Integrated ingestible marker system with pharmaceutical product

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INTEGRATED 1NGEST1BLE EVENT MARKER SYSTEM WITH PHARMACEUTICAL PRODUCT PROTEUS BIOMEDICAL, INC. C: 76381 WO 2011/068963 PCT/US2010/058721

INTEGRATED INGESTIBLE EVENT MARKER SYSTEM WITH PHARMACEUTICAL PRODUCT

Cross-Reference and Related Application [001] Pursuant to 35 U.S.C. § 119 (e), this application claims priority to the filing date of U.S. Provisional Patent Application Serial No. 61/266,103 filed on December 2, 2009 and titled INTEGRATED INGESTIBLE EVENT MARKER SYSTEM WITH PHARMACEUTICAL PRODUCT, the disclosure of which application is incorporated herein by reference.

[002] This application is related to and incorporates by reference the following applications: US Provisional Application Serial No. 61/416,150 field on November 22, 2010 and titled INGESTIBLE DEVICE WITH PHARMACEUTICAL PRODUCT; US Application 12/447,172 filed on October 25, 2007 and titled CONTROLLED ACTIVATION INGESTIBLE IDENTIFIER; US Provisional Application 60/862,925 filed on October 25, 2006 and titled CONTROLLED ACTIVATION PHARMA-INFORMATICS SYSTEM; PCT Application US2007/82563 and filed on October 25, 2007 and titled CONTROLLED ACTIVATION INGESTIBLE IDENTIFIER.

Field of Invention [003] The present invention relates to electronic devices with partial power sources and, more specifically, to electronic devices secured to a pharmaceutical product wherein the electronic devices are activated upon contact with a conducting fluid. WO 2011/068963 PCT/US2010/058721

Background [004] Pharmaceutical products are delivered to a user in many forms, including a pill. Integration of a pharmaceutical product with an ingestibie device is often a challenge due to the delicate nature of the electronic components as well as the difficulty in securing the electronic components to the pharmaceutical product, such as a pill or tablet or capsule. For example, tablets are typically made using a press that applies pressure to a powder form. The pressures produced by the press can often damage the electronic components that are placed inside the tablet or pill. Additionally, securing the electronic component to the surface of tablet using adhesive material often results in damage to the device caused by the adhesive, which may be a thermally or chemically activated type of adhesive. Furthermore, handling a small electronic device is often a challenge during the assembly process. Therefore, what is needed is a system and method for securing an ingestibie electronic device to a pharmaceutical product without damaging the ingestibie electronic device.

Summary [005] The present invention provides a system and method for securing an ingestibie electronic device to a pharmaceutical product without damaging the ingestibie electronic device. The product includes an electronic marker placed on the product in accordance with one aspect of the present invention. In accordance with another aspect of the present invention, the electronic marker is placed inside the product. Various embodiments are disclosed in accordance with the present invention that allow for protection and coating of the electronic marker. WO 2011/068963 PCT/US2010/058721

Description of the Drawings [006] Fig. 1 shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[007] Fig. 1A shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[008] Fig. 1B shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[009] Fig. 1C shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[010] Fig. 2 is an exploded view of the device assembly of Fig. 1.

[011] Fig. 2A is an exploded view of the device assembly of Fig. 1A.

[012] Fig. 2B is an exploded view of the device assembly of Fig. 1B.

[013] Fig. 2C is an exploded view of the device assembly of Fig. 1B.

[014] Fig. 3A shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[015] Fig. 3B shows a first tablet portion with a device assembly secured on one surface and a second tablet portion secured over the device assembly in accordance with one aspect of the present invention.

[016] Fig. 3C shows a device assembly with a laminated coating in accordance with one aspect of the present invention.

[017] Fig. 4 shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[018] Fig. 5 shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[019] Fig. 5A shows the assembling process of the tablet of Fig. 5.

[020] Fig. 5B shows the assembling process of the tablet of Fig. 5.

[021] Fig. 6 shows a tablet with a device assembly secured on one surface in accordance with one aspect of the present invention.

[022] Fig. 6A shows the assembling process of the tablet of Fig. 6. WO 2011/068963 PCT/US2010/058721 [023] Fig. 7 shows a tablet with a device assembly secured on one surface and a coating that surrounds the tablet in accordance with one aspect of the present invention.

[024] Fig. 8 shows a capsule with a device assembly secured on one end in accordance with one aspect of the present invention.

[025] Fig. 9 shows a capsule with a device assembly secured on the side surface in accordance with one aspect of the present invention.

[026] Fig. 10 is a flow process for assembling a device on a tablet in accordance with one aspect of the present invention.

[027] Fig. 11 is a flow process for assembling a device on a tablet in accordance with one aspect of the present invention.

[028] Fig. 12 is a flow process for assembling a device on a tablet in accordance with one aspect of the present invention.

[029] Fig. 13 is a flow process for assembling a device in a tablet in accordance with one aspect of the present invention.

[030] Fig. 14 is an assembling apparatus for assembling a device on a tablet.

[031] Fig. 15 is a close-up view of a portion of a portion of the apparatus of Fig. 14 with specific indication of the direction of force applied.

[032] Fig. 16 is a close-up view of a portion of a feeder assembly of the apparatus of Fig. 14.

[033] Fig. 17 is a close-up view of a portion of a feeder assembly that can be used with the apparatus of Fig. 14 in accordance with another aspect of the present invention.

[034] Fig. 18A is a close-up view of a portion of a feeder assembly that can be used with the apparatus of Fig. 14 in accordance with another aspect of the present invention.

[035] Fig. 18B is a close-up view of a portion of the feeder assembly shown in Fig. 18A at an advanced stage in the loading process.

[036] Fig. 19 is an assembly apparatus for the assembly of a device on a tablet in accordance with one aspect of the present invention. WO 2011/068963 PCT/US2010/058721 [037] Fig. 20 is a close-up view of a portion of the assembly apparatus of Fig. 19.

[038] Fig. 21 is a view of the assembly apparatus that includes additional components used in assembling the device onto a tablet or pill as shown partially in Fig. 19.

[039] Fig. 22 is a close-up view of a pressing tool in accordance with one aspect of the present invention.

[040] Figs. 23A-C show an assembly apparatus for assembling a device onto a tablet according to another aspect of the present invention.

[041] Figs 24A-C show a process for loading a feeder or a feeder assembly of any of Fig. 16, Fig. 17, Fig. 18A, and Fig. 18B.

[042] Fig. 25 shows an assembly apparatus using a process for assembling a device onto a tablet or pill in accordance with another aspect of the present invention.

Detailed Description [043] The present invention discloses multiple approaches to securing a device capable of indicating the occurrence of an event, such as ingestion, to an ingestibie product, such as a pharmaceutical product in the form of a pill or tablet. In order to better understand the process and systems involved the systems are described in greater detail with respect to the devices being secured within the product as well as the devices being secured onto the product’s outer surface. For example, the process of securing the device onto the product may be done using pressure, temperature, chemical reactions or a combination thereof. In accordance with one aspect of the present invention, the device is protected from these conditions through the various securing layers and protective layers disclosed herein. The materials used are effective in temperature ranges are 25-200 degrees Celsius, including a target range of 80-150 degrees Celsius and the duration of exposure time to such temperatures. The exposure times will vary WO 2011/068963 PCT/US2010/058721 from 0.1 sec to 50 sec, including a target range of 1 sec to 15 sec. Additionally, the device will be protected from forces involved, which range from 1 to 50 pounds, including 2-8 pounds, as well the pressures exerted during integration of the device with the pill, which pressures range from 100-400 PSI. Thus, the scope of the present invention includes use of materials to protect the device and product from the various environmental parameters (such as pressure, time, forces, chemical reactions, and combinations thereof) associated with the integration of the device with the pill.

[044] Furthermore, the scope of the present invention is not limited by the shape or type of product. For example, the product can be a pill, including capsule, a time-release oral dosage, a tablet, a gel capsule, a sub-lingual tablet or any oral dosage product. A pill may contain or be made of any of the following, alone or in combination: an active agent, a drug, a placebo, vitamins, or any food material. In accordance with one aspect of the present invention, the product has the device positioned inside or secured to the interior of the product. In an alternative arrangement, the device is secured to the exterior of the product.

[045] Referring now to Fig. 1, an example of a pill 20 having a convex surface is shown with a marker assembly 22 secured on the outside. Additionally, the marker assembly 22 conforms to the shape of the pill 20. In the current example, as shown in Fig. 2, the marker assembly 22 includes an ingestible event marker or an ionic emission module (IEM) unit 24, a lower protective layer 26, an upper protective layer 28, an adhesive or securing layer 30, and a decorative or printing layer 32. In accordance with one aspect of the present invention, a nonconduction outer portion or skirt of the I EM unit 24 includes holes 24a, as shown in Fig. 2A distributed around the IEM unit 24 so that layers 26 and 28 maybe laminated together at connection 25, as shown in Fig. 1 A, through the holes 24a as the layers 26 and 28 are secured to or laminated onto the IEM unit 24.

[046] Referring now to Fig. 1B and 2B, in accordance with another aspect of the present invention, the protective player 26 and the securing layer 30 of Fig. 1 are preplaced by a plurality of securing dots or portions 27. As shown in Fig. 1C and 6 WO 2011/068963 PCT/US2010/058721 2C, in accordance with another aspect of the present invention, the protective player 26 is included and the securing layer 30 of Fig. 1 is preplaced by a plurality of securing dots or portions 27. The marker assembly 22 is separated from the pill 20 by an air gap and, hence, able to be secured to the pill 20 regardless of the shape of the pill 20 since the dots 27 deform and adjust to contour to the shape of the pill 20. Thus, when the shape of the pill 20 is such that the marker assembly 22 cannot be easily conformed to the shape of the pill 20, the dots 27 will deform and adapt. This ensures a secure connection between the shape of the pill 20 and the shape of the marker assembly 22. The dots 27 are distributed about the marker assembly 22 and used to connect the marker assembly 22 to the pill 20. Furthermore, the thickness or amount of securing materials needed to secure each marker assembly 22 to the pill 20 would be reduced.

[047] The IEM unit 24 includes a control unit surrounded by the skirt and two dissimilar materials (not shown), each of which dissimilar material is electrically connected to the control unit and isolated from each other. The dissimilar materials represent a portion of a power source or may be referred to as a partial power source and when in contact with a conducting fluid, produce a voltage potential across the materials as the materials dissolve. Once the IEM unit 24 comes into contact with a conducting fluid, such as body fluids found in the stomach, then the tEM unit 24 is activated and a current flow is produced by the dissimilar materials dissolving into solution and the voltage potential is produced between the dissimilar materials as they go from solid state to solution.

[048] According to another aspect of the present invention, the securing layer 30 may also be replaced by a layer that includes the properties of adhesion and releasing. For example, the release functionality is achieved by incorporating a disintegrant (e.g. Sodium starch glycolate) or water soluble excipient (e.g. Hydroxypropyl cellulose). Thus, then when the assembly 22 gets wet, the layer 30 would eject the marker assembly 22 from the pill 20. Accordingly, to the extent that reference is made in the present invention to an adhesive or securing layer, the scope of the present invention contemplates the use of either a layer WO 2011/068963 PCT/US2010/058721 that has adhesive properties or a layer that has both adhesive and releasing properties. The scope of the present invention is not limited by the shape of the marker assembly 22. The IEM concept can be expanded to a "galvanic tablet" or dosage form where the drug release rate is galvanically controlled by an integrated circuit (1C). The dosage form would consist of a chip, connected to a partial power source (e.g. a CuCI-Mg materials similar to the material used with IEM), and also connected to a matrix containing a drug compound. Once activated, the 1C controls the rate of drug discharge by controlling the current or potential applied to the matrix. An example of this is a matrix consisting of a drug compound, a binder, and an electrochemically soluble material, e.g., a salt. Electrochemical conversion of the salt to a soluble species erodes or creates pores in the matrix that releases the drug at a precise rate corresponding to the charge passed.

[049] The 1C can control the charge applied to the matrix at any desirable rate, e.g., to achieve constant drug discharge, pulsatile discharge, gradually ramped drug delivery. Discharge can be in response to a physiological signal sensed by the 1C, e.g., local pH, impedance, motility, location in the Gl tract, bleeding. Discharge can also be externally triggered, e.g. the 1C may contain an RF antenna that allows the patient or a medical monitor, e.g. personal health companion, blood monitor, to set off drug release in response to a physical condition like pain. IEM configurations of interest include, but are not limited to: those described in: PCT application serial no. PCT/US2006/016370 published as WO/2006/116718 WO/2008/052136 WO/2008/063626 WO/2008/066617 WO/2008/095183 WO/2008/101107 WO/2008/112577 WO/2008/112578 PCT application serial no. PCT/US2007/082563 published as PCT application serial no. PCT/US2007/024225 published as PCT application serial no. PCT/US2007/022257 published as PCT application serial no. PCT/US2008/052845 published as PCT application serial no. PCT/US2008/053999 published as PCT application serial no. PCT/US2008/056296 published as PCT application serial no. PCT/US2008/056299 published as PCT application serial no. PCT/US2008/077753 published as WO 2009/042812; U.S. Patent Application Serial No. 12/546,017; and United WO 2011/068963 PCT/US2010/058721

States Provisional Application Serial Nos. 61/142,849; 61/142,861; 61/173,511; 61/173,564; and 61/177,611; the disclosures of which applications are herein incorporated by reference.

[050] The dosage form is capable of providing very precise drug concentrations in the blood, rapid dose delivery for pain management, or localized delivery in the Gl tract. Medical applications may include Gl disease, e.g., motility, colitis, pain management, localized delivery to tumors, customized dosing of therapeutics, e.g., immunosuppressants, and others.

[051] Other release mechanisms are also possible: the drug matrix may contain an electroactive drug-binding polymer, e.g. Nation, proteins, whose state of charge or degree of swelling can be altered by application of a current or potential. Application of a potential by the IC alters the binding properties of the polymer to the drug to effectuate release of the drug. Another possible mechanism is that the IC controls the concentration of a solution species around the dosage form, e.g. H+, which in turn can increase/decrease the solubility of the drug matrix and modulate drug release. The current may also be applied to an outer layer of the dosage form rather than the entire matrix to control the dissolution rate of a coating.

[052] The power source and the drug matrix can be distinct or the same. For example, a matrix may contain CuCI as the electrochemically active species. CuCI can act both as a cathode to power the IC and as a species whose conversion (to copper and chloride ions) releases the drug. The IC location may be in the bulk of the dosage form or on the surface. The sensors can be incorporated into the IC and used to trigger drug release or report physiological conditions to a receiver unit, e.g., pH, impedance, chemical sensor, temperature (detect bleeding). The sheath, coating, or manifold may be used to confine the matrix so that dissolution occurs only at one surface while the other surfaces are coated by a sheath that prevents dissolution. A coating may also be applied to prevent drug release until the drug reaches a desired location in the Gl tract, e.g. intestine or colon. WO 2011/068963 PCT/US2010/058721 [053] One example of a pain management scenario is that there is usually a basal rate of pain relief from a long-acting opioid (e.g., Oxycontin) coupled with self-titrated short-acting opioid for breakthrough pain. This paradigm is used for both injectable and oral regimens. This invention could handle both basal and breakthrough pain in the same pill or cluster of pills, or one could use the invention solely for the breakthrough component, if the patient were also taking a standard long-acting oral agent. This relates to conceiving of this as an Ingestible Patient-Controlled Analgesia system (analogous to the in-hospital, IV-based PCA). One aspect of the present invention includes stably associating the I EM with a pharmaceutically inactive excipient material designed to: 1) protect the IEM from moisture, handling and the nearby environment; and 2) protect the active pharmaceutical elsewhere in the formulation from damage or degradation by the IEM itself. One or more protective IEM ’’sandwiches11 could be developed such that the final IEM plus excipient module could be reliably integrated into the final tablet or capsule oral dosage form with minimal risk of deleterious effects on product dissolution or stability. Over time, once characterization of IEM sandwich performance has been completed in association with active pharmaceuticals bracketing the range of essential drug characteristics, e.g., pH, dissolution, bioavailability, solubility, regulatory clearance-related testing of an iEM-enabled medication might be streamlined, leading to a quicker time-to-market for what would in essence become a new form of proprietary medication, one where the market exclusivity would not necessarily depend upon the molecular composition-of-matter patent, but on the incorporation of the IEM and the attendant capabilities enabled by such incorporation.

[054] Referring now to Fig. 3A, a pill 40 having a near planar or flat surface is shown with a marker assembly 42 secured on the outside. The marker assembly 42 conforms to the shape of the pill 40. In the current example, the marker assembly 42 includes an IEM unit 44, a lower protective layer 46, an upper protective layer 48, an adhesive or securing layer 50 and a decorative or printing layer 52. io WO 2011/068963 PCT/US2010/058721 [055] Referring now the Fig. 3B, in accordance with another aspect of the present invention, the pill 40 is shown with a first tablet portion 41. A marker assembly 42a is shown secured to the surface of the first tablet portion 41. The marker assembly 42a is covered by a second tablet portion 43. The portion 41 and the portion 43 may be similar or different materials. For example, in accordance with one aspect of the present invention, the portion 41 may be the drug product and the portion 43 may be fast dissolving material. The marker assembly 42a may be similar to the marker assembly 42 of Fig. 3A or it may simply be just the IEM unit 44 with the lower layer 46 and the upper layer 48.

[056] Referring now to Fig. 3B and Fig. 3C, in accordance with another aspect of the present invention, the marker assembly 42a may be replaced by the marker assembly 42b of Fig. 3C. The marker assembly 42B includes the IEM unit 44 and a lamination or film coating 45. The laminated layer is made of a dissolvable material that delays the activation of the IEM unit 44 once the portion 41 and portion 43 of the pill 40 have dissolved or disintegrated to release the marker assembly 42b. The film coating 45 may be made of a variety of materials or films, such as polymer films, including polyethylene oxide, hydroxyprpyl cellulose, and triethyl citrate. Other films that can be used include any dissolvable polymer or plasticizer. The film coating 45 provides a moisture barrier and dissolves under the proper conditions to delay activation of the IEM unit 44. The film coating 45 is designed to provide sufficient delay in exposure of the IEM unit to the surrounding fluids relative to the disintegration and dispersion of the pill 40. The film coating 45 may include any of the following: soluble materials, barrier materials (such as lipids, polyvinyl alcohol), processing aids (such as plasticizers, adhesion promoters), and stabilizers. Furthermore, the film coating 45 may be manufactured via lamination, application of a coating solution or slurry followed by a cure. For example, in accordance with one aspect of the present invention, the film coating 44 may be laminated to the IEM unit 44, wherein the edge or extremities of the IEM unit 44 are exposed as shown in Fig. 3A. For example, in accordance with another aspect of the present invention, the film coating 44 may be laminated around the IEM unit 44 to form a pocket, 11 WO 2011/068963 PCT/US2010/058721 wherein the edge or extremities of the IEM unit 44 are covered as shown in Fig. 3B. In accordance with other aspects of the present invention, the film coating 45 may be formed around the IEM unit 44 using dry compression, such as a tablet press.

[057] It will also be apparent that the various layers disclosed can be eliminated or combined depending on the material employed and the properties thereof. For example, referring to Fig. 2, the lower protective layer 26 and securing layer 30 may be combined into a single layer, which is shown in Fig. 4. More specifically and referring to Fig. 4, a pill 52 is shown having a convex surface, although a planar or concave surface may be employed without limiting the scope of the present invention. A marker assembly 54 is secured to the pill 52. In the current example, the marker assembly 54 includes a lower layer 56, an upper layer 58, and a device 60, such as an IEM. According to one aspect of the present invention, the lower layer 56 is a material that combines both the adhesive and protective properties of layer 30 and layer 26 of Fig. 2, respectively. In a similar manner, upper layer 58 is a material that combines the protective and decorative properties of layer 28 and layer 32 of Fig. 2, respectively. Also, in the current example, the marker assembly 54 is a different size relative to the pill 52. The scope of the present invention is not limited by the shape or size of the marker assembly 54 in this example or any other example disclosed herein.

[058] Referring now to Fig. 5, a pill 62 is shown having a convex surface, although a planar or concave surface may be employed without limiting the scope of the present invention. A marker assembly 64 is secured to the pill 62. In the current example, the marker assembly 64 includes an upper layer 66 and a device 68, such as an IEM. In the current example, the adhesive layer and its properties, such as the adhesive layer 30 of Fig. 2, may be part of the coating on the pill 62. Alternatively, according to another aspect of the present invention, the adhesive layer may be part of the device 68. In yet another aspect of the present invention the adhesive properties may be provided by the upper layer 66 at the contact points with the pill 62. Thus, depending on the properties of the 12 WO 2011/068963 PCT/US2010/058721 materials selected, the properties of each layer can be altered to the specific needs of that aspect as shown in the various examples.

[059] Referring now to Fig. 5A, the process of assembling the marker assembly 64 onto the pill 62 is shown in accordance with one aspect of the present invention. The marker assembly 64 is built one layer at a time onto the pill 62. The device 68 is positioned on the pill 62. The device 68 is then formed to the shape of the pill 62. The device 68 can be shaped to the shape of the pill 62 using any standard method, e.g., heat and/or pressure. Then the upper layer 66 is added and shaped to the shape of the pill 62 as well as secured thereto using pressure and/or heat.

[060] Referring now to Fig. 5B, the process of assembling the marker assembly 64 onto the pill 62 is shown in accordance with another aspect of the present invention. In this example, the marker assembly 64 is assembled prior to being presented to the pill 62. The marker assembly 64 is positioned on the pill 62. Then the marker assembly 64 is secured to and formed to the shape of the pill 62 using heat and/or pressure.

[061] Referring now to Fig. 6 and Fig. 6A, in yet another example according to another aspect of the present invention, a pill 70 includes a convex surface, although a planar or concave surface may be employed without limiting the scope of the present invention. A marker assembly 72 is formed to the shape of and secured to the pill 70 using heat and/or pressure. In the current example, the marker assembly 72 includes a device coating layer 74 and a device 74a, such as an IEM. In the current example, the adhesive layer and its properties and the protective layer and its properties, such as the adhesive layer 30 and protective layers 26 and 28 of Fig. 2, are part of the device coating layer 74. Additionally, the properties of the decorative layer 32 of Fig. 2 may also be part of the device coating layer 74.

[062] Referring now to Fig. 7, in yet another example according to another aspect of the present invention, a pill 76 includes a convex surface, although a planar or concave surface may be employed without limiting the scope of the present invention. A marker 78 is secured to the pill 76. An enclosing layer 80 13 WO 2011/((68963 PCT/US2010/058721 surrounds the pill 76 and the marker 78. In the current example, the properties of the adhesive layer, the protective layers, and the decorative layer (such as the layer 30 and layers 26/28 and layer 32 of Fig. 2, respectively) may be part of the enclosing layer 80. In an alternative aspect of the present invention, the marker 78 may have the adhesive properties instead of or in addition to the enclosing layer 80.

[063] Referring now to Fig. 8, in yet another example according to another aspect of the present invention, a capsule 84 is shown. A marker 86 is secured to one end of the capsule 84. A layer 88 surrounds the marker 86 and is also secured to the capsule. In the current example, the properties of the adhesive layer, the protective layers, and the decorative layer (such as the layer 30 and layers 26/28 and layer 32 of Fig. 2, respectively) may be incorporated into the layer 88. In an alternative aspect of the present invention, the marker 86 may have the adhesive properties instead of or in addition to the layer 88.

[064] Referring now to Fig. 9, in yet another example according to another aspect of the present invention, a capsule 90 is shown. A marker assembly 92 is secured to mid-portion the capsule 90. The marker assembly 92 surrounds the circumference of the capsule 90. However, the marker assembly 92 may be designed to only partially surround the capsule 90 (not shown), in accordance with another aspect of the present invention. In the current example, the properties of the adhesive layer, the protective layers, and the decorative layer (such as the layer 30 and layers 26/28 and layer 32 of Fig. 2, respectively) may be incorporated into the marker assembly 92.

[065] Referring now to Fig. 10, the process steps of securing a device or a device assembly onto a tablet or pill is shown beginning with the step 100 wherein a raw core tablet or pill is created. At step 102, the device or the device assembly is attached to the raw core tablet to create an assembled tablet. At step 104, a sub coating is added to the assembled tablet to create a coated tablet. At step 106, which is an optional step, color coating is added to the coated tablet to create a color coated tablet. At step 108, which is an optional 14 WO 2011/068963 PCT/US2010/058721 step, the color coated tablet is imprinted to produce an imprinted tablet that is ready for distribution.

[066] Referring now to Fig. 11, the process steps of securing a device or a device assembly onto a tablet or pill in accordance with another aspect of the present invention is shown beginning with the step 110 wherein a raw core tablet or pill is created. At step 112, a sub coating is added to the raw core tablet to create a coated tablet. At step 114, the device or the device assembly is attached to the coated tablet to create an assembled coated tablet. At step 116, which is an optional step, color coating is added to the assembled coated tablet to create a color coated tablet. At step 118, which is an optional step, the color coated tablet is imprinted to produce an imprinted tablet that is ready for distribution.

[067] Referring now to Fig. 12, the process steps of securing a device or a device assembly onto a tablet or pill in accordance with yet another aspect of the present invention is shown beginning with the step 120 wherein a raw core tablet or pill is created. At step 122, a sub coating is added to the raw core tablet to create a coated tablet. At step 124, color coating is added to the coated tablet to create a color coated tablet. At step 126, a device or the device assembly is attached to the color coated tablet to create an assembled color coated tablet. At step 128, a second coating is added to the assembled color coated tablet to create an enclosed assembled tablet. At step 129, which is an optional step, the enclosed assembled tablet is imprinted to produce an imprinted tablet that is ready for distribution.

[068] Referring now to Fig. 14, Fig. 15, and Fig. 16, a tablet press 150 is shown. The press 150 rotates in a counter-clockwise direction as shown. The press 150 includes die cavity or punch cavity 152 and an ejection tray 154. Starting at position A, as shown, the pharmaceutical product is deposited in the cavity 152. The press 150 rotates to position B, which is positioned below a transfer wheel 160. The wheel 160 includes several openings 162. As the wheel 160 passes position C, each opening 162 passes under a feeder 170, as shown in Fig. 16. 15 WO 2011/068963 PCT/US2010/058721 [069] The feeder 170 contains marker devices 200. The device 200 is an (EM that is activated upon contact with a conducting fluid. The scope of the present invention is not limited by the environment or type of the conducting fluid. Once ingested, the device 200 comes into contact with a conducting fluid, such as stomach fluids, and the device 200 is activated. Referring again to the instance where the device 200 is used with the product that is ingested by the living organism, when the product that includes the device 200 is taken or ingested, the device 200 comes into contact with the conducting liquid of the body and a voltage potential is created and the system is activated. A portion of the power source is provided by the device 200, while another portion of the power source is provided by the conducting fluid, [070] Referring again to Fig. 14 and Fig. 15, each time an opening 162 passes under the feeder 170, one of the devices 200 is dropped into the opening 162 directly under the feeder 170. As shown in Fig. 15, a force "F" is shown to assist the movement of the device 200 from the feeder 170 into the opening 162. The force may be provided by the use of a vacuum through a suction tube 168. In accordance with other aspects of the present invention, the force may be provided by a spring, an air burst, or an ejection pin in addition to gravity. The wheel 160 rotates to position B. At position B, the device 200 located in the opening 162 is dropped into the cavity 152 of the press 150. The press 150 rotates to the position D where additional pharmaceutical product is deposited into the cavity 152 on top of the device 200. The press 150 continues to move in the counter-clockwise direction and at position E, the content of the cavity 152 is pressed under high pressure to form a tablet with the device 200 inside. The completed tablet is ejected and moved to a collection point through the ejection tray 154 for further processing, such as coating layers as needed.

[071] Referring now to Fig. 17, a feeder assembly 172 is shown as alternative embodiment and in accordance with another aspect of the present invention. The feeder assembly 172 can be used in place of the feeder 170 of the Fig. 14. The feeder assembly 172 includes a plurality of supporting fingers 174 that hold each device 200 in position. The fingers 174 are connected to a belt 176. The 16 WO 2011/068963 PCT/US2010/058721 fingers 174 lower the device 200 toward the wheel 160 of Fig. 14. When the fingers 174 reach the lower portion near the wheel 160, the fingers 174 move apart and drop the device 200 into the opening 162 of the wheel 160.

[072] Referring now to Fig. 18A and Fig. 18B, in accordance with another aspect of the present invention, the feeder assembly 172 includes an ejector 173 with a spring 175. As the opening 162 moves under the feeder assembly 172, the ejector 173 pushes the device 200 into the opening 162 of the wheel 160.

[073] Referring now to Fig. 24A, Fig. 24B, and Fig. 24C, an alternative example of a feeder assembly 170a is shown positioned below a cutting tool 170b. A web sheet 177 is positioned between the feeder assembly 170a and the tool 170b. The web sheet 177 delivers devices 179 to a position above the feeder assembly 170a. As shown in Fig. 24B, the tool 170b moves toward the feeder assembly 170a and cuts out the device 179. An ejector 170c moves downward to push the device 179 out of the tool 170b and into the feeder assembly 170a. As shown in Fig. 24C, the process continues and the devices 179 are fed into the feeder assembly 170a. This process can be used to load the feeder 170 of Fig. 16. In accordance with another aspect of the present invention, the feeder assembly 170a can be used to replace the feeder 170 of Fig. 14 and Fig. 16.

[074] Referring now to Fig. 13, the process steps of assembling a device 200 within the tablet or pill is shown beginning with the step 130 wherein the powder/raw material is loaded into the mold. At step 132 the device 200 is inserted into the mold. At step 134 more powder/raw material is added and a raw core tablet or pill is created. At step 134 a coating layer is added to the raw core tablet to create a coated tablet. At step 138, color coating is added to the coated tablet to create a color coated tablet. At step 139, which is an optional step, the color coated tablet is imprinted to produce an imprinted tablet that is ready for distribution.

[075] In accordance with another aspect of the present invention, the device 200 may be secured to the exterior of the product. The process of assembling or securing the device 200 to the exterior of the product can be done using an assembly array. Referring now to Fig. 19 and Fig. 20, a wheel 180 is shown that 17 WO 2011/068963 PCT/US2010/058721 includes positional grooves 182. The grooves 182 are shown in greater detail in Fig. 20. Each groove 182 has an opening 184 therein, A vacuum is created through the opening 184 that draws pills 186 into position as the pills 186 are delivered to the wheel 180 from a hopper tray 188. In accordance with other aspects of the present invention, the pills 186 can be positioned by other methods than vacuum draw. The pills 186 can be vibrated into position or brushed over with some form of sweeper so they fall into the hole and excess are brushed off. As the wheel 180 rotates the pill 186 moves to station 1 where an adhesive layer is applied. As the wheel 180 moves to station 2, the device 200 is secured to each pill 186. As the wheel 180 moves to station 3 a protective layer is applied. As the wheel 180 moves to station 4, a decorative or printed layer is applied. Thereafter, the complete and printed tablets or pills 186 are removed from the wheel 180 to a central collection point for further processing or distribution. The scope of the present invention is not limited by the number of stations on the wheel 180. For example, there wheel 180 can be designed to have one station, at which station a pre-assembled device is applied to the pill 186. The pre-assembled device can be as simple as the IEM with an adhesive layer or as discussed above with respect to Fig. 1.

[076] Referring now to Fig. 21, at each station shown in Fig. 19 various assembly steps are carried out including installation of the device on the tablet as well as other components or parts. A portion of a delivery arm 230 is shown positioned over a portion of the pills 186. The delivery arm 230 moves between the wheel 180 and a web 232. The web 232 contains devices 234 arranged in order to allow for the delivery arm 230 to pick up the devices 234. The delivery arm 230 removes the devices 234 from the web 232 and secures the devices 234 to the pills 186. In accordance with another aspect of the present invention the devices 234 are cut or punched out of the web 232. At other stations, other delivery arms remove or punch out or cut out other materials from different web rolls and secure those materials to the pills 186. For example, the delivery arm can remove a protection layer from the web sheet and secure it to a tablet with a device already secured thereto. According to another aspect of the present 18 WO 2011/068963 PCT/US2010/058721 invention, the devices positioned on the web may be a marker assembly unit such that a single installation process is all that is needed and each station can be used to perform the single task of moving the marker assembly from the web to the pill 186 using the delivery arm 230.

[077] Referring now to Fig. 22, an assembly process is shown wherein a tool 210 includes a cavity 212. The tool 210 is positioned above an assembly device 214, which includes circuitry 214a, prior to formation of the device onto a pill or tablet 216. The tool 210 is formed to the shape of the tablet 216 and is lowered onto the device 214. Through the application of temperature and pressure the device 214 is reformed as device 218 and secured to the tablet 216 as device 220. The cavity 212 prevents pressure from being applied to the circuitry 214a of the device 214.

[078] Refeming now to Fig. 23A, Fig. 23B, and Fig. 23C, according to another aspect of the present invention, an alternative assembly process is shown wherein a pressing tool or cutting tool 240 is positioned above a press table 242. The table 242 includes grooves 246 that have a central hole 248. The tablet 250 is held in the groove 246 using a vacuum suction applied through the hole 248. A web sheet 252 is positioned between the table 242 and the tool 240. The sheet 252 includes devices 254. To begin the assembly process, the tool 240 moves toward the table 242. The sheet 252 is punched and the device 254 is secured to the tablet 250 as shown in Fig. 23B. At a different station or position in the assembly process, a sheet 256 that includes a different layer in the assembly process is positioned between the table 242 that now holds the tablet 250 with the device 254 secured thereto and a cutting tool 260. The cutting tool 260 moves toward the table 242 and secures the layer 256 onto the tablet 250 (not shown) to form a coated tablet 250 with a device 254 assembled thereto.

[079] Referring now to Fig. 25, an assembly process is shown in accordance with another aspect of the present invention. An assembly unit 300 includes a press 302 and a press 304. The press 302 is positioned above a web 308. The web 308 has devices 306 positioned and held in place on the web 308. Devices 306 have an adhesive layer holding them to the web 308 and a second adhesive 19 WO 2011/068963 PCT/US2010/058721 layer positioned on the opposite side adjacent to the tablets 312. As the web 308 moves from a roller 310a to a roller 310b, the devices are presented and positioned above tablets 312, which are positioned on a tablet feeder belt 314. The feeder belt 314 moves the tablets 312 towards the press 304 as the devices 306 move toward the press 302. As the tablets 312 approach the press 304, each tablet 312 falls into a groove 304a of the press 304. The tablet 312 is then lifted by the press 304 toward the press 302 as the press 302 pushes the device 306 toward the press 304. At position 318 the device 306 is pressed onto the tablet 312 and secured thereto. As the press 302 and press 304 rotate the web 308 moves toward the roller 310b. At the same time, an assembled tablet 320 is lowered onto a take away roller belt 322 that moves the assembled tablet 320 away from the press 302 and the press 304. The assembled tablets 320 may be moved to the next phase of the process including packaging for distribution or additional preparation steps such as adding additional layers or coatings.

[080] Embodiments of interest include high-throughput fabrication processes, e.g., where details regarding such embodiments are provided above and/or in United States Provisional Application Serial No. 61/142,849; the disclosure of which is herein incorporated by reference.

[081] As described herein, a system of the present invention is used with a conducting fluid to indicate the event marked by contact between the conducting fluid and the system. For example, the system of the present disclosure may be used with a pharmaceutical product and the event that is indicated is when the product is taken or ingested. The term “ingested” or "ingest” or “ingesting" is understood to mean any introduction of the system internal to the in-vivo. For example, ingesting includes simply placing the system in the mouth all the way to the descending colon. Thus, the term ingesting refers to any instant in time when the system is introduced to an environment that contains a conducting fluid. Another example would be a situation when a non-conducting fluid is mixed with a conducting fluid. In such a situation the system would be present in the nonconduction fluid and when the two fluids are mixed, the system comes into contact with the conducting fluid and the system is activated. Yet another 20 WO 2011/068963 PCT/US2010/058721 example would be the situation when the presence of certain conducting fluids needed to be detected. In such instances, the presence of the system, which would be activated, within the conducting fluid could be detected and, hence, the presence of the respective fluid would be detected.

[082] 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.

[083] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual 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 recited method can be carried out in the order of events recited or in any other order which is logically possible.

[084] 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.

[085] 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 embodiments of the invention as well as specific examples thereof, 21 WO 2011/068963 PCT/US2010/058721 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 embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims. 22 □ΊΟϋ&'ΒΠ 7Ί&'Β , crnxBn ;w:n ατα ίπίβ^π pnow pnszn irn nr -|bob ,ρνιη ηχΒ- ιβοβγιβ πιβήβ πβ^πιββ np’ioz .ςγιχμβπ τμββ mprtnn pmfr’ oxnm . r. Geodau«r □ιηπη Pi?

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