Apparatus comprising a miniature ingestible device

222279/3 PCT/US2011/031536 WO 2011/127252

MINIATURE INGESTIBLE DEVICE

Field of Invention [003] The present invention relates to electronic devices and, more specifically, to electronic devices for use with a pharmaceutical product.

Background [004] Capsules are made of a material that becomes gel-like once in contact with fluids. Such gel-like materials can interfere with the operation of an ingestible device that relies upon contact with the surrounding fluid when the device is carried inside the capsule. For example, gelatinous materials have low conductivity and, hence, if the device operates using conduction through fluids, then it will not operate properly. Thus, it is important to prevent the gel-like 1 222279/3 WO 2011/127252 PCT/US2011/031536 material of the capsule, as it is disintegrating, from coming into contact with the device’s components.

[005] Additionally, capsules contain pharmaceutical materials that can interact with or damage the device. For example, as the capsule disintegrated, the pharmaceutical material will dissolve into the surrounding fluid and change the chemical composition of the fluid immediately surrounding the pharmaceutical material and the change may prevent the device from operating optimally. The content of the capsule may include material, such as a drug or excipient or compound, that when dissolved at high concentrations, will interfere with the operation of the ingested device placed within the same capsule. As the material enters the solution at the site where the capsule is dissolving, there is a high concentration localized around the device. The stomach motion and diffusion disperses the capsule content throughout the stomach and reduces the concentration. During this time, the device will not operate properly optimally if activated in the localized high concentration areas.

[006] Also, during long term storage the pharmaceutical material may begin to interact with the device and prevent optimal performance when the device is activated. For example, the product inside the capsule may be acidic and harmful to the electronic components. Alternatively, the content may be too basic, which can also harm the electronics. Furthermore, the material or product within the capsule will start to interact with the surrounding fluids, once the capsule is ingested and the capsule starts to disintegrate.

[007] Therefore, what is needed is a device that is manufactured and assembled, such that the capsule walls or other materials present in the fluid environment immediately surrounding the device do not interfere with optimal performance of the device.

Summary [008] The present invention discloses multiple approaches to preventing the capsule walls and other material from interfering with the performance of a device once the device is activated by surrounding fluid. 2 222279/3 PCT/US2011/031536 WO 2011/127252

Description of the Drawings [009] Fig. 1 shows a capsule containing a miniature ingestible device and an active agent in accordance with the present invention.

[010] Fig. 2A shows a miniature ingestible device with a powder excipient in miniature tablet form in accordance with one aspect of the present invention.

[011] Fig. 2B shows a miniature ingestible device with a film and powder in the form of a miniature tablet in accordance with one aspect of the present invention [012] Fig. 2C shows a miniature ingestible device with a film in accordance with one aspect of the present invention.

[013] Fig. 2D shows a miniature ingestible device with a powder glued to an ingestible device in accordance with one aspect of the present invention.

[014] Fig. 2E shows a miniature ingestible device with a film in accordance with one aspect of the present invention.

[015] Fig. 2F shows a miniature ingestible device with a film surrounded by a powder in accordance with one aspect of the present invention.

[016] Fig. 3 shows a capsule containing a miniature ingestible device and an active agent prior to coming in contact with a fluid.

[017] Fig. 4 shows the capsule of Fig. 3 at the initial stage on contacting the fluid with the walls of the capsule beginning to collapse and the miniature ingestible device in accordance with the present invention.

[018] Fig. 5 shows the capsule of Fig. 4 at a more advanced stage of being in contact with the fluid in accordance with the present invention..

[019] Fig. 6 shows an assembly unit for creating a miniature ingestible device in accordance with the present invention.

[020] Fig. 7 shows an assembly unit for creating a miniature ingestible device in accordance with the present invention.

[021] Fig. 8 shows an assembly unit for creating a miniature ingestible device in accordance with the present invention.

[022] Fig. 9 shows an assembly unit for creating a miniature ingestible device in accordance with the present invention. 3 222279/3 WO 2011/127252 PCT/US2011/031536 [023] Fig. 10 shows one end of a capsule with a miniature ingestible device.

[024] Fig. 11 is a flow process for manufacturing a miniature ingestible device.

Detailed Description [025] In accordance with the teachings of the present invention, a miniature ingestible device (MID) may be created using excipients and films. In accordance with the various aspects of the present invention, an ingestible event marker (or an ionic emission module, herein ΊΕΜ”) such as the one disclosed in US Patent Application Serial Number 12/564,017, entitled COMMUNICATION SYSTEM WITH PARTIAL POWER SOURCE and filed on September 21, 2009, may be covered with a disintegrating or a super-disintegrating material and/or a disintegrating film using various methods of manufacture to produce the MID. The MID, in accordance with various aspects of the present invention, may have a coating or lamination surrounding the I EM and separating and isolating the IEM from the pharmaceutical product or drug within the capsule once the capsule is ingested as well as from the capsule itself as the capsule walls begin to collapse during the disintegration process. In various aspects, the MID or device can be co-encapsulated with an active agent in a gel capsule, or other capsule or carrier. The subject compositions include an active agent/carrier component. The term "active agent" refers to a composition, which may be a solid or fluid, e.g., liquid, which has an amount of active agent, e.g., a dosage, present in a pharmaceutically acceptable carrier. The active agent may comprise, for example, a pharmaceutical product such as a tablet, capsule, softgel, powder, and other medicament forms.

[026] Referring now to Fig. 1, a capsule 10 includes a product 12 with a cavity 14. As understood in accordance with the present invention, the product 12 may be any pharmaceutical product or active agent. Also within the cavity 14 of the capsule 10 is a miniature ingestible device (MID) 20. The cavity 14 may also be filled with any excipient or product, in accordance with the teaching of the present invention. The capsule 10 is made of a dissolvable/disintegrating material, such as gelatin or hydroxypropyl methylcellulose (HPMC) material. Upon ingestion 4 222279/3 WO 2011/127252 and contact with fluid, the walls of the capsule 10 turn into a soft gel-like material, due to contact with fluids.

[027] Referring now to Fig. 2A, in accordance with one aspect of the present invention, a MID 20a is shown with an excipient material 22a surrounding an I EM 24. The scope of the present invention is not limited by the type of electronic device positioned within the excipient material 22a. Any electronic device may be used. Furthermore, the scope of the present invention is not limited by the type of excipient material used. For example, in accordance with one aspect of the present invention, the excipient material 22a may be a disintegrating material or a super disintegrating material. Example of materials include, but are not limited to, crospovidone disintegrants (e.g., Kollidon® disintegrants from BASF), polyvinyl polymer distintegrants, (e.g., Polyplasdone® disintegrants), croscarmellose sodium disintegrants (e.g., Ac-Di-Sol® distintegrants), sodium starch glycolates (e.g., Primojel® disintegrants, Explotab® disintegrants, and Vivastar® disintegrants), povidone, starch, and microcrystaliine cellulose.

[028] The MID 20a, in accordance with another aspect of the present invention, may be coated with a soluble polymer or film, such as HPMC or hydro hydroxypropyl cellulose (HPC) or blends thereof, whose function is to further delay the dissolution or disintegration of the tablet to allow for a delayed or timed separation of the IEM 24 from the capsule, such as capsule 10 of Fig. 1. Examples of the film materials may include any one or combination of the following: HPC, polyethylene oxide (PEO), forms of sugar such as sucrose or dextrose, sugar-alcohol such as Mannitol or Zylitol. To the film material additional materials may be added, including any one or combination of the following: plasticizer and/or salt, which includes sodium, potassium chloride, or any edible salt compound. Thus, in accordance with various aspects of the present invention, examples of the film materials include, but is not limited to: a combination of HPC and plasticizer with any one of PEO, sugar, or sugar-alcohol; a combination of HPC and plasticizer, a combination of PEO and plasticizer, and any of the foregoing combinations with salt. The scope of the 5 222279/3 WO 2011/127252 PCT/US2011/031536 present invention is not limited by the exact chemical composition of the film material and any combination of the above may be used to produce the film material as discussed in the present invention.

[029] Referring now to Fig. 2B, in accordance with another aspect of the present invention, an MID 20b is shown with the excipient material 22a surrounding the IEM 24. Furthermore, the MID 20b includes a film material 32 positioned on the top surface and bottom surface of MID 20b and physically in contact with or laminated to the excipient material 22a. In accordance with another aspect of the present invention, the film material 32 is soluble and disintegrates upon contact with fluid. In accordance with another aspect of the present invention, the film material 32 does not disintegrate upon contact with fluid. The MID 20b is manufactured such that the excipient material 22a is exposed on the ends as shown, in accordance with another aspect of the present invention.

[030] Referring now to Fig. 2C, in accordance with another aspect of the present invention an MID 20c is shown with a film material 22c surrounding the IEM 24. In accordance with another aspect of the present invention, the film material 22c disintegrate upon contact with fluid. The film material 22c may be made of and includes the following examples: at least one of polyethylene oxide and hydroxypropyl cellulose with a plasticizer comprising at least one of triethylcitrate, glycerol, dibutyl sebacate, and polyethylene glycol.

[031] Referring now to Fig. 2D, an MID 20d in shown with an excipient material 22a in a preformed shape. The excipient material 22a is glued or laminated onto the IEM 24 using a material 30. The material 30 may be a liquid adhesive or a dry adhesive that is pressure sensitive. The excipient material 22a is shown in a dome like shape with an air gap between the excipient material 22a and the IEM 24. However, the scope of the present invention is not limited by the shape of the excipient material 22a or the distance separating the excipient material 22a from the IEM 24. In accordance with other aspects of the present invention, the excipient material 22a may be shaped to fit the dimension of the IEM 24 exactly on the inner surface and maintain a dome or convex shape on the exterior. This is helpful in the handling and assembly process of the MID 20d into the capsule, 6 222279/3 WO 2011/127252 PCT/US2011/031536 such as shown in Fig. 1 given that many of the pharmaceutical manufacturing facilities are designed to handle convex shaped objects.

[032] Referring now to Fig. 2E, an MID 20e includes a film 22e surrounding the IEM 24. The MID 20e is shown with a gap 26 separating the IEM 24 from film 22e. The scope of the present invention is not limited by the type of material used to make the film 22e. The film 22e is similar to the film 32 of Fig. 2B and may be made of any suitable material, including but not limited to: of polyethylene oxide and hydroxypropyl cellulose with a plasticizer comprising at least one of triethylcitrate, glycerol, dibutyl sebacate, and polyethylene glycol. The scope of the present invention is not limited by the size of the gap 26. In accordance with another aspect of the present invention, the gap 26 may be minimal so that portions of the film 22e are in contact with the IEM 24. In accordance with another aspect of the present invention, the gap 26 may be filled with a material or a drug as appropriate.

[033] Referring now to Fig. 2F, an MID 20f is shown with an IEM 24 surrounded by a film 22f. The film 22f is surrounded by the excipient material 22a. As shown, the film 22f is in direct contact with the IEM 24 and surrounds the IEM 24. Furthermore, the MID 20f is shown with the excipient material 22a surrounding and in contact with the film 22f.

[034] In accordance with the teaching of the present invention, the shape of the various MIDs 20 shown through Figs. 2A, 2B, 2C, 2D, 2E, and 2F as illustrative and not intended as a limitation. For example, the shape of the MID 24, in accordance with various aspects of the present invention, may be oval or rectangular or something in between, for example, vertical sides and convex top and bottom.

[035] Referring now to Figs. 3, 4, and 5, a capsule 10 is shown with an MID 20. There may be other materials, including pharmaceutical material or drugs or active agents, inside the capsule 10. However, for the purpose of demonstrating the designation steps of the capsule and the MID 20, only these two elements are shown. In Fig. 3 the capsule 10 is shown when it is stored and not in contact with fluid. Once the capsule 10 comes into contact with fluid, the capsule 10 7 222279/3 WO 2011/127252 PCT/US2011/031536 begins to disintegrate and the walls of the capsule 10 start to collapse to become capsule 10a. Fluid AA enters the cavity defined by the capsule 10a. As such, fluid BB comes into contact with MID 20. In accordance with one aspect of the present invention, the excipient material of the MID 20 begins to dissolve and expand and the MID 20 starts to lose its shape and becomes the MID 40. As shown in Fig. 5, at a more advanced stage with longer contact with the fluid AA that entered the capsule 10, the capsule 10 is shown with the walls falling apart and collapsing as capsule pieces 10b. The fluid advances to contact the MID 20 as fluid BB to resulting in further expansion and disintegration of MID 20, which is shown as MID 50.

[036] Referring now to Fig. 6, a process for creating an MID, in accordance with one aspect of the present invention, includes loading an excipient material 60a into a press 62. The mass of the excipient material 60a used is in the order of 0.045g of powder material. However, the scope of the present invention is not limited by amount of material used. The I EM 24 is placed in the press 62. Then additional excipient material 60b, similar in mass to the amount of excipient material 60a, is added into the press 62 and on top of the I EM 24. Then a plunger 64 is used to apply pressure and assemble the materials into the MID, such as the MID 20a of Fig. 1. The pressure used to assemble the MID varies and the scope of the present invention is not limited thereby. Industry standard combined with the tolerances for the amount of pressure that can be applied the I EM 24 are the deciding factors. In accordance with one aspect of the present invention, typical pressures are in the order of 1000 psi.

[037] Referring now to Fig. 7, a process for creating an MID, in accordance with one aspect of the present invention, includes placing a film material 70 on a press table 72. The I EM 24 is placed on top of the film material 70 and another sheet of film material 70 is place on top of the I EM 24. The film material 70 is sized such that edges 70a, 70b, 70c, and 70d extend beyond the edges of the I EM 24. Then a thermal plunger 74 is used to apply pressure and heat to the film material 70 such that the edges 70a and 70b are laminated or secured together. Similarly, the edges 70c and 70d are laminated together. 8 222279/3 WO 2011/127252 PCT/US2011/031536 [038] Referring now to Fig. 8, a process for creating an MID, in accordance with one aspect of the present invention, includes placing a film material 80 on a press table 82. An internal MID 20, such as the one created by the process shown in Fig. 6, is placed on top of the film material 80 and another sheet of film material 80 is place on top of the internal MID 20. The film material 80 is sized such that edges 80a, 80b, 80c, and 80d extend beyond the edges of the internal MID 20. Then a thermal plunger 84 is used to apply pressure and heat to the film material 80 such that the edges 80a and 80b are laminated or secured together. Similarly, the edges 80c and 80d are laminated together.

[039] Referring now to Fig. 9, the process for creating an MID 96, such as the MID 20b of Fig. 2B, includes the process of placing a film material 90, similar to the film material disclosed throughout the present invention, on a press table 92, similar to the press table 72 of Fig. 7. Then a second film 90 is placed on top of the MID 20. Then a thermal plunger 94 is used to apply pressure and heat to the film materials 90 to secure the film material to the top and bottom of the MID 20, which results in the MID 96 with the side edges exposed.

[040] Referring now to Fig. 10, the MID 96 of Fig. 9 is placed within one end of the capsule 10, such as the capsule 10 of Fig. 1, in accordance with one aspect of the present invention. The MID 96, includes film materials 90 that do not dissolve or are not soluble. As such, when the fluid comes into contact with the MID 20, the MID 20 expands and breaks apart the walls of the capsule 10 to further ensure separation of the I EM 24, which is within the MID 20, from the capsule material.

[041] Referring now to Fig. 11, the process for manufacturing or assembling the MID, such as the MID 20, in accordance with the present invention begin at step 1110. At step 1120 the first material is added to the assembly unit. As noted above the first material may be in powder form or a film material and loaded into a press on placed on a press table, respectively. At step 1130, the device, such as the IEM , is loaded into the assembly unit. At step 1140 a second material is added. At step 1150 the assembly in completed by securing the materials and the device to form the MID. As noted above, securing may be done with 9 222279/3 WO 2011/127252 pressure, thermal, or glue materials. The scope of the present invention is not limited by the approach used to secure and produce the MID.

[042] As noted above, the film material may be made of a variety of materials or films, such as polymer films that include polyethylene oxide, hydroxypropyl cellulose, and triethyl citrate. Other films that can be used include any soluble polymer, plasticizer. The film material, in accordance with one aspect of the present invention, provides a moisture barrier and dissolves under the proper conditions to delay activation of the I EM or device. The film layer is designed to provide sufficient delay in exposure of the device to the surrounding fluids relative to the disintegration and dispersion of the capsule material and the content of the capsule. The film layer may includes the soluble materials, barrier materials (such as lipids, polyvihyl alcohol), processing aids (such as plasticizers, adhesion promoters), and stabilizers. Furthermore, the film may be manufactured via lamination, application of a coating solution or slurry followed by a cure. In accordance with other aspects of the present invention, the film or layer may be formed using dry compression, such as a tablet press.

[043] There are a variety of active agents or pharmaceutical products that can be placed inside of a capsule. For example, there are FDA approved drugs, drugs that are disclosed chemically in a patent application or in an issued patent, there are drugs are disclosed in the Orange Book as part of the approved drug products, and generics. In accordance with the teachings of the present inventions, any one or combination of such drugs may be placed within the capsule along with the device. Each of those drugs may have a specific and unique impact on the operation of the device as well as the disintegration of the film used because of the unique chemical composition. As such, the type of material uses as the film material may vary to be compatible to the chemical composition of the products used. Thus, the scope of the present invention is not limited by the type of content of the capsule and the film or coating layer around the electronic components of the device.

[044] In accordance with another aspect and benefit of the present invention, the film or coating will also prevent the interaction components of the device with io 222279/3 WO 2011/127252 PCT/US2011/031536 the drug inside the capsule and as such the device will not alter or impact the effectiveness of the drug.

[045] As noted above various disintegration materials may be used to surround the electronic components. For example, a disintegrant may be sodium starch glycolate or a water soluble excipient such as hydroxypropyl cellulose. It will also be apparent that the various layers disclosed can be eliminated or combined depending on the material employed and the properties thereof.

[046] As described herein, 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 product 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 MID 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 I EM within the MID is activated. Yet another 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.

[047] According to another aspect embodiments of the invention may defined in at least one of the following clauses.

[048] Clause 1: A device for placement within a capsule, comprising: an ingestible element; and a material in physical communication with at least part of the ingestible element, wherein the material facilitates physical separation of the ingestible element from at least a portion of the capsule during a disintegration.

[049] Clause 2: The device of clause 1, wherein the ingestible unit comprises an ingestible event marker.

[050] Clause 3: The device of clause 1 or 2, wherein the material comprises a disintegrant and comprises at least one of povidone, crospovidone, 11 222279/3 WO 2011/127252 croscarmellose sodium, sodium starch glycolate, starch, and microcrystalline cellulose.

[051] Clause 4: The device of clause 3, wherein the super-disintegrant is physically coupled to the ingestible unit using pressure.

[052] Clause 5: The device of clause 3, wherein the super-disintegrant is physically coupled to the ingestible unit using an adhesive material.

[053] Clause 6: The device of any of the preceding clauses, wherein the material includes a soluble film material that comprises at least one of polyethylene oxide and hydroxypropyl cellulose with a plasticizer comprising at least one of triethylcitrate, glycerol, dibutyl sebacate, and polyethylene glycol.

[054] Clause 7:The device of any of the preceding clauses, wherein the film material is physically coupled to the ingestible unit using thermal application.

[055] Clause 8: A unit including a pharmaceutical product, wherein the unit is ingestible and activated upon contact with a fluid, the unit comprising: a capsule including a wall, wherein the capsule defines a cavity for holding the pharmaceutical product and wherein the wall loses its shape and disintegrates upon contact with the fluid: and a device, preferably a device according to any of the preceding clauses, the device including a partial power source located within the cavity of the capsule, wherein the device is capable of encoding information in a current flow, which occurs when the device is activated as the partial power source contacts the fluid, the device further comprising: a first surface with a first portion of the partial power source; a second surface with a second portion of the partial power source; and a control unit for encoding the information in the current flow, wherein the control unit is electrically coupled between the first and second portions of the partial power source; and a material positioned over the first portion and the second portion of the partial power source, wherein the material disintegrates upon contact with the 12 222279/3 WO 2011/127252 fluid to provide physical separation between the device and the disintegrating wall of the capsule.

[056] Clause 9: The unit of clause 8, wherein the material surrounds the device and is secured to itself to define a cavity between the material and the device.

[057] Clause 10: A system for tracking delivery of a pharmaceutical agent, the system comprising: a capsule defining a cavity; miniature ingestible tablet located in the cavity of the capsule, the miniature ingestible tablet comprising: an ingestible device according to any of clauses 1 -7, preferably a device in a unit according to any of clauses 8-9, the device being activated upon contact with a fluid and comprising an ingestible element and a tablet material in physical communication with at least part of the ingestible device; and a material at least partially surrounding the miniature ingestible tablet, wherein the tablet material facilitates physical separation of the ingestible device from at least a portion of the capsule during a disintegration process.

[058] Clause 11: The system of clause 10, wherein the material and/or the tablet material is a soluble film material that includes at least one of polyethylene oxide and hydroxypropyl cellulose with a plasticizer comprising at least one of triethylcitrate, glycerol, dibutyl sebacate, and polyethylene glycol.

[059] Clause 12: The system of clause 11, wherein the material is a nonsoluble film material that defines an opening at either end of the miniature ingestible tablet such that when the tablet material comes in contact with the fluid and expands the film material controls the direction of expansion.

[060] Clause 13: The system of clause 11 or 12, wherein the film material delays contact between the fluid and the ingestible device to delay activation.

[061] Clause 14: A method of manufacturing a device, preferably for assembly into a pharmaceutical product to prevent damage to the device and allow for handling and manipulation of the device during assembly and for reliable 13 222279/3 WO 2011/127252 PCT/US2011/031536 activation of the device upon ingestion of the pharmaceutical product, the method comprising the steps of: providing a first layer of material; positioning the device including a first portion and a second portion, wherein the first portion of the device is in contact with the first layer of material; providing a second layer of material, wherein the second layer of material is in contact with the second portion of the device; and securing the first and second material to the device to produce a miniature ingestible marker.

[062] Clause 15: The method of clause 14, further comprising the step of physically associating the miniature ingestible marker with the pharmaceutical product, wherein physically associating the miniature ingestible marker with the pharmaceutical product comprises incorporating the miniature ingestible marker in a gelatin capsule.

[063] Clause 16: The method according to clause 14 or 15, wherein the device is a device according to any of clauses 1-7.

[064] 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.

[065] 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. 14 222279/3 WO 2011/127252 PCT/US2011/031536 [066] 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.

[067] 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, 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. 15