Intake electronically triggered drug delivery system

Abstract

The present disclosure relates to an ingestible capsule configured to release a therapeutic agent (26) by an electrothermal chemical reaction. The capsule includes a chamber having inflatable microcapsules (20) and a therapeutic agent (26). The interior of the microcapsule (20) includes a heating wire and a chemical substance in communication with the heating wire such that a chemical reaction begins when the chemical substance is heated by the heating wire to generate a gas. The ingestible capsule also has capsule electronics including a sensor and a controller. The controller may process sensed data from the sensors and electrically trigger the heating wires to generate heat sufficient to induce a chemical reaction to generate a gas to inflate the respective microcapsules (20) to a sufficient size and configuration to expel the therapeutic agent (26) out of the capsule upon detection of physiological activity indicative of a medical condition.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 433,856, filed December 20, 2022, and U.S. Provisional Application No. 63 / 451,718, filed March 13, 2023, the entire contents of both applications are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to an ingestible capsule configured to release a therapeutic agent through an electrothermal chemical reaction. Background Art

[0004] Ingestible capsules that deliver therapeutic agents through thermochemical reactions have been described in the prior art. For example, CN-100534544 describes a remote-controlled sustained-release electronic capsule for releasing drugs in the digestive tract. The capsule consists of a housing, a power supply unit, a control circuit, a piston, a drug release channel, and a driver with a propulsion device. The propulsion device, consisting of an igniter, a propellant chamber, a nozzle, and a propellant, applies a propulsive force to the piston, opening the drug release channel and slowly releasing the drug. CN-113769250 describes a drug delivery capsule comprising a housing, a soft bag disposed within the housing, and a drug delivery channel communicating with the bag and the exterior of the housing. The soft bag is placed within a medicine box, and a gas box filled with pressurized gas is located within the device cavity. A connecting channel connecting the medicine box and the gas box is provided on a partition. The drug delivery capsule is also equipped with a valve assembly for controlling the opening and closing of the connecting channel. Pressurized gas pre-stored in the device cavity is controlled to enter the medicine box, allowing the pressurized gas to occupy the space in the medicine box. The soft bag is squeezed and compressed, causing the drug to flow out of the bag. CN-108686292 describes a drug-releasing capsule comprising a control cabinet, a first drug-releasing compartment, and a second drug-releasing compartment. The control cabinet includes a wireless receiving module, a microbattery, and two microprocessors. After the drug-releasing capsule reaches the gastrointestinal tract, the control cabinet receives an external trigger signal for the first time, causing the first drug-releasing compartment to release the drug. The second drug-releasing compartment releases the drug when the control cabinet receives an external trigger signal for the second time.

[0005] However, existing capsules do not provide a mechanism for controlling the timing of drug release. An ideal treatment would be to release the drug from the capsule immediately when the patient's symptoms are detected. Summary of the Invention

[0006] In one aspect, the present disclosure provides an ingestible capsule for improving a medical condition in a patient, comprising a first portion and a second portion. The first portion may include a chamber containing a microcapsule and a therapeutic agent. The microcapsule may have an outer surface and include a heating filament and a chemical in communication with the heating filament, such that when the chemical is heated by the heating filament, a chemical reaction occurs to produce gas. The therapeutic agent may be disposed on the exterior of the microcapsule, and a lid may be coupled to the chamber and configured to releasably retain the therapeutic agent. The second portion of the ingestible capsule may include capsule electronics, including a sensor and a controller. The sensor may be configured to detect a parameter and generate a sensor signal in response to the detection. The controller may be operably coupled to the chamber and programmed to receive the sensor signal, identify or estimate a biomarker associated with the medical condition based on the sensor signal, determine whether a physiological activity characteristic of the medical condition has occurred based on the identification or estimation, and, upon determining that an event has occurred, electrically trigger the heating filament to generate heat sufficient to initiate a chemical reaction, thereby generating gas to expand the microcapsule to a sufficient size and configuration to remove the lid, thereby ejecting the therapeutic agent from the chamber into the gastrointestinal tract.

[0007] On the other hand, the present disclosure provides an ingestible capsule having a first portion, a second portion, and a longitudinal axis extending therethrough. The first portion may include a plurality of chambers radially arranged around the longitudinal axis of the ingestible capsule. Each of the plurality of chambers may include a microcapsule and a therapeutic agent. The microcapsule may have an outer surface and include a heating wire and a chemical substance in communication with the heating wire such that when the chemical substance is heated by the heating wire, a chemical reaction occurs to produce a gas. The therapeutic agent may be disposed on the outside of the microcapsule. The ingestible capsule may also include a plurality of lids, each lid being connected to a corresponding one of the plurality of chambers and being configured to releasably retain the therapeutic agent. The second portion of the ingestible capsule may include capsule electronics, which include a sensor and a controller. The sensor may be configured to detect a parameter and generate a sensor signal in response to the detection. A controller may be operably coupled to each of the plurality of chambers and programmed to receive a sensor signal, identify or estimate a biomarker associated with a medical condition based on the sensor signal, determine whether a physiological activity characteristic of the medical condition has occurred based on the identification or estimation, and electrically trigger the heating wire to generate heat sufficient to initiate the chemical reaction, thereby generating the gas to expand the corresponding microcapsule to a size and configuration sufficient to remove the corresponding lid, thereby ejecting the therapeutic agent from the corresponding one of the plurality of chambers into the gastrointestinal tract upon determining that the event has occurred. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 is a perspective view of an ingestible capsule according to one aspect of the present disclosure.

[0009] Figure 2 There is no lid Figure 1 A perspective view of an ingestible capsule showing the interior of the chamber of the ingestible capsule and the microcapsules therein.

[0010] Figure 3 There is no lid Figure 1 A perspective view of an ingestible capsule is provided to illustrate the interior of the chamber of the ingestible capsule and the therapeutic agent therein.

[0011] Figure 4 yes Figure 1 Schematic diagram of an ingestible capsule depicting the release of therapeutic agent from the chamber of the ingestible capsule as the microcapsules expand and the lid is removed.

[0012] Figure 5 is a schematic block diagram illustrating components of an ingestible capsule according to one aspect of the present disclosure.

[0013] Figure 6 is a block diagram depicting steps that a controller of an ingestible capsule is programmed to perform according to one aspect of the present disclosure.

[0014] Figure 7 is a perspective view of an ingestible capsule according to one aspect of the present disclosure.

[0015] Figure 8 yes Figure 7 A side partial cross-sectional view of a first portion of an ingestible capsule illustrating the interior of the chamber of the ingestible capsule and the microcapsules therein.

[0016] Figure 9 yes Figure 7 A side partial cross-sectional view of a first portion of an ingestible capsule illustrating the interior of the chamber of the ingestible capsule and the therapeutic agent therein.

[0017] Figure 10 yes Figure 7 Schematic diagram of an ingestible capsule depicting the release of therapeutic agent from the chamber of the ingestible capsule as the microcapsules expand and the lid is removed.

[0018] Figure 11 is a block diagram of a multi-stage analytical algorithm for controlling the release of a therapeutic agent according to one aspect of the present disclosure.

[0019] Figure 12 is a perspective view of an ingestible capsule according to one aspect of the present disclosure.

[0020] Figure 13 yes Figure 12 A side partial cross-sectional view of a first portion of an ingestible capsule illustrating the interior of the chamber of the ingestible capsule and the microcapsules therein.

[0021] Figure 14 yes Figure 12 Schematic diagram of an ingestible capsule depicting the release of therapeutic agent from the chamber of the ingestible capsule as the microcapsules expand and the lid is removed.

[0022] Figure 15 is a schematic diagram of an ingestible capsule according to one aspect of the present disclosure, depicting the release of a therapeutic agent from a chamber of the ingestible capsule upon expansion of the microcapsule and release of the cap.

[0023] Figure 16 is a schematic block diagram illustrating components of an ingestible capsule according to one aspect of the present disclosure.

[0024] Figure 17 is a side partial cross-sectional view of a first portion of an ingestible capsule according to one aspect of the present disclosure, showing the interior of the chamber.

[0025] Figure 18 is a schematic diagram of a portion of an ingestible capsule prior to release of a therapeutic agent according to one aspect of the present disclosure.

[0026] Figure 19 yes Figure 18 Schematic diagram of a portion of an ingestible capsule after release of the therapeutic agent.

[0027] Figure 20 is a perspective view of an ingestible capsule with gastric retaining arms in a non-deployed configuration according to one aspect of the present disclosure.

[0028] Figure 21 yes Figure 20 A perspective view of an ingestible capsule of FIG. 1 with the stomach-retaining arms in an expanded configuration. DETAILED DESCRIPTION

[0029] Unless otherwise specified, the terms "a," "an," and "the" used herein with respect to a described element include at least one or more of the described element, including combinations thereof. Furthermore, unless otherwise specified, the terms "or" and "and" refer to "and / or" and combinations thereof. "Substantially" means that the shape or structure of the described element need not have the mathematically exact shape or structure of the described element, but rather may have a shape or structure that would be considered by a person skilled in the art to typically or approximately have the shape or structure of the described element. As used herein, "patient" includes mammals, such as humans. The terms "top," "bottom," "upper," "lower," "above," "below," and "around" refer to the position or orientation of components as shown in the accompanying drawings. Terms such as "first," "second," and the like are used to distinguish one element from another and are not used in a quantitative sense unless otherwise specified. The term "plurality" includes two or more of the described components. Furthermore, when an element is referred to as being "on," "attached," "connected," "coupled," "in contact with," "connected to," "extending from," etc., the other element may be directly on, attached to, connected to, coupled to, in contact with, connected to, or extending from the other element, or intervening elements may be present. In contrast, when an element is referred to as, for example, being "directly on," "directly attached," "directly connected," "directly coupled," "directly in contact with," "in direct communication with," or "extending directly from" another element, there are no intervening elements present. An element positioned "adjacent" another element may have portions that overlap or underlie the adjacent element. As used herein, a "controller" may include a single controller or a plurality of controllers.

[0030] The present disclosure relates to an ingestible capsule that can be configured to release a therapeutic agent within the gastrointestinal tract (e.g., the stomach) based on an electrical trigger command to improve the medical condition of a patient suffering from the disease. The ingestible capsule can include a single chamber or multiple chambers for containing the therapeutic agent. It should be noted that any suitable aspects or features of an ingestible capsule having a single chamber can be included in an ingestible capsule having multiple chambers, and vice versa. Figures 1 to 5 Aspects of an ingestible capsule 10 having a single chamber are depicted. The ingestible capsule 10 can include a first portion 12 and a second portion 14. A chamber 16 can be disposed in the first portion 12, and capsule electronics 18 operably coupled to the chamber 16 can be disposed in the second portion 14.

[0031] In particular, the chamber 16 may include a microcapsule 20, which may include a heating wire 22 and a chemical substance 24 in communication with the heating wire 22, so that when the chemical substance is heated by the heating wire to produce gas, the chemical reaction begins. The heating wire can be any suitable electrically driven heating component. For example, the heating wire can be formed by a tightly coiled tungsten wire (or other wire, such as a nickel-chromium alloy or an iron compound) or other conductor that obtains a suitable temperature when an electric current flows through it. As another example, the heating wire can be a printed film component. Typically, between about 10 milliamperes (mA) and about 250 mA is the preferred current amount for activating the heating wire. The chemical substance around the heating wire can be any suitable chemical substance that can trigger a chemical reaction when heated by the heating wire. For example, the chemical substance can be a mixture of carbon, sulfur and potassium nitrate or similar chemicals. Typically, a chemical substance between about 0.5 milligrams (mg) and about 2.0 mg is the preferred amount of chemical substance for the chemical reaction. During the chemical reaction, gases such as carbon dioxide and / or nitrogen are produced. By containing the heated ingredients and chemicals within a microcapsule within a chamber, the compound / substance produced as a result of the chemical reaction can be trapped within the capsule and not released into the patient. The microcapsule can have an outer surface made of a gas permeable material or membrane (e.g., gas permeable polydimethylsiloxane (PDMS)) so that after inflation and ejection of the therapeutic agent payload (as described below), the microcapsule releases the gas produced during the chemical reaction and deflates while retaining any solid material from the chemical reaction within the microcapsule. Thus, such solid material is not released into the patient. Figure 3 As shown, chamber 16 may also include a therapeutic agent 26 disposed outside of the microcapsules. Specifically, the therapeutic agent may be disposed around and / or on top of the microcapsules. A cap 28 may be attached to chamber 16 and may be configured to releasably retain the therapeutic agent. In other words, the cap may retain the therapeutic agent within the chamber until the cap is commanded to be released, as described below.

[0032] Further references Figure 5, the capsule electronics 18, which may be a printed circuit board ("PCB"), may include a sensor 30 configured to detect a parameter and generate a sensor signal in response to the detection, and a controller 32 that may receive and process the sensor signal. The sensor may be any suitable sensor that can provide sensed data for determining whether the therapeutic agent should be released. Likewise, the parameter detected by the sensor may be any suitable parameter for making the same determination. The sensor may be, for example, an accelerometer, body temperature, light, photoplethysmography, voltage, electric field, magnetic field, voltammetry, force, capacitance, pressure, or a combination thereof. In certain aspects, the sensor is an accelerometer, including, for example, a 3-axis accelerometer or a 6-axis accelerometer. The parameter detected by the sensor may be, for example, an acceleration associated with movement of the ingestible capsule within the gastrointestinal tract. Further Reference Figure 6 Controller 32 may be in communication with the sensor and programmed to receive a sensor signal generated by the sensor at step 34 and, based on the sensor signal, identify or estimate a biomarker associated with the medical condition at step 36. The biomarker may be any suitable biomarker for determining whether the therapeutic agent should be released. For example, the biomarker may be heart rate, RR interval, heart rate variability, body movement, digestive tract movement, bowel movement, body posture, activity level, body temperature, body temperature variability, respiratory rate, respiratory depth, tidal volume, tissue oxygenation, SpO2, pH, the presence or absence of respiration, autonomic tone, or a combination thereof. In certain aspects, the biomarker is respiratory rate, heart rate, peristaltic motility level, systemic motor activity level, body temperature, or a combination thereof. In step 38, the controller may determine, based on the identification or estimation of step 36, whether a physiological activity characteristic of the medical condition has occurred. In certain aspects, the controller may determine whether the biomarker falls outside a threshold or range of a biomarker indicating that a physiological activity characteristic of the medical condition has occurred. The physiological activity may be any suitable event for determining whether the therapeutic agent should be released. For example, the physiological activity may be respiratory impairment, motor impairment, cardiac impairment, asphyxia, or a combination thereof. At step 40, the controller may electrically trigger the ejection of the therapeutic agent upon determining that physiological activity has occurred. Specifically, the controller may be programmed to electrically trigger the heating wire to generate sufficient heat to initiate a chemical reaction, thereby generating gas to expand the microcapsule to a sufficient size and configuration to remove the cover upon determining that physiological activity has occurred, thereby expelling the therapeutic agent from the chamber (e.g., Figure 4 The foregoing steps are non-exclusive, and the controller may be programmed to perform other additional steps.

[0033] Return Reference Figure 5, the controller 32 can be electrically coupled to the heating wire 22 via a wire / conductor 42. In this way, the heating wire 22 can be electrically triggered by the controller via a pair of wires / conductors 42a and 42b, which connect the heating wire of the chamber to the capsule electronics. An adhesive can be used to seal the ends of the wires / conductors in the microcapsule that are electrically coupled to the heating wire. The controller 32 can be powered by a power source 82, such as an internal battery. The electrical signal for generating heat in the heating field can be programmed by the controller, for example, based on a wireless command signal received by the integrated radio module 84, which is transmitted to the controller, or based on an algorithm that can use physiological data from the sensor 30 to determine that the therapeutic agent should be released when a specific clinical event or biomarker is detected as described above.

[0034] As mentioned above, the ingestible capsule may include multiple chambers, and embodiments of this configuration are described in Figures 7 to 10 . The ingestible capsule 44 has a first portion 46, a second portion 48 and a longitudinal axis X extending therethrough. A plurality of chambers 50 may be provided in the first portion 46 and radially arranged about the longitudinal axis X of the ingestible capsule. Figures 7 to 10 Seven chambers are shown arranged radially about the longitudinal axis of the ingestible capsule, but the ingestible capsule may include a different number of chambers and may have different chamber arrangements. For example, the number of chambers may range from 1 to 10, depending on the size of the desired therapeutic agent payload. Each chamber may be wedge-shaped and bend inwardly at the end of the first portion of the ingestible capsule, as shown. Figure 8 The best shown in FIG. 5 is to maximize volumetric efficiency while maintaining the dome-shaped ends of the capsule shell to maintain a standard form factor for a capsule suitable for swallowing. The standard form factor for an ingestible capsule can be 0.000 to 5.000.

[0035] Similar to the above-described embodiment, each of the plurality of chambers 50 may include a microcapsule 52 containing a heating wire and a chemical in communication with the heating wire such that when the chemical is heated by the heating wire to generate a gas, a chemical reaction begins. The chamber 50 may also include a therapeutic agent 54 disposed outside the microcapsule. The ingestible capsule may also include a plurality of lids 60, each lid being connected to a corresponding one of the plurality of chambers 50 and configured to releasably retain the therapeutic agent 54. The second portion 48 of the ingestible capsule 44 may include capsule electronics, which may include a sensor and a controller, similar to the sensors and controllers disclosed above. In particular, the sensor may be configured to detect a parameter and generate a sensor signal in response to the detection. The controller may be operably coupled to each of the plurality of chambers 50 and may be programmed to perform the steps described above. In particular, the controller can be programmed to receive a sensor signal; identify or estimate a biomarker associated with a medical condition based on the sensor signal; determine, based on the identification or estimation, whether a physiological activity characteristic of the medical condition has occurred; and electrically trigger the heating wire to generate heat sufficient to initiate a chemical reaction, thereby generating a gas to expand the corresponding microcapsule to a sufficient size and configuration, thereby removing the corresponding cover and thereby releasing the therapeutic agent from the corresponding one of the plurality of chambers (e.g., Figure 10 ) is ejected into the gastrointestinal tract. The foregoing steps are non-exclusive, and the controller can be programmed to perform other additional steps. The controller can be programmed to release a single therapeutic agent or multiple therapeutic agents, including multiple different types of therapeutic agents. The controller can also be programmed to release therapeutic agents of the same dose, different doses, or different release times. In some aspects, the controller can be programmed to independently and selectively release therapeutic agents from multiple chambers. For example, the controller can be programmed to independently and selectively release multiple doses of therapeutic agents from the gastrointestinal tract based on an electrical trigger command. In some aspects, the controller can be programmed to drive the release of therapeutic agents from multiple chambers based on a specific schedule.

[0036] In another embodiment, and with reference to Figures 12 to 15 The ingestible capsule 86 may include stacked sets of radially configured chambers 88 that can provide multiple (e.g., 14) independent doses of therapeutic agent 90. Each chamber may operate in a manner similar to that disclosed above, with packaged microcapsules 92 (e.g., Figure 13 As shown), the microcapsule 92 expands (as shown Figure 14 ) to separate the chamber cover 94 and release the therapeutic agent 90 from the chamber. In one embodiment, referring to Figure 5As microcapsule 92B expands and releases therapeutic agent 90B, chamber lid 94B can be hinged and remain attached to the outer surface defining chamber 88B along lid edge 96. This configuration can be advantageous because the lid does not completely detach from the outer surface of the capsule.

[0037] Reference Figure 11 Specific non-limiting embodiments of the ingestible capsule are disclosed, particularly the steps that a controller can be programmed to perform. The controller can collect raw data (e.g., parameters) 64 from one or more sensors and use an algorithm 62 to trigger the release of the therapeutic agent from the chamber. The collected raw data can be, for example, 3-axis accelerometer data and temperature data. The data passed between the steps of the algorithm 62 can include multi-channel or multivariate data.

[0038] In block 66, the sensor data may be filtered and / or preprocessed, for example by low-pass filtering the accelerometer data to isolate possible respiratory or cardiac events, or to allow for an assessment of motion. The accelerometer data may be filtered, for example, with a filter such as a 4th order Butterworth filter, for example, but not limited to, a bandpass filter with a passband of 0.1 Hz to 0.5 Hz to emphasize respiratory activity, a bandpass filter with a passband of 0.67 Hz to 3.33 Hz to emphasize cardiac activity, a bandpass filter with a passband of 0.1 Hz to 3.33 Hz to emphasize respiratory and cardiac activity, a low-pass filter with a cutoff frequency of 0.067 Hz to emphasize peristaltic motion, a bandpass filter with a passband of 0.067 Hz to 3.33 Hz to emphasize broad spectrum motion events, or combinations or variations thereof. The preprocessing in block 66 may also include downsampling, for example, from 25 Hz to 12.5 Hz, including downsampling after applying the low-pass filter, to save memory and processing time in later steps.

[0039] The pre-processed and / or raw sensor data may be transformed in block 68 to produce transformed data suitable for feature extraction. The transforms applied in block 68 may include one or more of the following combinations, but are not limited to: Fourier transforms, Hilbert transforms, wavelet transforms, empirical mode decomposition, autoregressive spectral determination, principal component analysis, or independent component analysis. For example, the pre-processed data in a frame of 0.5 second duration may be Hann windowed and subjected to a fast Fourier transform (FFT). For example, the FFT results for 30 seconds of data may be stored in a rolling buffer such that averaging over the buffer produces a continuously updated estimate of the periodogram.

[0040] The transformed data can be analyzed in box 70 to extract features suitable for physiological activity detection. For example, preprocessed and / or raw sensor data can be passed directly to box 70 for feature extraction, alternatively or additionally. The extracted features can be, for example, the location and significance of spectral peaks (i.e., the difference between a peak and its lowest adjacent valley), a flag indicating whether each peak is observed on multiple channels, and a flag indicating whether each peak is observed on the channel with the maximum total power. The extracted features can include one or more of the following or a combination thereof, but are not limited to: zero crossings; power spectrum; band power; spectral peak location; spectral peak width; spectral peak prominence; channel total power; consistency of spectral peaks between multiple channels; spectral consistency of peaks estimated with historical data; presence of harmonic frequency relationships between peaks; 1 / f, 1 / f 2 Or a power spectrum normalized to a decay curve; the alignment of the spectral peak positions with a priori expected frequency bands; or a combination thereof.

[0041] The features extracted in block 70 can be passed to one or more biomarker estimation algorithms in block 72; in some aspects, data from the previous steps can be passed directly to block 72. The estimated biomarkers can include, but are not limited to, respiratory rate, respiratory amplitude, heart rate, tidal volume, peristaltic motion level, whole-body activity level, body temperature, and autonomic tone. In some aspects, five biomarkers can be estimated in block 72: respiratory rate, by selecting the frequency of the most significant peak that occurs simultaneously in two or more channels after normalizing the 1 / f decay curve in the respiratory frequency band; heart rate, by selecting the frequency of the most significant peak that occurs simultaneously in two or more channels in the cardiac frequency band and that is not aligned with a harmonic of the respiratory peak; peristaltic motion level, by selecting the total power across channels in the peristaltic frequency band; overall motor activity level, by selecting the total broad-spectrum power across channels; and body temperature.

[0042] The biomarker estimates may be further smoothed or subjected to additional analysis; additionally or alternatively, in block 72, the biomarkers may be estimated from the features and other data using methods such as linear models, support vector machines, neural networks, convolutional neural networks, tree-based classification, decision tree models, or similar methods. In some aspects, respiratory rate and heart rate may be estimated using a neural network model whose input is the power spectrum of the accelerometer data and / or related features extracted in block 70, and which has been trained on individual or group data to provide respiratory rate and heart rate estimates that are consistent with measurements taken using traditional methods such as polysomnography. In another aspect, respiratory rate and heart rate may be estimated by first using a decision tree model to generate a quality score for each peak identified in the power spectrum using the features extracted in block 70, after which respiratory rate and heart rate may be determined from the peak with the highest quality score in the respiratory and cardiac bands, respectively.

[0043] The biomarkers estimated in block 72 may be passed to a physiological activity detection model in block 74; additionally or alternatively, physiological activity detection may utilize data passed directly from previous blocks. Detected physiological activity may include, but is not limited to, respiratory impairment including a lack of breathing, motor impairment including a lack of physical movement, cardiac impairment, apnea, or a combination thereof. Physiological activity detection may include, for example, rule-based respiratory impairment detection. For example, a respiratory impairment event may be detected if the respiratory rate estimated in block 72 remains below a threshold, such as 4 breaths per minute, for more than five consecutive minutes, while physical movement may be negligible. Additionally or alternatively, physiological activity detection may be performed in block 74 using, for example, a linear model, a support vector machine, a neural network, a convolutional neural network, a tree-based classification, a decision tree model, or the like. At block 76, physiological activity detection may trigger the initiation of a therapeutic agent; for example, detection of sustained respiratory impairment may trigger the release of a therapeutic agent.

[0044] In embodiments of an ingestible capsule having multiple chambers, the detection of physiological activity occurring in block 74 may trigger multiple releases of the therapeutic agent. For example, detection of respiratory impairment may trigger a first release of the therapeutic agent, after which the algorithm 62 continues to run, and subsequent detection of respiratory impairment may trigger additional releases of the therapeutic agent.

[0045] The output of one or more stages of the algorithm 62 can be stored, for example, in a multi-level memory module 78, implemented using devices such as FRAM, flash memory, dynamic RAM, or EEPROM. The multi-level memory module 78 can optimize memory usage efficiency; for example, the available memory can simultaneously hold one hour of raw data in a first rolling buffer, one day of transformed data in a second rolling buffer, and a complete record of feature extraction, biomarker estimation, physiological activity detection activity, and therapeutic agent initiation over a one-month device lifespan in a third rolling buffer.

[0046] The output of one or more stages of algorithm 62 can be provided to, for example, an external host via wireless telemetry protocol 80, which is implemented through communication between the controller and the integrated radio module. Telemetry 80 can include, for example, a real-time data stream or a data stream stored in a multi-stage storage module 78. The controller can also receive commands from the host, such as commands to modify parameters, models, thresholds, or portions of the algorithm used in algorithm 62; commands to deliver therapeutic agents; or commands to transmit raw sensor data, compressed biomarker data, or physiological activity detection data to the host. The external host can be a device such as, but not limited to, a smartphone, computer, tablet, or smartwatch. The external host can also use data obtained via telemetry 80 to perform training or optimization of models used in algorithm 62, for example. For example, the external host can train a neural network to estimate heart rate using feature extraction data from block 70 and a separate externally worn device (e.g., a Holter monitor), after which the trained neural network weights can be transmitted to the controller and the behavior of block 72 in algorithm 62 can be updated. In another example, an external host may use the data from box 66 to identify univariate or multivariate wavelets or empirical patterns that describe heartbeat or respiration, after which information describing the wavelets or empirical patterns may be transmitted to the controller and the behavior of box 68 in algorithm 62 may be updated.

[0047] In alternative embodiments, the algorithm 62 may be implemented in an ingestible capsule that does not have a drug delivery mechanism for monitoring, detection, or diagnostic purposes, or may be used to add monitoring, detection, or diagnostic capabilities to an ingestible capsule that has a drug delivery mechanism.

[0048] The embodiments disclosed above generally relate to an ingestible capsule in which sensed data obtained from a sensor can be processed by a controller to determine when to release a therapeutic agent to improve a medical condition. In certain aspects, the capsule electronics can include components for confirming that the therapeutic agent has been released, and if not, re-commanding the release of the therapeutic agent. For example, referring to Figure 16The capsule electronics 98 of the ingestible capsule 100 may include an impedance detection circuit comprising an impedance sensor 102 operatively coupled to a controller 104 and configured to measure the impedance of the heater filament 106 and generate an impedance signal based on the measurement. The controller 104 may be programmed to receive the impedance signal and determine whether the impedance value is below or above a predetermined threshold level, thereby determining whether the microcapsule has expanded and, therefore, whether the therapeutic agent has been ejected from the microcapsule 108. The controller may be programmed to re-command the release of the therapeutic agent upon determining that the impedance value is below the predetermined threshold. Specifically, when the heater filament 106 initiates a chemical reaction (when the chemical substance 110 is heated by the heater filament to generate gas), causing the microcapsule 108 to expand and release the therapeutic agent, the heater filament 106 may be damaged by the reaction force, resulting in an open circuit between the heater filament electrical connections 112a and 112b. The impedance sensor 102 can measure the resistance of the heating wire, and when the heating wire is intact, before receiving a command to release the therapeutic agent, the resistance of the heating wire can be measured, and if it is below a predetermined threshold (e.g., 20 ohms), the impedance sensor deems the heating wire intact. After the microcapsule is triggered to release the therapeutic agent and the heating wire is disconnected, the resistance can be measured at a value above a predetermined threshold (e.g., >100 kilo-ohms). Being able to use a sensor to confirm the actuation of the microcapsule (and therefore the release of the therapeutic agent) can provide additional safety and performance for the drug delivery system.

[0049] In one embodiment, referring to Figure 17The ingestible capsule can include a chamber 122 containing an optical sensor, comprising an LED 124 and a photodiode 126 electrically connected to a cable 128 that can interface with the capsule electronics of the ingestible capsule, particularly a controller. The optical sensor can be used to detect when a therapeutic agent is released from the chamber by measuring changes in the intensity of light received / sensed by the photodiode 126 when the LED 124 is illuminated. The controller can be programmed to: a) command the photodiode to sense the light intensity within the chamber; b) command the release of the therapeutic agent from the chamber; c) re-command the photodiode to re-sense the light intensity within the chamber; and d) re-command the release of the therapeutic agent from the chamber upon determining that the light intensity measurement from step a) is substantially the same as the light intensity measurement from step c). In particular, when the lid covering the chamber is intact and connected to the corresponding chamber, and the therapeutic agent is present in the chamber, the photodiode can measure a specific voltage that is correlated to the light intensity. After the therapeutic agent has been released and the lid has been opened / separated from the chamber, the voltage from the photodiode 126, which is proportional to the intensity of the reflected light from the LED 124, can change by an amount that exceeds a predetermined threshold. A command to sense the reflected light can be issued by the controller, and the photodiode voltage can be measured by the controller. After a specified interval after the controller has issued the therapeutic agent release command, the controller can confirm whether the therapeutic agent has actually been released by using the readings from the optical sensor. If the optical sensor does not detect a change, meaning the lid is not open and the therapeutic agent has not been released, another attempt to release the therapeutic agent can be commanded. Similar to Figure 16 The sensor described in Figure 17 The optical sensor shown can provide additional safety and performance capabilities to the drug delivery system to confirm that the therapeutic agent has been released when commanded. Other sensors such as, but not limited to, temperature sensors, thermal mass flow sensors, or capacitance sensors can also be used.

[0050] Reference Figure 18 and Figure 19 In one embodiment, a structure can be incorporated into the lid 114 of the ingestible capsule and attached to or near the heater wire 116, such as a tab 118 of the lid 114 that projects inwardly toward the heater wire 116 or its electrical connectors 120a and 120b and is molded around or hooked around the structure so that conductivity through the heater wire 116 is broken when the lid has been sufficiently opened to deliver the therapeutic agent 122. This capability can provide additional certainty that the therapeutic agent has been released, as well as enhance the ability of the electrical sensor to detect or confirm release, without requiring additional conductors to be routed from the capsule electronics to the first portion of the ingestible capsule.

[0051] In one embodiment, referring to Figures 20 to 21, the ingestible capsule 130 may further include a gastric retention arm 132, as described in U.S. Provisional Application No. 63 / 327,108, filed on April 4, 2022, which is incorporated herein by reference in its entirety. Figure 20 shows the configuration of the ingestible capsule when the stomach retaining arms are not deployed, Figure 21 The configuration of the ingestible capsule is shown when the stomach retaining arms are deployed.

[0052] The ingestible capsules disclosed herein can be applied to a variety of indications where it is desired to deliver, for example, a single dose of a therapeutic agent or multiple doses of a therapeutic agent at a specific time based on, for example, user input or based on detection of a clinically relevant event requiring intervention. Table 1 provides non-limiting indications and treatment methods for the ingestible capsules disclosed herein.

[0053] Table I

[0054]

[0055]

[0056]

[0057] Each disclosed aspect and embodiment of the present disclosure may be considered individually or in combination with other aspects, embodiments and variations of the present disclosure. In addition, although certain features of the embodiments and aspects of the present disclosure may only be shown in certain drawings or otherwise described in certain parts of the present disclosure, these features may be incorporated into other embodiments and aspects shown in other drawings or other parts of the present disclosure. Similarly, certain features of the embodiments and aspects of the present disclosure shown in certain drawings or described in certain parts of the present disclosure may be optional or deleted from these embodiments and aspects. In addition, when a range is described, all points within the range are included in the present disclosure. In addition, unless otherwise stated, the steps of the method of the present disclosure are not limited to any particular order of execution. In addition, all references cited herein are incorporated by reference in their entirety.

Claims

1. An ingestible capsule for improving a medical condition in a patient suffering from an illness, the ingestible capsule having a first portion and a second portion, and comprising: A chamber provided in the first portion comprises: a microcapsule having an outer surface and comprising a heating filament and a chemical substance in communication with the heating filament such that when the chemical substance is heated by the heating filament, a chemical reaction occurs to produce a gas; and a therapeutic agent disposed on the exterior of the microcapsule; a cap coupled to the chamber and capable of releasably retaining the therapeutic agent; and The capsule electronic components provided in the second part include: a sensor capable of detecting a parameter and generating a sensor signal in response to said detection; and A controller is operatively coupled to the chamber and is programmed to: receiving the sensor signal; identifying or estimating a biomarker associated with the medical condition based on the sensor signal; Based on the identification or estimation, determining whether a physiological activity characteristic of the medical condition has occurred; and When it is determined that the physiological activity characteristic has occurred, the heating wire is energized to generate heat sufficient to initiate the chemical reaction, thereby generating the gas to expand the microcapsule to a size and configuration sufficient to remove the lid, thereby ejecting the therapeutic agent from the chamber into the gastrointestinal tract.

2. The ingestible capsule according to claim 1, wherein The sensors include accelerometers, body temperature, light, photoplethysmography, voltage, electric field, magnetic field, voltammetry, force, capacitance, pressure, or a combination thereof.

3. The ingestible capsule of claim 1, wherein The sensor includes an accelerometer sensor.

4. The ingestible capsule according to claim 3, wherein The accelerometer sensor includes a 3-axis accelerometer sensor or a 6-axis accelerometer sensor.

5. The ingestible capsule of claim 1, wherein The parameter is the acceleration associated with the movement of the capsule within the gastrointestinal tract.

6. The ingestible capsule of claim 1, wherein The biomarker is heart rate, RR interval, heart rate variability, body movement, gastrointestinal movement, intestinal movement, body posture, activity level, sleep stage, body temperature, body temperature variability, respiratory rate, respiratory depth, tidal volume, tissue oxygenation, SpO2, pH, presence or absence of breathing, autonomic tone, or a combination thereof.

7. The ingestible capsule of claim 1, wherein: The biomarker is respiratory rate, heart rate, peristaltic motion level, whole body motion level, body temperature, or a combination thereof.

8. The ingestible capsule of claim 1, wherein The physiological events include respiratory injury, sports injury, cardiac injury, asphyxia, or a combination thereof.

9. The ingestible capsule of claim 1, wherein: The controller is programmed to determine whether the biomarker falls outside a threshold or range for the biomarker indicated by a physiological activity characteristic of the medical condition.

10. The ingestible capsule of claim 1, wherein At least a portion of the outer surface of the microcapsule comprises a gas permeable material or film.

11. The ingestible capsule of claim 1 , further comprising an impedance detection circuit operatively coupled to the controller for measuring the impedance of the heating wire and generating an impedance signal.

12. The ingestible capsule of claim 11, wherein The controller is programmed to receive the impedance signal and determine whether the impedance value is below or above a predetermined threshold level to determine whether the microcapsule has expanded and thus determine whether the therapeutic agent has been ejected from the microcapsule.

13. The ingestible capsule of claim 12, wherein: The controller is programmed to re-command release of the therapeutic agent upon determining that the impedance value is below the predetermined threshold.

14. The ingestible capsule of claim 1, further comprising a photodiode and a light emitting diode (LED), the photodiode for sensing an intensity of light received by the photodiode when the LED emits light.

15. The ingestible capsule of claim 14, wherein The controller is programmed to: a) commanding the photodiode to sense the light intensity within the chamber; b) commanding release of the therapeutic agent from the chamber; c) re-commanding the photodiode to re-sense the light intensity in the chamber; as well as d) upon determining that the light intensity measurement from step a) is substantially the same as the light intensity measurement from step c), re-commanding release of the therapeutic agent from the chamber.

16. An ingestible capsule for improving a medical condition in a patient, the ingestible capsule having a first portion, a second portion, and a longitudinal axis extending therethrough, the ingestible capsule comprising: a plurality of chambers disposed in the first portion and radially arranged about the longitudinal axis of the ingestible capsule, each chamber comprising: a microcapsule having an outer surface and comprising a heating filament and a chemical substance in communication with the heating filament, such that when the chemical substance is heated by the heating filament, a chemical reaction occurs to produce a gas; and a therapeutic agent disposed on the exterior of the microcapsule; a plurality of covers, each cover coupled to a respective one of the plurality of chambers and configured to releasably retain the therapeutic agent; and The capsule electronic components provided in the second part include: a sensor configured to detect a parameter and generate a sensor signal in response to the detection; and a controller operatively coupled to each of the plurality of chambers and programmed to: receiving the sensor signal; identifying or estimating a biomarker associated with the medical condition based on the sensor signal; Based on the identification or estimation, determining whether a physiological activity characteristic of the medical condition has occurred; and The heating wire is energized to generate heat sufficient to initiate the chemical reaction, thereby generating the gas to expand the corresponding microcapsule to a size and configuration sufficient to remove the corresponding lid, thereby ejecting the therapeutic agent from each of the plurality of chambers into the gastrointestinal tract when it is determined that the event has occurred.

17. The ingestible capsule of claim 16, wherein The controller is programmed to command the independent and selective release of the therapeutic agent from each of the plurality of chambers.

18. The ingestible capsule of claim 16, wherein The dosage and / or type of the therapeutic agent in at least one chamber of the plurality of chambers is different from the dosage and / or type of the therapeutic agent in at least another chamber of the plurality of chambers.

19. The ingestible capsule of claim 16, wherein: The controller is programmed to control the timing of release of the therapeutic agent from at least one of the plurality of chambers to be different from the timing of release of the therapeutic agent from at least another of the plurality of chambers.

20. The ingestible capsule of claim 16, wherein The controller is programmed to control the release of the therapeutic agent from the plurality of chambers based on a specific schedule.

21. The ingestible capsule of claim 16, wherein: At least a portion of the outer surface of the microcapsule comprises a gas permeable material or film.

22. The ingestible capsule of claim 16, wherein Each of the plurality of covers is hingedly attached to a corresponding chamber of the plurality of chambers and is configured to releasably retain the therapeutic agent.

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