ENHANCED INGESTIBLE EVENT INDICATORS AND METHODS FOR MAKING AND USING THE SAME
Improved ingestible event markers are provided. Aspects of the markers may include the presence of a matrix layer that includes a binder and source of an electron acceptor. Alternatively or in addition to the matrix layer, aspects of the markers may include a large surface area electrode having a surface area that exceeds the surface area of the circuitry of the marker. Aspects further include methods of making and using the ingestible event markers.
This application claims priority to U.S. Provisional Application No. 61/935,768, filed Feb. 4, 2014, entitled ENHANCED INGESTIBLE EVENT INDICATORS AND METHODS FOR MAKING AND USING THE SAME, the disclosure of which is incorporated herein by reference in its entirety.
INTRODUCTIONA variety of different ingestible compositions have been developed for nutritional, therapeutic and non-therapeutic uses. Examples of different types of ingestible compositions include orally ingestible tablets, capsules and liquids. A given orally ingestible formulation may include a variety of different components, such as active agents, carrier materials (including binders, bulking agents and other excipients), flavoring agents, coloring agents, etc.
More recently, ingestible compositions which include a device component, such as an ingestible event marker, have been developed. Use of such ingestible devices allows one to monitor the actual ingestion of an ingestible composition, and has broad applicability to a variety of different applications.
Furthermore, ingestible devices that include electronic circuitry have been proposed for use in a variety of different medical applications, including both diagnostic and therapeutic applications. These devices typically require an internal power supply for operation, such as an internal and self-contained power source. The electronic circuit components of the device are enclosed by an inert indigestible housing (e.g., glass housing) that passes through the body internally. Other examples include an ingestible data recorder capsule medical device that includes electronic circuits (e.g., sensor, recorder, battery) housed in a capsule made of inert materials.
In other examples, fragile radio frequency identification (RFID) tags are used in drug ingestion monitoring applications. In order for the RFID tags to be operational, each requires an internal power supply. The RFID tags are antenna structures that are configured to transmit a radio-frequency signal through the body.
Among the many shortcomings of existing devices is that the power source is internal to device and such power sources are costly to produce and potentially harmful to the surrounding environment if the power source leaks or is damaged. Additionally, having antennas extending from the device is a concern as related to the antennas getting damaged or causing a problem when the device is used in-vivo.
SUMMARYEnhanced ingestible event markers are provided. Aspects of the markers may include the presence of a matrix layer that includes a binder and source of an electron acceptor. Alternatively or in addition to the matrix layer, aspects of the markers may include a large surface area electrode having a surface area that exceeds the surface area of the circuitry of the marker. Aspects further include methods of making and using the ingestible event markers.
In some aspects, a system (e.g., event marker system) comprises a control device including a logic module, e.g., integrated circuit. First and second portions of a non-conductive membrane (skirt) are disposed on first and second sides, respectively, of the control device. A first material and a second material are electrically coupled to the logic module. The first and second materials are selected to provide a voltage potential difference as a result of the first and second materials being in contact with a conductive fluid, thus providing a source of power. The logic module is configured to control conductance between the first and second materials for producing a signal that is remotely detectable by a receiver. At least one of the first and second materials is disposed above or below at least one of the portions of the non-conductive membrane.
In some aspects, a system (e.g., event marker system) comprises a control device including a logic module. A first material is electrically coupled to the logic module, wherein the first material is an anode. A second material is electrically coupled to the logic module, wherein the second material is a cathode. An acidulating agent is disposed on a same side of the control device as the cathode. The first and second materials are selected to provide a voltage potential difference as a result of the first and second materials being in contact with a conductive fluid, thus providing a source of power. The logic module is configured to control conductance between the first and second materials for producing a signal that is remotely detectable by a receiver.
In some aspects, a system comprises a control device including a logic module. First and second portions of a non-conductive membrane (skirt) are disposed on first and second sides, respectively, of the control device. A first material is electrically coupled to the logic module, wherein at least a portion of the first material is disposed above the control device. A first layer of a second material is electrically coupled to the logic module, wherein the first layer is disposed below the control device. A third material, which is conductive, is coupled to the first layer of the second material. A second layer of the second material is electrically coupled to the first layer by the third material. The first and second materials are selected to provide a voltage potential difference as a result of the first material and the second layer of the second material being in contact with a conductive fluid, thus providing a source of power. The logic module is configured to control conductance between the first material and the second layer of the second material for producing a signal that is remotely detectable by a receiver.
Enhanced ingestible event markers are provided. Aspects of the markers may include the presence of a matrix layer that includes a binder and source of an electron acceptor. Alternatively or in addition to the matrix layer, aspects of the markers may include a large surface area electrode having a surface area that exceeds the surface area of the circuitry of the marker. Aspects further include methods of making and using the ingestible event markers.
Ingestible Event MarkersAs summarized above, aspects of the invention include improved ingestible event markers (IEMs). In describing various aspects, the ingestible event markers will be described first in general terms, followed by a detailed description of the matrix and high surface area electrode aspects which may be present in the ingestible event markers.
Ingestible event markers are ingestible devices. As the ingestible event markers are ingestible, they are configured to be ingested or swallowed, i.e., taken into the stomach by drawing through the throat and esophagus with a voluntary muscular action. Accordingly, the devices are dimensioned so as to be capable of being ingested. In some instances, the devices have a longest dimension of 30 mm or less, such as 20 mm or less, e.g., 10 mm or less, including 5 mm or less. The volume of the ingestible event marker may also vary so long as the composition is suitable for ingestion, where the volume in some instances may be 25 mm3 or less, such as 15 mm3 or less, including 10 mm3 or less.
Ingestible event markers (i.e., IEM, also known as an ingestible event indicators) include an identifier circuitry component (also referred to herein as a controller or control device) and, optionally, a current path extender, e.g., a membrane, sometimes referred to herein as a “skirt”. Various aspects of an IEM may include a control device for altering conductance; and a partial power source. The partial power source may include a first material electrically coupled to the control device; and a second material electrically coupled to the control device and electrically isolated from the first material, where the first and second materials are dissimilar.
Upon ingestion, the IEM contacts a conducting fluid, e.g., stomach fluid. When the IEM is in contact with the conducting liquid, a current path is formed through the conducting liquid between the first and second materials. The voltage potential created between the materials provides the power for operating the IEM as well as produces the current flow through the conducting fluid and the system. In one aspect, the IEM operates in direct current mode. In an alternative aspect, the IEM controls the direction of the current so that the direction of current is reversed in a cyclic manner, similar to alternating current. The current path through the system is controlled by the control device. Completion of the current path allows for the current to flow and in turn a receiver, not shown, can detect the presence of the current and recognize that the system has been activated and the desired event is occurring or has occurred.
In one aspect, the two materials are similar in function to the two electrodes needed for a direct current power source, such as a battery. The conducting liquid acts as the electrolyte needed to complete the power source. The completed power source is defined by the electrochemical reaction between the dissimilar materials of the IEM and the completion of the power source is enabled by the fluids of the body. The completed power source may be viewed as a power source that exploits electrochemical conduction in an ionic or a conducting solution such as gastric fluid, blood, or other bodily fluids and some tissues.
In certain aspects, the complete power source or supply is one that is made up of active electrode materials, electrolytes, and inactive materials, such as current collectors and packaging. The active materials are any pair of materials with different electrochemical potentials. Suitable materials are not restricted to metals, and in certain aspects the paired materials are chosen from metals and non-metals, e.g., a pair made up of a metal (such as Mg) and a salt (such as CuI). With respect to the active electrode materials, any pairing of substances—metals, salts, or intercalation compounds—with suitably different electrochemical potentials (voltage) and low interfacial resistance are suitable. Where desired, the voltage provided by the two dissimilar electrochemical materials upon contact of the materials of the power source with the target physiological site is 0.001 V or higher, including 0.01 V or higher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5 volts or higher, and including 1.0 volts or higher, where in certain aspects, the voltage ranges from about 0.001 to about 10 volts, such as from about 0.01 to about 10 V.
Anode materials of interest include, but are not limited to: magnesium, zinc, sodium, lithium, iron and alloys thereof, e.g., Al and Zn alloys of Mg, which may or may not be intercalated with a variety of materials such, as graphite with Li, K, Ca, Na, Mg, and the like. Cathode materials of interest include, but are not limited to, metallic salts, e.g., copper salts, such as copper salts of iodide, chloride, bromide, sulfate, formate, gluconate, Fe3+ salts, e.g., (such as iron sulfate, iron gluconate, iron citrate, iron phosphates (include iron orthophosphate and iron pyrophosphate) etc.), silver salts (such as AgCl, etc.); metals, e.g., gold, platinum, titanium, etc.; other conductive materials, e.g., graphite, etc., and the like. Where metals are employed, 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 doping agents in certain aspects include, but are not limited to: sulfur, iodine and the like. In certain aspects, the electrode materials are cuprous iodine (CuI) or cuprous chloride (CuCl) as the anode and magnesium (Mg) metal or magnesium alloy as the cathode. Aspects of the present invention use electrode materials that are not harmful to the human body.
With respect to current signatures produced by the IEMs, the current signatures may distinguish one class of event indicator from other types or may be universally unique, such as where the current signature is analogous to a human fingerprint which is distinct from any other fingerprint of any other individual and therefore uniquely identifies an individual on a universal level. In various aspects, the control circuit may generate a variety of different types of communications, including but not limited to: RF signals, magnetic signals, conductive (near-field) signals, acoustic signals, etc.
In various aspects, the IEM may further include a current path extender, such as a membrane, which produces a virtual dipole length between the pair of dissimilar materials (functioning as transmission elements) that is longer than the actual dipole length. In addition to controlling the magnitude of the current path between the materials, such a membrane (sometimes referred to herein as “amplifier” or “skirt”) is used to increase the “length” of the current path and, hence, act to boost the conductance path, as disclosed in the PCT application no. PCT/US2008/077753 published as WO2009/042812 and in U.S. Pat. No. 7,978,064, the entire contents of which are incorporated herein by reference. Throughout the disclosure herein, the terms “membrane”, “skirt” and “amplifier” are used interchangeably with the term “current path extender” without impacting the scope or the present aspects and the claims herein.
Various aspects of IEMs of interest (including protocols for the fabrication thereof) are described in PCT Application Serial No. PCT/US2006/016370 published as WO/2006/116718; PCT Application Serial No. PCT/US2007/082563 published as WO/2008/052136; PCT Application Serial No. PCT/US2007/024225 published as WO/2008/063626; PCT Application Serial No. PCT/US2007/022257 published as WO/2008/066617; PCT Application Serial No. PCT/US2008/052845 published as WO/2008/095183; PCT Application Serial No. PCT/US2008/053999 published as WO/2008/101107; PCT Application Serial No. PCT/US2008/056296 published as WO/2008/112577; PCT Application Serial No. PCT/US2008/056299 published as WO/2008/112578; PCT Application Serial No. PCT/US2008/077753 published as WO2009/042812; PCT Application Serial No. PCT/US2008/085048 published as WO2009/070773; PCT Application Serial No. PCT/US2009/36231 published as WO2009/111664; PCT Application Serial No. PCT/US2009/049618 published as WO2010/005877; PCT Application Serial No. PCT/US2009/053721 published as WO2010/019778; PCT Application Serial No. PCT/US2009/060713 published as WO2010/045385; PCT Application Serial No. PCT/US2009/064472 published as WO2010/057049; PCT Application Serial No. PCT/US2009/067584 published as WO2010/068818; PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115; PCT Application Serial No. PCT/US2010/020142 published as WO2010/080765; PCT Application Serial No. PCT/US2010/020140 published as WO2010/080764; PCT Application Serial No. PCT/US2010/020269 published as WO2010/080843; PCT Application Serial No. PCT/US2010/028518 published as WO2010/111403; PCT Application Serial No. PCT/US2010/032590 published as WO2010/129288; PCT Application Serial No. PCT/US2010/034186 published as WO2010/132331; PCT Application Serial No. PCT/US2010/055522 published as WO2011/057024; the disclosures of which are herein incorporated by reference.
In certain aspects, the ingestible IEMs are disrupted upon administration to a subject. As such, in certain aspects, the compositions are physically broken, e.g., dissolved, degraded, eroded, etc., following delivery to a body, e.g., via ingestion, injection, etc. The compositions of these aspects are distinguished from devices that are configured to be ingested and survive transit through the gastrointestinal tract substantially, if not completely, intact.
Where desired, an active agent (e.g., as described above) may be present in one or more of the IEM components, e.g., in the electrochemical materials, the support, the membrane, etc. Examples of such configurations are described in PCT Application Serial No. PCT/US2010/032590 published as WO2010/129288; the disclosures of which are herein incorporated by reference.
With reference to
In the specific example of the system 30 combined with the pharmaceutical product, as the product or pill is ingested, the system 30 is activated. The system 30 controls conductance to produce a unique current signature that is detected, thereby signifying that the pharmaceutical product has been taken. In other aspects, the current signature may contain information on the ingredients of the ingested pharmaceutical product which may include their chemical composition, date of manufacture, batch number, etc., among other desired information related to the pharmaceutical product which may be a placebo as well. The system 30 includes a framework 32. The framework 32 is a chassis for the system 30 and multiple components are attached to, deposited upon, or secured to the framework 32. In this aspect of the system 30, a digestible material 34 is physically associated with the framework 32. The material 34 may be chemically deposited on, evaporated onto, secured to, or built-up on the framework all of which may be referred to herein as “deposit” with respect to the framework 32. The material 34 is deposited on one side of the framework 32. The materials of interest that can be used as material 34 include, but are not limited to those described above. The material 34 is deposited by using any convenience protocol, including but not limited to physical vapor deposition, electro-deposition, or plasma deposition, liquid deposition, among other protocols. The material 34 may be from about 0.05 to about 500 μm thick, such as from about 5 to about 100 μm thick. The shape may be controlled by shadow mask deposition, or photolithography and etching. Additionally, even though only one region is shown for depositing the material, each system 30 may contain two or more electrically unique regions where the material 34 may be deposited, as desired. It should be noted that while the electrode materials described in connection with
At a different side, which may be the opposite side as shown in
Thus, when the system 30 is in contact with the conducting fluid, e.g., a liquid, a current path, an example is shown in
The voltage potential created between the materials 34 and 36 provides the power for operating the system as well as produces the current flow through the conducting fluid and the system. In one aspect, the system operates in direct current mode. In an alternative aspect, the system controls the direction of the current so that the direction of current is reversed in a cyclic manner, similar to alternating current. As the system reaches the conducting fluid or the electrolyte, where the fluid or electrolyte component is provided by a physiological fluid, e.g., stomach acid, the path for current flow between the materials 34 and 36 is completed external to the system 230; the current path through the system 30 is controlled by the control device 38. Completion of the current path allows for the current to flow, through conductive communication through the stomach, and in turn to a receiver, not shown, the receiver capable of detecting the presence of the current signature containing information and further recognize that the system 30 has been activated and the desired event is occurring or has occurred.
In one aspect, the two materials 34 and 36 are similar in function to the two electrodes needed for a direct current power source, such as a battery. The conducting liquid acts as the electrolyte needed to complete the power source. The completed power source described is defined by the physical chemical reaction between the materials 34 and 36 of the system 30 and the surrounding fluids of the body. The completed power source may be viewed as a power source that exploits reverse electrolysis in an ionic or a conductive solution such as gastric fluid, blood, or other bodily fluids and some tissues. Additionally, the environment may be something other than a body and the liquid may be any conducting liquid. For example, the conducting fluid may be salt water or a metallic based paint.
Referring again to
As described above, in various aspects, the event indicator may further include a current path extender such as a membrane which, for example, produces a virtual dipole length between the pair of transmission elements that is larger than the actual dipole length. As illustrated in
As can be seen in the aspect depicted in
Referring now to
Referring now to
The control device 38 can vary the duration of a fixed ionic exchange rate or current flow magnitude while keeping the rate or magnitude near constant, similar to when the frequency is modulated and the amplitude is constant. Also, the control device 38 can vary the level of the ionic exchange rate or the magnitude of the current flow while keeping the duration near constant. Thus, using various combinations of changes in duration and altering the rate or magnitude, the control device 38 encodes information in the current flow or the ionic exchange. For example, the control device 38 may use, but is not limited to any of the following techniques namely, Binary Phase-Shift Keying (PSK), Frequency modulation, Amplitude modulation, on-off keying, and PSK with on-off keying.
As indicated above, the various aspects disclosed herein, such as systems 30 and 440 of
As indicated above, the system, such as system 30 and 440, control the conductance between the dissimilar materials and, hence, the rate of ionic exchange or the current flow. Through altering the conductance in a specific manner the system is capable of encoding information in the ionic exchange and the current signature. The ionic exchange or the current signature is used to uniquely identify the specific system. Additionally, the systems 30 and 440 are capable of producing various different unique exchanges or signatures and, thus, provide additional information. For example, a second current signature based on a second conductance alteration pattern may be used to provide additional information, which information may be related to the physical environment. To further illustrate, a first current signature may be a very low current state that maintains an oscillator on the chip and a second current signature may be a current state at least a factor of ten higher than the current state associated with the first current signature.
Referring now to
The control module 662 is also electrically coupled to and in communication with the sensor modules 672 and 274. In the aspect shown, the sensor module 672 is part of the control device 38 and the sensor module 74 is a separate component. In alternative aspects, either of the sensor modules, 672 and 74, can be used without the other and the scope of the present invention is not limited by the structural or functional location of the sensor modules 672 or 74. Additionally, any component of the system 30 may be functionally or structurally moved, combined, or repositioned without limiting the scope of the present invention as claimed. Thus, it is possible to have one single structure, for example a processor, which is designed to perform the functions of all of the following modules: the control module 662, the clock 664, the memory 666, and the sensor module 672 or 274. On the other hand, it is also within the scope of the present invention to have each of these functional components located in independent structures that are linked electrically and able to communicate.
Referring again to
Referring now to
As indicated above, the control device 38 can be programmed in advance to output a pre-defined current signature. In another aspect, the system can include a receiver system that can receive programming information when the system is activated. In another aspect, not shown, the switch 664 and the memory 666 can be combined into one device.
In addition to the above components, the system 30 may also include one or other electronic components. Electrical components of interest include, but are not limited to: additional logic and/or memory elements, e.g., in the form of an integrated circuit; a power regulation device, e.g., battery, fuel cell or capacitor; a sensor, a stimulator, etc.; a signal transmission element, e.g., in the form of an antenna, electrode, coil, etc.; a passive element, e.g., an inductor, resistor, etc.
The above description provides a general review of various aspects of IEMs. As summarized above, aspects of the improved IEMs of the present disclosure include at least one of: a matrix layer that includes a binder and an electron acceptor; and an electrode having a surface area that exceeds the surface area of the circuitry of the marker. Each of these aspects is now described in greater detail below.
Matrix Layer that Includes a Binder and Source of an Electron Acceptor
Where desired, an IEM may have a matrix layer that includes a source of an electron acceptor and a binder, i.e., an electron acceptor source matrix layer. The matrix layer is a material structure, e.g., in the form of a film or coating, which is a component of the IEM. While the dimensions of the matrix layer may vary, in some instances the layer has a thickness of 10 microns or greater, such as 50 microns or greater, including 100 microns or greater, and ranges in thickness in some instances from 10 to 1000, such as 20 to 200 and including 30 to 60 microns. The top and bottom surfaces of the layer may have a variety of different configurations, including but not limited to rectangular, trapezoidal, triangular, etc.; curvilinear, such as circular, ovoid or other curvilinear shape, etc. Where the layer has a surface which may be defined by length and width, these dimensions may vary, where in some instances the length ranges from 1 to 20, such as 2 to 10 and including 3 to 6 mm and the width ranges from 1 to 20, such as 2 to 10 and including 3 to 6 mm. A matrix layer, when present, may be stably associated with the cathode material of the IEM. By “stably associated” is meant that the matrix layer and cathode do not separate from each other, at least until after the IEM has performed its intended function.
As summarized above, matrix layers of interest include a source of an electron acceptor (i.e., an electron acceptor source) present in a binder. In other words, the source of the electron acceptor is dispersed in or distributed throughout the binder, or at least a portion thereof, such as 10% or more of the binder, e.g., 20% or more, 25% or more, 50% or more, 75% or more, including 90% or more of the binder. The source of the electron acceptor is a component, which may be a distinct compound from the binder material or a functional moiety of the binder material, and can serve as a source of hydrogen ions upon contact with an aqueous medium. The hydrogen ions produced upon contact with an aqueous medium are then reduced to H2 at the cathode surface.
In some instances, the electron acceptor source is an acidulant. The term “acidulant” refers to a compound that dissolves upon contact with an aqueous medium to produce hydrogen ions. Acidulants of interest include both polymeric and non-polymeric compounds, where the compounds may be organic or inorganic, so long as the acidulant is suitable for ingestion, i.e., is non-toxic, at least in the amounts present in the IEM. Acidulants of interest include, but are not limited to: organic acids, such as glycolic acid, lactic acid, methyl lactic acid, polycarboxylic acids, e.g., malic acid, citric acid, tartronic acid, tartaric acid, succinic acid, etc.; anionic polymers, i.e., polymers that include monomeric units having an acidic functional group, such as a carboxyl, sulfate, sulfonate, phosphate or phosphonate groups; etc. Suitable anionic polymers include alginates, e.g., alginic acid and salts thereof, polyacrylic acid, dextran sulfate, carboxymethylcellulose, hyaluronic acid, polyglucuronic acid, polymanuronic acid, polygalacturonic acid, polyarabinic acid; chrondroitin sulfate and dextran phosphate. Suitable cationic polymers include chitosan, polyethylenimine, poly-L-lysine, and dimethylaminodextran. Of interest in some instances are polysaccharide anionic polymers.
Polysaccharide anionic polymers of interest include alginates, e.g., alginic acid and salts thereof. Alginic acid (i.e., alginate) is a linear copolymer with homopolymeric blocks of (1-4)-linked β-D-mannuronate (M) residues and α-L-guluronate (G) residues. The residues are covalently linked together in different sequences or blocks. The residues can appear in homopolymeric blocks of consecutive G-residues (G-blocks), consecutive M-residues (M-blocks) or alternating M and G-residues (MG-blocks). Also of interest are salts of alginic acid, e.g., sodium alginate, calcium alginate, potassium alginate, etc. The molecular weight of the alginate (e.g., alginic acid or alginate salt thereof) may vary, ranging in some instances from 10,000 to 600,000 Daltons, such as 50,000 to 100,000 Daltons. When present, the amount of the acidulant may vary, and may range in some instances from 0.01 to 50, such as 0.1 to 25 and including 0.1 to 15 dry weight % of the matrix layer.
In addition to the electron acceptor, the matrix layer also includes a binder. The binder is a component of the matrix layer which may be made up of a single material or two or more different materials. Any material (or combination of materials) may be employed as the binder so long as the material(s) is ingestible (e.g., as described above) and functions to keep other components of the matrix, e.g., the acidulant, near the cathode surface when the IEM contacts an aqueous medium. Materials of interest for the binder include pharmaceutically acceptable polymeric materials, including but not limited to, cellulosic materials, such as ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimaleate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol phthalate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose based cross-linked polymers in which the degree of crosslinking is low so as to facilitate adsorption of water and expansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000 k), polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic and cationic hydrogels, zein, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyethylene oxides (molecular weight 100 k to 5000 k), diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof, pharmaceutically acceptable acrylic polymers, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers, etc. Of interest are in some instances are polysaccharides, e.g., sodium alginate, sodium carboxymethyl cellulose, etc.
In addition to the binder and electron acceptor, the matrix may further include a surfactant agent (i.e., a wetting agent). The term “surfactant” is employed in its conventional sense to refer to a compound that reduces the surface tension of a liquid, causing the liquid to spread across or penetrate more easily the surface of a solid. Surfactants of interest include pharmaceutically acceptable anionic surfactants, cationic surfactants, amphoteric (amphipathic/amphiphilic) surfactants, and non-ionic surfactants. Suitable pharmaceutically acceptable anionic surfactants include, for example, monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates, sulfuric acid esters, and alkyl sulfates. Suitable pharmaceutically acceptable non-ionic surfactants include, for example, polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylate alcohols, ethoxylated/propoxylated block polymers, and propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl fatty acid esters, SPAN's (e.g., sorbitan esters), TWEEN's sucrose esters, and glucose (dextrose) esters. When present, the amount of the surfactant may vary, and may range in some instances from 0.01 to 25, such as 0.1 to 15 and including 0.01 to 10 dry weight % of the matrix layer.
In some instances, the matrix layer may further include a conductivity enhancer. A conductivity enhancer is a material (or combination of materials) that enhances conductivity of the layer upon contact with an aqueous medium. Examples of such components include pore forming agents (i.e., porogens). The term “porogen” as used herein, refers to a chemical compound that is included in the film and, upon contact with an aqueous medium, is removed from the film, e.g., via diffusion, dissolution, and/or degradation, to leave a pore in the resultant film. The diameter of the pores produced by the porogen may vary, ranging in some instances from 1 to 1000 μm, such as 1 to 500 μm and including 1 to 250 μm. Porogens of interest include both inorganic and organic porogens. Inorganic porogens of interest include, but are not limited to: inorganic salts, e.g., NaCl, MgCl2, CaCl2, NH4Cl, NH4PO4, NH4CO3; soluble biocompatible salts; sugars (e.g., sugar alcohols), polysaccharides (e.g., dextran (poly(dextrose)), water soluble small molecules, natural or synthetic polymers, oligomers, or monomers that are water soluble or degrade quickly under physiological conditions, including but not limited to: polyethylene glycol, polyvinyl alcohol, poly(vinylpyrollidone), pullulan, poly(glycolide), poly(lactide), poly(lactide-co-glycolide), other polyesters, and starches. When present, the total amount of porogen component made up of one or more porogens may vary. In some instances, the amount of porogen component may range from 1 to 40, including from 5 to 10 dry weight percent of the layer.
Another type of conductivity enhancer that may be present in the matrix layer is conductive particle conductive enhancers. Such conductivity enhancers include particles made up of a conductive material. Conductive materials of interest include, but are not limited to, metals, e.g., gold, silver, etc., graphite, etc. While the dimensions of such particles may vary, in some instances the particles have a diameter ranging from 0.1 to 1000 microns, such as 1 to 500 microns, including 1 to 100 microns. When present in the matrix layer, the amount of the particles may range from 1 to 40, including 5 to 10 dry weight percent of the layer.
In some instances, a buffering agent may also be present in the matrix layer. Any convenient buffering agent may be employed, where a suitable buffering agent will be selected based on the pH level in the layer that is desired. Examples of buffering agents of interest include, but are not limited to: alkali earth metal buffering agent, a calcium buffering agent, a magnesium buffering agent, and an aluminum buffering, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, magnesium oxide, magnesium aluminate, magnesium carbonate, magnesium silicate, magnesium citrate, aluminum hydroxide, aluminum phosphate, aluminum hydroxide/magnesium carbonate, potassium carbonate, potassium citrate, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, aluminum magnesium hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium (polyphosphate, sodium dihydrogen phosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium gluconate, calcium bicarbonate, calcium citrate, calcium phosphate magnesium phosphate, potassium phosphate, sodium phosphate, trihydroxymethylaminomethane, an amino acid, an acid salt of an amino acid, an alkali salt of an amino acid, and combinations of any of the foregoing. When present in the matrix layer, the amount of the buffering agent may range from 0.1 to 25, including 0.1 to 15 dry weight percent of the layer.
An example of an IEM which includes a matrix layer as described above is depicted in
With respect to cathode layer 720, this can be fabricated from any convenient material, including the materials described above. As such, cathode materials of interest include, but are not limited to, metallic salts, e.g., copper salts, such as copper salts of iodide, chloride, bromide, sulfate, formate, gluconate, Fe3+ salts, e.g., (such as iron sulfate, iron gluconate, iron citrate, iron phosphates (include iron orthophosphate and iron pyrophosphate) etc.), silver salts (such as AgCl, etc.); metals, e.g., gold, platinum, titanium, etc.; other conductive materials, e.g., graphite, etc., and the like. In some instances, the cathode is copper-free, meaning that copper is not present in the cathode. Examples of cathode materials in such instances include, but are not limited to: gold, platinum, graphite, iron salts, silver salts, etc. Copper-free cathodes may have a number of advantages as compared to cathodes which include copper, including but not limited to improved acceptance by the body, better storage stability, etc.
Also provided are methods of manufacturing IEMs that include an electron acceptor source matrix layer. Aspects of the methods include combining an IEM and matrix layer, e.g., as described above, in a manner sufficient such that the matrix layer is stably associated with an electrode, e.g., the cathode, of the IEM. Any convenient manufacturing protocol may be employed, where protocols of interest include both manual and automated protocols, as well as protocols that include both manual and automated steps. Protocols of interest that find use in various aspects of the fabrication methods described herein include lamination, molding, pressing, extrusion, stamping, coating (such as spray coating and dipping), gluing, etc. In some instances, fabrication protocols as described in PCT application serial nos. PCT/US2010/020142 published as WO 2010/080765; PCT/US2006/016370 published as WO 2006/116718 and PCT/US2008/077753 published as WO2009/042812 (the disclosures of which applications are herein incorporated by reference); are employed. By “stably associating” is meant that the IEM component and matrix component do not separate from each other, at least until desired during intended use, e.g., following passage into the intestine of a subject. Any convenient approach for stably associating the components may be employed.
Where an ingestible event marker with a matrix layer stably associated with a cathode is desired, e.g., as illustrated in
In a variation of the above protocol, a fabrication process may be one in which the matrix layer is fabricated at the same time that the cathode component of the IEM is stably associated therewith. For example, a molding process may be employed where liquid matrix layer precursor composition is positioned in a mold, followed by placement of an ingestible component (e.g., IEM) on the precursor material. The solvent component of the liquid composition may be removed to associate the matrix layer with the dissimilar material of the ingestible event marker. Temperature modulation may be employed where appropriate. Following solidification of the precursor material, the resultant final product may be removed from the mold.
In yet another fabrication protocol of interest, a coating process may be employed to stably associate the ingestible component with the matrix layer component. For example, a premade IEM be provided, e.g., as described in PCT application serial nos. PCT/US2010/020142 published as WO 2010/080765; PCT/US2006/016370 published as WO 2006/116718 and PCT/US2008/077753 published as WO2009/042812; the disclosures of which applications are herein incorporated by reference. This premade IEM may then be spray coated with a liquid precursor composition of the matrix layer. Following spray coating, the coating material may be allowed to produce the desired product.
Where desired, aspects of the above described or other suitable protocols may be combined to produce a fabrication protocol. For example, a molding process may be employed to make a product and the product spray coated with a further material, such as a soluble material.
Large Surface Area ElectrodesAs summarized above, aspects may include IEMs with at least one large surface area electrode. Large surface area electrodes are electrodes having a surface area that exceeds the surface area of the side of the circuitry in the IEM with which the electrode is associated. While the dimensions of the large surface area electrode may vary, in some instances the dimensions are selected so that the electrode provides an enhanced amplitude of the change in conductance (as compared to an IEM in which the electrodes are commensurate is surface area with the surface area of the circuitry component), where the magnitude of the enhancement may be 1.2 or greater, such as 1.5 or greater, including 1.75 or greater, e.g., 2.0 or greater, 2.5 or greater, 3.0 or greater, etc. The difference in surface areas between the large surface area electrode and the surface area of the circuitry component with which the large surface area electrode is associated may vary, where the magnitude of the difference ranges, in some instances, from 1 to 15, such as 2 to 9 and including 3 to 8 mm2. In some instances, the large surface area electrode has a surface area of 1.5 mm2 or greater, including 2 mm2 or greater, e.g., 4 mm2 or greater, including 9 mm2 or greater, where the surface area may range in some instances from 1.5 to 16 mm2, such as 4 to 9 mm2.
The cathode and/or the anode may be a large surface area electrode, e.g., as described above. As such, the IEM may include both a large surface area anode and a large surface area cathode. Alternatively, the IEM may include a large surface area anode and a cathode that is commensurate in surface area with the surface area of the side of the circuitry component with which it is associated. In yet other instances, the IEM may include a large surface area cathode and an anode that is commensurate in surface area with the surface area of the side of the circuitry component with which it is associated.
Where the IEM includes a signal amplifier, a large surface area electrode (such as the anode and/or cathode) may extend over at least a portion of the surface of the signal amplifier. In such instances, the portion of the signal amplifier surface which is covered by the large surface area electrode (which may be the anode and/or the cathode) may vary, and in some instances ranges from 50 to 100%, such as 75 to 100%. In these IEMs, the large surface area electrode may be viewed as being at least partially supported by the signal amplifier, i.e., the signal amplifier provides at least a portion of the mechanical support for the electrode.
Also shown in
Turning now briefly to
In one example configuration shown in
The configuration of
A configuration in which both the cathode and anode are confined to regions directly above or below the IC (or equivalently, in which neither the cathode nor anode includes a portion above or below a skirt portion) may be referred to as a baseline configuration. Relative to the baseline configuration, the off-chip cathode configuration of
IEMs that include at least one large surface area electrode, e.g., as described above, may be fabricated using any convenient protocol. One type of fabrication protocol of interest is what is referred to herein as “printing” based protocol, in which at least one component of the IEM is produced by depositing a liquid precursor of that component (e.g., which may be referred to herein as an “ink”) and then allowing the precursor to solidify to the produce the desired component. An example of a printing based protocol is illustrated in
Another type of fabrication protocol of interest is what is referred to herein as a “lamination” based protocol, in which at least one component of the IEM is produced by a lamination process, in which a preformed layer is employed as an IEM component. An example of a printing based protocol is illustrated in
In various aspects (e.g., described in relation to
Various materials can be used for the cathode and/or anode, and the current (associated with ionic exchange) and/or amplitude of a signal used for communication with a receiver (discussed further below) are increased mainly due to the geometric characteristic of increased area for the anode and/or cathode, and independent of the specific materials used for the anode and/or cathode. Various sizes for anodes and cathodes have been tested. The size of the cathode does not have to be the same as the size of the anode. For example, a 5 mm skirt has been tested with cathodes of diameters 1 mm, 2 mm, and 3 mm, and with anodes of diameters 1 mm, 2 mm, and 3 mm. In each case, as the diameter of the cathode (or anode) increases, amplitude increases as well, and the increase is greater when the cathode and anode are both increased in size.
In certain aspects, CuCl and/or copper may be eliminated, e.g., by using alternative cathode materials such as AgCl. The elimination of copper is advantageous because systems that do not contain copper are less toxic (and thus better for ingestion), easier to process and store (due to decreased sensitivity to moisture), and provide equivalent or better ingestible event marker performance as systems that contain copper. Increased area of a cathode and/or electrode in certain aspects results in increased battery stability, a more stable frequency (for communications with a receiver, as discussed below), and increased signal-to-noise ratio (SNR). Alternative cathode materials (other than CuCl) may include but are not limited to: iron salts (e.g., ferrous gluconate, ferrous sulfate); gold; copper cupric gluconate; cupric sulfate; tartarate; malate; citrate; iodate; alginate. These alternate cathode materials may not yield equivalent comparable performance as an equivalently sized CuCl cathode, but the increase in cathode (and/or anode) area in certain aspects may compensate for that factor. For example, in certain aspects the cathode and/or anode may be increased in area by a factor between about ten and about fifteen, e.g., a factor of 13 as area is increased from about 0.74 mm2 to about 9.62 mm2. In some aspects, at the anode, a magnesium alloy may be used instead of pure magnesium. For example, additives such as aluminum or zinc may be include in the anode to enhance discharge performance at the anode.
Referring to
Where desired, an IEM may be stably associated in some manner to another ingestible component, e.g., pharmaceutically acceptable carrier component (e.g., as described above). By “stably associated” is meant that the event indicator and second ingestible component, e.g., a pharmaceutically acceptable carrier component, do not separate from each other, at least until administered to the subject in need thereof, e.g., by ingestion.
Pharmaceutically acceptable solid carrier configurations include tablet and capsule configurations. While the pharmaceutically acceptable solid carrier may have a solid configuration, the solid configuration may include a liquid component, such as is found in a liquid capsule, which includes a liquid component present in a solid capsule. In some instances, the pharmaceutically acceptable solid carrier is configured to impart a controlled release profile to an active agent that is associated with the pharmaceutically acceptable solid carrier. Examples of pharmaceutically acceptable solid carriers of interest can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985).
Where desired, the pharmaceutically acceptable solid carrier may include an active agent. Active agents of interest include pharmaceutically active agents as well as non-pharmaceutical active agents, such as diagnostic agents. The phrase “pharmaceutically active agent” (also referred to herein as drugs) refers to a compound or mixture of compounds which 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. Pharmaceutically active agents are distinguishable from such components as excipients, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. The pharmaceutically active agent may be any molecule, as well as binding portion or fragment thereof, that is capable of modulating a biological process in a living subject. In certain aspects, the pharmaceutically active agent may be a substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication. The pharmaceutically active agent is capable of interacting with a target in a living subject. The target may be a number of different types of naturally occurring structures, where targets of interest include both intracellular and extracellular targets. Such targets may be proteins, phospholipids, nucleic acids and the like, where proteins are of particular interest. Specific proteinaceous targets of interest include, without limitation, enzymes, e.g., kinases, phosphatases, reductases, cyclooxygenases, proteases and the like, targets comprising domains involved in protein-protein interactions, such as the SH2, SH3, PTB and PDZ domains, structural proteins, e.g., actin, tubulin, etc., membrane receptors, immunoglobulins, e.g., IgE, cell adhesion receptors, such as integrins, etc., ion channels, transmembrane pumps, transcription factors, signaling proteins, and the like. Broad categories of active agents of interest include, but are not limited to: cardiovascular agents; pain-relief agents, e.g., analgesics, anesthetics, anti-inflammatory agents, etc.; nerve-acting agents; chemotherapeutic (e.g., anti-neoplastic) agents; neurological agents, e.g., anti-convulsants, etc. The amount of active agent that is present in the solid carrier may vary. In some instances, the amount of active agent that is present may range from 0.01 to 100% by weight.
Further examples of pharmaceutically acceptable solid carriers and active agents which may or may not be included therein are described in PCT Application Serial No. PCT/US2006/016370 published as WO/2006/116718; PCT Application Serial No. PCT/US2007/082563 published as WO/2008/052136; PCT Application Serial No. PCT/US2007/024225 published as WO/2008/063626; PCT Application Serial No. PCT/US2007/022257 published as WO/2008/066617; PCT Application Serial No. PCT/US2008/052845 published as WO/2008/095183; PCT Application Serial No. PCT/US2008/053999 published as WO/2008/101107; PCT Application Serial No. PCT/US2008/056296 published as WO/2008/112577; PCT Application Serial No. PCT/US2008/056299 published as WO/2008/112578; PCT Application Serial No. PCT/US2008/077753 published as WO2009/042812; PCT Application Serial No. PCT/US2008/085048 published as WO2009/070773; PCT Application Serial No. PCT/US2009/36231 published as WO2009/111664; PCT Application Serial No. PCT/US2009/049618 published as WO2010/005877; PCT Application Serial No. PCT/US2009/053721 published as WO2010/019778; PCT Application Serial No. PCT/US2009/060713 published as WO2010/045385; PCT Application Serial No. PCT/US2009/064472 published as WO2010/057049; PCT Application Serial No. PCT/US2009/067584 published as WO2010/068818; PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115; PCT Application Serial No. PCT/US2010/020142 published as WO2010/080765; PCT Application Serial No. PCT/US2010/020140 published as WO2010/080764; PCT Application Serial No. PCT/US2010/020269 published as WO2010/080843; PCT Application Serial No. PCT/US2010/028518 published as WO2010/111403; PCT Application Serial No. PCT/US2010/032590 published as WO2010/129288; PCT Application Serial No. PCT/US2010/034186 published as WO2010/132331; PCT Application Serial No. PCT/US2010/055522 published as WO2011/057024; the disclosures of which are herein incorporated by reference.
SystemsAlso provided are systems that include an ingestible device, e.g., an IEM, and a detection component, e.g., in the form of a receiver. Receivers of interest are those configured to detect, e.g., receive, a communication from an IEM. The signal detection component may vary significantly depending on the nature of the communication that is generated by the ingestible device. As such, the receiver may be configured to receive a variety of different types of signals, including but not limited to: RF signals, magnetic signals, conductive (near field) signals, acoustic signals, etc. In certain aspects, the receiver is configured to receive a signal conductively from an IEM, such that the two components use the body of the patient as a communication medium. As such, communication that is transferred between event indicator and the receiver travels through the body, and requires the body as the conduction medium. The IEM communication may be transmitted through and received from the skin and other body tissues of the subject body in the form of electrical alternating current (a.c.) voltage signals that are conducted through the body tissues. This communication protocol has the advantage that the receivers may be adaptably arranged at any desired location on the body of the subject, whereby the receivers are automatically connected to the required electrical conductor for achieving the signal transmission, i.e., the signal transmission is carried out through the electrical conductor provided by the skin and other body tissues of the subject.
The receivers of interest include external, semi-implantable, and implantable receivers. In external aspects, the receiver is ex vivo, by which is meant that the receiver is present outside of the body during use. Examples include wearable patches, e.g., adhesive patches, torso bands, wrist(s) or arm bands, jewelry, apparel, mobile devices such as phones, attachments to mobile devices, etc. Where the receiver is implanted, the receiver is in vivo. Examples include cardiac can and leads, under-the-skin implants, etc. Semi-implantable devices include those designed to be partially implanted under the skin.
In certain aspects, the receiver may be configured to provide data associated with a received signal to a location external to said subject. For example, the receiver may be configured to provide data to an external data receiver, e.g., which may be in the form of a monitor (such as a bedside monitor), a computer, a personal digital assistant (PDA), phone, messaging device, smart phone, etc. The receiver may be configured to retransmit data of a received communication to the location external to said subject. Alternatively, the receiver may be configured to be interrogated by an external interrogation device to provide data of a received signal to an external location.
Receivers may be configured variously, e.g., with various signal receiving elements, such as electrodes, various integrated circuit components, one or more power components (such as power receivers or batteries), signal transmission components, housing components, etc.
In one aspect, for example, the receiver includes one or more of: a high power-low power module; an intermediary module; a power supply module configured to activate and deactivate one or more power supplies to a high power processing block; a serial peripheral interface bus connecting master and slave blocks; and a multi-purpose connector, as further described in PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115, infra.
Receivers of interest include, but are not limited to, those receivers disclosed in: PCT Application Serial No. PCT/US2006/016370 published as WO 2006/116718; PCT Application Serial No. PCT/US2008/52845 published as WO 2008/095183; PCT Application Serial No. PCT/US2007/024225 published as WO 2008/063626; PCT Application Serial No. PCT/US2008/085048 published as WO 009/070773; PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115; and PCT Application Serial No. US2012/047076 filed on Jul. 21, 2012; the disclosures of which applications (and particularly receiver components thereof) are herein incorporated by reference.
In certain embodiments, the signal receiver includes a set of two or more, such as two or three, electrodes that provide for dual functions of signal receiving and sensing. For example, in addition to receiving signal, the electrodes can also serve additional sensing functions. In certain embodiments, the electrodes are used to generate electrocardiogram data. From that data, there are many kinds of processing that can be done, e.g., to detect various cardiac events, such as tachycardia, fibrillations, heart rate, etc. The obtained electrocardiogram data can be used to titrate medications, or be used for alerts when an important change or significant abnormality in the heart rate or rhythm is detected. This data is also helpful in certain embodiments for monitoring heart rate in patients who do not have pacemakers or as an alternative to patients who might normally require a Holter monitor or a Cardiac Event Monitor, portable devices for continuously monitoring the electrical activity of the heart for twenty-four hours or other devices. An extended recording period is useful for observing occasional cardiac arrthymias that are difficult to identify in shorter time periods.
In some instances, two or more different demodulation protocols may be employed to decode a given received signal. In some instances, both a coherent demodulation protocol and a differential coherent demodulation protocol may be employed.
In addition to demodulation, the trans-body communication module may include a forward error correction module, which module provides additional gain to combat interference from other unwanted signals and noise. Forward error correction functional modules of interest include those described in PCT Application Serial No. PCT/US2007/024225 published as WO 2008/063626; the disclosure of which application is herein incorporated by reference. In some instances, the forward error correction module may employ any convenient protocol, such as Reed-Solomon, Golay, Hamming, BCH, and Turbo protocols to identify and correct (within bounds) decoding errors.
Receivers of the invention may further employ a beacon functionality module. In various aspects, a beacon switching module may employ one or more of the following: a beacon wakeup module, a beacon signal module, a wave/frequency module, a multiple frequency module, and a modulated signal module.
A view of a beacon module is provided in the functional block diagram shown in 11. The scheme outlined in
Multiplexer 1320 is electrically coupled to both high band pass filter 1330 and low band pass filter 1340. The high and low frequency signal chains provide for programmable gain to cover the desired level or range. In this specific aspect, high band pass filter 1330 passes frequencies in the 10 KHz to 34 KHz band while filtering out noise from out-of-band frequencies. This high frequency band may vary, and may include, for example, a range of 3 KHz to 300 KHz. The passing frequencies are then amplified by amplifier 1332 before being converted into a digital signal by converter 834 for input into high power processor 1380 (shown as a DSP) which is electrically coupled to the high frequency signal chain.
Low band pass filter 1340 is shown passing lower frequencies in the range of 0.5 Hz to 150 Hz while filtering out out-of-band frequencies. The frequency band may vary, and may include, for example, frequencies less than 300 Hz, such as less than 200 Hz, including less than 150 Hz. The passing frequency signals are amplified by amplifier 1342. Also shown is accelerometer 1350 electrically coupled to second multiplexer 1360. Multiplexer 1360 multiplexes the signals from the accelerometer with the amplified signals from amplifier 1342. The multiplexed signals are then converted to digital signals by converter 1364 which is also electrically coupled to low power processor 1370.
In one aspect, a digital accelerometer (such as one manufactured by Analog Devices), may be implemented in place of accelerometer 1350. Various advantages may be achieved by using a digital accelerometer. For example, because the signals the digital accelerometer would produce signals already in digital format, the digital accelerometer could bypass converter 1364 and electrically couple to the low power microcontroller 1370—in which case multiplexer 1360 would no longer be required. Also, the digital signal may be configured to turn itself on when detecting motion, further conserving power. In addition, continuous step counting may be implemented. The digital accelerometer may include a FIFO buffer to help control the flow of data sent to the low power processor 1370. For instance, data may be buffered in the FIFO until full, at which time the processor may be triggered to turn awaken from an idle state and receive the data.
Low power processor 1370 may be, for example, an MSP430 microcontroller from Texas Instruments. Low power processor 1370 of receiver 800 maintains the idle state, which as stated earlier, requires minimal current draw—e.g., 10 μA or less, or 1 μA or less.
High power processor 1380 may be, for example, a VC5509 digital signal process from Texas Instruments. The high power processor 1380 performs the signal processing actions during the active state. These actions, as stated earlier, require larger amounts of current than the idle state—e.g., currents of 30 μA or more, such as 50 μA or more—and may include, for example, actions such as scanning for conductively transmitted signals, processing conductively transmitted signals when received, obtaining and/or processing physiological data, etc.
The receiver may include a hardware accelerator module to process data signals. The hardware accelerator module may be implemented instead of, for example, a DSP. Being a more specialized computation unit, it performs aspects of the signal processing algorithm with fewer transistors (less cost and power) compared to the more general purpose DSP. The blocks of hardware may be used to “accelerate” the performance of important specific function(s). Some architectures for hardware accelerators may be “programmable” via microcode or VLIW assembly. In the course of use, their functions may be accessed by calls to function libraries.
The hardware accelerator (HWA) module comprises an HWA input block to receive an input signal that is to be processed and instructions for processing the input signal; and, an HWA processing block to process the input signal according to the received instructions and to generate a resulting output signal. The resulting output signal may be transmitted as needed by an HWA output block.
An example of a system of the invention is shown in
Systems of the invention may include an external device which is distinct from the receiver (which may be implanted or topically applied in certain aspects), where this external device provides a number of functionalities. Such an apparatus can include the capacity to provide feedback and appropriate clinical regulation to the patient. Such a device can take any of a number of forms. By example, the device can be configured to sit on the bed next to the patient, e.g., a bedside monitor. Other formats include, but are not limited to, PDAs, phones, such as smart phones, computers, etc. The device can read out the information described in more detail in other sections of the subject patent application, both from pharmaceutical ingestion reporting and from physiological sensing devices, such as is produced internally by a pacemaker device or a dedicated implant for detection of the pill. The purpose of the external apparatus is to get the data out of the patient and into an external device. One feature of the external apparatus is its ability to provide pharmacologic and physiologic information in a form that can be transmitted through a transmission medium, such as a telephone line, to a remote location such as a clinician or to a central monitoring agency.
Methods of UseAspects of the invention further include methods of using the compositions, such as those described above. Aspects of such methods include administering an ingestible composition to a subject, e.g., by self-administration or via the assistance of another, such as a health care practitioner. Such methods may include placing the ingestible composition in the mouth of a subject such that the subject swallows the ingestible composition. In this manner, the subject ingests the ingestible composition. Ingestible compositions may be employed with a variety of subjects. Subjects of interest include “mammals” including animals classified in the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In certain aspects, the subjects will be humans.
Following ingestion, the methods may include receiving a signal emitted from an ingestible composition, such as an IEM comprising ingestible composition, e.g., at a receiver, such as described above. In some instances, the received signal is a conductively transmitted signal.
Ingestible compositions may be employed in a variety of different applications. Applications of interest in which the ingestible composition comprises an IEM include, but are not limited to: monitoring patient compliance with prescribed therapeutic regimens; tailoring therapeutic regimens based on patient compliance; monitoring patient compliance in clinical trials; monitoring usage of controlled substances; monitoring the occurrence of a personal event of interest, such as the onset of symptoms, etc., and the like. Applications of interest are further described in PCT Application Serial No. PCT/US2006/016370 published as WO/2006/116718; PCT Application Serial No. PCT/US2007/082563 published as WO/2008/052136; PCT Application Serial No. PCT/US2007/024225 published as WO/2008/063626; PCT Application Serial No. PCT/US2007/022257 published as WO/2008/066617; PCT Application Serial No. PCT/US2008/052845 published as WO/2008/095183; PCT Application Serial No. PCT/US2008/053999 published as WO/2008/101107; PCT Application Serial No. PCT/US2008/056296 published as WO/2008/112577; PCT Application Serial No. PCT/US2008/056299 published as WO/2008/112578; and PCT Application Serial No. PCT/US2008/077753 published as WO2009/042812; the disclosures of which applications is herein incorporated by reference.
KitsAlso provided are kits that include one or more ingestible compositions, such as described above. In those aspects having a plurality of ingestible compositions, the ingestible compositions may be packaged in a single container, e.g., a single tube, bottle, vial, and the like, or one or more dosage amounts may be individually packaged such that certain kits may have more than one container of ingestible compositions. In certain aspects the kits may also include a receiver, such as reviewed above. In certain aspects, the kits may also include an external monitor device, e.g., as described above, which may provide for communication with a remote location, e.g., a doctor's office, a central facility etc., which obtains and processes data obtained about the usage of the composition.
The subject kits may also include instructions for how to practice the subject methods using the components of the kit. 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, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other aspects, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other aspects, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this aspect is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.
Some or all components of the subject kits may be packaged in suitable packaging to maintain sterility. In many aspects of the subject kits, the components of the kit are packaged in a kit containment element to make a single, easily handled unit, where the kit containment element, e.g., box or analogous structure, may or may not be an airtight container, e.g., to further preserve the sterility of some or all of the components of the kit.
It is to be understood that this invention is not limited to particular aspects described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects 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. 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, representative illustrative methods and materials are now described.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference 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 further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects 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 aspects without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which 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 is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
Accordingly, the preceding merely illustrates the principles of the invention. It will 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 to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors 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 aspects 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 and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary aspects shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.
Claims
1. An ingestible event marker comprising:
- a support;
- circuitry associated with the support;
- an anode material electrically coupled to the circuitry and associated with the support; and
- a cathode material electrically coupled to the circuitry, wherein the cathode material is associated with the support and is electrically isolated from the first material; and
- a matrix layer associated with a surface of the cathode material, wherein the matrix layer comprises a binder and an electron acceptor source.
2. The ingestible event marker according to claim 1, wherein the binder comprises a polymer.
3. The ingestible event marker according to claim 2, wherein the polymer is a polysaccharide.
4. The ingestible event marker according to claim 1, wherein the electron acceptors source is an acidulant that is present in the matrix layer.
5. The ingestible event marker according to claim 4, wherein the acidulant is selected from the group consisting of alginic acid, tartaric acid, malic acid and citric acid.
6. The ingestible event marker according to claim 1, wherein the matrix layer further comprises a surfactant.
7. The ingestible event marker according to claim 1, wherein the matrix layer further comprises a conductivity enhancer.
8. The ingestible event marker according to claim 7, wherein the conductivity enhancer comprises conductive particles.
9. The ingestible event marker according to claim 7, wherein the conductivity enhancer is a salt.
10. The ingestible event marker according to claim 1, wherein the anode material comprises a metal.
11. The ingestible event marker according to claim 10, wherein the metal is selected from the group consisting of magnesium, zinc, sodium, lithium and iron and alloys thereof.
12. The ingestible event marker according to claim 1, wherein the cathode material is copper-free.
13. The ingestible event marker according to claim 12, wherein the cathode material comprises a material selected from the group consisting of gold, platinum and graphite.
14. The ingestible event marker according to claim 1, wherein the ingestible event marker further comprises a signal amplifier.
15. The ingestible event marker according to claim 1, wherein the ingestible event marker further comprises an active agent.
16. The ingestible event marker according to claim 1, wherein the ingestible event marker further comprises a pharmaceutically acceptable carrier.
17. The ingestible event marker according to claim 1, wherein at least one of the cathode and anode is a large surface area electrode.
18. A system comprising:
- an ingestible event marker comprising: a support; circuitry associated with the support; an anode material electrically coupled to the circuitry and associated with the support; and a cathode material electrically coupled to the circuitry, wherein the cathode material is associated with the support and is electrically isolated from the first material; and a matrix layer associated with a surface of the cathode material, wherein the matrix layer comprises a binder and an electron acceptor; and
- a receiver configured to receive a communication associated with the ingestible event marker.
19. A method comprising combining an ingestible event marker having a cathode material and a matrix layer comprising a binder and an electron acceptor in a manner such that the matrix layer is associated with a surface of the cathode material.
20. The method according to claim 19, wherein the method comprises one or more protocols selected from the group consisting of laminating, pressing, stamping, extruding, molding, gluing and coating.
21-65. (canceled)
Type: Application
Filed: Feb 3, 2015
Publication Date: Dec 1, 2016
Inventors: Patricia Johnson (San Carlos, CA), Raymond Schmidt (San Mateo, CA), Anuj Patel (San Francisco, CA), Kevin Cheng (San Francisco, CA), Kosuke Iwai (Berkeley, CA), Hooman Hafezi (Redwood City, CA)
Application Number: 15/116,198
