CONDITIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/160,987, filed on March 15, 2021, the entire contents of which are incorporated herein by reference.

BACKGROUND

[0002] Gastroesophageal reflux disease (GERD) is a very common condition typically involving symptoms such as heartburn and/or regurgitation and usually divided into erosive and non-erosive sub-types based on endoscopic presentation. Since the 1970s, the mainstay of GERD treatment has been based on parietal cell gastric acid suppression. Initially, acid suppression was managed by H2 receptor antagonists such as cimetidine and ranitidine and later, since the 1990s, usually by proton pump inhibitors (PPIs) such as omeprazole and lansoprazole. PPI therapy is very popular, with estimates in the US of over 100 million PPIs prescribed per year.

[0003] A recent population-based survey (Delshad et al 2020) found that 44% of the 72,000 US adults sampled had suffered symptoms of GERD in the past and as many as 31% of those surveyed were suffering them at the time of the study. Although the mainstay of GERD treatment, Delshad also found that as many as 54% of those being treated for GERD with daily PPI therapy were still complaining of persistent, troublesome GERD symptoms at least twice a week. Similar findings have also been described in earlier studies and meta-analysis, for instance, El-Serag et al 2010, who found the overall prevalence of GERD in the North American population as being between 17 - 28% of the studies then reviewed and poor response to PPI therapy as being between 31 - 62% of patients, depending on study type. Taken, together, these studies suggest that as many as 3% of the US adult population might be regularly administering PPI medications without symptomatic relief.

[0004] The phenomenon of patients complaining of GERD symptoms despite regular treatment with PPIs is well known and of considerable concern to both the patients and the prescribing population and has led to a splintering of the diagnosis into conditions which might be more closely attributable to reflux pathologies and those which might be less so.

[0005] In 1999, the Committee on Functional Esophageal Disorders, Multinational Working Teams to Develop Diagnostic Criteria for Functional Gastrointestinal Disorders (Rome II) proposed the classification of a new condition, which they termed Functional Heartburn. At that time, the committee defined the condition as episodic retrosternal burning in the absence of pathologic gastroesophageal reflux, pathology-based motility disorders, or structural explanations. Integral to the definition of the Rome II group was that the sufferers maintained normal esophageal acid exposure. Since 1999, the defining of functional gastrointestinal disorders and their diagnosis have been the source of much debate and have gone through multiple changes and iterations.

[0006] The latest Rome working group, Rome IV, in 2016 proposed a three-way test for patients complaining of GERD symptoms despite regular treatment with PPIs, based on normal endoscopy findings, symptom history analysis and esophageal pH testing ± esophageal pH impedance testing. This three-way test has been proposed as a method of identifying which patients are undertreated sufferers of non-erosive reflux (NERD) and which patients might need alternative therapies as having either Functional Heartburn or Reflux Hypersensitivity. According to the Rome IV guidelines, the differentiation between incorrectly treated and undertreated lies with the findings of normal or abnormal esophageal pH.

[0007] Measuring esophageal pH is usually performed on a patient by the utilization of a wireless pH capsule, such as Medtronic’s Bravo ^® capsule. Placement of the wireless capsule into the lower esophageal wall is performed on the sedated patient and frequently involves not only catheterization but also endoscopy. Esophageal pH can also be measured during impedance studies which commonly involve a two stage process whereby the patient first undertakes an esophageal manometry study to measure the strength and function of esophageal musculature and only then, if found appropriate, the physician will insert the impedance probe into the patient’s esophagus via their nasal passage. The patient will wear the probe for at least 24 hours before they need to return to their healthcare professional for it to be removed. A less common alternative and older approach to esophageal pH testing and impedance studies is the Heidelberg pH monitoring capsule, wherein a polyacylate capsule containing a microelectronic transmitter and two electrodes is swallowed by a subject and the device held in the subject esophagus or stomach by a tethering tape attached at one end to the device and at the other, taped to the subject’s cheek. As with the esophageal impedance probes, once the pH monitoring of the Heidelberg capsule is completed, the device is withdrawn back up from the esophagus or stomach and out through the mouth.

[0008] Esophageal pH testing, esophageal pH impedance testing and Heidelberg capsule assessments are cumbersome, resource intensive and potentially expensive processes involving multiple and uncomfortable visits to healthcare professionals. The availability of these services also places them outside of the reach of many of the treated population. As such, there remains a great need for an alternative, simpler and cheaper alternative to identify variability in the stomach’s pH and thereby allow for differentiation between undertreated and incorrectly treated GERD patients.

SUMMARY

[0009] In one embodiment, the present invention relates to gastroretentive devices configured to remain in the stomach of a human subject for at least twelve hours following oral administration and wherein the devices comprise a sensor configured to measure intragastric pH at least once every thirty minutes for at least twelve hours.

[0010] In another embodiment, the present invention relates to methods of administering gastroretentive devices and their use in measuring intragastric pH.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a schematic of an electronic sensor for measuring intragastric pH

[0012] FIG. 2 is a simplified drawing of a gastroretentive device comprising a sensor for measuring intragastric pH DETAILED DESCRIPTION

[0013] The present inventions may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part of this disclosure. It is to be understood that these inventions are not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed inventions.

[0014] The entire disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference.

[0015] As employed above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings.

[0016] In the present disclosure the singular forms “a,” “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a particle” is a reference to one or more of such particles and equivalents thereof known to those skilled in the art, and so forth. Furthermore, when indicating that a certain element “may be” X, Y, or Z, it is not intended by such usage to exclude in all instances other choices for the element.

[0017] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. As used herein, “about X” (where X is a numerical value) preferably refers to ±10% of the recited value, inclusive. For example, the phrase “about 8” preferably refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase “about 8%” preferably refers to a value of 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of “1 to 5” is recited, the recited range should be construed as optionally including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of “1 to 5” is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply “wherein 2 is not included.” The phrase “at least about x” is intended to embrace both “about x” and “at least x”. It is also understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “2 - 5 hours” includes 2 hours, 2.1 hours, 2.2 hours, 2.3 hours etc... up to 5 hours.

[0018] The present invention relates to methods of utilizing a gastroretentive device to monitor intragastric pH, of processing and analyzing the results of such monitoring and of using said analysis to assist in the differential diagnosis of patients possibly not responding fully to their prescribed medications.

[0019] In one embodiment, the present invention relates to gastroretentive devices configured to remain in the stomach of a human subject for at least twelve hours following oral administration and wherein the devices comprise a sensor configured to measure intragastric pH at least once every thirty minutes for at least twelve hours.

[0020] Gastroretentive devices allow for orally administered compositions to have an extended gastric residence time. Examples of gastroretentive devices include a) high density compositions which are heavy and dense enough to withstand in vivo peristaltic movement yet remain intact in spite of the gastrointestinal disturbances b) compositions containing magnetic elements and the application of an external magnet positioned on the abdomen c) swelling and/or expandable compositions which are designed to increase in size to become bigger than the diameter of pyloric sphincter and remain logged there until they are biodegraded d) floating tablets and gels where the bulk density of the compositions attains less than the density of gastric fluid after a certain lag time e) mucoadhesive gels which attach inside the lumen of the stomach wall f) mechanically expanding devices which open once inside the stomach to become larger than the diameter of the pyloric sphincter and g) mechanical devices which attach, typically by hooks or suction, inside the lumen of the stomach wall.

[0021] Further examples of gastroretentive devices include those described in Guan (2009), Devereux (1990) Clarke (1995), Ito (1990), Fujimori (1991), Groning (1996), Gupta (2009), Gupta (2010), W02015083171, US20120077878, W02011090725, W02010019915, W02008030830, W02007072495, W02005101983, W02005079752, W02004032906, WOOl 10419, W02003035029, W00200213, W02003015745, W02001097783, W02000038655, W02000038650, US20030049325, US4126672, US4814179, W02007109904, WO2018232413, WO2016066256, W02014060952, WO2014014348, WO2013054285, US20130017264, WO2012159077, W02012004231, WO2011004799, W02009153632, W02008087882, W02007106960, W02006063858, W02003037299, W02003011255, W02001058424, WO1999007342, EP3398615, WO2016087952, W02013090893, W02012070028, W02005056708, W02005007074, US20050013863, W02003089506, EP1238663, WO1998052547, WO2012059815, US20110066175, W02010035273, WO2009144558, W02008027945, W02003105812, W02015083171, WO2015187746, W02017096054, WO2018102799, WO2018213582, WO2019111132, US4735804, US5002772 and EP1915990, each of which is incorporated, in their entirety, herein by reference.

[0022] As used herein, the term “oral administration” or “orally administered” shall refer to the swallowing or otherwise ingestion via the mouth of a subject of a composition and shall be to the exclusion of the transfer of a composition via the mouth by endoscope and/or catheter and/or wherein the composition remains in material connection with the subject’s mouth or face after being swallowed and for the duration of the time that said composition is attempting to measure esophageal and/or intragastric pH. Orally administered is to be understood to be distinct and different to endoscopically or catheter transferred compositions, such as the Bravo ^® capsule, wherein the composition is transferred, or assisted in its transfer, to a subject’s esophageal or stomach mucosal lining via the subject’s mouth. Orally administered is also to be understood to be distinct and different to compositions such as esophageal impedance catheters and/or Heidelberg capsules wherein the composition remains in material connection with the subject’s mouth or face for the period of time that such devices might monitor intragastric pH.

[0023] In one embodiment of the invention, gastroretentive devices are configured to remain in the stomach of a human subject for at least twelve hours following oral administration. In another embodiment of the invention, devices are configured to remain in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration.

[0024] In one embodiment of the invention, the gastroretentive device of the invention is configured to remain in the stomach of a human subject for at least twelve or more hours and maintains its gastric retention during both fasted and fed states, i.e., the gastroretentive mechanism can be food independent or alternatively, not sufficiently influenced by the presence, or absence, of food so as to lose its gastroretentive properties.

[0025] Following retention in the stomach for at least twelve hours, the gastroretentive devices of the present invention are configured to lose their ability to remain in the stomach, whether by disintegration, bioerosion, detachment, loss of buoyancy or release from any other relevant retention mechanism, and the entire device, or parts thereof, can pass through the pylorus and into the gastrointestinal tract prior to their excretion.

[0026] In one embodiment of the invention, the gastroretentive devices comprise a sensor configured to measure intragastric pH.

[0027] As used herein, the term “intragastric pH” refers to the measurement of acidity as recorded within the stomach.

[0028] In one embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty minutes. In another embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second. [0029] In one embodiment of the invention, the sensor is configured to measure intragastric pH for at least twelve hours.

[0030] In one embodiment of the invention, the sensor is configured to measure intragastric pH for at least twelve hours following oral administration. In another embodiment of the invention, the sensor is configured to measure intragastric pH for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration.

[0031] In one embodiment of the invention, the sensor is configured to measure intragastric pH for the entire time period during which the gastroretentive device is configured to remain in the stomach of a human subject. In another embodiment of the invention, the sensor is configured to measure intragastric pH for part of the time period during which the gastroretentive device is configured to remain in the stomach of a human subject. In one embodiment of the invention, the sensor is configured to measure pH only whilst in the stomach. In one embodiment of the invention, the sensor is configured to stop measuring pH after passing through the pylorus and into the gastrointestinal tract. In one embodiment of the invention, the sensor is configured to stop measuring pH at about twelve, eighteen, twenty four, thirty six, forty eight, sixty, seventy two, eighty four, ninety six, one hundred and eight, one hundred and twenty, after one hundred and thirty two, one hundred and forty four, one hundred and fifty six, or one hundred and sixty eight hours following oral administration. In one embodiment of the invention, the sensor is activated to record intragastric pH prior to oral administration. In another embodiment of the invention, the sensor is activated to record intragastric pH after it is exposed to gastric fluid.

[0032] In one embodiment of the invention, the sensor is configured to measure intragastric pH during both the subject’s fasted and fed states, i.e., measurement of intragastric pH by the sensor is food independent. In one embodiment of the invention, the sensor is configured to measure intragastric pH whether the subject is in either an upright, sitting, prone or supine position, i.e., measurement of intragastric pH by the sensor is independent of the subject’s posture and/or pose. In one embodiment of the invention, the sensor is configured to measure intragastric pH regardless of the time of day, i.e., measurement of intragastric pH by the sensor can occur during either/both daytime and nighttime hours.

[0033] In one embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty minutes and for at least twelve hours. In another embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty, at least once every ten or at least once every minute and for at least twelve hours or at least once every thirty or at least once every ten seconds and for at least twelve hours.

[0034] In one embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty minutes and for at least twenty four hours. In another embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty, at least once every ten or at least once every minute and for at least twenty four hours or at least once every thirty or at least once every ten seconds and for at least twenty four hours.

[0035] In one embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty minutes and for at least forty eight hours. In another embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty, at least once every ten or at least once every minute and for at least forty eight hours or at least once every thirty or at least once every ten seconds and for at least forty eight hours.

[0036] In one embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty minutes and for at least seventy two hours. In another embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty, at least once every or ten at least once every minute and for at least seventy two hours or at least once every thirty or at least once every ten seconds and for at least seventy two hours.

[0037] In one embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty minutes and for at least ninety six hours. In another embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty, at least once every ten or at least once every minute and for at least ninety six hours or at least once every thirty or at least once every ten seconds and for at least ninety six hours.

[0038] In one embodiment of the invention, gastroretentive devices are configured to remain in the stomach of a human subject for at least twelve hours following oral administration and the devices comprise a sensor configured to measure intragastric pH. In another embodiment of the invention, devices are configured to remain in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration and the devices comprise a sensor configured to measure intragastric pH. In one embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty minutes. In another embodiment of the invention, the sensor is configured to measure intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second. In one embodiment of the invention, the sensor is configured to measure intragastric pH for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours. [0039] In one embodiment of the invention, the gastroretentive devices are configured to remain in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration and wherein the devices comprise a sensor configured to measure intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours.

[0040] In such embodiments, it is understood that for the duration of time that the gastroretentive device remains in the stomach, the sensor measures the pH as present in the stomach, i.e., the intragastric pH, and not as found in other locations such as the esophagus and/or duodenum.

[0041] In one embodiment of the invention, the gastroretentive device is configured to remain mobile within the gastric environment. As used herein, the term “mobile within the gastric environment” shall refer to the situation wherein a composition can move freely or unabetted within the gastric environment and is not attached or affixed to the gastric mucosal lining. In one embodiment of the invention a gastroretentive device mobile within the gastric environment will float on the surface of the gastric fluid. In another embodiment of the invention a gastroretentive device mobile within the gastric environment will move within the gastric fluid and its position in the stomach at any specific time will be determined due to its interactions with gastric fluid, gastric peristaltic forces and the presence, or absence, of food within the stomach. In one embodiment of the invention, the mechanism whereby the gastroretentive device remains mobile within the stomach environment is the same mechanism which provides the device with its gastroretentive properties. In another embodiment of the invention, the mechanism whereby the gastroretentive device remains mobile within the stomach environment is distinct from the mechanism which provides the device with its gastroretentive properties.

[0042] In one embodiment of the invention, the gastroretentive device is configured to attach to the gastric mucosal lining. Gastroretentive devices can attach to the gastric mucosal lining via methods generally known in the art and include via mucoadhesion and mechanical attachment via suction and/or hooks. It is to be understood that a gastroretentive device configured to attach to the gastric mucosal lining is designed to utilize said attachment for the purposes of its gastric retention and that the device, upon release of the attachment, will be readily available to exit the stomach via the pylorus.

[0043] In one embodiment of the invention, the measurements of intragastric pH as taken by both a gastroretentive device mobile within the gastric environment and a device configured to attach to the gastric mucosal lining will be similar over a predefined time period. In another embodiment of the invention, the measurements of intragastric pH as taken by a gastroretentive device mobile within the gastric environment and a device configured to attach to the gastric mucosal lining will be different over a predefined time period. In one embodiment of the invention, the difference in measurements of intragastric pH as taken by a gastroretentive device mobile within the gastric environment and a device configured to attach to the gastric mucosal lining will occur in the time period following the subject’s ingestion of food. In one embodiment of the invention, the difference in measurements of intragastric pH as taken by a gastroretentive device mobile within the gastric environment and a device configured to attach to the gastric mucosal lining will occur in the time period when the subject is a supine and/or prone position. [0044] In one embodiment of the invention, gastroretentive devices are configured to remain mobile within the gastric environment of a human subject for at least twelve hours following oral administration. In another embodiment of the invention, devices are configured to remain mobile within the gastric environment of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration.

[0045] In one embodiment of the invention, gastroretentive devices are configured to attach to the gastric mucosal lining of a human subject for at least twelve hours following oral administration. In another embodiment of the invention, devices are configured to attach to the gastric mucosal lining of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration.

[0046] In one embodiment of the invention, the sensor configured to measure intragastric pH is housed within the gastroretentive device. Examples of devices housing a sensor include those wherein the sensor is found within a cavity in the device and those where the sensor is embedded within an element of the device. In another embodiment of the invention, the sensor configured to measure intragastric pH is attached to the gastroretentive device. In one embodiment of the invention, inclusion of a sensor configured to measure intragastric pH in a device is necessary for the device to maintain gastroretentive properties, i.e., the device’s gastroretention is dependent on the presence of the sensor. In another embodiment of the invention, inclusion of a sensor configured to measure intragastric pH in a device is not necessary for the device to maintain gastroretentive properties, i.e., the device is gastroretentive independent of the inclusion of the sensor. [0047] In one embodiment of the invention, the gastroretentive device is configured to not leave the gastric environment for at least twelve hours following oral administration. In another embodiment of the invention, the device is configured to not leave the gastric environment for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration.

[0048] In one embodiment of the invention, both the gastroretentive device and the associated sensor, as configured to measure intragastric pH, are configured to not leave the gastric environment for at least twelve hours following oral administration. In another embodiment of the invention, both the gastroretentive device and the associated sensor, as configured to measure intragastric pH, are configured to not leave the gastric environment for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following oral administration. In such embodiments, it is understood that while the gastroretentive device remains in the stomach, the sensor measures the pH as present in the stomach and not as found in other locations, such as the esophagus and/or duodenum.

[0049] In one embodiment of the invention, the gastroretentive device further comprises a retainer configured to retain the device prior to oral administration in a form suitable for being swallowed by the subject. Examples of retainers include wrappers, capsules or bands surrounding the device. In one embodiment of the invention, the retainer is configured to erode upon exposure to gastric fluid. In one embodiment of the invention, the retainer erodes upon exposure to gastric fluid within ten minutes.

[0050] In one embodiment of the invention, the sensor configured to measure intragastric pH comprises electronic circuitry, a power source, an electrode for measuring pH a transmitter, and, optionally, an amplifier. A graphical schematic of one such sensor is shown in Figure 1.

[0051] In one embodiment of the invention, the sensors comprise an electrode for measuring multiple pH measurements. In one embodiment of the invention, the electrode for measuring pH is calibrated to measure pH in the range 0 - 8. In one embodiment of the invention, the electrode for measuring pH are pre-calibrated prior to the electrode’s inclusion within the gastroretentive device. In one embodiment of the invention, the electrode’s pH measurement criteria are pre-calibrated to allow the electrode to measure pH in the range 0 - 8. In one embodiment of the invention, the electrode is calibrated to measure pH to an accuracy of 0.1, e.g., the electrode is calibrated to accurately distinguish between, for example, pH 2.3 and 2.4, or, for example, between pH 4.0 and 4.1.

[0052] In one embodiment of the invention, the electrode is programmed to measure pH at multiple time points and with a predetermined frequency of measurement. In one embodiment of the invention, the frequency of measurement is at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second. It is understood that the electrode measures pH with the same degree of accuracy and uniformity at each and every time point that measurements are taken.

[0053] In one embodiment of the invention, the sensor configured to measure intragastric pH comprises a transmitter which provides for a means of transmitting the pH measurement as taken by the sensor’s electrode. In one embodiment of the invention, the transmitter is in direct communication with the electrode for measuring pH. In another embodiment of the invention, the transmitter is indirectly connected to the electrode for measuring pH via a second unit. In one embodiment of the invention, the transmitter is indirectly connected to the electrode for measuring pH via an amplifier. In one embodiment of the invention, the transmitter comprises an uplink antenna.

[0054] In one embodiment of the invention, the transmission of the pH measurement is time-stamped. In one embodiment of the invention, the transmitter provides for transmission of the time-stamped pH measurements immediately after their measurement. In another embodiment of the invention, the transmitter provides for the cumulative transmission of the pH measurements at a time after their measurement. In one embodiment of the invention, the sensor is configured to transmit that it has passed through the pylorus and into the gastrointestinal tract.

[0055] In one embodiment of the invention, the sensor configured to measure intragastric pH comprises a power source. Examples of suitable power sources include silver-oxide batteries and the like. In one embodiment of the invention, the power source is configured to provide sufficient power to provide for all the sensor’s pH measurements and transmissions. In one embodiment of the invention, the power source provides power for all the sensor’s pH measurements and transmissions for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours. In one embodiment of the invention, the power source has a minimal shelf life at least as long as that of the gastroretentive device. In one embodiment of the invention, the power source provides power for all circuitry and elements of the sensor. In one embodiment of the invention, the power source comprises an ON/OFF mechanism. In one embodiment of the invention, the power source only provides power to the sensor’s circuitry and elements once the ON/OFF mechanism has been activated to ON.

[0056] In one embodiment of the invention, the sensor configured to measure intragastric pH also comprises a second unit. In such embodiments, the second unit communicates directly and separately with both the electrode for measuring pH and the transmitter. In one embodiment of the invention, the second unit comprises an amplifier, an analog-to-digital converter, a controller and a memory device. In such an embodiment, the electrode for measuring pH communicates with the amplifier providing it with the pH measurements taken, the amplifier communicates with the analog-to-digital converter and the analog-to-digital converter communicates with the controller. In such embodiments, the controller communicates with both the memory device, to which it transfers and receives the pH measurements, and the transmitter to which it communicates the pH measurements it has received from the memory device. Also in such embodiments, the memory device is configured to store the pH measurements for the predetermined time period prior to their cumulative transmission.

[0057] In one embodiment of the invention, the sensor configured to measure intragastric pH is also configured to communicate directly with an external monitoring device designed to receive and electronically record the pH measurements. In one embodiment of the invention, the external monitor device’s receiver comprises a communication system. Examples of suitable communication systems include inductive communication technologies and Sub-GHz systems. Examples of suitable external monitoring devices include handheld or portable recorders, recorders held against the subject’s skin by magnets and/or an adhesive patch, mobile phones, laptops and the like. In one embodiment of the invention, the communication between the sensor configured to measure intragastric pH and the external monitoring device is by wireless transmission, Bluetooth transmission, near field communication or by radio waves.

[0058] In one embodiment of the invention, the external monitoring device communicates with a microprocessor to transfer the pH measurements it has recorded from the sensor’s transmissions. In one embodiment of the invention, the microprocessor is within a cellular phone. In another embodiment of the invention, the microprocessor is within a computer. In one embodiment of the invention, the communication between the external monitoring device and the microprocessor is by wireless transmission, Bluetooth transmission, near field communication or by radio waves.

[0059] In one embodiment of the invention, the external monitoring device is configured for recording of the subject’s activities and/or symptoms for at least the duration of time the gastroretentive device is configured to remain in the stomach. In such embodiments, the external monitoring device also transfers to the microprocessor the time-stamped records of the subject’s activities and/or symptoms. In another embodiment of the invention, the device comprising the microprocessor is configured for recording of the subject’s activities and/or symptoms for at least the duration of time the gastroretentive device is configured to remain in the stomach. Examples of activities that can be recorded include the start and end time for eating and/or drinking and/or taking medication and the subject’s position, whether standing, sitting, prone or supine. Examples of symptoms that can be recorded include heartburn, chest pain, pressure on or in the chest, cough, wheezing, regurgitation, dyspepsia, nausea, belching and their start and end times.

[0060] In one embodiment of the invention, the sensor configured to measure intragastric pH communicates with the external monitoring device at fixed time intervals during the time the gastroretentive device is configured to remain in the stomach. In another embodiment of the invention, the sensor configured to measure intragastric pH communicates continuously with the external monitoring device during the time the gastroretentive device is configured to remain in the stomach. In another embodiment of the invention, the sensor configured to measure intragastric pH communicates with the external monitoring device only after the time the gastroretentive device is configured to have remained in the stomach. In another embodiment of the invention, the sensor configured to measure intragastric pH communicates with the external monitoring device only after the gastroretentive device has left the stomach via the pylorus. In one embodiment of the invention, the sensor configured to measure intragastric pH communicates with the external monitoring device to transmit that it has passed through the pylorus and into the gastrointestinal tract. In one embodiment of the invention, the external monitoring device is configured to stop receiving the communications of the sensor configured to measure intragastric pH at about twelve, eighteen, twenty four, thirty six, forty eight, sixty, seventy two, eighty four, ninety six, one hundred and eight, one hundred and twenty, one hundred and thirty two, one hundred and forty four, one hundred and fifty six, or one hundred and sixty eight hours following oral administration.

[0061] In the present invention, the sensor configured to measure intragastric pH communicates with the external monitoring device by transmitting to the external device time-stamped pH measurements. In all such embodiments, the time-stamp of pH data relates to the time of the pH measurement itself, and the time-stamped record of the subject’s activities relates to the time of the recording itself, rather than to the time of the transmission to the secondary device.

[0062] In one embodiment of the invention, the external monitoring device is portable and configured to be worn and/or carried by the subject for at least the duration of time the gastroretentive device is configured to remain in the stomach. In one embodiment of the invention, the external monitoring device is a single use device capable of electronically recording only one dataset of pH measurements. In another embodiment of the invention, the external monitoring device is a reusable device capable of electronically recording more than one dataset of pH measurements.

[0063] The present invention also relates to methods of administering a gastroretentive device configured to remain in the stomach of a human subject for at least twelve hours following administration and wherein the device comprises a sensor configured to measure intragastric pH at least once every thirty minutes for at least twelve hours and wherein the subject has been diagnosed, or suspected, as suffering from PPI-insensitive GERD and to methods thereof of measuring the subject’s intragastric pH. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0064] As used herein, the term “Gastroesophageal reflux disease” or “GERD” shall refer to a condition that develops when the reflux of a subject’s stomach contents causes said subject troublesome symptoms and/or complications (The Montreal Definition and Classification of Gastroesophageal Reflux Disease: A Global Evidence- Based Consensus, Vatik et al, 2006).

[0065] In one embodiment of the invention, a subject is diagnosed as suffering, or suspected as suffering, from GERD by an appropriate health care professional empirically based on the subject’s presentations of symptoms typically associated with GERD such as heartburn, regurgitation, nausea, dyspepsia, belching, chronic cough and/or bloating. In another embodiment, a subject is diagnosed as suffering, or suspected as suffering, from GERD by an appropriate health care professional based on the findings of appropriate diagnostic tests and studies such as an upper endoscopy, a Barium swallow radiograph study, an esophageal manometry study, an esophageal impedance study and/or an esophageal pH monitoring study. [0066] A subject’s diagnosis of GERD can be further classified based on the findings of an upper endoscopy, by the identifiable presence, or absence, of esophageal mucosal damage, as either erosive esophagitis (EE)/erosive reflux disease (ERD) or non- erosive reflux disease (NERD) respectively.

[0067] As used herein, the term “Proton Pump Inhibitor” or “PPI” shall refer to the class of approved and experimental medicaments whose mechanism of action includes the irreversible blockage of the gastric parietal cell H ⁺ /K ⁺ ATPase system. Examples of commercially available PPIs include omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole.

[0068] As used herein, the term “PPI insensitive GERD” shall refer to the clinical presentation of a subject, who complains of ongoing symptoms typically associated with GERD no less than a week after they had initiated acid suppression medication therapy. The term “PPI insensitive GERD” shall also be understood to be synonymous and interchangeable with other such terms in the art including refractory GERD, PPI-refractory GERD, persistent GERD, persistent acid reflux, refractory NERD, GERD with incomplete response and the like.

[0069] In one embodiment of the invention, PPI insensitive GERD has been diagnosed in the subject by a healthcare professional. In another embodiment of the invention, PPI insensitive GERD has been diagnosed in the subject by the subject themselves. In one embodiment of the invention, PPI insensitive GERD is suspected as occurring in the subject by a healthcare professional. In another embodiment of the invention, PPI insensitive GERD is suspected as occurring in the subject by the subject themselves.

[0070] In one embodiment of the invention, the gastroretentive device remains in the stomach of the subject for at least twelve hours following administration. In another embodiment of the invention, the gastroretentive device remains in the stomach of the subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours following administration. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0071] In one embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty minutes. In another embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second.

[0072] In one embodiment of the invention, following administration, the sensor measures intragastric pH for at least twelve hours. In another embodiment of the invention, following administration, the sensor measures intragastric pH at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours.

[0073] In one embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty minutes for at least twelve hours. In another embodiment of the invention, following administration, the sensor measures intragastric pH at time intervals at least once every thirty, at least once every ten or at least once every minute and for at least twelve hours or at least once every thirty or at least once every ten seconds and for at least twelve hours.

[0074] In one embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty minutes and for at least twenty four hours. In another embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty, at least once every ten or at least once every minute and for at least twenty four hours or at least once every thirty or at least once every ten seconds and for at least twenty four hours.

[0075] In one embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty minutes and for at least forty eight hours. In another embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty, at least once every ten or at least once every minute and for at least forty eight hours or at least once every thirty or at least once every ten seconds and for at least forty eight hours.

[0076] In one embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty minutes and for at least seventy two hours. In another embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty, at least once every or ten at least once every minute and for at least seventy two hours or at least once every thirty or at least once every ten seconds and for at least seventy two hours.

[0077] In one embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty minutes and for at least ninety six hours. In another embodiment of the invention, following administration, the sensor measures intragastric pH at least once every thirty, at least once every ten or at least once every minute and for at least ninety six hours or at least once every thirty or at least once every ten seconds and for at least ninety six hours.

[0078] In one embodiment of the invention, following administration, the gastroretentive device remains in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours and the device comprise a sensor configured to measure intragastric pH. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0079] In one embodiment of the invention, following administration, the gastroretentive device remains in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours and the sensor measures intragastric pH at least once every thirty minutes. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0080] In another embodiment of the invention, following administration the gastroretentive device remains in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours the sensor measures intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0081] In one embodiment of the invention, following administration, the gastroretentive device remains in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours and the sensor measures intragastric pH for at least twelve hours. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0082] In another embodiment of the invention, following administration, the gastroretentive device remains in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours and the sensor measures intragastric pH for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0083] In one embodiment of the invention, following administration, the gastroretentive devices remain in the stomach of a human subject for at least twelve hours, the sensor measures intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second and for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0084] In one embodiment of the invention, following administration, the gastroretentive devices remain in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours, the sensor measures intragastric pH at least once every thirty minutes and for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0085] In one embodiment of the invention, following administration, the gastroretentive devices remain in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours, the sensor measures intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second and for at least twelve hours. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0086] In one embodiment of the invention, following administration, the gastroretentive devices remain in the stomach of a human subject for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours, the sensor measures intragastric pH at least once every thirty, at least once every twenty, at least once every fifteen, at least once every ten, at least once every eight, at least once every six, at least once every five, at least once every four, at least once every three or at least once every two minutes, or at least once every sixty, at least once every forty five, at least once every thirty, at least once every twenty, at least once every fifteen seconds, at least once every twelve seconds, at least once every ten seconds, at least once every nine, at least once every eight, at least once every seven, at least once every six, at least once every five, at least once every four, at least once every three, at least once every two or at least once every second and for at least twelve, at least eighteen, at least twenty four, at least thirty six, at least forty eight, at least sixty, at least seventy two, at least eighty four, at least ninety six, at least one hundred and eight hours, at least one hundred and twenty, at least one hundred and thirty two, at least one hundred and forty four, at least one hundred and fifty six or at least one hundred and sixty eight hours. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement.

[0087] In one embodiment of the invention, following measurement of intragastric pH, the sensor transmits the intragastric pH measurements to an external monitoring device. In one embodiment of the invention, following measurement of intragastric pH, the sensor transmits the intragastric pH measurements to an external monitoring device by wireless transmission, Bluetooth transmission, near field communication or by radio waves.

[0088] In one embodiment of the invention, following measurement of intragastric pH, the sensor transmits time-stamped intragastric pH measurements to an external monitoring device. In one embodiment of the invention, following measurement of intragastric pH, the sensor transmits time-stamped intragastric pH measurements to an external monitoring device immediately after their measurement. In another embodiment of the invention, following measurement of intragastric pH, the sensor transmits time- stamped intragastric pH measurements to an external monitoring device at a time after their measurement. In one embodiment of the invention, following measurement of intragastric pH, the sensor transmits to an external monitoring device that it has passed through the pylorus and into the gastrointestinal tract.

[0089] In one embodiment of the invention, following measurement of intragastric pH, the sensor communicates with the external monitoring device at fixed time intervals during the time the gastroretentive device remains in the stomach. In another embodiment of the invention, following measurement of intragastric pH, the sensor communicates continuously with the external monitoring device during the time the gastroretentive device remains in the stomach. In another embodiment of the invention, following measurement of intragastric pH, the sensor communicates with the external monitoring device only after the time the gastroretentive device is configured to have remained in the stomach. In another embodiment of the invention, following measurement of intragastric pH, the sensor communicates with the external monitoring device only after the gastroretentive device has left the stomach via the pylorus.

[0090] In the present invention, the sensor measures intragastric pH and communicates with the external monitoring device by transmitting to the external device time-stamped pH measurements. In all such embodiments, the time-stamp of pH data relates to the time of the pH measurement itself, and the time-stamped record of the subject’s activities relates to the time of the recording itself, rather than to the time of the transmission to the secondary device.

[0091] In one embodiment of the invention, following transmission of the intragastric pH measurements to an external monitoring device, the measurements, together with the subject’s recorded activities and/or symptoms, are processed. In one embodiment of the invention, the processing occurs within the external monitoring device. In another embodiment of the invention, the processing occurs within a microprocessor to which the external monitoring device has transmitted the intragastric pH measurements, activities and symptom records. In another embodiment of the invention, the processing occurs remotely after the remote site has received the intragastric pH measurements, activities and symptom records transmitted from either the external monitoring device or the microprocessor. The processing of the intragastric pH measurements, activities and symptom records will typically be performed by dedicated computer software such as generally available from suppliers such as Medtronic or Diversatek or as custom designed for the purpose of processing said measurements.

[0092] In one embodiment of the invention, the processing comprises the electronic analysis of the transmitted pH measurements, activities and symptom records and the presentation of the analysis. In one embodiment of the invention, the presentation of the analysis is to the subject. In another embodiment of the invention, the presentation of the analysis is to a healthcare professional. In one embodiment of the invention, the healthcare professional is a suitably qualified human skilled in the art. In another embodiment of the invention, the healthcare professional is a pre-programmed artificial intelligence.

[0093] In one embodiment of the invention, the presentation of the analysis comprises graphical imagery. In another embodiment of the invention, the presentation of the analysis comprises tabulated data. In another embodiment of the invention, the presentation of the analysis comprises both graphical imagery and tabulated data.

[0094] In one embodiment of the invention, the graphical imagery comprises a graphical representation of pH tracing wherein the imagery represents a graphical representation of the measured intragastric pH as plotted against the measurement’s time- stamps. In one embodiment of the invention, the pH tracing further comprises graphical representation of the subject’s activities as plotted against their time-stamps. In another embodiment of the invention, the pH tracing further comprises graphical representation of the subject’s symptoms as plotted against their time-stamps. In another embodiment of the invention, the pH tracing further comprises graphical representation of the subject’s activities and symptoms as plotted against their respective time-stamps. In one embodiment of the invention, the pH tracing further comprises graphical representation of artifact readings. In one embodiment of the invention, the determination of artifact readings is by a healthcare professional. In another embodiment of the invention, the determination of artifact readings is by the subject according to their interpretation of instructions received from a healthcare professional.

[0095] In one embodiment of the invention, the tabulated data comprises determinations calculated from the intragastric pH measurements. In another embodiment of the invention, the tabulated data comprises indicia calculated from the intragastric pH measurements. In another embodiment of the invention, the tabulated data comprises both determinations and indicia calculated from the intragastric pH measurements.

[0096] In one embodiment of the invention, the determinations calculated from the intragastric pH measurements comprise the percentage time the intragastric pH was less than pH 4. In another embodiment of the invention, the determinations calculated from the intragastric pH measurements comprise the summation of the number of reflux episodes. In another embodiment of the invention, the determinations calculated from the intragastric pH measurements comprise the calculation of the length of the longest episode of reflux.

[0097] In one embodiment of the invention, the percentage time the intragastric pH was less than pH 4 comprises the total time that intragastric pH measurements were taken and the intragastric pH was less than pH 4. In another embodiment of the invention, the percentage time the intragastric pH was less than pH 4 comprises the total time that the subject was prone and/or supine and the intragastric pH was less than pH 4. In another embodiment of the invention, the percentage time the intragastric pH was less than pH 4 comprises the total time that the subject was upright and the intragastric pH was less than pH 4. In one embodiment of the invention, the percentage time the intragastric pH was less than pH 4 includes within the total time that intragastric pH measurements were taken, the time-period that the subject was post-prandial. In another embodiment of the invention, the percentage time the intragastric pH was less than pH 4 excludes from the total time that intragastric pH measurements were taken, the time- period that the subject was post-prandial.

[0098] As used herein, the term “acid exposure time” or “AET” refers to the total time that intragastric pH measurements were taken, the term “acid exposure time supine” or “AET supine” refers to the total time the subject was prone and/or supine and the term “acid exposure time upright” or “AET upright” refers to the total time the subject was upright and wherein the intragastric pH was below a predetermined level. Unless specified otherwise, the predetermined level is less than pH 4.

[0099] As used herein, the term “% acid exposure time” or “% AET” refers the percentage of the total time that intragastric pH measurements were taken, the term “% acid exposure time supine” or “AET supine” refers the percentage of the total time the subject was prone and/or supine, wherein intragastric pH measurements were taken and the term “% acid exposure time upright” or “AET upright” refers the percentage of the total time the subject was upright, wherein intragastric pH measurements were taken and wherein the intragastric pH was below a predetermined level. Unless specified otherwise, the predetermined level is less than pH 4.

[00100] In one embodiment of the invention, the summation of the number of reflux episodes comprises the summation of the total number of reflux episodes as occurring over the time period of intragastric pH measurement. In another embodiment of the invention, the summation of the number of reflux episodes comprises the summation of the total number of reflux episodes lasting longer than five minutes as occurring over the time period of intragastric pH measurement. In one embodiment of the invention, the summation of the number of reflux episodes comprises the number of reflux episodes over the total time period of intragastric pH measurement. In another embodiment of the invention, the summation of the number of reflux episodes comprises the separate number of reflux episodes over the time period the subject was upright, prone, supine and/or post-prandial.

[00101] In one embodiment of the invention, the calculation of the length of the longest episode of reflux comprises the calculation of the length of the longest episode of reflux over the total time period of intragastric pH measurement. In another embodiment of the invention, the calculation of the length of the longest episode of reflux comprises the calculation of the length of the longest episode of reflux over the time period the subject was upright, supine, prone and/or post-prandial.

[00102] In one embodiment of the invention, the determinations calculated from the intragastric pH measurements comprise the AET, the AET supine, the AET upright, the % AET, the % AET supine, the % AET upright, the total number or reflux episodes, the total number of reflux episodes lasting longer than five minutes and/or the length of the longest episode of reflux. In one embodiment of the invention, the determinations calculated from the intragastric pH measurements comprise the determinations over the total time period of intragastric pH measurement. In another embodiment of the invention, the determinations calculated from the intragastric pH measurements comprise the determinations over the time period the subject was upright, supine, prone and/or post-prandial.

[00103] In one embodiment of the invention, the indicia calculated from the intragastric pH measurements comprises the DeMeester score. In another embodiment of the invention, the indicia calculated from the intragastric pH measurements comprises the Symptom index (SI). In another embodiment of the invention, the indicia calculated from the intragastric pH measurements comprises the Symptom association probability (SAP). In another embodiment of the invention, the indicia calculated from the intragastric pH measurements comprise the DeMeester score, the SI and the SAP. The definitions and methods of calculating the DeMeester score, the SI and the SAP are as generally known to those of skill in the art.

[00104] In one embodiment of the invention, the presentation of the analysis allows for a healthcare professional to further clarify the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD. In another embodiment of the invention, the presentation of the analysis allows for the external monitoring device to further clarify the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD. In one embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD is based solely on the findings of the analysis. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD is based on the findings of the analysis together with the healthcare professional’s review of the subject’s symptomology. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD is based on the findings of the analysis together with the healthcare professional’s review of the subject’s symptomology and the of other diagnostic tests, such as an upper endoscopy, which the subject will have recently undertaken. [00105] In one embodiment of the invention, the clarification of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination of the adequacy of the subject’s acid suppression medication therapy. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI- insensitive GERD comprises a determination of whether the subject’s acid suppression medication therapy should be continued, amended or halted. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination of the subject’s compliance with their acid suppression medication therapy. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a diagnosis that the subject is suffering from functional heartburn. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a diagnosis that the subject is suffering from reflux hypersensitivity. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject is suffering from suspected functional heartburn. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject is suffering from suspected reflux hypersensitivity. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject is suffering from suspected functional heartburn or reflux hypersensitivity. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject is not suffering from GERD. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject is suspected of not suffering from GERD. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject has a differential diagnosis of functional heartburn and/or reflux hypersensitivity. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject has a differential diagnosis of suspected functional heartburn and/or reflux hypersensitivity. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject does not has a differential diagnosis of NERD or GERD. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI- insensitive GERD comprises a determination that the subject does not need to undergo, or can delay undergoing, an upper endoscopy. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that the subject does not need to undergo esophageal pH testing. In another embodiment of the invention, the clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD comprises a determination that reflux testing can be delayed, is not required or should be recommended.

[00106] Clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD can be determined based on the analysis of the subject’s intragastric pH measurements, possibly further involving a review of the subject’s symptomology and, as available, a review of the subject’s recent additional diagnostic test findings. Such clarifications will then be available to provide further guidance about possible modifications to the subject’s treatment and/or medications according to the standard practices in the art. For example, in the event that the analysis of the subject’s intragastric pH measurements are considered to show that intragastric pH is less than pH 4 for only a limited period of time, the analysis is indicative of the efficacious nature of the acid suppression medication therapy and a determination of the adequacy of the subject’s acid suppression medication therapy and of their compliance to the medication can be made. This could possibly also lead to a determination by a healthcare professional that the subject does not need to undergo an upper endoscopy. Likewise, in the event that the analysis of the subject’s intragastric pH measurements are considered by the healthcare professional to show that intragastric pH is less than pH 4 for an extended period of time, the a determination that the subject’s acid suppression medication therapy is inadequate is more likely and the subject might require amendments to their therapy such as increasing the dose or dosing schedule or the introduction of additional acid suppression medications. As intragastric pH is generally understood to vary according to the location of its sampling and possibly with the presence of food, it is to be understood that the nature of the gastroretentive device might affect the determination of what could be considered a limited or an extended period of time. Namely, gastroretentive devices which are configured to attach to the gastric mucosal lining might present with a different intragastric pH analysis than those devices which are configured to remain mobile within the gastric environment and among the devices configured to remain mobile within the gastric environment, differences in intragastric pH analysis might be present between those devices designed to float on the surface of gastric fluid and those which move within the gastric fluid and whose positioning might be more influenced by gastric peristaltic activity. Between these different device types, further differences might also be present between the analyses of different devices in the post-prandial period.

[00107] In the event that the healthcare professional considers both the analysis of the subject’s intragastric pH measurements and their symptomology, further clarification of the diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD could be available. For example, in the event that the analysis of the subject’s intragastric pH measurements are considered to show intragastric pH is less than pH 4 for only a limited period of time, a healthcare professional might, after consideration of the subject’s symptoms provide a determination that the subject is suffering from suspected functional heartburn and/or reflux hypersensitivity. Likewise, in the event that the analysis of the subject’s intragastric pH measurements are considered to show that intragastric pH is less than pH 4 for an extended period of time, the healthcare professional might, after consideration of the subject’s symptoms, provide a diagnosis of GERD and suggest that the subject undergo upper endoscopy to further clarify the diagnosis. Examples of such further clarifications include a diagnosis or determination that the subject is suffering from suspected functional heartburn and/or reflux hypersensitivity, a differential diagnosis that the subject is suffering from suspected functional heartburn and/or reflux hypersensitivity, a determination that the subject is, or is not, suspected of not suffering from either NERD or GERD and, in the event that the gastroretentive device was administered orally, a determination that the subject does, or does not, need to undergo an upper endoscopy.

[00108] In the event that the healthcare professional has the opportunity to consider the analysis of the subject’s intragastric pH measurements, their symptomology and the findings of their recent additional diagnostic tests, such as upper endoscopy, a more definitive clarification of the further diagnosis of the subject’s diagnosed or suspected PPI-insensitive GERD could be available. For example, in the event that the analysis of the subject’s intragastric pH measurements are considered to show intragastric pH is less than pH 4 for only a limited period of time, a healthcare professional might, after consideration of the subject’s symptoms and the findings of their recent additional diagnostic tests, provide a confirmed diagnosis that the subject is suffering from functional heartburn and/or reflux hypersensitivity. Likewise, in the event that the analysis of the subject’s intragastric pH measurements are considered to show that intragastric pH is less than pH 4 for an extended period of time, the healthcare professional might, after consideration of the subject’s symptoms, and the findings of their recent additional diagnostic tests, provide a confirmed diagnosis of NERD or erosive esophagitis. Examples of such further clarifications include a diagnosis or determination that the subject is suffering from functional heartburn and/or reflux hypersensitivity, a differential diagnosis that the subject is suffering from functional heartburn and/or reflux hypersensitivity and a determination that the subject is, or is not, not suffering from either NERD or GERD. The treatment of functional heartburn and reflux hypersensitivity, whether confirmed or only suspected, is as is generally accepted in the art.

[00109] In one embodiment of the invention, the clarification of the subject’s diagnosed or suspected PPI-insensitive GERD occurs at a physical meeting of the subject and the healthcare professional. In another embodiment of the invention, the clarification of the subject’s diagnosed or suspected PPI-insensitive GERD occurs at a virtual meeting of the subject and the healthcare professional. In another embodiment of the invention, the clarification of the subject’s diagnosed or suspected PPI-insensitive GERD occurs after the external monitoring device has processed and analyzed the intragastric pH measurements and presented the subject with at least part of the analysis. It is understood that virtual meetings between the subject and the healthcare professional and the remote transmission of the pH measurements and their processing and analysis, or the alternative processing and analysis by the external monitoring device, allow for the subject to both orally administer the gastroretentive device of the invention and receive further clarifications regarding their diagnosis in an at-home setting, without the necessity for physical examination or treatment in a clinic or hospital by a healthcare professional. Such methods provide a significant improvement and advantage over those cumbersome, expensive, labor intensive and invasive procedures known in the art.

[00110] As used herein, the term “acid suppression medication” shall refer to those medications whose primary pharmacological function is to raise intragastric pH. Examples of acid suppression medications include PPIs, ¾ receptor antagonists such as cimetidine and ranitidine, potassium-competitive acid blockers such as vonoprazan and antacids such as magnesium hydroxide and calcium carbonate.

[00111] As used herein, the term “reflux hypersensitivity” shall refer to the clinical presentation of a subject, wherein the subject complains of retrosternal esophageal symptoms such as heartburn or chest pain and wherein the subject lacks evidence of reflux on endoscopy or abnormal acid burden on monitoring, but shows triggering of symptoms by physiologic reflux and without alternative identifiable histopathologic mucosal abnormalities, major esophageal motor disorders or other structural explanations.

[00112] As used herein, the term “functional heartburn” shall refer to the clinical presentation of a subject, wherein the subject complains of retrosternal burning discomfort or pain refractory to optimal antisecretory therapy, in the absence of conclusive evidence of GERD and without alternative identifiable histopathologic mucosal abnormalities, major esophageal motor disorders or other structural explanations.

[00113] In one embodiment of the invention, prior to the administration, the subject has tested positive for H. pylori infection. In another embodiment of the invention, prior to the administration, the subject has tested negative for H. pylori infection. In another embodiment of the invention, prior to the administration, the subject’s H. pylori infection status is unknown. As the effect of PPIs on intragastric pH in subjects who have tested positive for H. pylori is generally understood to be greater than in those who have tested negative, it is to be understood that such a finding might also affect the analysis of the intragastric pH measurements.

[00114] The present invention also relates to a method of clarifying the diagnosis of a subject diagnosed, or suspected, as suffering from PPI-insensitive GERD.

[00115] In one embodiment of the invention, the method of clarification comprises the steps of a) administering to the subject a gastroretentive device comprising a sensor configured to measure intragastric pH at least once every thirty minutes for at least twelve hours wherein the device is configured to remain in the stomach for at least twelve hours following oral administration; b) using the device’s sensor to measure the subject’s intragastric pH at least once every thirty minutes for a minimum of at least twelve hours; and c) utilizing the measurements acquired from the sensor to further clarify the subject’s diagnosis. In one embodiment of the invention, the administration is orally. In another embodiment of the invention, the administration is via endoscopic placement

[00116] In one embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination of the adequacy of the subject’s acid suppression medication therapy. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination of whether the subject’s acid suppression medication therapy should be continued, amended or halted. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination of the subject’s compliance with their acid suppression medication therapy. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a diagnosis that the subject is suffering from functional heartburn. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a diagnosis that the subject is suffering from reflux hypersensitivity. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject is suffering from suspected functional heartburn. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject is suffering from suspected reflux hypersensitivity. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject is suffering from suspected functional heartburn or reflux hypersensitivity. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject is not suffering from GERD. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject is suspected of not suffering from GERD. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject has a differential diagnosis of functional heartburn and/or reflux hypersensitivity. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject has a differential diagnosis of suspected functional heartburn and/or reflux hypersensitivity. In another embodiment of the invention, the further clarification of the subject’s diagnosis comprises a determination that the subject does not has a differential diagnosis of NERD or GERD.

[00117] The present disclosure will be better understood by reference to the Examples, which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative as described more fully in the claims which follow thereafter.

EXAMPLES

Example 1: Manufacture of gastroretentive devices Example la: mechanically expanding gastroretentive device

[00118] A gastroretentive device is manufactured according to the procedures described in WO2019111132, which is incorporated in its entirety, herein, by reference.

A graphical representation of such a device is shown in Figure 2. Erodible tablets designed to dissociate in gastric fluid over at least twelve hours are placed within the arm 1001 adjacent to each hinge assembly and are available for exposure to gastric fluids via the lateral openings 1002. A sensor configured to measure intragastric pH over a time period of at least twelve hours is placed centrally within the arm 1003 and is available for exposure to gastric fluids via the central opening of the arm 1004.

Example lb: swellable gastroretentive device [00119] A gastroretentive device is manufactured according to the procedures described in WO2007109904, which is incorporated in its entirety, herein by reference. A cluster of swellable material is stored in an absorbable container, kept closed and attached to a porous carrier unit by a surgical suture. Included inside the carrier unit is a compartment comprising an internal cavity, which hosts a sensor configured to measure intragastric pH via exposure to gastric fluid through the unit’s pores. Example 1c: swellable gastroretentive device [00120] A gastroretentive device is manufactured according to the procedures described in WO2003015745, which is incorporated in its entirety, herein by reference. Locust Bean Gum (0 g-1 g) is added to 100mol water at 70 - 75°C with constant stirring. To the resulting solution, at 80 - 85°C, Xanthan Gum is added with constant stirring. 10ml of polyethylene glycol (PEG 400) is added to the resulting mixture following which, a sensor configured to measure intragastric pH is incorporated into the gel and remains suspended within it. This sensor-containing gel is then cut into a desired size. Following drying for 12-18 hours, the dried films containing sensors are compressed in a punch and die with a hydraulic press to fit into a '000' capsule. Example 1d: floating gastroretentive device [00121] A gastroretentive device is manufactured according to the procedures described in WO2012159077, which is incorporated in its entirety, herein by reference. A gelatin capsule body is dipped into coating solution comprising Ethocel ^® , triethyl citrate and acetone for 10 seconds per dipping time every 10 minutes for four cycles. The capsule bodies is then placed in the oven at 40°C to remove all the solvent for 12 hours. The resultant capsule bodies are further processed by immersing in water to remove the gelatin layer, to yield a completely impermeable capsule body. A sensor configured to measure intragastric pH is inserted into the mouth of the impermeable capsule body and positioned flush with the end of the impermeable capsule body with an air compartment concentrated at the bottom of the impermeable capsule body. Example 2: Measurement of intragastric pH [00122] A sample of 40 subjects diagnosed, post upper endoscopy, as suffering from PPI-insensitive GERD without signs of erosive esophagitis undergo simultaneous intragastric pH monitoring over twenty four hours following ingestion of the device of Example 1 and nasal insertion of a dual channel Digitrapper ^® pH catheter. The catheter’s esophageal pH sensor is placed approximately 6 cm above the level of the esophageal sphincter, whereas the distal pH sensor is located 15 cm below the esophageal sensor thereby allowing for measurement of both esophageal and intragastric antral pH. As per the Rome IV criteria, review of the esophageal pH measurements after twenty four hours allows for a determination of pathological AET and a diagnosis of NERD in a portion of the subjects. The remaining subjects are diagnosed as either suffering from functional heartburn or reflux hypersensitivity based on their presented symptoms. Analysis of the intragastric antral pH from the catheter’s distal sensor and the gastric fluid’s pH from the device’s sensor allow for alternative determinations of pathological AET and, together with review of the patient’s symptoms, diagnoses of NERD, functional heartburn and/or reflux hypersensitivity.