Ingestible device with dissolving needles for improved gastric delivery - Patent Application 20070122999

Abstract

Introduced herein is an ingestible device capable of delivering a drug directly to tissues along the digestive tract. Administration of the drug stored in the ingestible device can be achieved through a combination of features. The ingestible device can include a plunging mechanism to which a needle is connected and a dissolvable trigger mechanism that holds the plunging mechanism in a first position. After ingestion, the trigger mechanism can be exposed to bodily fluids to cause dissolution. When the trigger mechanism dissolves, the plunging mechanism can move from the first position to a second position, thereby extending the needle into the tissue in which the ingestible device is housed. Second, the needle can also dissolve upon exposure to bodily fluids to ensure safe passage of the ingestible device through the digestive tract.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 387,266, filed December 13, 2022, and entitled "Ingestible Device with Dissolvable Needle for Improved Gastric Delivery," which is incorporated herein by reference in its entirety.

[0002] Various embodiments relate to devices designed to administer a drug while placed in a living body and then pass through the living body through the gastrointestinal tract. [Background technology]

[0003] Pharmaceuticals (also called "drugs") are an important part of medicine that relies on continuous advances in pharmacology to diagnose, cure, treat, or prevent disease. The term "administration" is generally used to refer to the process by which an individual takes a drug. Drugs are generally designed for enteral administration, where the active ingredient enters the body via the digestive tract and requires little or no monitoring. For example, many of the most common drugs are intended to be administered orally in dosages in tablet, capsule, or liquid form.

[0004] Medication in solid unit dosage form, i.e., tablets and capsules, has several advantages. Medication can be designed and / or manufactured to be easy to swallow as well as to control the release rate of the active ingredient. While oral ingestion of medication in solid unit dosage form is a fairly simple route of administration, absorption of the active ingredient is a complex process.

[0005] Most orally administered drugs are believed to be absorbed into the gastrointestinal tract via passive diffusion or active transport. Passive diffusion is widely considered to be the more important mechanism, and relies on the active ingredient's migration down the concentration gradient across the mucosa into the circulatory system. The migration itself is highly dependent on the size of the concentration gradient, but the rate at which migration occurs can vary widely. For example, the migration rate can depend on the molecular weight and size of the active ingredient, lipid solubility, mucosal blood flow, mucosal surface area, and mucosal permeability, among other variables. For this reason, it can be difficult to predict how quickly an orally administered drug will be absorbed by the body. [Brief explanation of the drawings]

[0006] [Figure 1] 1 includes a cross-sectional view of an example ingestible device designed to administer a drug while traveling through a living organism, such as a human or animal body. [Figure 2A] 1 shows an ingestible device in a "storage state" prior to ingestion by a living organism. [Figure 2B] 1 shows the ingestible device in an "inserted state." [Figure 2C] 1 shows the ingestible device in the "injected state." [Figure 2D] 1 shows the ingestible device in a "passable state" after the needles have dissolved. [Figures 3A-3D] Each includes simplified diagrams of the retracted, inserted, injected, and passable states. [Figure 4] Several possible implementations of the trigger mechanism are shown. [Figure 5] 1 shows how, after ingestion via the mouth, an ingestible device can pass through the esophagus before settling into the stomach. [Figure 6] Included is a timing diagram showing at a high level how the dissolution rates of the different components can be compared to one another.

[0007] For purposes of illustration, various embodiments are shown in the drawings. However, those skilled in the art will recognize that alternative embodiments may be employed without departing from the principles of the present disclosure. Thus, while certain specific embodiments are shown in the drawings, the techniques described herein are susceptible to various modifications. DETAILED DESCRIPTION OF THE INVENTION

[0008] Modern research has begun to explore ways to improve the absorption of orally administered medications. For example, several entities are developing digital pills (also called "smart pills") that can electromechanically accomplish medication delivery after ingestion. Digital pills typically monitor aspects of the body and therefore use this information to influence their operation. However, the nature of this information can vary. For example, a digital pill may include a sensor that assists in determining its position, and medication may not be administered until the output generated by the sensor indicates that the digital pill has been placed in place.

[0009] Despite showing promise, digital pills are still susceptible to error. For example, erroneous sensor output can result in medication being administered at an improper location. As another example, the electromechanical means used to achieve administration can malfunction. Furthermore, even if the medication is successfully administered at the proper location, absorption still relies on passive diffusion, which, as discussed above, can be difficult to accurately predict.

[0010] There are also some drugs that are simply not suitable for oral administration. These drugs may irritate the stomach or experience inconsistent degradation, or they may simply be poorly absorbed in the digestive tract. Historically, many of these drugs have been administered via injection. However, such an approach has drawbacks, including the risk of infection from penetrating the skin, the need for a sterile environment, etc.

[0011] Introduced herein is an ingestible device (also called a "pill") that can address the aforementioned problems by delivering medication directly to tissues along the digestive tract. As discussed further below, administration of medication stored in the ingestible device can be achieved through a combination of features.

[0012] First, the ingestible device may include an actuation mechanism including (i) a plunging mechanism to which a needle is connected and (ii) a dissolvable trigger mechanism that holds the plunging mechanism in a first position. The term "trigger mechanism" may be used to refer to a mechanical component that physically inhibits movement of the plunging mechanism (and thus administration of the medicament through the needle). After ingestion, the trigger mechanism may be exposed to bodily fluids, causing it to dissolve. Once the trigger mechanism dissolves, the plunging mechanism may move from the first position to a second position, thereby extending the needle into the tissue in which the ingestible device is housed. Such features enable the ingestible device to actuate at a predictable time measured relative to ingestion, without the need for an external stimulus (e.g., a signal emanating from outside the body) or an internal stimulus (e.g., an output generated by a sensor).

[0013] Second, the needle can also dissolve through exposure to bodily fluids. During operation, the beveled end of the needle can extend into tissue after the trigger mechanism of the actuation mechanism dissolves. Over a period of time, the agent in the ingestible device can be delivered through the needle and into the tissue. The needle can be designed so that dissolution occurs after a predetermined period of time. The beveled end is sharp enough to penetrate tissue and therefore needs to be contained as the ingestible device passes through the digestive tract. Dissolving the needle eliminates the need to return the needle to the ingestible device to ensure safe passage through the digestive tract.

[0014] term References in this disclosure to "an embodiment" or "some embodiments" mean that the described feature, function, structure, or characteristic is included in at least one embodiment. Appearances of such phrases do not necessarily refer to the same embodiment, or necessarily to mutually exclusive alternative embodiments.

[0015] The term "based on" should be interpreted in an inclusive sense, rather than an exclusive sense, i.e., "including, but not limited to." Accordingly, the term "based on" is intended to mean "based at least in part on," unless expressly specified otherwise.

[0016] The terms "connected" and "coupled," and variations thereof, are intended to include any connection or coupling between two or more elements, either direct or indirect. The connection or coupling may be physical, logical, or a combination thereof. For example, elements may be electrically or communicatively connected to each other even though they do not share a physical connection.

[0017] The term "module" may broadly refer to software, firmware, hardware, or a combination thereof. A module is typically a functional component that generates one or more outputs based on one or more inputs. A computer program may include or utilize one or more modules. For example, a computer program may utilize multiple modules responsible for completing different tasks, or a computer program may utilize a single module responsible for completing multiple tasks.

[0018] When used in reference to a list of items, the word "or" is intended to encompass all of the following interpretations: any of the items in the list, all of the items in the list, and any combination of the items in the list.

[0019] The term "biocompatible" means not harmful to living tissue. Thus, the term "biocompatible material" can be used to refer to any material that is not harmful to living tissue, regardless of whether its biocompatibility is currently known or unknown.

[0020] The term "compressed state" may be used to refer to any state in which the spring is at least partially compressed, while the term "uncompressed state" may be used to refer to any state in which the spring is substantially uncompressed. Those skilled in the art will recognize that whether a spring is fully compressed or partially compressed while constrained, or fully uncompressed or substantially uncompressed while unconstrained, may depend on the properties (e.g., design and size) of the spring.

[0021] Overview of Ingestible Devices Figure 1 includes a cross-sectional view of an example ingestible device 100 designed to administer a medication as it travels through a living organism, such as a human or animal body. Note that Figure 1 and other figures in this disclosure are not drawn to scale. Features may be shown greatly enlarged for clarity.

[0022] As shown in FIG. 1 , ingestible device 100 may include capsule 102 having cylindrical body 104 and atraumatic ends 106A-B. One example of an atraumatic end is a rounded shape that does not cause injury when contacting biological tissue, such as the approximately hemispherical end shown in FIG. 1 . This geometric shape is commonly referred to as a "spherical cylinder." While ingestible device 100 shown in FIG. 1 has approximately hemispherical ends, in other embodiments, ingestible device 100 may have other atraumatic end shapes. For example, at least one end of capsule 102 may have a flat portion that can lie against biological tissue. Cylindrical body 104 and atraumatic ends 106A-B may be referred to as the "structural components" of capsule 102. To avoid contamination of the interior cavity defined by the cylindrical body 104 and / or the atraumatic ends 106A-B, the structural components may be sealingly connected to one another.

[0023] Note that in some embodiments, the cylindrical body 104 is integrally formed with one of the atraumatic shaped ends. For example, the cylindrical body 104 may be integrally formed with the atraumatic shaped end 106A, and thus these structural components may not need to be connected to one another. Instead, components may be installed within these structural components, and then the atraumatic shaped end 106B may be connected thereto.

[0024] In some embodiments, these structural components comprise the same material. For example, these structural components may comprise another biocompatible material, such as a plastic, metal, metal alloy, ceramic, polymer, or naturally occurring material with mechanical properties comparable to plastic. In other embodiments, these structural components comprise different materials. For example, atraumatic end 106B, through which needle 108 extends, may be composed of a polymer or metal alloy, while the other atraumatic end 106A and cylindrical body 104 may be composed of plastic. This significant weight difference can help ensure that ingestible device 100 is properly aligned with the biological tissue into which the agent is to be injected, as discussed further below. Additionally, these structural components may have a coating that inhibits exposure to and degradation from bodily fluids. For example, these structural components may be coated with a polymer, sugar, or sugar alcohol via a dipping or spraying process; the coating may improve the safety, durability, or operational efficiency of ingestible device 100. For example, a polymer coating may provide lubrication to aid passage through the esophagus, but may be chemically designed to denature, dissolve, or otherwise degrade in the stomach, yet remain robust in the mouth and esophagus and during normal handling.

[0025] Whether these structural components comprise the same or different materials, capsule 102 may be formed in a variety of ways. For example, these structural components may be machined, injection molded, printed (e.g., with a three-dimensional printer), or otherwise formed to house the components of ingestible device 100.

[0026] 1, atraumatic shaped end 106A can be largely or completely empty to provide buoyancy. Here, for example, the inner surface of atraumatic shaped end 106A defines an empty cavity 110. However, relatively lightweight components can be placed within atraumatic shaped end 106A without significantly affecting buoyancy. Such a design allows ingestible device 100 to naturally orient longitudinally when in bodily fluids, as discussed further below.

[0027] Alternatively, ballast 112 may be placed within atraumatic end 106B. Ballast 112 may comprise any material capable of providing stability. Examples of such materials include metals, metal alloys (e.g., stainless steel, titanium alloys, cobalt-chromium alloys), ceramics (e.g., tungsten carbide), and the like. In FIG. 1 , ballast 112 is connected to a longitudinal segment of capsule 102 such that the ballast forms atraumatic end 106B. In such embodiments, ballast 112 is partially or fully exposed to bodily fluids after ingestion of ingestible device 100 and, therefore, may comprise a biocompatible material. However, in some embodiments, ballast 112 is positioned inside atraumatic end 106B. In such embodiments, ballast 112 is not exposed to bodily fluids, and therefore, ballast 112 may or may not comprise a biocompatible material.

[0028] As discussed further below, at least one of these structural components may comprise a dissolvable material. For example, assume that capsule 102 includes atraumatic end 106A and cylindrical body 104, but not atraumatic end 106B (thus exposing ballast 112 to bodily fluids). Atraumatic end 106A and / or cylindrical body 104 may comprise a material that dissolves after a predetermined period of exposure to bodily fluids. The material may be a water-soluble polymer, or a mixture or combination of soluble and insoluble materials. Examples of soluble materials include polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), dextran, polyethylene oxide, polyvinyl alcohol (PVA), polyacrylic acid (PAA), hydroxypropyl methylcellulose (HPMC), etc. Examples of insoluble materials include polycarbonate, polystyrene, etc. Generally, the predetermined time period is long enough for (i) trigger mechanism 116 of actuation mechanism 114 and (ii) needle 108 to dissolve before the predetermined time period has elapsed. Dissolving atraumatic shaped end 106A, atraumatic shaped end 106B, or cylindrical body 104 may help reduce the size of ingestible device 100 and facilitate easier passage of ingestible device 100 through the digestive tract after the medication has been administered.

[0029] As shown in FIG. 1 , the atraumatic end 106B may include an opening 122 through which the needle 108 can extend. The actuation mechanism 114 may be responsible for moving the needle 108 from a first position, in which its beveled end is disposed inside the capsule 102, to a second position, in which its beveled end is disposed outside the capsule 102. As discussed further below, the actuation mechanism 114 may include a trigger mechanism 116 that is exposed to bodily fluids through another opening 124 in the capsule 102 after ingestion, a plunger mechanism 118 that is held in the first position by the trigger mechanism 116, and a spring 120 that is held in a compressed state by the plunger mechanism 118 while in the first position. The trigger mechanism 116 may comprise a material that dissolves after exposure to bodily fluids. After the dissolution of the trigger mechanism 116, the spring 120 transitions from a compressed state to an uncompressed state, thereby moving the plunging mechanism 118 from the first position to the second position. The needle 108 may be connected either directly or indirectly to a plunger mechanism 118, such that movement of the plunger mechanism 118 may correspond to movement of the needle 108. The term "plunger mechanism" may be used to refer to a mechanical component that allows medication to be administered through rapid repositioning. Approaches for moving the needle 108 are discussed in more detail below.

[0030] The capsule 102 may have any of a variety of different sizes, such as any of those sizes listed in Table I. Generally, the size of the capsule 102 depends on its contents (e.g., the amount of medication stored therein). [Table 1]

[0031] 2A-D show ingestible device 200 at different stages of administration.

[0032] FIG. 2A shows ingestible device 200 prior to ingestion by a living organism. At this stage, ingestible device 200 may be described as being in a "storage stage." As discussed above, ingestible device 200 may comprise capsule 202 having a central longitudinal axis 204 (or simply "central axis") defined therethrough. Capsule 202 may have substantially cylindrical segments interconnected between a pair of rounded ends. In embodiments where the rounded ends are in the form of hemispheres, this shape may be referred to as a "spherical cylinder." Inside the substantially cylindrical segment, reservoir 206 may generally store a drug in liquid form. The amount of drug that can be stored in reservoir 206 may depend on the size of capsule 202. Generally, reservoir 206 may store between 25 and 200 microliters (μL) (preferably between 50 and 100 μL). 2A, reservoir 206 may be defined in part by seal 208. A bottom surface of seal 208, which may define a perimeter of reservoir 206, may be approximately perpendicular to central axis 204 while in the first position (also referred to as the "upper position").

[0033] Needle 210 may be positioned generally along central axis 204. Needle 210 may include a hollow shaft 212 having a port 214 defined therein and a beveled end 216. While ingestible device 200 is shown in FIGS. 2A-D as having a single port, embodiments of ingestible device 200 may have multiple ports (e.g., arranged circumferentially around needle 210) so that medicament may be administered more quickly. Medication within reservoir 206 may be able to enter hollow shaft 212 through port 214 and exit through beveled end 216. In FIG. 2A, needle 210 is positioned in a first position corresponding to a retracted state. When needle 210 is positioned in the first position, port 214 may be concealed to prevent medicament from entering hollow shaft 212. For example, port 214 may be covered by seal 208 through which needle 210 extends, as shown in FIG. 2A.

[0034] 2B-C, beveled end 216 has a regular 45° bevel. However, beveled end 216 may be designed differently depending on the tissue into which needle 210 is inserted, the force with which needle 210 is inserted into the tissue, etc. Thus, beveled end 216 may have a 22° bevel, a 30° bevel, a 35° bevel, a 45° bevel, etc. In some embodiments, end 216 may not be beveled at all, but instead has a blunt 90° bevel. Furthermore, beveled end 216 may have a long bevel, a medium bevel, a short bevel, a multi-bevel, or a scalpel bevel. Furthermore, needle 210 may have other configurations in some embodiments. For example, ingestible device 200 may have a plurality of relatively small "microneedles" arranged in an array, and the entire microneedle array may be actuated according to the approaches described herein. As another example, ingestible device 200 may include a single needle, such as a macroneedle (e.g., constructed from epoxy), which has one or more openings (also called "gills") along its length through which a drug may exit. As another example, ingestible device 200 may include barbed projections with one or more openings through which a drug may exit. These openings may be located along its length or near its ends (e.g., located adjacent to barbs that embed into tissue and inhibit extraction). In such embodiments, the barbed projections may be dissolvable to ensure that ingestible device 200 can be easily removed from the tissue to which the drug is administered. Thus, ingestible device 200 may be described as simply having "projections" through which a drug may be expelled into or near the tissue.

[0035] As described above, ingestible device 200 may include an actuation mechanism that, during operation, moves needle 210 along central axis 204 from a first position, where beveled end 216 is disposed inside capsule 202, to a second position, where beveled end 216 is disposed outside capsule 202. The actuation mechanism may include (i) trigger mechanism 218, (ii) plunger mechanism 220, and (iii) first spring 222. In embodiments in which a ballast forms one of the atraumatic shaped ends, the ballast may have an opening defined therethrough along central axis 204 to accommodate actuation of needle 210 along central axis 204.

[0036] After ingestion, trigger mechanism 218 can be exposed to bodily fluids through an opening (not shown) in capsule 202. Trigger mechanism 218 can comprise a material that dissolves after a predetermined period of exposure to bodily fluids. The material can be, for example, a soluble polymer. Trigger mechanism 218 can have a variety of forms depending on the design of the actuation mechanism (more specifically, plunger mechanism 220, which is held in place by trigger mechanism 218). In FIG. 2A , for example, trigger mechanism 218 is a pin that extends laterally through an opening (e.g., a hole or slot) in plunger mechanism 220. The opening in capsule 202 through which bodily fluids can contact trigger mechanism 218 can be located nearly anywhere along the periphery of capsule 202. For example, the opening can be along the axial axis of the pin, such that the opening is proximate one end of the pin. As another example, the opening can be along the radial axis of the pin, such that the opening is centrally located along the length of the pin. If trigger mechanism 218 is to be exposed to a greater amount of bodily fluid (e.g., to promote dissolution), two or more openings may be defined through capsule 202. For example, the openings may take the form of slots extending radially around at least a portion of the circumference of capsule 202.

[0037] Additionally, the size of the trigger mechanism 218 can be varied to achieve a desired rate of dissolution. Generally, thinner trigger mechanisms dissolve faster than thicker trigger mechanisms. The trigger mechanism 218 can have a diameter of 1.0 to 2.5 millimeters. The length of the trigger mechanism 218 can depend on the size of the capsule 202. For example, the trigger mechanism 218 can have a length of 3.0 to 10.0 millimeters.

[0038] 2A, plunger mechanism 220 may initially be held in a first position by trigger mechanism 218. While in the first position, plunger mechanism 220 may hold first spring 222 (also referred to as an "insertion spring") in a compressed state. Needle 210 may be connected to plunger mechanism 220, such that movement of plunger mechanism 220 may correspond to movement of needle 210, as discussed further below with reference to FIGS. 2B-C.

[0039] Another spring 224 (referred to as a "second spring" or "injection spring") may be interconnected between the plunger mechanism 220 and the seal 208. When the plunger mechanism 220 is in the first position shown in FIG. 2A , the second spring 224 may be in an uncompressed or lightly compressed state. When the second spring 224 is in an uncompressed state, the seal 208 is suspended such that little or no pressure is applied to the agent in the reservoir 206. The tandem nature of the first spring 222 and the second spring 224 may allow the agent to be stored in a low-pressure configuration, which may also allow the insertion of the needle 210 into the tissue to be decoupled in time and force from the delivery of the agent to the tissue, allowing for more robust insertion and more reliable timing of the agent delivery.

[0040] In some embodiments, the mucoadhesive disk 228 is secured along the edge of the ballast-weighted capsule 202, as shown in FIG. 2A. The term "mucoadhesion" is generally used to refer to adhesion that occurs between two surfaces, one of which is essentially the mucosa. The mucoadhesive disk 228 may comprise any material that can at least temporarily improve adhesion of the ingestible device 200 to the tissue through which the drug is excreted. The mucoadhesive disk 228 may comprise a polymer with hydrophilic groups (e.g., hydroxyl, carboxyl, amide, or sulfate) that adhere to the tissue through interactions such as hydrogen bonding, hydrophobic interactions, or electrostatic interactions. For example, the polymer may be coated along the mucoadhesive disk 228, or the mucoadhesive disk 228 may be composed entirely of the polymer. In some embodiments, the polymer is dissolvable. Dissolution of the polymer may allow the mucoadhesive disk 228 to be more easily removed from the tissue. For example, adhesion may simply decrease due to dissolution of the polymer, or dissolution of the polymer may result in dissolution of the mucoadhesive disk 228 itself.

[0041] 2B , after trigger mechanism 218 dissolves, plunging mechanism 220 may move from a first position to a second position in response to first spring 222 transitioning from a compressed state to a non-compressed state. In FIG. 2B , the dissolution of trigger mechanism 218 causes plunging mechanism 220 to move "downward" along central axis 204. Because needle 210 is connected to plunging mechanism 220, movement of plunging mechanism 220 may correspond to movement of needle 210 along central axis 204. Specifically, beveled end 216 of needle 210 may extend through another opening 226 in capsule 202. In the event that ingestible device 200 is positioned adjacent to tissue, such movement of needle 210 may cause beveled end 216 to penetrate the surface of the tissue. Accordingly, FIG. 2B illustrates ingestible device 200 in an "inserted state."

[0042] In FIG. 2B , the needle 210 is positioned in a second position corresponding to an insertion state. When the needle 210 is positioned in the second position, the port 214 may be accessible to allow the agent to enter the hollow shaft 212. At a high level, the port 214 is positioned within the periphery of the reservoir 206 while the needle 210 is positioned in the second position. However, the needle 210 is preferably designed such that the port 214 is positioned near the "bottom" of the reservoir 206, as shown in FIG. 2B . The agent may be able to flow more easily into the hollow shaft 212 when the port 214 is positioned closer to the "bottom" of the reservoir 206. Additionally, by locating port 214 near the "bottom" of reservoir 206, more medication may be administered because port 214 is less likely to be obscured by seal 208 as it moves "downward," for example, from a first position (also referred to as the "upper position") to a second position (also referred to as the "lower position") along central axis 204. Seal 208 is located in the upper position in Figure 2A, while seal 208 is located in the lower position in Figure 2C.

[0043] 2B, the second spring 224 can be compressed by the "downward" movement of the plunging mechanism 220 along the central axis 204. This compression is due to the force exerted on the bottom surface of the seal 208 by the drug stored in the reservoir 206. At a high level, the drug is sufficiently constrained (and therefore pressurized) to exert a force on the bottom surface of the seal 208.

[0044] Referring now to FIG. 2C , as medication enters needle 210 through port 214 and exits needle 210 through beveled end 216, the amount of medication in reservoir 206 decreases (and therefore the force exerted on the bottom surface of seal 208 also decreases). Thus, FIG. 2C shows ingestible device 200 in an "injection state." Over time, second spring 224 transitions from a compressed state to a non-compressed state. Such transition will "push" medication through port 214 and into needle 210. Generally, second spring 224 is designed such that seal 208 is positioned near the bottom of reservoir 206 when second spring 224 returns to its non-compressed state, as shown in FIG. 2C . In other words, the second spring 224, in combination with the seal 208, the first spring 222, and the plunger mechanism 220, can be designed to deliver most, if not all, of the medication to the tissue through the beveled end 216 of the needle.

[0045] Note that during operation, the insertion and injection phases shown in Figures 2B and 2C, respectively, tend to occur in rapid succession. For example, ingestible device 200 may only be in the insertion phase briefly (e.g., tens or hundreds of milliseconds) as second spring 224 rapidly compresses as shown in Figure 2B and then expands as shown in Figure 2C.

[0046] As described above, needle 210 may comprise a material that dissolves upon exposure to bodily fluids. During operation, beveled end 216 of needle 210 may extend into tissue during the insertion phase, and medicament may flow through beveled end 216 of needle 210 into tissue during the injection phase. Ingestible device 208 (more specifically, its actuation mechanism, reservoir 206, seal 208, and needle 210) may be designed so that medicament is administered largely, if not completely, over a time interval having a known length. For example, the time interval may be several seconds to several minutes. As discussed further below, needle 210 may be designed so that dissolution occurs after the time interval has elapsed. Because beveled end 216 is sharp enough to penetrate tissue, it must be contained if ingestible device 200 exits the body by passing through the digestive tract. Dissolving needle 210 eliminates the need to return needle 210 to capsule 202 to ensure safe passage through the digestive tract. FIG. 2D shows ingestible device 200 in a “passable state” after needle 210 has dissolved.

[0047] 3A-D include simplified diagrams of the retracted, inserted, injected, and passable states, respectively. For simplicity, only the trigger mechanism 302, plunger mechanism 304, and actuation mechanism including first spring 306, second spring 308, seal 310, and needle 312 are shown for capsule 300.

[0048] After ingestion, trigger mechanism 302 may be exposed to bodily fluids through an opening in capsule 300. Trigger mechanism 302 may hold plunger mechanism 304 in a first position, and while plunger mechanism 304 is in the first position, plunger mechanism 304 may hold first spring 306 in a compressed state, as shown in FIG. 3A . Furthermore, because needle 312 is connected to plunger mechanism 304, trigger mechanism 302 may also hold needle 312 in the first position, albeit indirectly via plunger mechanism 304. While needle 312 is in the first position, (i) the port through which the medication enters may be hidden, and (ii) the beveled end through which the medication exits may be fully retained within capsule 300. For example, the port may be centrally located along the length of needle 312 such that the port is covered by seal 310.

[0049] As described above, trigger mechanism 302 may be constructed of a material that dissolves upon exposure to bodily fluids. After trigger mechanism 302 dissolves, plunger mechanism 304 may move from a first position to a second position, as shown in FIG. 3B. Movement of plunger mechanism 304 may be caused by first spring 306 transitioning from a compressed state to a decompressed state. Such action may cause the beveled end of needle 312 to extend through the opening of capsule 300, as shown in FIG. 3B. The stroke length of needle 312 may depend on various factors, including the length of needle 312, the length of first spring 306, the amount of compression of first spring 306, etc. However, the stroke length during the insertion phase, commonly referred to as the "insertion stroke," may be between 2 and 5 millimeters (preferably between 2.5 and 3.5 millimeters).

[0050] As the plunger mechanism 304 moves toward the second position, the second spring 308 may become more compressed. Stated another way, the movement of the plunger mechanism 304 may cause the second spring 308 to transition from an uncompressed state to a compressed state. Note that the second spring 308 may not necessarily be fully compressed as shown in FIG. 3B , but may instead be partially compressed due to the resistive force exerted by the seal 310. The second spring 308 then transitions from the compressed state back to the uncompressed state. As shown in FIG. 3C , the return of the second spring 308 to its uncompressed state may cause the seal 310 to move from the first position ( FIG. 3B ) to the second position ( FIG. 3C ). While not shown in detail here, the seal 310 may move through the reservoir 314 and “push” the drug in the reservoir 314 through the port and into the needle 312. The agent may travel through the hollow shaft of the needle 312 and then beveled out the end of the needle 312 .

[0051] In some embodiments, movement of the seal 310 does not cause any further movement of the needle 312. Stated another way, in some embodiments, the stroke length of the needle 312 may not increase during the injection phase. However, in other embodiments, the needle 312 is extended further as the seal 310 moves. This may be caused by further movement of the plunger mechanism 304 as the reservoir empties of medication. The stroke length during the injection phase, commonly referred to as the "injection stroke," may be 1 to 3 millimeters (preferably 1.5 to 2.0 millimeters). The injection stroke may be optimized based on the target volume of medication to be delivered and the configuration of the reservoir 314. For example, a 000-size capsule may require fewer strokes to deliver the same amount of medication compared to a 0-size capsule because it has a larger cross-sectional area available for the reservoir 314.

[0052] Needle 312 may also be constructed of a material that dissolves, softens, or otherwise denatures after exposure to bodily fluids to reduce the likelihood of tissue damage during passage through the digestive tract. Thus, needle 312, or at least a portion thereof (e.g., the beveled end), may dissolve. Generally, needle 312 is designed or constructed so that a sufficient time for administration purposes (e.g., 2-30 minutes, preferably 5-10 minutes) elapses before dissolution begins. As shown in FIG. 3D, the dissolution of needle 312 allows that end of capsule 300 to become atraumatic again.

[0053] 4 illustrates several possible implementations of trigger mechanism 402. Specifically, FIG. 4 illustrates a "centered design," in which trigger mechanism 402 extends within plunger mechanism 404, and a "lateral design," in which trigger mechanism 402 runs alongside plunger mechanism 404. Those skilled in the art will recognize that these implementations are intended to illustrate, rather than limit, the nature of trigger mechanism 402.

[0054] In a "center design," trigger mechanism 402 may extend into an opening in plunger mechanism 404. The opening may be a notch, as shown in FIG. 4, or the opening may be an opening that extends completely through plunger mechanism 404 generally along latitudinal axis 408. When held in place by trigger mechanism 402, plunger mechanism 404 may be oriented lengthwise generally along longitudinal axis 406. As described above, after ingestion, trigger mechanism 402 may be exposed to bodily fluids through the opening in capsule 400, and upon dissolution, plunger mechanism 404 may move "downward" along longitudinal axis 406 such that the beveled end of the needle extends through capsule 400.

[0055] In a "lateral design," the trigger mechanism 402 can run alongside the plunger mechanism 404. As shown in FIG. 4, the plunger mechanism 404 can be angled (e.g., 5-10 degrees relative to the longitudinal axis 406) so that the latching component 410 engages the structural component 412. The structural component 412 can be partially complementary to the latching component 410 such that engagement between these components inhibits movement of the plunging mechanism 404 while the trigger mechanism 402 is in place. Generally, the latching component 410 and the structural component 412 are designed to allow a maximum axial movement of 0.1-0.5 millimeters (preferably about 0.2-0.3 millimeters) along the latitudinal axis 408. The structural component 412 can be fixed to the interior surface of the capsule 400, or the structural component 412 can be part of the capsule 400. For example, structural component 412 may represent the interior surface of a cylindrical body (e.g., cylindrical body 104 in FIG. 1) or the end of an atraumatic shape (e.g., atraumatic end 106A in FIG. 1). At a high level, trigger mechanism 402 may "pin" latching component 410 of plunger mechanism 404 to structural component 412.

[0056] As shown in FIG. 4 , the trigger mechanism 402 can tilt the plunger mechanism 404 away from the longitudinal axis 406, and upon melting of the trigger mechanism 402, the design of the plunger mechanism 404 (more specifically, the latching component 410) can allow it to self-align with the longitudinal axis 406 and release from its “pinned” position. After melting of the trigger mechanism 402, a diametric reduction of the structural component 412 can allow actuation of the plunger mechanism 404. The diametric reduction can vary based on the design (e.g., shape and dimensions) of the latching component 410. For example, if the latching component 410 has an approximately inverted bell shape, then a diametric reduction of 0.3 to 0.7 millimeters can allow actuation. Following melting of the trigger mechanism 402, the plunger mechanism 404 can move “downward” along the longitudinal axis 406 and laterally along the latitudinal axis 408 toward the longitudinal axis 406. Thus, the plunger mechanism 404 may "straighten" as it moves "downward."

[0057] Having a dissolvable trigger mechanism can be an important feature of an ingestible device because it allows needle actuation to be "passive," in the sense that no active actuation (e.g., using a motor) is required. In a "lateral design," trigger mechanism 402 prevents movement of plunger mechanism 404 prior to dissolution, but trigger mechanism 402 does not need to be constructed from a material with high strength. Simply put, when trigger mechanism 402 is positioned alongside plunger mechanism 404, little material strength is required because this design eliminates reliance on reduced shear strength. Furthermore, trigger mechanism 402 can be axisymmetric with this design, which can facilitate the manufacturing and assembly process.

[0058] Overview of passive kinetic and dissolution processes 5 shows how, after ingestion via the mouth, an ingestible device 500 may pass through the esophagus until settling in the stomach. Once in the stomach, the ingestible device 500 may naturally assume a longitudinal orientation (also referred to as a "vertical orientation"). The ingestible device 500 may have a central axis 502 defined therethrough, and when the ingestible device 500 is in the vertical orientation, the central axis 502 may be approximately perpendicular to a surface 504 of the tissue into which the agent is being infused.

[0059] As described above, the ingestible device 500 can naturally rest in a vertical position along the fundus of the stomach. Generally, this is achieved by designing a first end of the ingestible device 500 (e.g., atraumatic shaped end 106A in FIG. 1 ) to provide buoyancy and a second end of the ingestible device 500 (e.g., atraumatic shaped end 106B in FIG. 1 ) to provide ballast. For example, the first end can be mostly or completely empty to provide buoyancy, and the second end can include a high-density component (e.g., composed of a metal, metal alloy, ceramic, etc.) to ensure proper orientation within the stomach.

[0060] In some embodiments, the mucoadhesive is coated along at least the second end of the ingestible device 500. Stated another way, the mucoadhesive may be coated along at least the outer surface of one end of the ingestible device 500. Similar to the mucoadhesive disk 228 of FIGS. 2A-D, the mucoadhesive coating can adhere the ingestible device 500 to tissue, ensuring more reliable delivery of the agent contained in the ingestible device 500. The mucoadhesive coating may comprise a polymer with hydrophilic groups (e.g., hydroxyl, carboxyl, amide, or sulfate) that attach to tissue through interactions such as hydrogen bonding, hydrophobic interactions, or electrostatic interactions. Note that in some embodiments, the mucoadhesive coating is constructed or applied to reduce its adhesiveness over time. For example, assume the ingestible device 500 is designed so that its needles dissolve after a first time interval. It may be desirable for the mucoadhesive coating to lose its adhesiveness after or just before the first time interval so that the ingestible device 500 can be more easily removed from the tissue surface 504. Thus, the mucoadhesive coating may be designed to dissolve, allowing the ingestible device 500 to pass through the digestive tract intact.

[0061] This approach to gastric drug delivery may be preferable over conventional drugs with solid unit dosage forms that rely heavily on passive diffusion. For example, the esophageal transit time of the ingestible device 500 may be 5 minutes or less after ingestion, allowing the drug to be administered shortly thereafter (e.g., within 5-20 minutes of ingestion, preferably within 5-10 minutes of ingestion), whereas conventional drugs may not be absorbed for 120 minutes or more. Therefore, using the ingestible devices presented herein, drugs can be administered more rapidly and take effect. Because stomach tissue generally averages about 5 millimeters thick, compared to intestinal tissue, which generally averages about 1 millimeter, there is also an improved safety margin by administering drugs to the stomach.

[0062] FIG. 6 includes a timing diagram illustrating at a high level how the dissolution rates of different components may compare to one another. As noted above, various components of ingestible device 600 may be constructed from dissolvable materials. For example, trigger mechanism 602 may be constructed at least partially from a first dissolvable material, and needle 604 may be constructed at least partially from a second dissolvable material. Additionally, capsule 606 may be constructed at least partially from a third dissolvable material. For example, any combination of cylindrical body (e.g., cylindrical body 104 of FIG. 1) and atraumatic shaped end (e.g., atraumatic shaped end 106A-B of FIG. 1) may comprise a third dissolvable material.

[0063] The first dissolvable material can be selected, engineered, or manufactured (e.g., in the form of trigger mechanism 602) to dissolve at a first approximately known rate. Because the rate at which the first dissolvable material dissolves is predictable, the total time it takes for trigger mechanism 602 to dissolve can also be predictable. For example, trigger mechanism 602 can be designed, manufactured, and installed within capsule 606 so that dissolution takes 2 to 20 minutes (and preferably 5 to 10 minutes). Preferably, the first approximately known rate should be fast enough to allow the drug to be administered quickly, but slow enough to allow sufficient time for ingestible device 600 to reach a desired organ (e.g., the stomach) before significant dissolution occurs. The first dissolvable material should have sufficient flexural strength to hold the compressed spring in place and dissolve rapidly upon exposure to liquid. Preferably, the first dissolvable material should also be easy to process for scale-up. For example, the first dissolvable material can be a sugar alcohol such as sorbitol or isomalt, zein protein, PEG, or PVP. The mechanical properties and dissolution rate of the sugar alcohol-based trigger mechanism 602 can be "tuned" by mixing it with additives such as talc or PVP powder, or by coating it with a thin polymer-based moisture barrier layer. Other water-soluble materials such as polyvinyl alcohol (PVA), butene-diol vinyl alcohol copolymer (BVOH), or blends can also be used to slow the dissolution rate.

[0064] The second dissolvable material may be selected, engineered, or manufactured (e.g., in the form of needle 604) to dissolve at a second, approximately known rate. Because the rate at which the second dissolvable material dissolves is predictable, the total time it takes for needle 604 to dissolve may also be predictable. For example, needle 604 may be designed, manufactured, and placed within capsule 606 so that dissolution takes 2-30 minutes (and preferably 5-10 minutes). Note that because needle 604 is initially housed within capsule 606, dissolution may not begin until needle 604 extends outside capsule 606. Thus, dissolution of needle 604 may occur 4-50 minutes (preferably 10-20 minutes) after ingestion of ingestible device 600. The second dissolvable material may be zein protein, PVP, PEG, or a combination thereof. Other biodegradable polymers such as polylactic acid (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolide), as well as water-soluble materials such as dextran, sugar alcohols, etc., can also be used in different combinations.

[0065] As noted above, only a portion of needle 604 may comprise the second dissolvable material. For example, assume needle 604 is designed so that only its beveled end extends through the end of capsule 606 during the insertion and injection phase. In such a scenario, no further dissolution of needle 604 is required to make the end atraumatic again, and therefore only the beveled end may comprise the second dissolvable material.

[0066] As described above, needle 604 has a centrally located port through which the agent can flow; this centrally located port may initially be obscured (e.g., by a seal) to prevent entry of the agent before ingestible device 600 is properly seated against tissue. This design allows the agent to be separated from needle 604 during retraction. Once needle 604 is inserted into tissue, the port may transition, for example, from within the seal to a position near the bottom of the reservoir. This movement opens the lumen of needle 604 to the agent, allowing the agent to be dispensed. Until such time as the port is exposed to the agent, there is no path for distribution, and therefore the reservoir may remain sealed.

[0067] The third dissolvable material may be selected, created, or manufactured (e.g., in the form of capsule 606) to dissolve at a third approximately known rate that is slower than the first and second approximately known rates. Because the rate at which the third dissolvable material dissolves is predictable, the total time it takes for capsule 606, or at least a portion thereof, to dissolve may also be predictable. For example, capsule 606 may be designed or manufactured to take 20 to 75 minutes (and preferably 30 to 50 minutes) to dissolve. The third dissolvable material may be a plastic material such as polycarbonate or polystyrene, a water-soluble material such as polyethylene oxide (e.g., Polyox™), or a combination thereof.

[0068] Like the trigger mechanism 602, the capsule 606 is exposed to bodily fluids immediately after ingestion. To ensure proper administration of the medication, the third approximately known rate is generally slower than the first approximately known rate by at least a predetermined amount. For example, the needle 604 may dissolve in approximately 10, 25, 40, or 50% of the time it takes the capsule 606 to dissolve. The second approximately known rate may be slower than the first approximately known rate, or the second approximately known rate may be faster than the first approximately known rate. At a high level, the second approximately known rate may depend on the rate at which the medication is expected to be administered. Preferably, the needle 604 should not significantly dissolve until at least a predetermined amount (e.g., 80, 90, 95, or 98 percent) of the medication has been administered to the tissue. The term "significantly dissolve" may be used to refer to the stage at which the structural integrity of the component is affected by dissolution.

[0069] Note that in some embodiments, capsule 606 may have a mucoadhesive coating 608 applied thereto. Mucoadhesive coating 608 may comprise any material capable of at least temporarily improving adhesion of ingestible device 600 to the tissue through which the drug is excreted. In some embodiments, the mucoadhesive material is also dissolvable. Dissolution of the mucoadhesive material may help ensure that ingestible device 600 is easily removed from the tissue. The mucoadhesive material may be comprised of a material that takes 20-75 minutes (and preferably 30-50 minutes) to dissolve. Thus, the mucoadhesive material may dissolve at approximately the same rate as capsule 606. In some embodiments, the mucoadhesive material dissolves at a faster rate than capsule 606, while in other embodiments, the mucoadhesive material dissolves at a slower rate than capsule 606.

[0070] The rates at which the trigger mechanism 602, needle 604, capsule 606, and mucoadhesive coating 608 dissolve can vary based on, for example, the time at which the medication is expected to be administered. This time can vary based on the amount of medication stored in the ingestible device 600, the viscosity of the medication stored in the ingestible device 600, the properties of the spring, the seal that achieves the administration, etc. Although the rates can vary, the general relationship between the rates can be predictable. Generally, the trigger mechanism 602 dissolves at the fastest rate. In embodiments in which the capsule 606 includes a mucoadhesive coating 608, the mucoadhesive coating 608 can dissolve at a faster rate than the needle 604 (i.e., so that the needle 604 can be exposed to bodily fluids immediately after the medication is administered), at a slower rate than the needle 604 (i.e., so that the needle can at least partially degrade before the ingestible device 600 is removed from the tissue), or at a rate similar to the needle 604. Alternatively, capsule 606 may dissolve at the slowest rate to ensure that the insertion and injection steps are fully completed before capsule 606 begins to dissolve.

[0071] remarks The foregoing description of various embodiments of the claimed subject matter has been provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the claimed subject matter to the precise form disclosed. Many modifications and variations will be apparent to those skilled in the art. The embodiments have been chosen and described in order to best explain the principles of the invention and its practical application, thereby enabling those skilled in the relevant art to understand the claimed subject matter, its various embodiments, and various modifications suitable for the particular use contemplated.

[0072] Although the detailed description describes specific embodiments and the best mode contemplated, no matter how detailed the detailed description is, the technology can be implemented in many ways. The embodiments can vary considerably in implementation details and still be encompassed by this specification. Specific terms used when describing certain features or aspects of various embodiments should not be construed as meaning that the terms are redefined herein to be limited to any particular characteristic, feature, or aspect of the technology to which they relate. In general, the terms used in the following claims should not be construed to limit the technology to the specific embodiments disclosed herein unless those terms are explicitly defined herein. Thus, the actual scope of the technology encompasses not only the disclosed embodiments, but also all equivalent ways of practicing or implementing the embodiments.

[0073] The language used herein has been chosen primarily for readability and instructional purposes and may not have been chosen to delineate or limit the subject matter. Accordingly, it is intended that the scope of the technology be limited not by this detailed description, but rather by any claims that may be published in an application based on this specification. Accordingly, the disclosure of various embodiments is intended to be illustrative, but not limiting, of the scope of the technology set forth in the following claims.

Claims

1. 1. A device designed for uptake by a living organism, said device comprising: a capsule having a central axis defined therethrough; a reservoir in which the drug is stored in liquid form, a reservoir defined at least in part by a seal generally perpendicular to the central axis while the reservoir is in a first position; a trigger mechanism that is exposed to bodily fluids through a first opening in the capsule after ingestion, a trigger mechanism comprising a first material that dissolves after exposure to the bodily fluid for a first period of time; a plunger mechanism held in a first position by the trigger mechanism; a protrusion connected to the plunger mechanism and fully retained within the capsule when the plunger mechanism is in the first position, the protrusion having a port through which the agent can enter and a beveled end through which the agent can exit; the protrusions comprising a second material that dissolves after exposure to the bodily fluid for a second period of time that is longer than the first period of time; a first spring held in compression by the plunger mechanism while in the first position; a second spring interconnected in an uncompressed state between the plunger mechanism and the seal; After the trigger mechanism has dissolved, the plunger mechanism moves from the first position to the second position by the first spring transitioning from the compressed state to the uncompressed state, thereby (i) the beveled end of the protrusion extends through a second opening of the capsule into body tissue; (ii) the second spring transitions from the uncompressed state to a compressed state; the seal moves from the first position to the second position by the second spring transitioning from the compressed state back to the uncompressed state, thereby allowing the medicament to enter the protrusion through the port and exit through the beveled end; After the protrusions are dissolved, A device wherein the capsule detaches from the body tissue for passage through the body.

2. 10. The device of claim 1, wherein the capsule has substantially cylindrical segments interconnected between a first rounded segment and a second rounded segment.

3. further comprising a ballast positioned within the first rounded segment; 3. The device of claim 2, wherein the ballast causes the capsule to naturally position itself vertically while in the bodily fluid, the central axis being approximately perpendicular to the surface of the bodily tissue.

4. The device of claim 3 , wherein the second rounded segment is mostly or completely empty to provide buoyancy.

5. The device of claim 1 , wherein the port in the protrusion is blocked by the seal when the plunger mechanism is in the first position.

6. The device of claim 1 , wherein the protrusions comprise a second material that dissolves after exposure to the bodily fluid for a second period of time that is longer than the first period of time.

7. the trigger mechanism is positioned laterally adjacent to the plunger mechanism latch; 2. The device of claim 1, wherein when the plunger mechanism is held in the first position, the latch is laterally offset from the central axis such that the latch engages a structural feature along an interior surface of the capsule.

8. 1. A device designed for uptake by a living organism, said device comprising: a capsule having a central axis defined therethrough; A needle comprising a material that dissolves after exposure to bodily fluids for a predetermined period of time, The needle (i) a hollow shaft with a port through which the medicament in the capsule can enter; and (ii) a needle having a beveled end through which the medicament can exit; an actuation mechanism that, during operation, moves the needle along the central axis from a first position, in which the beveled end is disposed inside the capsule, to a second position, in which the beveled end is disposed outside the capsule.

9. The actuation mechanism a trigger mechanism that is exposed to bodily fluids through a first opening in the capsule after ingestion, a trigger mechanism comprising a second material that dissolves after exposure to the bodily fluid for a second predetermined period of time; a plunger mechanism to which the needle is connected, a plunger mechanism held in a first position by the trigger mechanism; 9. The device of claim 8, comprising a spring held in compression by the plunger mechanism while in the first position.

10. 10. The device of claim 9, wherein after the trigger mechanism dissolves, the plunger mechanism moves from the first position to the second position by the spring transitioning from the compressed state to the uncompressed state, whereby the beveled end extends through the second opening of the capsule.

11. 10. The device of claim 9, wherein the second predetermined time is between 5 minutes and 20 minutes.

12. The device of claim 11, wherein the predetermined time is between 20 minutes and 60 minutes.

13. Further comprising a reservoir in which the drug is stored; The device of claim 9 , wherein the reservoir is at least partially defined by a seal that is generally perpendicular to the central axis while in the first position.

14. The device of claim 13 , further comprising a spring interconnected in an uncompressed state between the actuation mechanism and the seal.

15. 15. The device of claim 14, wherein when the actuation mechanism is actuated, the seal moves along the central axis toward the end of the capsule from which the beveled end of the needle extends, thereby pressurizing the medication within the reservoir.

16. the capsule having substantially cylindrical segments interconnected between a first rounded segment and a second rounded segment, and the device comprising:

10. The device of claim 9, further comprising a mucoadhesive coated on at least an exterior surface of the first rounded segment of the capsule.

17. further comprising a ballast positioned within the first rounded segment of the capsule; 17. The device of claim 16, wherein the ballast causes the capsule to be naturally positioned vertically while in the body fluid, and the central axis is approximately perpendicular to a surface of the body tissue through which the beveled end extends when the actuation mechanism is actuated.

18. 1. A device designed for uptake by a living organism, said device comprising: a capsule containing a reservoir of drug; a needle having a beveled end through which the medicament can exit; a needle, the needle extendable through a first opening of the capsule; An actuation mechanism comprising: a plunger mechanism to which the needle is connected; and an actuation mechanism including a trigger mechanism that retains the plunger mechanism in a first position and that is exposed to bodily fluids through a second opening in the capsule after ingestion; the trigger mechanism comprises a first material that dissolves after exposure to the bodily fluid for a first period of time, thereby allowing the plunger mechanism to move from the first position to a second position such that the needle extends through the first opening of the capsule; The device, wherein the needle comprises a second material that dissolves after exposure to the bodily fluid for a second period of time that is longer than the first period of time.

19. 20. The device of claim 18, wherein at least a portion of the capsule comprises a third material that dissolves after exposure to the bodily fluid for a third period of time that is longer than the first and second periods of time.

20. 19. The device of claim 18, wherein the needle has a total stroke length of between 2 millimeters and 5 millimeters.

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