HK1183979B - In-body power source having high surface area electrode - Google Patents

Description

In-vivo power source with high surface area electrodes

The application is a divisional application of the original Chinese patent application 200880004919.0.

Cross reference to related applications

As per 35u.s.c. § 119(e), this application claims priority on the filing date of U.S. provisional patent application serial No. 60/889,870 filed on 14.2.2007; the disclosure of this application is incorporated herein by reference.

Introduction to

As medical technology advances, many diagnostic and therapeutic activities are being performed with smaller and smaller implantable medical or ingestible medical devices. Implantable and ingestible medical devices may be configured to perform a variety of different functions, including but not limited to: a diagnostic function, for example, wherein the device includes one or more sensors; therapeutic functions, for example, wherein the device enables a therapeutic effect to be achieved, such as delivery of electrical pulses, delivery of pharmaceutically active agents; and so on.

With implantable and ingestible medical and related technologies, there is a continuing desire to make devices smaller, for example, to provide increased ease of use. In order to reduce the size, the individual elements of the device must be designed with reduced overall physical dimensions and yet remain functional.

One type of component found in many implantable and ingestible devices is a power source, e.g., a battery, a capacitor, etc. There is a continuing interest in the development of smaller and smaller power sources that have sufficient and reliable functionality so that they can be used in vivo devices such as implantable and ingestible devices.

Disclosure of Invention

A power source is provided to enable in vivo devices, such as implantable and ingestible devices. Aspects of the in-vivo power source of the invention include a solid support, a first high surface area electrode, and a second electrode. Embodiments of the internal power source are configured to emit a detectable signal when in contact with the target physiological site. Methods of making and using the power supply of the present invention are also provided.

Drawings

Fig. 1 illustrates one embodiment of a battery having a porous cathode bottom layer according to one embodiment of the present invention.

Fig. 2 provides details of some implementations of electronic circuitry of various embodiments of the present invention.

Detailed Description

A power source is provided to enable an in vivo device, such as an implantable or ingestible device. Aspects of the in-vivo power source of the invention include a solid support, a first high surface area electrode, and a second electrode. Embodiments of the internal power source are configured to emit a detectable signal when in contact with the target physiological site. Methods of making and using the power supply of the present invention are also provided.

In describing the present invention in further detail, reference is first made to embodiments of an in-vivo power source and an in-vivo device including the in-vivo power source, followed by a discussion of systems having devices including in-vivo power sources and methods of using such devices and systems. Also reviewed in more detail below is a kit (kit) comprising a device having an in-vivo power source of the present invention.

In-body power source and device including the same

As summarized above, the present invention provides a power source configured for in-vivo devices. An in-vivo device is a device configured for use within a living body. Examples of in vivo devices include, but are not limited to: implantable devices, e.g., implantable therapeutic devices, implantable diagnostic devices, e.g., sensors, etc.; and ingestible devices, e.g., ingestible event markers (eventharkers) (e.g., as described in more detail below), and the like.

An in-body power supply according to an embodiment of the present invention includes: a solid support; a first high surface electrode present on a surface of the solid support; and a second electrode. The solid support may vary depending on the nature of the device in which the in vivo power source is utilized. In certain embodiments, the solid support is small, e.g., wherein it is sized to have a width ranging from about 0.01mm to about 100mm, e.g., from about 0.1mm to about 20mm, including from about 0.5mm to about 2 mm; a length ranging from about 0.01mm to about 100mm, for example, from about 0.1mm to about 20mm, including a range from about 0.5mm to about 2mm, and a height ranging from about 0.01mm to about 10mm, for example, from about 0.05mm to about 2mm, including from about 0.1mm to about 0.5 mm. The solid support element can take a variety of different configurations, such as, but not limited to: a slice configuration, a cylindrical configuration, a spherical configuration, a disk configuration, and the like, wherein the particular configuration may be selected based on the intended application, method of manufacture, and the like. Although the material used to fabricate the solid support may vary significantly with the particular device for which the in-vivo power source is configured, in certain embodiments the solid support is constructed of a semiconductor material, such as silicon. In preparation for the production of the porous underlayer, for example, as explained below, portions of the surface of the solid support may comprise an electrically conductive material, e.g., a metal or metal alloy, such as, but not limited to, gold and the like.

In certain embodiments, the solid support is a semiconductor support comprising one or more circuit elements, wherein in certain embodiments the support is an integrated circuit. When present, an integrated circuit includes many different functional blocks, i.e., modules. Within a given solid support, at least some (e.g., two or more, up to and including all) of the functional blocks, such as power supplies, processors, transmitters, etc., may be present in a single integrated circuit. By a single integrated circuit is meant a single circuit structure comprising all the different desired functional blocks for the device. In these embodiments, the integrated circuit is a monolithic integrated circuit (also known as an IC, microcircuit, microchip, silicon chip, computer chip or chip) that is a miniaturized electronic circuit (which may include semiconductor devices, as well as passive components) fabricated in the surface of a thin substrate of semiconductor material. The integrated circuits of some embodiments of the present invention may be hybrid integrated circuits, which are miniaturized electronic circuits composed of individual semiconductor devices and passive components bonded to a substrate or circuit board.

As mentioned above, one type of in-vivo device in which the power source of the present invention finds use is an ingestible event marker. For ease of illustration, the in-body power source will now be further described in terms of embodiments in which the in-body power source is part of an identifier of an ingestible event marker. However, as noted above, the in-body power source of the present invention finds use in devices other than ingestible event markers, and thus the in-body power source of the present invention is not limited to those configured for Ingestible Event Markers (IEMs).

The identifier of the IEM composition (composition) is one that produces a detectable signal when the identifier is in contact with the target physiological site. The identifiers of the present compositions may vary with the particular embodiment and intended application of the compositions so long as they are activated (i.e., turned on) when in contact with the target physiological site (e.g., stomach). As such, the identifier may be one that emits a signal when it contacts a target (i.e., physiological) site. The identifier may be any element or device capable of providing a detectable signal upon activation (e.g., upon contact with a target site). In certain embodiments, the signal is emitted upon contact of the composition with a physiological target site (e.g., stomach) identifier. According to embodiments, the target physiological site or location may vary, wherein representative target physiological sites of interest include, but are not limited to: in locations in the gastrointestinal tract such as the mouth, esophagus, stomach, small intestine, large intestine, etc. In certain embodiments, the identifier is configured to be activated when in contact with fluid in the target site (regardless of the specific composition of the target site).

Depending on the needs of a particular application, the signal obtained from the identifier may be a generic signal, e.g., a signal that merely identifies that the composition has contacted the target site, or a unique signal, e.g., a signal that somehow uniquely identifies that a particular ingestible event marker in a set or plurality of different markers in a batch has contacted the target physiological site. As such, the identifier may be one that, when used with a batch of unit doses (e.g., a batch of tablets), emits a signal that is indistinguishable from the signal emitted by the identifier of any other unit dose member in the batch. In other embodiments, the identifier emits a signal that uniquely identifies that particular identifier. Thus, in some embodiments the identifiers emit unique signals that distinguish one type of identifier from another type of identifier. In some embodiments, the identifier emits a unique signal that distinguishes that identifier from other identifiers. In certain embodiments, the identifier emits a signal that is unique, i.e., distinguishable from the signal emitted by any other identifier once generated, where such a signal may be considered a generally unique signal (e.g., similar to a human fingerprint, which is different from any other fingerprint of any other individual, and thus uniquely identifies an individual based on a general level). In one embodiment, the signal may directly convey information about a given event, or provide an identifier that may be used to retrieve information about the event from a database (i.e., a database linking identifiers and components).

The identifier may generate a number of different types of signals, including but not limited to: RF signals, magnetic signals, conducted (near-field) signals, acoustic signals, and the like. Of interest in certain embodiments are the specific signals described in the in-approval PCT application Ser. No. PCT/US2006/16370 filed on 28.4.2006; the disclosure of various types of signals in this application are specifically incorporated herein by reference. The transfer time of the identifier can vary, wherein in certain embodiments the transfer time can range from about 0.1 μ sec to about 48 hours or more, for example, from about 0.1 μ sec to about 24 hours or more, such as from about 0.1 μ sec to about 4 hours or more, such as from about 1 sec to about 4 hours, including from about 1 minute to about 10 minutes. Depending on the given embodiment, the identifier may send the signal once or twice or more so that the signal may be considered a redundant signal.

The identifiers of the present compositions may vary with the particular embodiment and intended application of the composition, so long as they are activated (i.e., turned on) when in contact with the target physiological site (e.g., stomach). As such, the identifier may be one that emits a signal when it contacts a target (i.e., physiological) site. Additionally or alternatively, the identifier may be one that emits a signal when interrogated after it has been activated. The identifier element of an embodiment of the present invention has: (a) an activation element; and (b) a signal generating element, wherein the signal generating element is activated by the activation element to generate the identification signal (e.g., as explained above).

An activation element is an element that activates the signal generating element of the identifier to provide a signal (e.g., by transmission or when interrogated) upon contact of the composition with a target physiological site of interest, such as the stomach or the like. As reviewed in pending PCT application Serial No. PCT/US2006/016370, activation of the recognizer can be accomplished in a number of different ways, including, but not limited to: battery completion, battery connection, and the like. The various activation means disclosed in this co-pending application may be readily adapted to provide activation as described herein, and as such, their entirety is incorporated herein by reference.

Embodiments of the activation element based on a battery completion format use the in-vivo battery source of the present invention, wherein the in-vivo battery source comprises a cathode, an anode, and an electrolyte when activated. In such embodiments, when the cathode and anode are contacted by gastric fluid, the gastric fluid acts as the electrolyte portion of the cell, thereby allowing the added gastric fluid portion to complete the cell.

In certain embodiments, the battery used is one that includes two different electrochemical materials that make up the two electrodes of the battery, e.g., the anode and the cathode. When the electrode material is contacted with a body fluid such as stomach acid or other type of fluid (either alone or in combination with a dried conductive medium precursor), a potential difference, i.e., a voltage, is generated between the electrodes as a result of the respective oxidation and reduction reactions occurring at the two electrodes (resulting in a voltaic cell or battery). Thus, in embodiments of the present invention, the in-vivo power source is configured such that a voltage is generated when two different materials are exposed to a target site (e.g., stomach, alimentary tract, etc.). The two different materials in the electrolyte are at different potentials. In some of these embodiments, the in-vivo battery power source may be considered a power source that utilizes electrochemical reactions in ionic solutions such as gastric fluid, blood or other body fluids, and certain tissues.

The different materials from which the electrodes are constructed may be made of any two materials that are appropriate to the environment in which the identifier will operate. The active material is any pair of materials having different electrochemical potentials. For example, in certain embodiments in which the ionic solution includes stomach acid, the electrodes may be made of noble metals (e.g., gold, silver, platinum, palladium, or the like) so that they do not corrode prematurely. Alternatively, the electrodes may be made of aluminium or any other electrically conductive material whose lifetime in the applicable ionic solution is long enough to enable the identifier to perform its intended function. Suitable materials are not limited to metals, and in certain embodiments the pair of materials is selected from metals and non-metals, such as a pair consisting of a metal (e.g., Mg) and a salt (e.g., CuI). As for the active electrode material, any pair of substances (metal, salt, or addition type compound) having suitably different electrochemical potentials (voltages) and low interfacial resistances is suitable.

A variety of different materials may be used as battery electrodes. In certain embodiments, the electrode material is selected to provide a voltage sufficient to drive the signal generating element of the identifier when in contact with the target physiological site (e.g., the stomach). In certain embodiments, the voltage provided by the electrode material when the metal of the power source is in contact with the target physiological site is 0.001V or more, including 0.01V or more, such as 0.1V or more, for example, 0.3V or more, including 0.5 volts or more, and including 1.0 volts or more, wherein in certain embodiments the voltage ranges from about 0.001 to about 10 volts, such as from about 0.01 to about 10V.

Materials and pairs of interest include, but are not limited to, those disclosed in table 1 below.

And (3) protecting the anode: certain high energy anode materials such as Li, Na, and other alkali metals are unstable in their pure form in the presence of water or oxygen. However if stabilized these can be used in aqueous environments. An example of this stabilization is the so-called "protected lithium anode" developed by Polyplus corporation (berkeley, CA), where a polymer film is deposited onto the surface of the lithium metal to protect it from rapid oxidation and allow its use in an aqueous or air environment. (Polyplus has IP under examination for this).

Dissolved oxygen may also serve as the cathode. In this case, dissolved oxygen in the body fluid will be reduced to OH on a suitable catalytic surface such as Pt or gold^-. Also of interest is the hydrogen dissolved in the hydrogen reduction reaction.

In certain embodiments, one or both of the metals may be doped with a non-metal, for example, to increase the voltage output of the cell. Non-metals that may be used as dopants in certain embodiments include, but are not limited to: sulfur, iodine, and the like.

In certain embodiments, the electrode material is copper iodide (CuI) or copper chloride (CuCl) as the cathode and magnesium (Mg) metal or magnesium alloy as the anode. Embodiments of the present invention use electrode materials that are harmless to the human body.

As outlined above, the in-body power source of the present invention, e.g., a battery comprising electrodes of two different materials (as reviewed immediately above), comprises at least one high surface area electrode, e.g., a high surface area cathode and/or a high surface area anode. By high surface area electrode is meant an electrode having a surface area that is about 2 times or more, such as about 10 times or more, the surface area of the solid support covered by the electrode in a power source (e.g., a battery). In certain embodiments, the surface area of the electrodes ranges from about0.01mm²To about 100mm²E.g. from about 0.1mm²To about 50mm²And comprises from about 1mm²To about 10mm². In certain embodiments, a high surface area electrode is obtained by having an electrode composed of active electrode material (e.g., where illustrative active cathode and anode are provided above) present on a porous substrate. In certain embodiments, all of the electrodes are high surface area electrodes, while in other embodiments only some of the electrodes (e.g., one of the electrodes) are high surface area electrodes.

According to particular embodiments, the cathode and anode may be present on the same carrier or different carriers, e.g., where two or more different carriers are joined together to create a battery structure, e.g., as is present in a "flip-chip" embodiment. Similarly, the number of cathodes and anodes in a given cell may vary widely from embodiment to embodiment, for example, a given embodiment in this embodiment may include a single cell with one anode and cathode, a single cell with multiple anodes and/or cathodes, or two or more separate cells each comprised of one or more cathodes and/or anodes. Battery configurations of interest include, but are not limited to: PCT application serial number PCT/US2006/16370 filed on 28 th.2006 and named "pharmaco-informatics system", PCT application serial number PCT/US2007/022257 filed on 17 th.10 th.2007 and named "in vivo low-pressure oscillator for medical device", PCT application serial number PCT/US2007/82563 filed on 25 th.10 th.2007 and named "controllably activatable ingestible identifier", US patent application serial number 11/776,480 filed on 11 th.7 th.2007 and named "acoustics-pharmaco-informatics system", and those disclosed in PCT/US2008/52845 filed on 1 st 2 th.2008 and named "ingestible event marker system"; the disclosures of these applications (and in particular the battery configurations disclosed herein) are incorporated herein by reference.

Fig. 1 provides a schematic diagram of a battery power source including a high surface area electrode, and in particular a high surface area cathode, according to an embodiment of the invention. The battery 100 shown in fig. 1 includes a solid support 120 having an upper surface 140. Present on the upper surface 140 are a cathode 160 and an anode 180. Cathode 160 includes a porous underlayer 150 and an active cathode material 170. Each of these elements is now described in more detail below. Although the embodiment is described in which the cathode includes a porous underlayer, in some embodiments the anode includes a porous underlayer, and in still other embodiments both the cathode and the anode have porous underlayers. Both the cathode and the anode are present on the surface of the solid support. In certain embodiments, such as that shown in fig. 1, both electrodes are present on the same surface of the solid support. In other embodiments, the two electrodes may be present on different surfaces of the carrier, e.g. opposite surfaces of the carrier.

The porous bottom layer 150 is a layer that mechanically supports the active electrode (e.g., cathode) material 170, improves adhesion, and/or increases the surface area of the electrode, and provides a current path between the cathode material and the elements (e.g., circuitry) present on the solid support 120 (described in more detail below). The porous underlayer may be made of a number of different materials, such as electrically conductive materials, e.g., copper, titanium, aluminum, graphite, gold, platinum, iridium, etc., where the material may be a pure material or a material composed of two or more elements, such as found in alloys and the like. With respect to the cathode, materials of interest for the cathode porous underlayer include, but are not limited to: au, Cu, Pt, Ir, Pd, Rh, Ru, and binary and ternary alloys thereof. With respect to the anode, materials of interest for the anode porous underlayer include, but are not limited to: ti and alloys thereof (e.g., Ti-W, Ti-Cr, TiN), W, W-C, and the like. The thickness of the underlayer can vary, with thicknesses ranging from about 0.01 to about 100 μm, such as from about 0.05 to about 50 μm and including from about 0.01 to about 10 μm in certain embodiments. The dimensions of the porous underlayer with respect to length and width on the surface of the solid support may or may not be coextensive with the same dimensions of the active cathode material, as desired.

As outlined above, the bottom layer may be rough or porous. The porosity or roughness of the underlayer can vary so long as it gives the electrode (e.g., cathode) the desired surface area. In certain embodiments, the porosity or roughness of the underlayer is selected to provide an effective surface area enhancement of about 1.5 times or more to about 1000 times or more, e.g., from about 2 to about 100 times or more, e.g., from about 2 to about 10 times or more, the surface area obtainable from a comparable electrode without a porous underlayer. The surface area enhancement can be determined by comparing the electrochemical capacitance or cyclic voltammogram of a rough or porous electrode with that of a smooth electrode of the same material. Roughness may also be determined by other techniques, such as Atomic Force Microscopy (AFM), electron microscopy, electrochemical impedance spectroscopy, or Brunauer-Emmett-Teller (BET) analysis.

The porous cathode bottom layer may be fabricated using any convenient protocol. In certain embodiments, a flat finishing protocol is used. Planar processing techniques such as micro-electromechanical systems (MEMS) fabrication techniques, including surface micromachining and bulk micromachining techniques, may be used. Deposition techniques that may be used in some embodiments of fabricating the structure include, but are not limited to: electrodeposition (e.g., electroplating), cathodic arc deposition, plasma spraying, sputtering, electron beam evaporation, physical vapor deposition, chemical vapor deposition, plasma enhanced chemical vapor deposition, and the like. Material removal techniques include, but are not limited to: reactive ion etching, anisotropic chemical etching, isotropic chemical etching, planarization (depositing metal and then dissolving selected areas to make it rough and porous), for example, by chemical mechanical polishing, laser ablation, Electrical Discharge Machining (EDM), electrolytic dissolution/electropolishing, and the like. Another protocol of interest is electroless plating as a deposition method. In these deposition protocols, metal is deposited from solution by a reducing agent. The deposited metal layer may be used to coat an already existing rough non-conductive/weakly conductive surface layer or particles (e.g. carbon, alumina, polymers, zeolites, silica, amorphous carbon, nanotubes, etc.). The non-conductive layer may be deposited by any suitable planar processing method, such as cathodic arc, electrophoretic deposition, or paste/glue containing particles, among others. Also of interest are photolithography protocols. Of interest in certain embodiments is the use of planar processing protocols in which structures are built up or removed from a surface or surfaces of an initially planar substrate using a number of different material removal and deposition protocols applied to the substrate in a sequential manner. Illustrative manufacturing methods of interest are described in more detail in co-pending PCT application Ser. No. PCT/US 2006/016370; the disclosure of which is incorporated herein by reference.

For porous underlayers, the electrodeposition protocol is used in certain embodiments. In the case where the porous cathode bottom layer includes a metal, electroplating (electrodeposition of the metal) may be used. In certain embodiments, the electroplating protocol used is one in which the current density and/or agitation of the solution is selected so as to impart a desired roughness or porosity to the deposited porous cathode underlayer. In certain embodiments, metal (e.g., copper) films are deposited in electroplating baths at the mass transfer limit. The phrase "mass transfer limit" means that the current density is optimized based on the concentration of metal ions in the bath and the flow rate of the bath so that deposition occurs at the substantially maximum limit at which metal ions can reach the surface. Deposition at the mass transfer limit produces dendritic shapes of the deposited material in certain embodiments. The current density may vary depending on the particular metal and its ionic concentration. In certain embodiments, the selected current density ranges from about 5 to about 2000 milliamps/cm²(mAmps/cm²) E.g., from about 50 to about 400mAmps/cm²E.g., about 200mAmps/cm². The plating (Plate up) can be carried out in a suitable plating bath, for example a stirred plating bath, a stirred paddle bath or a fountain bath. The fluid flow rate (fluid flow) may be selected in combination with the applied current density to obtain the desired porosity or roughness. In a plating bath having a rotary agitator, the agitation rate may be between about 0 and about 200rpm, such as between about 50 and about 500 rpm. With respect to metal ion concentration, relatively low metal ion concentrations may be used to obtain rough deposition at lower current densities and relatively high ion concentrations may be used to obtain rough deposition at higher current densities. In some embodiments of the present invention, the,the metal ion concentration ranges from 0.001mol/L to 4mol/L, for example from 0.05mol/L to 1 mol/L. The flow rate used during deposition also affects the properties of the deposited film. Lower current densities may use lower flow rates.

Where desired, various additives may be included in the electroplating bath to enhance the desired porosity. Additives that may be included in the solution include, but are not limited to: organic acids, e.g., acetic acid, citric acid, e.g., polymers, e.g., PEG, and the like. The plating solution may also include alcohols (e.g., ethanol), amines, and thiols (e.g., thiourea). Typical copper plating bath compositions (e.g., acidic, e.g., sulfuric/copper sulfate, and basic, e.g., pyrophosphate or chromate solutions) may also be used. In the case of polymer addition, the polymer may be a linear or branched water soluble polymer, such as a poly (alkylene glycol), for example poly (ethylene glycol) (PEG). Other related polymers are also suitable for use in the practice of the present invention and the use of the term PEG or poly (ethylene glycol) is meant to be inclusive and not exclusive in this respect. In certain embodiments, the polymer has from 2 to about 300 ends. In certain embodiments, the polymer is transparent, colorless, odorless, water soluble, thermally stable, inert to many chemical agents, does not hydrolyze or deteriorate, and is non-toxic. In certain embodiments, the polymer is biocompatible, which is to say that the polymer is capable of co-existing with living tissue or organs without causing harm. In certain embodiments, the polymer is non-immunogenic, which is to say that the polymer does not produce an immune response in vivo. In certain embodiments, the polymer is of the formula Ra- (CH)₂CH₂O)m-CH₂CH₂PEG of (A), wherein m is from about 3 to about 4000, or from about 3 to about 2000, and Ra is hydrogen, -OH, CH₃-O-、CH₂CH₂-O-or CH₃CH₂CH₂-O-. The polymers may be linear or branched. In certain embodiments, the branched polymer has a central branched core portion and a plurality of linear polymer chains bonded to the central branched core. PEG includes branched formsBranched PEG may be represented in general form as Rb (-PEG-OH) n, where Rb represents a core moiety such as glycerol or pentaerythritol, and n represents the number of arms and is from 2 to 300. in certain embodiments, PM is PEG of linear or branched type suitable polymers that may be used include, but are not limited to, poly (alkylene glycols), such as poly (ethylene glycol) (PEG) and poly (propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, and the like, poly (ethoxypolyol), poly (enol), poly (vinyl pyrrolidone), poly (hydroxypropyl methacrylamide), poly (α -hydroxy acid), poly (vinyl alcohol), polyphosphazene, polyoxazoline, and copolymers, terpolymers, derivatives, and mixtures thereof the molecular weight of each chain of the polymer may range from about 100Da to about 100,000Da, or from about 6,000Da to about 80,000 Da. suitable polymers including copolymers, terpolymers, derivatives, and mixtures thereof including those commercially available from PEG 400, 2000, and any desired PEG-containing molecular weight, such as PEG, e.g., PEG-100, 2000, and PEG derivatives thereof, including those commercially available in the trade.

Additives of interest include, but are not limited to: accelerators, inhibitors, humectants, levelers, and bath stabilizers. Promoters of interest include, but are not limited to: thiols, such as thiourea and 3-sulfopropyl disulfide, where the promoter of interest accelerates the metal (e.g., copper) deposition rate by itself or in combination with other additives. In certain embodiments, the promoter additive is present at a concentration ranging from 1ppB to 1000ppm, for example 10ppB to 500 ppm. In certain embodiments, the concentration of the additive is used in conjunction with a flow rate that provides dendritic nodules that grow at a substantially exponential rate, e.g., where the ends of a branch are present in a relatively promoter-rich environment and the ends of an opposing branch near the surface are present in a relatively promoter-poor environment. In some of these embodiments, the flow rate is set to have a diffusion layer thickness that provides this type of growth where the diffusion layer thickness can range from 0.01 to 500 μm, e.g., 1 to 100 μm.

In certain embodiments, the accelerating additive is used in combination with the inhibiting additive. Inhibiting additives of interest are compounds that physically block the surface of the metal, where such additives include, but are not limited to: polyethylene glycol, amino compounds and organic compounds. By physically obstructing the surface of the solid support, growth at the distal end of the surface of the deposited structure may be enhanced relative to growth at the proximal end of the surface.

In these embodiments, some concentration and type of accelerating additive that negates the effect of the inhibiting additive may be used, with the accelerator dislodging the inhibitor. In certain of these embodiments, a solution having an inhibiting additive and an accelerating additive is used, wherein the concentration of the inhibiting additive is mass transfer limited. Any portion of the solution that achieves a little bit of movement of the nodules will enter a region of higher concentration of the accelerator and will then undergo exponential growth to provide the desired amount of roughness. In these embodiments, the area near the surface is heavily inhibited by the inhibitor. The portion of the growing nodule that sticks into solution is contacted with an accelerant that can come in to drive out the inhibitor and provide the desired dendritic pattern or nodule.

An alternative to using an inhibitor (e.g., as explained above) is to use a protocol that includes a co-evolution of gases, where blocking bubbles are created at the surface of the solid support during deposition. In these examples, deposition conditions are selected that generate a gas (e.g., hydrogen gas) at the surface of the solid support on which the metal is deposited. Where desired, the size of the bubbles generated in these procedures may be adjusted by using surface tension agents, such as acetic acid, polyethylene glycol, or other agents that control wetting properties, in a manner that provides bubbles of the desired size. Relatively less wetting agent may be used to provide larger, e.g., micron-sized pores, while relatively more wetting agent may be used for smaller-sized pores.

The gas co-evolution protocol may be used with a suitable promoter in a manner similar to that described above with respect to the inhibitor, as both methods physically block the surface of the solid support and the presence of the promoter may be used to enhance growth at the distal end of the surface of the deposited structure. Thus, where the metal (e.g. copper) will be preferentially plated with the accelerating species as the current passes to the entire surface of the solid support, as opposed to regions, e.g. valleys between deposited structures, where there is no accelerating species, e.g. due to the presence of physical pinning agents, e.g. bubbles or inhibiting species, etc.

In another embodiment, a self-assembled monolayer or electro-implanted layer may be used, which is an organic, diazo-containing species that can actually be covalently bonded to the surface of a solid support. In a similar manner to the bubbles and suppressors described above, such deposition species may also physically block the surface to adjust the shape of the plated structure and provide a desired porous structure. By controlling the concentration of the core (nucleoli) of the electro-grafted layer or the density of the self-assembled monolayer, one can tailor the properties of the deposited metal structure. In certain embodiments, these protocols are used in cases where a metal different from the solid support is being deposited on the solid support. In certain embodiments, a masking approach is used to further tune the properties of the deposited structures on the surface of the solid support.

In other embodiments, a cathodic arc deposition protocol is used to produce the desired porous cathode underlayer. In such a protocol, a cathodic arc generates a plasma of metal ions in contact with the surface of the substrate under conditions sufficient to produce the desired structure of the porous cathode underlayer, e.g., as explained above. The ion plasma beam of metal ions generated by cathodic arc may be generated using any convenient protocol. In creating an ion beam using a cathodic arc protocol, an arc of sufficient power is created between a cathode and one or more anodes so as to create an ion beam of cathode material ions. The seed metal layer is created from at least one, but typically two or more conformal metal underlayers prior to deposition of the cathodic arc metal. These underlayers start with a thin adhesion layer comprising a metal including, but not limited to, TiN, Ti, W, Cr or alloys of these metals. This first metal layer improves adhesion of the thicker cathodic arc metals and may be sealed with noble metals including, but not limited to, Au, Pt, Ag, Cu, Pt, Ir, Pd, Rh, or Ru or alloys of these metals. A protective metal (cap metal) chemically seals the adhesion metal and is selected to also adhere well to thicker metal deposited with the cathodic arc process. Cathodic arc can be performed under a variety of conditions including, but not limited to, relatively high pressure inert gas (gas can be Ar, Ne, He, Xe or a simple mixture of these; pressure can range from over 50mT up to 1000mT) and neutral (unbiased) targets. In the case of higher pressure and neutral targets, this suppresses small ionized metal particles at the target surface during film growth in favor of larger macroscopic particles, producing films that can have peak-to-peak roughness values ranging from 0.2 to 10 times the average deposited film thickness. The grown films may be as thin as 0.25 μm and up to 25 μm, and in certain embodiments in the range of 3 to 10 μm thick, before they reach the roughness desired for the underlying electrode structure. Other convenient procedures for creating structures by cathodic arc deposition may be used, where procedures known in the art to which the present invention may be applicable include, but are not limited to: in U.S. patent nos. 6,929,727; 6,821,399, respectively; 6,770,178, respectively; 6,702,931, respectively; 6,663,755, respectively; 6,645,354, respectively; 6,608,432, respectively; 6,602,390, respectively; 6,548,817, respectively; 6,465,793, respectively; 6,465,780, respectively; 6,436,254, respectively; 6,409,898, respectively; 6,331,332, respectively; 6,319,369, respectively; 6,261,421, respectively; 6,224,726, respectively; 6,036,828, respectively; 6,031,239, respectively; 6,027,619, respectively; 6,026,763, respectively; 6,009,829, respectively; 5,972,185, respectively; 5,932,078, respectively; 5,902,462, respectively; 5,895,559, respectively; 5,518,597, respectively; 5,468,363, respectively; 5,401,543; 5,317,235, respectively; 5,282,944, respectively; 5,279,723, respectively; 5,269,896, respectively; 5,126,030, respectively; 4,936,960, respectively; and published U.S. application numbers: 20050249983, respectively; 20050189218, respectively; 20050181238, respectively; 20040168637, respectively; 20040103845, respectively; 20040055538, respectively; 20040026242, respectively; 20030209424, respectively; 20020144893, respectively; 20020140334 and 20020139662; the disclosures of which are incorporated herein by reference. These protocols are of interest in the deposition of a variety of different materials (e.g., copper, titanium, aluminum, etc.). Additional cathodic arc protocols and resulting structures include, but are not limited to: those described in published PCT application No. WO2007/149546 entitled "implantable therapeutic device comprising a cathodic arc fabricated structure," the disclosure of which is incorporated herein by reference.

In other embodiments, an electrophoretic deposition protocol may be used. Electrophoretic deposition (EPD) is a term used for a wide range of industrial processes and includes electrocoating, or electrocoating. In EPD, colloidal particles suspended in a liquid medium migrate (electrophoresis) under the influence of an electric field and deposit on a conductive surface. All colloidal particles that can be used to form stable suspensions and that can transport charges can be used for electrophoretic deposition. This includes material classes such as polymers, pigments, dyes, ceramics and metals. For example, where the material deposited is graphite, a suspension of graphite particles may be produced, wherein a surfactant may be included in the suspension to impart the desired charge to the graphite particles. The size for the graphite particles may vary, and in certain embodiments may range from about 0.1 to about 100 μm, such as from about 0.1 to about 2 μm. Any convenient surfactant capable of imparting the desired charge to the graphite particles in suspension may be included, including ionic and non-ionic surfactants. An electric field may then be applied to the suspension, wherein the applied electric field is sufficient to cause the graphite particles to migrate to the surface of the support and deposit into the form of the desired porous underlayer.

In other embodiments, the solid support surface is electrochemically modified, e.g., by electrochemical dissolution, wherein portions of the surface are selectively removed to provide the desired porous structure. For example, an anodic potential may be applied to the metal surface to dissolve the metal surface. Such methods may be used in conjunction with patterning photoresist layers and/or with additives to produce a desired pattern of roughness or nodules on the surface. In some of these embodiments, the metal layer is deposited first, for example by any convenient deposition protocol. Next, additives and/or a mask (e.g., photoresist) are used to selectively dissolve certain areas of the surface and roughen the surface.

In certain embodiments, a metal co-deposition and dissolution method is used. In these embodiments, two metals are deposited simultaneously, e.g., by cathodic arc, evaporation, sputtering, etc., to produce a composite layer, where the metals are (1) inert electrode metals, e.g., Pt, PtIr, Ir, Au, or Cu, etc., and (2) highly oxidizable and soluble metals, e.g., Mg, Zn, Li. The final deposited layer is composite, consisting of mostly metal 1 but with isolated domains (domains) of metal 2. The layer is then immersed in an electrolytic solution, for example, a solvent such as water or an organic acid (e.g., sulfuric acid, nitric acid, hydrochloric acid, or the like), a base (e.g., NaOH, aluminum etchant, or the like), a neutral salt (e.g., NaCl, KCl, CuSO4, magnesium, lithium, zinc salt), or an organic additive and a surfactant (e.g., polyethylene glycol, or the like). When immersed, metal 2 dissolves away, leaving a thin film of metal 1 including pores. The pore size will be the size of the particles of metal 2. In certain embodiments, for example where it is not desired to leave any metal 2 within the film, the deposition conditions for the second metal (deposition current, filtration, cathode temperature, etc.) are set to produce particles similar to the overall desired film thickness. The first metal particles may be selected to be smaller and denser than those of the second metal. Cathodic arc is particularly suitable for composite thin film deposition because it allows the deposition of particles having a controlled particle size. The dissolution step may be performed with an applied current (anodic dissolution) or it may be done without an applied current, in which case it is the result of a chemical reaction between metal 2 and the solution constituents and/or galvanic coupling between metal 1 and metal 2 forcing corrosion of metal 2. The above method may also be applied to non-metallic rough thin films, for example, any pair of materials deposited by cathodic arc, where one of them may be selectively dissolved or etched away to leave a porous layer. Also, the above method is not limited to two metals, i.e., 2 or more metals (or alloys) may be included in the composite film.

On top of the porous bottom layer is an active electrode (e.g., cathode) material. As reviewed above, the active electrode material can include a variety of different materials. Where the electrode is a cathode, in certain embodiments the cathode material comprises copper, with particular interest in certain embodiments being copper iodide (CuI) or copper chloride (CuCl) as the cathode material. Where desired, for example, for increasing the voltage of the cell, the active material may be doped with an additive element, such as sulfur, and the like.

The active cathode material may be provided onto the porous underlayer using any convenient protocol. In certain embodiments, a deposition protocol, such as electrodeposition or the like, such as electroplating, or evaporation, such as chemical vapor deposition, is used.

Also present in the cell is at least one anode. As reviewed above, the anode material can include a variety of different materials. In certain embodiments, the anode material comprises magnesium (Mg) metal or magnesium alloy. The active anode material may be provided onto the porous underlayer using any convenient protocol. In certain embodiments, a deposition protocol, such as electrodeposition or the like, such as electroplating, or evaporation, such as chemical vapor deposition, is used.

As recalled above, in certain embodiments, the solid support 120 is a circuit supporting element. The circuit-supporting elements may take any convenient configuration and, in some embodiments, are Integrated Circuit (IC) chips. The surface on which the electrode elements are placed may be a top surface, a bottom surface, or some other surface, such as a side surface (as desired), wherein in some embodiments the surface on which the electrode elements are at least partially present is the top surface of the IC chip.

The identifier of the present invention includes a signal generating element in addition to the battery element of the identifier described above. The signal generating element of the identifier element is a structure which emits a detectable signal when activated with the activation element, which signal may for example be a signal that can be received by a receiver, for example, as explained in more detail below. The signal generating element of some embodiments may be any convenient device capable of generating a detectable signal and/or adjusting the converted broadcast power when activated by an activation element. Detectable signals of interest include, but are not limited to: conductive signals, acoustic signals, and the like. As reviewed above, the signal emitted by the signal generator may be a generic or unique signal, with representative types of signals of interest including, but not limited to: frequency shifting the encoded signal; an amplitude modulated signal; frequency modulation signals; and so on.

In some embodiments, the signal generating element comprises circuitry that generates or generates a signal, as described in more detail below. The type of circuit selected may depend at least in part on the drive power supplied by the power supply of the identifier. For example, in the case where the driving power is 1.2 volts or more, a standard CMOS circuit may be used. In other embodiments where the drive power ranges from about 0.7 to about 1.2V, a sub-threshold circuit design may be used. For drive powers of about 0.7V or less, a zero threshold transistor design may be used.

In some embodiments, the signal generating element includes a Voltage Controlled Oscillator (VCO) that generates a digital clock signal in response to activation by the activation element. The VCO may be controlled with digital circuitry, which is assigned an address and which may control the VCO with a control voltage. This digital control circuit may be embedded on a chip comprising the activation element and the oscillator. The identification signal is transmitted using amplitude modulation or phase shift keying to encode the address.

The signal generating element may comprise a different transmitter element which serves to transmit the generated signal to a remote receiver, which may be internal or external to the patient, as will be recalled in more detail below. The transmitter elements, when present, may take many different configurations, depending, for example, on the type of signal being generated and to be transmitted. In certain embodiments, the transmitter element is comprised of one or more electrodes. In some embodiments, the transmitter element is formed by one or more wires, for example in the form of an antenna. In certain embodiments, the transmitter element is comprised of one or more coils. As such, the signal transmitter may include a variety of different transmitters, such as electrodes, an antenna (e.g., in the form of a wire) coil, and so forth. In some embodiments, the signal is sent through one or two electrodes or through one or two wires. The two-electrode transmitter is a dipole antenna (dipole); the transmitter of one electrode forms a monopole antenna. In some embodiments, the transmitter requires only one diode power drop. In some embodiments, the transmitter unit uses an electric dipole antenna or an electric monopole antenna to transmit signals.

Fig. 2 shows details of one implementation of an electronic circuit that may be used for the identifier according to the invention. On the left are two battery electrodes, metal 1 and metal 2(32 and 33). These metals, when in contact with the electrolyte (produced when in fluid contact with the target site either alone or in combination with a dried conductive medium precursor, as reviewed above), form a battery that provides power to the oscillator 61, in this case as shown schematically. Metal 132 provides a low voltage (ground) to oscillator 61. Metal 233 provides high voltage (V) to oscillator 61_high). When the oscillator 61 starts to operate, it generates a clock signal 62 and an inverted clock signal 63, which are opposite to each other. These two clock signals enter a counter 64 which simply counts the number of clock cycles and stores the count in a number of registers. In the example shown here, an 8-bit counter is used. Thus, the output of the counter 64 starts with a value of "00000000", becomes "00000001" at the first clock cycle, and continues until "11111111". An 8-bit output of counter 64 is coupled to an input of an address multiplexer (mux) 65. In one embodiment, multiplexer 65 comprises an address interpreter, which may be hardwired in the circuit and generates a control voltage to control oscillator 61. The multiplexer 65 uses the output of the counter 64 to copy the address in a serial bit stream, which is further provided to the signal transmission driving circuit. Multiple pathsThe multiplexer 65 may also be used to control the duty cycle of the signal transmission. In one embodiment, multiplexer 65 counts the turn-on signal transmission only one sixteenth of the time using the clock generated by counter 64. Such a low duty cycle conserves power and also allows other devices to transmit without interfering with their signals. The address for a given chip may be 8 bits, 16 bits, or 32 bits. Where desired, more than 8 bits may be used in a product, for example where the identifier is for a different type of pharmaceutical agent and each medicament is desired to have its own private address.

According to one embodiment, multiplexer 65 generates a control voltage that serially encodes the address and is used to vary the output frequency of oscillator 61. For example, a 1 megahertz signal is generated by the oscillator when the control voltage is low, i.e., when the serial address bit is at 0. When the control voltage is high, i.e. when the address bit is 1, a 2 mhz signal is generated by the oscillator. Alternatively, this may be 10 mhz and 20 mhz, or a phase shift keying approach where the device is limited to adjusting the phase. The purpose of multiplexer 65 is to control the frequency of the oscillator or an AC alternative embodiment of the amplified signal of the oscillator.

The output of multiplexer 65 is coupled to an electrode driver 66 which can drive the electrodes to apply different potentials to the solution, drive an oscillating current through the coil to generate a magnetic signal, or drive a single electrode to push or pull charge to or from the solution. Thus, the device broadcasts a sequence of 0's and 1's, which constitute the addresses stored in multiplexer 65. That address will be broadcast repeatedly and will continue to be broadcast until either metal 1 or metal 2(32 and 33) is consumed and dissolved in the solution, at which time the battery is no longer operational.

Other configurations for the signal generating elements are of course possible. Other configurations of interest include, but are not limited to: PCT application Ser. No. PCT/US2006/016370, filed on 28.4.2006 and entitled "pharmaceutical informatics System"; PCT application serial No. PCT/US2007/022257, filed on 17.10.2007 and entitled "in vivo low pressure oscillator for medical device"; PCT application serial No. PCT/US2007/82563, filed on 25.10.2007 and entitled "controllably activated ingestible identifier"; U.S. patent application serial No. 11/776,480, filed on 11/7/2007 and entitled "acoustics and pharmacology system"; and those described in PCT/US2008/52845 filed on 1/2/2008 and entitled "ingestible event marker system"; the disclosures of these applications (and in particular the signal generating elements thereof) are incorporated herein by reference.

The identifier may be manufactured using any convenient machining technique. In certain embodiments, a planar machining protocol is used to fabricate a power supply having surface electrodes, wherein the surface electrodes include at least an anode and a cathode at least partially on the same surface of the circuit-supporting element. In some embodiments, the planar processing protocol is used in a wafer bonding protocol to manufacture a battery source. Planar processing techniques, such as micro-electromechanical systems (MEMS) manufacturing techniques, including surface micromachining and bulk micromachining techniques, may be used. Deposition techniques that may be used in some embodiments of fabricating the structure include, but are not limited to: electrodeposition (e.g., electroplating), cathodic arc deposition, plasma spraying, sputtering, electron beam evaporation, physical vapor deposition, chemical vapor deposition, plasma enhanced chemical vapor deposition, and the like. Material removal techniques include, but are not limited to: reactive ion etching, anisotropic chemical etching, isotropic chemical etching, planarization, for example, by chemical mechanical polishing, laser ablation, Electrical Discharge Machining (EDM), and the like. Also of interest are lithographic protocols. Of interest in certain embodiments is the use of planar processing protocols in which structures are built up or removed from a surface or surfaces of an initially planar substrate using a number of different material removal and deposition protocols applied to the substrate in a sequential manner. Illustrative manufacturing methods of interest are described in more detail in co-pending PCT application Ser. No. PCT/US2006/016370, the disclosure of which is incorporated herein by reference.

Optional physiologically acceptable carrier element

The identifier of the invention as described above comprising an in vivo power source may be present in (i.e. be combined with) a physiologically acceptable carrier element, such as a composition or carrier agent (vehicle) that assists in ingesting the identifier and/or protects the identifier until it reaches the target site of interest. By "physiologically acceptable carrier element" is meant a composition that can be a solid or a fluid (e.g., a liquid), which is ingestible.

Common carriers and excipients, such as corn starch or gelatin, lactose, glucose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid are of interest. Commonly used disintegrants in the formulations of the invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

The liquid composition may comprise a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier, such as ethanol, glycerol, sorbitol, non-aqueous solvents such as polyethylene glycol and the like, oil or water, with suspending agents, preservatives, surfactants, wetting agents, fragrances or colorants. Alternatively, the liquid formulation may be prepared from a reconstitutable powder. For example, a powder comprising the active compound, suspending agent, sucrose and sweetener may be reconstituted with water to form a suspension; and syrups can be prepared from a powder containing the active ingredient, sucrose and a sweetener.

The compositions in the form of tablets or pills may be prepared using any suitable pharmaceutical carrier commonly used for preparing solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example, polyvinylpyrrolidone. The tablets may also be provided with a coloured film coating or comprise a colour as part of the carrier. In addition, the active compounds may be formulated in controlled release dosage form as tablets comprising a hydrophilic or hydrophobic matrix.

"controlled release," "sustained release," and similar terms are used to indicate a mode of administration of an active agent that occurs when the active agent is released from an administration carrier agent at a determinable and controllable rate over a period of time, rather than immediately dispersed upon application or injection. Controlled or sustained release can extend over hours, days or months and can vary as a function of different factors. For the pharmaceutical compositions of the present invention, the rate of release will depend on the type of excipient selected in the composition and the concentration of the excipient. Another determinant of release rate is the rate of hydrolysis of linkages (linkages) between and within the units of the polyorthoester. The rate of hydrolysis can in turn be controlled by the composition of the polyorthoester and the number of hydrolysable bonds in the polyorthoester. Other factors that determine the rate of release of the active agent from the present pharmaceutical composition include: the particle size of the active agent in the matrix, the acidity (for the interior or exterior of the matrix) and the physical and chemical characteristics of the medium.

Compositions in capsule form may be prepared using conventional encapsulation procedures, for example, by including the active compound and excipients in a hard gelatin capsule. Alternatively, a semi-solid matrix of the active compound and high molecular weight polyethylene glycol can be prepared and filled into hard gelatin capsules; or a solution of the active compound in polyethylene glycol or a suspension in an edible oil (e.g., liquid paraffin or fractionated coconut oil) may be prepared and filled into soft gelatin capsules.

Tablet binders which may be included are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, sucrose, starch and ethylcellulose. Lubricants that may be used include magnesium stearate or other metal stearates, stearic acid, silicone oil, talc, waxes, oils and colloidal silica.

Fragrances such as peppermint, oil of wintergreen, cherry flavoring or the like may also be used. In addition, it may be desirable to add a colorant to make the dosage form more appealing in appearance or to help identify the product.

Other ingredients suitable for use in the formulations of the present invention may be found in Remington's pharmaceutical sciences, machine Publishing Company, Philadelphia, Pa., 17th ed. (1985).

Optional active agent

In certain embodiments, the identifier is not associated with a pharmaceutically active agent. As such, the identifier and any carrier or other ingredient that constitutes an ingestible event marker does not include an active agent.

In yet other embodiments, the identifier is associated with the active agent, for example, where the active agent is present in a carrier composition that includes the identifier. By "active agent/carrier component" is meant a composition present in a pharmaceutically acceptable carrier, which may be a solid or a fluid (e.g., a liquid), having an amount of active agent, e.g., a dosage.

An "active agent" includes any compound or mixture of compounds that produces a physiological effect, e.g., a beneficial or useful effect, when in contact with a living organism (e.g., a mammal, such as a human, etc.). Active agents can be distinguished from ingredients such as carrier agents, carriers, diluents, lubricants, binders, or other formulation aids, and encapsulated or otherwise protected ingredients. The active agent may be any molecule, as well as binding moieties or binding fragments thereof, which are capable of modulating biological processes in a living body. In certain embodiments, the active agent may be a substance used in the diagnosis, treatment, or prevention of a disease or a substance used as a component of a medicament. In certain embodiments, the active agent may be a chemical substance, such as an anesthetic or hallucinogen, that affects the central nervous system and causes a change in behavior.

Active agents (i.e., drugs) are capable of interacting with targets in a living body. The target may be a number of different types of naturally occurring structures, with the target of interest including both intracellular and extracellular targets. Such targets may be proteins, phospholipids, nucleic acids and analogues thereof, wherein proteins are of particular interest. Specific protein targets of interest include, without limitation, enzymes (e.g., kinases, phosphatases, reductases, cyclooxygenases, proteases, and analogs thereof), targets comprising domains involved in protein-protein interactions (e.g., SH2, SH3, PTB, and PDZ domains), structural proteins (e.g., actin, tubulin, etc.), membrane receptors, immunoglobulins (e.g., IgE), cell adhesion receptors (e.g., integrins, etc.), ion channels, transmembrane pumps, transcription factors, signaling proteins, and analogs thereof.

The active agent (i.e., drug) may include one or more functional groups necessary for structural interaction with a target, e.g., groups necessary for hydrophobic, hydrophilic, electrostatic, or even covalent interactions, depending on the particular drug and its intended target. Where the target is a protein, the drug moiety may include functional groups necessary for structural interaction with the protein, such as hydrogen bonding, hydrophobic-hydrophobic interactions, electrostatic interactions, and the like, and may include at least amine, amide, thiol, carbonyl, hydroxyl, or carboxyl groups, such as at least two of these functional chemical groups.

The drug of interest may comprise a ring carbon or heterocyclic structure and/or an aromatic or polyaromatic structure substituted with one or more of the functional groups described above. Also contemplated as part of the drug are structures found in biomolecules, including peptides, carbohydrates, fatty acids, steroids, purines, pyrimidines, or derivatives, structural analogs, or combinations thereof. Such compounds can be screened to identify those of interest, with a variety of different screening protocols known in the art.

The active agent may be derived from naturally occurring or synthetic compounds, which may be obtained from a variety of sources, including libraries of synthetic or natural compounds. For example, many approaches are available for the random and directed synthesis of a variety of organic compounds and biological macromolecules, including the preparation of random oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily generated. In addition, natural or synthetically produced libraries and compounds are readily modified by conventional chemical, physical and biochemical methods and can be used to produce combinatorial libraries. Known pharmacological agents may be subject to directed or random chemical modifications, such as acylation, alkylation, esterification, amidation, and the like, to produce structural analogs.

Thus, the active agent may be obtained from a library of naturally occurring or synthetic molecules, including libraries of compounds generated by combinatorial methods, i.e., a diverse combinatorial library of compounds. When obtained from such a library, the drug moiety used will have some desirable activity demonstrated in an appropriate screening assay for activity. Combinatorial libraries, and methods of generating and screening such libraries are known in the art and are described in: 5,741,713, respectively; 5,734,018, respectively; 5,731,423, respectively; 5,721,099, respectively; 5,708,153; 5,698,673, respectively; 5,688,997, respectively; 5,688,696, respectively; 5,684,711, respectively; 5,641,862, respectively; 5,639,603, respectively; 5,593,853, respectively; 5,574,656, respectively; 5,571,698; 5,565,324; 5,549,974, respectively; 5,545,568, respectively; 5,541,061, respectively; 5,525,735, respectively; 5,463,564, respectively; 5,440,016, respectively; 5,438,119, respectively; 5,223,409, the disclosure of which is incorporated herein by reference.

A wide variety of active agents of interest include, but are not limited to: a cardiovascular agent; analgesics, e.g., analgesics, anesthetics, anti-inflammatory agents, and the like; (ii) a neuroactive agent; chemotherapeutic (e.g., anti-tumor) agents; and so on.

Various manufacturing procedures may be used to produce the compositions as described above, for example, where the identifier is present in a pharmaceutically acceptable carrier or vehicle, which may also include one or more active agents. In making such a composition, the identifier is stably associated with the agent in some manner. By stably associated is meant that the identifier and the agent are not separated from each other, at least prior to administration (e.g., by ingestion) to a subject in need thereof. The identifier can be stably associated with the pharmaceutical carrier/active agent component of the composition in a number of different ways. In certain embodiments, where the carrier/active agent component is a solid structure (e.g., a tablet or pill), the carrier/active agent component is manufactured in a manner that provides a cavity for the identifier. The identifier is then placed into the cavity and the cavity is sealed, for example with a biocompatible material, to produce the final composition. For example, in certain embodiments the tablet is produced using a die that includes features that create cavities in the final compressed tablet. The identifier is placed into the cavity and the cavity is sealed to produce the final tablet. In a variation of this embodiment, removable elements are used to compress the tablets into, for example, the shape of a rod or other convenient shape. The removable element is then removed to create a cavity in the tablet. The identifier is placed into the cavity and the cavity is sealed to produce the final tablet. In another variation of this embodiment, a tablet without any cavities is first produced and then the cavities are created in the tablet, for example by laser drilling. The identifier is placed into the cavity and the cavity is sealed to produce the final tablet. In other embodiments, the tablet is produced by combining the identifier with a daughter of the tablet, wherein the daughter may be a pre-made daughter or manufactured sequentially. For example, in certain embodiments, the tablet is produced by first making the lower half of the tablet, placing the signal generating element in place of the lower half of the tablet, and then placing the top portion of the tablet over the lower half and signal generating element to produce the final desired composition. In certain embodiments, the tablet is produced around the identifier such that the identifier is located within the produced tablet. For example, the identifier (which may or may not be encapsulated in a biocompatible compliant material such as gelatin to protect the signal generating element)) is combined with a carrier/active agent precursor (e.g., a powder) and compressed or molded into a tablet in such a manner that the identifier is located at an interior location of the tablet. Instead of molding or compression molding, in certain embodiments, the carrier/active agent component is sprayed onto the identifier in a manner that creates a tablet structure. In another embodiment, the active agent/carrier component precursor is a liquid formulation that is combined with the identifier and then cured to produce the final composition. In other embodiments, the pre-formed tablet may be assembled with the identifier by stably attaching the identifier to the tablet. Of interest are procedures that do not alter the properties of the tablet, e.g., dissolution, etc. For example, a gelatin unit that snap fits onto one end of a tablet and integrates an identifier with the tablet is used in certain embodiments. The gelatin unit is colored in some embodiments to easily identify the tablet that has been fitted with the signal generating element. Where the composition has an active agent/carrier composition filled capsule configuration, such as a gelatin capsule filled configuration, the identifier may be integrated with the capsule component (e.g., upper or lower capsule), and the active agent/carrier composition filled capsule to produce the final composition. The methods of manufacture reviewed above are illustrative of the many different methods in which the compositions of the invention can be made.

In certain embodiments, the identifier is disturbed when administered to the subject. As such, in certain embodiments, upon delivery to the body, e.g., by ingestion, injection, etc., these compositions are physically disrupted, e.g., dissolved, degraded, corroded, etc. The compositions of these embodiments differ from devices that are configured to be ingested and remain intact during transit substantially, if not completely, through the gastrointestinal tract.

System for controlling a power supply

Also provided are systems comprising the present compositions. In certain embodiments, the system of the present invention comprises one or more devices comprising an in-body power source of the present invention, e.g., an identifier as reviewed above, and a signal detection element, e.g., in the form of a receiver. The signal detecting element may vary significantly with the nature of the signal generated by the signal generating element of the composition, e.g., as reviewed above.

The signal receivers of the system of embodiments of the present invention are those configured to receive signals from the identifier, e.g., for receiving signals emitted by the identifier when the identifier is in contact with the target physiological site after ingestion by the identifier. The signal receiver may vary significantly with the nature of the signal generated by the signal generating element, for example, as reviewed below. As such, the signal receiver may be configured to receive a variety of different types of signals, including but not limited to: RF signals, magnetic signals, conducted (near-field) signals, acoustic signals, and the like, as noted above. In certain embodiments, the receiver is configured to conductively receive a signal from another element, such as an identifier, such that both elements use the patient's body as the communication medium. As such, the signal transmitted between the identifier and the receiver passes through the body and requires the body as a conductive medium. The signal emitted by the identifier may be transmitted through and received from the skin and other body tissue of the subject's body in the form of an electrical alternating current (a.c.) voltage signal conducted by the body tissue. Thus, such embodiments do not require any additional cables or hard-wired connections, or even radio link connections, for transmitting sensor data from the autonomous sensor units to the central transmitting and receiving unit and other elements of the system, as the sensor data is exchanged directly through the skin and other body tissue of the subject. This communication protocol has the advantage that the receiver is adaptively arranged at any desired location on the body of the subject, whereby the receiver is automatically connected to the required electrical conductors for enabling signal transmission, i.e. signal transmission is achieved by providing electrical conductors through the skin and other body tissue of the subject. In some embodiments, the signal detection element is one that is activated when a signal emitted from the identifier is detected. In certain embodiments, the signal receiver is capable of (i.e., configured to) simultaneously detect multiple different signals, e.g., 2 or more, 5 or more, 10 or more, etc.

The signal receiver may comprise a plurality of different types of signal receiver elements, wherein the properties of the receiver elements necessarily vary with the properties of the signal generated by the signal generating element. In certain embodiments, the signal receiver may include one or more electrodes (e.g., 2 or more electrodes, 3 or more electrodes, including a plurality, e.g., 2 or more, 3 or more, 4 or more pairs of electrodes, etc.) for detecting the signal emitted by the signal generating element. In a certain embodiment, the receiver device will be provided with two electrodes dispersed at a distance (e.g., a distance that allows the electrodes to detect a differential voltage). This distance may vary, and in certain embodiments ranges from about 0.1 to about 5cm, such as from about 0.5 to about 2.5cm, for example, about 1 cm. In an alternative embodiment, a receiver using a single electrode is used. In certain embodiments, the signal detection element may comprise one or more coils for detecting the signal emitted by the signal generating element. In some embodiments, the signal detection element may comprise a sound detection element for detecting the signal emitted by the signal generating element. In some embodiments, multiple pairs of electrodes (e.g., as reviewed above) are provided, for example to increase the probability of detection of a signal.

Signal receivers of interest include external and implantable signal receivers. In an external embodiment, the signal receiver is external, by which is meant that the receiver is present outside the body during use. In the case where the receiver is implanted, the signal receiver is in vivo. The signal receiver is configured to be stably associated with the body, e.g., either inside or outside the body, at least during the time it receives the signal emitted from the IEM.

Signal receivers of interest include, but are not limited to, PCT application serial No. PCT/US2006/016370, filed on 28.4.2006 and entitled "pharmaceutical informatics system"; and those disclosed in PCT/US2008/52845 filed on 1/2/2008 and entitled "ingestible event marker system"; the disclosures of these applications (and in particular the signal receiving elements thereof) are incorporated herein by reference.

In certain embodiments, the signal receiver is configured to provide data of the received signal to a location external to the subject. For example, the signal receiver may be configured to provide data to an external data receiver, which may for example take the form of a monitor (e.g. bedside monitor), a computer (e.g. PC or MAC), a Personal Digital Assistant (PDA), a telephone, a smartphone, or the like. In one embodiment, if the signal receiver fails to detect a signal indicating that the bolus has been swallowed, the signal receiver may send a signal to the PDA or smartphone of the subject alerting the subject to taking the bolus, which may then provide a prompt to the user to take the medication, such as a display or alarm on the PDA, a prompt obtained by the user by receiving a telephone call (e.g., a recorded message) on the smartphone, or the like. The signal receiver may be configured to forward data of the received signal to a location external to the subject. Alternatively, the signal receiver may be configured to be interrogated by an external interrogation device to provide data of the received signal to an external location.

As such, in some embodiments the system includes an external device (which may be implanted or administered locally in some embodiments) that is distinct from the receiver, where this external device provides a number of functions. Such devices may include the ability to provide feedback and appropriate clinical adjustments to the patient. Such devices may take any of a number of forms. For example, the device may be configured to be positioned on a bed and in close proximity to a patient, e.g., a bedside monitor. Other forms include, but are not limited to, PDAs, smart phones, home computers, and the like. The device may read information from the drug intake reports and from the physiological sensing device that is described in more detail in other parts of the treated patient application, such as information generated internally by the pacemaker device or a dedicated implant for detecting the bolus. The purpose of the external device is to acquire data from the patient and access the external device. One feature of the external device is its ability to provide pharmacological and physiological information in a form that can be transmitted over a transmission medium (e.g., a telephone line) to a remote location, such as a clinician or central monitoring facility.

Method of producing a composite material

Aspects of the invention also include methods of using in-vivo devices comprising the in-vivo power sources of the invention. Generally, the methods of the present invention will include placing an intracorporeal device in the body of a subject in some manner, such as by implanting the device in the subject, by ingesting the device, and the like. The device can be used in a variety of subjects. Usually such subjects are "mammals" or

"mammal," where these terms are used broadly to describe organisms within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, monkeys). In certain embodiments, the subject will be a human. After placement of the device within the body of the subject, the device is used for a variety of purposes, such as sensing one or more physiological parameters, performing one or more therapies, identifying a physical event of interest, and the like.

In certain embodiments, the in-vivo device is an ingestible device, wherein the in-vivo power source is part of an identifier of the device. In such embodiments, the identifier is ingested and the signal emitted by the identifier is detected, for example, with a receiver as described above. Such a method is filed on 28.4.2006 and is entitled "drug information System" PCT application Ser. No. PCT/US 2006/016370; and further described in PCT/US2008/52845, filed on 1/2/2008 and entitled "ingestible event marker system"; the disclosures of these applications (and in particular the signal receiving elements thereof) are incorporated herein by reference.

Function of

Devices comprising an in-body power source of the invention may be used in a variety of different applications, including therapeutic and non-therapeutic applications. Specific applications of interest include, but are not limited to: PCT application Ser. No. PCT/US2006/016370, filed on 28.4.2006 and entitled "drug information System"; and those applications described in PCT/US2008/52845 filed on 1/2/2008 and entitled "ingestible event marker system"; the disclosures of these applications (and in particular the signal receiving elements thereof) are incorporated herein by reference.

The IEM in the in vivo device of the present invention may be used in a variety of different applications, which may be medical and non-medical in nature. Various illustrative applications are now reviewed in greater detail below.

Some applications involve the use of IEMs to mark by themselves physical events of interest, such as the onset of physiological parameters (e.g., symptoms of interest, etc.), the onset of activity, etc. For example, in certain embodiments, the event marker is used to mark the onset of a symptom of interest. In such a case, when the individual perceives the symptom of interest, e.g., begins to feel fever, nausea, excitement, etc., the individual may eat the IEM to indicate the occurrence of the symptom of interest. For example, the patient may begin to feel uncomfortable and eat into the event marker in response to this uncomfortable feeling. When eating, the marker sends a signal to the receiver, whereupon it can record the receipt of the signal for further use, e.g. for combination with physiological data, etc. In certain embodiments, the received signal is used to provide context for any physiological data obtained from the patient, e.g., from an implantable recorder or the like through sensors on the receiver.

Another symptom of concern is pain. In these embodiments, an ingestible event marker may be used as a pain marker. For example, in the case of patient-monitored pain, if the patient does not feel pain, the patient may eat a first type of marker. If the patient feels pain, the patient may eat a second type of marker. Different types of markers may be distinguishable, for example in a coded colour, if desired, to assist in their identification and appropriate use by the patient. For example, the indicator of ingestion may be color-coded blue when the patient does not feel pain, and the indicator of ingestion may be color-coded yellow when the patient has pain. Instead of having different types of markers, a protocol may be used in which the amount of marker ingested and thus, for example, the signal obtained from a single marker or two or more markers may be used to indicate the degree of a symptom of interest, such as pain. Thus, if an individual has intense pain, the individual may take four positive pain pills at the same time, while only one marker may be taken in response to mild pain.

In such embodiments, the onset of the symptom of interest, as indicated by ingestion of the event marker and detection of the signal by the receiver, may be used as a point of relevance at which to begin recording one or more physiological parameters of interest, for example, by using an implantable physiological detector. In these cases, the signal transmitted from the marker is received by a receiver, which then causes a physiological parameter Recorder (e.g., a recent @ Plus Insertable Loop Recorder (ILR), medtronic corporation) to begin recording data and save the data, e.g., for later use. For example, an implantable physiological parameter recorder may have only a limited amount of time possible for recording (e.g., 42 minutes). In such a case, the data may be automatically overwritten unless the data is marked or indicated in some manner for protection. In the present method, the IEM may be ingested to mark the onset of the symptom of interest when the symptom is felt by the patient, and the receiver may act on the recorder to protect data obtained near the time of the signal (later, or even some time earlier) from being overwritten when the signal is received. The system may also be configured to operate in response not only to ingestion of the time marker, but also to a physiologically sensed parameter (e.g., pH). In this manner, the method finds use as an event recorder in marking the stream of diagnostic information and protecting it from overwriting so that it can be viewed by a physician at a later date.

In certain embodiments, the event marker provides context for later interpretation of a given physiological data set. For example, if a party uses an activity sensor and a party co-administers an event marker and a particular medication, a party may notice any change in activity brought about by that medication. If a decrease in activity is observed after a person takes both the event marker and the medication, the decrease indicates that the medication may cause the person to decrease their activity, for example, by causing them to feel drowsy or actually causing them to fall asleep. Such data may be used to adjust the dosage of a drug or to base a decision to switch to an alternative drug.

In some embodiments, the event marker is used to build a database of a plurality of events. Such a database can be used to find commonalities between multiple flagged events. Simple or complex procedures for finding commonalities among multiple posted events may be used. For example, multiple events may be averaged. Techniques such as impulse response theory may alternatively be used, where such techniques provide information about what is just a common feature in a set of multiple sensor streams that are related to a particular event.

The IEM system of the present invention enables one to use subjective symptoms, such as "i feel slightly uncomfortable" etc., to give context and context to the obtained objective measures of what is actually happening physiologically. Thus, if someone takes an event marker every time they feel an anomaly, one can reference a database of objective sensor data and find common features in the database. Such a method can be used to find potential causes of subjective mood. For example, such methods may be used to determine that a person has some variation in their blood pressure whenever they feel slightly uncomfortable, and the link between subjective symptoms and objective physiological data may be used in their diagnosis. In this manner, the negotiable event marker brings context from any other source to the discrete data. As such, the use of an oral medication event marker provides context for any other associated health monitoring information or health events.

In certain embodiments, the event marker may be an alarm marker such that ingestion of the marker causes an alarm signal to be sent from the patient, e.g., an alarm signal indicating that the patient requires medical assistance or the like. For example, the patient may enter an event marker when the patient feels the onset of a symptom of interest (e.g., chest pain, shortness of breath, etc.). The signal emitted from the event marker may be received by a receiver, which may then cause an alarm to occur and be distributed to a medical professional.

In certain embodiments, event markers are used to activate or initiate a therapeutic effect, e.g., to activate an implantable pulse generator to deliver electrotherapy, to activate an implantable drug delivery device to administer a dose of medication, to activate a physiological sensor to initiate data acquisition, etc. For example, in the case of a patient having a neurostimulator for treating migraine, the patient may eat the IEM when the symptom of the sensation begins. The emitted signal will then activate the neurostimulator into a stimulation mode and thereby cause the implant to deliver therapy. Alternatively, if there is an implanted drug delivery device, e.g., a device to deliver a neoplastic agent, ingestion of the IEM may cause the implanted device to deliver the active agent.

In certain embodiments, the event marker is used to deliver information to an implanted medical device within the patient. For example, the ingestible event marker may transmit a signal including update data for an implanted medical device, such as firmware update data for an implantable pulse generator (e.g., pacemaker), and the like. In such a case, the signal may include an update code conductively propagated from the IEM to the medical device, wherein the firmware of the medical device is upgraded when the signal and code are received.

Other applications where event markers may be used by themselves are for marking or recording the onset of a physical non-medical event, such as commute time, the start of an exercise regimen, sleep time, smoking (e.g., so that it may be recorded how much smoke a person has drawn, etc.), etc.

As noted above, embodiments of the invention feature an event marker co-ingested with another composition of matter (e.g., a pharmaceutical composition, a food, etc.), where the event marker may or may not be present in the same composition as the co-ingested matter. For example, event markers may be used to track ingestion of a medication, where a party co-administers the marker and a medication of interest. Applications where co-administration of drugs and markers is of interest include, but are not limited to, clinical studies, titration of drugs (e.g., antihypertensive drugs, etc.). Where desired, the IEM may be provided only in another tablet when the filling is substantially all pharmaceutical in nature.

Instead of co-ingestion event markers and another composition (e.g., medication, food, etc.), the markers and the other composition may be mixed together, for example, by the end user. For example, an IEM in capsule form may be opened by an end user and filled with a pharmaceutical composition. The resulting mixed capsule and active agent can then be ingested by the end user. Instead of the end user, the pharmacist or the person providing healthcare may perform the mixing step.

In other embodiments, the presented indicator has been mixed with the other composition at the source of its manufacture (e.g., the manufacturer or producer of the pharmaceutical composition). Examples of such compositions include those described in PCT application Ser. No. PCT/US 2006/016370; the disclosure of which is incorporated herein by reference.

In certain embodiments, the IEM of the present invention is used to allow a party to view on an individual basis what a given result is regarding what drugs an individual is taking and their effect on the indicator associated with the desired effect. For example, where a given patient is prescribed multiple medications, and there are multiple different physiological parameters that are monitored according to indicators of how the patient responds to the prescribed treatment regimen, a given drug as indicated by a given indicator may be evaluated in terms of its effect on one or more physiological parameters of interest. Following this evaluation, adjustments may be made accordingly. As such, automated operations may be used to adjust therapy based on individual responses. For example, in the case where the patient is undergoing tumor therapy, the event marker may be used to provide real-time context to the acquired physiological parameter data. The resulting annotated real-time data may be used to make decisions about whether to continue therapy, or to change to a new therapy.

In certain embodiments, dosing events (as indicated by IEMs) are correlated with sensor data to display a graph, for example, from pharmacokinetic and/or pharmacodynamic model aspects, of how a given drug acts. Sensors were used for IEM labeling of dosing events to obtain pharmacokinetic models. Once a party has a pharmacokinetic model, the party can use the dosing event to drive the model and predict serum drug concentrations and responses. One may find that this patient does not feel very well at this time, as determined from various sensors. One may review the pharmacokinetic model and state that the level of this drug in the blood is decreasing when the patient is sensed to be not feeling well. This data is then used to make decisions to increase dosing frequency or increase the dose at a given dosing event. The event marker provides a method to develop the model and then apply it.

In the case where the IEM is co-administered with a medicament (e.g., as two different compositions or a single composition, as explained above), the system of the present invention, such as the system shown in fig. 12, enables a dynamic feedback and therapy loop: follow up the timing and level of administration, measure response to treatment, and recommend an altered dose administration based on the physiologic and molecular profiles of the individual patients. For example, patients with heart failure symptoms take a variety of medications daily, primarily to reduce the burden on the heart and improve the quality of life of the patient. The main supportive drugs for therapy include vasodilator converting enzyme (ACE) inhibitors, beta blockers and diuretics. For the medication to be effective, the patient follows their treatment regimen and it is crucial to take the required dose at the appropriate time. Multiple studies in the clinical literature demonstrate that over 50% of patients with grade II and III heart failure do not receive treatment with the recommended guidelines, and that only 40-60% of those that are appropriately titrated follow therapy. With the present system, patient compliance with therapy for heart failure patients can be monitored, and compliance performance can be linked to key physiological measurements to facilitate optimization of physician therapy.

In certain embodiments, the system of the present invention may be used to obtain a collection of information including sensor data and drug administration data. For example, a party may combine heart rate, respiration rate, multi-axis acceleration data, some information about fluid status, and some information about temperature, and derive an index that will inform about the overall activity of the subject, which may be used to generate a physiological index, such as an activity index, etc. For example, when there is an increase in temperature, the heart rate increases somewhat, and breathing is faster, which can be used as an indication that the body is alive. By calibrating this, the number of calories burned by the body at that time can be determined. In another example, pulse or multi-axis acceleration data for a particular cadence setting may indicate that a person is climbing a group of stairs, from which one may infer how much energy they have used. In another embodiment, body fat measurements (e.g., from impedance data) may be combined with activity indices generated from a combination of measured biomarkers to produce a physiological index useful for management of weight loss or cardiovascular health programs. This information can be combined with cardiac performance indicators to get a suitable picture of overall health, which can be combined with medication administration data. In another embodiment, one may find that, for example, a particular drug is associated with a small increase in body temperature or a change in electrocardiogram. A party may develop a pharmacodynamic model for the metabolism of the drug and use the information from the receiver to substantially fit the free parameters in that model to give a more accurate estimate of the levels actually present in the subject's serum. This information can be fed back to the dosing regimen. In another embodiment, a party may combine information from sensors that measure contractions (e.g., with strain gauges) and also monitor fetal heart rate for high risk pregnancy monitoring.

In certain embodiments, the subject specific information collected using the system of the present invention may be transmitted to a location where it is combined with data from one or more additional individuals to provide a collection of data that is a combination of data collected from 2 or more, e.g., 5 or more, 10 or more, 25 or more, 50 or more, 100 or more, 1000 or more individuals. The combined data may then be manipulated, e.g., sorted according to different criteria, and provided for one or more different types of groupings, e.g., patient groupings, healthcare practitioner groupings, etc., where manipulation of the data may be, e.g., to limit access to the data types accessible to any given grouping to that grouping. For example, data may be collected from 100 different individuals suffering from the same condition and taking the same medication. The data can be processed and used to develop easily understandable displays regarding patient compliance with drug dosage regimens and general health. The members of the group can access this information and see how their compliance matches with other patient members of the group, and whether they enjoy the benefits that others are experiencing. In another embodiment, physicians may also gain access to the manipulation of this combined data to see how their patients match the patients of other physicians and to obtain useful information about how real patients respond to a given treatment regimen. Additional functionality may be provided for packets granting access to the combined data, where such functionality may include, but is not limited to: ability to annotate data, chat functionality, security rights, etc.

The inventive pharmacokinetic model satisfies the need for real-time adjustment of drug dosing regimens in response to varying serum levels in vivo. A pharmacokinetic model may predict or measure the serum levels of a given drug in vivo. This data can then be used to calculate when the patient should take the next dose. An alarm may be triggered at that time to remind the patient to take a dose. If the serum level is still high, an alarm may be triggered to remind the patient not to take the next dose at the originally prescribed time interval. The pharmacokinetic model may be used in conjunction with a drug ingestion monitoring system comprising an IEM (e.g., as described above). Data from this system as well as demographic, measurement, and patient input data may be incorporated into the model. With data from multiple sources, very powerful and accurate tools can be developed.

In some embodiments, the data collected by the receiver may be used directly by the pharmacokinetic model to determine when to administer, what drug it is, and in what amount. This information can be used to calculate an estimate of the serum level of the drug in the patient. Based on the calculated serum levels, the pharmacokinetic model may alert the patient to indicate that the serum levels are too high and near or above toxic levels, or that the serum levels are too low and they should take another dose. The pharmacokinetic model may run on the implanted receiver itself or on an external system that receives data from the implanted receiver.

A simplified version of the pharmacokinetic model may assume that each patient is the same and use average population data to model serum levels. More complex and more accurate models can be obtained by entering additional information about the patient. This information may be entered by a user, such as a physician, or collected by a receiver from an associated sensor. The information that may be used to adjust the model includes, among other factors, other medications taken, the disease suffered by the patient, the patient's organ function, enzyme levels, metabolism, weight, age, and the like. Information may also be entered by the patient himself, for example if they feel low in blood sugar, or suffer from pain or dizziness. This can be used as additional evidence to verify the prediction of the model.

Examples of food applications include the following. In certain conditions, such as diabetes, it can be important what and when a patient eats. In such a case, the event marker of the present invention is associated or linked to the type of food consumed by the patient. For example, a person may have a set of event markers for different food items, and the person may take them with the food. From the data generated, a party can complete an individual metabolic profile for an individual. One side knows how much calories the patient has consumed. By obtaining activity and heart rate and ambient temperature versus body temperature data, one can calculate how much calories a person consumes. Thus, the patient may be provided with guidance as to what food to eat and when to eat. Non-diseased patients may also follow food intake in this manner. For example, an athlete following a strict training diet may use IEMs to better monitor food intake and the effects of food intake on one or more physiological parameters of interest.

As reviewed in the discussion above, the IEM system of the present invention finds use in both therapeutic and non-therapeutic applications. In therapeutic applications, the IEM may or may not be mixed with a pharmaceutically active agent. In those embodiments in which the IEM is mixed with an active agent, the resulting mixed composition may be considered a pharmaco-informatics enabled pharmaceutical composition.

In such a pharmakoinformatics embodiment, a composition comprising an IEM and an active agent in an effective amount is administered to a subject in need of the active agent present in the composition, where "effective amount" refers to a dose sufficient to produce a desired result (e.g., amelioration of the condition or symptoms associated therewith, completion of a desired physiological change, etc.). The amount administered may also be considered a therapeutically effective amount. "therapeutically effective amount" refers to an amount sufficient to effect treatment of a disease when administered to a subject for treatment of the disease.

The composition may be administered to a subject in any convenient manner that produces the desired effect, wherein the route of administration depends, at least in part, on the particular form of the composition, e.g., as reviewed above. As reviewed above, the composition can be designed into a variety of formulations for therapeutic administration including, but not limited to, solid, semi-solid, or liquid, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, and injections. Thus, administration of the composition may be accomplished in a variety of ways, including, but not limited to: oral, buccal, rectal, gastrointestinal, intraperitoneal, intradermal, transdermal, intratracheal, etc. In pharmaceutical dosage forms, a given composition may be administered alone or together with other pharmaceutically active compounds, for example, it may also be a composition having a signal-generating element stably associated therewith.

The present methods find use in the treatment of a variety of different conditions, including disease states. The conditions specifically treatable by the present compositions are as diverse as the types of active agents that may be present in the present compositions. Thus, conditions include, but are not limited to: cardiovascular diseases, cell proliferative diseases, such as neoplastic diseases, autoimmune diseases, endocrine abnormality diseases, infectious diseases, pain treatment, and the like.

By treatment is meant an improvement in at least the symptoms associated with the distressing condition of the subject, where improvement is used in a broad sense to mean a reduction in at least the size of the parameter (e.g., the symptoms associated with the pathological condition being treated). As such, treatment also includes situations in which the pathological state, or at least the symptoms associated therewith, are completely inhibited (e.g., prevented from occurring, stopped, e.g., terminated), such that the subject is no longer afflicted with the pathological state, or at least the symptoms that characterize the pathological state. Thus, "treatment" or "therapy" of a disease includes preventing the disease from occurring in an animal that can predispose to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from symptoms or side effects of the disease (which includes palliative treatment), and relieving the disease (which attenuates the disease). For the purposes of the present invention, "disease" includes pain.

In certain embodiments, the present methods, as described above, are methods of managing a condition, e.g., over an extended period of time, e.g., 1 week or more, 1 month or more, 6 months or more, 1 year or more, 2 years or more, 5 years or more, etc. The present methods may be used with one or more additional disease control regimens, e.g., electrical stimulation based regimens in cardiovascular disease control, such as pacing regimens, cardiac resynchronization regimens, etc.; daily forms, such as diet and/or exercise regimens for a variety of different conditions; and so on.

In certain embodiments, the method comprises modulating treatment-protocol-based data obtained from the compositions. For example, data may be obtained that includes information regarding patient compliance with a prescribed treatment regimen. This data (with or without additional physiological data), e.g., data obtained using one or more sensors (e.g., the sensor devices described above), may be used, e.g., with a suitable decision tool as desired, to make a decision whether a given treatment regime should be continued or modified in some way (e.g., by modification of a medication regime and/or an implant activity regime). As such, the inventive methods include methods wherein the treatment regimen is modified based on signals obtained from those compositions.

Also provided in certain embodiments are methods of determining the history of a composition of the invention, wherein the composition comprises an active agent, a marker element, and a pharmaceutically acceptable carrier. In some embodiments where the marker transmits a signal in response to interrogation, the marker is interrogated to obtain the signal, for example by a reader or other suitable interrogation device. The obtained signals are then used to determine historical information about the composition (e.g., source, chain of custody, etc.).

In certain embodiments, a system consisting of a plurality of distinct IEMs is used, e.g., 2 or more distinct IEMs, 3 or more distinct IEMs, 4 or more distinct IEMs, etc., including 5 or more, 7 or more, 10 or more distinct IEMs. Distinct IEMs may be configured to provide distinguishable signals, e.g., where the signals are distinguishable in terms of the nature of the signals themselves, the timing of the signal transmission, etc. For example, each IEM in such a group may transmit a differently encoded signal. Alternatively, each IEM may be configured to emit a signal at a different physiological target site, e.g., where each IEM is configured to be activated at a different physiological target site, e.g., where a first IEM is activated in the mouth, a second is activated in the esophagus, a third is activated in the small intestine, and a fourth is activated in the large intestine. Such a group of a plurality of different distinguishable IEMs finds use in a variety of applications. For example, with the 4IEM group described above, the group can be used in diagnostic applications to determine the function of the digestive system, e.g., motility through the digestive tract, gastric emptying, etc. For example, by noting when each IEM emits its corresponding signal, a graph of signal times can be generated from which information about the function of the digestive tract can be obtained.

The present invention provides new tools of clinician importance in the clinician's treatment device: automatic detection and identification of the medicament actually delivered into the body. The applications of this new information device and system are multifaceted. Applications include, but are not limited to: (1) monitoring patient compliance with a prescribed treatment regimen; (2) adjusting a treatment regimen based on the patient's compliance; (3) monitoring patient compliance in a clinical trial; (4) monitoring the use of a controllable substance; and the like. Each of these different illustrative applications is reviewed in detail in the co-pending PCT application Serial No. PCT/US2006/016370, infra; the disclosure of which is incorporated herein by reference.

Additional applications in which the present system finds use include those illustrated in U.S. patent No. 6,804,558, the disclosure of which is incorporated herein by reference. For example, the present system may be used in a medical information communication system that allows monitoring the performance of an Implantable Medical Device (IMD) implanted within a patient, monitoring the health of the patient, and/or remotely administering therapy to the patient via the IMD. The signal receiver of the present invention, for example in an external form such as an emergency bandage or an implanted form, communicates with the IMD and is capable of two-way communication with a communication module, a mobile phone and/or a Personal Digital Assistant (PDA) placed outside the body of the patient. The system may include an IMD, a signal receiver and/or mobile phone and/or PDA having a communication module, a remote computer system, and a communication system capable of two-way communication, wherein the communication module, mobile phone and/or PDA is capable of receiving information from the IMD or forwarding information thereto via the signal receiver (which may be internal or external to the patient, as reviewed above).

Additional applications in which the receivers of the present invention may find use include, but are not limited to: fertility monitoring, body fat monitoring, satiety control, total blood volume monitoring, cholesterol monitoring, smoking detection, and the like.

Medicine box (kit)

Also provided are kits comprising one or more of the in vivo devices of the invention. The kit may include one or more in vivo devices (e.g., as described above). In those embodiments having multiple in-vivo devices, this may be packaged in a single container, e.g., a single tube, bottle, vial, and the like, or one or more doses may be packaged individually such that certain kits may have more than one container of in-vivo devices. The kit may also include a signal receiving element in certain embodiments (as reviewed above). In certain embodiments, the kit may further include an external monitoring device, e.g., as explained above, which may provide communication with a remote location (e.g., a doctor's office, central facility, etc.) that obtains and processes the obtained data regarding the use of the composition

The kit may also include instructions for how to use the components of the kit to practice the method. The instructions may be recorded on a suitable recording medium or substrate. For example, the instructions may be printed on a substrate (e.g., paper or plastic, etc.). As such, the instructions may be present in the kit as a package instruction, in a label of a container of the kit or component thereof (e.g., associated with a package or sub-package), and the like. In other embodiments, the instructions are presented as electronically stored data files on a suitable computer readable storage medium, such as a CD-ROM, a floppy disk, or the like. In other embodiments, the actual instructions are not present in the kit, but a method of obtaining the instructions from a remote source is provided, for example, via the internet. An example of this embodiment is a kit that includes a web site where the instructions can be viewed and/or from which the instructions can be downloaded. This method of obtaining the instructions is recorded on a suitable substrate, as is the instructions.

Some or all of the components of the present kits may be packaged in suitable packages to maintain sterility. In many embodiments of the present kits, the components of the kit are packaged in a kit containing element, such as a case or similar structure, which may or may not be an airtight container, e.g., to further maintain the sterility of some or all of the components of the kit, to form a single, easily handled unit.

It is to be understood that the invention is not limited to the specific embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges that do not include either or both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the representative illustrative methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and were set forth in its entirety herein to disclose and describe the methods and/or materials in connection with which the publications were cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," only "and the like in connection with the recitation of claim elements, or use of a limitation of" negative.

Certain ranges are set forth herein wherein the term "about" is added to a numerical value. The term "about" is used herein to provide literal support to the precise number to which it precedes, as well as numbers that are close or approximate to the number to which the term precedes. In determining whether a number is near or approximate to a specifically recited number, a near or approximate unrecited number may be a number that provides substantial equivalence to the specifically recited number in the context in which it is presented.

As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete elements and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method may be performed in the order of events recited or in any other order that is logically possible.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Accordingly, the foregoing merely illustrates the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended expressly to be only for pedagogical purposes to aid the reader in understanding the principles of the invention and the concepts contributed by the inventor(s) to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the invention is not intended to be limited to the exemplary embodiments shown and described herein. With the true scope and spirit of the invention being indicated by the following claims.

It is noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," only "and the like in connection with the recitation of claim elements, or use of a limitation of" negative.

As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete elements and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method may be performed in the order of events recited or in any other order that is logically possible.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Accordingly, the foregoing merely illustrates the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended expressly to be only for pedagogical purposes to aid the reader in understanding the principles of the invention and the concepts contributed by the inventor(s) to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the invention is not intended to be limited to the exemplary embodiments shown and described herein. With the true scope and spirit of the invention being indicated by the following claims.

Claims (24)

1. An in-body power supply, comprising:

(a) a solid support;

(b) a first high surface electrode present on the surface of the solid support; and

(c) a second electrode;

wherein upon contact of the first high surface area electrode with the second electrode with a body fluid, a potential difference is generated between the two electrodes as a result of respective oxidation and reduction reactions occurring at the two electrodes, wherein the first high surface area electrode is made of an active electrode material present on a porous electrode substrate configured to provide surface area enhancement, and

wherein the first high surface electrode is an electrode having a surface area 2 times or more the surface area of the solid support covered by the electrode.

2. The in-body power supply according to claim 1, wherein said solid support comprises a semiconductor material.

3. The in-body power supply according to claim 2, wherein said solid support comprises an integrated circuit.

4. The in-body power supply of claim 1, wherein said first high surface area electrode is a cathode.

5. The in-body power supply of claim 1, wherein said first high surface area electrode is an anode.

6. The in-body power source according to claim 1, wherein said second electrode is present on a surface of said solid support.

7. The in-body power supply according to claim 6, wherein said first high surface electrode and said second electrode are present on the same surface of said solid support.

8. The in-body power supply according to claim 6, wherein said first high surface electrode and said second electrode are present on opposite surfaces of said solid support.

9. The in-body power supply according to claim 1, wherein said porous electrode bottom layer is electrodeposited.

10. The in-body power supply according to claim 1, wherein said porous electrode bottom layer is generated by cathodic arc.

11. The in-body power supply according to claim 1, wherein said porous electrode bottom layer is produced by electrophoretic deposition.

12. The in-body power supply of claim 1, wherein the in-body power supply is configured to emit a detectable signal upon contact with a target physiological site.

13. The in-body power source according to claim 12, wherein said in-body power source is present in a pharmaceutically acceptable carrier composition.

14. The in-body power supply according to claim 13, wherein said pharmaceutically acceptable carrier composition is a tablet.

15. The in-body power source according to claim 13, wherein said pharmaceutically acceptable carrier composition is a capsule.

16. A power supply system comprising:

(a) the in-body power supply of any one of claims 12 to 15; and

(b) a receiver for detecting a signal generated by the in-vivo power source.

17. The system of claim 16, wherein the receiver is an in-vivo receiver.

18. The system of claim 16, wherein the receiver is an extracorporeal receiver.

19. The system of any one of claims 16 to 18, wherein the system further comprises at least one of a data storage unit, a data processing unit, a data display unit, a data transmission unit, a notification mechanism, and a user interface.

20. A method of using a power supply, comprising:

ingesting an in-vivo power source as defined in any one of claims 12 to 15; and

detecting a signal emitted by the in-vivo power source.

21. A kit, comprising:

the in-body power supply of any one of claims 1 to 15.

22. The kit of claim 21, wherein said kit comprises a plurality of said in-vivo power sources.

23. The kit of claim 21, wherein said kit further comprises a receiver.

24. The kit of claim 21, wherein said kit further comprises at least one of a data storage unit, a data processing unit, a data display unit, a data transmission unit, a notification mechanism, and a user interface.