Classifications

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Definitions

• TECHNICAL FIELD This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with an integrin inhibitor (e.g., an integrin cufr inhibitor).
• an integrin inhibitor e.g., an integrin cufr inhibitor.
• Integrins are proteins that function by attaching the cell cytoskeleton to the extracellular matrix (ECM). Integrins can also sense whether adhesion has occurred and transduce a signal to the interior of the cell.
• the integrin family of proteins consists of a variety of alpha and beta subtypes, which together form transmembrane heterodimers.
• One type of integrin heterodimer is the cufr integrin heterodimer.
• the gastrointestinal (GI) tract generally provides a therapeutic medium for an individual's body.
• therapeutic drugs may need to be dispensed to specified locations within the small intestine or large intestine, which is more effective than oral administration of the therapeutic drugs to cure or alleviate the symptoms of some medical conditions.
• therapeutic drugs dispensed directly within the small intestine would not be contaminated, digested or otherwise compromised in the stomach, and thus allow a higher dose to be delivered at a specific location within the small intestine.
• dispensing therapeutic drugs directly within the small intestine inside a human body can be difficult, because a device or mechanism (e.g., special formulation) would be needed to transport a therapeutically effective dose of drug to a desired location within the small intestine and then automatically deliver the therapeutic drug at the desired location.
• a device or mechanism e.g., special formulation
• Dispensing therapeutic drugs directly within other locations in the GI tract of the human body can be similarly difficult.
• Such a device or mechanism also would also need to be operated in a safe manner in that the device or mechanism needs to physically enter the human body.
• IBD inflammatory bowel disease
• the present disclosure provides novel treatment paradigms for inflammatory conditions of the gastrointestinal tract.
• the methods and compositions described herein allow for the regio-specific release of therapeutic drugs at or near the site of disease in the gastrointestinal tract.
• a therapeutic drug By releasing a therapeutic drug locally instead of systemically, the bioavailability of the drug can be increased at the site of injury and/or decreased in the systemic circulation, thereby resulting in improved overall safety and/or efficacy and fewer adverse side effects.
• Advantages may include one or more of increased drug engagement at the target, leading to new and more efficacious treatment regimens, and/or lower systemic drug levels, which can translate to reduced toxicity and reduced immunogenicity, e.g., in the case of biologies.
• releasing a therapeutic drug locally also provides for new modes of action that may be unique to local delivery in the GI tract as opposed to systemic administration. For patients, clinicians and payors, this can mean an easier or simpler route of administration, fewer co-medicaments (e.g., immunomodulators), fewer side effects, and/or better outcomes.
• co-medicaments e.g., immunomodulators
• the methods can include one or more of:
• GI disease in the GI tract of a subject and/or mapping, sampling, and/or assessing a patient response to a therapeutic agent, e.g., in the patient's GI tract; and/or
• GI disease in the GI tract of the subject and/or one or more markers of patient response to a therapeutic agent, e.g., in the patient's GI tract;
• a therapeutic agent e.g., proximate to the site of a GI disease.
• the present disclosure accordingly provides patients and physicians more
• personalized treatment options for GI disorders by facilitating regimens which can release a therapeutic agent according to desired (e.g., customized or optimized) dosage, timing, and/or location parameters.
• the treatment methods can employ one or more ingestible devices to achieve the benefits disclosed herein.
• a method of treating a disease of the gastrointestinal tract in a subject comprising:
• the pharmaceutical formulation is released at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.
• the pharmaceutical formulation is
• the pharmaceutical formulation is released from an ingestible device.
• the ingestible device comprises a housing, a reservoir containing the pharmaceutical formulation, and a release mechanism for releasing the pharmaceutical formulation from the device,
• the reservoir is releasably or permanently attached to the exterior of the housing or internal to the housing.
• a method of treating a disease of the gastrointestinal tract in a subject comprising:
• an ingestible device comprising a housing, a reservoir containing a pharmaceutical formulation, and a release mechanism for releasing the pharmaceutical formulation from the device
• the reservoir is releasably or permanently attached to the exterior of the housing or internal to the housing;
• the pharmaceutical formulation comprises an integrin inhibitor
• the ingestible device releases the pharmaceutical formulation at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.
• the housing is non-biodegradable in the GI tract.
• the release of the formulation is triggered autonomously.
• the device is programmed to release the formulation with one or more release profiles that may be the same or different at one or more locations.
• the device is programmed to release the formulation at a location proximate to one or more sites of disease.
• the location of one or more sites of disease is predetermined.
• the reservoir is made of a material that allows the formulation to leave the reservoir, such as a biodegradable material.
• the release of the formulation is triggered by a preprogrammed algorithm. In some embodiments, the release of the formulation is triggered by data from a sensor or detector to identify the location of the device. In some more particular embodiments, the data is not based solely on a physiological parameter (such as pH, temperature, and/or transit time).
• a physiological parameter such as pH, temperature, and/or transit time
• the device comprises a detector configured to detect light reflectance from an environment external to the housing.
• the release is triggered autonomously or based on the detected reflectance.
• the device releases the formulation at substantially the same time as one or more sites of disease are detected.
• the one or more sites of disease are detected by the device (e.g., by imaging the GI tract).
• the release mechanism is an actuation system. In some embodiments, the release mechanism is a chemical actuation system. In some embodiments, the release mechanism is a mechanical actuation system. In some embodiments, the release mechanism is an electrical actuation system. In some embodiments, the actuation system comprises a pump and releasing the formulation comprises pumping the formulation out of the reservoir. In some embodiments, the actuation system comprises a gas generating cell. In some embodiments, the device further comprises an anchoring mechanism. In some embodiments, the formulation comprises a therapeutically effective amount of the integrin inhibitor. In some embodiments, the formulation comprises a human equivalent dose (HED) of the integrin inhibitor.
• HED human equivalent dose
• the device is a device capable of releasing a solid integrin inhibitor or a solid formulation comprising the integrin inhibitor. In some embodiments, the device is a device capable of releasing a liquid integrin inhibitor or a liquid formulation comprising the integrin inhibitor. Accordingly, in some embodiments of the methods herein, the pharmaceutical formulation release from the device is a solid formulation. Accordingly, in some embodiments of the methods herein, the pharmaceutical formulation release from the device is a liquid formulation.
• the devices disclosed herein are capable of releasing a integrin inhibitor or a formulation comprising the integrin inhibitor irrespective of the particular type of integrin inhibitor.
• the integrin inhibitor may be a small molecule, a biological, a nucleic acid, an antibody, a fusion protein, and so on.
• provided herein is a method of releasing an integrin inhibitor into the gastrointestinal tract of a subject for treating one or more sites of disease within the gastrointestinal tract, the method comprising:
• ingestible device comprises
• a detector configured to detect the presence of the one or more sites of disease
• a controller or processor configured to trigger the release of the integrin inhibitor proximate to the one or more sites of disease in response to the detector detecting the presence of the one or more sites of disease.
• a method of releasing an integrin inhibitor into the gastrointestinal tract of a subject for treating one or more pre-determined sites of disease within the gastrointestinal tract comprising:
• ingestible device comprises
• a detector configured to detect the location of the device within the gastrointestinal tract
• controller or processor configured to trigger the release of the integrin inhibitor proximate to the one or more predetermined sites of disease in response to the detector detecting a location of the device that corresponds to the location of the one or more predetermined sites of disease.
• provided herein is a method of releasing an integrin inhibitor into the gastrointestinal tract of a subject for treating one or more sites of disease within the gastrointestinal tract, the method comprising:
• provided herein is a method of releasing an integrin inhibitor into the gastrointestinal tract of a subject for treating one or more sites of disease within the gastrointestinal tract, the method comprising:
• a disease of the gastrointestinal tract in a subject comprising:
• the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor.
• a disease of the large intestine in a subject comprising:
• the method comprises administering endoscopically to the subject a therapeutically effective amount of the integrin inhibitor.
• a disease of the gastrointestinal tract in a subject comprising:
• the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor.
• a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor.
• the method comprises administering to the subj ect a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor, wherein the pharmaceutical composition is an ingestible device, and the method comprises administering orally to the subject the pharmaceutical composition.
• a disease of the gastrointestinal tract in a subject comprising:
• the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the integrin inhibitor, wherein the method provides a concentration of the integrin inhibitor in the plasma of the subject that is less than 3 ⁇ g/ml.
• a disease of the large intestine in a subject comprising:
• the method comprises administering endoscopically to the subject a therapeutically effective amount of the integrin inhibitor.
• an integrin inhibitor for use in a method of treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the integrin inhibitor, wherein the integrin inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease
• the present invention provides a composition comprising or consisting of an ingestible device loaded with a therapeutically effective amount of an integrin inhibitor, for use in a method of treatment, wherein the method comprises orally administering the composition to the subject, wherein the integrin inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.
• the present invention provides an ingestible device loaded with a therapeutically effective amount of an integrin inhibitor, wherein the device is controllable to release the integrin inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.
• the device may be for use in a method of treatment of the human or animal body, for example, any method as described herein.
• the present invention provides an ingestible device for use in a method of treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject the ingestible device loaded with a
• an integrin inhibitor wherein the integrin inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.
• An ingestible device as used in the present invention may comprise one or more mechanical and/or electrical mechanisms which actively control release of the integrin inhibitor.
• the ingestible device as used in the present invention may comprise a release mechanism for release of the integrin inhibitor (e.g., from a reservoir comprising the integrin inhibitor) and an actuator controlling the release mechanism.
• the ingestible device comprises:
• an ingestible housing comprising a reservoir having a therapeutically effective amount of the integrin inhibitor stored therein;
• a release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin inhibitor from the reservoir to the exterior of the device;
• the ingestible device comprises:
• a housing defined by a first end, a second end substantially opposite from the first end;
• a reservoir located within the housing and containing the integrin inhibitor wherein a first end of the reservoir is attached to the first end of the housing;
• the exit valve can be considered as the release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin inhibitor from the reservoir to the exterior of the device, and the mechanism for releasing the integrin inhibitor from the reservoir can be considered as the actuator.
• the one or more disease sites may have been pre-determined (e.g., determined in a step preceding the administration of the composition of the present invention).
• the disease site(s) may have been determined by imaging the gastrointestinal tract.
• the disease site(s) may have been pre-determined by endoscopy (e.g., a step of colonoscopy, enteroscopy, or using a capsule endoscope). Determination that the device is proximate to the disease site may therefore comprise a determining that the device is in a location corresponding to this previously-determined disease site.
• the location of the device in the gut may be detected by tracking the device.
• the device may comprise a localization mechanism which may be a communication system for transmitting localization data, e.g., by radiofrequency transmission.
• the device may additionally or alternatively comprise a communication system for receiving a signal remotely triggering the actuator and thus causing release of the integrin inhibitor. The signal may be sent when it is determined that the device is in the correct location in the gut.
• the ingestible device may comprise:
• an ingestible housing comprising a reservoir having a therapeutically effective amount of the integrin inhibitor stored therein;
• a release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin inhibitor from the reservoir to the exterior of the device;
• a communication system for transmitting localization data to an external receiver and for receiving a signal from an external transmitter
• an actuator which changes the state of the release mechanism from the closed to the open state and which can be triggered by the signal.
• the ingestible device as used in the present invention may comprise an environmental sensor for detecting the location of the device in the gut and/or for detecting the presence of disease in the GI tract.
• the environment sensor may be an image sensor for obtaining images in vivo.
• Detecting the presence of disease may comprise, for example, detecting the presence of inflamed tissue, and/or lesions such as ulceration e.g., aphthoid ulcerations, "punched-out ulcers" and/or superficial ulcers of the mucosa, cobblestoning, stenosis, granulomas, crypt abscesses, fissures, e.g., extensive linear fissures, villous atrophy, fibrosis, and/or bleeding.
• ulceration e.g., aphthoid ulcerations, "punched-out ulcers" and/or superficial ulcers of the mucosa, cobblestoning, stenosis, granulomas, crypt abscesses, fissures, e.g., extensive linear fissures, villous atrophy, fibrosis, and/or bleeding.
• Detecting the presence of disease may also comprise molecular sensing, such as detecting the amount of an inflammatory cytokine or other marker of inflammation. Such a marker can be measured locally from a biopsy or systemically in the serum.
• actuation of the release mechanism may be triggered by a processor or controller communicably coupled to the environmental sensor.
• the device may not require any external signal or control in order to release the drug.
• the ingestible device may comprise:
• an ingestible housing comprising a reservoir having a therapeutically effective amount of the integrin inhibitor stored therein;
• a release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin inhibitor from the reservoir to the exterior of the device;
• a detector for detecting the location of the device in the gut and/or the presence of diseased tissue
• a processor or controller which is coupled to the detector and to the actuator and which triggers the actuator to cause the release mechanism to transition from its closed state to its open state when it is determined that the device is in the presence of diseased tissue and/or in a location in the gut that has been predetermined to be proximal to diseased tissue.
• an ingestible housing comprising a reservoir having a therapeutically effective amount of the integrin inhibitor stored therein;
• a detector coupled to the ingestible housing, the detector configured to detect when the ingestible housing is proximate to a respective disease site of the one of the one or more sites of disease;
• valve system in fluid communication with the reservoir system; and a controller communicably coupled to the valve system and the detector, the controller configured to cause the valve system to open in response to the detector detecting that the ingestible housing is proximate to the respective disease site so as to release the therapeutically effective amount of the integrin inhibitor at the respective disease site.
• detection that the ingestible housing is proximate to the respective disease site may be based on environmental data indicating the location of the device in the GI tract (and reference to a pre-determined disease site) or on environmental data directly indicating the presence of diseased tissue.
• the device may further comprise a communication system adapted to transmit the environment data to an external receiver (e.g., outside of the body).
• This data may be used, for example, for diagnostic purposes.
• the external receiver may comprise means for displaying the data.
• this data may be analyzed externally to the device and used to determine when the drug should be released: an external signal may then be sent to the device to trigger release of the drug.
• the communication system may further be adapted to receive a signal remotely triggering the actuator and thus causing release of the integrin inhibitor.
• the signal may be sent from an external transmitter in response to receipt/analysis and/or assessment of the environmental data, e.g., data indicating that the device has reached the desired location of the gut (where the location of the diseased tissue has been pre- determined) and/or data indicating the presence of diseased tissue.
• “External" may be "outside of the body”.
• the ingestible device may comprise:
• an ingestible housing comprising a reservoir having a therapeutically effective amount of the integrin inhibitor stored therein;
• a release mechanism having a closed state which retains the integrin inhibitor in the reservoir and an open state which releases the integrin inhibitor from the reservoir to the exterior of the device;
• an environmental detector for detecting environmental data indicating the location of the device in the gut and/or the presence of diseased tissue
• a communication system for transmitting the environmental data to an external receiver and for receiving a signal from an external transmitter
• the device comprises one or more environmental detectors, e.g., comprises an image detector
• the compositions may be used both for disease detection and for disease treatment.
• an integrin inhibitor for use in a method of detecting and treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the integrin inhibitor, wherein the ingestible device comprises an environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the integrin inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, as detected by the environmental sensor.
• the device may be according to any of the embodiments described herein.
• compositions for use in a method of detecting and treating a disease of the gastrointestinal tract in a subject comprising or consists of an ingestible device loaded with a therapeutically effective amount of an integrin inhibitor, wherein the ingestible device comprises an environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the integrin inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, as detected by the environmental sensor.
• the device may be according to any of the embodiments described herein.
• the method of treatment may comprise:
• ii) assessing the environmental data to confirm the presence of the disease; and iii) when the presence of the disease is confirmed, sending from an external transmitter to the ingestible device a signal triggering release of the integrin inhibitor.
• the presence of disease may be confirmed based on the presence of inflamed tissue and/or lesions associated with any of the disease states referred to herein.
• the presence of disease may be confirmed based on the presence of inflammation, ulceration e.g., aphthoid ulcerations, "punched-out ulcers" and/or superficial ulcers of the mucosa, cobblestoning, stenosis, granulomas, crypt abscesses, fissures, e.g., extensive linear fissures, villous atrophy, fibrosis, and/or bleeding.
• the present invention may relate to a system comprising: an ingestible device loaded with a therapeutically effective amount of an integrin inhibitor, a release mechanism for release of the integrin inhibitor (e.g., from a reservoir comprising the integrin inhibitor), an actuator controlling the release mechanism, an environmental sensor for determining the location of the device in the gut and/or for detecting the presence of diseased tissue and a communication system adapted to transmit the environment data and receive a signal triggering the actuator;
• a receiver and display module for receiving and displaying outside of the body the environment data from the ingestible device
• a transmitter for sending to the ingestible device a signal triggering the actuator.
• the ingestible device may further comprise an anchoring system for anchoring the device or a portion thereof in a location and an actuator for the anchoring system. This may be triggered in response to a determination that the device is at a location in the gastrointestinal tract of the subject proximate to one or more sites of disease. For instance, this may be detected by the environmental sensor.
• the triggering may be controlled by a processor in the device, that is, autonomously.
• a device where the triggering is controlled by a processor in the device is said to be an autonomous device. Alternatively, it may be controlled by a signal sent from outside of the body, as described above.
• disease of the GI tract may be an inflammatory bowel disease.
• the disease of the GI tract is ulcerative colitis.
• the disease of the GI tract is Crohn's disease.
• gastrointestinal tract diseases that can be treated include, without limitation, inflammatory bowel disease (IBD), Crohn's disease (e.g., active Crohn's disease, refractory Crohn's disease, or fistulizing Crohn's disease), ulcerative colitis, indeterminate colitis, microscopic colitis, infectious colitis, drug or chemical-induced colitis, diverticulitis, and ischemic colitis, gastritis, peptic ulcers, stress ulcers, bleeding ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, short-bowel (anastomosis) syndrome, a hypersecretory state associated with systemic mastocytosis or basophilic leukemia or hyperhistaminemia, Celiac disease (e.g., nontropical Sprue), enteropathy associated with IBD
• Crohn's disease e.g., active Crohn's disease, refractory Crohn'
• gastroenteritis colitis associated with radiotherapy or chemotherapy
• colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency- 1 chronic granulomatous disease
• food allergies gastritis, infectious gastritis or enterocolitis (e.g., Helicobacter pylori- infected chronic active gastritis), other forms of gastrointestinal inflammation caused by an infectious agent, pseudomembranous colitis, hemorrhagic colitis, hemolytic-uremic syndrome colitis, diversion colitis, irritable bowel syndrome, irritable colon syndrome, and pouchitis.
• apparatuses, compositions, and methods disclosed herein are used to treat one gastrointestinal disease. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat more than one gastrointestinal disease. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat multiple gastrointestinal diseases that occur in the same area of the gastrointestinal tract (e.g., each disease can occur in the small intestine, large intestine, colon, or any sub-region thereof). In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat multiple gastrointestinal diseases that occur in different areas of the
• administration e.g., local administration to the gastrointestinal tract
• administration of integrin inhibitor is useful in the treatment of gastrointestinal diseases including, but not limited to, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, or any of the other gastrointestinal diseases described herein.
• IBD inflammatory bowel disease
• ulcerative colitis Crohn's disease
• Crohn's disease or any of the other gastrointestinal diseases described herein.
• any details or embodiments described herein for methods of treatment apply equally to an integrin inhibitor, composition or ingestible device for use in said treatment.
• Any details or embodiments described for a device apply equally to methods of treatment using the device, or to an integrin inhibitor or composition for use in a method of treatment involving the device.
• FIG. 1 is a view of an example embodiment of an ingestible device, in accordance with some embodiments of the disclosure
• FIG. 2 is an exploded view of the ingestible device of FIG. 1, in accordance with some embodiments of the disclosure
• FIG. 3 is a diagram of an ingestible device during an example transit through a GI tract, in accordance with some embodiments of the disclosure
• FIG. 4 is a diagram of an ingestible device during an example transit through a jejunum, in accordance with some embodiments of the disclosure
• FIG. 5 is a flowchart of illustrative steps for determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure
• FIG. 6 is a flowchart of illustrative steps for detecting transitions from a stomach to a duodenum and from a duodenum back to a stomach, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 7 is a plot illustrating data collected during an example operation of an ingestible device, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 8 is another plot illustrating data collected during an example operation of an ingestible device, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 9 is a flowchart of illustrative steps for detecting a transition from a duodenum to a jejunum, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 10 is a plot illustrating data collected during an example operation of an ingestible device, which may be used when detecting a transition from a duodenum to a jejunum, in accordance with some embodiments of the disclosure;
• FIG. 11 is a plot illustrating muscle contractions detected by an ingestible device over time, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 12 is a flowchart of illustrative steps for detecting a transition from a jejenum to an ileum, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 13 is a flowchart of illustrative steps for detecting a transition from a jejenum to an ileum, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure
• FIG. 14 is a flowchart of illustrative steps for detecting a transition from an ileum to a cecum, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 15 is a flowchart of illustrative steps for detecting a transition from a cecum to a colon, which may be used when determining a location of an ingestible device as it transits through a GI tract, in accordance with some embodiments of the disclosure;
• FIG. 16 illustrates an ingestible device for delivering a substance in the GI tract
• FIG. 17 illustrates aspects of a mechanism for an ingestible device with a gas generating cell configured to generate a gas to dispense a substance
• FIG. 18 illustrates an ingestible device having a piston to push for drug delivery
• FIG. 19 illustrates an ingestible device having a bellow structure for a storage reservoir of dispensable substances
• FIG. 20 illustrates an ingestible device having a flexible diaphragm to deform for drug delivery
• FIG. 21 shows an illustrative embodiment of an ingestible device with multiple openings in the housing
• FIG. 22 shows a highly cross-section of an ingestible device including a valve system and a sampling system
• FIG. 23 illustrates a valve system
• FIGs. 24A and 24B illustrate a portion of a two-stage valve system in its first and second stages, respectively;
• FIGs. 25A and 25B illustrate a portion of a two-stage valve system in its first and second stages, respectively;
• FIGs. 26A and 26B illustrate a portion of a two-stage valve system in its first and second stages, respectively;
• FIG. 27 illustrates a more detailed view of an ingestible device including a valve system and a sampling system
• FIG. 28 illustrates a portion of an ingestible device including a sampling system and a two-stage valve system in its second stage;
• FIG. 29 is a highly schematic illustrate of an ingestible device.
• FIG. 30 is a graph showing the percentage (%) change in body weight at day 14 ( ⁇ SEM) for DSS mice treated with anti-IL-12 p40 antibody intraperitoneally (10 mg/kg) every third day (Q3D) or intracecally (10 mg/kg or 1 mg/kg) daily (QD), when compared to mice treated with anti-IL-12 p40 antibody intraperitoneally (10 mg/kg) every third day (Q3D) and vehicle control (Vehicle). Mann-Whitney's U -1 - test and Student's t-test were used for statistical analysis on non-Gaussian and Gaussian data respectively. A value of p ⁇ 0.05 was considered significant (Graph Pad Software, Inc.).
• FIG. 31 is a graph showing the concentration of anti-IL-12 p40 rat IgG2A ⁇ g/mL) in plasma of anti-IL-12 p40 intraperitoneally (10 mg/kg) and intracecally (10 mg/kg and 1 mg/kg) administered treatment groups given daily (QD) or every third day (Q3D) when compared to vehicle control (Vehicle) and when IP is compared to IC.
• ELISA analysis was used to determine the concentration of anti-IL-12 p40 (IgG2A). Data presented as mean ⁇ SEM. Mann-Whitney's U -1 - test and Student's t-test were used for statistical analysis on non- Gaussian and Gaussian data respectively. A value of p ⁇ 0.05 was considered significant (Graph Pad Software, Inc.).
• FIG. 32 is a graph showing the concentration of anti-IL-12 p40 antibody (IgG2A) ⁇ g/mL) in the cecum and colon content of anti-IL-12 p40 antibody intraperitoneally (10 mg/kg) and intracecally (10 mg/kg and 1 mg/kg) administered treatment groups given daily (QD) or every third day (Q3D), when compared to vehicle control (Vehicle) and when IP is compared to IC.
• ELISA analysis was used to determine the concentration of rat IgG2A. Data presented as mean ⁇ SEM. Mann-Whitney's U- test and Student's t-test were used for statistical analysis on non-Gaussian and Gaussian data respectively. A value ⁇ ⁇ 0.05 was considered significant (Graph Pad Software, Inc.).
• FIG. 33 is a graph showing the mean overall tissue immunolabel scores (intensity and extent) in acute DSS colitis mouse colon of anti-IL-12 p40 antibody intracecally -treated versus vehicle control-treated DSS mice. Data presented as mean ⁇ SEM.
• FIG. 34 is a graph showing the mean location-specific immunolabel scores in acute DSS colitis mouse colon of anti-IL-12 p40 intracecally -treated versus vehicle control-treated DSS mice. Data presented as mean ⁇ SEM. Mann-Whitney's U- test and Student's t-test were used for statistical analysis on non-Gaussian and Gaussian data respectively. A value of p ⁇ 0.05 was considered significant (Graph Pad Software, Inc.).
• FIG. 35 is a graph showing the ratio of anti-IL-12 p40 antibody in the colon tissue to the plasma concentration of the anti-IL-12 p40 antibody in mice treated with the anti-IL-12 p40 antibody on day 0 (Q0) or day 3 (Q3D) of the study, when measured at the same time point after the initial dosing. An outlier animal was removed from Group 5.
• FIG. 36 is a graph showing the concentration of 11-1 ⁇ ⁇ g/mL) in colon tissue lysate of acute DSS colitis mice treated with anti-IL-12 p40 intraperitoneally (10 mg/kg) every third day (Q3D) or intracecally (10 mg/kg or 1 mg/kg) adminitsered daily (QD), when compared to vehicle control (Vehicle).
• FIG. 37 is a graph showing the concentration of 11-6 ⁇ g/mL) in colon tissue lysate of acute DSS colitis mice treated with anti-IL-12 p40 intraperitoneally (10 mg/kg) every third day (Q3D) or intracecally (10 mg/kg or 1 mg/kg) administered daily (QD), when compared to vehicle control (Vehicle). Data presented as mean ⁇ SEM. Mann-Whitney's U- test and Student's t-test were used for statistical analysis on non-Gaussian and Gaussian data respectively. A value ⁇ ⁇ 0.05 was considered significant (Graph Pad Software, Inc.
• FIG. 38 is a graph showing the concentration of I1-17A ⁇ g/mL) in colon tissue lysate of acute DSS colitis mice treated with anti-IL-12 p40 intraperitoneally (10 mg/kg) every third day (Q3D) or intracecally (10 mg/kg and 1 mg/kg) administered daily (QD), when compared to vehicle control (Vehicle). Data presented as mean ⁇ SEM. Mann-Whitney's U- test and Student's t-test were used for statistical analysis on non-Gaussian and Gaussian data respectively. A value ⁇ ⁇ 0.05 was considered significant (Graph Pad Software, Inc.).
• FIG. 39 is a graph showing the percentage (%) change in body weight at day 14 ( ⁇ SEM) for DSS mice treated with DATK32 (anti-a4 7) antibody intraperitoneally (25 mg/kg) every third day (Q3D) or intracecally (25 mg/kg or 5 mg/kg) administered daily (QD), when compared to vehicle control (Vehicle) and when IC is compared to IP.
• FIG. 40 is a graph showing the plasma concentration of DATK32 rat IgG2A ⁇ g/mL) of intraperitoneally (25mg/kg) and intracecally (25 mg/kg and 5 mg/kg) administered treatment groups given daily (QD) or every third day (Q3D), where IP is compared to IC.
• FIG. 41 is a graph showing the concentration of DATK32 rat IgG2A antibody ⁇ g/mL) in cecum and colon content of intraperitoneally (25mg/kg) or intracecally (25 mg/kg and 5 mg/kg) administered treatment groups given daily (QD) or every third day (Q3D), where IP is compared to IC.
• FIG. 42 is a graph showing the concentration of DATK32 rat IgG2A ⁇ g/mL) in the colon content of intraperitoneally (25mg/kg) or intracecally (25 mg/kg and 5 mg/kg) administered treatment groups given daily (QD), and concentration over time (1, 2 ,4, 24, and 48 hours), where IP is compared to IC.
• FIG. 43 is a graph showing the concentration of DATK32 rat IgG2A ⁇ g/g) in colon tissue of intraperitoneally (25mg/kg) or intracecally (25 mg/kg and 5 mg/kg) administered treatment groups given daily (QD) or every third day (Q3D), where IP is compared to IC.
• FIG. 44 is a graph showing the concentration of DATK32 rat IgG2A ⁇ g/g) in the colon tissue of intraperitoneally (25mg/kg) or intracecally (25 mg/kg and 5 mg/kg) administered treatment groups given daily (QD), and the concentration over time (1, 2, 4, 24, and 48 hours) was determined, where IP is compared to IC.
• FIG. 45 is a graph showing the mean overall tissue immunolabel scores (intensity and extent) in acute DSS colitis mouse colon of DATK32 (anti-a4 7) antibody treated versus vehicle control (Vehicle) treated DSS mice. The data are presented as mean ⁇ SEM.
• FIG. 46 is a graph showing the mean location-specific immunolabel scores in acute DSS colitis mouse colon of DATK32 (anti-a4 7) antibody -treated versus vehicle control (Vehicle)-treated DSS mice. Data presented as mean ⁇ SEM. Mann-Whitney's U- test and Student's t-test were used for statistical analysis on non-Gaussian and Gaussian data respectively. A value ⁇ ⁇ 0.05 was considered significant (Graph Pad Software, Inc.).
• FIG. 47 is a graph showing the ratio of the DATK-32 antibody in the colon tissue to the plasma concentration of the DATK-32 antibody in mice treated with the DATK-32 antibody on day 0 (Q0) or day 3 (Q3D) of the study (Groups 9-12), when measured after initial dosing.
• FIG. 48 is a graph showing the mean percentage of Th memory cells (mean ⁇ SEM) in blood for DATK32 (anti-a4 7) antibody intraperitoneally (25mg/kg) or intracecally (25 mg/kg or 5 mg/kg) administered treatment groups given daily (QD) or every third day (Q3D), when compared to vehicle control (Vehicle) and when IP is compared to IC.
• Mean percentage Th memory cells were measured using FACS analysis. Data presented as mean ⁇ SEM. Mann-Whitney's U- test and Student's t-test were used for statistical analysis on non- Gaussian and Gaussian data respectively. A value ⁇ ⁇ 0.05 was considered significant (Graph Pad Software, Inc.).
• FIG. 49 is an exemplary image of a histological section of a distal transverse colon of Animal 1501 showing no significant lesions (i.e., normal colon).
• FIG. 50 is an exemplary image of a histological section of a distal transverse colon of Animal 2501 (treated with TNBS) showing areas of necrosis and inflammation.
• FIG. 51 is a representative graph of plasma adalimumab concentrations over time following a single subcutaneous (SQ) or topical administration of adalimumab.
• FIG. 52 is a representative table of the plasma adalimumab concentrations ⁇ g/mL) as shown in Figure 4.6.
• FIG. 53 is a graph showing the concentration of TNFa (pg/mL per mg of total protein) in non-inflamed and inflamed colon tissue after intracecal administration of adalimumab, as measured 6, 12, 24, and 24 hours after the initial dosing.
• FIG. 54 is a graph showing the concentration of TNFa (pg/mL per mg of total protein) in colon tissue after subcutaneous or intracecal (topical) administration of adalimumab, as measured 48 hours after the initial dosing.
• FIG. 55 is a graph showing the percentage (%) change in body weight at day 14 ( ⁇ SEM) in acute DSS colitis mice treated with cyclosporine A orally (10 mg/kg) every third day (Q3D) or intracecally (10 mg/kg or 3 mg/kg) daily (QD), when compared to vehicle control (Vehicle). Data presented as mean ⁇ SEM. Mann-Whitney's U- test and Student's t- test were used for statistical analysis on non-Gaussian and Gaussian data respectively. A value of p ⁇ 0.05 was considered significant (Graph Pad Software, Inc.). FIG.
• CsA plasma cyclosporine A
• PO orally
• IC intracecally
• FIG. 57 is a graph showing the colon tissue cyclosporine A (CsA) (ng/g)
• FIG. 58 is a graph showing the peak colon tissue cyclosporine A (CsA) (ng/g) concentration in acute DSS colitis mice treated daily (QD) with orally (PO) (10 mg/kg) or intracecally (IC) (10 mg/kg or 3 mg/kg) administered CsA. Data presented as mean ⁇ SEM.
• CsA colon tissue cyclosporine A
• FIG. 59 is a graph showing the trough tissue concentration of cyclosporine (CsA) (ng/g) in colon of acute DSS colitis mice treated daily (QD) with orally (PO) (10 mg/kg) or intracecally (IC) (10 mg/kg or 3 mg/kg) administered CsA. Data presented as mean ⁇ SEM.
• CsA cyclosporine
• FIG. 60 is a graph showing the interleukin-2 (11-2) concentration ⁇ g/mL) in colon tissue of acute DSS colitis mice treated daily (QD) with orally (PO) (10 mg/kg) or intracecally (IC) (10 mg/kg or 3 mg/kg) administered CsA, where PO is compared to IC.
• PO orally
• IC intracecally
• FIG. 61 is a graph showing the interleukin-6 (11-6) concentration ⁇ g/mL) in colon tissue of acute DSS colitis mice treated daily (QD) with orally (PO) (10 mg/kg) or intracecally (IC) (10 mg/kg or 3 mg/kg) administered CsA. Data presented as mean ⁇ SEM.
• FIG. 62 illustrates a nonlimiting example of a system for collecting, communicating and/or analyzing data about a subject, using an ingestible device.
• FIGs. 63A-F are graphs showing rat IgG2A concentration as measured in (A) colon homogenate, (B) mLN homogenate, (C) small intestine homogenate, (D) cecum contents, (E) colon contents, and (F) plasma by ELISA.
• Standards were prepared with plasma matrix. Samples were diluted 1 :50 before analysis. Sample 20 was removed from cecum contents analysis graph (outlier). *p ⁇ 0.05; **p ⁇ 0.01; ****p ⁇ 0.001 were determined using the unpaired t test.
• FIG. 64 illustrates a tapered silicon bellows.
• FIG. 65 illustrates a tapered silicone bellows in the simulated device jig.
• FIG. 66 illustrates a smooth PVC bellows.
• FIG. 67 illustrates a smooth PVC bellows in the simulated device jig.
• FIG. 68 demonstrates a principle of a competition assay performed in an experiment.
• FIG. 69 shows AlphaLISA data.
• FIG. 70 shows AlphaLISA data.
• FIG. 71 shows AlphaLISA data.
• FIG. 72 is a flowchart of illustrative steps of a clinical protocol, in accordance with some embodiments of the disclosure.
• FIG. 73 is a graph showing the level of FAM-SMAD7-AS oligonucleotide in the cecum tissue of DSS-induced colitis mice at 12-hours. The bars represent from left to right, Groups 2 through 5 in the experiment described in Example 9.
• FIG. 74 is a graph showing the level of FAM-SMAD7-AS oligonucleotide in the colon tissue of DSS-induced colitis mice at 12-hours. The bars represent from left to right, Groups 2 through 5 in the experiment described in Example 9.
• FIG. 75 is a graph showing the level of FAM-SMAD7-AS oligonucleotide in the cecum contents of DSS-induced colitis mice at 12-hours. The bars represent from left to right, Groups 2 through 5 in the experiment described in Example 9.
• FIG. 76 is a graph showing the mean concentration of tacrolimus in the cecum tissue and the proximal colon tissue 12 hours after intra-cecal or oral administration of tacrolimus to swine as described in Example 10.
• a method of treating a disease of the gastrointestinal tract in a subject comprises administering to the subject a pharmaceutical formulation comprising an integrin inhibitor; the pharmaceutical formulation is released in the subject's gastrointestinal tract proximate to one or more sites of disease.
• the pharmaceutical formulation comprises a therapeutically effective amount of an integrin inhibitor.
• the formulation is contained in an ingestible device, and the device releases the formulation at a location proximate to the site of disease.
• the location of the site of disease may be predetermined.
• an ingestible device the location of which within the GI tract can be accurately determined as disclosed herein, may be used to sample one or more locations in the GI tract and to detect one or more analytes, including markers of the disease, in the GI tract of the subject.
• a pharmaceutical formulation may be then administered in an ingestible device and released at a location proximate to the predetermined site of disease. The release of the formulation may be triggered
• a "formulation" of an integrin inhibitor may refer to either the integrin inhibitor in pure form, such as, for example, a lyophilized integrin inhibitor, or a mixture of the integrin inhibitor with one or more physiologically acceptable carriers, excipients or stabilizers.
• therapeutic formulations or medicaments can be prepared by mixing the integrin inhibitor having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
• Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids;
• antioxidants including ascorbic acid and methionine; preservatives (such as statin), statin, statin, statin
• octadecyldimethylbenzyl ammonium chloride hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) antibody; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbito
• Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20
• insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20
• sHASEGPs and methods of use including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968.
• a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
• additional glycosaminoglycanases such as chondroitinases.
• Exemplary lyophilized formulations are described in US Patent No. 6,267,958.
• Aqueous formulations include those described in US Patent No. 6,171,586 and WO2006/044908, the latter formulations including a histidine- acetate buffer.
• a formulation of an integrin inhibitor as disclosed herein, e.g., sustained-release formulations, can further include a mucoadhesive agent, e.g., one or more of polyvinyl pyrolidine, methyl cellulose, sodium carboxyl methyl cellulose, hydroxyl propyl cellulose, carbopol, a polyacrylate, chitosan, a eudragit analogue, a polymer, and a thiomer. Additional examples of mucoadhesive agents that can be included in a formulation with an integrin inhibitor are described in, e.g., Peppas et al, Biomaterials 17(16): 1553-1561, 1996;
• components of a formulation may include any one of the following components, or any combination thereof:
• the method comprises administering to the subject a pharmaceutical composition that is a formulation as disclosed herein.
• the formulation is a dosage form, which may be, as an example, a solid form such as, for example, a capsule, a tablet, a sachet, or a lozenge; or which may be, as an example, a liquid form such as, for example, a solution, a suspension, an emulsion, or a syrup.
• the formulation is not comprised in an ingestible device. In some embodiments wherein the formulation is not comprised in an ingestible device, the formulation may be suitable for oral administration. The formulation may be, for example, a solid dosage form or a liquid dosage form as disclosed herein. In some embodiments wherein the formulation is not comprised in an ingestible device, the formulation may be suitable for rectal administration. The formulation may be, for example, a dosage form such as a suppository or an enema. In embodiments where the formulation is not comprised in an ingestible device, the formulation releases the integrin inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.
• Such localized release may be achieved, for example, with a formulation comprising an enteric coating.
• Such localized release may be achieved, an another example, with a formulation comprising a core comprising one or more polymers suitable for controlled release of an active substance.
• a non-limiting list of such polymers includes: poly(2-(diethylamino)ethyl methacrylate, 2-(dimethylamino)ethyl methacrylate, poly(ethylene glycol), poly(2- aminoethyl methacrylate), (2-hydroxypropyl)methacrylamide, poly( -benzyl-l-aspartate), poly(N-isopropylacrylamide), and cellulose derivatives.
• the formulation is comprised in an ingestible device as disclosed herein.
• the formulation may be suitable for oral administration.
• the formulation may be, for example, a solid dosage form or a liquid dosage form as disclosed herein.
• the formulation is suitable for introduction and optionally for storage in the device.
• the formulation is suitable for introduction and optionally for storage in a reservoir comprised in the device.
• the formulation is suitable for introduction and optionally for storage in a reservoir comprised in the device.
• a reservoir comprising a therapeutically effective amount of an integrin inhibitor, wherein the reservoir is configured to fit into an ingestible device.
• the reservoir comprising a therapeutically effective amount of an integrin inhibitor is attachable to an ingestible device.
• the reservoir comprising a therapeutically effective amount of an integrin inhibitor is capable of anchoring itself to the subject's tissue.
• the reservoir capable of anchoring itself to the subject's tissue comprises silicone.
• the reservoir capable of anchoring itself to the subject's tissue comprises polyvinyl chloride.
• the formulation is suitable for introduction in a spray catheter, as disclosed herein.
• the formulation herein may also contain more than one active compound as necessary for the particular indication being treated, for example, those with complementary activities that do not adversely affect each other.
• the formulation may further comprise another integrin inhibitor or a chemotherapeutic agent.
• Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
• the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for
• hydroxymethylcellulose or gelatin-microcapsule and poly-(methylmethacylate) microcapsule respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in
• the formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.
• Sustained-release preparations may be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the integrin inhibitor, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxy ethyl-methacrylate), or poly(vinylalcohol)), polylactides (U. S. Pat. No.
• copolymers of L-glutamic acid and y ethyl-L-glutamate non-degradable ethylene-vinyl acetate
• degradable lactic acid-gly colic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-gly colic acid copolymer and leuprolide acetate)
• poly-D-(-)-3-hydroxybutyric acid While polymers such as ethylene- vinyl acetate and lactic acid-gly colic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.
• encapsulated integrin inhibitors When encapsulated integrin inhibitors remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37°C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.
• compositions may contain one or more integrin inhibitors.
• the pharmaceutical formulations may be formulated in any manner known in the art.
• the formulations include one or more of the following components: a sterile diluent (e.g., sterile water or saline), a fixed oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents, antibacterial or antifungal agents, such as benzyl alcohol or methyl parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like, antioxidants, such as ascorbic acid or sodium bisulfite, chelating agents, such as
• ethylenediaminetetraacetic acid ethylenediaminetetraacetic acid
• buffers such as acetates, citrates, or phosphates
• isotonic agents such as sugars (e.g., dextrose), polyalcohols (e.g., mannitol or sorbitol), or salts (e.g., sodium chloride), or any combination thereof.
• Liposomal suspensions can also be used as pharmaceutically acceptable carriers (see, e.g., U.S. Patent No. 4,522,811, incorporated by reference herein in its entirety).
• the formulations can be formulated and enclosed in ampules, disposable syringes, or multiple dose vials.
• proper fluidity can be maintained by, for example, the use of a coating, such as lecithin, or a surfactant.
• Controlled release of the integrin inhibitor can be achieved by implants and microencapsulated delivery systems, which can include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid; Alza Corporation and Nova Pharmaceutical, Inc.).
• biodegradable, biocompatible polymers e.g., ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid; Alza Corporation and Nova Pharmaceutical, Inc.
• the integrin inhibitor is present in a pharmaceutical formulation within the device.
• the integrin inhibitor is present in solution within the device.
• the integrin inhibitor is present in a suspension in a liquid medium within the device.
• the integrin inhibitor is present as a pure, powder (e.g., lyophilized) form of the integrin inhibitor.
• Gastrointestinal inflammatory disorders are a group of chronic disorders that cause inflammation and/or ulceration in the mucous membrane. These disorders include, for example, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, indeterminate colitis and infectious colitis), mucositis (e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis and proctitis), necrotizing enterocolitis and esophagitis.
• inflammatory bowel disease e.g., Crohn's disease, ulcerative colitis, indeterminate colitis and infectious colitis
• mucositis e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis and proctitis
• necrotizing enterocolitis and esophagitis necrotizing enterocolitis and esophagitis.
• IBD ulcerative colitis
• the GI tract can be divided into four main different sections, the oesophagus, stomach, small intestine and large intestine or colon.
• the small intestine possesses three main subcompartments: the duodenum, jejunum and ileum.
• the large intestine consists of six sections: the cecum, ascending colon, transverse colon, ascending colon, sigmoid colon, and the rectum.
• the small intestine is about 6 m long, its diameter is 2.5 to 3 cm and the transit time through it is typically 3 hours.
• the duodenum has a C-shape, and is 30 cm long.
• the jejunum is 2.4 m in length and the ileum is 3.6 m in length and their surface areas are 180 m 2 and 280 m 2 respectively.
• the large intestine is 1.5 m long, its diameter is between 6.3 and 6.5 cm, the transit time though this section is 20 hours and has a reduced surface area of approximately 150 m 2 .
• the higher surface area of the small intestine enhances its capacity for systemic drug absorption.
• corticosteroids and immunomodulator therapy e.g., azathioprine, 6 mercaptopurine, and methotrexate administered via traditional routes such as tablet form, oral suspension, or intravenously
• azathioprine, 6 mercaptopurine, and methotrexate administered via traditional routes such as tablet form, oral suspension, or intravenously
• steroids e.g., azathioprine, 6 mercaptopurine, and methotrexate administered via traditional routes such as tablet form, oral suspension, or intravenously
• TNF-a tumor necrosis factor alpha
• infliximab a chimeric antibody
• adalimumab a fully human antibody
• AEs adverse events associated with anti TNFs include elevated rates of bacterial infection, including tuberculosis, and, more rarely, lymphoma and demyelination (Chang et al, Nat Clin Pract Gastroenterol Hepatology 3:220 (2006); Hoentjen et al., World J. Gastroenterol. 15(17):2067 (2009)).
• IBD Inflammatory bowel syndrome
• GI gastrointestinal
• Crohn's disease a chronic transmural inflammatory disease
• UC ulcerative colitis
• CD Crohn's disease
• Crohn's disease is the granular, reddish-purple edematous thickening of the bowel wall. With the development of inflammation, these granulomas often lose their circumscribed borders and integrate with the surrounding tissue. Diarrhea and obstruction of the bowel are the predominant clinical features. As with ulcerative colitis, the course of Crohn's disease may be continuous or relapsing, mild or severe, but unlike ulcerative colitis, Crohn's disease is not curable by resection of the involved segment of bowel.
• Crohn's disease may involve any part of the alimentary tract from the mouth to the anus, although typically it appears in the ileocolic, small-intestinal or colonic- anorectal regions. Histopathologically, the disease manifests by discontinuous
• the inflammatory infiltrate is mixed, consisting of lymphocytes (both T and B cells), plasma cells, macrophages, and neutrophils. There is a disproportionate increase in IgM- and IgG-secreting plasma cells, macrophages and neutrophils.
• CDAI Crohn's Disease Activity Index
• Backward stepwise regression analysis identified eight independent predictors which are the number of liquid or soft stools, severity of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for anti-diarrheal drugs, presence of an abdominal mass, hematocrit, and body weight.
• the final score is a composite of these eight items, adjusted using regression coefficients and standardization to construct an overall CDAI score, ranging from 0 to 600 with higher score indicating greater disease activity.
• CDAI ⁇ 150 is defined as clinical remission
• 150 to 219 is defined as mildly active disease
• 220 to 450 is defined as moderately active disease
• above 450 is defined as very severe disease (Best WR, et al, Gastroenterology 77:843-6, 1979).
• Vedolizumab and natalizumab have been approved on the basis of demonstrated clinical remission, i.e. CDAI ⁇ 150.
• CDAI has been in use for over 40 years, and has served as the basis for drug approval, it has several limitations as an outcome measure for clinical trials. For example, most of the overall score comes from the patient diary card items (pain, number of liquid bowel movements, and general well-being), which are vaguely defined and not standardized terms (Sandler et al, J. Clin. Epidemiol 41 :451-8, 1988; Thia et al, Infiamm. Bowel Dis 17: 105-11, 2011). In addition, measurement of pain is based on a four- point scale rather than an updated seven-point scale. The remaining 5 index items contribute very little to identifying an efficacy signal and may be a source of measurement noise.
• CDAI Compact Disc
• PR02 and PR03 tools are such adaptations of the CDAI and have been recently described in Khanna et al, Aliment Pharmacol. Ther. 41 : 77-86, 2015.
• the PR02 evaluates the frequency of loose/liquid stools and abdominal pain ⁇ Id).
• These items are derived and weighted accordingly from the CDAI and are the CDAI diary card items, along with general well-being, that contribute most to the observed clinical benefit measured by CDAI (Sandler et al, J. Clin. Epidemiol 41 :451-8, 1988; Thia et al, Inflamm Bowel Dis 17: 105-11, 2011; Kim et al, Gastroenterology 146: (5 supplement 1) S-368,
• the remission score of ⁇ 11 is the CDAI-weighted sum of the average stool frequency and pain scores in a 7-day period, which yielded optimum sensitivity and specificity for identification of CDAI remission (score of ⁇ 150) in a retrospective data
• SES- CD was developed and validated (Daperno et al, Gastrointest. Endosc. 60(4):505-12, 2004).
• the SES-CD consists of four endoscopic variables (size of ulcers,
• the current treatment goals for CD are to induce and maintain symptom improvement, induce mucosal healing, avoid surgery, and improve quality of life (Lichtenstein GR, et al, Am J Gastroenterol 104:465-83, 2009; Van Assche G, et al, J Crohns Colitis. 4:63-101, 2010).
• the current therapy of IBD usually involves the administration of antiinflammatory or immunosuppressive agents, such as sulfasalazine, corticosteroids, 6- mercaptopurine/azathioprine, or cyclosporine, all of which are not typically delivered by localized release of a drug at the site or location of disease.
• biologies like TNF-alpha inhibitors and IL-12/IL-23 blockers are used to treat IBD. If anti-inflammatoiy/immunosuppressive/biologic therapies fail, colectomies are the last line of defense.
• the typical operation for CD not involving the rectum is resection (removal of a diseased segment of bowel) and anastomosis (reconnection) without an ostomy. Sections of the small or large intestine may be removed. About 30% of CD patients will need surgery within the first year after diagnosis. In the subsequent years, the rate is about 5% per year.
• CD is characterized by a high rate of recurrence; about 5% of patients need a second surgery each year after initial surgery.
• Refining a diagnosis of inflammatory bowel disease involves evaluating the progression status of the diseases using standard classification criteria.
• the classification systems used in IBD include the Truelove and Witts Index (Truelove S. C. and Witts, L.J. Br Med J. 1955;2: 1041-1048), which classifies colitis as mild, moderate, or severe, as well as Lennard- Jones. (Lennard-Jones JE. Scand J Gastroenterol Suppl 1989; 170:2-6) and the simple clinical colitis activity index (SCCAI). (Walmsley et. al. Gut. 1998; 43:29-32) These systems track such variables as daily bowel movements, rectal bleeding, temperature, heart rate, hemoglobin levels, erythrocyte sedimentation rate, weight, hematocrit score, and the level of serum albumin.
• UC ulcerative colitis
• CD can appear anywhere in the bowel, with occasional involvement of stomach, esophagus and duodenum, and the lesions are usually described as extensive linear fissures.
• Ulcerative colitis afflicts the large intestine.
• the course of the disease may be continuous or relapsing, mild or severe.
• the earliest lesion is an inflammatory infiltration with abscess formation at the base of the crypts of Lieberkuhn. Coalescence of these distended and ruptured crypts tends to separate the overlying mucosa from its blood supply, leading to ulceration.
• Symptoms of the disease include cramping, lower abdominal pain, rectal bleeding, and frequent, loose discharges consisting mainly of blood, pus and mucus with scanty fecal particles.
• a total colectomy may be required for acute, severe or chronic, unremitting ulcerative colitis.
• UC ulcerative colitis
• antibody and “immunoglobulin” are used interchangeably in the broadest sense and include monoclonal antibodies (for example, full length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific, trispecific etc. antibodies so long as they exhibit the desired biological activity) and may also include certain antibody fragments (as described in greater detail herein).
• An antibody can be human, humanized and/or affinity matured.
• Antibody fragments comprise only a portion of an intact antibody, where in certain embodiments, the portion retains at least one, and typically most or all, of the functions normally associated with that portion when present in an intact antibody.
• an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen.
• an antibody fragment for example one that comprises the Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half-life modulation, ADCC function and complement binding.
• an antibody fragment is a monovalent antibody that has an in vivo half-life substantially similar to an intact antibody.
• such an antibody fragment may comprise on antigen binding arm linked to an Fc sequence capable of conferring in vivo stability to the fragment.
• monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
• the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al, Proc. Natl. Acad. Sci. USA 81 :6851-6855 (1984)).
• Treatment regimen refers to a combination of dosage, frequency of administration, or duration of treatment, with or without addition of a second medication.
• Effective treatment regimen refers to a treatment regimen that will offer beneficial response to a patient receiving the treatment.
• Effective amount refers to an amount of drug that offers beneficial response to a patient receiving the treatment.
• an effective amount may be a Human
• Dispensable refers to any substance that may be released from an ingestible device as disclosed herein, or from a component of the device such as a reservoir.
• a dispensable substance may be an integrin inhibitor, and/or a formulation comprising an integrin inhibitor.
• Patient response or “patient responsiveness” can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of disease progression, including slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) reduction in lesional size; (4) inhibition (i.e., reduction, slowing down or complete stopping) of disease cell infiltration into adjacent peripheral organs and/or tissues; (5) inhibition (i.e., reduction, slowing down or complete stopping) of disease spread; (6) decrease of auto-immune response, which may, but does not have to, result in the regression or ablation of the disease lesion; (7) relief, to some extent, of one or more symptoms associated with the disorder; (8) increase in the length of disease-free presentation following treatment; and/or (9) decreased mortality at a given point of time following treatment.
• responsiveness refers to a measurable response, including complete response (CR) and partial response (PR).
• Partial response refers to a decrease of at least 50% in the severity of inflammation, in response to treatment.
• a "beneficial response" of a patient to treatment with a therapeutic agent and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for or suffering from a gastrointestinal inflammatory disorder from or as a result of the treatment with the agent.
• Such benefit includes cellular or biological responses, a complete response, a partial response, a stable disease (without progression or relapse), or a response with a later relapse of the patient from or as a result of the treatment with the agent.
• non-response or “lack of response” or similar wording means an absence of a complete response, a partial response, or a beneficial response to treatment with a therapeutic agent.
• a patient maintains responsiveness to a treatment" when the patient' s responsiveness does not decrease with time during the course of a treatment.
• a "symptom" of a disease or disorder is any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by a subj ect and indicative of disease.
• integrin inhibitor refers to an agent which decreases the expression of one or more integrins and/or decreases the binding of an integrin ligand to one or more integrins that play a role in the recruitment, extravasation, and/or activation of a leukocyte.
• the integrin inhibitor specifically binds to at least a portion of a ligand binding site on a target integrin.
• the integrin inhibitor specifically binds to a target integrin at the same site as an endogenous ligand.
• the integrin inhibitor decreases the level of expression of the target integrin in a mammalian cell.
• the integrin inhibitor specifically binds to an integrin ligand.
• Non-limiting examples of integrins that can be targeted by any of the integrin inhibitors described herein include: ⁇ 2 ⁇ 1 integrin, ⁇ ⁇ integrin, ⁇ 4 ⁇ 7 integrin, integrin ⁇ 4 ⁇ 1 (VLA-4), E-selectin, ICAM-1, ⁇ 5 ⁇ 1 integrin, ⁇ 4 ⁇ 1 integrin, VLA-4, ⁇ 2 ⁇ 1 integrin, ⁇ 5 ⁇ 3 integrin, ⁇ 5 ⁇ 5 integrin, ⁇ ) ⁇ 3 integrin, VCAMl and MAdCAM- 1.
• a non-limiting example of integrin inhibitor that can decrease the expression and/or activity of ⁇ 4 ⁇ 7 integrin is FTY720.
• a non-limiting example of an integrin inhibitor that specifically targets MAdCAM is PF-547659 (Pfizer).
• Non-limiting examples of an integrin inhibitor that specifically targets ⁇ 4 ⁇ 7 is AJM300 (Ajinomoto), etrolizumab (Genentech), and vedolizumab
• the integrin inhibitor is an ⁇ 3 ⁇ 4 ⁇ 3 integrin inhibitor.
• the ⁇ 3 ⁇ 4 ⁇ 3 integrin inhibitor is abciximab (ReoPro®, c7E3; Kononczuk et al, Curr. Drug Targets 16(13): 1429-1437, 2015; Jiang et al., Appl. Microbiol. Biotechnol.
• the integrin inhibitor is an aL-selective integrin inhibitor. In some embodiments, the integrin inhibitor is a ⁇ 2 integrin inhibitor.
• the integrin inhibitor is an a4 integrin (e.g., an ⁇ 4 ⁇ 1 integrin (e.g., Very Late Antigen-4 (VLA-4), CD49d, or CD29)) inhibitor, an ⁇ 4 ⁇ 7 integrin inhibitor.
• an a4 integrin e.g., an ⁇ 4 ⁇ 1 integrin (e.g., Very Late Antigen-4 (VLA-4), CD49d, or CD29)
• VLA-4 Very Late Antigen-4
• CD49d CD49d
• CD29 CD29
• the integrin inhibitor targets endothelial VCAMl, fibronectin, mucosal addressin cellular adhesion molecule-1 (MAdCAM-1), vitronectin, tenascin-C, osteopontin (OPN), nephronectin, agiostatin, tissue-type transglutaminase, factor XIII, Von Willebrand factor (VWF), an ADAM protein, an ICAM protein, collagen, e-cadherin, laminin, fibulin-5, or ⁇ .
• MAdCAM-1 mucosal addressin cellular adhesion molecule-1
• OPN osteopontin
• nephronectin nephronectin
• agiostatin tissue-type transglutaminase
• factor XIII factor XIII
• VWF Von Willebrand factor
• ADAM protein an ICAM protein
• collagen collagen
• e-cadherin laminin
• fibulin-5 or ⁇ .
• the a4 integrin inhibitor is natalizumab (Tysabri®; Targan et al, Gastroenterology 132(5): 1672-1683, 2007; Sandborn et al, N. Engl. J. Med. 353(18): 1912-1925, 2005; Nakamura et al, Intern. Med. 56(2):211-214, 2017; and Singh et al, J. Pediatr. Gastroenterol. Nutr. 62(6): 863-866, 2016).
• natalizumab Tysabri®; Targan et al, Gastroenterology 132(5): 1672-1683, 2007; Sandborn et al, N. Engl. J. Med. 353(18): 1912-1925, 2005; Nakamura et al, Intern. Med. 56(2):211-214, 2017; and Singh et al, J. Pediatr. Gastroenterol. Nutr. 62(6): 863-866, 2016).
• the integrin inhibitor is an endogenous integrin inhibitor (e.g., SHARPIN (Rantala et al., Ni . Cell. Biol. 13(11): 1315-1324, 2011).
• SHARPIN Rasterala et al., Ni . Cell. Biol. 13(11): 1315-1324, 2011.
• the integrin inhibitor is an av integrin (e.g., an ⁇ 5 ⁇ 1 integrin, an ⁇ 5 ⁇ 3 integrin, an ⁇ 5 ⁇ 5 integrin inhibitor, and/or an ⁇ 5 ⁇ 6 integrin) inhibitor.
• an av integrin e.g., an ⁇ 5 ⁇ 1 integrin, an ⁇ 5 ⁇ 3 integrin, an ⁇ 5 ⁇ 5 integrin inhibitor, and/or an ⁇ 5 ⁇ 6 integrin
• the integrin inhibitor is an ⁇ 5 ⁇ 1 integrin inhibitor.
• the integrin inhibitor is a VCAMl inhibitor. In some embodiments, the VCAMl inhibitor targets the extracellular domain of tissue factor.
• an integrin inhibitor is an inhibitory nucleic acid, an antibody or antigen-binding fragment thereof, a fusion protein, an integrin antagonist, a cyclic peptide, a disintegrin, a peptidomimetic, or a small molecule.
• the inhibitory nucleic acid is a small hairpin RNA, a small interfering RNA, an antisense, an aptamer, or a microRNA.
• VCAMl Vascular Cell Adhesion Molecule 1 (VCAMl) inhibitors
• a VCAMl inhibitory agent is an inhibitory nucleic acid.
• the inhibitory nucleic acid is an antisense nucleic acid, a small interfering RNA, or a microRNA. Examples of aspects of these different inhibitory nucleic acids are described below. Any of the examples of inhibitory nucleic acids that can decrease expression of a VCAMl in a mammalian cell can be synthesized in vitro.
• inhibitory nucleic acids specifically bind (e.g., hybridize) to an mRNA encoding VCAMl to treat inflammatory diseases (e.g., chronic inflammation, irritable bowel syndrome (IBS), rheumatoid arthritis, ulcerative colitis, Crohn's Disease, psoriasis, multiple sclerosis, or auto-inflammatory disease).
• inflammatory diseases e.g., chronic inflammation, irritable bowel syndrome (IBS), rheumatoid arthritis, ulcerative colitis, Crohn's Disease, psoriasis, multiple sclerosis, or auto-inflammatory disease.
• Inhibitory nucleic acids that can decrease the expression of VCAMl expression in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of VCAMl mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 28-30).
• An antisense nucleic acid molecule can be complementary to all or part of a non- coding region of the coding strand of a nucleotide sequence encoding a VCAMl protein.
• Non-coding regions are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.
• the VCAMl antisense nucleic acid comprises
• the VCAMl antisense nucleic acid comprises AACCCTTATTTGTGTCCCACC (SEQ ID NO: 32). In some embodiments, the VCAMl antisense nucleic acid comprises
• the VCAMl antisense nucleic acid comprises CAC GAGGCCACCACTCATCTC (SEQ ID NO: 34). In some embodiments, the VCAMl antisense nucleic acid comprises
• the VCAMl antisense nucleic acid comprises AACTCCTCCAGTTCTCTCATC (SEQ ID NO: 36). In some embodiments, the VCAMl antisense nucleic acid comprises
• VCAMl antisense nucleic acid ACCTGTGTGTGCCTGGGAGGG (SEQ ID NO: 37). Additional VCAMl antisense nucleic acid are known in the art, e.g., in US 5,596,090, incorporated in its entirety herein.
• Antisense nucleic acids targeting a nucleic acid encoding a VCAMl can be designed using the software available at the Integrated DNA Technologies website.
• An antisense nucleic acid can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides or more in length.
• An antisense oligonucleotide can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art.
• an antisense nucleic acid can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.
• modified nucleotides which can be used to generate an antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl- 2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7- methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5'-
• the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).
• the antisense nucleic acid comprises a 2'0-methoxyethyl nucleotide. See, e.g., Rijcken et al, Gut 51 : 529-535. 2002).
• the antisense nucleic acid molecules described herein can be prepared in vitro and administered to a mammal, e.g., a human. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a VCAMl protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation.
• the hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix.
• the antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., a lentivirus, a retrovirus, or an adenovirus vector).
• An antisense nucleic acid can be an a-anomeric nucleic acid molecule.
• An a- anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, ⁇ -units, the strands run parallel to each other (Gaultier et al, Nucleic Acids Res. 15:6625-6641, 1987).
• the antisense nucleic acid can also comprise a 2'-0-methylribonucleotide (Inoue et al, Nucleic Acids Res. 15:6131-6148, 1987) or a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987).
• an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding a VCAMl protein (e.g., specificity for a VCAMl mRNA, e.g., specificity for SEQ ID NO: 28, 29, or 30).
• Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region.
• ribozymes e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)
• ribozymes can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA.
• a ribozyme having specificity for a VCAMl mRNA can be designed based upon the nucleotide sequence of any of the VCAMl mRNA sequences disclosed herein.
• a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a VCAMl mRNA (see, e.g., U.S. Patent. Nos. 4,987,071 and 5,116,742).
• VCAMl mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science
• An inhibitor nucleic acid can also be a nucleic acid molecule that forms triple helical structures.
• expression of a VCAMl polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the VCAMl polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells.
• the promoter and/or enhancer e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state
• inhibitory nucleic acids can be modified at the base moiety, sugar moiety, or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule.
• the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al, Bioorganic Medicinal Chem. 4(l):5-23, 1996).
• PNAs Peptide nucleic acids
• DNA mimics DNA mimics
• pseudopeptide backbone a pseudopeptide backbone
• the neutral backbone of PNAs allows for specific hybridization to DNA and RNA under conditions of low ionic strength.
• the synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al, Proc. Natl. Acad. Sci.
• PNAs can be used as antisense or antigene agents for sequence- specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.
• PNAs can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art.
• PNA- DNA chimeras can be generated which may combine the advantageous properties of PNA and DNA.
• Such chimeras allow DNA recognition enzymes, e.g., RNAse H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity.
• PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation.
• PNA-DNA chimeras can be performed as described in Finn et al., Nucleic Acids Res. 24:3357-63, 1996.
• a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry and modified nucleoside analogs.
• Compounds such as 5'-(4-methoxytrityl)arnino-5'-deoxy-thymidine phosphoramidite can be used as a link between the PNA and the 5' end of DNA (Mag et al, Nucleic Acids Res. 17:5973-88, 1989).
• PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al., Nucleic Acids Res. 24:3357-63, 1996).
• chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment (Peterser et al., Bioorganic Med. Chem. Lett. 5: 1119-11124, 1975).
• the inhibitory nucleic acids can include other appended groups such as peptides, or agents facilitating transport across the cell membrane (see, Letsinger et al., Proc. Natl. Acad. Sci. U.S.A.
• inhibitory nucleic acids can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al, Bio/Techniques, 6:958-976, 1988) or intercalating agents (see, e.g., Zon, Pharm. Res., 5:539-549, 1988).
• the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.
• RNAi RNA interference
• dsRNA double-stranded RNA
• siRNAs short interfering RNAs
• the RISC targets the homologous transcript by base pairing interactions between one of the siRNA strands and the endogenous mRNA. It then cleaves the mRNA about 12 nucleotides from the 3' terminus of the siRNA (see Sharp et al, Genes Dev. 15:485-490, 2001, and Hammond et al, Nature Rev. Gen. 2: 110-119, 2001).
• RNA-mediated gene silencing can be induced in a mammalian cell in many ways, e.g., by enforcing endogenous expression of RNA hairpins (see, Paddison et al, Proc. Natl. Acad. Sci. U.S.A. 99: 1443-1448, 2002) or, as noted above, by transfection of small (21-23 nt) dsRNA (reviewed in Caplen, Trends Biotech. 20:49-51, 2002).
• Methods for modulating gene expression with RNAi are described, e.g., in U.S. Patent No. 6,506,559 and US
• Standard molecular biology techniques can be used to generate siRNAs.
• Short interfering RNAs can be chemically synthesized, recombinantly produced, e.g., by expressing RNA from a template DNA, such as a plasmid, or obtained from commercial vendors, such as Dharmacon.
• the RNA used to mediate RNAi can include synthetic or modified nucleotides, such as phosphorothioate nucleotides.
• Methods of transfecting cells with siRNA or with plasmids engineered to make siRNA are routine in the art.
• the siRNA molecules used to decrease expression of a VCAMl mRNA can vary in a number of ways.
• RNA molecules can include a 3' hydroxyl group and strands of 21, 22, or 23 consecutive nucleotides. They can be blunt ended or include an overhanging end at either the 3' end, the 5' end, or both ends.
• at least one strand of the RNA molecule can have a 3' overhang from about 1 to about 6 nucleotides (e.g., 1-5, 1-3, 2-4 or 3-5 nucleotides (whether pyrimidine or purine nucleotides) in length. Where both strands include an overhang, the length of the overhangs may be the same or different for each strand.
• the 3' overhangs can be stabilized against degradation (by, e.g., including purine nucleotides, such as adenosine or guanosine nucleotides or replacing pyrimidine nucleotides by modified analogues (e.g., substitution of uridine 2-nucleotide 3' overhangs by 2'-deoxythymidine is tolerated and does not affect the efficiency of RNAi).
• purine nucleotides such as adenosine or guanosine nucleotides
• pyrimidine nucleotides by modified analogues (e.g., substitution of uridine 2-nucleotide 3' overhangs by 2'-deoxythymidine is tolerated and does not affect the efficiency of RNAi).
• siRNA can be used in the methods of decreasing VCAMl mRNA, provided it has sufficient homology to the target of interest (e.g., a sequence present in any one of SEQ ID NOs: 28-30, e.g., a target sequence encompassing the translation start site or the first exon of the mRNA).
• the target of interest e.g., a sequence present in any one of SEQ ID NOs: 28-30, e.g., a target sequence encompassing the translation start site or the first exon of the mRNA.
• the siRNA can range from about 21 base pairs of the gene to the full length of the gene or more (e.g., about 20 to about 30 base pairs, about 50 to about 60 base pairs, about 60 to about 70 base pairs, about 70 to about 80 base pairs, about 80 to about 90 base pairs, or about 90 to about 100 base pairs).
• Non-limiting examples of short interfering RNA (siRNA) that target nucleic acid that encodes VCAMl are described in, e.g., Ho et ⁇ ., ⁇ BiomedEng. 44(4): 895-902, 2016.
• Inhibitory nucleic acids targeting VCAMl also include microRNAs (e.g., miR-126 (Harris et al, PNAS 105(5): 1516-1521, 2008; Asgeirsdottir et al, Am J Physiol Renal Physiol 302: F1630-F1639, 2012), miR-181b (Sun et al, J Clin Invest. 122(6): 1973-1990, 2012).
• miR-126 Haarris et al, PNAS 105(5): 1516-1521, 2008
• Asgeirsdottir et al Am J Physiol Renal Physiol 302: F1630-F1639, 2012
• miR-181b Un et al, J Clin Invest. 122(6): 1973-1990, 2012.
• a therapeutically effective amount of an inhibitory nucleic acid targeting VCAMl can be administered to a subject (e.g., a human subject) in need thereof.
• the inhibitory nucleic acid can be about 10 nucleotides to about 40 nucleotides (e.g., about 10 to about 30 nucleotides, about 10 to about 25 nucleotides, about 10 to about 20 nucleotides, about 10 to about 15 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35
• an inhibitory nucleic acid can bind specifically to a target nucleic acid under stringent conditions, e.g., those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 °C. for short oligonucleotides (e.g., 10 to 50 nucleotide). Stringent conditions can also be achieved with the addition of destabilizing agents such as formamide.
• the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding a VCAM1) with a Tm of greater than 20 °C, greater than 22 °C, greater than 24 °C, greater than 26 °C, greater than 28 °C, greater than 30 °C, greater than 32 °C, greater than 34 °C, greater than 36 °C, greater than 38 °C, greater than 40 °C, greater than 42 °C, greater than 44 °C, greater than 46 °C, greater than 48 °C, greater than 50 °C, greater than 52 °C, greater than 54 °C, greater than 56 °C, greater than 58 °C, greater than 60 °C, greater than 62 °C, greater than 64 °C, greater than 66 °C, greater than 68 °C, greater than 70 °C, greater than 72 °C,
• a target nucleic acid e.g., a
• the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding a VCAM1) with a Tm of about 20 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, about 28 °C, about 26 °C, about 24 °C, or about 22 °C (
• the inhibitory nucleic acid can be formulated in a nanoparticle (e.g., a nanoparticle including one or more synthetic polymers, e.g., Patil et al,
• the nanoparticle can be a mucoadhesive particle (e.g., nanoparticles having a positively-charged exterior surface) (Andersen et al., Methods Mol. Biol. 555:77-86, 2009).
• the nanoparticle can have a neutrally-charged exterior surface.
• the inhibitory nucleic acid can be formulated, e.g., as a liposome (Buyens et al, J. Control Release 158(3): 362-370, 2012; Scarabel et al, Expert Opin. Drug Deliv.
• a micelle e.g., a mixed micelle
• a microemulsion WO 11/004395
• a nanoemulsion or a solid lipid nanoparticle
• a pharmaceutical composition can include a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein).
• a pharmaceutical composition consists of a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein).
• the sterile saline is a pharmaceutical grade saline.
• a pharmaceutical composition can include one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water.
• a pharmaceutical composition consists of one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water.
• a pharmaceutical composition includes one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and phosphate-buffered saline (PBS).
• a pharmaceutical composition consists of one or more inhibitory nucleic acids (e.g., any of the inhibitory nucleic acids described herein) and sterile phosphate-buffered saline (PBS).
• the sterile saline is a pharmaceutical grade PBS.
• one or more inhibitory nucleic acids may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations.
• compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
• compositions including one or more inhibitory nucleic acids encompass any pharmaceutically acceptable salts, esters, or salts of such esters.
• Non-limiting examples of pharmaceutical compositions include pharmaceutically acceptable salts of inhibitory nucleic acids.
• Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.
• prodrugs that can include additional nucleosides at one or both ends of an inhibitory nucleic acid which are cleaved by endogenous nucleases within the body, to form the active inhibitory nucleic acid.
• Lipid moieties can be used to formulate an inhibitory nucleic acid.
• the inhibitory nucleic acid is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids.
• inhibitory nucleic acid complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid.
• a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to a particular cell or tissue in a mammal.
• a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to fat tissue in a mammal.
• a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to muscle tissue.
• compositions provided herein comprise one or more inhibitory nucleic acid and one or more excipients.
• excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
• a pharmaceutical composition provided herein includes liposomes and emulsions. Liposomes and emulsions can be used to formulate hydrophobic compounds. In some examples, certain organic solvents such as dimethylsulfoxide are used.
• a pharmaceutical composition provided herein includes one or more tissue-specific delivery molecules designed to deliver one or more inhibitory nucleic acids to specific tissues or cell types in a mammal.
• a pharmaceutical composition can include liposomes coated with a tissue-specific antibody.
• a pharmaceutical composition provided herein can include a co-solvent system.
• co-solvent systems include benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
• VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM and 65% w/v polyethylene glycol 300.
• surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
• a pharmaceutical composition can be formulated for oral administration. In some examples, pharmaceutical compositions are formulated for buccal administration.
• a pharmaceutical composition is formulated for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In some of these
• a pharmaceutical composition includes a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
• aqueous solution such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
• other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
• injectable suspensions are prepared using appropriate liquid carriers, suspending agents, and the like.
• Some pharmaceutical compositions for injection are formulated in unit dosage form, e.g., in ampoules or in multi-dose containers.
• Some pharmaceutical compositions for injection are suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
• Solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
• a therapeutically effective amount of an inhibitory nucleic acid targeting VCAM1 can be administered to a subject (e.g., a human subject) in need of thereof.
• the inhibitory nucleic acids are 10 to 40 (e.g., 10 to 30, 10 to 25, 10 to 20, 10 to 15, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40) nucleotides in length.
• inhibitory nucleic acids may comprise at least one modified nucleic acid at either the 5 ' or 3 ' end of the DNA or RN A.
• the VCAM1 inhibitor is an antibody or an antigen-binding fragment thereof (e.g., a Fab or a scFv).
• the antibody can be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof.
• an antibody can be a scFv-Fc, a VHH domain, a VNAR domain, a (scFv)2, a minibody, or a BiTE.
• an antibody can be a DVD-Ig, and a dual- affinity re-targeting antibody (DART), a triomab, kih IgG with a common LC, a crossmab, an ortho-Fab IgQ a 2-in-l-IgQ IgG-ScFv, scFv2-Fc, a bi-nanobody, tanden antibody, a DART- Fc, a scFv-HAS-scFv, DNL-Fab3, DAF (two-in-one or four-in-one), DutaMab, DT-IgG, knobs-in-holes common LC, knobs-in-holes assembly, charge pair antibody, Fab-arm exchange antibody, SEEDbody, Triomab, LUZ-Y, Fcab, k -body, orthogonal Fab, DVD-IgQ IgG(H)-scFv, scFv-(H)
• DART
• Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab')2 fragment, and a Fab' fragment.
• Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an IgG (e.g., an antigen-binding fragment of IgGl, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgQ e.g., human or humanized IgGl, IgG2, IgG3, or IgG4); an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgAl or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgAl or IgA2); an antigen-binding fragment of an IgD (e.
• any of the antibodies or antigen-binding fragments thereof described herein can bind to any of the VCAMls described herein or any of the VCAM1 ligands described herein.
• the VCAM1 antibody is a monoclonal antibody.
• the antibody can be a Fab fragment of a monoclonal chimeric mouse-human antibody, or a variant thereof.
• the VCAM1 antibody is a humanized monoclonal antibody.
• Non-limiting examples of human VCAM1 antibodies are V6 and V7 described in Park et al, Atherosclerosis 226(2):356-363, 2013.
• the antibody comprises or consists of an antigen-binding fragment of MK1.91 (Soriano et al, Laboratory Investigation 80(10): 1541, 2000).
• the inhibitor is one of the following:
• the inhibitor is:
• pan- ⁇ antibody e.g., OS2966 (Carbonell et al, Cancer Res. 73(10):3145-3154, 2013); or
• a monoclonal antibody e.g., 17E6 (Castel et al, Eur. J. Cell. Biol. 79(7):502-512,
• an a4 antagonist e.g., firategrast (Miller et al, Lancet Neurol. 11(2): 131-139, 2012)
• an ⁇ 4 ⁇ 1 antagonist e.g., IVL745 (Norris et al, J. Allergy Clin. Immunol. 116(4):761- 767, 2005;
• valategrast (R411) (Cox et al., Nat. Rev. Drug Discov. 9(10): 804-820, 2010);
• GW559090X (Ravensberg et al, Allergy 61(9): 1097-1103, 2006), TR14035 (Sircar et al., Bioorg. Med. Chem. 10(6):2051-2066, 2002; Cortijo et al, Br. J. Pharmacol. 147(6):661- 670, 2006);
• an ⁇ 3 antagonist e.g., L0000845704, SB273005;
• an ⁇ 5 ⁇ 1 antagonist e.g., JSM6427
• JSM-6427 JSM-6427 or a variant thereof (Zahn et al, Arch. Ophthalmol.127(10): 1329-1335, 2009;
• any of the antibodies or antigen-binding fragments described herein has a dissociation constant (KD) of less than 1 x 10 "5 M (e.g., less than 0.5 x 10 "5 M, less than 1 x 10 "6 M, less than 0.5 x 10 "6 M, less than 1 x 10 "7 M, less than 0.5 x 10 "7 M, less than 1 x 10 "8 M, less than 0.5 x 10 "8 M, less than 1 x 10 "9 M, less than 0.5 x 10 "9 M, less than 1 x 10 "10 M, less than 0.5 x 10 "10 M, less than 1 x 10 "11 M, less than 0.5 x 10 "11 M, or less than 1 x 10 "12 M), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).
• SPR surface plasmon resonance
• any of the antibodies or antigen-binding fragments described herein has a KD of about 1 x 10 " 12 M to about 1 x 10 "5 M, about 0.5 x 10 "5 M, about 1 x 10 "6 M, about 0.5 x 10 "6 M, about 1 x 10 "7 M, about 0.5 x 10 "7 M, about 1 x 10 "8 M, about 0.5 x 10 " 8 M, about 1 x 10 "9 M, about 0.5 x 10 "9 M, about 1 x 10 "10 ⁇ , about 0.5 x 10 " 10 ⁇ , about 1 x 10 "1 1 M, or about 0.5 x 10 "1 1 M (inclusive); about 0.5 x 10 " 11 M to about 1 x 10 "5 M, about 0.5 x 10 "5 M, about 1 x 10 "6 M, about 0.5 x 10 "6 M, about 1 x 10 "7 M, about 0.5 x 10 "7 M, about 1 x 10 "8 M, about 0.5
• any of the antibodies or antigen-binding fragments described herein has a Koff of about 1 x 10 "6 s "1 to about 1 x 10 "3 s “1 , about 0.5 x 10 "3 s “1 , about 1 x 10 "4 s “ 1 , about 0.5 x 10 "4 s “1 , about 1 x 10 "5 s “1 , or about 0.5 x 10 "5 s “1 (inclusive); about 0.5 x 10 "5 s “1 to about 1 x 10 "3 s “1 , about 0.5 x 10 "3 s “1 , about 1 x 10 "4 s “1 , about 0.5 x 10 "4 s “1 , or about 1 x 10 "5 s “1 (inclusive); about 1 x 10 "5 s “1 to about 1 x 10 "3 s “1 , about 0.5 x 10 "3 s “1 , about 1 x 10 "4 s “ 1 , or about
• any of the antibodies or antigen-binding fragments described herein has a Kon of about 1 x 10 2 M' 1 to about 1 x lO ⁇ 1 , about 0.5 x 10 6 M'V 1 , about 1 x 10 s M-V 1 , about 0.5 x 10 5 M'V 1 , about 1 x 10 4 M'V 1 , about 0.5 x 10 4 M'V 1 , about 1 x 10 3 M'V 1 , or about 0.5 x 10 3 M'V 1 (inclusive); about 0.5 x 10 3 M'V 1 to about 1 x 10 6 M'V 1 , about 0.5 x 10 6 M ' V 1 , about 1 x 10 s M ⁇ s "1 , about 0.5 x 10 5 M ' V 1 , about 1 x 10 4 M ' V 1 , about 0.5 x 10 4 M-y 1 , or about 1 x 10 3 M ' V 1 (inclusive); about 1 x 10 3 M '
• inhibitory nucleic acids specifically bind (e.g., hybridize) to a nucleic acid encoding an integrin or an integrin ligand to treat inflammatory diseases (e.g., chronic inflammation, irritable bowel syndrome (IBS), rheumatoid arthritis, ulcerative colitis, Crohn's Disease, or auto-inflammatory disease).
• inflammatory diseases e.g., chronic inflammation, irritable bowel syndrome (IBS), rheumatoid arthritis, ulcerative colitis, Crohn's Disease, or auto-inflammatory disease.
• the inhibitory nucleic acid can be an antisense nucleic acid, a ribozyme, a small interfering RNA, a small hairpin RNA, or a microRNA. Examples of aspects of these different inhibitory nucleic acids are described below.
• inhibitory nucleic acids that can decrease expression of a target integrin or a target integrin ligand (e.g., any of the exemplary target integrins or any of the exemplary integrin ligands described herein) in a mammalian cell can be synthesized in vitro.
• Inhibitory nucleic acids that can decrease the expression of target integrin mRNA or a target integrin ligand mRNA (e.g., any of the exemplary integrins described herein or any of the exemplary integrin ligands described herein) in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of target integrin mRNA or a target integrin ligand mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 1-27).
• antisense nucleic acid molecules i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of target integrin mRNA or a target integrin ligand mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 1-27).
• Integrin a2 (ITGA) (NCBI Ref.: NM 002203.3) (SEQ ID NO: 1)
• Integrin allb (a2b) (NCBI Ref.: NM 000419.4; SEQ ID NO: 2)
• VLA-4 Integrin a4 (VLA-4) (NCBI Ref.: NM 000885.5; SEQ ID NO: 3)
• Integrin ⁇ (NCBI Ref.: NM 002211.3; SEQ ID NO: 5)
• Integrin ⁇ 3 (NCBI Ref.: NM 000212.2; SEQ ID NO: 6)
• Integrin ⁇ 5 (NCBI Ref.: NM 002213.4; SEQ ID NO: 7)
• Integrin ⁇ 7 (NCBI Ref.: NM 000889.2; SEQ ID NO: 8)
• ICAM-1 (NCBI Ref.: NM 000201.2; SEQ ID NO: 10)
• TGF-P (NCBI Ref.: NM 000660.6; SEQ ID NO: 11)
• VCAM-1 (NCBI Ref.: NM 001078.3; SEQ ID NO: 13)
• Angiostatin (PLG) (NCBI Ref.: NM 000301.3; SEQ ID NO: 19)
• Tissue transglutaminase factor XIII (F13A1) (NCBI Ref.: NM 000129.3; SEQ ID NO: 20)
• ADAM2 (NCBI Ref.: NM 001278113.1; SEQ ID NO: 22)
• ICAM1 (NCBI Ref.: NM 000201.2; SEQ ID NO: 23)
• Fibulin-5 (NCBI Ref.: NM 006329.3; SEQ ID NO: 27)
• An antisense nucleic acid molecule can be complementary to all or part of a non- coding region of the coding strand of a nucleotide sequence encoding a target integrin or a target integrin ligand (e.g., any of the exemplary target integrins or any of the exemplary integrin ligands described herein).
• Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.
• nucleic acid encoding a target integrin e.g., any of the exemplary target integrins described herein
• a nucleic acid encoding an integrin ligand e.g., any of the exemplary integrin ligands described herein
• Antisense nucleic acids targeting a nucleic acid encoding a target integrin (e.g., any of the exemplary integrins described herein) or a nucleic acid encoding an integrin ligand (e.g., any of the exemplary integrin ligands described herein) can be designed using the software available at the Integrated DNA Technologies website.
• An antisense nucleic acid can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides or more in length.
• An antisense oligonucleotide can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art.
• an antisense nucleic acid can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.
• modified nucleotides which can be used to generate an antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl- 2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7- methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5'-
• the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).
• the antisense nucleic acid molecules described herein can be prepared in vitro and administered to a mammal, e.g., a human.
• a target integrin e.g., any of the exemplary target integrins described herein
• a integrin ligand e.g., any of the exemplary integrin ligands described herein
• the hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix.
• the antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., a lentivirus, a retrovirus, or an adenovirus vector).
• An antisense nucleic acid can be an a-anomeric nucleic acid molecule.
• An a- anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, ⁇ -units, the strands run parallel to each other (Gaultier et al, Nucleic Acids Res. 15:6625-6641, 1987).
• the antisense nucleic acid can also comprise a 2'-0-methylribonucleotide (Inoue et al, Nucleic Acids Res. 15:6131-6148, 1987) or a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987).
• Exemplary integrin inhibitors that are antisense nucleic acids include ATL1102 (e.g., Limmroth et al., Neurology 83(20):1780-1788, 2014; Li et al, Dig. Liver Dis. 39(6):557-565, 2007; Goto et al, Inflamm. Bowel Dis. 12(8):758-765, 2006).
• an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein).
• Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a
• ribozymes e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)
• ribozymes can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA.
• a ribozyme having specificity for a target integrin e.g., any of the exemplary target integrins described herein
• an integrin ligand e.g., any of the exemplary integrin ligands described herein
• a ribozyme having specificity for a target integrin can be designed based upon the nucleotide sequence of any of the integrin mRNA sequences or integrin ligand mRNA sequences disclosed herein or known in the art.
• a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a target integrin mRNA or an integrin ligand mRNA (see, e.g., U.S. Patent. Nos. 4,987,071 and 5,116,742).
• an integrin mRNA e.g., any of the exemplary integrin mRNAs described herein
• an integrin ligand mRNA e.g., any of the exemplary integrin ligand mRNAs described herein
• An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures.
• expression of a target integrin e.g., any of the exemplary target integrins described herein
• an integrin ligand e.g., any of the exemplary integrin ligands described herein
• the target integrin e.g., any of the exemplary target integrins described herein
• the integrin ligand e.g., any of the exemplary integrin ligands described herein
• the promoter and/or enhancer e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state
• inhibitory nucleic acids can be modified at the base moiety, sugar moiety, or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule.
• the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al, Bioorganic Medicinal Chem. 4(l):5-23, 1996).
• Peptide nucleic acids PNAs are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained.
• PNAs The neutral backbone of PNAs allows for specific hybridization to DNA and RNA under conditions of low ionic strength.
• the synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al, Proc. Natl. Acad. Sci.
• PNAs can be used as antisense or antigene agents for sequence- specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.
• PNAs can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art.
• PNA- DNA chimeras can be generated which may combine the advantageous properties of PNA and DNA.
• Such chimeras allow DNA recognition enzymes, e.g., RNAse H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity.
• PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation.
• PNA-DNA chimeras can be performed as described in Finn et al., Nucleic Acids Res. 24:3357-63, 1996.
• a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry and modified nucleoside analogs.
• Compounds such as 5'-(4-methoxytrityl)arnino-5'-deoxy-thymidine phosphoramidite can be used as a link between the PNA and the 5' end of DNA (Mag et al, Nucleic Acids Res. 17:5973-88, 1989).
• PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al., Nucleic Acids Res. 24:3357-63, 1996).
• chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment (Peterser et al., Bioorganic Med. Chem. Lett. 5: 1119-11124, 1975).
• the inhibitory nucleic acids can include other appended groups such as peptides, or agents facilitating transport across the cell membrane (see, Letsinger et al., Proc. Natl. Acad. Sci. U.SA. 86:6553-6556, 1989; Lemaitre et al, Proc. Natl. Acad. Sci. U.S.A. 84:648-652, 1989; and WO 88/09810).
• the inhibitory nucleic acids can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al, Bio/Techniques 6:958-976, 1988) or intercalating agents (see, e.g., Zon, Pharm.
• the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.
• RNAi RNA interference
• double-stranded RNA corresponding to a portion of the gene to be silenced (e.g., a gene encoding a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein)) is introduced into a mammalian cell.
• the dsRNA is digested into 21-23 nucleotide- long duplexes called short interfering RNAs (or siRNAs), which bind to a nuclease complex to form what is known as the RNA-induced silencing complex (or RISC).
• siRNAs short interfering RNAs
• the RISC targets the homologous transcript by base pairing interactions between one of the siRNA strands and the endogenous mRNA. It then cleaves the mRNA about 12 nucleotides from the 3' terminus of the siRNA (see Sharp et al, Genes Dev. 15:485-490, 2001, and Hammond et al., Nature Rev. Gen. 2: 110-119, 2001).
• RNA-mediated gene silencing can be induced in a mammalian cell in many ways, e.g., by enforcing endogenous expression of RNA hairpins (see, Paddison et al, Proc. Natl. Acad. Sci. U.S.A. 99: 1443-1448, 2002) or, as noted above, by transfection of small (21-23 nt) dsRNA (reviewed in Caplen, Trends Biotech. 20:49-51, 2002).
• Methods for modulating gene expression with RNAi are described, e.g., in U.S. Patent No. 6,506,559 and US
• Standard molecular biology techniques can be used to generate siRNAs.
• Short interfering RNAs can be chemically synthesized, recombinantly produced, e.g., by expressing RNA from a template DNA, such as a plasmid, or obtained from commercial vendors, such as Dharmacon.
• the RNA used to mediate RNAi can include synthetic or modified nucleotides, such as phosphorothioate nucleotides.
• siRNA molecules used to decrease expression of a target integrin can vary in a number of ways. For example, they can include a 3' hydroxyl group and strands of 21, 22, or 23 consecutive nucleotides. They can be blunt ended or include an overhanging end at either the 3' end, the 5' end, or both ends.
• At least one strand of the RNA molecule can have a 3' overhang from about 1 to about 6 nucleotides (e.g., 1-5, 1-3, 2-4, or 3-5 nucleotides (whether pyrimidine or purine nucleotides) in length. Where both strands include an overhang, the length of the overhangs may be the same or different for each strand.
• the 3' overhangs can be stabilized against degradation (by, e.g., including purine nucleotides, such as adenosine or guanosine nucleotides or replacing pyrimidine nucleotides by modified analogues (e.g., substitution of uridine 2-nucleotide 3' overhangs by 2'-deoxythymidine is tolerated and does not affect the efficiency of RNAi).
• purine nucleotides such as adenosine or guanosine nucleotides
• pyrimidine nucleotides by modified analogues (e.g., substitution of uridine 2-nucleotide 3' overhangs by 2'-deoxythymidine is tolerated and does not affect the efficiency of RNAi).
• siRNA can be used in the methods of decreasing a target integrin (e.g., any of the exemplary target integrins described herein) mRNA or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) mRNA, provided it has sufficient homology to the target of interest (e.g., a sequence present in any one of SEQ ID NOs: 1-27, e.g., a target sequence encompassing the translation start site or the first exon of the mRNA).
• a target integrin e.g., any of the exemplary target integrins described herein
• an integrin ligand e.g., any of the exemplary integrin ligands described herein
• the siRNA can range from about 21 base pairs of the gene to the full length of the gene or more (e.g., about 20 to about 30 base pairs, about 50 to about 60 base pairs, about 60 to about 70 base pairs, about 70 to about 80 base pairs, about 80 to about 90 base pairs, or about 90 to about 100 base pairs).
• inhibitory nucleic acids preferentially bind (e.g., hybridize) to a nucleic acid encoding a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein).
• a target integrin e.g., any of the exemplary target integrins described herein
• an integrin ligand e.g., any of the exemplary integrin ligands described herein
• integrin inhibitors that are short interfering RNAs (siRNAs) are described in Wang et al, Cancer Cell Int. 16:90, 2016).
• the integrin inhibitor is a short hairpin RNA (shRNA).
• Non-limiting examples of integrin inhibitors that are microRNA include miR-124 (Cai et al, Sci. Rep. 7:40733, 2017), miR-134 (Qin et al., Oncol. Rep. 37(2):823-830, 2017), miR-92b (Ma et al., Oncotarget 8(4):6681-6690, 2007), miR-17 (Gong et al, Oncol. Rep. 36(4), 2016), miR-338 (Chen et al, Oncol. Rep. 36(3): 1467-74, 2016), and miR-30a-5p (Li et al, Int. J. Oncol. 48(3): 1155-1164, 2016).
• the integrin inhibitor can include modified bases/locked nucleic acids (LNAs).
• the integrin inhibitor is an aptamer (e.g., Berg et al, Mol. Ther. Nucl. Acids 5:e294, 2016; and Hussain et al, Nucleic Acid Ther. 23(3):203- 212, 2013). Additional examples of integrin inhibitors that are inhibitory nucleic acids are described in Juliano et al, Therctnostics 1 :211-219, 2011; Millard et al., Therctnostics 1 : 154- 188, 2011 ; and Teoh et al, Curr. Mol. Med. 15:714-734, 2015.
• the integrin inhibitor is an antisense nucleic acid, e.g., alicaforsen (Yacyshyn et al, Clin.
• a therapeutically effective amount of an inhibitory nucleic acid targeting a nucleic acid encoding a target integrin (e.g., any of the exemplary target integrins described herein) or an integrin ligand (e.g., any of the exemplary integrin ligands described herein) can be administered to a subject (e.g., a human subject) in need thereof.
• a target integrin e.g., any of the exemplary target integrins described herein
• an integrin ligand e.g., any of the exemplary integrin ligands described herein
• the inhibitory nucleic acid can be about 10 nucleotides to about 40 nucleotides (e.g., about 10 to about 30 nucleotides, about 10 to about 25 nucleotides, about 10 to about 20 nucleotides, about 10 to about 15 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35
• thermal melting point refers to the temperature, under defined ionic strength, pH, and inhibitory nucleic acid concentration, at which 50% of the inhibitory nucleic acids complementary to the target sequence hybridize to the target sequence at equilibrium.
• an inhibitory nucleic acid can bind specifically to a target nucleic acid under stingent conditions, e.g., those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 °C. for short oligonucleotides (e.g., 10 to 50 nucleotide). Stringent conditions can also be achieved with the addition of destabilizing agents such as formamide.
• the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding a target integrin, e.g., any of the exemplary target integrins described herein, or a nucleic acid encoding an integrin ligand, e.g., any of the exemplary integrin ligands described herein) with a Tm of greater than 20 °C, greater than 22 °C, greater than 24 °C, greater than 26 °C, greater than 28 °C, greater than 30 °C, greater than 32 °C, greater than 34 °C, greater than 36 °C, greater than 38 °C, greater than 40 °C, greater than 42 °C, greater than 44 °C, greater than 46 °C, greater than 48 °C, greater than 50 °C, greater than 52 °C, greater than 54 °C, greater than 56 °
• a target nucleic acid e.g., a
• the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding a target integrin, e.g., any of the exemplary target integrins described herein, or a nucleic acid encoding an integrin ligand, e.g., any of the exemplary integrin ligands described herein) with a Tm of about 20 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C
• a target nucleic acid e.g.,
• the inhibitory nucleic acid can be formulated in a nanoparticle (e.g., a nanoparticle including one or more synthetic polymers, e.g., Patil et al,
• the nanoparticle can be a mucoadhesive particle (e.g., nanoparticles having a positively-charged exterior surface) (Andersen et al., Methods Mol. Biol. 555:77-86, 2009). In some embodiments, the nanoparticle can have a neutrally-charged exterior surface.
• the inhibitory nucleic acid can be formulated, e.g., as a liposome (Buyens et al, J. Control Release 158(3): 362-370, 2012; Scarabel et al, Expert Opin. Drug Deliv.
• a pharmaceutical composition can include a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein).
• a pharmaceutical composition consists of a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein).
• the sterile saline is a pharmaceutical grade saline.
• a pharmaceutical composition can include one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water.
• a pharmaceutical composition consists of one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water.
• a pharmaceutical composition includes one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and phosphate-buffered saline (PBS).
• a pharmaceutical composition consists of one or more inhibitory nucleic acids (e.g., any of the inhibitory nucleic acids described herein) and sterile phosphate-buffered saline (PBS).
• the sterile saline is a pharmaceutical grade PBS.
• one or more inhibitory nucleic acids may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations.
• compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
• compositions including one or more inhibitory nucleic acids encompass any pharmaceutically acceptable salts, esters, or salts of such esters.
• Non-limiting examples of pharmaceutical compositions include pharmaceutically acceptable salts of inhibitory nucleic acids.
• Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.
• prodrugs that can include additional nucleosides at one or both ends of an inhibitory nucleic acid which are cleaved by endogenous nucleases within the body, to form the active inhibitory nucleic acid.
• Lipid moieties can be used to formulate an inhibitory nucleic acid.
• the inhibitory nucleic acid is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids.
• inhibitory nucleic acid complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid.
• a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to a particular cell or tissue in a mammal.
• a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to fat tissue in a mammal.
• a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to muscle tissue.
• compositions provided herein comprise one or more inhibitory nucleic acid and one or more excipients.
• excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin,
• a pharmaceutical composition provided herein includes liposomes and emulsions. Liposomes and emulsions can be used to formulate hydrophobic compounds. In some examples, certain organic solvents such as dimethylsulfoxide are used.
• a pharmaceutical composition provided herein includes one or more tissue-specific delivery molecules designed to deliver one or more inhibitory nucleic acids to specific tissues or cell types in a mammal.
• a pharmaceutical composition can include liposomes coated with a tissue-specific antibody.
• a pharmaceutical composition provided herein can include a co-solvent system.
• co-solvent systems include benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
• VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM and 65% w/v polyethylene glycol 300.
• surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
• a pharmaceutical composition can be formulated for oral administration. In some examples, pharmaceutical compositions are formulated for buccal administration.
• a pharmaceutical composition is formulated for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
• a pharmaceutical composition includes a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
• other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
• injectable suspensions are prepared using appropriate liquid carriers, suspending agents, and the like.
• Some pharmaceutical compositions for injection are formulated in unit dosage form, e.g., in ampoules or in multi-dose containers.
• Some pharmaceutical compositions for injection are suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
• Solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
• a therapeutically effective amount of an inhibitory nucleic acid targeting an integrin can be administered to a subject (e.g., a human subject) in need of thereof.
• the inhibitory nucleic acids are 10 to 40 (e.g., 10 to 30, 10 to 25, 10 to 20, 10 to 15, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40) nucleotides in length.
• inhibitory nucleic acids may comprise at least one modified nucleic acid at either the 5 ' or 3 ' end of the DNA or RN A.
• the integrin inhibitor is an antibody or an antigen-binding fragment thereof (e.g., a Fab or a scFv).
• the antibody can be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof.
• an antibody can be a scFv-Fc, a VHH domain, a VNAR domain, a (scFv)2, a minibody, or a BiTE.
• an antibody can be a DVD-Ig, and a dual- affinity re-targeting antibody (DART), a triomab, kih IgG with a common LC, a crossmab, an ortho-Fab IgQ a 2-in-l-IgQ IgG-ScFv, scFv2-Fc, a bi-nanobody, tanden antibody, a DART- Fc, a scFv-HAS-scFv, DNL-Fab3, DAF (two-in-one or four-in-one), DutaMab, DT-IgG, knobs-in-holes common LC, knobs-in-holes assembly, charge pair antibody, Fab-arm exchange antibody, SEEDbody, Triomab, LUZ-Y, Fcab, k -body, orthogonal Fab, DVD-IgQ IgG(H)-scFv, scFv-(H)
• DART
• Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab')2 fragment, and a Fab' fragment.
• Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an IgG (e.g., an antigen-binding fragment of IgGl, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgQ e.g., human or humanized IgGl, IgG2, IgG3, or IgG4); an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgAl or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgAl or IgA2); an antigen-binding fragment of an IgD (e.
• any of the antibodies or antigen-binding fragments thereof described herein can bind to any of the integrins described herein or any of the integrin ligands described herein.
• the antibody is a pan- ⁇ antibody (e.g., OS2966 (Carbonell et al., Cancer Res. 73(10):3145-3154, 2013).
• the integrin antibody is a monoclonal antibody (e.g., 17E6 (Castel et al., Eur. J. Cell. Biol. 79(7):502-512, 2000); Mitjans et al, Int. J. Cancer 87(5): 716-723, 2000)).
• the monoclonal antibody is vedolizumab (e.g., Entyvio®) or a variant thereof (Feagan et al., N. Engl. J. Med 369:699-710, 2013; Sandborn et al., N. Engl. J. Med. 369:711-721, 2013; Sands et al,
• the antibody can be a Fab fragment of a monoclonal chimeric mouse-human antibody (e.g., abciximab (ReoPro, c7E3), Kononczuk et al., Curr. Drug Targets 16(13): 1429-1437, 2015; Jiang et ⁇ ., ⁇ Microbiol. Biotechnol. 98(1): 105-114, 2014), or a variant thereof.
• the integrin antibody is a humanized monoclonal antibody.
• the humanized monoclonal antibody is natalizumab (Tysabri®) (Targan et al, Gastroenterology 132(5): 1672-1683, 2007; Sandborn et al., N. Engl. J. Med. 353(18): 1912-1925, 2005; Nakamura et al, Intern Med. 56(2):211- 214, 2017; Singh et al, J. Pediatr. Gastroenterol. Nutr. 62(6): 863-866, 2016).
• the humanized monoclonal antibody is vitaxin (MEDI-523) or a variant thereof (Huveneers et al, Int, J. Radiat. Biol.
• the humanized monoclonal antibody is etaracizumab (Abegrin®, MEDI-522, LM609) or a variant thereof (Hersey et al, Cancer 116(6): 1526-1534, 2010; Delbaldo et al, Invest New Drugs 26(l):35-43, 2008).
• the humanized monoclonal antibody is CNT095 (Intetumumab®) or a variant thereof (Jia et al, Anticancer Drugs 24(3):237-250, 2013; Heidenreich et ⁇ ., ⁇ . Oncol.
• the humanized monoclonal antibody is efalizumab (Raptiva®) or a variant thereof (Krueger et al, J. Invest. Dermatol. 128(11):2615-2624, 2008; Li et al, PNAS 106(11):4349-4354, 2009; Woolacott et al, Health Technol. Assess 10: 1-233, 2006).
• the humanized monoclonal antibody is STX-100 (Stromedix®) or a variant thereof (van Aarsen et al, Cancer Res.
• the humanized monoclonal antibody is 264RAD or a variant thereof (Eberlein et al, Oncogene 32(37):4406-4417, 2013).
• the humanized monoclonal antibody is rovelizumab or a variant thereof (Goodman et al, Trends Pharmacol. Sci 33:405-412, 2012). In some embodiments, the humanized monoclonal antibody is Cytolin® or a variant thereof (Ry chert et al, Virology J. 10: 120, 2013).
• the humanized monoclonal antibody is etrolizumab or a variant thereof (Vermeire et al., Lancet 384:309-318, 2014; Rutgeerts et al, Gut 62: 1122-1130, 2013; Lin et al., Gastroenterology 146:307-309, 2014; Ludviksson et al, J. Immunol. 162(8):4975-4982, 1999; Stefanich et al., Br. J. Pharmacol. 162(8): 1855- 1870, 2011).
• the humanized monoclonal antibody is abrilumab (AMG 181; MEDI-7183) or a variant thereof (Pan et al, Br.
• the humanized monoclonal antibody is PF-00547659 (SHP647) or a variant thereof (Vermeire et al, Gut 60(8): 1068-1075, 2011; Sandborn et al, Gastroenterology 1448(4):S-162, 2015).
• the humanized monoclonal antibody is SAN-300 (hAQC2) or a variant thereof (Karpusas et al., J. Mol. Biol. 327: 1031-1041, 2003).
• the humanized monoclonal antibody is DI176E6 (EMD 5257) or a variant thereof (Goodman et al., Trends Pharmacol. Sci 33:405-412, 2012; and Sheridan et al., Nat. Biotech. 32:205-207, 2014).
• the integrin antibody is a chimeric monoclonal antibody.
• the chimeric monoclonal antibody is volociximab or a variant thereof (Kuwada et al, Curr. Opin. Mol. Ther. 9(l):92-98, 2007; Ricart et al, Clin. Cancer Res. 14(23):7924-7929, 2008; Ramakrishnan et al, J. Exp. Ther. Oncol. 5(4):273-86, 2006; Bell- McGuinn et al, Gynecol. Oncol. 121 :273-279, 2011 ; Almokadem et al, Exp. Opin. Biol. Ther. 12:251-7, 2012).
• the antibody specifically binds one or more (e.g., 1, 2, 3, 4, or 5) integrin. In some embodiments, the antibody specifically binds an integrin dimer (e.g., MLN-00002, MLN02 (Feagan et al, Clin. Gastroenterol. Hepatol. 6(12): 1370-1377, 2008; Feagan et al., N. Engl. J. Med. 352(24):2499-2507, 2005). In certain embodiments, the antibody comprises or consists of an antigen-binding fragment of abciximab (ReoproTM) (Straub et al., Eur. J. Cardiothorac Surg.
• ReoproTM abciximab
• the integrin inhibitor is an antibody-drug conjugate (e.g., IMGN388 (Bendell et al., EJC Suppl 8(7): 152, 2010).
• the small molecule integrin inhibitor can be PTG-100, which is described in, e.g., Shames et al, "Pharmakokinetics and Pharmacodynamics of the Novel Oral Peptide Therapeutic PTG-100 ( ⁇ 4 ⁇ 7 Integrin Antagonist) in Normal Healthy
• any of the antibodies or antigen-binding fragments described herein has a dissociation constant (KD) of less than 1 x 10 "5 M (e.g., less than 0.5 x 10 "5 M, less than 1 x 10 "6 M, less than 0.5 x 10 "6 M, less than 1 x 10 "7 M, less than 0.5 x 10 "7 M, less than 1 x 10 "8 M, less than 0.5 x 10 "8 M, less than 1 x 10 "9 M, less than 0.5 x 10 "9 M, less than 1 x 10 "10 M, less than 0.5 x 10 "10 M, less than 1 x 10 "11 M, less than 0.5 x 10 "11 M, or less than 1 x 10 "12 M), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).
• SPR surface plasmon resonance
• any of the antibodies or antigen-binding fragments described herein has a KD of about 1 x 10 " 12 M to about 1 x 10 "5 M, about 0.5 x 10 "5 M, about 1 x 10 "6 M, about 0.5 x 10 "6 M, about 1 x 10 "7 M, about 0.5 x 10 "7 M, about 1 x 10 "8 M, about 0.5 x 10 " 8 M, about 1 x 10 "9 M, about 0.5 x 10 "9 M, about 1 x 10 "10 ⁇ , about 0.5 x 10 " 10 ⁇ , about 1 x 10 "1 1 M, or about 0.5 x 10 "1 1 M (inclusive); about 0.5 x 10 " 11 M to about 1 x 10 "5 M, about 0.5 x 10 "5 M, about 1 x 10 "6 M, about 0.5 x 10 "6 M, about 1 x 10 "7 M, about 0.5 x 10 "7 M, about 1 x 10 "8 M, about 0.5
• any of the antibodies or antigen-binding fragments described herein has a Koff of about 1 x 10 "6 s "1 to about 1 x 10 "3 s “1 , about 0.5 x 10 "3 s “1 , about 1 x 10 "4 s “ 1 , about 0.5 x 10 "4 s “1 , about 1 x 10 "5 s “1 , or about 0.5 x 10 "5 s “1 (inclusive); about 0.5 x 10 "5 s “1 to about 1 x 10 "3 s “1 , about 0.5 x 10 "3 s “1 , about 1 x 10 "4 s “1 , about 0.5 x 10 "4 s “1 , or about 1 x 10 "5 s “1 (inclusive); about 1 x 10 "5 s “1 to about 1 x 10 "3 s “1 , about 0.5 x 10 "3 s “1 , about 1 x 10 "4 s “ 1 , or about
• any of the antibodies or antigen-binding fragments described herein has a Kon of about 1 x 10 2 M' 1 to about 1 x lO ⁇ 1 , about 0.5 x 10 6 M'V 1 , about 1 x 10 s M-V 1 , about 0.5 x 10 5 M'V 1 , about 1 x 10 4 M'V 1 , about 0.5 x 10 4 M'V 1 , about 1 x 10 3 M ' V 1 , or about 0.5 x 10 3 M ' 1 (inclusive); about 0.5 x 10 3 M ' 1 to about 1 x 10 6 M ' V 1 , about 0.5 x 10 6 M ' V 1 , about 1 x 10 s M ⁇ s "1 , about 0.5 x 10 5 M ' V 1 , about 1 x 10 4 M ' V 1 , about 0.5 x 10 4 M-y 1 , or about 1 x 10 3 M ' V 1 (inclusive); about 1 x 10 3 M
• the integrin inhibitor is a fusion protein (e.g., an Fc fusion protein of an extracellular domain of an integrin or an integrin receptor), a soluble receptor (e.g., the extracellular domain of an integrin or an integrin receptor), or a recombinant integrin binding protein (e.g., an integrin ligand).
• a fusion protein e.g., an Fc fusion protein of an extracellular domain of an integrin or an integrin receptor
• a soluble receptor e.g., the extracellular domain of an integrin or an integrin receptor
• a recombinant integrin binding protein e.g., an integrin ligand
• the integrin inhibitor is a small molecule. In some embodiments, the integrin inhibitor is a small molecule.
• the small molecule is a non-peptide small molecule.
• the non-peptide small molecule is a RGD (ArgGlyAsp)-mimetic antagonist (e.g., tirofiban (Aggrastat®); Pierro et al, Eur. J. Ophthalmol. 26(4):e74-76, 2016; Guan et al, Eur. J. Pharmacol 761 : 144-152, 2015.
• the small molecule is a4 antagonist (e.g., firategrast (Miller et al, Lancet Neurol.
• the small molecule is ⁇ 4 ⁇ 1 antagonist (e.g., IVL745 (Norris et al, J. Allergy Clin. Immunol. 116(4):761-767, 2005; Cox et al, Nat. Rev. Drug Discov.
• ⁇ 4 ⁇ 1 antagonist e.g., IVL745 (Norris et al, J. Allergy Clin. Immunol. 116(4):761-767, 2005; Cox et al, Nat. Rev. Drug Discov.
• BIO-1211 Abraham et al., Am. J. Respir. Crit. Care Med. 162:603-611, 2000; Ramroodi et al., Immunol. Invest. 44(7):694-712, 2015; Lin et al., J. Med. Chem. 42(5):920-934, 1999
• HMR 1031 Diamant et al, Clin. Exp. Allergy 35(8): 1080-1087, 2005
• valategrast R411) (Cox et al., Nat. Rev. Drug Discov.
• the small molecule is ⁇ 3 antagonist (e.g., L0000845704, SB273005).
• the small molecule is ⁇ 5 ⁇ 1 antagonist (e.g., JSM6427).
• the small molecule is GLPG0974 (Vermeire et al, J.
• the small molecule is MK-0429 (Pickarksi et al, Oncol. Rep. 33(6):2737-45, 2015; Rosenthal et al., Asia Pac J. Clin. Oncol. 6:42-8, 2010).
• the small molecule is JSM-6427 or a variant thereof (Zahn et al, Arch.
• the small molecule targets a ⁇ 2 integrin. In some embodiments, the small molecule targets a ⁇ 2 integrin.
• the small molecule is SAR-118 (SARI 118) or a variant thereof (Zhong et al, ACS Med. Chem. Lett. 3(3):203-206, 2012; Suchard et al., J. Immunol. 184:3917-3926, 2010; Yandrapu et al, J. Ocul. Pharmacol. Ther. 29(2):236-248, 2013; Semba et al, Am. J.
• the small molecule is BMS-587101 or a variant thereof (Suchard et al, J. Immunol. 184(7):3917-3926, 2010; Potin et al, J. Med. Chem. 49:6946-6949, 2006). See e.g., Shimaoka et al, Immunity 19(3):391-402, 2003; U.S. Patent Nos. 7,138,417; 7,928,113; 7,943,660; and 9,216,174; US 2008/0242710; and US 2008/0300237. Cyclic Peptides
• the integrin inhibitor is a cyclic peptide. In some embodiments, the integrin inhibitor is a cyclic peptide.
• the cyclic peptide comprises or consists of an amino acid sequence as set forth in the amino acid sequence of a ligand recognition sequence of an endogenous integrin ligand. In some embodiments, the cyclic peptide competes for a target integrin ligand binding site with an endogenous integrin ligand. In some embodiments, the cyclic peptide includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8) D-amino acids. In some embodiments, the cyclic peptide is a synthetic cyclic peptide. In some embodiments, the synthetic cyclic peptide is a heptapeptide.
• the synthetic cyclic peptide is eptifabitide (IntegrilinTM), or a variant thereof.
• the cyclic peptide comprises a heterocyclic nucleic (e.g., a benzodiazepinone, a piperazine, a benzoazepinone, a nitroaryl, an isoxazoline, an indazole, or a phenol; Spalluto et al, Curr. Med. Chem. 12:51-70, 2005).
• the cyclic peptide is a macrocycle (see, e.g., Halland et al., ACS Med. Chem. Lett. 5(2): 193-198, 2014).
• the peptide is ALG-1001 or a variant thereof (Mathis et al, Retin. Phys. 9:70, 2012).
• the cyclic peptide is an imidazolone-phenylalanine derivative, a heteroaryl, hetrocyclic, and aryl derivative, a bicyclic-aromatic amino acid derivative, a cyclohexane-carboxylic acid derivative, a di-aryl substituted urea derivative, a multimeric L-alanine derivative, a L-alanine derivative, or a pyrimidyl-sulfonamide derivative (see, e.g., U.S. Patent Nos. 6,630,492; 6,794,506; 7,049,306; 7,371,854; 7,759,387; 8,030,328; 8,129,366; 7,820,687; 8,350,010; and 9,345,793).
• the integrin inhibitor is a peptidomimetic.
• the peptidomimetic has an integrin-ligand recognition motif (e.g., RGD, KTS, or MLD). See, e.g., Carron et al, Cancer Research 58: 1930-1935, 1998; Fanelli et al, Vascular Cell 6: 11, 2014; and De Marco et al, Curr. Top. Med. Chem. 16(3):343-359, 2016.
• the peptidomimetic is an RGD(ArgGlyAsp)-based peptide (US Patent No. 8,809,338, incorporated by reference in its entirety herein).
• RGD(ArgGlyAsp)-based peptide US Patent No. 8,809,338, incorporated by reference in its entirety herein.
• the RGD-based peptide can be cilengitide or a variant thereof (EMD 12974) (Mas-Moruno et al, Anticancer Agents Med. Chem. 10:753-768, 2010; Reardon et al., Future Oncol. 7(3):339-354, 2011 ; Beekman et al, Clin. Genitourin Cancer 4(4):299-302, 2006; SC56631 (e.g., Engleman et al, Am Soc. Clin. Invest. 99(9):2284-2292, 1997; Peng et al, Nature Chem Biol. 2:381-389, 2006).
• the peptidomimetic can be a Lys-Gly-Asp (KGD)-based peptide.
• the peptidomimetic can be vipegitide or a variant thereof (Momic et al, Drug Design Devel. Therapy 9:291-304, 2015).
• the peptidomimetic can be a peptide conjugated with an antimicrobial synthetic peptide, (e.g., ACDCRGDCFC conjugated with (KLAKLAK) 2 (Ellerby et al, Nat. Med. 5(9): 1032-1038, 1999). See, e.g., U.S. Patent No. 8,636,977.
• the integrin inhibitor can be a disintegrin.
• disintegrin refers to a low molecular weight peptide integrin inhibitor derived from a snake venom (e.g., pit viper venom).
• the disintegrin is a RGD(ArgGlyAsp)-, a KTS- or an MLD-based disintegrin.
• Non-limiting examples of disintegrins include accutin, accurhagin-C, albolabrin, alternagin-c, barbourin, basilicin, bitisgabonin-1, bitisgabonin-2, bitistatin, cerastin, cereberin, cumanastatin 1, contortrostatin, cotiarin, crotatroxin, dendroaspin, disba-01, durissin, echistatin, EC3, elegantin, eristicophin, eristostatin, EMS11, E04, E05, flavoridin, flavostatin, insularin, jarastatin, jerdonin, jerdostatin, lachesin, lebein (e.g., lebein-1, lebein- 2), leberagin-C, lebestatin, lutosin, molossin, obtustatin, ocellatusin, rhodocetin, rh
• a method of treating a disease of the gastrointestinal tract comprises administering to the subject a pharmaceutical formulation wherein the pharmaceutical formulation is delivered proximate to one or more sites of disease by one of various methods.
• the pharmaceutical formulation may be delivered via a medical device such as an endoscope, ingestible device, or reservoir; the pharmaceutical formulation may be a solid dosage form, a liquid dosage form, a suppository or an enema for rectal administration with different types of release such as sustained or delayed release.
• the pharmaceutical formulation is delivered proximate to one or more sites of disease by an endoscope, ingestible device, or reservoir containing the pharmaceutical formulation.
• the GI tract can be imaged using endoscopes, or more recently, by ingestible devices that are swallowed. Direct visualization of the GI mucosa is useful to detect subtle mucosal alterations, as in inflammatory bowel diseases, as well as any flat or sessile lesions.
• Endoscopes may comprise a catheter.
• the catheter may be a spray catheter.
• a spray catheter may be used to deliver dyes for diagnostic purposes.
• a spray catheter may be used to deliver a therapeutic agent at the site of disease in the GI tract.
• the Olypmus PW-205V is a ready-to-use spray catheter that enables efficient spraying for maximal differentiation of tissue structures during endoscopy, but may also be used to deliver drugs diseased tissue.
• MEMS micro-electromechanical systems
• Endoscopic capsules do not have the capability of accurately locating a site autonomously. They require doctor oversight over a period of hours in order to manually determine the location. Autonomous ingestible devices are advantageous in that regard.
• Ingestible devices are also advantageous over spray catheters in that they are less invasive, thereby allowing for regular dosing more frequently than spray catheters. Another advantage of ingestible devices is the greater ease with which they can access, relative to a catheter, certain sections of the GI tract such as the ascending colon, the cecum, and all portions of the small intestine.
• one or more different mechanisms can be used to determine the location of an ingestible device within the GI tract.
• Various implementations may be used for localization of ingestible devices within the GI tract.
• certain implementations can include one or more electromagnetic sensor coils, magnetic fields, electromagnetic waves, electric potential values, ultrasound positioning systems, gamma scintigraphy techniques or other radio-tracker technology have been described by others.
• imaging can be used to localize, for example, using anatomical landmarks or more complex algorithms for 3D reconstruction based on multiple images.
• Other technologies rely on radio frequency, which relies on sensors placed extemally on the body to receive the strength of signals emitted by the capsule.
• Ingestible devices may also be localized based on reflected light in the medium surrounding the device; pH;
• the disclosure provides an ingestible device, as well as related systems and methods that provide for determining the position of the ingestible device within the GI tract of a subject with very high accuracy.
• the ingestible device can be any suitable ingestible device, as well as related systems and methods that provide for determining the position of the ingestible device within the GI tract of a subject with very high accuracy.
• the ingestible device can be any suitable ingestible device, as well as related systems and methods that provide for determining the position of the ingestible device within the GI tract of a subject with very high accuracy.
• the ingestible device can
• the ingestible device includes one or more processing devices, and one more machine readable hardware storage devices.
• the one or more machine readable hardware storage devices store instructions that are executable by the one or more processing devices to determine the location of the ingestible device in a portion of a GI tract of the subject.
• the one or more machine readable hardware storage devices store instructions that are executable by the one or more processing devices to transmit data to an external device (e.g., a base station external to the subject, such as a base station carried on an article worn by the subject) capable of implementing the data to determine the location of the device within the GI tract of the subject.
• an external device e.g., a base station external to the subject, such as a base station carried on an article worn by the subject
• the location of the ingestible device within the GI tract of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%. In some embodiments, the location of the ingestible device within the GI tract of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the portion of the GI tract of the subject can include, for example, the esophagus, the stomach, duodenum, the jejunum, and/or the terminal ileum, cecum and colon. An exemplary and non-limiting embodiment is provided below in Example 13.
• the location of the ingestible device within the esophagus of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• An exemplary and non-limiting embodiment is provided below in Example 13.
• the location of the ingestible device within the stomach of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• An exemplary and non-limiting embodiment is provided below in Example 13.
• the location of the ingestible device within the duodenum of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• An exemplary and non-limiting embodiment is provided below in Example 13.
• the location of the ingestible device within the jejunum of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• An exemplary and non-limiting embodiment is provided below in Example 13.
• the location of the ingestible device within the terminal ileum, cecum and colon of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the location of the ingestible device within the cecum of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• An exemplary and non-limiting embodiment is provided below in Example 13.
• the portion of the portion of the GI tract of the subject can include, for example, the esophagus, the stomach, duodenum, the jejunum, and/or the terminal ileum, cecum and colon.
• the location of the ingestible device within the esophagus of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the location of the ingestible device within the stomach of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the location of the ingestible device within the duodenum of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the location of the ingestible device within the jejunum of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the location of the ingestible device within the terminal ileum, cecum and colon of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the location of the ingestible device within the cecum of the subject can be determined to an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.
• the term "reflectance” refers to a value derived from light emitted by the device, reflected back to the device, and received by a detector in or on the device. For example, in some embodiments this refers to light emitted by the device, wherein a portion of the light is reflected by a surface extemal to the device, and the light is received by a detector located in or on the device.
• an illumination refers to any electromagnetic emission.
• an illumination may be within the range of Infrared Light (IR), the visible spectrum and ultraviolet light (UV), and an illumination may have a majority of its power centered at a particular wavelength in the range of lOOnm to lOOOnm.
• a plurality of illuminations with different wavelengths may be used.
• the embodiments described herein may refer to the use of green or blue spectrums of light. However, it is understood that these embodiments may use any suitable light having a wavelength that is substantially or approximately within the green or blue spectra defined above, and the localization systems and methods described herein may use any suitable spectra of light.
• ingestible device 100 may be used to identify a location within a gastrointestinal (GI) tract.
• ingestible device 100 may be configured to autonomously determine whether it is located in the stomach, a particular portion of the small intestine such as a duodenum, jejunum, or ileum, or the large intestine by utilizing sensors operating with different wavelengths of light. Additionally, ingestible device 100 may be configured to autonomously determine whether it is located within certain portions of the small intestine or large intestine, such as the duodenum, the jejunum, the cecum, or the colon.
• Ingestible device 100 may have a housing 102 shaped similar to a pill or capsule.
• the housing 102 of ingestible device 100 may have a first end portion 104, and a second end portion 106.
• the first end portion 104 may include a first wall portion 108
• second end portion 106 may include a second wall portion 1 10.
• first end portion 104 and second end portion 106 of ingestible device 100 may be manufactured separately, and may be affixed together by a connecting portion 1 12.
• ingestible device 100 may include an optically transparent window 114.
• Optically transparent window 114 may be transparent to various types of illumination in the visible spectrum, infrared spectrum, or ultraviolet light spectrum, and ingestible device 100 may have various sensors and illuminators located within the housing 102, and behind the transparent window 114. This may allow ingestible device 100 to be configured to transmit illumination at different wavelengths through transparent window 1 14 to an environment external to housing 102 of ingestible device 100, and to detect a reflectance from a portion of the illumination that is reflected back through transparent window 1 14 from the environment external to housing 102. Ingestible device 100 may then use the detected level of reflectance in order to determine a location of ingestible device 100 within a GI tract.
• optically transparent window 114 may be of any shape and size, and may wrap around the circumference of ingestible device 100.
• ingestible device 100 may have multiple sets of sensors and illuminators positioned at different locations azimuthally behind window 114.
• ingestible device 100 may optionally include an opening 116 in the second wall portion 1 10.
• the second wall portion 1 10 may be configured to rotate around the longitudinal axis of ingestible device 100 (e.g., by means of a suitable motor or other actuator housed within ingestible device 100). This may allow ingestible device 100 to obtain a fluid sample from the GI tract, or release a substance into the GI tract, through opening 116.
• FIG. 2 shows an exploded view of ingestible device 100.
• ingestible device 100 may optionally include a rotation assembly 1 18.
• Optional rotation assembly 1 18 may include a motor 1 18-1 driven by a microcontroller (e.g., a microcontroller coupled to printed circuit board 120), a rotation position sensing ring 1 18-2, and a storage sub-unit 1 18-3 configured to fit snugly within the second end portion 104.
• rotation assembly 118 may cause second end portion 104, and opening 1 16, to rotate relative to the storage sub-unit 118-3.
• the cavity on the side of the storage sub-unit 118-3 may be exposed to the environment external to the housing 102 of ingestible device 100.
• the storage sub-unit 118-3 may be loaded with a medicament or other substance prior to the ingestible device 100 being administered to a subject.
• the medicament or other substance may be released from the ingestible device 100 by aligning opening 116 with the cavity within storage sub-unit 118-3.
• the storage sub-unit 118-3 may be configured to hold a fluid sample obtained from the GI tract.
• ingestible device 100 may be configured to align opening 116 with the cavity within storage sub-unit 118-3, thus allowing a fluid sample from the GI tract to enter the cavity within storage sub-unit 118-3. Afterwards, ingestible device 100 may be configured to seal the fluid sample within storage sub-unit 118-3 by further rotating the second end portion 106 relative to storage sub-unit 118-3.
• storage sub-unit 118-3 may also contain a hydrophilic sponge, which may enable ingestible device 100 to better draw certain types of fluid samples into ingestible device 100.
• ingestible device 100 may be configured to either obtain a sample from within the GI tract, or to release a substance into the GI tract, in response to determining that ingestible device 100 has reached a predetermined location within the GI tract.
• ingestible device 100 may be configured to obtain a fluid sample from the GI tract in response to determining that the ingestible device has entered the jejunum portion of the small intestine (e.g., as determined by process 900 discussed in relation to FIG. 9).
• Other ingestible devices capable of obtaining samples or releasing substances are discussed in commonly-assigned PCT Application No. PCT/CA2013/000133 filed February 15, 2013, commonly-assigned U.S. Provisional Application No.
• Ingestible device 100 may include a printed circuit board (PCB) 120, and a battery 128 configured to power PCB 120.
• PCB 120 may include a programmable microcontroller, and control and memory circuitry for holding and executing firmware or software for coordinating the operation of ingestible device 100, and the various components of ingestible device 100.
• PCB 120 may include memory circuitry for storing data, such as data sets of measurements collected by sensing sub-unit 126, or instructions to be executed by control circuitry to implement a localization process, such as, for example, one or more of the processes, discussed herein, including those discussed below in connection with one or more of the associated flow charts.
• PCB 120 may include a detector 122 and an illuminator 124, which together form sensing sub-unit 126.
• control circuitry within PCB 120 may include processing units, communication circuitry, or any other suitable type of circuitry for operating ingestible device 100.
• Only a single detector 122 and a single illuminator 124 forming a single sensing sub-unit 126 are shown. However, it is understood that in some embodiments there may be multiple sensing sub-units, each with a separate illuminator and detector, within ingestible device 100.
• sensing sub-unit 126 may be configured to generate an illumination using illuminator 124, which is directed through the window 114 in a radial direction away from ingestible device 100. This illumination may reflect off of the environment external to ingestible device 100, and the reflected light coming back into ingestible device 100 through window 114 may be detected as a reflectance by detector 122.
• window 114 may be of any suitable shape and size.
• window 114 may extend around a full circumference of ingestible device 100.
• there may be a plurality of sensing sub-units e.g., similar to sensing sub- unit 126) located at different positions behind the window.
• three sensing sub- units may be positioned behind the window at the same longitudinal location, but spaced 120 degrees apart azimuthally. This may enable ingestible device 100 to transmit illuminations in all directions radially around ingestible device 100, and to measure each of the corresponding reflectances.
• illuminator 124 may be capable of producing illumination at a variety of different wavelengths in the ultraviolet, infrared, or visible spectrum.
• illuminator 124 may be implemented by using Red-Green-Blue Light-Emitting diode packages (RGB-LED). These types of RGB-LED packages are able to transmit red, blue, or green illumination, or combinations of red, blue, or green illumination.
• detector 122 may be configured to sense reflected light of the same wavelengths as the illumination produced by illuminator 124.
• detector 122 may be configured to detect different reflectances produced by red, blue, or green illumination (e.g., through the use of an appropriately configured photodiode). These detected reflectances may be stored by ingestible device 100 (e.g., within memory circuitry of PCB 120), and may then be used by ingestible device 100 in determining a location of ingestible device 100 within the GI tract (e.g., through the use of process 500 (FIG. 5), process 600 (FIG. 6), or process 900 (FIG. 9)).
• ingestible device 100 is intended to be illustrative, and not limiting. It will be understood that modifications to the general shape and structure of the various devices and mechanisms described in relation to FIG. 1 and FIG. 2 may be made without significantly changing the functions and operations of the devices and mechanisms.
• ingestible device 100 may have a housing formed from a single piece of molded plastic, rather than being divided into a first end portion 104 and a second end portion 106.
• the location of window 114 within ingestible device 100 may be moved to some other location, such as the center of ingestible device 100, or to one of the ends of ingestible device 100.
• ingestible device 100 may be modified to replace detector 122 with an image sensor, and the ingestible device may be configured to measure relative levels of red, blue, or green light by decomposing a recorded image into its individual spectral components.
• ingestible devices with localization capabilities which may be utilized in order to implement the systems and methods discussed in relation to FIG. 1-11, are discussed in co-owned PCT Application No.
• FIG. 3 is a diagram of an ingestible device during an example transit through a gastrointestinal (GI) tract, in accordance with some embodiments of the disclosure.
• GI gastrointestinal
• Ingestible device 300 may include any portion of any other ingestible device discussed in this disclosure (e.g., ingestible device 100 (FIG. 1)), and may be any suitable type of ingestible device with localization capabilities.
• ingestible device 300 may be one embodiment of ingestible device 100 without the optional opening 116 (FIG. 1) or optional rotation assembly 118 (FIG. 2)).
• ingestible device 300 may be ingested by a subject, and as ingestible device 300 traverses the GI tract, ingestible device 300 may be configured to determine its location within the GI tract.
• the movement of ingestible device 300 and the amount of light detected by ingestible device 300 may vary substantially depending on the location of ingestible device 300 within the GI tract, and ingestible device 300 may be configured to use this information to determine a location of ingestible device 300 within the GI tract.
• ingestible device 300 may detect ambient light from the surrounding environment, or reflectances based on illumination generated by ingestible device 300 (e.g., generated by illuminator 124 (FIG. 1)), and use this information to determine a location of ingestible device 300 through processes, such as described herein.
• the current location of ingestible device 300, and the time that ingestible device 300 detected each transition between the various portions of the GI tract, may then be stored by ingestible device 300 (e.g., in memory circuitry of PCB 120 (FIG. 2)), and may be used for any suitable purpose.
• ingestible device 300 Shortly after ingestible device 300 is ingested, ingestible device will traverse the esophagus 302, which may connect the subject's mouth to a stomach 306.
• ingestible device 300 may be configured to determine that it has entered the esophagus portion GI tract by measuring the amount and type of light (e.g., via detector 122 (FIG. 2)) in the environment surrounding the ingestible device 300. For instance, ingestible device 300 may detect higher levels of light in the visible spectrum (e.g., via detector 122 (FIG. 2)) while outside the subject's body, as compared to the levels of light detected while within the GI tract.
• the visible spectrum e.g., via detector 122 (FIG. 2
• ingestible device 300 may have previously stored data (e.g., on memory circuitry of PCB 120 (FIG. 2)) indicating a typical level of light detected when outside of the body, and the ingestible device 300 may be configured to determine that entry to the body has occurred when a detected level of light (e.g., detected via detector 122 (FIG. 2)) has been reduced beyond a threshold level (e.g., at least a 20-30% reduction) for a sufficient period of time (e.g., 5.0 seconds).
• a detected level of light e.g., detected via detector 122 (FIG. 2)
• a threshold level e.g., at least a 20-30% reduction
• ingestible device 300 may be configured to detect a transition from esophagus 302 to stomach 306 by passing through sphincter 304.
• ingestible device 300 may be configured to determine whether it has entered stomach 306 based at least in part on a plurality of parameters, such as but not limited to the use of light or temperature measurements (e.g., via detector 122 (FIG. 2) or via a
• thermometer within ingestible device 300 may be configured to determine that ingestible device 300 has entered stomach 306 after detecting that a measured temperature of ingestible device 300 exceeds 31 degrees Celsius.
• ingestible device 300 may be configured to automatically determine it has entered stomach 306 after one minute (or another pre-set time duration parameter, 80 seconds, 90 seconds, etc.) has elapsed from the time that ingestible device 300 was ingested, or one minute (or another pre-set time duration parameter, 80 seconds, 90 seconds, etc.) from the time that ingestible device 300 detected that it has entered the GI tract.
• Stomach 306 is a relatively large, open, and cavernous organ, and therefore ingestible device 300 may have a relatively large range of motion.
• the motion of ingestible device 300 is relatively restricted within the tube-like structure of the duodenum 310, the jejunum 314, and the ileum (not shown), all of which collectively form the small intestine.
• the interior of stomach 306 has distinct optical properties from duodenum 310 and jejunum 314, which may enable ingestible device 300 to detect a transition from stomach 306 to duodenum 310 through the appropriate use of measured reflectances (e.g., through the use of reflectances measured by detector 122 (FIG. 2)), as used in conjunction with process 600 (FIG. 6)).
• ingestible device 300 may be configured to detect a pyloric transition from stomach 306 to duodenum 310 through the pylorus 308. For instance, in some embodiments, ingestible device 300 may be configured to periodically generate illumination in the green and blue wavelengths (e.g., via illuminator 124 (FIG. 2)), and measure the resulting reflectances (e.g., via detector 122 (FIG. 2)). Ingestible device 300 may be configured to then use a ratio of the detected green reflectance to the detected blue reflectance to determine whether ingestible device 300 is located within the stomach 306, or duodenum 310 (e.g., via process 600 (FIG. 6)).
• illumination in the green and blue wavelengths e.g., via illuminator 124 (FIG. 2)
• detector 122 FIG. 2
• Ingestible device 300 may be configured to then use a ratio of the detected green reflectance to the detected blue reflectance to determine whether ingestible device 300 is located
• ingestible device 300 may detect a pyloric transition from stomach 306 to duodenum 310, an example of which is discussed in relation to FIG. 6.
• ingestible device 300 may be configured to detect a reverse pyloric transition from duodenum 310 to stomach 306. Ingestible device 300 will typically transition naturally from stomach 306 to duodenum 310, and onward to jejunum 314 and the remainder of the GI tract. However, similar to other ingested substances, ingestible device 300 may occasionally transition from duodenum 310 back to stomach 306 as a result of motion of the subject, or due to the natural behavior of the organs with the GI tract.
• ingestible device 300 may be configured to continue to periodically generate illumination in the green and blue wavelengths (e.g., via illuminator 124 (FIG. 2)), and measure the resulting reflectances (e.g., via detector 122 (FIG. 2)) to detect whether or not ingestible device 300 has returned to stomach 306.
• illumination in the green and blue wavelengths e.g., via illuminator 124 (FIG. 2)
• detector 122 FIG. 2
• ingestible device 300 may be configured to detect a transition to the jejunum 314 through the duodenojejunal flexure 312.
• ingestible device 300 may be configured to use reflectances to detect peristaltic waves within the jejunum 314, caused by the contraction of the smooth muscle tissue lining the walls of the jejunum 314.
• ingestible device 300 may be configured to begin periodically transmitting illumination (and measuring the resulting reflectances (e.g., via detector 122 and illuminator 124 of sensing sub-unit 126 (FIG. 2)) at a sufficiently high frequency in order to detect muscle contractions within the jejunum 314.
• Ingestible device 300 may then determine that it has entered the jejunum 314 in response to having detected either a first muscle contraction, or a predetermined number of muscle contractions (e.g., after having detected three muscle contractions in sequence).
• the interaction of ingestible device 300 with the walls of jejunum 314 is also discussed in relation to FIG. 4, and an example of this detection process is described in additional detail in relation to FIG. 9.
• FIG. 4 is a diagram of an ingestible device during an example transit through a jejunum, in accordance with some embodiments of the disclosure.
• Diagrams 410, 420, 430, and 440 depict ingestible device 400 as it traverses through a jejunum (e.g., jejunum 314), and how ingestible device 400 interacts with peristaltic waves formed by walls 406A and 406B (collectively, walls 406) of the jejunum.
• ingestible device 400 may include any portion of any other ingestible device discussed in this disclosure (e.g., ingestible device 100 (FIG. 1) or ingestible device 300 (FIG.
• ingestible device 400 may be substantially similar to the ingestible device 300 (FIG. 3) or ingestible device 100 (FIG. 1), with window 404 being the same as window 1 14 (FIG. 1), and sensing sub-unit 402 being the same as sensing sub-unit 126 (FIG. 2).
• Diagram 410 depicts ingestible device 400 within the jejunum, when the walls 406 of the jejunum are relaxed.
• the confined tube-like structure of the jejunum naturally causes ingestible device 400 to be oriented longitudinally along the length of the jejunum, with window 404 facing walls 406.
• ingestible device 400 may use sensing sub-unit 402 to generate illumination (e.g., via illuminator 124 (FIG. 2)) oriented towards walls 406, and to detect the resulting reflectances (e.g., via detector 122 (FIG. 2)) from the portion of the illumination reflected off of walls 406 and back through window 404.
• illumination e.g., via illuminator 124 (FIG. 2)
• detector 122 FIG. 2
• ingestible device 400 may be configured to use sensing sub-unit 402 to generate illumination and measure the resulting reflectance with sufficient frequency to detect peristaltic waves within the jejunum. For instance, in a healthy human subject, peristaltic waves may occur at a rate of approximately 0.1 Hz to 0.2 Hz. Therefore, the ingestible device 400 may be configured to generate illumination and measure the resulting reflectance at least once every 2.5 seconds (i.e., the minimum rate necessary to detect a 0.2 Hz signal), and preferably at a higher rate, such as once every 0.5 seconds, which may improve the overall reliability of the detection process due to more data points being available.
• the ingestible device 400 need not gather measurements at precise intervals, and in some embodiments the ingestible device 400 may be adapted to analyze data gathered at more irregular intervals, provided that there are still a sufficient number of appropriately spaced data points to detect 0.1 Hz to 0.2 Hz signals.
• Diagram 420 depicts ingestible device 400 within the jejunum, when the walls 406 of the jejunum begin to contract and form a peristaltic wave.
• Diagram 420 depicts contracting portion 408A of wall 406A and contracting portion 408B of wall 406B (collectively, contracting portion 408 of wall 406) that form a peristaltic wave within the jejunum.
• the peristaltic wave proceeds along the length of the jejunum as different portions of wall 406 contract and relax, causing it to appear as if contracting portions 408 of wall 406 proceed along the length of the jejunum (i.e., as depicted by contracting portions 408 proceeding from left to right in diagrams 410-430).
• ingestible device 400 may detect a similar level of reflectance (e.g., through the use of illuminator 124 and detector 122 of sensing sub-unit 126 (FIG. 2)) as detected when there is no peristaltic wave occurring (e.g., as detected when ingestible device 400 is in the position indicated in diagram 410).
• Diagram 430 depicts ingestible device 400 within the jejunum, when the walls 406 of the jejunum continue to contract, squeezing around ingestible device 400. As the peristaltic wave proceeds along the length of the jejunum, contracting portions 408 of wall 406 may squeeze tightly around ingestible device 400, bringing the inner surface of wall 406 into contact with window 404.
• ingestible device 400 may detect a change in a reflectance detected as a result of illumination produced by sensing sub-unit 402.
• the absolute value of the change in the measured reflectance may depend on several factors, such as the optical properties of the window 404, the spectral components of the illumination, and the optical properties of the walls 406.
• ingestible device 400 may be configured to store a data set with the reflectance values over time, and search for periodic changes in the data set consistent with the frequency of the peristaltic waves (e.g., by analyzing the data set in the frequency domain, and searching for peaks between 0.1 Hz to 0.2 Hz).
• ingestible device 400 may detect muscle contractions due to peristaltic waves without foreknowledge of the exact changes in reflectance signal amplitude that may occur as a result of detecting the muscle contractions of the peristaltic wave.
• An example procedure for detecting muscle contractions is discussed further in relation to FIG. 9, and an example of a reflectance data set gathered while ingestible device 400 is located within the jejunum is discussed in relation to FIG. 10.
• Diagram 440 depicts ingestible device 400 within the jejunum, when the peristaltic wave has moved past ingestible device 400.
• Diagram 440 depicts contracting portions 408 that form the peristaltic wave within the jejunum having moved past the end of ingestible device 400.
• the peristaltic wave proceeds along the length of the jejunum as different portions of wall 406 contract and relax, causing it to appear as if contracting portions 408 of wall 406 proceed along the length of the jejunum (i.e., as depicted by contracting portions 408 proceeding from left to right in diagrams 410-430).
• ingestible device 400 may detect a similar level of reflectance (e.g., through the use of illuminator 124 and detector 122 of sensing sub-unit 126 (FIG. 2)) as detected when there is no peristaltic wave occurring (e.g., as detected when ingestible device 400 is in the position indicated in diagram 410, or diagram 420).
• a similar level of reflectance e.g., through the use of illuminator 124 and detector 122 of sensing sub-unit 126 (FIG. 2)
• peristaltic waves may occur with relatively predictable regularity. After the peristaltic wave has passed over ingestible device 400 (e.g., as depicted in diagram 440), the walls 406 of the j ejunum may relax again (e.g., as depicted in diagram 410), until the next peristaltic wave begins to form.
• ingestible device 400 may be configured to continue to gather reflectance value data while it is within the GI tract, and may store a data set with the reflectance values over time.
• ingestible device 400 may detect each of the muscle contractions as the peristaltic wave passes over ingestible device 400 (e.g., as depicted in diagram 430), and may enable ingestible device 400 to both count the number of muscle contractions that occur, and to determine that a current location of the ingestible device 400 is within the jejunum.
• ingestible device 400 may be configured to monitor for possible muscle contractions while is inside either the stomach or the duodenum, and may determine that ingestible device 400 has moved to the jejunum in response to detecting a muscle contraction consistent with a peristaltic wave.
• FIG. 5 is a flowchart illustrating some aspects of a localization process used by the ingestible device.
• FIG. 5 may be described in connection with the ingestible device 100 for illustrative purposes, this is not intended to be limiting, and either portions or the entirety of the localization procedure 500 described in FIG. 5 may be applied to any device discussed in this application (e.g., the ingestible devices 100, 300, and 400), and any of the ingestible devices may be used to perform one or more parts of the process described in FIG. 5.
• the features of FIG. 5 may be combined with any other systems, methods or processes described in this application. For example, portions of the process in FIG. 5 may be integrated into or combined with the pyloric transition detection procedure described by FIG. 6, or the jejunum detection process described by FIG. 9.
• the ingestible device gathers measurements (e.g., through detector 122 (FIG. 2)) of ambient light.
• ingestible device 100 may be configured to periodically measure (e.g., through detector 122 (FIG. 2)) the level of ambient light in the environment surrounding ingestible device 100.
• the type of ambient light being measured may depend on the configuration of detector 122 within ingestible device 100. For example, if detector 122 is configured to measure red, green, and blue wavelengths of light, ingestible device 100 may be configured to measure the ambient amount of red, green, and blue light from the surrounding environment.
• the amount of ambient light measured by ingestible device 100 will be larger in the area external to the body (e.g., a well-lit room where ingestible device 100 is being administered to a subject) and in the oral cavity of the subject, as compared to the ambient level of light measured by ingestible device 100 when inside of an esophagus, stomach, or other portion of the GI tract (e.g., esophagus 302, stomach 306, duodenum 310, or jejunum 314 (FIG. 3)).
• an esophagus, stomach, or other portion of the GI tract e.g., esophagus 302, stomach 306, duodenum 310, or jejunum 314 (FIG. 3).
• the ingestible device determines (e.g., via control circuitry within PCB 120 (FIG. 2)) whether the ingestible device has detected entry into the GI tract.
• ingestible device 100 may be configured to determine when the most recent measurement of ambient light (e.g., the measurement gathered at 502) indicates that the ingestible device has entered the GI tract.
• the first time that ingestible device 100 gatherers a measurement of ambient light at 502 ingestible device 100 may store that measurement (e.g., via storage circuitry within PCB 120 (FIG. 2)) as a typical level of ambient light external to the body.
• Ingestible device 100 may be configured to then compare the most recent measurement of ambient light to the typical level of ambient light external to the body (e.g., via control circuitry within PCB 120 (FIG.
• ingestible device 100 determines that ingestible device 100 has entered the GI tract when the most recent measurement of ambient light is substantially smaller than the typical level of ambient light external to the body. For example, ingestible device 100 may be configured to detect that it has entered the GI tract in response to determining that the most recent measurement of ambient light is less than or equal to 20% of the typical level of ambient light external to the body. If ingestible device 100 determines that it has detected entry into the GI tract (e.g., that ingestible device 100 has entered at least the esophagus 302 (FIG. 3)), process 500 proceeds to 506.
• process 500 proceeds back to 502 where the ingestible device 100 gathers further measurements.
• ingestible device 100 may be configured to wait a predetermined amount of time (e.g., five seconds, ten seconds, etc.), and then gather another measurement of the level of ambient light from the environment surrounding ingestible device 100.
• the ingestible device (e.g., ingestible device 100, 300, or 400) waits for a transition from the esophagus to the stomach (e.g., from esophagus 302 to stomach 306 (FIG.
• ingestible device 100 may be configured to determine that it has entered the stomach (e.g., stomach 306 (FIG. 3)) after waiting a predetermined period of time after having entered the GI tract. For instance, a typical esophageal transit time in a human patient may be on the order of 15-30 seconds. In this case, after having detected that ingestible device 100 has entered the GI tract at 504 (i.e., after detecting that ingestible device 100 has reached at least esophagus 302 (FIG.
• ingestible device 100 may be configured to wait one minute, or a similar amount of time longer than the typical esophageal transmit time (e.g., ninety-seconds), before automatically determining that ingestible device 100 has entered at least the stomach (e.g., stomach 306 (FIG. 3)).
• the typical esophageal transmit time e.g. ninety-seconds
• the ingestible device may also determine it has entered the stomach based on measurements of pH or temperature.
• ingestible device 100 may be configured to determine that it has entered the stomach if a temperature of ingestible device has increased to at least 31 degrees Celsius (i.e., consistent with the temperature inside the stomach), or if a measured pH of the environment surrounding ingestible device 100 is sufficiently acidic (i.e., consistent with the acidic nature of gastric juices that may be found inside the stomach).
• the ingestible device (e.g., ingestible device 100, 300, or 400) stores data indicating the ingestible device has entered the stomach (e.g., stomach 306 (FIG. 3)).
• ingestible device 100 may store data (e.g., within storage circuitry of PCB 120 (FIG. 2)) indicative of ingestible device 100 having entered at least the stomach.
• process 500 proceeds to 510 where ingestible device 100 may be configured to gather data to detect entry into the duodenum (e.g., duodenum 310 (FIG. 3)).
• process 500 may also simultaneously proceed from 508 to 520, where ingestible device 100 may be configured to gather data in order to detect muscle contractions and detect entry into the jejunum (e.g., jejunum 314 (FIG. 3)).
• ingestible device 100 may be configured to simultaneously monitor for entry into the duodenum at 516-518, as well as detect for entry into the jejunum at 520-524. This may allow ingestible device 100 to determine when it has entered the jejunum (e.g., as a result of detecting muscle contractions), even when it fails to first detect entry into the duodenum (e.g., as a result of very quick transit times of the ingestible device through the duodenum).
• the ingestible device gathers measurements of green and blue reflectance levels (e.g., through the use of illuminator 124 and detector 122 of sensing sub-unit 126 (FIG. 2)) while in the stomach (e.g., stomach 306 (FIG. 3)).
• ingestible device 100 may be configured to periodically gather measurements of green and blue reflectance levels while in the stomach.
• ingestible device 100 may be configured to transmit a green illumination and a blue illumination (e.g., via illuminator 124 (FIG. 2)) every five to fifteen seconds, and measure the resulting reflectance (e.g., via detector 122 (FIG.
• ingestible device 100 gathers a new set of measurements, the measurements may be added to a stored data set (e.g., stored within memory circuitry of PCB 120 (FIG. 2)). The ingestible device 100 may then use this data set to determine whether or not ingestible device 100 is still within a stomach (e.g., stomach 306 (FIG. 3)), or a duodenum (e.g., duodenum 310 (FIG. 3)).
• a stomach e.g., stomach 306 (FIG. 3)
• a duodenum e.g., duodenum 310 (FIG. 3)
• the ingestible device (e.g., ingestible device 100, 300, or 400) may be configured to detect a first reflectance based on generating an illumination of a first wavelength in approximately the green spectrum of light (between 495-600 nm), and detecting a second reflectance based on generating an illumination of the second wavelength in approximately the blue spectrum of light (between 400-495 nm).
• the ingestible device may ensure that the illumination in the green spectrum and the illumination in the blue spectrum have wavelengths separated by at least 50 nm. This may enable ingestible device 100 to sufficiently distinguish between the two wavelengths when detecting the reflectances (e.g., via detector 122 (FIG. 2)). It is understood that the separation of 50 nm is intended to be illustrative, and not limiting, and depending on the accuracy of the detectors within ingestible device 100, smaller separations may be possible to be used.
• the ingestible device determines (e.g., using control circuitry within PCB 120 (FIG. 2)) whether the ingestible device has detected a transition from the stomach (e.g., stomach 306 (FIG. 3)) to a duodenum (e.g., duodenum 310 (FIG. 3)) based on a ratio of green and blue (G/B) reflectance levels.
• ingestible device 100 may obtain (e.g., from memory circuitry of PCB 120 (FIG. 2)) a data set containing historical data for the respective ratio of the green reflectance to the blue reflectance as measured at a respective time.
• a duodenum (e.g., duodenum 310 (FIG. 3)) of a human subject reflects a higher ratio of green light to blue light, as compared to the ratio of green light to blue light that is reflected by a stomach (e.g., stomach 306 (FIG. 3)).
• ingestible device 100 may be configured to take a first set of ratios from the data set, representing the result of recent measurements, and compare them to a second set of ratios from the data set, representing the results of past measurements.
• the ingestible device 100 may determine that it has entered the duodenum (e.g., duodenum 310 (FIG. 3)) from the stomach (e.g., stomach 306 (FIG. 3)). If the ingestible device 100 detects a transition from the stomach (e.g., stomach 306 (FIG. 3)) to a duodenum (e.g., duodenum 310 (FIG.
• process 500 proceeds to 514, where ingestible device 100 stores data indicating that the ingestible device 100 has entered the duodenum (e.g., duodenum 310 (FIG. 3)).
• ingestible device 100 determines that the ingestible device has not transitioned from the stomach (e.g., stomach 306 (FIG. 3)) to the duodenum (e.g., duodenum 310 (FIG. 3)
• process 500 proceeds back to 510 to gather more measurements of green and blue reflectance levels while still in the stomach (e.g., stomach 306 (FIG. 3)).
• ingestible device 100 may be configured to take a mean of the second set of data, (e.g., the set of data previously recorded while in stomach 306 (FIG. 3)) and store this as a typical ratio of green light to blue light detected within the stomach (e.g., stomach 306 (FIG. 3)) (e.g., within memory circuitry of PCB 120 (FIG. 2)).
• a mean of the second set of data e.g., the set of data previously recorded while in stomach 306 (FIG. 3)
• a typical ratio of green light to blue light detected within the stomach e.g., stomach 306 (FIG. 3)
• PCB 120 FIG. 2
• This stored information may later be used by ingestible device 100 to determine when ingestible device 100 re-enters the stomach (e.g., stomach 306 (FIG. 3)) from the duodenum (e.g., duodenum 310 (FIG. 3)) as a result of a reverse pyloric transition.
• stomach e.g., stomach 306 (FIG. 3)
• duodenum e.g., duodenum 310 (FIG. 3)
• the ingestible device (e.g., ingestible device 100, 300, or 400) stores data indicating that the ingestible device has entered the duodenum (e.g., duodenum 310 (FIG. 3)).
• ingestible device 100 may store a flag within local memory (e.g., memory circuitry of PCB 120) indicating that the ingestible device 100 is currently in the duodenum.
• the ingestible device 100 may also store a timestamp indicating the time when ingestible device 100 entered the duodenum.
• process 500 proceeds to 520 where ingestible device 100 may be configured to gather data in order to detect muscle contractions and detect entry into the jejunum (e.g., jejunum 314 (FIG. 3)).
• ingestible device 100 may be configured to gather data additional data in order to detect re-entry into the stomach (e.g., stomach 306 (FIG. 3)) from the duodenum (e.g., duodenum 310 (FIG. 3)).
• the ingestible device gathers measurements (e.g., via sensing sub-unit 126 (FIG. 2)) of green and blue reflectance levels while in the duodenum (e.g., duodenum 310 (FIG. 3)).
• ingestible device 100 may be configured to periodically gather measurements (e.g., via sensing sub-unit 126 (FIG. 2)) of green and blue reflectance levels while in the duodenum, similar to the measurements made at 510 while in the stomach.
• ingestible device 100 may be configured to transmit a green illumination and a blue illumination (e.g., via illuminator 124 (FIG.
• ingestible device 100 may gather a new set of measurements, the measurements may be added to a stored data set (e.g., stored within memory circuitry of PCB 120 (FIG. 2)). The ingestible device 100 may then use this data set to determine whether or not ingestible device 100 is still within the duodenum (e.g., duodenum 310 (FIG. 3)), or if the ingestible device 100 has transitioned back into the stomach (e.g., stomach 306 (FIG. 3)).
• duodenum e.g., duodenum 310 (FIG. 3)
• stomach 306 FIG. 3
• the ingestible device determines a transition from the duodenum (e.g., duodenum 310 (FIG. 3)) to the stomach (e.g., stomach 306 (FIG. 3)) based on a ratio of the measured green reflectance levels to the measured blue reflectance levels.
• the duodenum e.g., duodenum 310 (FIG. 3)
• the stomach e.g., stomach 306 (FIG. 3)
• ingestible device 100 may compare the ratio of the measured green reflectance levels to the measured blue reflectance levels recently gathered by ingestible device 100 (e.g., measurements gathered at 516), and determine whether or not the ratio of the measured green reflectance levels to the measured blue reflectance levels is similar to the average ratio of the measured green reflectance levels to the measured blue reflectance levels seen in the stomach (e.g., stomach 306 (FIG. 3)). For instance, ingestible device 100 may retrieve data (e.g., from memory circuitry of PCB 120 (FIG.
• the ingestible device 100 determines that ingestible device 100 has transitioned back to the stomach if the recently measured ratio of the measured green reflectance levels to the measured blue reflectance levels is sufficiently similar to the average level in the stomach (e.g., within 20% of the average ratio of the measured green reflectance levels to the measured blue reflectance levels seen in the stomach, or within any other suitable threshold level). If the ingestible device detects a transition from the duodenum (e.g., duodenum 310 (FIG. 3)) to the stomach (e.g., stomach 306 (FIG.
• the duodenum e.g., duodenum 310 (FIG. 3
• process 500 proceeds to 508 to store data indicating the ingestible device has entered the stomach (e.g., stomach 306 (FIG. 3)), and continues to monitor for further transitions.
• the ingestible device does not detect a transition from the duodenum (e.g., duodenum 310 (FIG. 3)) to the stomach (e.g., stomach 306 (FIG. 3)
• process 500 proceeds to 516 to gather additional measurements of green and blue reflectance levels while in the duodenum (e.g., duodenum 310 (FIG. 3)), which may be used to continuously monitor for possible transitions back into the stomach.
• An example procedure for using measurements of green and blue reflectances to monitor for transitions between the stomach and the duodenum is discussed in greater detail in relation to FIG. 6.
• the ingestible device gathers periodic measurements of the reflectance levels (e.g., via sensing sub-unit 126 (FIG. 2)) while in the duodenum (e.g., duodenum 310 (FIG. 3)).
• the ingestible device e.g., ingestible device 100, 300, or 400
• these periodic measurements may enable ingestible device 100 to detect muscle contractions (e.g., muscle contractions due to a peristaltic wave as discussed in relation to FIG.
• Ingestible device 100 may be configured to gather periodic measurements using any suitable wavelength of illumination (e.g., by generating illumination using illuminator 124, and detecting the resulting reflectance using detector 122 (FIG. 2)), or combinations of wavelengths of illumination.
• ingestible device 100 may be configured to generate red, green, and blue illumination, store separate data sets indicative of red, green, and blue illumination, and analyze each of the data sets separately to search for frequency components in the recorded data indicative of detected muscle contractions.
• the measurements gathered by ingestible device 100 at 520 may be sufficiently fast as to detect peristaltic waves in a subject.
• peristaltic waves may occur at a rate of approximately 0.1 Hz to 0.2 Hz. Therefore, the ingestible device 400 may be configured to generate illumination and measure the resulting reflectance at least once every 2.5 seconds (i.e., the minimum rate necessary to detect a 0.2 Hz signal), and preferably at a higher rate, such as once every 0.5 seconds or faster, and store values indicative of the resulting reflectances in a data set (e.g., within memory circuitry of PCB 120 (FIG. 2)). After gathering additional data (e.g., after gathering one new data point, or a predetermined number of new data points), process 500 proceeds to 522, where ingestible device 100 determines whether or not a muscle contraction has been detected.
• the ingestible device determines
• ingestible device 100 may obtain a fixed amount of data stored as a result of measurements made at 520 (e.g., retrieve the past minute of data from memory circuitry within PCB 120 (FIG. 2)). Ingestible device 100 may then convert the obtained data into the frequency domain, and search for peaks in a frequency range that would be consistent with peristaltic waves.
• peristaltic waves may occur at a rate of approximately 0.1 Hz to 0.2 Hz, and an ingestible device 100 may be configured to search for peaks in the frequency domain representation of the data between 0.1 Hz and 0.2 Hz above a threshold value. If the ingestible device 100 detects a contraction based on the reflectance levels (e.g., based on detecting peaks in the frequency domain representation of the data between 0.1 Hz and 0.2 Hz), process 500 proceeds to 524 to store data indicating that the device has entered the jejunum.
• process 500 proceeds to 520 to gather periodic measurements of the reflectance levels while in the duodenum (e.g., duodenum 310 (FIG. 3)).
• the ingestible device e.g., ingestible device 100, 300, or 400
• may store data e.g., within memory circuitry of PCB 120 (FIG. 2)) indicating that a muscle contraction was detected, and process 500 will not proceed from 522 to 524 until a sufficient number of muscle contractions have been detected.
• the ingestible device (e.g., ingestible device 100, 300, or 400) stores data (e.g., within memory circuitry of PCB 120 (FIG. 2)) indicating that the device has entered the jejunum (e.g., jejunum 314 (FIG. 3)).
• data e.g., within memory circuitry of PCB 120 (FIG. 2)
• ingestible device 100 may determine that it has entered the jejunum 314, and is no longer inside of the duodenum (e.g., duodenum 310 (FIG. 3)) or the stomach (e.g., stomach 306 (FIG. 3)).
• the ingestible device 100 may continue to measure muscle contractions while in the jejunum, and may store data indicative of the frequency, number, or strength of the muscle contractions over time (e.g., within memory circuitry of PCB 120 (FIG. 2)).
• the ingestible device 100 may also be configured to monitor for one or more transitions. Such transitions can include a transition from the jejunum to the ileum, an ileoceacal transition from the ileum to the cecum, a transition from the cecum to the colon, or detect exit from the body (e.g., by measuring reflectances, temperature, or levels of ambient light).
• the ingestible device may also determine that it has entered the jejunum (e.g., jejunum 314 (FIG. 3)) after a predetermined amount of time has passed after having detected entry into the duodenum (e.g., duodenum 310 (FIG. 3)). For example, barring a reverse pyloric transition from the duodenum (e.g., duodenum 310 (FIG. 3)) back to the stomach (e.g., stomach 306 (FIG. 3)), the typical transit time for an ingestible device to reach the jejunum from the duodenum in a healthy human subject is less than three minutes.
• the ingestible device (e.g., ingestible device 100, 300, or 400) may therefore be configured to automatically determine that it has entered the jejunum after spending at least three minutes within the duodenum. This determination may be made separately from the determination made based on measured muscle contractions (e.g., the determination made at 522), and in some embodiments, ingestible device 100 may determine that it has entered the jejunum in response to either detecting muscle contractions, or after three minutes has elapsed from having entered the duodenum (e.g., as determined by storing data at 514 indicative of the time that ingestible device entered the duodenum).
• 512-518 of process 500 describe the ingestible device (e.g., ingestible device 100, 300, or 400) measuring green reflectances and blue reflectances, calculating a ratio of the two reflectances, and using this information to determine when the ingestible device has transitioned between the duodenum and stomach.
• the ingestible device e.g., ingestible device 100, 300, or 400
• other wavelengths of light may be used other than green and blue, provided that the wavelengths of light chosen have different reflective properties within the stomach and the duodenum (e.g., as a result of different reflection coefficients of the stomach tissue and the tissue of the duodenum).
• the steps and descriptions of the flowcharts of this disclosure, including FIG. 5, are merely illustrative. Any of the steps and descriptions of the flowcharts, including FIG. 5, may be modified, omitted, rearranged, and performed in alternate orders or in parallel, two or more of the steps may be combined, or any additional steps may be added, without departing from the scope of the present disclosure.
• the ingestible device 100 may calculate the mean and the standard deviation of multiple data sets in parallel in order to speed up the overall computation time.
• ingestible device 100 may gather data periodic measurements and detect possible muscle contractions (e.g., at 520-522) while simultaneously gathering green and blue reflectance levels to determine transitions to and from the stomach and duodenum (e.g., at 510-518).
• steps and descriptions of FIG. 5 may be combined with any other system, device, or method described in this application, including processes 600 (FIG. 6) and 900 (FIG. 9), and any of the ingestible devices or systems discussed in this application (e.g., ingestible devices 100, 300, or 400) could be used to perform one or more of the steps in FIG. 5.
• FIG. 6 is a flowchart illustrating some aspects of a process for detecting transitions from a stomach to a duodenum and from a duodenum back to a stomach, which may be used when determining a location of an ingestible device as it transits through a gastrointestinal (GI) tract, in accordance with some embodiments of the disclosure.
• process 600 may begin when an ingestible device first detects that it has entered the stomach, and will continue as long as the ingestible device determines that it is within the stomach or the duodenum.
• process 600 may only be terminated when an ingestible device determines that it has entered the jejunum, or otherwise progressed past the duodenum and the stomach.
• FIG. 6 may be described in connection with the ingestible device 100 for illustrative purposes, this is not intended to be limiting, and either portions or the entirety of the duodenum detection process 600 described in FIG. 6 may be applied to any device discussed in this application (e.g., the ingestible devices 100, 300, or 400), and any of the ingestible devices may be used to perform one or more parts of the process described in FIG. 6.
• the features of FIG. 6 may be combined with any other systems, methods or processes described in this application. For example, portions of the process described by the process in FIG. 6 may be integrated into process 500 discussed in relation to FIG. 5.
• the ingestible device retrieves a data set (e.g., from memory circuitry within PCB 120 (FIG. 2)) with ratios of the measured green reflectance levels to the measured blue reflectance levels over time.
• a data set e.g., from memory circuitry within PCB 120 (FIG. 2)
• ingestible device 100 may retrieve a data set from PCB 120 containing recently recorded ratios of the measured green reflectance levels to the measured blue reflectance levels (e.g., as recorded at 510 or 516 of process 500 (FIG. 5)).
• the retrieved data set may include the ratios of the measured green reflectance levels to the measured blue reflectance levels over time. Example plots of data sets of ratios of the measured green reflectance levels to the measured blue reflectance levels are discussed further in relation to FIG. 7 and FIG. 8.
• the ingestible device (e.g., ingestible device 100, 300, or 400) includes a new measurement (e.g., as made with sensing sub-unit 126 (FIG. 2)) of a ratio of the measured green reflectance level to the measured blue reflectance level in the data set.
• ingestible device 100 may be configured to occasionally record new data by transmitting green and blue illumination (e.g., via illuminator 124 (FIG. 2)), detecting the amount of reflectance received due to the green and blue illumination (e.g., via detector 122 (FIG. 2)), and storing data indicative of the amount of the received reflectance (e.g., in memory circuitry of PCB 120 (FIG. 2)).
• the ingestible device 100 may be configured to record new data every five to fifteen seconds, or at any other convenient interval of time.
• ingestible device 100 is described as storing and retrieving the ratio of the measured green reflectance levels to the measured blue reflectance levels (e.g., if the amount of detected green reflectance was identical to the amount of detected blue reflectance at a given time, the ratio of the green and blue reflectances would be "1.0" at that given time); however, it is understood that the green reflectance data and the blue reflectance data may be stored separately within the memory of ingestible device 100 (e.g., stored as two separate data sets within memory circuitry of PCB 120 (FIG. 2)).
• the ingestible device retrieves a first subset of recent data by applying a first sliding window filter to the data set.
• ingestible device 100 may use a sliding window filter to obtain a predetermined amount of the most recent data within the data set, which may include any new values of the ratio of the measured green reflectance level to the measured blue reflectance level obtained at 604.
• the ingestible device may be configured to select between ten and forty data points from the data set, or ingestible device 100 may be configured to select a predetermined range of data values between fifteen seconds of data and five minutes of data.
• ranges of data may be selected, depending on how frequently measurements are recorded, and the particular application at hand. For instance, any suitable amount of data may be selected in the sliding window, provided that it is sufficient to detect statistically significant differences between the data selected in a second sliding window (e.g., the second subset of data selected at 614).
• the ingestible device may also be configured to remove outliers from the data set, or to smooth out unwanted noise in the data set.
• ingestible device 100 may select the first subset of data, or any other subset of data, by first obtaining a raw set of values by applying a window filter to the data set (e.g., selecting a particular range of data to be included).
• Ingestible device 100 may then be configured to identify outliers in the raw set of values; for instance, by identifying data points that are over three standard deviations away from the mean value of the raw set of values, or any other suitable threshold.
• Ingestible device 100 may then determine the subset of data by removing outliers from the raw set of values. This may enable ingestible device 100 to avoid spurious information when determining whether or not it is located within the stomach or the duodenum.
• the ingestible device determines whether the most recently detected location was the duodenum (e.g., duodenum 310 (FIG. 3)).
• ingestible device 100 may store a data flag (e.g., within memory circuitry of PCB 120 (FIG. 2)) indicating the most recent portion of the GI tract that the ingestible device 100 detected itself to be within. For instance, every time ingestible device 100 detects entry to the stomach (e.g., detects entry into stomach 306 (FIG.
• a flag is stored in memory indicating the ingestible device 100 is in the stomach (e.g., as part of storing data at 612). If ingestible device 100 subsequently detects entry into the duodenum (e.g., detects entry into duodenum 310 (FIG. 3) as a result of a decision made at 624), another different flag is stored in memory indicating that the ingestible device 100 is in the duodenum (e.g., as part of storing data at 624). In this case, ingestible device 100 may retrieve the most recently stored flag at 608, and determine whether or not the flag indicates that the ingestible device 100 was most recently within the duodenum.
• process 600 proceeds to 610 where the ingestible device compares the recent measurements of the ratios of the measured green reflectance levels to the measured blue reflectance levels (e.g., measurements that include the recent measurement made at 606) to the typical ratios measured within the stomach, and uses this information to determine whether a reverse pyloric transition from the duodenum back to the stomach has occurred.
• the ingestible device compares the recent measurements of the ratios of the measured green reflectance levels to the measured blue reflectance levels (e.g., measurements that include the recent measurement made at 606) to the typical ratios measured within the stomach, and uses this information to determine whether a reverse pyloric transition from the duodenum back to the stomach has occurred.
• process 600 proceeds to 614 where the ingestible device compares the recent measurements of the ratios of the measured green reflectance levels to the measured blue reflectance levels (e.g., measurements that include the recent measurement made at 606) to past measurements, and uses this information to determine whether a pyloric transition from the stomach to the duodenum has occurred.
• Process 600 proceeds from 608 to 610 when the ingestible device determined that it was most recently in the duodenum.
• the ingestible device e.g., ingestible device 100, 300, or 400 determines (e.g., via control circuitry within PCB 120 (FIG. 2)) whether the current G/B signal is similar to a recorded average G/B signal in the stomach.
• ingestible device 100 may be configured to have previously stored data (e.g., within memory circuitry of PCB 120 (FIG. 2)) indicative of the average ratio of the measured green reflectance levels to the measured blue reflectance levels measured in the stomach.
• Ingestible device 100 may then retrieve this stored data indicative of the average ratio of the measured green reflectance levels to the measured blue reflectance levels in the stomach, and compare this against the recent measurements in order to determine whether or not ingestible device 100 has returned back to the stomach from the duodenum. For instance, ingestible device 100 may determine if the mean value of the first subset of recent data (i.e., the average value of the recently measured ratios of the measured green reflectance levels to the measured blue reflectance levels) is less than the average ratio of the measured green reflectance levels to the measured blue reflectance levels within the stomach, or less that the average ratio measured within the stomach plus a predetermined number times the standard deviation of the ratios measured within the stomach.
• the mean value of the first subset of recent data i.e., the average value of the recently measured ratios of the measured green reflectance levels to the measured blue reflectance levels
• the mean value of the first subset of recent data i.e., the average value of the recently measured ratios of the measured green reflectance levels to the
• ingestible device 100 may determine whether or not the mean value of the first subset of data is less than "1.0 + k*0.2,” where "k” is a number between zero and five. It is understood that, in some embodiments, the ingestible device 100 may be configured to use a different threshold level to determine whether or not the mean value of the first subset of recent data is sufficiently similar to the average ratio of the measured green reflectance levels to the measured blue reflectance levels within the stomach.
• process 600 proceeds to 612 where ingestible device 100 stores data indicating that it has re-entered the stomach from the duodenum.
• ingestible device 100 proceeds directly to 604, and continues to obtain new data on an ongoing basis.
• the ingestible device (e.g., ingestible device 100, 300, or 400) stores data indicating a reverse pyloric transition from the duodenum to the stomach was detected.
• ingestible device 100 may store a data flag (e.g., within memory circuitry of PCB 120 (FIG. 2)) indicating that the ingestible device 100 most recently detected itself to be within the stomach portion of the GI tract (e.g., stomach 306 (FIG. 3)).
• a data flag e.g., within memory circuitry of PCB 120 (FIG. 2)
• the ingestible device 100 most recently detected itself to be within the stomach portion of the GI tract e.g., stomach 306 (FIG. 3).
• ingestible device 100 may also store data (e.g., within memory circuitry of PCB 120 (FIG. 2)) indicating a time that ingestible device 100 detected the reverse pyloric transition from the duodenum to the stomach. This information may be used by ingestible device 100 at 608, and as a result process 600 may proceed from 608 to 614, rather than proceeding from 618 to 610. After ingestible device 100 stores the data indicating a reverse pyloric transition from the duodenum to the stomach was detected, process 600 proceeds to 604 where ingestible device 100 continues to gather additional measurements, and continues to monitor for further transitions between the stomach and the duodenum.
• data e.g., within memory circuitry of PCB 120 (FIG. 2)
• This information may be used by ingestible device 100 at 608, and as a result process 600 may proceed from 608 to 614, rather than proceeding from 618 to 610.
• process 600 proceeds to 604 where ingestible device 100 continues to
• Process 600 proceeds from 608 to 614 when the ingestible device determined that it was not most recently in the duodenum (e.g., as a result of having most recently been in the stomach instead).
• the ingestible device e.g., ingestible device 100, 300, or 400
• ingestible device 100 may use a sliding window filter to obtain a predetermined amount of older data from a past time range, which may be separated from recent time range used to select the first subset of data gathered at 606 by a predetermined period of time.
• any suitable amount of data may be selected by the first and second window filters, and the first and second window filters may be separated by any appropriate predetermined amount of time.
• the first window filter and the second window filter may each be configured to select a predetermined range of data values from the data set, the predetermined range being between fifteen seconds of data and five minutes of data.
• the recent measurements and the past measurements may then be separated by a predetermined period of time that is between one to five times the predetermined range of data values.
• ingestible device 100 may select the first subset of data and the second subset of data to each be one minute of data selected from the dataset (i.e., selected to have a predetermined range of one minute), and the first subset of data and the second subset of data are selected from recorded measurements that are at least two minutes apart (i.e., the predetermined period of time is two minutes, which is twice the range used to select the subsets of data using the window filters).
• ingestible device 100 may select the first subset of data and the second subset of data to each be five minutes of data selected from the dataset (i.e., selected to have a predetermined range of five minutes), and the first subset of data and the second subset of data are selected from recorded measurements that are at least 10 minutes apart (i.e., the predetermined period of time is two minutes, which is twice the range used to select the subsets of data using the window filters).
• ingestible device 100 may select the second subset of data at 614 from a time frame when ingestible device 100 is known to be within the stomach.
• ingestible device 100 may alternately select a previously recorded average and standard deviation for ratios of green reflectances and blue reflectances within the stomach (e.g., an average and standard deviation typical of data recorded within the stomach, as previously recorded within memory circuitry of PCB 120 at 620) in place of the second subset of data. In this case, ingestible device 100 may simply use the previously recorded average and previously recorded standard deviation when making a determination at 616, rather than expending resources to calculate the mean and standard deviation of the second subset.
• the ingestible device determines whether the difference between the mean of the second subset and the mean of the first subset is greater than a predetermined multiple of the standard deviation of the first subset. For example, ingestible device 100 may compute a difference between a mean of the first subset of recent data and a mean of a second subset of past data, and determine whether this difference is greater than three times the standard deviation of the second subset of past data. In some embodiments, it is understood that any convenient threshold level may be used other than three times the standard deviation, such as any value between one and five times the standard deviation.
• the ingestible device may instead set the threshold level based on the standard deviation of the second subset instead of the first subset.
• process 600 proceeds to 618. Otherwise, process 600 proceeds back to 604, where the ingestible device 604 continues to gather new data to be used in monitoring for transitions between the stomach (e.g., stomach 306 (FIG. 3)) and the duodenum (e.g., duodenum 310 (FIG. 3)).
• the ingestible device determines (e.g., via control circuitry within PCB 120 (FIG. 2)) whether the determination made at 616 is the first time that the difference between the mean of the first subset of recent data and the mean of the second subset of past data is calculated to be greater than the standard deviation of the second subset. If the ingestible device determines that this is the first time that the difference between the mean of the first subset and the mean of the second subset is calculated to be greater than the standard deviation of the second subset, process 600 proceeds to 620 to store the mean of the second subset of past data as an average G/B signal in the stomach.
• process 600 proceeds directly to 622.
• the ingestible device (e.g., ingestible device 100, 300, or 400) stores the mean of the second subset as an average G/B signal in the stomach.
• ingestible device 100 may be configured to store the mean of the second subset of past data (e.g., store within memory circuitry of PCB 120 (FIG. 2)) as the average ratio of the measured green reflectance levels to the measured blue reflectance levels measured in the stomach.
• PCB 120 FIG. 2
• ingestible device 100 may also store the standard deviation of the second subset of past data as a typical standard deviation of the ratios of the measured green reflectance levels to the measured blue reflectance levels detected within the stomach. This stored information may be used by the ingestible device later on (e.g., at 610) to compare against future data, which may enable the ingestible device to detect reverse pyloric transitions from the duodenum (e.g., duodenum 310 (FIG. 3)) back to the stomach (e.g., stomach 306 (FIG. 3)), and may generally be used in place of other experimental data gathered from the stomach (e.g., in place of the second subset of data at 616). After storing the mean of the second subset as an average G/B signal in the stomach, process 600 proceeds to 622.
• duodenum e.g., duodenum 310 (FIG. 3)
• stomach 306 FIG. 3
• the ingestible device determines whether a difference of the mean of the first subset of recent data to the mean of the second subset of past data is greater than a predetermined threshold, "M".
• the predetermined threshold, "M” will be sufficiently large to ensure that the mean of the first subset is substantially larger than the mean of the second subset, and may enable ingestible device 100 to ensure that it detected an actual transition to the duodenum. This may be particularly advantageous when the determination made at 616 is potentially unreliable due to the standard deviation of the second subset of past data being abnormally small.
• a typical value of the predetermined threshold "M,” may be on the order of 0.1 to 0.5. If ingestible device 100 determines that the difference of the mean of the first subset of recent data to the second subset of past data is greater than a predetermined threshold, process 600 proceeds to 624 to store data indicating that a pyloric transition from the stomach to the duodenum (e.g., from stomach 306 to duodenum 310 (FIG. 3)) was detected.
• a pyloric transition from the stomach to the duodenum e.g., from stomach 306 to duodenum 310 (FIG. 3)
• process 600 proceeds directly to 604 where ingestible device 100 continues to make new measurements and monitor for possible transitions between the stomach and the duodenum.
• the ingestible device instead of using a difference of the mean of the first subset of recent data to the mean of the second subset of past data, determines whether the ratio of the mean of the first subset of recent data to the mean of the second subset of past data is greater than a predetermined threshold, "M".
• the predetermined threshold, "M” will be sufficiently large to ensure that the mean of the first subset is substantially larger than the mean of the second subset, and may enable ingestible device 100 to ensure that it detected an actual transition to the duodenum.
• a typical value of the predetermined threshold "M,” may be on the order of 1.2 to 2.0. It is understood any convenient type of threshold or calculation may be used to determine whether or not the first subset of data and the second subset of data are both statistically distinct from one another, and also substantially different from one another in terms of overall average value.
• the ingestible device (e.g., ingestible device 100, 300, or 400) stores data indicating a pyloric transition from the stomach to the duodenum was detected.
• ingestible device 100 may store a data flag (e.g., within memory circuitry of PCB 120 (FIG. 2)) indicating that the ingestible device 100 most recently detected itself to be within the duodenum portion of the GI tract (e.g., duodenum 310 (FIG. 3)).
• ingestible device 100 may also store data (e.g., within memory circuitry of PCB 120 (FIG.
• process 600 may proceed from 608 to 610, rather than proceeding from 618 to 614.
• process 600 proceeds to 604 where ingestible device 100 continues to gather additional measurements, and continues to monitor for further transitions between the stomach and the duodenum.
• the steps and descriptions of the flowcharts of this disclosure, including FIG. 6, are merely illustrative. Any of the steps and descriptions of the flowcharts, including FIG. 6, may be modified, omitted, rearranged, and performed in alternate orders or in parallel, two or more of the steps may be combined, or any additional steps may be added, without departing from the scope of the present disclosure.
• the ingestible device 100 may calculate the mean and the standard deviation of multiple data sets in parallel in order to speed up the overall computation time.
• process 600 may be combined with any other system, device, or method described in this application, and any of the ingestible devices or systems discussed in this application could be used to perform one or more of the steps in FIG. 6.
• portions of process 600 may be incorporated into 508-516 of process 500 (FIG. 5), and may be part of a more general process for determining a location of the ingestible device.
• the ratio of detected blue and green light e.g., as measured and added to the data set at 604 may continue even outside of the stomach or duodenum, and similar information may be recorded by the ingestible device throughout its transit in the GI tract.
• Example plots of data sets of ratios of measured green and blue reflectance levels, which may be gathered throughout the GI tract, are discussed further in relation to FIG. 7 and FIG. 8 below.

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