HK1142794A - Ingestible event marker systems - Google Patents

Description

Ingestible event marker system

Cross Reference to Related Applications

According to 35u.s.c. § 119(e), the present application claims priority to the following applications: U.S. provisional patent application serial No.60/877,780 filed on 1/2/2007; U.S. provisional patent application serial No.60/889,871 filed on 14.2.2007; U.S. provisional patent application serial No.60/889,868 filed on 14.2.2007; U.S. provisional patent application serial No.60/941,144 filed on 1/6/2007; U.S. provisional patent application serial No.60/949,198 filed on 11/7/2007; U.S. provisional patent application serial No.60/949,223 filed on 11/7/2007; U.S. provisional patent application serial No.60/949,208 filed on 11/7/2007; and U.S. provisional patent application serial No.60/956,694 filed on 18.8.2007; the disclosures of all of these applications are incorporated herein by reference.

Background

There are many instances in medical and non-medical applications where one desires to annotate a personal event, i.e., an event that is specific to a given individual. Examples of medical applications in which one may desire to note events specific to a given individual include, but are not limited to, the onset (onset) of one or more physiological parameters of interest, including disease symptoms, administration of medication, and the like. Examples of non-medical applications in which it is desirable to label events specific to a given individual include, but are not limited to: ingestion of a certain type of food (e.g. for individuals controlling meals), initiation of an exercise program (regimen), etc.

Because there are many instances in which people desire to annotate personal events, a variety of different methods and techniques have been developed to make such annotation possible. For example, logbooks and techniques have been developed in which individuals, such as patients and/or their healthcare providers, are able to record the time and date of an event, such as by manual writing or data entry.

However, there remains a need for improvements in personal event monitoring. For example, manual logging when an event occurs can be time consuming and prone to error.

Disclosure of Invention

The present invention provides for quick and simple annotation of personal events of interest, i.e. events that are specific to a given individual. Events may vary widely in the scope of the onset of a physiological parameter of interest, such as disease symptoms, the onset of a given activity, administration of a therapeutic agent, and the like. The tagging or marking of personal events according to the present invention finds application in a variety of different applications, including medical and non-medical applications.

The present invention is made possible by the inventive system comprising an ingestible event marker (i.e., IEM) and a personal signal receiver. Embodiments of the IEM include an identifier, which may or may not be present in the physiologically acceptable carrier. The marker is characterized in that it is activated upon contact with a target internal physiological site of the body (e.g., a specific target environment, including a target chemical environment, a target physical environment, etc.), such as a target site within the alimentary tract. The personal signal receiver is configured to be associated with a physiological location, e.g., within or on the body, and to receive signals from the IEM. During use, the IEM broadcasts a signal that is received by the personal signal receiver. The signal receiver performs one or more subsequent operations, as needed, such as relaying the signal to a third external device, recording the signal, processing the recorded signal with additional data points, and so forth.

Drawings

FIG. 1 provides an illustration of a marker according to an embodiment of the present invention.

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

Fig. 3 illustrates an exemplary device configuration of an IEM IC according to one embodiment of the invention.

Fig. 4 shows an exemplary schematic diagram illustrating the design of an IEM IC according to one embodiment of the invention.

Fig. 5 illustrates an exemplary transmission sequence of a bit pattern (bit pattern) of "0010" according to one embodiment of the present invention. Each bit is represented by 16 clock cycles.

FIG. 6 shows exemplary waveforms for a 20kHz transmission of the sequence "10101" in accordance with one embodiment of the present invention.

FIG. 7 shows exemplary waveforms for a 10kHz transmission of the sequence "10101" in accordance with one embodiment of the present invention.

Fig. 8 shows an exemplary state diagram illustrating the operation of an IEM IC according to one embodiment of the invention.

Fig. 9 illustrates an exemplary IEM chip configuration in which two separate electrodes are used for battery and signal transmission, respectively.

FIG. 10 illustrates an exemplary chip configuration that minimizes circuit latch-up according to one embodiment of the invention.

Fig. 11 illustrates an exemplary layout that minimizes latch-up in an IEM.

Fig. 12 provides an exploded view of an IEM according to an embodiment of the present invention.

Fig. 13 illustrates a signal receiver according to an embodiment of the present invention.

Fig. 14 illustrates a signal receiver according to a second embodiment of the present invention.

Fig. 15 illustrates a signal receiver having Multiple Sensor Leads (MSL) according to another embodiment of the present invention.

Fig. 16 provides a view of an implantable pacemaker including a receiver component according to an embodiment of the present invention.

Fig. 17A and 17B provide additional information regarding aspects of embodiments of an external receiver according to embodiments of the invention.

Fig. 18 provides a view of a receiver/dispenser (pill dispenser) device according to an embodiment of the present invention.

FIG. 19 provides a view of a wristband receiver embodiment of the invention.

FIG. 20 shows a diagram of a system according to an embodiment of the invention.

Fig. 21 provides a view of an "intra-body" network including receivers according to an embodiment of the present invention.

Fig. 22 shows how the system of the invention interacts with external elements and how it is used, according to an embodiment of the invention.

Fig. 23 shows a plot of serum levels of a medicament over time, which shows an ideal situation in which a patient takes doses of medicament at regular intervals.

Fig. 24 shows a plot of serum levels of a medicament over time, illustrating a situation in which a patient takes doses of medicament at non-uniform time intervals.

Fig. 25-27 provide views of aspects of different embodiments of the present invention.

Fig. 28 provides a top view of a series battery pack according to one embodiment of the invention.

Fig. 29 provides a top view of a series connected battery pack according to another embodiment of the present invention.

Fig. 30 illustrates one embodiment of a planar or interdigitated structure of an implantable on-chip battery having two cathodes and one anode.

Fig. 31 illustrates one embodiment of a large plate (large plate) structure of an implantable on-chip battery pack.

Figure 32 shows one embodiment of a 3-d configuration of an implantable on-chip battery wherein three anodes are connected across a cathode.

Fig. 33 is another view of an embodiment of a 3-d structure of an implantable on-chip battery pack.

Fig. 34 is another embodiment of an implantable on-chip battery pack.

Fig. 35 is another embodiment of an implantable on-chip battery pack.

Fig. 36 is another embodiment of an implantable on-chip battery pack using wafer bonding as a method of manufacture.

Detailed Description

The present invention provides for quick and easy annotation of personal events of interest, i.e., events that are specific to a given individual. The event may vary widely, such as a disease symptom, the onset of a given action, and so forth. The tagging or marking of personal events according to the present invention finds application in a variety of different applications, including medical and non-medical applications.

The present invention is made possible by a system of the present invention that includes an ingestible event marker (i.e., an IEM) and a personal signal receiver configured to receive a signal emitted from the IEM. Embodiments of the IEM include an identifier, which may or may not be present in the physiologically acceptable carrier. The marker is characterized in that it is activated upon contact with an internal target site, such as a target site within the alimentary tract. The personal signal receiver is configured to be associated with a physiological location, e.g., within or on the body, and to receive a signal from the IEM.

In a more detailed further description of the invention, embodiments of the physical components of the system (e.g. the IEMS, the personal signal receiver and optional external devices) are first explained in detail. Next, the general method of using the system of the present invention is described. Following this description, an explanation is provided of various applications in which the systems and methods find use. Kits comprising components of the system, such as IEMs, receivers, etc., are also described in detail below.

Ingestible event marker compositions

Embodiments of the present invention include ingestible event marker compositions having a marker stably associated therewith. A marker of an IEM composition is a composition that generates (i.e., emits) a detectable signal upon contact of the marker with a target physiological vision (sight). The markers of the present compositions may vary depending on the particular embodiment of the composition and the intended application, so long as they are activated (i.e., turned on) upon contact with the target physiological site, such as the stomach. Thus, the marker may be one that emits a signal when it contacts a target body (i.e., physiological) site. The marker may be any component or device capable of providing a detectable signal after activation, for example upon contact with a target site. In certain embodiments, the marker emits a signal upon contact of the composition with a physiological target site as outlined above.

According to embodiments, the target physiological site or location may vary, wherein representative target physiological sites of interest include, but are not limited to: locations in the gastrointestinal tract such as the mouth, esophagus, stomach, small intestine, large intestine, etc. In certain embodiments, the marker is configured to be activated upon contact with a liquid in the target site, regardless of the specific composition of the target site.

The signal obtained from the marker may be a general (generic) signal, such as a signal that merely identifies that the composition contacted the target site, or may be a unique signal, such as a signal that uniquely identifies in some manner that a particular ingestible event marker of a set or plurality of different markers contacted the target physiological site, as desired for a particular application. Thus, the marker may be one in which: when used with a batch of unit doses (e.g. a batch of tablets), the identifier emits a signal that is indistinguishable from the signal emitted by the identifier of any other unit dose member of the batch. In still other embodiments, the marker transmits a signal that uniquely identifies the particular marker. Thus, in some embodiments, the markers emit unique signals that distinguish one type of marker from other types of markers. In some embodiments, the marker transmits a unique signal that distinguishes the marker from other markers. In some embodiments, the marker emits a unique signal, that is, the signal can be distinguished from the signal emitted by any other marker once generated, where such a signal can be considered a universally unique signal (e.g., similar to a human fingerprint that distinguishes from any other fingerprint of any other individual and thus uniquely identifies the individual at a universal level). In one embodiment, the signal may directly transmit information about a given event, or provide an identification code that can be used to retrieve information about the event from a database, i.e., a database linking compositions with identification codes.

The marker 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 pending PCT application serial No. PCT/US2006/16370 filed on 28.4.2006, the disclosure of the various types of signals in that application being specifically incorporated herein by reference. The transmission time of the marker may vary, where in certain embodiments the transmission time may be in the range of from about 0.1 mus to about 48 hours or more, such as in the range of from about 0.1 mus to about 24 hours or more, such as in the range of from about 0.1 mus to about 4 hours or more, such as in the range of from about 1s to about 4 hours, including from about 1 minute to about 10 minutes. Depending on the given embodiment, the marker may transmit the signal once or twice or more, so that the signal may be considered a redundant signal.

In certain embodiments, the marker is sized to be orally ingestible, e.g., by itself or in combination with a physiologically acceptable carrier component of the composition, so as to produce a composition that can be easily administered to a subject in need thereof. Thus, in some embodiments, the marker element is dimensioned to have: a width in the range of from about 0.05 to about 2mm or more, such as from about 0.05mm to about 1mm, such as from about 0.1mm to about 0.2 mm; a length in the range of from about 0.05 to about 2mm or more, such as from about 0.05mm to about 1mm, such as from about 0.1mm to about 0.2 mm; and a height in the range of from about 0.05 to about 2mm or more, such as from about 0.1mm to about 1mm, such as from about 0.05mm to about 0.3mm, including from about 0.1mm to about 0.2 mm. In certain embodiments, the marker is 1mm³Or less, such as 0.1mm³Or less, including 0.2mm³Or smaller. The marker element may take a number of different configurations, such as but not limited to: a chip configuration, a cylindrical configuration, a spherical configuration, a disk configuration, etc., wherein the specific configuration may be selected based on the intended application, method of manufacture, etc.

In some embodiments, the marker may be a marker that can be programmable post-manufacture. For example, the signal generated by the marker may be determined after production of the marker, wherein the marker may be field programmable, mass programmable, fuse blow programmable, and even reprogrammable. Of interest are embodiments in which the unencoded identifier is first generated and subsequently incorporated into the composition and then encoded to transmit an identification signal for the composition. Any convenient programming technique may be employed. In some embodiments, the programming technique employed is RFID technology. RFID smart tag technologies of interest that may be employed in subject identifiers include, but are not limited to: RFID smart tag technology described in U.S. patent nos. 7,035,877, 7,035,818, 7,032,822, 7,031,946, published application No.20050131281, and the like, the disclosures of all of which are incorporated herein by reference. Using RFID or other smart tag technology, the manufacturer/supplier can associate a unique ID code with a given identifier even after the identifier has been incorporated into the composition. In certain embodiments, each individual or entity involved in the treatment of the composition prior to use may incorporate information into the marker, for example in the form of programming with respect to the signal emitted by the marker, for example as described in U.S. patent No.7,031,946, the disclosure of which is incorporated herein by reference.

The identifier of some embodiments includes a memory element, wherein the memory element may vary in its capacity. In certain embodiments, the memory elements have a capacity in the range of from about 1 bit to 1 gigabit or more, such as 1 bit to 1 megabit, including from about 1 bit to about 128 bits. The specific volume employed may vary depending upon the application, e.g., depending upon whether the signal is a plain or encoded signal, and wherein the signal may or may not be labeled with some additional information, such as the name of the active agent(s) associated with the identifier, etc.

The marker member of the embodiment of the present invention has: (a) an activation component; and (b) a signal generating component, wherein the signal generating component is activated by the activation component to generate an identification signal, for example as described above.

An activation component is a component that activates a signal generating element of a marker by transmitting or via interrogation to provide a signal after the component is in contact with a target physiological site of interest, such as the stomach. As disclosed in co-pending PCT application serial No. PCT/US2006/016370, the activation of the marker may be accomplished using a number of different methods, where such methods include, but are not limited to: battery pack completion (battery pack completion), battery pack connection, etc. The different activation methods disclosed in this pending application may be readily adapted to provide the activation described herein, and are thus fully incorporated herein by reference.

An embodiment of the activation element based on a battery completion format employs a battery that, when completed, includes a cathode, an anode, and an electrolyte, wherein the electrolyte is composed at least in part using a liquid present at the target physiological site (in the case where the stomach is the target physiological site, then the gastric fluid present in the stomach). For example, when a gastric juice-activated IEM is ingested, it travels through the esophagus and into the stomach. The cathode and anode provided on the IEM do not constitute a complete battery. However, when the cathode and the anode are exposed to gastric juice, the gastric juice serves as an electrolyte component of the battery, and the battery is completed. Thus, when the IEM contacts the target site, a power source is provided to activate the marker. Then, the data signal is transmitted.

In certain embodiments, the battery employed is a battery comprising two different electrochemical materials that make up the two electrodes (e.g., anode and cathode) of the battery. When the electrode material is exposed and brought into contact with a body fluid, such as stomach acid or other types of fluids, a potential difference (i.e., a voltage) is generated between the two electrodes as a result of the respective oxidation and reduction reactions that occur in the two electrode materials. The two different materials in the electrolyte are at different potentials. For example, copper and zinc have different potentials when placed in a battery (cell). Similarly, gold and magnesium have different potentials.

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

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

Dissolved oxygen can also be used as a cathode. In this case, dissolved oxygen in the body fluid will be reduced to OH at a suitable catalytic surface such as Pt or gold^-. Other catalysts are also possible. Also of interest is dissolved hydrogen in the hydrogen reduction reaction.

In certain embodiments, one or both of the metals may be doped with a non-metal, for example, to enhance the voltage output of the battery. 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 cuprous iodide (CuI) or cuprous chloride 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.

In some of these embodiments, the battery power source may be considered to be a power source that utilizes electrochemical reactions in ionic solutions such as gastric juices, blood or other bodily fluids, and some tissues. FIG. 1 provides an illustration of a marker according to an embodiment of the present invention. The first and second electrode materials (32 and 33) are in an ionic solution 39, such as gastric fluid. This configuration produces a low voltage (V-) and a high voltage (V +) that are applied to circuit 40. The two outputs of this circuit 40 are E041 and E142, which are signal transmission electrodes. In an alternative embodiment, the signal generating element 30 comprises a single electrode. In an alternative embodiment, a coil for communication may be provided. In certain embodiments, structures are provided, such as membranes (membranes), that are larger than the chip defining the path for current to travel.

The electrodes 32 and 33 can be made of any two materials suitable for the environment in which the marker 30 will operate. The active material is any pair of materials having different electrochemical potentials. For example, in some embodiments where the ionic solution 39 is composed of gastric acid, the electrodes 32 and 33 may be made of a noble metal (e.g., gold, silver, platinum, palladium, etc.) so that they are not prematurely eroded. Alternatively, the electrodes can be made of aluminum or any other conductive material that has a sufficient life time in a suitable ionic solution to allow the marker 30 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 regards the active electrode material, any pair of substances-metals, salts or intercalation compounds-with suitably different electrochemical potentials (voltages) and low interlayer resistances is suitable.

In certain embodiments, the IEM is characterized as including series battery structures, wherein the series battery structures may be configured to substantially reduce, if not eliminate, short circuits between electrode elements of different battery structures in series. Because the battery of the present invention is a series battery, the battery includes two or more separate battery structures or cells, wherein the number of battery structures that may be present in a given series battery of the present invention may be two or more, three or more, four or more, five or more, etc., as desired for a given application of the battery. Each individual battery structure comprises at least one anode and at least one cathode, wherein the anode and cathode are present on the surface of a solid support, wherein the support for each anode and cathode may be the same or different.

Aspects of a series battery include configurations that substantially reduce, if not eliminate, short circuits between two or more batteries in a given series. Such short circuit elimination is provided despite the small area occupied by two or more battery packs in series, for example where the battery pack cells are present on the surface of a solid support. Embodiments of the present series battery include configurations in which: in this configuration, the resistance between the electrodes of two different battery structures of a series battery is much higher than the resistance between the electrodes in a given battery structure. In certain embodiments, the ratio of ionic resistance between the electrodes of two different battery structures as compared to the electrodes (i.e., anode and cathode) in a single battery structure is about 1.5 times or more, such as about 5 times or more, including about 10 times or more.

Depending on the particular series battery configuration, a number of different approaches are used that can reduce, if not eliminate, shorting between the batteries. Certain approaches that can be employed are described in more detail below, where the following approaches may or may not be used in combination, depending on the particular battery configuration of interest.

In certain embodiments, two or more cell stack structures are provided in series, wherein each cell stack structure comprises a chamber within which an anode and a cathode are disposed, e.g., on the same interior wall or different interior walls. The chamber has a variable volume, and in some embodiments, the volume of the chamber is from about 10^-12To about 10^-5L, e.g. from about 10^-11To about 10^-7L, and including from about 10^-10To about 10^-8And L. In certain embodiments, the chamber may include a quantity of dried conductive medium, for example as described in PCT application Ser. No. PCT/US07/82563, the disclosure of which is incorporated herein by reference.

In certain embodiments, a given chamber includes at least one liquid inlet port and at least one liquid outlet port, such that: when the composition in which the battery is present reaches the target site of interest, liquid, such as gastric fluid, can enter the chamber, and gas can exit the chamber once the liquid enters. Although the size of the liquid inlet and outlet ports may vary, in some embodiments the ports have a diameter in the range from about 0.01 μm to about 2mm, such as from about 5 μm to about 500 μm.

The ports of a given chamber are arranged relative to the ports of the other chambers to provide efficient ingress of liquid into the chamber and efficient egress of gas from the chamber, and the ports are also arranged such that there is substantially no, if any, short circuit between two or more different chambers of the series stack. Thus, the location of the port is selected in view of the battery pack structure itself and its physical relationship to other battery pack structures of the series battery pack. Any configuration of the fluid ports may be selected so long as the configuration provides the desired resistance ratio (e.g., as described above).

Fig. 28 provides a top view of a series battery according to one embodiment of the invention. In fig. 28, a series battery 150 is composed of two different battery structures 151A and 151B present on a surface 152 of a solid support 153. Battery structure 151A includes a cathode 154A and an anode 155A, while structure 151B includes a cathode 154B and an anode 155B. As shown, the cathode and anode of each cell stack structure reside within the chamber defined by boundaries 156A and 156B. In the wall 156A of the structure 151A there are ports 157A and 158A for the entry and exit of liquid into and from the chamber. Ports 157A and 158A of structure 151A are arranged relative to ports 157B and 158B of structure 151B to substantially eliminate, if not entirely, the possibility of a short circuit between the electrodes of structures 151A and 151B. In the configuration shown in fig. 28, ports 157A and 158A are disposed on opposite walls of boundary 156A, while ports 157B and 158B are disposed on opposite walls of boundary 156B. Further, ports 157A and 158A are present on opposing walls of their boundary element 156A relative to the placement of ports 157B and 158B in boundary element 156B.

Fig. 29 provides a top view of a series connected battery pack according to another embodiment of the present invention. In fig. 29, a series cell 160 is made up of two different cell structures 161A and 161B present on a surface 162 of a solid support 163. Battery structure 161A includes cathode 164A and anode 165A, while structure 161B includes cathode 164B and anode 165B. The structure shown in fig. 29 is different from that shown in fig. 28 in that the battery pack structures are stacked adjacent to each other. As shown, the cathode and anode of each cell stack structure reside within the chamber defined by boundaries 166A and 166B. Within the wall 166A of the structure 161A there are ports 167A and 168A for the ingress and egress of liquid into and out of the chamber. Ports 167A and 168A of structure 161A are arranged relative to ports 167B and 168B of structure 161B to substantially eliminate, if not entirely eliminate, the possibility of a short circuit between the electrodes of structures 161A and 161B.

In addition to or instead of positioning the fluid ports to provide a desired resistance ratio, the fluid ports may be modified to provide a desired resistance between the battery pack structures. For example, the port may include a selectively semi-permeable membrane. Any convenient semi-permeable membrane may be used. The semi-permeable membrane may comprise ePTFE,Polyurethane (polyurethane), silicone rubber, poly (lactide-co-glycolide) (PLGA), poly (caprolactone) (PCL), poly (ethylene glycol) (PEG), collagen, polypropylene, cellulose acetate, poly (1, 1-difluoroethylene fluoride) (PVDF), nafion, or other biocompatible materials. The pore size of the membrane may vary depending on the particular configuration, wherein, in certain embodiments, the membrane has a pore size (molecular weight cut off (MW cutoff) of about 1000d or less, for example about 500d or less, including about 250d or less, such as about 100d or less, for example about 50d or less). In certain embodiments, the membrane is a water-permeable only membrane, such that water (even if there are other liquid components at the target site) passes through the membrane to reach the dry conductive medium precursor of the marker.

In certain embodiments, the solid supports 153, 163 are circuit support elements. The circuit support elements may take any convenient configuration and in some embodiments are Integrated Circuit (IC) chips. The surface on which the electrode element is arranged may be an upper surface, a lower surface or some other surface, e.g. a side surface, as desired, wherein in some embodiments the surface on which the electrode element is at least partially present is the upper surface of the IC chip.

In certain embodiments, the series battery has a small form factor. The battery pack may be about 20mm³Or less, e.g. about 10mm³Or less, such as 1.0mm³Or less, including 0.1mm³Or less, including 0.02mm³Or smaller. In certain embodiments, the battery element is sized to: having a width in the range of from about 0.01mm to about 100mm, such as from about 0.1mm to about 20mm, including from about 0.5mm to about 2 mm; having a length in the range of from about 0.01mm to about 100mm, such as from about 0.1mm to about 20mm, including from about 0.5mm to about 2 mm; and having a height in the range of from about 0.01mm to about 10mm, such as from about 0.05mm to about 2mm, including from about 0.1mm to about 0.5 mm.

Series battery embodiments include those further described in U.S. provisional application serial No.60/889,871, the disclosure of which is incorporated herein by reference.

The signal generating component of the marker element is a structure that emits a detectable signal (e.g., a detectable signal that can be received by a receiver) upon activation by an activation component, for example, as described in more detail below. The signal generating component of some embodiments may be any convenient component or element capable of generating a detectable signal and/or modulating the transduced broadcast power upon activation by an activating component. Detectable signals of interest include, but are not limited to, conducted signals, acoustic signals, and the like. As mentioned above, the signal emitted by the signal generator may be a generic or unique signal, wherein representative types of signals of interest include, but are not limited to: frequency shift encoded signals, amplitude modulated signals, frequency modulated signals, etc.

In certain embodiments, the signal generating element comprises a circuit, as described in greater detail below, that generates or generates the signal. The type of circuit selected may depend at least in part on the drive power provided by the power supply of the marker. For example, in the case where the driving power is 1.2 volts or more, a standard CMOS circuit may be employed. In other embodiments where the drive power is in the range from about 0.7V to about 1.2V, a sub-threshold circuit design may be employed. For a drive power of about 0.7V or less, a zero-threshold (zero-threshold) transistor design may be employed.

In some embodiments, the signal generating component comprises a Voltage Controlled Oscillator (VCO) capable of generating a digital clock signal in response to activation by the activation component. The VCO can be controlled by digital circuitry that is assigned an address and that can control the VCO with a control voltage. The digital control circuit can be embedded on a chip comprising the activation component and the oscillator. The address is encoded using amplitude modulation or phase shift keying to transmit the identification signal.

The signal generating means may comprise a unique transmitter means for transmitting the generated signal to a remote receiver, which may be internal or external to the patient, as described in more detail below. The transmitter means (when present) may take many different configurations, for example depending on the type of signal 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 constituted 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. Thus, the signal transmitter may comprise a variety of different transmitters, such as electrodes, antennas (e.g., in the form of wires), coils, and the like. In some embodiments, the signal is transmitted using one or more electrodes or using one or more wires (two electrode transmitters are dipoles; one electrode transmitter forms a monopole). In some embodiments, the transmitter requires only one diode drop of power. In some embodiments, the transmitter unit transmits the signal using an electric dipole or an electric monopole antenna. In some embodiments, the marker employs a conductive near field mode of communication, in which the body itself is used as the conductive medium. In such embodiments, the signal is not a magnetic signal or a high frequency (RF) signal.

Fig. 2 shows details of one implementation of an electronic circuit that can be employed in a marker according to the present invention. On the left are two battery electrodes, metal 1 and metal 2(32 and 33). These metals, when in contact with the electrolyte, form a battery that provides power to the oscillator 61, in this case shown as a schematic diagram. Metal 132 provides a low voltage (ground) to oscillator 61. Metal 233 provides high voltage (V) to oscillator 61_high). When the oscillator 61 becomes operable, 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, and the counter 64 simply counts the number of clock cycles and stores the count into a plurality of registers. In the example shown here, an 8-bit counter is employed. Therefore, the output of the counter 64 starts at the value "00000000", changes to "00000001" in the first clock cycle, and continues until "11111111". The 8-bit output of counter 64 is coupled to an input of an address multiplexer (mux) 65. In one embodiment, mux 65 contains an address interpreter that can be hard-wired in the circuit and generate a control voltage to control oscillator 61. mux 65 uses the output of counter 64 to reproduce the address in a serial bit stream, which is further fed to the signal transmission driver circuit. mux 65 can also be used to control the duty cycle of the signal transmission. In one embodiment, mux 65 uses the clock count generated by counter 64 to turn on signaling only for the time of 1/16. Such a low duty cycle saves power and also allows other devices to transmit without interfering with their signals. The address for a given chip can be 8 bits, 16 bits, or 32 bits.

According to one embodiment, mux 65 generates a control voltage that serially encodes an address and is used to change the output frequency of oscillator 61. For example, when the control voltage is low, that is, when the serial address bits are at 0, a 1 megaHz signal is generated with an oscillator. When the control voltage is high, that is, when the address bit is at 1, a 2 mhz signal is generated with an oscillator. Alternatively, this can be 10 mhz and 20 mhz, or a phase shift keying approach, where the device is limited to modulating the phase. The purpose of mux 65 is to control the frequency of the oscillator or an alternate embodiment of the oscillating amplified signal.

The output of mux 65 is coupled to an electrode drive 66, which electrode drive 66 can drive electrodes to apply a differential potential to the solution, drive an oscillating current through a coil to generate a magnetic signal, or drive a single monopole to push or pull charge from the solution.

In this manner, the device broadcasts a sequence of 0 s and 1s that make up the address stored in mux 65. The address will be broadcast repeatedly and will continue to broadcast until either metal 1 or metal 2(32 and 33) is consumed and dissolved into solution, at which point the battery will no longer operate.

Other configurations for the signal generating means are of course possible. Other configurations of interest include, but are not limited to, those described in the following applications: co-pending PCT application Ser. No. PCT/US2006/016370 and provisional application Ser. No.60/807060 filed at 11, 7/2006, the disclosures of which are incorporated herein by reference.

In certain embodiments, the activation component includes a power storage element. For example, a duty cycle configuration may be employed, for example, where slow energy from the battery pack is stored in a power storage element, such as a capacitor, which then provides a burst of power that is deployed to the signal generating component. In some embodiments, the activation component includes a timing element that modulates (e.g., delays) power transmission to the signal generating element, whereby signals from different components, such as different IEMs, that are applied (administers) at substantially the same time are generated at different times and are therefore distinguishable.

In certain embodiments, the components or functional blocks of the identifier of the ingestible event marker reside on an integrated circuit, wherein the integrated circuit includes a number of different functional blocks, i.e., modules. Within a given marker, at least some (e.g., two or more up to and including all) of the functional blocks, e.g., power supplies, transmitters, etc., may be present in a single integrated circuit in the receiver. By a single integrated circuit is meant a single circuit structure comprising all the different functional blocks. Thus, an 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 substrate of semiconductor material. The integrated circuits of some embodiments of the present invention may be hybrid integrated circuits, which are miniaturized electronic circuits made up of individual semiconductor devices and passive components bonded to a substrate or circuit board.

Embodiments of the present invention provide a low power, miniaturized ingestible marker that includes an Integrated Circuit (IC) that automatically activates itself upon contact with a patient's bodily fluids, emits a predetermined signal based on locally generated power, and deactivates itself after a certain period of time. In these embodiments, the IEM uses a body fluid of the patient, such as stomach acid, to form the voltaic cell, as described above. In addition, the IEM uses a specific circuit that changes the impedance of the closed circuit forming the voltaic cell to create an external signal by modulating the amplitude and waveform of the current flowing through the patient's tissue and body fluids. As described in more detail below, such a circuit configuration allows the circuit to operate at a low voltage and generate a signal strong enough to be detected by a receiver in contact with the patient's body.

The IC of the IEM can be packaged with an integrated voltaic cell, which can be fabricated on the same substrate as the IC circuit. This wafer level integration significantly reduces the die and simplifies the manufacturing process. As a result, the cost per IEM is appreciably reduced. In one embodiment, anode and cathode electrode materials are fabricated on each side of the substrate such that the IC logic is disposed between the two electrodes. In one embodiment, the logic circuit is disposed at a location selected to minimize the area of vertical overlap with the anode electrode or the cathode electrode.

Fig. 3 illustrates an exemplary device configuration of an IEM IC according to one embodiment of the invention. In one embodiment, the substrate 204 of the IC chip is coupled to the anode of the voltaic cell (S1), which can be a magnesium (Mg) layer 206 coated on the back side of the substrate 204. On the opposite side of the substrate 204 is a layer 202 of cathode (S2) material, which in this example is copper chloride (CuCl). The electrodes 202 and 206, and the body fluid used as the electrolyte, form a voltaic cell. The IEM IC circuit fabricated on substrate 204 is an "external" circuit that forms the return circuit for the voltaic cells. In essence, the IEM IC changes the impedance of this "external" circuit, thereby changing the amount of current flowing through the body fluid. A receiving circuit, for example, in contact with the body fluid, located on an individual health receiver described in more detail below, is capable of detecting this current change and receiving the encoded message.

Note that the two electrodes S1 and S2 of the voltaic cell also serve as transfer electrodes for the IC. This configuration significantly reduces the complexity of the IC chip. Furthermore, because liquid-metal interfaces often exhibit high impedance, the use of discrete electrode pairs other than voltaic cell electrodes introduces additional high impedance to the circuit, thereby reducing transmission efficiency and increasing power consumption. Thus, the use of voltaic cell electrodes for transmission also improves the power efficiency of the IC circuit.

The IC of the IEM acts as an ingestible transmitter that transmits a unique identification code upon power-up. The IC can be packaged in a pharmaceutically acceptable vehicle (vehicle), such as described above. When the IEM is swallowed and enters the stomach, the integrated voltaic cell or battery uses the stomach acid as the battery electrolyte to power the main chip and then begin broadcasting. Furthermore, several pills can be ingested and delivered simultaneously. During operation, a unique identification code, for example using BPSK modulation, is broadcast. The broadcast can be received and demodulated using, for example, a receiver that is implanted under the skin or in contact with the body tissue of the patient, as described below. The receiver can decode and store the identification code using the time stamp.

In one embodiment, the IEM IC includes an impedance detection circuit. The circuit is configured to detect an impedance between the anode and cathode electrodes. When the electrodes are not immersed in an electrolyte such as gastric acid, the impedance between the electrodes is high and the IC is not activated. When the electrode is in contact with the electrolyte and the impedance detection circuit detects a drop in impedance, the IC is activated.

Embodiments of the present invention allow pellets to operate at exceptionally low voltages. In general, ICs can operate with a power supply of 0.8-2V. In one embodiment, the IC is configured to operate with a power supply of approximately 1.0-1.6V. In addition, voltaic cells exhibit an internal resistance of 200-10K ohms. In one embodiment, the voltaic cell exhibits an internal resistance of about 500-5K ohms. The IC also provides an ultra-stable carrier clock frequency, facilitating error-resilient communication.

In one embodiment, the IC includes a three-part circuit. The first part is an impedance detection circuit using a battery pack as a power source. The second part is the main circuit that broadcasts the message. The impedance detection circuit is capable of maintaining the main circuit at substantially zero power consumption until the battery pack detects an impedance below 10K ohms. When the impedance drops to about 10K ohms, the main circuit is activated and the impedance detection circuit is able to disconnect its coupling to the battery pack. The third part is a monitoring circuit (watchdog circuit) designed to protect the patient's safety in the event of a dangerous situation.

Fig. 4 presents an exemplary schematic diagram illustrating the design of an IEM IC in accordance with one embodiment of the present invention. In general, the IEM chip has a battery section 302 and an IC circuit 304. The battery portion 302 includes voltaic cell electrodes that form voltaic cells when coupled with an electrolyte. The two battery electrodes are coupled to a high voltage rail (VCC) of the IC circuit and ground, respectively. IC circuit 304 includes pass switch transistor 306, recharge transistor 308, recharge protection diode 310, recharge capacitor 316, local oscillator 314, and control logic 312. The local oscillator 314 generates one or more carrier frequencies that are used by the control logic 312 to issue a transmit command (labeled "broadcast") to turn the transmit switch transistor 306 on and off. For example, oscillator 316 can produce a 20KHz signal based on which control logic 312 can generate a Binary Phase Shift Keying (BPSK) encoded message. The control logic 312 then turns the transistor 306 on and off to transmit these messages.

When transistor 312 is turned on, a low impedance external return circuit is provided between the two voltaic cell electrodes. Thereby, the current flowing through the patient's body is also increased. When transistor 312 is turned off, the external return circuit between the two voltaic cell electrodes presents a high impedance. Accordingly, the current flowing through the patient's body is significantly reduced. Note that the maximum current (current draw) of the remaining circuits, such as oscillator 314 and control logic 312, is low enough to have a significant difference between the body current for the broadcast and quiet periods.

When transistor 306 is turned on, the two voltaic cell electrodes are effectively shorted. As a result, the voltage provided by the electrodes is significantly lower than the voltage at which the transistor 306 is turned off. To ensure that the control logic 312 continues to operate properly, the recharge capacitor 316 provides the required Voltage (VCC) to the control logic 312. Note that the recharge capacitor 316 is recharged while the IC chip is in a quiescent period, i.e., while the transistor 306 remains off. When transistor 306 is turned on, which causes a voltage drop between the battery electrodes, diode 310 prevents the charge stored in capacitor 316 from flowing back to the battery electrodes. In one embodiment, diode 310 is a schottky diode to ensure fast switching time.

It is possible that during the transfer period oscillator 314 and/or control logic 312 has depleted the charge stored in capacitor 316, causing VCC to drop below a certain threshold. For example, the voltage provided by the recharge capacitor 316 may drop below the voltage provided by the voltaic cell. The difference between these two voltages may not be large enough to turn on the schottky diode 310. In this case, the control logic 312 can issue a recharge signal to turn on the recharge switch transistor 308, the recharge switch transistor 308 couples the battery pack voltage to the capacitor 316 and recharges the capacitor 316.

In one embodiment, the communication between the IEM IC and the receiver is simplex. That is, the IEM IC only transmits signals and does not receive any signals. The communication is performed by the patient's body tissue and body fluid via a direct coupling between the IC electrodes and the receiver circuit. The transmission is performed at two frequencies, for example, one 10kHz and the other 20 kHz. Other numbers of frequencies and other frequency values are also possible. Generally speaking, different data packet formats can be used with the system of the present invention. In one embodiment, the transmitted data packet is 40 bits long, 16 of which are used as the synchronization/preamble pattern. The remaining 24 bits carry the payload that encodes the identifier of the IEM. In one embodiment, the payload can also include a Forward Error Correction (FEC) code to facilitate more robust transmission (robust). In one embodiment, the data bits occupy 16 cycles of the carrier clock. The bits are BPSK encoded. Other coding schemes are also possible. In yet another embodiment, the 16-bit synchronization/preamble pattern includes 12 bits for synchronization and 4 bits for preamble.

Table 1 shows an exemplary packet format of a 16IEM chip according to one embodiment of the invention.

Chip ID # | synchronization | preamble | 24 bit payload | disable broadcast mode

0000000000000 | 1010 | 110010111000110010111000 | is disabled by 984 bits

1000000000000 | 1010 | 101001011100101001011100 | is disabled by 984 bits

2000000000000 | 1010 | 100100101110100100101110 | is disabled by 984 bits

3000000000000 | 1010 | 100010010111100010010111 | is disabled by 984 bits

4000000000000 | 1010 | 110001001011110001001011 | is disabled by 984 bits

5000000000000 | 1010 | 111000100101111000100101 | is disabled by 984 bits

6000000000000 | 1010 | 111100010010111100010010 | is disabled by 984 bits

7000000000000 | 1010 | 101110001001101110001001 | is disabled by 984 bits

8000000000000 | 1010 | 110111000100110111000100 | is disabled by 984 bits

9000000000000 | 1010 | 100101110001011010001110 | is disabled by 984 bits

10000000000000 | 1010 | 110010111000001101000111 | is disabled by 984 bits

11000000000000 | 1010 | 101001011100010110100011 | is disabled by 984 bits

12000000000000 | 1010 | 100100101110011011010001 | is disabled by 984 bits

13000000000000 | 1010 | 100010010111011101101000 | is disabled by 984 bits

14000000000000 | 1010 | 110001001011001110110100 | is disabled by 984 bits

15000000000000 | 1010 | 111000100101000111011010 | is disabled by 984 bits

TABLE 1

Fig. 5 shows an exemplary transmission sequence of a bit pattern of "0010" according to one embodiment of the present invention. Each bit is represented by 16 clock cycles. Depending on the battery pack configuration, it may be desirable to limit the duty cycle of the drive transistor 306 in order to maintain sufficient power to the oscillator. In one embodiment, the "on" state of the drive transistor 306 is maintained substantially equal to or less than 25 μ s. Thus, during a 20kHz transmission where the clock period is 50 μ s, the driver is turned on for 25 μ s and turned off for 25 μ s. During 10kHz transmission, the driver is turned on for 25 μ s and turned off for 75 μ s. A logic "0" transmission begins at the rising edge of the data clock cycle and lasts 16 clock cycles. Accordingly, a logic "1" transmission begins on the falling edge of the data clock cycle and also lasts 16 cycles. Note that other duty cycle configurations and coding schemes are also possible.

FIG. 6 shows an exemplary waveform for a 20kHz transmission of the sequence "10101" according to one embodiment of the invention. Note that for purposes of illustration, each logic bit takes 3 clock cycles instead of 16 cycles. FIG. 7 shows an exemplary waveform for a 10kHz transmission of the sequence "10101" of one embodiment of the present invention. Note that each logic bit is also shortened to 3 clock cycles.

In certain embodiments, the operation of the IEM can be divided into the following four periods: storage period, retention period, broadcast period, and power down (power down). During the storage period, the IC is turned off and typically consumes less than 5 mA. During the hold period, the IC is turned on. However, broadcasting is disabled to allow the oscillator clock signal to stabilize. In one embodiment, the packet is transmitted 256 times during the broadcast period. During each transmission, the transmit driver transistor operates to transmit a packet and is then turned off for a period of time. When the transmitter driver transistor is turned off, the rest of the IEM IC remains powered on. In one embodiment, the average duty cycle during the entire broadcast period is maintained at about 3.9%. Other values of the average duty cycle are also possible. During the power down period, the IEM IC is gradually (graceful) powered down. The broadcast is completely disconnected. FIG. 8 shows an exemplary state diagram illustrating the operation of an IC according to one embodiment of the invention. During operation, the system first enters a storage period 702, when the impedance detection circuit operates to detect the impedance between the two battery poles. At the same time, the IC is power-gated off. After the impedance detection circuit detects a low impedance, e.g., about 10k ohms, the circuit releases the IEM IC from the power-gated off state. Correspondingly, the system enters a hold period 704. During the hold period 704, the broadcast function of the chip is disabled for approximately 10 seconds to allow the clock signal to stabilize. The system then enters a broadcast period 706. During this period, the data packet is broadcast twice in one cycle, once at 10kHz and once at 20kHz, with a periodic pattern of ON for 32ms and OFF for 768ms for 10kHz and ON for 64ms and OFF for 1536ms for 20 kHz. Each cycle is about 2.4 seconds and the system completes 256 cycles in about 10 minutes. Note that at each frequency, the transmission duty cycle of the chip is kept at about 3.9%. During the remaining 96.1% of the time, the recharge capacitor is recharged. The system then enters a power down state 708, at which time the oscillator is stopped and the chip is power gated down. Note that if for some reason the chip continuously keeps broadcasting until the end of the 10 minute broadcast period, the system resets the power of the chip and starts the broadcast process again. This may occur, for example, when the conductivity of the stomach (conductivity) suddenly drops such that the oscillator and its generated clock do not operate properly.

Table 2 presents an exemplary set of operating parameters of an IC in accordance with one embodiment of the present invention.

TABLE 2

Table 3 presents DC parameters for a set of exemplary IEM circuits according to an embodiment of the present invention.

TABLE 3

Table 4 presents AC parameters for a set of exemplary IEM circuits according to one embodiment of the present invention. Note that for practical chip designs, the target value can be +/-5% to +/-10% outside the temperature, supply voltage, and threshold voltage ranges of the transistors.

Description of the Specification Unit

Min Typ Max

frequency of the f _ osc oscillator 256320384 kHz

f1_ broadcast low broadcast frequency 81012 kHz

f2_ broadcast high broadcast frequency 162024 kHz

T _ brdcsten 81012 seconds when enabling chip to power on

Hold time before broadcast

Time for T _ brdcstoff to broadcast 81012 minutes

The Amplitude V of the Signal Amplitude is 1.6-1.57-1.45 volts

＝Vbat-(voltage-drop-over-R R＝500

battary) Vbattery and rbaattery V1.6-1.6

Is 5K (can be neglected)

For slow periods, VCC decreases ZoutputTRX)

(drop) is so much that the output V is 1.2 to 1.14 to 1.08

The impedance of the driver increases, which will decrease R to 500

Amplitude V of less signal is 1.2-1.2

The output voltage is at Rbatt and R-5K (can be neglected)

Voltage divider between ZoutputTRX)

As a result of (A)

TABLE 4

Regarding the physical size of the IEM chip, the size of the chip can be in the range of 0.1mm²To 10mm²In the meantime. Because of the particular IC configuration, embodiments of the present invention are able to provide an IEM chip that is small enough to be included in most types of pills. For example, an IEM IC chip can have less than 2 x 2mm²The size of (c). In one embodiment, the IC chip can be 1 × 1mm²Or less. In one embodiment, the chip is 1mm by 1 mm. The lower side of the substrate of the chip serves as the S1 electrode, and S2 is a pad fabricated on the upper side of the substrate. The size of the bonding pad can be 2500 μm²To 0.25mm²In the meantime. In one embodiment, the pads are about 85 μm by 85 μm.

Although the previous description discloses a chip configuration using the same electrodes for battery and signal transmission, in certain embodiments separate electrodes are used for power generation and signal transmission.

Fig. 9 shows one exemplary IEM chip configuration in which two discrete electrodes are used for battery and signal transmission, respectively. A ground electrode 802 is fabricated on the underside of substrate 800. On the upper side of the substrate 800 are a battery electrode 804 and a transfer electrode 806. Also fabricated on substrate 800 is a circuit region 808. During operation, the battery formed by electrodes 802 and 804 provides power to the circuitry within region 808. This circuit drives the transmit electrodes 806 and 802 and produces a change in current in the patient. It is possible that current flowing from the transfer electrode 806 to the ground electrode 802 may flow under the circuit region 808, resulting in a change in the electrical potential in the circuit element. This potential change can cause undesirable latch-up in the transistors in circuit region 808.

One way to avoid this latch-up is to separate the transmission electrode region from the circuit region so that there is minimal lateral current under the circuit that would change the potential. For example, the substrate contact can be located in a region that is capable of diverting current flowing from the circuit region. FIG. 10 illustrates an exemplary chip configuration that minimizes circuit latch-up according to one embodiment of the present invention. As shown in fig. 10, the substrate contact regions may be disposed at four corners of the substrate. As a result, the electrode circuit flowing to the substrate is turned to the four corners, leaving the circuit area in the middle. Similarly, a particular layout design can be used for the chip configuration of the merged electrodes. Fig. 11 shows an exemplary layout that minimizes latch-up in an IEM chip. As shown in fig. 11, on the bottom of the substrate 1000 is a Mg electrode 1002. On the upper side of the substrate 1000 is a CuCl electrode 1006. Electrodes 1002 and 1006 function as both battery electrodes and transmission electrodes. Below the CuCl electrodes 1006 are a number of transfer driver circuit regions 1004, which are located at the periphery of the layout. A control logic circuit region 1008 is located at the center of the chip. In this way, the current flowing from the transfer driver to the Mg electrode 1002 is diverted away from the control logic circuit region 1008, thereby avoiding any latch-up in the transistor.

Fig. 12 provides an exploded view of a particular embodiment of an IEM according to the present invention. In fig. 12, IEM 1200 comprises a silicon dioxide substrate 1201, for example having a thickness of 300 μm. On the lower surface there is an electrode layer 1202 of magnesium, for example with a thickness of 8 μm. Between the Mg electrode layer 1202 and the lower surface of the substrate 1201 is arranged, for example, a layer having a thickness of 1000Titanium layer 1203. An electrode layer (CuCl)1204 having a thickness of, for example, 6 μm is disposed on the upper surface of the substrate 1201. Arranged between the upper electrode layer 1204 and the substrate 1201 is, for example, a layer having a thickness of 1000And a layer of gold 1206, for example having a thickness of 5 μm.

While the above signal generation and transmission scheme (protocol) is described in terms of activation and transmission occurring substantially simultaneously, e.g., after contact with a target site and/or environment, in certain embodiments, the activation of the IEM and transmission of the signal can be discrete events, i.e., can occur at different times separated by periods of time. For example, the IEM may include a conductive medium that provides activation prior to ingestion. In certain embodiments, the IEM is encapsulated in a liquid, an electrolyte sponge, or other conductive medium so that it can be externally activated prior to ingestion. In these embodiments, the receiver is configured to detect the emitted signal only when the signal is emitted from the target region of interest. For example, the system may be configured such that transmission occurs only when in contact with body tissue, thereby ensuring proper event marking. For example, activation can occur by manipulation of the IEM. A pressure sensitive membrane that ruptures upon manipulation or contact may be employed, wherein the rupture causes the electrolyte material to be able to connect the battery elements. Alternatively, degradation of the capsule in the stomach can also release the stored electrolyte and activate the IEM. The IEM is encapsulated in a sponge (composed of a conductive material that holds water in the vicinity of the IEM), allowing activation to occur when a small amount of liquid is present. This configuration counteracts poor transport properties when the conductive liquid is absent.

Note that other layout designs are possible. In addition, silicon-on-insulator (SOI) fabrication techniques can be used to insulate the logic control circuitry area from the conductive substrate so that the transmission current cannot interfere with the control circuitry.

In certain embodiments, the marker composition is disrupted upon administration to the subject. Thus, in certain embodiments, the composition is physically disrupted, e.g., dissolved, degraded, corroded, etc., after being transported to the body via, e.g., ingestion, injection, etc. The compositions of these embodiments are distinguished from devices that are configured to be ingested and undergo substantially, if not completely, transport through the gastrointestinal tract.

In certain embodiments, the marker does not include an imaging system, such as a camera or other visualization or imaging element, or a component thereof, such as a CCD element, an illumination element, or the like. In certain embodiments, the marker does not include a sensing element other than an activator that detects contact with the target physiological site, for example, for sensing a physiological parameter. In certain embodiments, the marker does not include a pusher element. In some embodiments, the marker does not include a sampling element, such as a fluid acquisition element (fluidnetival element). In certain embodiments, the marker does not include an actuatable activator-delivery element, such as an element that retains the activator in the composition until a signal is received that causes the delivery element to release the activator.

The marker may be manufactured using any convenient processing technique. In certain embodiments, a planar processing scheme is employed 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 a circuit-supporting element. In certain embodiments, a planar processing scheme is employed in a wafer bonding scheme to create a battery source. Planar processing schemes including surface micro-machining and bulk micro-machining techniques, such as micro-electromechanical systems (MEMS) fabrication techniques, may be employed. Deposition techniques that may be employed 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, e.g., via chemical mechanical polishing, laser grinding, Electrical Discharge Machining (EDM), and the like. Also of interest are lithography schemes. Of interest in certain embodiments is the use of planar processing schemes in which structures are built and/or removed from one or more surfaces of an initially planar substrate using a plurality of different material removal and deposition schemes 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.

In some fabrication schemes, a sacrificial layer is used. For example, in certain three-dimensional embodiments, such as those described in more detail below, where a gap or spacing is desired, sacrificial layers may be employed during manufacturing, where the sacrificial layers are removed in whole or in part prior to use of the battery. Sacrificial layer materials of interest include, but are not limited to, photoresists that can be hard baked (hard bakes) to make them stable. Once the deposition of the upper electrode is complete, the sacrificial photoresist layer can be removed using any convenient scheme, such as using acetone. Other materials that can be used as sacrificial layers include, but are not limited to: silicon nitride, silicon dioxide, benzocyclobutene (benzocyclobutene), or tungsten. Other methods of removing the sacrificial layer include, but are not limited to, vapor phase removal, dry etch removal, and hydrogen peroxide.

As described above, in certain embodiments, a planar process manufacturing scheme, such as MEMS, is employed to manufacture a battery pack comprising an anode and a cathode that are at least partially present on the same surface of a circuit-supporting element. "present at least partially on the same surface of the circuit supporting element" means that at least a part of the cathode and at least a part of the anode are present on the same surface of the circuit supporting element, wherein both electrodes may be present entirely on the surface of the circuit supporting element, one electrode may be present entirely on the surface and the other electrode is present only partially on the surface, for example, wherein the other electrode comprises a portion present on a surface different from the surface on which the first electrode is arranged, and wherein both electrodes are present partially on the same surface and then partially on different surfaces. The implantable on-chip battery pack can be deposited on the chip in a variety of ways. 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 arranged may be an upper surface, a lower 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 upper surface of the IC chip.

Using MEMS fabrication techniques, the battery pack of embodiments of the present invention can be fabricated to have very small dimensions, for example, as previously described. The electrodes of the battery can be deposited in a variety of thicknesses, for example in the range from about 0.001 to about 1000 μm, such as from about 0.5 to about 10 μm. Wherein a gap is present between the electrodes, said gap having a width in the range from about 0.001 to about 1000 μm, such as from about 1 to about 10 μm.

In one embodiment, two cathodes are deposited on the surface of the chip, and an anode separates the two cathodes. A dielectric layer is deposited between the electrodes and the circuit chip, and circuit contacts penetrate the chip surface. This configuration allows a plurality of battery packs to be arranged in series, which provides a larger voltage to be applied to the circuit chip after the battery packs are activated by contact with the target site. Fig. 30 shows a planar interdigitated battery layout. A dielectric material 9 is deposited on the circuit chip 5 containing the circuit contacts 7. An anode 3 separates the first cathode 1 from the second cathode 2. Embodiments employing this configuration include embodiments in which the battery packs are in series (e.g., as described above), which provides a higher voltage that the circuit can use once in contact with the target physiological site. In certain embodiments, this configuration also provides low battery impedance because the electrodes are then closely arranged together. This embodiment is characterized in that both the cathode and the anode elements are present entirely on the same surface of the chip.

In another embodiment, at least one of the anode and cathode elements is present partly on the same surface as the other electrode, but also partly on another surface of the chip, e.g. a side, a bottom surface, etc. For example, the anode may be present on a small portion of one side of the surface of the circuit chip, and wound around the side to cover the bottom of the circuit chip. The cathode is present on the remainder of the upper surface of the circuit chip and provides a small gap between the cathode and the anode. In one aspect, the large cathode plate covers most of the upper surface of the circuit chip, while the anode covers the lower surface of the circuit chip and wraps the side to the upper surface. Two electrodes (e.g., plates) can be connected to the circuit chip via circuit contacts through a dielectric layer on the upper surface of the chip. Fig. 31 shows the dielectric material 9 covering the circuit chip 5. The cathode 1 is deposited over a large part of the upper surface of the dielectric material 9. The anode 3 is deposited over the remaining part of the upper surface and the side and lower surfaces of the circuit chip 5, leaving a separation between the upper cathode 1 and anode 3. In certain embodiments, the separation is in the range from about 0.001 to about 1000 μm, such as from about 0.1 to about 100 μm, for example about 2.0 μm. In some embodiments, the circuit chip 5 may be flipped during manufacture so that the anode 3 is deposited on the lower surface of the chip 5. Circuit contacts 7 for both the anode 3 and the cathode 1 are provided on the upper surface of the circuit chip 5, running down through the dielectric 9. This configuration provides a large electrode area because it uses both the upper and lower faces and one of the side faces of the circuit chip 5.

In another embodiment, the cathode is disposed on the upper surface of the circuit chip, for example in the form of a layer deposited over a dielectric on the upper surface of the circuit chip. During fabrication, a sacrificial layer is then deposited over the cathode layer. An anode layer is then deposited over the sacrificial layer. The sacrificial layer can then be removed and a gap left to provide an area for target site liquids, such as electrolytic gastric juices, to contact the anode and cathode. With this embodiment it is possible to stack further electrode layers one on top of the other after depositing a further sacrificial layer on the anode. In doing so, the implantable on-chip battery packs can be arranged in series, for example, where a vertical series configuration is desired. Fig. 32 shows the dielectric layer 9 disposed on the circuit chip 5. The cathode 1 is deposited on the dielectric layer 9 and is passed to the circuit contact 7. A sacrificial layer (not shown) is deposited over the cathode 1 to provide a substrate for the anode 3 to be deposited. Once the sacrificial layer is deposited, its surface can be etched to provide a rougher surface. Thus, after the anode 3 is deposited on the sacrificial layer, the bottom of the anode 3 will conform to the rough surface. The sacrificial layer can also be deposited using cathodic arc, which deposits the sacrificial layer in a rough and porous manner. A plurality of anodes 3 can be deposited in a plurality of sizes to supply a plurality of voltages to the chip circuit 5. Once the anode 3 is deposited, the sacrificial layer can be removed to create a gap, wherein in certain embodiments the gap is in the range from about 0.001 to about 1000 μm, such as from about 0.1 to about 100 μm, and including from 1 to about 10 μm. In certain embodiments, the gap between the anode 3 and the cathode 1 is selected to provide a battery having a desired impedance and different currents. The area of the anode 3 can also be made to provide different voltages to the circuit chip 5 as required. Thus, the anode 3 can be manufactured to provide multiple voltages and multiple impedances and currents to the same chip using a minimum of chip space.

In another embodiment, a cathode layer is deposited over a dielectric on the surface of the chip, and a plurality of anodes are deposited over different areas of the cathode. The method includes depositing a sacrificial layer to separate the anode from the cathode during fabrication, and creating a gap between the common cathode and two or more anodes disposed over the cathode by removing the sacrificial layer. As can be seen from fig. 33, the anode 3 may be anchored to an outer region of the circuit chip 5. At point 4, a circuit contact for the anode 3 may be arranged. Fig. 33 differs from fig. 32 in that only two anodes 3 are deposited on the cathode 1. The two anodes 3 are also of different sizes and therefore provide different surface areas. The anode 3 can be manufactured to meet the requirements of the application. If multiple voltages are required, the anode 3 can be made of different materials. If multiple currents are required, the anode 3 can be deposited in multiple sizes. If multiple impedances are required, the anode 3 can be deposited with different sized gaps between the anode 3 and the cathode 1.

In another embodiment, two anode plates are present on the surface of the circuit chip with a cathode circuit contact deposited in the middle of the surface. The cathode is then attached to the circuit contact in such a way that it hangs over the anode, thereby forming a gap between the cathode and the anode. Fig. 34 shows another embodiment of an implantable on-chip capacitor using the space above the circuit chip 5. An insulating layer 171 is formed on the surface of the circuit chip 5. A circuit contact for the cathode 1 is formed at the center of the chip, while the anode 3 is formed on either side, leaving a gap between the circuit contact and the anode 3. During manufacture, a sacrificial layer is then deposited on the anode 3 to form a substrate for the cathode 1. Once the cathode 1 is deposited, the sacrificial layer is removed to provide a space for liquid to enter.

In another embodiment, a cathode is present on a surface of the circuit chip, wherein the anode is arranged in a manner sufficient to provide an open cavity over and at least partially surrounding the cathode. An opening is provided that allows electrolyte to flow into the cavity, which creates a current path between the anode and the cathode. A plurality of openings may be provided as desired, for example to ensure that no air is trapped within the cavity. In fig. 35, the anode 3 surrounds the cathode 1, thereby creating a cavity 173 into which electrolyte will enter. An insulating layer 11 separates the cathode 1 from the circuit chip 5. After contact with the target site, electrolyte will enter the cavity 173 through the opening 175. Openings 175 may be provided in opposite corners of the cavity 173 to ensure that no air is trapped in the cavity. The configuration of fig. 35 may be required in some instances. For example, when a sufficient amount of electrolyte may not be present in the stomach, the implantable on-chip battery can be manufactured to contain the liquid in contact with the electrodes around the electrodes, as shown, for example, in fig. 35. By doing so, the stack will ensure that there is a continuous reaction, but if it is open, liquid can enter and exit the reaction zone and cause the stack to stop.

When a given battery cell includes a cavity such as shown in fig. 35, a surface coating for regulating the flow of liquid into and out of the cavity may be employed as desired. In some embodiments, a portion of the surface of the cavity, such as the inner surface of the cavity, may be modified to provide desired liquid flow characteristics. For example, the surface energy of one or more surfaces of the liquid port and the cavity may be modified to provide enhanced liquid flow into the cavity. For example, the surface energy of one or more surfaces of the cavity may be increased so that the surface becomes more hydrophilic. A variety of different surface energy modification schemes may be employed, wherein the particular scheme selected may depend on the particular composition of the barrier layer (barrier) and the desired surface energy characteristics. For example, if it is desired to increase the surface energy of a given surface, that surface may be subjected to a plasma treatment in contact with a surface energy modifying polymer solution, such as described, for example, in US patents nos. 5948227 and 6042710, each of which is fully incorporated herein for all purposes. In certain embodiments, a hydrophilic substance may be employed to attract and retain the electrolyte in the cavity, for example as described in PCT application Serial No. PCT/US07/82563, the disclosure of which is incorporated herein by reference.

In certain embodiments, one or more surfaces of the battery, such as the interior surfaces of the cavity, are modified to accommodate bubble formation and placement on the surfaces. For example, activation of the stack may result in bubble generation, such as hydrogen bubble generation. Surface modification may be employed so that, for example, bubbles generated on the active cathode during activation are drawn from the cathode to another location, e.g., a location remote from the cathode, outside the chamber, etc.

The above-described embodiments are examples of batteries produced by the planar processing scheme of the present invention, wherein at least one anode and at least one cathode are present on the same surface of the circuit-supporting element. The above description is not intended to be limiting, as other embodiments having the above common features may be produced.

In another embodiment of the present invention, a planar processing scheme is employed in a wafer bonding scheme to create a battery source. In some of these embodiments, a dielectric can be deposited on the circuit chip. A cathode layer can then be deposited on the dielectric. The anode can be deposited on a separate support wafer. The anode can then be bonded to the bottom of the circuit chip at a point where the support wafer can be etched away to allow the anode surface to make contact with the electrolyte. As such, another manufacturing technique that can be used to manufacture implantable on-chip battery packs is wafer bonding. The implantable on-chip battery pack can be manufactured using two wafers, such as in the embodiment of fig. 36. The circuit chip 5 provides a substrate for the cathode 1, which cathode 1 is deposited on top of the dielectric 9. This constitutes a first wafer assembly 179. The second wafer assembly 178 is comprised of a support wafer 177 and an anode 3. The anode 3 is deposited on the surface of the support wafer 177. The anode 3 is then bonded to the circuit chip 5, and the bulk support wafer 177 is etched away to expose areas of the anode 3. The amount of the support wafer 177 that is etched away depends on the desired area of the anode 3. This manufacturing method can be used for implantable on-chip battery packs because it can be arranged in the support wafer 177 if more circuitry is desired.

All of the embodiments and figures discussed above can be modified to swap the cathode for the (switch) anode and vice versa to provide other additional disclosed configurations of the present invention. Examples of additional planar processing fabrication contemplated include those described in U.S. provisional application serial No.60889868, the disclosure of which is incorporated herein by reference.

Optional physiologically acceptable carrier component

In addition to the marker components described above, the ingestible event marker may be present in (i.e., incorporated into) a physiologically acceptable carrier component, such as a composition or vehicle that assists in the ingestion of the marker and/or protects the marker until it reaches the target site of interest. "physiologically acceptable carrier means" is used to denote a composition that can be an ingestible solid or fluid (e.g., a liquid).

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

Liquid compositions may include suspensions or solutions of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s), e.g., ethanol, glycerol, sorbitol, non-aqueous solvents such as polyethylene glycol, oils, or water, with suspending agents, preservatives, surfactants, wetting agents, flavoring agents, or coloring agents. Alternatively, liquid formulations can be prepared from reconstitutable powders. For example, a powder comprising the active compound, suspending agent, sucrose, and sweetener can be reconstituted with water to form a suspension; and a syrup can be prepared from a powder containing the active ingredient, sucrose and sweetener.

The compositions in the form of tablets or pills can be prepared using any suitable pharmaceutical carrier(s) conventionally used for the preparation of solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders (binders) such as polyvinylpyrrolidone. The tablets can also be provided with a coating of coloured film or be included as a colour as part of the carrier(s). Furthermore, the active compounds can be configured in the form of controlled release agents as tablets comprising hydrophilic or hydrophobic matrices.

"controlled release," "sustained release," and similar terms are used to refer to the mode of delivery of an active agent that occurs when the active agent is released from a delivery vehicle at an identifiable and controlled rate over a period of time, rather than diffusing immediately upon administration or injection. Controlled or sustained release may extend for hours, days or months, and may vary as a function of a number of factors. For the pharmaceutical compositions of the present invention, the release rate will depend on the type of excipient selected and the concentration of the excipient in the composition. Another determinant of release rate is the rate of hydrolysis of linkages (linkages) between and among units of polyorthoesters (polyorthoesters). 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, the acidity (internal or external to the matrix) of the medium, and the physical and chemical properties of the active agent in the matrix.

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

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

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

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

Optional active agent

In certain embodiments, the ingestible event marker does not include a pharmaceutically active agent. Thus, the identifier, as well as any carrier or other component comprising the ingestible event marker, does not include an active agent.

In other embodiments, the ingestible event marker includes an active agent. By "active agent/carrier component" is meant a composition, which may be a solid or a fluid (e.g., a liquid), having an amount, e.g., a dose, of active agent present in a pharmaceutically acceptable carrier. The active agent/carrier component may be referred to as a "dosage formulation".

An "active agent" includes any compound or mixture of compounds that produces a physiological result (e.g., a beneficial or useful result) upon contact with a living organism (e.g., a mammal such as a human). The active agent is distinct from ingredients such as vehicles, carriers, diluents, lubricants, binders, and other formulating aids (formulating aids) as well as encapsulating or otherwise protecting ingredients. The active agent can be any molecule, as well as a binding moiety or fragment thereof, that is capable of modulating a biological process in a living subject. In certain embodiments, the active agent may be a substance for 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.

The active agent (i.e., drug) is capable of interacting with a target in a living subject. The target may be a number of different types of naturally occurring structures, wherein the target of interest includes both intracellular and extracellular targets. The target may be a protein, phospholipid, nucleic acid, etc., with proteins being of particular interest. Targets for specific proteins of interest include, but are not limited to, enzymes such as kinases, phosphatases, reductases, cyclooxygenases, proteases, and the like, targets including domains involved in protein-protein interactions (such as SH2, SH3, PTB, and PDZ domains), structural proteins such as actin, tubulin, and the like, membrane receptors, immunoglobulins such as IgE, cell adhesion receptors such as integrins, and the like, ion channels, transmembrane pumps, transcription factors (transcription factors), signaling proteins, and the like.

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

Drugs of interest may include cyclic carbons (cyclic carbons) or heterocyclic structures and/or aromatic or polycyclic aromatic structures substituted with one or more of the functional groups described above. Also of interest as drug bases are structures found in biomolecules, including peptides, carbohydrates, fatty acids, steroids, purines, pyrimidines, and their derivatives, structural analogs, or combinations thereof. These compounds can be screened to identify those of interest, where a variety of different screening protocols are known in the art.

The active agent may be derived from naturally occurring or synthetic compounds that may be obtained from a wide variety of sources, including libraries of synthetic or natural compounds. For example, a number of approaches are available for the random and directed synthesis of a wide variety of organic compounds and biomolecules (including the preparation of randomized oligonucleotides and oligopeptides). Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts (extracts) can be obtained or readily produced. In addition, natural or synthetically produced libraries and compounds are readily modified by conventional chemical, physical and biochemical methods and can be used to generate combinatorial libraries. Known agents may be subject to directed or random chemical modifications, such as acylation, alkylation, esterification, amination (amidification), etc., to produce structural analogs.

Thus, active agents can be obtained from libraries of naturally occurring or synthetic molecules (including libraries of compounds produced by combinatorial methods, i.e., compound diversity combinatorial libraries). When obtained from these libraries, the drug base employed will have some desired activity that has been demonstrated in an appropriate screening assay for activity. Combinatorial libraries and methods for generating and screening these libraries are known in the art and are described in the following patent documents: 5741713, respectively; 5734018, respectively; 5731423, respectively; 5721099, respectively; 5708153, respectively; 5698673, respectively; 5688997, respectively; 5688696, respectively; 5684711, respectively; 5641862, respectively; 5639603, respectively; 5593853, respectively; 5574656, respectively; 5571698, respectively; 5565324, respectively; 5549974, respectively; 5545568, respectively; 5541061, respectively; 5525735, respectively; 5463564, respectively; 5440016, respectively; 5438119, respectively; 5223409, the disclosures of which are incorporated herein by reference.

A broad class of active agents of interest includes, but is not limited to: a cardiovascular agent; pain relief agents such as analgesics, anesthetics, anti-inflammatory agents, and the like; (ii) a neuroactive agent; chemotherapeutic (anti-tumor) agents; and the like.

Personal signal receiver

As mentioned above, in addition to the IEM, the system of the present invention further comprises a signal receiver configured to receive a signal from the identifier of the IEM, i.e. a signal emitted by the IEM after ingestion of the IEM when the IEM comes into contact with the target physiological site. The signal receiver may vary significantly depending on the characteristics of the signal generated by the signal generating element, for example as described below. Thus, 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 component (e.g., an identifier of an IEM) such that both components use the patient's body as a communication medium. Thus, signals transmitted between the identifier and the receiver of the IEM travel through the body and require the body as a conductive medium. The signal emitted by the marker may be transmitted through or received from the skin and other body tissue of the subject's body in the form of an alternating (a.c.) voltage signal conducted through the body tissue. As a result, these embodiments do not require any additional cables or hard-wired connections, or even radio link connections for transmitting sensor data from the master sensor unit to the central transmitting and receiving unit and other components of the system, as the sensor data is exchanged directly via the subject's skin and other body tissue. The communication scheme has the following advantages: the receiver may be adaptively arranged at any desired position on the subject's body, whereby the receiver is automatically connected to the required electrical conductors for enabling signal transmission, i.e. signal transmission is performed through electrical conductors provided by the subject's skin and other body tissue. Where the receiver comprises a sensing element (see below), multiple receiver/sensor elements may be distributed throughout the body and able to communicate with each other via the body conductive medium scheme. The body-based data transmission additionally has the advantage that the required transmit power is extremely small. This avoids interference with the electrical operation of other devices and also helps prevent unwanted interception or eavesdropping and monitoring of sensitive medical data. The resulting very low power consumption is also advantageous for achieving the goal of long-term monitoring, especially in applications with limited power supplies.

The signal receiver is configured to receive a signal from the identification element of the IEM. Thereby, the signal receiver is configured such that it can recognize the signal emitted from the identifier of the IEM. In some embodiments, the signal detection component is a component that is activated upon detection of a signal emitted from the marker. In certain embodiments, the signal receiver is capable of (i.e., configured to) simultaneously detect a plurality of, e.g., 2 or more, 5 or more, 10 or more, etc., medical information-enabling compositions (enabled compositions).

The signal receiver may comprise a plurality of different types of signal receiver elements, wherein the characteristics of the receiver elements have to be changed in dependence of the characteristics 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 pairs, 3 or more pairs, 4 or more pairs, etc.) for detecting the signal emitted by the signal generating element. In some embodiments, the receiver device will be configured with two electrodes spread at a distance, such as a distance that allows the electrodes to detect a differential voltage. The distance may vary, and in certain embodiments is in the range of from about 0.1 to about 5cm, such as from about 0.5 to about 2.5cm, such as about 1 cm. In certain embodiments, the first electrode is in contact with an electrically conductive body element, such as blood, and the second electrode is in contact with a body element that is electrically insulated relative to the electrically conductive body element, such as adipose tissue (fat). In an alternative embodiment, a receiver using a single electrode is employed. In some embodiments, the signal detection component may include one or more coils for detecting the signal emitted by the signal generating element. In certain embodiments, the signal detection component comprises an acoustic detection element for detecting the signal emitted by the signal generating element. In certain embodiments, multiple pairs of electrodes (e.g., as described above) are provided, for example, to increase the probability of detection of a signal.

Signal receivers of interest include both external and implantable signal receivers. In an external embodiment, the signal receiver is ex vivo, which means 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., in vivo or in vitro, at least during the time the signal receiver receives the signal emitted from the IEM.

Broadly speaking, the receivers of the present invention may be mobile or fixed relative to the patient to which they are configured to be applied. Moving embodiments of the signal receiver include embodiments dimensioned to be stably associated with the living subject in a manner that does not substantially affect movement of the living subject. Thus, an embodiment of the signal receiver has a size such that: when applied to a subject such as a human subject, does not cause the subject to experience any difference in mobility. In these embodiments, the receiver is sized such that its dimensions do not hinder the physical mobility of the subject.

In some embodiments, the signal receiver can be configured to have a very small size. When the signal receiver has a small size, in some embodiments, the signal receiver occupies about 5cm³Or less volume of space, such as about 3cm³Or less, including about 1cm³Or less. In some embodiments, the desired functionality of the signal receiver is achieved using a rechargeable battery pack.

In addition to receiving signals from the identifier of the ingestible event marker, the signal receiver may further include one or more different physiological parameter sensing capabilities. Physiological parameter sensing capability refers to the ability to sense a physiological parameter or biomarker, such as but not limited to: heart rate, respiration rate, temperature, pressure, chemical composition of a fluid such as analyte detection in blood (chemical composition), fluid status, blood flow rate, accelerometer motion data, IEGM (intracardiac electrogram) data, and the like. In the case of a signal receiver having physiological parameter or biomarker sensing capabilities, the number of different parameters or biomarkers that the signal receiver may sense may vary, e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 10 or more, etc. The term "biomarker" refers to an anatomical, physiological, biochemical, or molecular parameter associated with the presence and severity of a particular disease state. Biomarkers can be detected and measured using a variety of methods including physical examination, laboratory assays, and medical imaging. Depending on the particular embodiment, the signal receiver may implement one or more of these sensing functions using signal receiving elements (e.g., using electrodes of the receiver for signal receiving and sensing applications), or the signal receiver may include one or more different sensing elements that are different from the signal receiving elements. The number of different sensing elements that may be present on (or at least coupled to) the signal receiver may vary and may be 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 10 or more, etc.

In certain embodiments, the signal receiver includes a set of 2 or more electrodes that provide the dual functions of signal reception and sensing. For example, the electrodes can serve an additional sensing function in addition to receiving signals. In certain embodiments, the electrodes are used to generate electrocardiographic data. From this data, many types of processing can be done, for example, detecting various cardiac events such as tachycardia, fibrillation, heart rate, etc. The obtained electrocardiographic data can be used for titrating a medicament or for alerting when a significant change or significant abnormality in heart rate or rhythm is detected. In certain embodiments, this data can also help monitor heart rate in patients without a cardiac pacemaker (e.g., monitoring heart rate in patients with anorexia nervosa), or as an alternative to patients who may typically require a hall (Holter) monitor or cardiac event monitor, a portable device for monitoring the electrical behavior of the heart for 24 consecutive hours, or other devices. An extended recording period can be used to observe sudden arrhythmias that are difficult to discern over a shorter period.

Another sensing capability that can be achieved with two electrodes of a signal receiver employs measuring the impedance between the electrodes. The measured impedance will have some component determined by the thoracic impedance, which is related to breathing. In this way, impedance data can be employed to obtain the breathing rate of the subject. The electrodes may also serve as sensors of the fluid state of the subject. The liquid state has long been a very important parameter, especially for heart failure patients who use diuretics. The liquid state obtained can be used for titration of a medicament. The obtained fluid status can also be used for warning, since just before a person enters a hospital their lungs start to fill with fluid, which can be detected with the system. In addition to measuring the fluid state, impedance measurements can also be used to detect body fat. In certain embodiments, the electrodermal response may be monitored (see, for example, the discussion found in the website address http:// butler. cc. tut. fi/. malmivuo/bem/bamboo/27. htm).

As mentioned above, one or more further physiological sensors, different from the electrodes, may be included in the signal receiver. For example, a temperature sensor such as a thermistor may be included in the signal receiver. Alternatively, a Resistive Temperature Device (RTD), for example made of platinum, may be employed to obtain an accurate temperature measurement. Another embodiment of interest is an implantable fertility monitor that can be implemented by monitoring the temperature of a subject over time, such as the temperature of a body core (core body), and if desired, can be combined with additional sensed physiological parameters. Additional physiological sensors may include LEDs and photodiodes coupled to pulse oximetry, which may be used to measure blood oxygenation (oxygenation), which may also give information about pulse pressure. Magnetic susceptibility sensors can also be used to measure anemia. See, for example, published U.S. patent application No. 20010029329.

Further, embodiments of the signal receiver include a pressure sensor, for example, wherein the signal receiver is implanted adjacent to an artery to obtain a measurement of arterial blood pressure. For example, pressure in the body is obtained by placing a pressure sensitive membrane on the surface of the signal receiver. For example, a diaphragm on the signal receiver side is brought near an artery or vein so that it pushes the pressure sensor when the artery pulsates. With proper calibration, absolute pressure readings are obtained. Alternatively, a sensor having a stent-in-sheath (outriggercuff) configuration is employed, for example, wherein the sensor is looped over a (cuff around) vessel (e.g., an artery). In certain embodiments there is a strain gauge to measure the pressure deformation, which is then attached to the signal receiver. In another embodiment, a strain gauge is used to detect contractions. These embodiments find use in a variety of different applications, such as monitoring high risk pregnancies.

The signal receiver may also include an analyte detection sensor. For example, a specific chemical sensor may be integrated into the signal receiver to detect the presence of multiple agents, such as glucose, BNP (B-type natriuretic peptide, which is associated with heart disease), and the like. In certain embodiments, a selective porous impedance cell (cell) is employed, wherein oxygen changes the PH of the cell, and the changed conductivity is then measured. Where the signal receiver comprises an analyte detecting sensing element, the sensing element can be configured in the signal receiver in a number of different ways. For example, a sensor may be provided that includes a selectively permeable membrane that is permeable to the agent desired to be detected, with an isolated cell behind it, and the agent passing through the membrane and altering a characteristic (typically an electrical characteristic) of the cell, which is then measured. In some embodiments, a small reservoir (reservoir) on the signal receiver side is employed (across which the membrane spans) and the electronic circuitry behind it is measured. Also of interest are chemical field effect tube sensors based on the binding of an analyte to the sensor resulting in a change in conductivity. In certain embodiments, materials are employed whose electrical properties (or other properties) are altered when a material, such as a protein analyte, binds thereto.

Sensors of interest also include, but are not limited to, those described in the following applications by at least some of the inventors of the present application: U.S. patent application No.10/734490, entitled "Method and system for monitoring and treating hemidynamic parameters," published as 20040193021; U.S. patent application No.11/219305, entitled "Methods and apparatus for tissue activation and monitoring", published as 20060058588; international application No. PCT/US2005/046815 entitled "Implantable Addressable Segmented Electrodes"; U.S. patent application No.11/324,196 entitled "Implantable Accelerometer-based Cardiac Wall Position Detector"; U.S. patent application No.10/764,429 entitled "Method and Apparatus for Enhancing Cardiac Pacing"; U.S. patent application No.10/764,127 entitled "Methods and Systems for Measuring cardio parameters"; U.S. patent application No.10/764,125 entitled "Method and system for Remote Hemodynamic Monitoring"; international application No. PCT/US2005/046815 entitled "Implantable Hermetially Sealed Structures"; U.S. application No.11/368,259 entitled "fiber Tissue Motion Sensor"; international application No. PCT/US2004/041430 entitled "Implantable Pressure Sensors"; U.S. patent application No.11/249,152 entitled "transplantable Doppler mobility System" and claiming priority to U.S. provisional patent application No.60/617,618; and International application Ser. No. PCT/USUS05/39535 entitled "Cardiac Motion Characterization by StrainGauge". These applications are incorporated herein by reference in their entirety.

Of interest in some embodiments are signal receivers that may be considered autonomous sensor units. In some of these embodiments, the sensor unit includes a sensor and a pair of transmit/receive electrodes adapted to be disposed on a skin or body surface of a subject. The receiver may further include: a central transmitting and receiving unit adapted to be arranged on a subject's body; and a portable data recording unit. The autonomous sensor unit is adapted to acquire sensor data, i.e. medical and/or physical data, from the body of the subject, such as one or more of pulse rate, blood oxygen content, blood glucose content, other blood component data, blood pressure data, electrocardiogram data, electroencephalogram data, respiration rate data, perspiration data, body temperature data, behavior, motion, electrode impedance, etc. Further, the component includes the capability to receive a signal from an internal device (e.g., an identifier of an IEM). The transmit/receive electrodes of each autonomous sensor unit are adapted to transmit acquired sensor signals into the subject's body such that these sensor data are transmitted to the central transmit and receive unit via the subject's skin and/or other body tissue. Other signals, such as monitoring signals and polling signals, can be transmitted from the central transmitting and receiving unit through the subject's body tissue to the sensor units, wherein these signals are picked up with the transmitting/receiving electrodes of the respective sensor units.

The basic system according to the invention comprises a sensor unit, a body transceiver and a data recorder or data recording device (loader) which allows data to be recorded in an electronic memory card or on a magnetic data carrier or the like, or to be downloaded via a suitable interface to a computer such as a personal computer or an on-board computer system for performing further processing or evaluation. The data transmission from the body transceiver to the data recording device or data recorder is performed using telemetry, for example using a radio link, so that the transmission range is limited to a few meters, for example less than 10 meters. The portable data recording device itself can be worn, for example, in a pocket of the subject's clothing or on a belt.

The sensors integrated into the system of the present invention are primarily sensors for measuring a medical or physical condition of a subject, for example, measuring parameters such as the subject's body temperature, EKG, pulse, blood oxygen saturation and/or skin conductivity. However, it is also possible to incorporate further so-called ambient sensors into the system of the invention, for example sensors adapted to measure prevailing ambient air quality such as oxygen content, ambient temperature and/or the respective position of the sensor using the Global Positioning System (GPS), etc. Thus, sensor data transmitted or exchanged via the skin or other body tissue of the subject is not limited to data relating to the medical or physical condition of the subject, but can also provide information about the environment of the subject. All of these different types of data are received, processed and forwarded using the body transceiver. Alternatively, the various data streams of interest may be fused (fuse) or otherwise associated/processed at a remote location, such as a network.

In certain embodiments, the signal receiver (i.e., the signal detection component) is an implantable component. Implantable means that the signal receiver is designed, i.e. configured, for implantation into a subject, e.g. on a semi-permanent or permanent basis. In these embodiments, the signal receiver is located within the living body during use. Implantable means that the receiver is configured to maintain function for 2 or more days (such as about 1 week or more, about 4 weeks or more, about 6 months or more, about 1 year or more, for example about 5 years or more) when present in a physiological environment, including a high salt, high humidity environment found within the body. In certain embodiments, the implantable circuit is configured to maintain functionality when implanted at a physiological site for a period of time in a range from about 1 year to about 80 years or more, such as from about 5 years to about 70 years or more, and including periods in a range from about 10 years to about 50 years or more.

For implantable embodiments, the signal receiver may have any convenient shape, including but not limited to a capsule shape, a disk shape, and the like. The signal receiver may be configured to be disposed at a number of different locations, such as the abdomen, the small of the back, the shoulder (e.g., with an implantable pacemaker disposed therein), and so forth.

The implantable receiver of the present invention generally includes a power source. In certain embodiments, the power source of the receiver is a rechargeable battery pack. The power supply may have a natural life of 2 weeks and the recharge automatically turns off the coil(s) in the patient's bed so that it is recharged steadily. In some embodiments, the signal receiver may be a signal receiver powered with an RF signal during use.

In certain implantable embodiments, the signal receiver is a stand-alone device in that it is not physically connected to any other type of implantable device. In other embodiments, the implantable signal receiver may be physically coupled to a second implantable device, such as a device that serves as a platform for one or more physiological sensors, wherein the device may be a lead such as a cardiovascular lead (lead), wherein in some of these embodiments the cardiovascular lead includes one or more different physiological sensors, for example, wherein the lead is a multi-sensor lead (MSL). Implantable devices of interest also include, but are not limited to, implantable pacemakers (e.g., ICDs), neurostimulator devices, implantable loop recorders, and the like.

Aspects of the invention include a receiver having at least a receiver element in the form of one or more electrodes (e.g., two spaced apart electrodes) and a power generating element, such as a battery, wherein the battery may be rechargeable or the like, as described above. In certain embodiments, the power generating element is converted to wirelessly receive power from an external location.

Additional elements that may be present in the signal receiver include, but are not limited to: a signal demodulator, e.g., for decoding signals transmitted from ingestible event markers; a signal transmitter, for example, for transmitting a signal from the signal receiver to an external location; a data storage element, e.g. for storing data about the received signal, physiological parameter data, medical record data, etc.; a clock element, for example, for associating a particular time with an event such as receipt of a signal; a preamplifier; a microprocessor, for example, for coordinating one or more different functions of the signal receiver.

Aspects of an implantable version of the signal receiver will have a biocompatible housing, two or more sensing electrodes, a power source, which can be a primary battery (primary cell) or a rechargeable battery pack, or a power source powered with inductive broadcast to a coil (broad inductive to a coil). The signal receiver may also have a circuit comprising: a demodulator for decoding the transmitted signal; some memory for recording events; a clock; and a path to transmit outside the body. In some embodiments, the clock and transmit functions may be omitted. The transmitter can be an RF link or a conductive link for transferring information from the local data storage to an external data storage device.

The demodulator component (when present) can be any convenient demodulator configured to demodulate a signal transmitted from the identifier of the medical information-enabled pharmaceutical composition. In some embodiments, the demodulator is in an in-vivo transport decoder, which allows accurate signal decoding of low-level signals using small-scale chips with very low power consumption, even in the presence of significant noise. In one embodiment, the in vivo transmission decoder is designed to decode a signal modulated using Binary Phase Shift Keying (BPSK). The Costas loop can then be used to demodulate the signal. The binary code is recovered by applying a symbol recovery technique to the Costas loop output. In some embodiments, the in-vivo transport decoder can include an Automatic Gain Control (AGC) block. The AGC block is able to determine the strongest frequency component and signal power of the incoming signal. The strongest frequency of the signal can be used to adjust the filter and voltage controlled oscillator in other parts of the algorithm. This can help the receiver actively adapt to changes in the frequency of the incoming signal and to drifts in the frequency of the incoming signal. By measuring the signal power, the AGC block can then calculate and apply the gain required to normalize the signal power by a predetermined value. The gain can be further adjusted by reading the signal power at the Costas loop. In one embodiment, an in vivo transport decoder can actively adjust the sampling rate of an incoming signal to accommodate conditions such as the presence of an amount of noise. For example, if the signal-to-noise ratio (SNR) is sufficient, the sampling rate can be maintained at a lower value. The sampling rate can be increased if the SNR falls below a set threshold during the decoding process. In this way, the sampling rate can be kept as low as possible without compromising the accuracy of the recovered signal. By actively adjusting the sampling rate as low as possible, the algorithm saves power. Additional aspects of the In Vivo transport Decoder are provided In pending U.S. provisional application serial No.60/866,581, entitled "In-Vivo Transmission Decoder," the disclosure of which is incorporated herein by reference.

In some embodiments, the components or functional blocks of the present receiver are present on an integrated circuit, wherein the integrated circuit comprises a number of different functional blocks, i.e. modules. In a given receiver, at least some (e.g., two or more up to all) of the functional blocks may be present in a single integrated circuit in the receiver. A single integrated circuit represents a single circuit structure that includes all of the different functional blocks. Thus, an 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 made up of individual semiconductor devices and passive components bonded to a substrate or circuit board.

FIG. 13 provides a schematic illustration of a functional block diagram according to an embodiment of the present invention. In fig. 13, the receiver 10 includes first and second electrodes e₀And e₁(11 and 12, respectively) separated by a distance X and acting as an antenna to receive signals generated by the identifier of the medical information enabled pharmaceutical composition. The distance X may vary, and in certain embodiments ranges from about 0.5 to about 5cm, such as from about 0.5 to about 1.5cm, for example about 1 cm. The amplifier 13 detects a differential signal across the electrodes. The detected signal then enters the demodulator 14. Also shown is a memory 15 for storing demodulated data. The clock 16 writing to the memory marks the event with a time-stamp. The transmit circuit (Tx) (16) transfers data from the memory to an external receiver (not shown). There is also a power supply 17 for powering all the microelectronic elements. In the embodiment shown, there is also a microprocessor 18 which coordinates functions between all of these blocks. Finally, a coil 19 wound around the periphery provides an RF transmission output. As summarized above, all of the different functional blocks shown in the embodiment of fig. 13 can be located on the same integrated circuit.

An alternative embodiment is shown in fig. 14. The main part of the receiver 20 comprises all the functions listed previously (not shown) and e₀(21). Also shown is e at the end of the wire 23₁. The configuration provides e₀And e₁Sufficient to function as an effective receiver and also minimize the overall size of receiver 20.

As described above, in certain embodiments, the signal receiver is physically coupled to a medical carrier, such as a lead, having one or more different physiological sensors thereon. In this embodiment, the lead may have one or more (e.g., two or more, three or more, four or more, 5 or more, about 10 or more, about 15 or more, etc.) different physiological sensors, where the sensor may be any sensor of interest, including those mentioned above. Fig. 15 provides a representation of a signal receiver specifically configured for monitoring and treating a cardiac condition. In fig. 15, receiver 50 comprises a main receiver part 51 and a cardiovascular lead 52, wherein lead 52 comprises a number of different sensors and may thus be referred to as a multi-sensor lead or MSL. Also shown on lead 52 are a conductive blood flow sensor 53, a temperature sensor 54 arranged to measure the temperature of blood entering the heart, a temperature sensor 55 arranged to measure the temperature of the coronary sinus, sensing electrodes 56 and stimulation electrodes 57 arranged to measure the movement of the relevant cardiac tissue. The sensing and stimulation electrodes may be ring electrodes or segmented electrodes. A segmented electrode structure means an electrode structure comprising two or more (e.g. three or more, including four or more) completely different electrode elements. Examples of segmented electrode structures are disclosed in the following patent documents: application Ser. No. PCT/US2005/031559 entitled "Methods and Apparatus for tissue activation and Monitoring" filed on 9/1 2006; application PCT/US2005/46811 entitled "Implantable Addressable Segmented Electrodes" filed on 22.12.2005, the disclosure of various Segmented electrode structures of which is incorporated herein by reference. One or more such electrode assemblies may be disposed along a cardiac pacing lead.

In the embodiment shown in fig. 15, the MSL travels down the receiver into the heart and can be applied to measure cardiac parameters of interest, such as blood temperature, heart rate, blood pressure, motion data including synchronization data, IEGM data, and compliance with medical treatment (compliance). The obtained data is stored in the receiver. Embodiments of this configuration can be used as an early heart failure diagnostic tool. This configuration may be placed in a subject before severe heart failure in order to closely monitor them and prevent them from further deterioration. Finally (ultitime), when stimulation therapy is required, the receiver may be replaced with an implantable pacemaker, which may then employ stimulation electrodes to provide appropriate pacing therapy to the patient.

The signal receiver can be a component of the implantable device that includes other functions. For example, the signal receiver can be a component of an implantable pacemaker 58, such as a pacemaker or the like. Fig. 16 provides a view of an implantable pacemaker 58 including a receiver component 59 including a receiving circuit 59A and a receiving electrode 59B according to an embodiment of the present invention. An external interface antenna 60 and pacing electronics 61 are also shown.

When the signal receivers are external, they may be configured in any convenient manner. The external arrangement may include any of the elements described above with respect to the implantable embodiment as desired. Thus, the external receiver may include circuitry as shown in fig. 13 and described above. Thus, elements as described above, such as signal receivers, transmitters, memories, processors, demodulators, etc., may be present in the external receiver of the present invention as desired. For example, a functional illustration of circuitry that may be present in an external receiver of the present invention is provided in fig. 17A and 17B. Fig. 17A provides a functional block diagram illustration of a receiver 70 according to the present invention, wherein the receiver includes an external interface block 71, wherein the external interface block may include a wireless communication element (e.g., an antenna), a serial port, a conductive interface, and the like. There is also a signal receiving circuit block 72. There is also a receive electrode function 73. Fig. 17B provides a view of circuitry 74 found in a receiver according to an embodiment of the invention. The circuit 74 includes an external interface 75, a memory 76, a Digital Signal Processor (DSP)77, and a Real Time Clock (RTC) 78. Also shown are analog to digital converter (ADC)79, preamplifier 80, optional reference (common mode cancellation circuit) 81 and electrodes 82.

In certain embodiments, the signal receiver is configured to be associated with a desired skin location. Thus, in certain embodiments, the external signal receiver is configured to be in contact with a local (topical) skin location of the subject. Configurations of interest include, but are not limited to, patches (patches), wristbands (wristbands), belts (belts), fastening bands (harnesss), devices configured to be associated with articles of clothing, such as shoes, necklaces, etc., or other body-associated devices, such as hearing aids, eyeglasses, etc. For example, a watch or a belt worn externally and provided with suitable receiving elements (such as electrodes or electrode pairs described in more detail below) can be used as a signal receiver according to one embodiment of the invention.

In certain external embodiments, the receiver may be configured to be in contact with or associated with the patient only temporarily, i.e., temporarily (e.g., while the ingestible event marker is actually being ingested). For example, the receiver may be configured as an external device with two finger electrodes or handles. After ingestion of the IEM, the patient touches the electrodes or fully grasps the handle to create a conductive circuit with the receiver. After the signal is emitted from the IEM, for example when the IEM contacts the stomach, the receiver is utilized to pick up the signal emitted by the identifier of the IEM. At this point, the receiver may provide an indication to the patient, for example by way of an audible or visual signal, that a signal from the IEM has been received. As noted above, in certain external embodiments, the receiver is configured to be in contact with or associated with the patient only temporarily, i.e., temporarily (e.g., while a pill, ingestible marker, etc. is actually being ingested). For example, the receiver may be configured as an external device, such as the dispensing bin 83 shown in fig. 18. The dispensing box 83 includes two finger electrodes 84A and 84B. In some embodiments, the electrodes take the form of a handle or other form that facilitates patient contact. During use, the patient initially activates the device and receiver by opening the cover 86. To alert the patient that it is time to take the medication, the cassette may be configured to provide a signal or alarm. After the dose has been removed from the bin (where the dose is present in compartment 87), a first signal, for example a red light, may be provided, for example at indicator light 85. The patient then ingests the tablet comprising the IEM and touches the right finger electrode 84B with the right finger and the left finger electrode 84A with the left finger to complete the conductive circuit with the receiver. After the signal is emitted from the IEM associated with the pill, for example when the pill dissolves in the stomach, the signal emitted by the identifier of the pill is picked up with the receiver. At this point, the receiver may provide an indication to the patient, for example in the form of an audible or visual signal (such as a green light), that a signal from the pill has been received. The patient can release the receptacle until the next time the patient plans to take a pill. The box 83 includes detection circuitry, memory, and a transmit function 88, for example as described above. This embodiment has application in a wide variety of different situations, such as tuberculosis patients for long-term treatment sessions.

FIG. 19 provides a view of a wristband receiver embodiment of the invention. As shown, the receiver is in the form of a wrist strap 90 that includes a top contact 91 and a bottom contact 92, wherein the bottom contact is for contacting the patient's wrist. The top contact is used for the patient to touch with the right finger during use. During use of the device, after ingestion of the IEM, the patient then contacts contact 91 on receiver 93 with the right finger, receiver 93 also contacting the left wrist via contact 92, completing the circuit. After detecting the IEM generated signal, the patient can remove the finger from the receiver.

The system can be used to monitor patient compliance with a course of therapy, for example, where ingestion of an IEM is associated with administration of a therapeutically active agent (as described in more detail below). The patient can then release the receptacle until the next time the patient calculates to take the active agent. This embodiment has application in a wide variety of different settings, such as tuberculosis patients for long-term treatment sessions, where embodiments of the system are described in more detail further below.

In certain embodiments, the external signal receiver comprises miniaturized electronic components integrated with the electrodes to form an emergency bandage-type patch. The patch includes electrodes that contact the skin when applied. The first aid bandage-type patch may be configured to be disposed on a desired target skin site of the subject, such as the chest, back, sides of the torso, and the like. In these embodiments, the receiver circuit may be configured to receive a signal from an in-subject device, for example from the identifier IEM. Emergency bandage-type receivers that may be readily adapted for use in the present system include, but are not limited to, those described in U.S. patent No.6315719, et al, the disclosure of which is incorporated herein by reference.

For an external signal receiver, an embodiment includes a structure having an electrode opposite the skin, a demodulator, a memory, and a power source. The communication may be wireless or performed via one or more conductive media (e.g., wires, optical fibers, etc.). In some embodiments, the same electrode is used for both receiving and transmitting signals. One example is a wristwatch form, which is in conductive contact with the body, where in order to move data from the implant to the wristwatch, currents will be emitted from the pads (pads) and those currents will be received by the wristwatch. There are many RF technologies that can be employed for transmission out of the body, such as inductive schemes employing coils. Alternatively, an electric field can be employed, where insulated electrodes would be used rather than conductively contacted electrodes.

When the signal receiver comprises an external component, the component may have an output means for providing, for example, audio and/or visual feedback; examples include audible alarms, LEDs, display screens, etc. The external component may also comprise an interface port via which the component can be connected to a computer for reading out data stored therein.

The signal receiver described above is described primarily in terms of being configured to receive a signal from an Ingestible Event Marker (IEM). However, the signal receiver of the present invention may be configured as a signal receiver that receives signals from the following composition: the pharmaceutical information enables a pharmaceutical composition (e.g., as described in PCT application serial No. us 2006/016370); ingestible event markers (e.g., as described in provisional application serial No.60/949,223); or smart parenteral devices (e.g., as described in PCT/US 2007/15547), the disclosures of which are incorporated herein by reference or similar devices.

System operation

In the method of the IEM system of the present invention, when an individual wants to mark or annotate a personal event of interest, the individual ingests one or more ingestible event markers of the present invention. The marker may be ingested by the subject using any convenient means capable of producing the desired result, wherein the administration path depends at least in part on the particular form of the composition, e.g., as described above, and involves ingesting the ingestible event marker, e.g., by swallowing the composition. Many different types of individuals can practice the method. Typically, such individuals are "mammals" or "mammalian", where these terms are used broadly to describe organisms in the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., rats, guinea pigs, and mice), and primates (e.g., humans, chimpanzees, and monkeys). In a representative embodiment, the subject will be a human.

Depending on the particular application, the method may include ingesting the event marker itself or in conjunction with another substance component (composition of matter), wherein in the latter embodiment the marker may be ingested with the other substance component or combined with the other substance component and then ingested. The marker and the other substance components, if ingested together, may be ingested sequentially or simultaneously. A given method may include the ingestion of one signal identifier or two or more identifiers (which may be the same or different) depending on a given application. In some embodiments, multiple markers may be employed to mark an event, for example to indicate the extent of the event regardless of its identity. Different markers can be employed to indicate different types of events.

Once the ingestible event marker reaches the target physiological site, the identifier of the IEM emits a detectable signal, e.g., as described above. The signal receiver may process the received data in a variety of ways (e.g., in the form of a signal transmitted from an ingestible event marker). In some embodiments, the signal receiver simply forwards the data to an external device (e.g., using conventional RF communication), e.g., immediately or after a period of time, in which case the data is stored in a storage element of the receiver. Thus, in certain embodiments, the signal receiver stores the received data for subsequent forwarding to an external device or for processing of subsequent data (e.g., detecting a change in a certain parameter over time). For example, the implanted collector may include conventional RF circuitry (e.g., operating in the 405MHz medical device band) with which the physician can communicate, for example, using a data acquisition device (e.g., wan, as known in the art). In other embodiments, the signal receiver processes the received data to determine whether some action is to be taken, such as operating an effector under its control, thereby activating a visual or audible alarm, transmitting a control signal to an effector located elsewhere within the body, and so forth. The signal receiver may perform any combination of these and/or other operations using the received data.

In certain embodiments, the data recorded on the data storage element of the receiver includes at least one, if not all, of the time, date, and identifier (e.g., a globally unique serial number) of each composition administered to the patient, wherein the identifier may be the common name of the composition or an encoded version thereof. The data recorded on the data storage element of the receiver may also include medical record information, e.g., identification information, such as, but not limited to, name, age, treatment record, etc., of the subject with which the receiver is associated. In certain embodiments, the data of interest comprises hemodynamic measurements. In some embodiments, the data of interest includes cardiac tissue characteristics. In certain embodiments, the data of interest includes pressure, volume measurements, temperature, behavior, respiration rate, pH, and the like.

In certain embodiments, the signal receiver is part of a system or network of sensors, receivers, and optionally other devices internal and external to the body that provides a variety of different types of information that is ultimately collected and processed with a processor, such as an external processor, which is then able to provide contextual data about the patient as output. For example, the sensor may be a component of an in vivo network of devices capable of providing output to an external collector of data, including data regarding pill intake, one or more physiological sensing parameters, implantable device operation, and the like. An external collector of data (e.g. in the form of a healthcare server) then combines the data provided by the receiver with further relevant data about the patient, such as weight, weather, medical record data, etc., and may process the different data to provide highly specific and contextual patient specific data.

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 take the form of a monitor (such as a bedside monitor), a computer (e.g., a PC or MAC), a Personal Digital Assistant (PDA), a telephone, a messaging device, a smart phone, or the like, for example. In one embodiment, if the signal receiver fails to detect a signal indicating that a pill has been ingested, the signal receiver can transmit a reminder to take the pill to the subject's PDA or smartphone, which can then provide a reminder to the user to take the medication by receiving a phone call (e.g., a recorded message) or the like on the smartphone, such as a display or alarm on the PDA. 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 thereby be configured to be interrogated by an external interrogation device to provide data of the received signal to an external location.

Thus, in some embodiments, the system includes an external device that is different from the receiver (which in some embodiments may be implanted or applied locally), wherein the external device provides a number of functions. The device can include the ability to provide feedback and appropriate clinical adjustments to the patient. The device can take any of a number of forms. For example, the device can be configured to sit on a bed beside the patient, such as a bedside monitor. Other forms include, but are not limited to, PDAs, smart phones, home computers, and the like. The device is capable of reading out information described in more detail in other parts of the present patent application, such as information generated internally by a pacemaker device or a dedicated implant for detecting a pill, both from a medical intake report and from a physiological sensing device. The purpose of the external device is to obtain data from the patient and input it to an external device. One feature of the external device is its ability to provide pharmacological and physiological information to a remote location, such as a clinician or central monitoring facility (agency), in a form that can be transmitted over a transmission medium, such as a telephone line.

FIG. 20 provides a schematic diagram of a system according to an embodiment of the invention. In fig. 20, the system 100 includes an ingestible event marker 104 and a personal condition receiver 102. In the system shown in figure w0, IEM 104 is a pill equipped with an identifier in the form of an embedded digestible microchip-based data transmitter. When ingested, the data transmitter is activated for a short period of time and sends a unique signal to the data receiver 102. In the case of multi-drug treatment, each pill ingested by the patient will have a different electronic signal for detection, provided, for example, by a different IEM that is taken as part of or with the drug dose. Microchips are composed of silicon-based materials that easily pass through the digestive tract and other compounds that have long been used as vitamins.

Also shown in the system of figure w0 is a receiver 102, which is a wearable (e.g., as a patch) or subcutaneous implantable receiver sized, containing a detector for recording ingestion of the IEM, and also including physiological sensors for monitoring respiration, heart rate, temperature, blood pressure, and/or other key biomarkers. In certain embodiments, the receiver is part of an existing medical implant, such as a pump device, an implantable cardiac defibrillator, a neurological device, or the like (see, e.g., fig. 16). In certain embodiments, the receiver 102 stores other important and relevant healthcare data, such as a patient's medical record.

The external recorder is not shown in fig. 20. However, as summarized above, the system may include one or more external elements. Software can be installed on a handheld PDA such as a blackberry or a laptop or desktop computer, enabling reliable wireless data transfer from the receiver and distribution of user control information to physicians and caregivers. These systems allow data collected by the patient regarding actual time and drug dose levels to be integrated with physiological parameters and presented to the patient and physician in a manner that supports better individual performance as well as clinical decisions and disease management by the caregiver.

Fig. 21 shows an embodiment of the system of the present invention comprising an IEM and a receiver, as well as additional physiological parameter sensors and data sources for non-physiological parameters. In fig. 21, patient 110 ingests IEM 111 with a pharmaceutically active agent. IEM 111 emits a signal upon contact with gastric fluid, which is received by receiver 112. The receiver 112 also receives information from the neurostimulator 113, the pressure sensor 114, O₂The sensors 115 and pedometer 116 in the patient's shoe acquire the data. These various data streams are transmitted by the receiver to an external server. The external server 117 processes these IEM annotated data streams and additional information 118, such as the patient's medical records, weather data, blood pressure data, and weight data, to obtain contextualized data. The following table shows the different sensor types that may be employed in the system of the present invention, as well as the types of data obtained therefrom. The data obtained from these various components of the system of these embodiments may be at the network layer as desiredAre fused (fuse), e.g., for subsequent use by a healthcare professional.

As noted above, in certain embodiments of interest, the receiver element comprises a semiconductor support member. Any of a number of different approaches may be used to manufacture the receiver structure and its components. For example, molding, deposition, and material removal (e.g., planar processing techniques such as micro-electromechanical system (MEMS) fabrication techniques, including surface micromachining and bulk micromachining techniques) may be employed. Deposition techniques that may be employed in some embodiments of the fabricated structure include, but are not limited to: 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, e.g., via chemical mechanical polishing, laser grinding, Electrical Discharge Machining (EDM), and the like. Also of interest are lithography schemes. Of interest in certain embodiments is the use of planar processing schemes in which structures are built and/or removed from one or more surfaces of an initially planar substrate by using a plurality of different material removal and deposition schemes applied to the substrate in a sequential manner. Exemplary 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.

In some embodiments, off-the-shelf (offtake) components may be used to fabricate the receiver. For example, off-the-shelf instrumentation amplifiers for input amplifiers may be employed, e.g., in bare chip form. Custom logic in an FPGA or ASIC may be used that manipulates the demodulator, memory, microprocessor functions, and all interface functions. The transmitter may be a finished chip, e.g. manufactured by Zarlink, in a hybrid communication band, which is approved for medical implants. The clock may be a stand-alone clock or the device may have a microprocessor with a built-in clock.

Use of

The present ingestible event marker, system, and method of use may be used in a variety of different applications, which may be both medical and non-medical in nature. Various illustrative applications are now described in more detail below.

As described above, some applications include using the ingestible identifier itself to mark personal events of interest, such as the onset of a physiological parameter (such as symptom(s) of interest), the onset of behavior, and the like. For example, in certain embodiments, an event marker is used to mark the onset of a symptom of interest. In this example, when an individual becomes aware of a symptom of interest, e.g., begins to feel flushed, nausea, excitement, etc., the individual may ingest an IEM to mark the occurrence of the symptom of interest, for example. For example, the patient may begin to feel discomfort and ingest the event marker in response to the discomfort feeling. After ingestion, the marker transmits a signal to a receiver, which is then able to record the receipt of the signal for further use, e.g. for combination with a physiological signal or the like. In certain embodiments, the received signal is used to provide context for any physiological data obtained from the patient, e.g., with sensors on the receiver, by an implantable recorder or the like.

Another symptom of concern is pain. In these embodiments, the ingestible event marker may serve as a pain marker. For example, in the case where the patient is being monitored for pain, if the patient does not feel pain, the patient may ingest the first type of marker. If the patient feels pain, the patient may ingest a second type of marker. Different types of markers can be distinguished, for example color coded to assist in their identification and proper use by the patient, if desired. For example, a marker to be ingested when the patient is not feeling pain may be coded in blue, while a marker to be ingested when the patient is pain may be coded in yellow. Instead of having different types of markers, such a scheme may be employed: the amount of marker ingested and thus the signal obtained, for example, from a single marker or two or more markers, is used to indicate the level of a symptom of interest such as pain. Therefore, if an individual has intense pain, the individual takes four analgesic (positive pain) pills at the same time, while in response to mild pain the individual may take only one marker.

In these embodiments, the onset of the symptom of interest, as marked with ingestion of the event marker and detection of the signal by the receiver, may serve as a point of correlation at which recording of one or more physiological parameters of interest is initiated, for example, by using an implantable physiological monitor. In these examples, the signal emitted from the marker is received by a receiver, which then causes a physiological parameter recorder (such as by Medtronic, incAn insertable electrical loop recorder (ILR)) begins recording data and saving the data, for example, for later use. For example, an implantable physiological parameter recorder may only have a limited amount of possible time for recording (such as 42 minutes). In this case, the data may be automatically overwritten unless it is marked or flagged in some way for protection. In the present method, the IEM may be ingested to mark the onset of the symptom of interest when perceived by the patient, and the receiver may act with a recorder after receiving the signal to protect data obtained approximately around the time of the signal (some time after or even before) from being overwritten. The system may be further configured to operate not only in response to ingestion of the event marker, but also in response to a physiological sensing parameter, such as pH. Thus, the method finds use as an event recorder in marking a stream of diagnostic information and protecting it from being overwritten, so that a physician can view the stream of diagnostic information at a later date.

In certain embodiments, the event marker provides context for interpreting a given set of physiological data at a later time. For example, if an activity sensor (activity sensor) is being employed and an event marker is administered along with a particular drug, any changes in activity brought about by that drug can be noted. If a decline in activity is observed after a person takes the event marker and medication, the decline indicates that the medication may cause the person to reduce their activity, for example, by causing them to feel sleepy or actually causing them to fall asleep. This data can be used to adjust the drug dosage or as a basis for deciding to switch to an alternative medicament.

In certain embodiments, the event marker is used to build a database of multiple events. The database may be used to find commonalities between multiple tagged events. A simple or complex scheme for finding commonalities between multiple tagged events may be employed. For example, multiple events may be averaged. Alternative techniques such as impulse response theory may be employed where the technique provides information about what happens to be a common feature in a set of multiple sensor streams tied to a particular event.

The IEM system of the present invention enables subjective symptoms, such as "i feel fun", to be used to give context and context to objective measurements obtained from a situation that is actually physiologically ongoing. Thus, if they take event markers whenever they feel abnormal, they can reference a database of objective sensor data and find common features in the database. This method can be used to find the root cause of subjective perception. For example, the method may be used to determine that a person has some change in blood pressure whenever they feel happy, and to determine that the link between subjective symptoms and objective physiological data can be used for their diagnosis. Thus, a generalizable (generalizable) event marker brings context to discrete data from any other source. Thus, the use of an oral agent event marker provides context for any other associated health monitoring information or health events.

In certain embodiments, the event marker can be a warning marker, such that ingestion of the marker results in an alarm signal being sent from the patient, e.g., indicating that the patient requires medical assistance. For example, when a patient feels the onset of a symptom of interest, such as chest pain, shortness of breath, etc., the patient may ingest an event marker. The signal emitted from the event marker may be received by a receiver, which may then cause an alarm to be generated and distributed to a medical professional.

In certain embodiments, the event marker is used to initiate or initiate a therapeutic action, such as activating (activate) an implantable pacemaker to deliver electrical therapy, activating an implanted drug delivery device to administer a dose of drug, activating a physiological sensor to begin acquiring data, and the like. For example, where a patient has a neurostimulator for treating migraine, the patient is able to ingest an IEM once an onset of aura is perceived. The emitted signal will then activate the neurostimulator into a stimulation mode, causing the implant to deliver therapy. Alternatively, if there is an implanted drug delivery device, such as a device that delivers an oncotic agent (oncotic agent), ingestion of the IEM enables 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 that includes upgrade data for an implanted medical device, such as firmware upgrade data for an implantable pacemaker, e.g., a pacemaker. In this example, the signal may include an upgrade code conductively broadcast from the IEM to the medical device, wherein upon receipt of the signal and code, the firmware of the medical device is upgraded.

Other applications for which event markers may themselves be used are to mark or mark the beginning of non-medical personal events, such as commute time, the beginning of exercise programs, sleep times, smoking (e.g., a person can record how much he has smoked), etc.

As indicated above, an embodiment of the invention is characterized in that the event marker is ingested together with another substance component, such as a pharmaceutical component, a food, etc. For example, an event marker may be used to track ingestion of a medicament, where a person administers the marker along with a medication of interest. Applications of interest in which the co-administration of a drug and a marker includes, but is not limited to: clinical studies, such as drug titration of blood pressure drugs, and the like. If desired, the IEM can be provided as just another pill when dispensed (fill) primarily at the pharmacy.

Instead of ingesting the event marker together with another composition, e.g. a drug, a food, etc., the marker and the other composition may be mixed together, e.g. by the end user. For example, an IEM in the form of a capsule can be opened by an end user and filled with a pharmaceutical composition. The resulting mixed capsule and active agent may then be ingested by the end user. Instead of the end user, the pharmacist or the care provider may perform the mixing step.

In other embodiments, the marker has been mixed with other compositions at the source of manufacture of the other compositions, such as the manufacturer or producer of the pharmaceutical composition. Examples of such compositions include those described in PCT application Ser. No. PCT/US2006/016370, the disclosure of which is incorporated herein by reference.

In certain embodiments, the IEM of the present invention is used to allow for viewing on an individual basis the effect of given results on an individual taking medication versus their effect on indicators correlated to a desired effect. For example, where multiple regimens of agents are prescribed for a given patient and there are multiple different physiological parameters that are monitored as indicators of how the patient responds to the prescribed therapy regimen, a given drug labeled by a given marker can be evaluated in terms of its effect on one or more physiological parameters of interest. Based on this evaluation, adjustments can be made accordingly. In this way, automation can be applied to adaptive (tailor) therapy based on individual responses. For example, in the case of a patient undergoing oncotic therapy (oncotic therapy), the event marker can be used to provide a real-time context to the acquired physiological parameter data. The resulting annotated real-time data can be used to make a determination as to whether to continue treatment or change to a new treatment.

In certain embodiments, dosing events (as labeled by IEMs) are correlated with sensor data to derive a graph of how a given drug functions, e.g., according to pharmacokinetic and/or pharmacodynamic models. The sensors are used with IEM labeling of dosing events to obtain a pharmacokinetic model. Once a pharmacokinetic model is available, dosing events can be used to drive the model and predict serum drug levels and responses. As determined by the plurality of sensors, it may be found that the patient condition is not so good at this time. When the patient is sensed to be less good, the pharmacokinetic model can be reviewed and indicate that the level of the drug in the (say) blood is decreasing. This data is then used to make decisions to increase the frequency of dosing or to increase the dosage for a given dosing event. The event marker provides a way to develop the model and then apply it.

When the IEM is administered with a medicament, e.g., as two separate compositions or a single composition (as previously described), the system of the present invention (such as the system shown in fig. 12) enables the following dynamic feedback and treatment loop (loop): tracking the timing and levels of agents, measuring responses to treatment, and recommending altered dosing based on the physiology and molecular profile of the individual patient. For example, symptomatic heart failure patients take a variety of drugs daily, primarily with the goal of reducing heart load and improving the quality of life of the patient. Treatment relies primarily on (mainstay) including Angiotensin Converting Enzyme (ACE) inhibitors, beta blockers and diuretics. For medical treatment to be effective, patients must adhere to their prescribed regimen and take the required dose at the appropriate time. Various studies conducted in the clinical literature have shown that more than 50% of patients with class II and class III heart failure do not receive the treatment recommended by the guidelines (guidelidine), and that only 40-60% of those patients with properly titrated class II and class III heart failure adhere to this regimen. With the present system, heart failure patients can be monitored to let the patients adhere to treatment, and adherence performance can be linked to key physiological measurements to facilitate treatment optimization by physicians. In fig. 22, the system 120 includes a pharmaceutical composition 121 that includes an IEM. Also present in the system 120 is a receiver 122 (labeled "Raisin" in the figure) configured to detect the signal emitted from the identifier of the pharmaceutical composition 121. The implanted receiver 122 also includes physiological sensing capabilities. The implanted receiver 122 is configured to transmit data to the external PDA 123, which external PDA 123 in turn transmits the data to the server 124. The server 124 may be configured as desired, for example, to provide patient directed permission (patient directed permission). For example, the server may be configured to allow a home caregiver to participate in a patient's treatment regimen, e.g., via an interface (such as a network interface) that allows the home caregiver to monitor alarms and trends generated by the server, and provide support back to the patient (as indicated by arrow 126). The server may also be configured to provide responses directly to the patient (as indicated by arrow 127), for example in the form of patient alerts, patient incentives (incitations), and the like. The server 124 may also interact with a health care professional (e.g., RN, physician) 128, which can use data processing algorithms to obtain, for example, health index summaries, alerts, cross-patient benchmarks, etc., as well as provide informed clinical communications and support back to the patient (as shown by arrow 129).

In certain embodiments, the system of the present invention may be used to obtain an aggregation of information including sensor data and administration data. For example, heart rate, respiration rate, multi-axis acceleration data, something about the fluid state, and something about the temperature can be combined together and an index that informs about the overall activity of the subject can be derived, which can be used to generate a physiological index, such as an activity index. For example, as the temperature rises, the heart rate goes a little up and the breathing rate accelerates, which can be used as an indication that the person is active. By calibrating this, the amount of calories burned by the individual at that moment can be determined. In another example, a particular pulse rhythm set or multi-axis acceleration data can indicate that an individual is walking up a set of steps, and thus people can infer how much energy they are using. In another embodiment, body fat measurements (e.g., from impedance data) can be combined with an activity index generated from a combination of measured biomarkers to generate a physiological index for managing weight loss or cardiovascular healthcare programs. This information can be combined with cardiac performance indicators to get a good picture of overall health, which can be combined with medical treatment administration data. In another embodiment, it may be found that, for example, a particular drug is associated with a slight increase in body temperature or a change in electrocardiogram. A pharmacodynamic model can be established for drug metabolism and information from the receiver used to substantially fit the free parameters into the 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, information from sensors measuring contractions (e.g., using strain gauges) and also monitoring fetal heart rate can be combined, which are used as high risk pregnancy monitors.

In certain embodiments, 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 data set that is a composite (composite) 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, etc.) individuals. The aggregated data can then be processed, e.g., sorted, according to different criteria and made available to one or more different types of groups, e.g., patient groups, healthcare physician groups, etc., where the processing of the data can be such as to limit access to any given group to the types of data that the group can access. For example, data can be collected from 100 different individuals who are subjected to the same condition and who are taking the same agent. The data can be processed and used to develop an easy to follow (easy tofollow) display regarding patient compliance with drug dosage regimens and overall health. Patient members of the group can access this information and see how their compliance matches other patient members in the group and whether they enjoy the benefits that other members are experiencing. In another embodiment, physicians can also be granted access to the processing of the integrated data to see how their patients match with those of other physicians, and to obtain useful information about how the actual patient responds to a given treatment regimen. Additional functionality can be provided to the group that is given access to the integrated data, wherein the functionality can include, but is not limited to, the ability to annotate data, chat functionality, security privileges, and the like.

The pharmacokinetic model of the invention allows for the drug dosing regimen to be adjusted in real time in response to changing serum levels in vivo. Pharmacokinetic models are capable of predicting or measuring serum levels of a given agent in vivo. This data can then be used to calculate when the patient should take the next dose of medicament. At which time an alarm can be triggered to alert the patient to take a dose. If the serum level remains high, an alarm can be triggered to alert the patient not to take the next dose at the originally prescribed time interval. The pharmacokinetic model can be used in conjunction with a medication intake monitoring system, such as those described above, including IEMs. Data from this system can be integrated into the model as well as demographic, measurement, and patient input data. Using data from multiple sources, very powerful and accurate tools can be developed.

In some embodiments, the data collected by the receiver can be used directly by the pharmacokinetic model to determine when, what, and in what amount the medicament was administered. This information can be used to calculate an estimate of the serum level of the agent in the patient. Based on the calculated serum levels, the pharmacokinetic model can send an alert to 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 that they should take another dose. The pharmacokinetic model can be run on the implanted receiver itself or on an external system that receives data from the implanted receiver.

A simple form of pharmacokinetic model can assume that each patient is the same, and average population data is used to model serum levels. More complex and accurate models can be obtained by entering additional information about the patient. This information can be input by a user, such as a physician, or collected by a receiver from an associated sensor. Information that can be used to adjust the model includes factors such as other medications being taken, the disease the patient is experiencing, the patient's organ function, enzyme levels, metabolism, weight, and age. Information can also be entered by the patient himself, such as if the patient feels hypoglycemic or has pain or dizziness. This can be used as further evidence to verify the prediction of the model.

Serum levels can also be estimated based on physiological parameters such as body temperature and heart rate. For example, if a patient is taking a beta blocker that affects heart rate, there will be feedback placed into the model. If the heart rate rises, and there are no other physiological causes for this (such as increased activity), the model can assume that it is rising due to beta blocker depletion.

In other embodiments, the actual serum levels can be measured directly with an implanted receiver and used in the model. Many serum level sensors have a limited number of wells (wells) that can be used for measurements. In this case, several measurements can be taken at an early stage to derive the initial model parameters. Thereafter, serum levels can be periodically measured and compared to model estimates. Serum levels can be measured at regular intervals, or in certain circumstances (such as the time of high uncertainty), or at a time related to another event such as ingestion of a pill. The model can be adjusted using an optimal estimation technique to adapt the model to the data. Models are well known in the art for technical compliance. In one embodiment, techniques such as those discussed in "Optimal Control and Estimation" of Robert f.stengel (Dover Publications, 1994), which is incorporated herein by reference, can be used to conform the model to the measurement data.

By collecting some initial data from individual patients, the pharmacokinetic model can be adjusted to fit the individual. During hospital visits, patients often receive routine tests, which collect a wide range of data. During this time, serum levels can be measured. In the case of a patient equipped with a system that records the consumption of a medicament, the system will know when the medicament was taken and can use this information in conjunction with the measured serum levels to conform to the model. Alternatively, information about the time, type, and amount of medication administered can be entered by the health care administrator. Without the patient otherwise receiving a test, the physician can decide whether the test should be performed specifically for the purpose of collecting data to which the pharmacokinetic model is fitted.

When a medicament is first introduced into a patient, it will not be a steady state, and the response measured in vivo does not necessarily indicate how the body reacts after adapting to the medicament. This can be included in the model. Also, later measurements from the implanted unit can help adjust the model to steady state.

Once the model is fitted to an individual patient, it can be run on an implant device in the patient. The implant device can wirelessly communicate with an external device to relay model data as well as measurement data, such as the patient's actual medication administration plan. The implant can also send an alert to an external device to send a message to the patient, such as to take another dose of medicament. In some cases, such as if the patient takes too much medication, the pharmacokinetic model can send an alert to the patient informing them to see the doctor. Also, the pharmacokinetic model can directly contact a doctor or hospital if a medical problem is detected.

In other embodiments, data collected from a subset of the population that includes the patient can be used to present the initial model. For example, a model can be developed by looking at population data that more closely resembles drug interactions in patients experiencing kidney failure. The model can then be used as a starting point for any patient with kidney failure and then adjusted for any other data entered.

Other agents administered can greatly affect the way in which individual drugs are handled in the body. When combined with a medical information system, the receiver will know when to take multiple medications and can adjust the model accordingly.

Dynamic dosing regimens made possible by pharmacokinetic modeling can be a very valuable tool for prescribing patients. In the case of insulin, the level of insulin in the body depends on factors such as the metabolism and formation (formulation) of insulin. The pharmacokinetic model can take these factors into account when determining the serum level of insulin. Also, blood glucose can be measured directly and incorporated into the model. Using this information, the pharmacokinetic model can alert the patient when it determines that another injection (shot) of insulin should be administered.

The pharmacokinetic model can also incorporate the patient's sleep habits in determining the recommended timing of the dose. Because the patient is not able to administer a dose of medication while sleeping, the pharmacokinetic model is able to track the typical time the patient sleeps and use this information to determine when the dose should be taken to keep the serum levels within an optimal range.

In some cases, where different amounts of drug may be administered in a particular dose, it can be incorporated into the model. For example, the patient can be instructed to take one or two pills depending on the current serum level and other factors.

Fig. 23 shows an ideal case in which the drug dose is taken at time 2, and the serum level 4 rises and then decays. Another dose was taken at times 3,5, 7 and 9. Serum level 4 was consistently within the therapeutic range 8. The time of dose administration is evenly divided and the decay always occurs at the same rate. The graph shows the ideal situation on which the prescribed dosing regimen is based.

Fig. 24 shows a hypothetical graph illustrating a more realistic situation in which doses of medicament are taken at non-uniform intervals. The doses were taken at times 10, 12, 14, 16 and 17. The therapeutic range 18 is bounded by a poisoning limit 20 and a lower limit 22. Due to the non-uniform dosing schedule, the serum concentration in this graph rises above the toxic limit 20 and also falls below the lower limit 22. The pharmacokinetic model will be used to avoid the situation in figure 24. At point 14, the system can send an alert to the patient to inform them that the dose is not to be taken at this time. The system can inform the patient of the next time they should take the dose. In the case of implants, the alert can be sent wirelessly to an external unit, such as a Personal Digital Assistant (PDA), computer, watch, cellular phone, or other device, that can display a message to the patient. The time at which the next dose should be taken can vary as new measurements are obtained and the displayed message can be changed accordingly. The system will assume that the patient is not compliant with the message displayed to them. When the pharmacokinetic model is used in conjunction with a system that detects the intake of a medicament, the system will record when the medicament is taken. Alternatively, the system can determine that a dose was taken when the estimated or measured serum level rises. The system can be configured to continue to remind the patient to take a dose until it determines that a dose has been taken. Alternatively, the patient can enter data into the system that they have taken a dose.

The pharmacokinetic Model can be used in conjunction with a more robust Model, such as that discussed in U.S. provisional application serial No.60/893,545 entitled "ET Constrained Heart Model," filed on 7.3.2007, which is incorporated herein by reference in its entirety. When sufficient data is incorporated into the model, the model can become predictive to the individual patient. This allows the physician to experiment different treatment options on the model rather than on the patient themselves. For example, a physician can study the effect that different dosage regimens will have on a patient and select the best treatment based on the results. The data collected using the implanted receiver, as well as data from health records, and data entered by medical personnel and patients themselves, can all be incorporated directly into the model.

In an embodiment of the pharmacokinetic model, several free parameters can be adjusted until the results of the model conform to the patient's measurements. When the outcome of the model matches the patient's measurements, then a conclusion can be drawn that the model is predictive for that particular patient, and the treatment is based on those predictions.

The newly collected or entered data can be checked against the model and the model can be fitted to the new data, keeping up with the patient's changes, making the model more accurate. If the incoming data deviates significantly from what the model predicts, this may be a sign that the patient is doing something else, and an alarm can be sent to alert of the deviation. This can be very powerful in identifying a patient's change before it progresses to more significant symptoms.

Figure 25 provides an illustration of the use of an embodiment of the system to provide an estimate of dose response from longitudinal blood pressure measurements. In fig. 26, it is evident that given a longitudinal blood pressure trace knowing the pill intake time (e.g., as provided by the IEM system of the present invention), individual dose responses can be determined using a generalized linear model of pharmacokinetics. An example of a generalized linear model of dose response that may be employed is shown in fig. 26. Fig. 27 provides an illustration of different physiological sensing nodosity (the element labeled "Raisin" is a personal health receiver according to the present invention) that may find use in the system of the present invention.

Examples of food applications include the following. In certain conditions, such as diabetes, it may be important what, when, and when the patient eats. In this example, the event marker of the present invention is adapted (keyed) or linked to the type of food consumed by the patient. For example, it is possible to have a set of event markers for different food items and to administer them along with the food items. From the resulting data, complete individual metabolic profiles for the individual can be accomplished. It is known how much calories the patient has consumed. By obtaining activity and heart rate and ambient temperature versus body temperature data, it is possible to calculate how many calories are consumed. As a result, guidance can be provided to the patient, such as what food to eat and when to eat. Patients without disease can also follow food intake in this way. For example, an athlete following a strictly trained diet may employ IEMs to better monitor food intake and the effect of food intake on one or more physiological parameters of interest.

As discussed 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 where the IEM is mixed with an active agent, the resulting mixed composition can be considered a pharmaceutical information-enabled pharmaceutical composition.

In this medical information embodiment, an effective amount of a composition comprising an IEM and an active agent is administered to a subject in need of the active agent present in the composition, where an "effective amount" represents a dose sufficient to produce a desired result, such as an improvement in a condition or symptom associated therewith, achievement of a desired physiological change, and the like. The amount administered may also be considered a therapeutically effective amount. By "therapeutically effective amount" is meant an amount sufficient to effect treatment of a disease when administered to a subject to treat the disease.

The composition can be administered to the subject in any convenient manner that produces the desired result, where the route of administration depends at least in part on the particular morphology of the composition, such as described above. As noted above, the compositions can be formed into a variety of compositions for therapeutic administration, including, but not limited to, solids, semi-solids, or liquids, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, and injections. Thus, administration of the composition can be accomplished in a variety of ways, including but not limited to: oral, buccal (buccal), rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal (intratracheal), etc. administration. In the form of a pharmaceutical dosage, a given composition can be administered alone or in combination with other pharmaceutically active compounds, for example it can also be a composition having a signal-generating element stably associated therewith.

The present methods find use in a variety of different situations, including the treatment of disease conditions. The particular condition that can be treated with the composition will vary with the type of active agent that can be present in the composition. Thus, conditions include, but are not limited to, cardiovascular disease, cell proliferative disease such as neoplastic disease, autoimmune disease, hormonal abnormality, infectious disease, pain management (pain management), and the like.

Treatment represents at least a worsening of a symptom associated with a condition afflicting the subject, wherein worsening is used in a broad sense to represent at least a reduction in the size of a parameter, such as a symptom associated with the condition being treated. Thus, treatment also includes situations in which the condition, or at least the symptoms associated therewith, are completely suppressed, e.g., prevented from occurring or from ceasing, e.g., terminating, so that the subject is no longer experiencing the condition, or is no longer experiencing at least the symptoms indicative of the condition. Thus, "treatment" of a disease includes preventing the disease from occurring in an animal that may be predisposed 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 alleviation of symptoms or side effects of the disease (including palliative treatment), and relieving the disease (resulting in regression of the disease). For the purposes of the present invention, "disease" includes pain.

In certain embodiments, as described above, the present methods are methods of managing a condition, for example, over an extended period of time, such as 1 week or more, 1 month or more, 6 months or more, 1 year or more, 2 years or more, 5 years or more, and the like. The present methods may be used in conjunction with one or more additional disease management protocols, such as electrical stimulation-based protocols in cardiovascular disease management, such as pacing protocols, cardiac resynchronization protocols, and the like; lifestyle, such as a diet and/or exercise regimen for a variety of different conditions, etc.

In certain embodiments, the method comprises adjusting the treatment regimen based on data obtained from the composition. For example, data may be obtained that includes information regarding patient compliance with prescribed treatment regimens. This data, with or without further physiological data, e.g. obtained using one or more sensors such as the aforementioned sensor devices, may be used, e.g. as required, together with appropriate decision tools to make a decision whether a given treatment regime should be maintained or modified in some way, e.g. by modifying the drug regime and/or the implant behaviour regime. Thus, the methods of the invention include methods in which the treatment regimen is modified based on the signals obtained from the composition(s).

In certain embodiments, there is also provided a method 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, for example with wan or other suitable interrogation device, to obtain the signal. The obtained signals are then used to determine historical information about the composition, such as source, chain of custody, and the like.

In certain embodiments, a system is employed that is made up of a plurality of different IEMs, such as 2 or more different IEMs, 3 or more different IEMs, 4 or more different IEMs, etc., including 5 or more, 7 or more, 10 or more different IEMs. The different IEMs may also be configured to provide distinguishable signals, for example, where the signals may be distinguished according to characteristics of the signals themselves, timing of signal transmission, and the like. For example, each IEM in the group may transmit a different 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 target physiological site, e.g., a first IEM is activated in the mouth, a second IEM is activated in the esophagus, a third IEM is activated in the small intestine, and a fourth IEM is activated in the large intestine. This set of a plurality of different distinguishable IEMs finds use in a variety of different applications. For example, when having the 4IEM group described above, the group can be used in diagnostic applications to determine the function of the digestive system, e.g., through motility (motility) of the digestive tract, gastric emptying, etc. For example, by noting when each IEM emits its respective signal, a signal time map can be generated from which information about gut function can be obtained.

The present invention provides clinicians with an important new tool in their medical devices: automatic detection and identification of the pharmaceutical agent actually delivered into the body. The application of this new information device and system is multi-fold. Applications include, but are not limited to: (1) monitoring patient compliance with an prescribed treatment regimen; (2) adjusting the treatment regimen based on patient compliance; (3) monitoring patient compliance in a clinical trial; (4) monitoring the use of the controlled substance; and the like. Each of these different exemplary applications is described in more detail below in co-pending PCT application Serial No. PCT/US2006/016370, the disclosure of which is incorporated herein by reference.

Additional applications for which the present system finds use include those described in U.S. patent No.6804558, 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 performance of an Implantable Medical Device (IMD) implanted in a patient; monitoring the health condition of the patient; and/or remotely deliver therapy to the patient via the IEM. The signal receiver of the present invention, for example in an external or implanted form such as an emergency bandage, 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), located outside the patient's body. The system may include an IMD, a signal receiver capable of receiving information from the IMD or relaying information to the IMD via the signal receiver, along with a communication module and/or a mobile phone and/or PDA, which is internal or external to the patient, as described above, a remote computer system, and a communication system capable of two-way communication.

Additional applications in which the receiver 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.

Computer readable medium & programming

In certain embodiments, the system further comprises an element for storing data, i.e. a data storage element, wherein the element is present on an external device such as a bedside monitor, a PDA, a smartphone, etc. Typically, the data storage element is a computer readable medium. The term "computer-readable medium" as used herein refers to any storage or transmission medium that participates in providing instructions and/or data to a computer for execution and/or processing. Examples of storage media include floppy disks, magnetic tape, CD-ROMs, hard disk drives, ROMs, or integrated circuits, magneto-optical disks, or a computer-readable card, such as a PCMCIA card, or the like, whether or not such devices are internal or external to a computer. A file containing information may be "stored" on a computer-readable medium, where "storing" means recording the information so that it can be accessed and retrieved by a computer at a later date. With respect to computer-readable media, "persistent storage" means persistent storage. The persistent memory is not erased by terminating power to the computer or processor. Computer hard drive ROM (i.e., ROM that is not used as virtual memory), CD-ROM, floppy disk, and DVD are all examples of permanent memory. Random Access Memory (RAM) is an example of non-persistent memory. The files in persistent storage may be editable and rewritable.

The present invention also provides computer-executable instructions (i.e., programming) for performing the above-described methods, such as for programming the IEM, receiver, and other components of the system. Computer-executable instructions reside on a computer-readable medium. Accordingly, the present invention provides a computer readable medium containing programming for detecting and processing signals generated by the compositions of the present invention, e.g., as described above.

Thus, in certain embodiments, the system comprises one or more of: a data storage element, a data processing element, a data display element, a data transmission element, a notification mechanism, and a user interface. These further elements may be integrated into the receiver and/or be present on an external device, e.g. a device configured for processing data and making decisions, forwarding data to a remote location, which provides these actions, etc.

The above system is described in terms of communication between a marker on a pharmaceutical composition and a receiver. However, the system is not limited thereto. In a broader sense, the system consists of two or more different modules communicating with each other, for example using the transmitter/receiver functionality described above, for example using a monopole transmitter (e.g. an antenna) as described above. Thus, the above-described marker element may be integrated into any of a number of different devices, for example for providing a communication system between two self-powered devices in the body, wherein the self-powered devices may be sensors, data receivers and storage elements, effectors, etc. In an exemplary system, one of these devices may be a sensor, while the other may be a communication hub for communicating with the outside world. Embodiments of the present invention may take many forms. There can be many sensors, many transmitters and one receiver. They can be transceivers so that all of them can transmit and receive in sequence according to a known communication protocol. In certain embodiments, the communication device between two or more independent devices is a monopolar system, for example as described above. In these systems, each of these transmitters may be configured to transmit high frequency signals into the body in turn using a monopole that pulls charge into and out of the body, the monopole being a large capacitor and a conductor. A receiver, a monopole receiver, detects charge in and out of the body at this frequency and decodes encrypted signals such as amplitude modulated signals or frequency modulated signals. This embodiment of the invention has a wide range of applications. For example, multiple sensors can be placed and implanted on multiple sites of the body, which measure position or acceleration. They are able to transmit this information over a communications medium without the need for wires to connect to a central hub.

External member

Kits for practicing the present methods are also provided. The kit may include components of the IEM system of the present invention, such as one or more IEMs (including multiple sets of distinguishable IEMs), one or more receivers, a third external device, and the like, as described above. Further, the kit may include one or more dosage compositions, such as a pharmaceutical information enabled dosage composition or a composition to be administered with an IEM. The amount of one or more doses of the pharmaceutical agent provided in the kit may be sufficient for a single application or multiple applications. Thus, in certain embodiments of the kit, a single dose amount of medicament is present in the kit, while in certain other embodiments, multiple doses of medicament may be present in the kit. In those embodiments having multiple dose quantities of medicament, the medicaments may be packaged in a single container, such as a single tube, bottle, vial, or the like, or one or more dose quantities may be packaged separately so that certain kits may have more than one medicament container.

Suitable means for delivering one or more agents to a subject may also be provided in the kit. As noted above, the particular delivery devices provided in the kit are specified with the particular medicament employed, for example: specific forms of the agent, such as whether the agent is formed into a formulation in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injectables, inhalants, aerosols, and the like; and specific modes of administration, such as oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal. Thus, certain systems may include suppository applicators, syringes, i.v. bags and tubes (tubing), electrodes, and the like.

In certain embodiments, the kit may further comprise an external monitoring device, such as described above, capable of providing communication with, for example, a physician's office, central facility, or the like, which obtains and processes data obtained regarding the use of the composition.

In certain embodiments, the kit may include an intelligent parenteral delivery System that provides specific identification and detection of a parenteral beneficial agent (beneficial agent) or a beneficial agent that enters the body by other methods, such as by use of a syringe, inhaler, or other device that administers a drug, such as those described in co-pending application serial No. pct/US2007/015547 entitled "smartpartial Administration System," filed on 6.7.2007, the disclosure of which is incorporated herein by reference.

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 such as paper or plastic. Thus, the instructions may be present in the kit as package instructions in the form of a label or the like for the container of the kit or for a component thereof (i.e., associated with the package or sub-package). In other embodiments, the instructions are present as an electronically stored data file that resides on a suitable computer-readable storage medium, such as a CD-ROM, diskette, or the like. In other embodiments, the actual instructions are not present in the kit, but rather provide a means for obtaining the instructions from a remote source, for example via the internet. One example of this embodiment is a kit comprising a network address from which instructions can be viewed and/or downloaded. The means for obtaining the instructions are recorded on a suitable substrate just like the instructions.

Some or all of the components of the kit may be packaged in a suitable package to maintain sterility. In many embodiments of the present kits, the components of the kit are packaged in kit housing elements, such as cassettes or similar structures, which may or may not be sealed containers, for example, to further maintain the sterility of some or all of the components of the kit, to produce a single and easily handled unit.

It is to be understood that the invention is not limited to the specific embodiments described, as these 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 excluding 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. Representative exemplary methods and materials are now described, 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.

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 are 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 intended to exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only," etc., in connection with the recitation of claim elements, or use of a "negative" limitation.

As will be apparent to those of skill in the art upon reading this disclosure, each of the various embodiments described and illustrated herein has discrete components 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 described methods can be performed in the order of events described, 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.

Thus, 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 aid the reader in understanding the principles of the invention and the concepts contributed by the inventor 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. Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention is embodied by the appended claims.

Claims (73)

1. A system, comprising:

an ingestible event marker composition that emits a signal upon contact with a target physiological site and that does not include an active agent; and

a signal receiver configured to receive the signal generated by the ingestible event marker, wherein the receiver is sized to be stably associated with a living subject in a manner that does not substantially affect movement of the living subject.

2. The system according to claim 1, wherein the IEM comprises an integrated circuit that includes both a signal generation function and a power supply function.

3. The system of claim 2, wherein the power supply function includes first and second different electrode materials.

4. The system of claim 3, wherein the first and second electrode materials are present on different surfaces of a solid support comprising the integrated circuit.

5. The system of claim 1, wherein the signal receiver comprises at least one electrode.

6. The system of claim 1, wherein the signal receiver comprises two electrodes.

7. The system of claim 1, wherein the signal receiver further comprises a power generating element.

8. The system of claim 1, wherein the signal receiver further comprises a data storage element.

9. The system of claim 1, wherein the signal receiver further comprises a physiological sensor.

10. The system of claim 9, wherein the physiological sensor is configured to provide data selected from the group consisting of: respiration, heart rate, temperature, and blood pressure.

11. The system of claim 1, wherein the signal receiver comprises:

(i) first and second electrodes configured to receive a signal;

(ii) a signal demodulator;

(iii) a signal transmitter;

(iv) a data storage element; and

(v) a power source.

12. The system of claim 11, wherein the signal receiver comprises an integrated circuit including at least one element selected from the group consisting of: (i) first and second electrodes configured to receive a signal; (ii) a signal demodulator; (iii) a signal transmitter; and (iv) a data storage element.

13. The system of claim 12, wherein the signal receiver further comprises a clock element.

14. The system of claim 13, wherein the signal receiver further comprises a preamplifier.

15. The system of claim 14, wherein the signal receiver further comprises a microprocessor.

16. The system of claim 11, wherein the first and second electrodes are configured to receive signals and sense biomarkers.

17. The system of claim 16, wherein the biomarkers are selected from the group consisting of: electrocardiogram, heart rate, respiration rate and fluid status.

18. The system of claim 16, wherein the signal receiver further comprises a physiological sensor distinct from the first and second electrodes.

19. The system of claim 18, wherein the physiological sensor different from the first and second electrodes is selected from the group consisting of: temperature sensors, pressure sensors and analyte detectors, motion sensors or strain gauges.

20. The system of claim 1, wherein the system further comprises an external data receiver configured to receive data from the signal receiver.

21. The system of claim 20, wherein the external data receiver further comprises at least one of a data storage element, a data processing element, a data display element, a data transmission element, and a notification mechanism and user interface.

22. The system of claim 21, wherein the external data receiver is selected from the group consisting of: bedside monitors, PDAs, cell phones, and personal computers.

23. An ingestible event marker composition that emits a signal upon contact with a target physiological site and does not include an active agent.

24. The ingestible event marker according to claim 23, wherein said IEM comprises an integrated circuit containing both a signal generation function and a power supply function.

25. The ingestible event marker according to claim 24, wherein said power supply function comprises first and second different electrode materials.

26. The ingestible event marker according to claim 25, wherein said first and second electrode materials are present on different surfaces of a solid support comprising said integrated circuit.

27. The ingestible event marker according to claim 23, wherein said event marker comprises a battery element comprising a short-circuit resistive series battery.

28. The ingestible event marker according to claim 27, wherein said short-circuit resistive series battery is comprised of two or more battery configurations.

29. The ingestible event marker according to claim 28, wherein each said battery structure comprises a chamber having an anode and a cathode.

30. The ingestible event marker according to claim 29, wherein said chamber comprises a liquid inlet port and a liquid outlet port.

31. The ingestible event marker according to claim 30, wherein at least one of said ports comprises a semi-permeable membrane.

32. The ingestible event marker according to claim 28, wherein said two or more battery structures share a common boundary.

33. The ingestible event marker according to claim 28, wherein said two or more battery structures do not share a common boundary.

34. The ingestible event marker according to claim 23, wherein said ingestible event marker comprises a battery element produced using a planar processing protocol.

35. The ingestible event marker according to claim 34, wherein said marker is activated upon liquid contact with a target site present at a target site.

36. The ingestible event marker according to claim 35, wherein said identifier comprises:

(i) a solid support; and

(ii) first and second electrodes, wherein the first and second electrodes: (a) at least partially present on the same surface of the solid support; or (B) present on different solid supports that are bonded to each other.

37. The ingestible event marker according to claim 36, wherein said first and second electrodes are present on the same surface of said solid support.

38. The ingestible event marker according to claim 37, wherein said ingestible event marker comprises two cathodes flanking an anode on an upper surface of said solid support.

39. The ingestible event marker according to claim 38, wherein said ingestible event marker comprises: a cathode residing entirely on the upper surface of the solid support; and an anode partially present on the upper surface of the solid support and partially present on the other surface of the solid support.

40. The ingestible event marker according to claim 38, wherein said marker comprises two or more anodes disposed over a common cathode on an upper surface of said solid support.

41. The ingestible event marker according to claim 38, wherein said marker comprises two or more anodes disposed below a common cathode on an upper surface of said solid support.

42. The ingestible event marker according to claim 38, wherein said marker comprises a chamber defined by a cathode and an anode, wherein said anode comprises one or more openings.

43. The ingestible event marker according to claim 37, wherein said first and second electrodes are present on different solid supports that are bonded to each other.

44. A signal receiver configured to receive a signal generated by a marker of a pharmaceutical composition, and dimensioned to be stably associated with a living subject in a manner that does not substantially affect movement of the living subject.

45. The signal receiver of claim 44, wherein the signal receiver further comprises a power generating element.

46. The signal receiver of claim 44, wherein the signal receiver further comprises a data storage element.

47. A signal receiver as claimed in claim 44 wherein said signal receiver further comprises a physiological sensor.

48. The signal receiver of claim 47, wherein the physiological sensor is configured to provide data selected from the group consisting of: respiration, heart rate, temperature, and blood pressure.

49. The signal receiver of claim 44, wherein the signal receiver comprises at least one electrode.

50. The signal receiver of claim 49, wherein the signal receiver comprises two electrodes.

51. The signal receiver of claim 50, wherein the signal receiver comprises at least three electrodes.

52. The signal receiver of claim 44, wherein the signal receiver comprises:

(i) first and second electrodes configured to receive a signal;

(ii) a signal demodulator;

(iii) a signal transmitter;

(iv) a data storage element; and

(v) a power source.

53. The signal receiver of claim 52, wherein the signal receiver comprises an integrated circuit comprising at least one element selected from the group consisting of: (i) first and second electrodes configured to receive a signal; (ii) a signal demodulator; (iii) a signal transmitter; and (iv) a data storage element.

54. The signal receiver of claim 53, wherein the signal receiver further comprises a clock element.

55. The signal receiver of claim 54, wherein the signal receiver further comprises a preamplifier.

56. The signal receiver of claim 55, wherein the signal receiver further comprises a microprocessor.

57. The signal receiver of claim 53, wherein the first and second electrodes are configured to receive a signal and sense a biomarker.

58. The signal receiver of claim 57, wherein the biomarker is selected from the group consisting of: electrocardiogram, heart rate, respiration rate and fluid status.

59. A signal receiver as in claim 53, wherein said signal receiver further comprises a physiological sensor distinct from said first and second electrodes.

60. The signal receiver of claim 59, wherein the physiological sensor different from the first and second electrodes is selected from the group consisting of: temperature sensors, pressure sensors and analyte detectors, motion sensors or strain gauges.

61. A method, comprising:

(A) administering to a subject an ingestible event marker that emits a signal upon contact with a target physiological site and that does not include an active agent; and

(b) detecting the signal emitted from the marker with a signal receiver.

62. The method of claim 61, wherein the method further comprises sensing at least one biomarker of the subject using the signal receiver.

63. The method of claim 62, wherein the method further comprises transmitting data from the signal receiver to an external data receiver.

64. The method of claim 61, further comprising implanting a receiver for detecting the signal generated by the marker at a location of the subject.

65. The method of claim 61, further comprising associating the receiver with a local position of the subject.

66. The method of claim 65, wherein the method is a method of treating a condition in a subject.

67. The method of claim 66, wherein the condition is a cardiovascular condition.

68. The method of claim 67, further comprising estimating the subject's response to the agent.

69. The method of claim 68, wherein the estimating further comprises generating a physiological index based on data from a plurality of biomarkers.

70. The method of claim 69, wherein the method further comprises adjusting a treatment regimen for the subject based on the estimation.

71. A kit, comprising:

an ingestible event marker that emits a signal upon contact with a target physiological site and that does not include an active agent; and

a signal receiver.

72. The kit according to claim 71, wherein the kit comprises two or more ingestible event markers.

73. The kit according to claim 72, wherein the two or more ingestible event markers are distinguishable.