, by means of a biocompatible, pharmaceutically acceptable contact adhesive without injury to the body surface or identifiable patient discomfort, throughout the normal range of body motion and for the time period in which drug or agent is to be delivered. 
     Those skilled in the art may readily determine the flexibility or rigidity of a particular component or zone in an electrotransport system by using the following test method. Although any number of stress-strain testing apparatus may be used to determine flexural rigidity, one preferred apparatus is an Instron stress-strain testing machine Model No. 1122 which may be used interchangeably with a number of different tension load cells. A preferred load cell for testing the flexible connector means of the present invention is the Instron 2000 gm tension load cell Model No. A 30-38(A). A preferred tension load cell for measuring the flexural rigidity of the rigid zones according to the present invention is an Instron 500 kg tension load cell. A tension load cell used to determine the parameters used in this application is described below with reference to FIG.  12 . 
     FIG .  2  shows an exploded view of an electrotransport delivery device  10 ′ of this invention in which the rigid housing  12 ′ and  14 ′ (which contain the battery(ies) and any associated electronic circuitry) are shown separated from a flexible sheet  20  which is secured to the underside of housings  12 ′,  14 ′ during use of device. Sheet  20  may be attached to the underside of housings  12 ′ and  14 ′ by conventional means, e.g., an adhesive, rivets, or snap connectors (not shown in the figure) or combination of these attachment means. The skin contacting undersurface of sheet  20  may itself be tacky, (e.g., tacky polyisobutylene) or may be coated with an appropriate biocompatible contact adhesive (e.g., a silicone adhesive). In this manner, device  10 ′ may be adhered to a patient&#39;s skin by flexible, biocompatible adhesive sheet  20 . Sheet  20  is substantially the same size as the outer profile of housings  12 ′,  14 ′ and thus does not extend beyond the outer periphery of housings  12 ′,  14 ′. Sheet  20  is preferably comprised of a material which is substantially impermeable to the passage of ions therethrough, e.g., a hydrophobic adhesive material. Provided within the sheet  20  are wells  21  and  22  which contain, on the “donor” side, the agent to be delivered by electrotransport contained within a hydrophobic gel, and on the “counter” side, a biocompatible electrolyte salt contained within a hydrophilic gel. Wells  21  and  22  preferably contain a reservoir  23  or  24 , which reservoir is comprised or a hydrophilic polymer (e.g., a gel) loaded with either the beneficial agent or the biocompatible electrolyte salt, respectively. Thus, each of reservoirs  23  and  24  contain an agent or salt, and preferably an ionizable agent or salt, which is suitable for delivery into the body. Sheet  20  is adapted to be secured to the bottom of housings  12 ′ and  14 ′ in a manner which electrically connects the reservoirs  23  and  24  with appropriate current conducting members within housings  12 ′,  14 ′ respectively. 
     A flexible hinge  16 ″ provides a flexible coupling between the two rigid zones comprising housings  12 ′ and  14 ′. Components in housing  12 ′ can be electronically connected to components in housing  14 ′ across the flexible coupling of this invention e.g., when the flexible connector means includes a flexible, conductive electronic circuit or component thereof. This is discussed in greater detail below. 
     One preferred example of a flexible coupler means or hinge  16  comprises a flexible plastic material, or what is sometimes referred to in this art as a “living hinge”. A side view of such a hinge  16 ″ is shown in partial section detail in FIG.  2 A. The hinge  16 ″ of FIG. 2A is a compound hinge comprised of a polymeric web  33  having three fold lines  11 ,  13  and  15 . Fold lines  11 ,  13  and  15  are generally perpendicular to the plane of FIG.  2 A. Adhesive  18  and base  17  also are shown in FIG.  2 A. Base  17  has a relatively thinner flex zone or line  35  which, as shown, is a “V”. Polymeric web  33  and flex line  35  permit rigid segments  12 ′,  14 ′ to bend with respect to each other. Web  33  and flex line  35  are aligned so that they can be flexed substantially in unison. 
     FIG. 3 shows an alternative, perspective embodiment of the invention. Electrotransport delivery device  30  includes two rigid zones comprised of rigid housings  32  and  34 . Rigid housings  32 ,  34  contains batteries  37  (shown in phantom) and other electronic circuitry (not shown). Housing  32  optionally contains an indicator  44  and a bolus switch  46 . Bolus switch  46 , when activated by the patient or a medical professional, provides a higher level of electrical current for a predetermined or predeterminable period of time. This produces a correspondingly higher drug delivery over the predetermined time, providing a bolus of drug to the patient. Indicator  44  (an LED) provides an indication of whether the bolus is activated. 
     Housings  32 ,  34  are flexibly coupled by hinge  36  which flexes around imaginary axis  38 . Thus in this embodiment, like devices  10  and  10 ′, the flexible means flexes about an axis or line of flex. Housings  32 ,  34  bend or flex about hinge  36 , from the substantially planar position shown to a non-planar position shown in phantom by reference numeral  40 . The rigid, substantially planar housings  32 ,  34  are attached to an adhesive sheet  42  which is used to adhere device  30  to a body surface. Because of hinge  36 , the rigid planar housings can be flexed about imaginary axis  38  in order to comfortably conform to a generally curved or contoured portion of a patient&#39;s body to which device  30  is attached via adhesive sheet  42 . 
     FIG. 4 is an exploded view of a device  50  of the invention. As shown, device  50  includes two substantially rigid ( e.g., molded polypropylene) housings  52 ,  54  coupled by a flexible, uniaxial hinge  56 . Rigid housing  52  houses one or more electronic circuit components  58  (e.g., capacitors, transistors, an oscillators, or a pulse generator, etc.), while rigid housing  54  houses batteries  36 . The rigidity of both these case segments is dictated by functional concerns, e.g., protection of internal components, and the rigidity of the internal components themselves. 
     As shown, circuit component  58  and batteries  37  are disposed on a flexible printed circuit board  60 . Flexible printed circuit board  60  typically has a plurality of circuit traces (not shown in the FIG) interconnecting batteries  37  and circuit components(s)  58 . Flexible printed circuit board  60  has at least one flexible hinge or axis of flex  62  which cooperates with cover hinge  56  to provide two substantially parallel and closely adjacent axes or lines of flexibility which together define a flexible connector means comprising a plane or zone of flexibility or flex. 
     Printed circuit board  60  may be coupled or connected to rigid housing members  52 ,  54  by any appropriate means e.g., an adhesive, snap connectors, rivets, etc. Printed circuit board  60  is coupled to sheet  20  containing reservoirs  23  and  24  by conventional means as described earlier with regard to FIG.  2 . 
     FIG. 5 is an exploded view of another device  100  according to the present invention. Device  100  has a rigid, two-halved upper cover or housing  102 . Upper housing  102  comprises two substantially planar, rigid, halves  104 ,  106  coupled or connected by a flexible compound hinge  108 . As with the device  50  of FIG. 4, device  100  has a bolus switch  110  which may be activated by the patient or a medical professional after the device is positioned on the patient&#39;s body. Housing  102  also has a peripheral lip which improves the level of comfort experienced by the patient wearing the device. Generally speaking a peripheral lip must have sufficient width to comfortably hold the device against the patient&#39;s skin during the full range of body motion without excessively distorting the skin surface to which it adheres so as to cause pain or discomfort. 
     Device  100  further includes a lower housing  114 , and a flexible circuit  116  which sits on lower housing or base component  114 . Lower housing  114  comprises two substantially rigid sections,  119 ,  121  connected by a flexible hinge  123 . Flex circuit  116  includes a necked segment  117  which electronically couples its two halves. Positioned over flexible circuit  116  is a battery spacer  120  which holds the batteries (not shown) in position over the battery terminal contacts  118  of flexible circuit  116 . Lower housing  114  has a flexible peripheral lip or edge  125  which extends beyond or outside the profile of the device defined by upper housing  102 . Such a lip is a preferred construction because it enhances the ability of the device to be held to a patient&#39;s skin during drug delivery (e.g., by an adhesive) without distorting the patient&#39;s skin so as to cause discomfort. Generally speaking, the wide lip must be more flexible than the rigid segments to which it is attached in order to achieve this comfort and comformability objective. 
     Also of importance in FIG. 5 is the substantial coincidence or planarity of hinge  108  in upper housing  102 , necked segment  117  of circuit  116  and the flexible hinge  123  in lower housing  114 . These three elements provide flexible physical and electrical coupling between the substantially rigid halves of the device shown in FIG.  5 . These elements in combination illustrate a planar flex means or flexible connector means of this invention. It is well within the design choice of those skilled in this art to determine which of the various assembly components shall be hinged so that physical connection is achieved. For example, the two halves  104 ,  106  of upper housings  102  may comprise separate pieces if the lower housing  114  and the lower hinge  123  are sufficiently strong so as to retain the physical proximity of the rigid sections of the assembly. Alternatively, upper housing  102  may be comprised of a single hinged piece (e.g., halves  104 ,  106  physically coupled by hinge  108 ) and lower housing  114  may comprise physically separate sections  119 ,  121 . These design variations are well within the skill of one familiar with this art. 
     FIG. 6 illustrates an embodiment of the present invention in which the electrotransport device  150  has multiple rigid modules  152 ,  154 ,  156 ,  158  and a plurality of flexible connector means or regions  160 ,  162 . Device  150  therefore has two separate and distinct flexible regions  160 ,  162 . The axes of flex of regions  160  and  162  are substantially perpendicular. An array of independent, rigid, but physically connected modules  152 ,  154 ,  156 ,  158  connected by flexible regions  160 ,  162  is generated. 
     Of particular note from FIG. 6 is the curved shape of the skin contacting surfaces of electrotransport device  150 . As can be seen, flexible region  160  divides device  150  into two rigid segments  151 ,  153 . Each of the segments  151 ,  153  has a curved skin contacting surface,  155 ,  157 , respectively. The curved (as opposed to planar) surfaces  155 ,  157  are preferred because many likely device application sites on the body are curved and/or have roughly a cylindrical shape. For example, the arms legs, torso, neck, and fingers all have substantially curved or cylindrical surfaces. A rigid segment  151 ,  153  having a surface  155 ,  157  with a radius of cylindrical curvature in the range of 40 to 60 mm is preferred for conforming to the arms of human adults having different body sizes, shapes and physiques. A rigid segment  151 ,  153  having a surface  155 ,  157  in the range of about 12 to 18 mm radius of cylindrical curvature is preferred for conforming to the fingers and toes of human adults. A range of about 60 to 90 mm radius of cylindrical curvature is preferred for surfaces conforming to the legs of human adults. A rigid segment  151 ,  153  having a surface  155 ,  157  with greater than about a 125 mm radius of cylindrical curvature is preferred for conforming to the torsos of human adults. The radius of a curved, rigid segment is selected substantially to match the smallest body site (e.g., torso) sizes encountered in the patient population group to which the device is to be applied. In this manner, the largest possible area of skin contact will result. The resulting enhanced conformity of the device  150  to the body surface, particularly along the edges of the modules  153  and  155 , will reduce the likelihood that a module will snag (e.g., on the patient&#39;s clothing) and peel off the skin during wear. By virtue of the cylindrical, concave underside of surfaces  155  and  157 , forces which tends to bias the edges of modules  151  and  153  away from the skin contact surface, which forces are typically observed during the attachment of a flat, single-piece rigid device on the skin of a patient, can be greatly reduced. 
     By utilization of an array of smaller rigid modules  152 ,  154 ,  156  and  158 , disposed on a suitably flexible web or sheet (e.g., sheet  19  shown in FIGS. 2,  4  and  5 ), the individual modules can be quite thick and also quite rigid and yet the entire device  150  remains flexible (i.e., more able to conform to the natural shape of a body surface). This is due primarily to the presence of flexible regions  160  and  162 . This observation is particularly applicable if the rigid modules are adequately separated ( e.g., by flexible regions  160  and  162 ) on a flexible connecting “web” or film and the skin contacting surfaces of the modules are curved, angled or radiussed, as depicted in FIG.  6 . Generally speaking, it is necessary for any bridge between individual modules be thin and substantially coplanar, otherwise a structure will be produced that will be extremely stiff and non-conformable. 
     FIG. 7 shows a further embodiment of this invention. Device  170  is comprised of multiple rigid modules  172 ,  174 ,  176  and  178  which are physically coupled by means of a flexible web  180 . This arrangement provides two flexible regions having substantially perpendicular axes of flex. The rigid modules  172 ,  174 ,  176  and  178  are also electronically coupled to one another (at  182 ,  184 ,  186  and  188 ) by flexible electronic circuits. In this embodiment the flexible coupling means includes the portion of web  180  between the rigid segments  172 ,  174 ,  176 , and  178  and circuit couplings  182 ,  184 ,  186 , and  188  and the underlying sheet (e.g., sheet  19 ) which is not shown in FIG.  7 . Like device  150  the individual rigid segments of device  170  are curved or are concave on their skin facing surfaces (e.g., their underside surfaces) to enhance skin contact as described above. Web  180  is adhesive on its bottom side to attach sheet  19  (not shown) thereto. The skin contacting surface of sheet  19  is either itself tacky or is coated with a biocompatible skin contact adhesive in order to hold the device  170  in drug transmitting relation to the patient&#39;s skin. 
     Electrotransport devices  150  and  170  illustrated in FIGS. 6 and 7, respectively, demonstrate a further important embodiment of the present invention. The level of comfort experienced by the wearer of a rigid electrotransport system of a certain size may be increased by dividing the overall size of the device into a number of smaller subunits (e.g., subunits such as the rigid modules  152 ,  154 ,  156  and  158  shown in FIG. 6 or the rigid modules  172 ,  174 ,  176  and  178 ), each of which subunits may itself be rigid as defined herein. However, rather than a single large rigid device, the smaller rigid subunits are interconnected by way of flexible connector means as defined herein. Preferably, the individual rigid subunits have lateral dimensions (i.e., lengths and widths as measured roughly parallel to the body surface to which the electrotransport system is applied) in the range of 10-35 mm, more preferably in the range of 15-25 mm. Most preferably, the individual rigid subunits have lateral dimensions within these ranges and also have skin contacting surfaces with radii of cylindrical curvature as described above. 
     FIGS. 8, and  9  are top views of another embodiment  200  of the present invention. Device  200  has an “according-type”, flexible connector means  202 , which couples, both physically and electronically, rigid device components  204 ,  206 . Device components  204 ,  206  are adhered to a patient&#39;s body by means of web  208  which has a biocompatible adhesive on it skin contacting side (not shown). Various web profiles may be employed depending upon the body application site and artistic considerations. 
     FIG.&#39;s  10  and  11  illustrate two further embodiments of this invention. Devices  300  and  302  each have a flexible but non-stretchable connector means  304 ,  306 , respectively, which electronically and physically couple rigid components  308 ,  310  and  312 ,  314 , respectively. The rigid components may contain batteries or electronic circuit components with no particular significance being attached to which rigid components are included within the respective rigid assemblies. The connector means of FIG. 10 is a plurality of fairly rigid rubber connectors having partial lateral slices projecting inwardly from the edge while in FIG. 11 the connector means is a rubber coated band. 
     FIG. 13 illustrates the single rigid electrotransport assembly embodiment  500  of the invention. A single rigid assembly similar to that of FIG. 13 is described in detail in U.S. Pat. No. 5,158,537, the pertinent portions of which are incorporated by reference herein. Assembly  500  comprises electrode assemblies  502 ,  504 , separated by insulating layer  506 . Electrode assemblies  502 ,  504  each have drug and electrolyte reservoirs  508 ,  510  as well as associated electronics  512  and current distribution members  514 ,  514 ′. An adhesive layer  515  is used to hold device  500  to a patient&#39;s skin. 
     Electrotransport assembly  500  has a skin or body proximal side  516  and an exterior or body dital side  518 . Body proximal side  516  has a curved configuration (indicated by arrows  520 ) which enhances the ability of the rigid assembly to adhere to the site of drug delivery as well as be understood. The radius of curvature of body proximal side  516  will be adjusted substantially to match the radius of curvature of the body site on which the device is to be attached. 
     The above-described invention provides a great deal of device design latitude. For example, by utilization of detachable couplers or connectors in conjunction with the flexible connector means, individual device components, or even entire subassemblies may be made detachable. For example, a substantially rigid battery subassembly could be detached from the rest of the electrotransport assembly and replaced when the battery is discharged. Alternatively, a discharged drug source could be detached and replaced (for replenishment) or a different drug (or a different drug concentration) may be substituted. 
     This invention relates primarily to electrotransport devices having inherently rigid structures or zones. In one practice, zones of an electrotransport apparatus are joined by specialized flexural or flexible membrane structures which allow the rigid elements to be oriented in different planes without peeling away from the patient&#39;s skin. This permits the electrotransport device structure as a whole to “bend” or “flex” to conform to cylindrical or even free form geometry, thus maintaining an intimate adhesive contact with the skin. 
     The invention consists of, in the case of an electrotransport system, a multi-layered (electrode/circuit/drug reservoir/salt reservoir, wicking layer, skin adhesive-ion conducting, and electron-conducting assembly adhesive) structure which, because of it novel configuration remains flexible and conformable to preferred mounting site on the human body. There are other applications for this structural configuration which will be obvious to those skilled in this field: Skin-mounted infusion devices, skin-mounted passive transdermal devices, diagnostic devices and monitoring devices that should be attached to the skin. The “other applications” have two things (requirements) in common which make them benefit from this invention: (1) the need to be intimately attached to a significant area of skin and (2) the essentially, rigid nature of their structure, which are not compatible requirements. 
     In this invention, the largest, non-reducible (not able to be broken into sub-modules) element of the system that is structurally rigid and cannot itself be reconfigured to curve-match to the mounting site, can be taken as the standard module size in an array of rigid elements flexibly connected into a conformable, essentially planar structure. In the example of this invention applied to the design of an electrotransport system, the largest rigid element is generally the “button cell” battery. As shown in the Figures, the basic module is drawn around the battery, closely enveloping it but presenting a 50 millimeter cylindrical section surface on one side for attachment to the body on sites as small as the 90th percentile female arm and larger. Other modules of identical size may contain other rigid components smaller than the battery. In the example in FIG. 6, four modules are joined to form the flexible array. 
     FIG. 12 illustrates a test fixture for testing the flexural rigidity of an electrotransport system  10  on the Instron stress-strain testing machine Model No. 1122. The tension load cell  401  of the Instron stress-strain testing machine is attached to device  10  by means of a clamp  403  and a cable  405 , each of which exhibit minimal (i.e., &lt;1%) tensile elasticity (e.g., clamp  403  and cable  405  are composed of a metal such as stainless steel). As shown in FIG. 12 the test apparatus is set up to test the flexural rigidity of flexible hinge  16  which is located between rigid housing  12  and  14 . In this set-up, clamp  403  is clamped onto rigid housing  12  while rigid housing  12  is at rest in a substantially horizontal orientation. Another clamp  407  holds housing  14  substantially along its width and length right up to the flexible hinge  16 . Those skilled in the art will appreciate that the clamp  407  must be custom designed to test a particular system  10 . For example, clamp  407  has an opening  408  in which the rigid housing  14  is held. The angle of the axis of opening  408  is determined by the shape of device  10  when device  10  is in a non-flexed (i.e., rest) condition. Those skilled in the art will also appreciate that clamp  407  will have an opening  408  with an axis at varying angles to the horizontal depending upon the shape of the particular device being tested. For example, if the electrotransport device had a substantially planer configuration (rather than the slightly bent or V-shaped configuration of device  10 ) in a non-flexed rest condition, then the axis of opening  408  would be substantially horizontal. 
     Clamp  407  is securely fastened by conventional means to the moveable cross-head of the Instron stress-strain testing machine. The length (1) of cable  405  is preferably long enough to satisfy the following relation: 
     
       
           l/L≦ 10 
       
     
     wherein L is the moment arm (see FIG. 12) and 1 is the distance from the test device to the load cell  401 , in order to minimize the effect of the horizontal movement of the clamped end of housing  12  as device  10  flexes around hinge  16 . 
     The flexural rigidity of hinge  16  is measured according to the following procedure. First, the cross-head  409  is moved downwardly to take all slack out of cable  405 . Housing  12  should be substantially horizontal at the point where testing is begun. The cross-head  409  is moved downwardly at a cross-head speed of 50 mm/min. causing the rigid housings  12 ,  14  to bend at an angle θ from the rest position, while the Instron testing machine plots the force-deflection curve. The flexural rigidity, which is the product of the Young&#39;s modulus (E) and the moment of inertia (I), is then calculated from the loads and deflection angles measured by the Instron stress-strain testing machine using the following equation:        EI   =       WL   2       2                 θ                              
     where: 
     E=Young&#39;s modulus (or modulus of elasticity); 
     I=moment of inertia; 
     W=the applied load; 
     L=the moment arm; and 
     θ=the angle of deflection 
     Those skilled in the art will readily appreciate how the apparatus illustrated in FIG. 12 may be modified in order to test the flexural rigidity on one of the rigid housing  12 ,  14 . For example in order to test the flexural rigidity of rigid housing  14 , the housing  12  may be removed (e.g., by cutting the system along flexible hinge  16 ). The rigid housing  14  is then placed within a horizontal opening  408  within clamp  407 . A sufficient portion of rigid housing  14  must extend out from clamp  407  in order to enable clamp  403  to be attached hereto. 
     The terms “agent” or “drug” are used extensively herein. As used herein, the expressions “agent” and “drug” are used interchangeably and are intended to have their broadest interpretation as any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial, effect. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, including gastrointestinal and urinary antispasmodics, anticholinergics, antiulceratives, sympathomimetrics, xanthine derivatives, cardiovascular preparations including calcium channel blockers, beta agonists, beta-blockers, antiarrythmics, antihypertensives, ACE inhibitors, benzodiazepine antagonists, diuretics, vasodilators, including general, coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetrics, prostaglandins, proteins, peptides, polypeptides and other macromolecules, psychostimulants, sedatives and tranquilizers. 
     The present invention can be used to iontophoretically deliver the following drugs: α-2b interferon, alfentanyl, amphotericin B, angiopeptin, atenolol, baclofen, beclomethasone, betamethasone, bisphosphonates, bromocriptine, buserelin, buspirone, buprenorphine, calcitonin, ciclopirox olamine, copper, cromolyn sodium, desmopressin, diclofenac diflorasone, diltiazem, dobutamine, dopamine agonists, dopamine agonists, doxazosin, droperidol, enalapril, fentanyl, encainide, flumazenil, G-CSF, GM-CSF, M-CSF, GHRF, GHRH, gonadorelin, goserelin, granisetron, haloperidol, hydrocortisone, indomethacin insulin, insulinotropin, interleukin, isosorbide dinitrate, ketoprofen, ketoprofen, ketorolac, leuprolide, LHRH, lidocaine, lisinopril, LMW heparin, melatonin, methotrexate, metoclopramide, miconazole, midazolam, nafarelin, nicardipine, nifedipene, NMDA antagonists, octreotide, ondansetron, oxybutynin, PGE 1 , piroxicam, pramipexole, prazosin, prednisolone, prostaglandins, ranitidine, ritodrine, scopolamine, seglitide, sufentanil, terbutaline, testosterone, tetracaine, tropisetron, vapreotide, vasopressin, verapamil, warfarin, zacopride, zinc, zotasetron. 
     This invention is also believed to be useful in the iontophoretic delivery. of peptides, polypeptides and other macromolecules typically having a molecular weight of at least about 300 daltons, and typically 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 limitation, LHRH, LHRH analogs such as buserelin, gonadorelin, napharelin and leuprolide, GHRH, GHRF, insulin, insulinotropin, heparin, calcitonin, octreotide, endorphin, TRH, NT-36 (chemical name: N=[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate, etc,), follicle luteoids, αANF, growth factors such as growth factor releasing factor (GFRF), BMSH, TGF-β, somatostatin, atrial natriuretic peptide, bradykinin, somatotropin, platelet-derived growth factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin (ACTH), epidermal growth factor, erythropoietin, epoprostenol (platelet aggregation inhibitor), follicle stimulating hormone, glucagon, hirulogs, hyaluronidase, interferon, insulin-like growth factors, interleukin- 2 , menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmospressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, antidiuretic hormone antagonists, bradykinin antagonists, CD4, ceredase, CSF&#39;s, enkephalins, FAB fragments, IgE. peptide suppressors, IGF-1, neuropeptide Y, neurotrophic factors, opiate peptides, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, pentigetide, protein C, protein S, ramoplanin, renin inhibitors, thymosin alpha-1, thrombolytics, TNF, vaccines, vasopressin antagonist analogs, alpha-1 anti-trypsin (recombinant). 
     Generally speaking, it is most preferable to use a water soluble form of 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 as ionization, dissociation, or dissolution, are within the definition of “agent” or “drug” herein. “Drug” or “agent” is to be understood to include charged and uncharged species as described above. 
     Numerous characteristics and advantages of the invention covered by this document have been set forth in the foregoing description. It will be understood, however, that this disclosure is, in many respects, only illustrative. Changes may be made in details, particularly in matters of shape, size, and arrangement of parts without exceeding the scope of the invention. The invention&#39;s scope is, of course, defined in the language in which the appended claims are expressed.