Swallowable capsule and method for stimulating incretin production within intestinal tract

Abstract

To provide apparatuses and methods for stimulating L-cells of the small intestine to produce incretins and other peptides for the treatment of various diseases and conditions including diabetes and obesity.SOLUTION: Embodiments of the invention provide apparatuses and methods for stimulating L-cells in the intestinal tract to produce incretins for the treatment of conditions including diabetes and obesity. Many embodiments provide methods and apparatuses for the treatment of diabetes by electrically stimulating L-cells to secrete incretins to stimulate or otherwise modulate the production of insulin. Particular embodiments provide a swallowable capsule for stimulating L-cells in the intestinal tract as the capsule moves through the tract.SELECTED DRAWING: None

Description

[Technical field]

[0001] (Related Applications) This application is the subject of U.S. Provisional Patent Application No. 61 / 273,389, filed August 3, 2009, entitled “SWALLOWABLE CAPSULE AND METHOD FOR STIMULATING INCRETIN PRODUCTION WITHIN THE FIELD.” This application claims the benefit of priority to "INTESTINAL TRACT," filed on November 1, 2006. The aforementioned priority application is incorporated herein by reference in its entirety.

[0002] FIELD OF THEINVENTION FIELD OF THE DISCLOSURE The embodiments described herein relate to devices and methods for electrically stimulating cells of the GI system to produce polypeptides for the treatment of various conditions, such as diabetes and obesity. More specifically, embodiments of the invention relate to the treatment of diabetes by electrically stimulating cells of the gastro-intestinal (GI) system to produce glucose-regulating hormones, such as incretins. [Background technology]

[0003] (background) The increased consumption of high-fat and / or high-calorie foods found in the Western diet has led to an epidemic of diabetes and obesity in the United States and other developed countries. Diabetes is a disease in which the body does not produce enough or respond properly to insulin, a hormone produced by the pancreas. Insulin is needed to turn sugar and other foods into energy. In diabetes, the body does not make enough insulin or does not use the insulin it has as well as it should, or both. This causes sugar to build up in the blood, often resulting in a variety of complications. The American Diabetes Association reported in 2009 that 23.6 million children and adults in the United States have diabetes (equivalent to about 7.8% of the total population). While about 17.9 million people in the United States alone have been diagnosed with diabetes, about one in four people with diabetes (5.7 million) are unaware that they have the disease.

[0004] The main types of diabetes include type 1, type 2 and gestational diabetes. Type 1 diabetes results from the body's inability to produce insulin. It is estimated that 5-10% of Americans diagnosed with diabetes have type 1 diabetes. Currently, almost all people with type 1 diabetes must take insulin injections.

[0005] Type 2 diabetes results from the body's inability to use insulin properly, combined with a relative insulin deficiency. Most Americans diagnosed with diabetes have type 2 diabetes. Many people destined to develop type 2 diabetes spend many years in a prediabetic state. This has been described as "America's largest health epidemic," a condition that occurs when blood glucose levels are higher than normal, but not high enough to be diagnosed as type 2 diabetes. As of 2009, 57 million Americans had prediabetes. In developed countries, diabetes is the leading cause of adult blindness in non-elderly adults and the leading cause of non-traumatic amputations in adults. Additionally, diabetic nephropathy is the leading cause of kidney dialysis in the United States.

[0006] Most forms of diabetes are treatable, in part because insulin became medically available in the 1920s. Many diabetics now monitor their own blood glucose using blood glucose meters and administer their own insulin injections at least once a day. However, this approach has many complications due to over or under delivery of insulin, as well as the inability to regulate blood glucose in the long term. If the disease is not adequately controlled, acute complications can occur, including hypoglycemia, diabetic ketoacidosis, or nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, chronic renal failure, retinal damage (which can lead to blindness), nerve damage, and microvascular damage (which can cause erectile dysfunction and delayed wound healing). Delayed wound healing, especially in the feet, can lead to gangrene and potentially amputation.

[0007] Other forms of drug therapy are available, such as Metformin (known as GLUCOPHAGE). However, this drug is only indicated for the treatment of type II non-insulin dependent diabetes mellitus and has many side effects, including a variety of gastrointestinal side effects. It also cannot be used by patients with renal disease. Other forms of treatment include implantable insulin pumps, but these are costly and are ultimately rejected by the body. Thus, improved forms of treatment for diabetes and other glucose regulation disorders are needed.

[0008] Obesity, defined as a body mass index (BMI) greater than 30, is a major health problem in the United States and other countries. It is estimated that one in three Americans and more than 300 million people worldwide are obese. Complications of obesity include numerous serious life-threatening diseases, including hypertension, diabetes, coronary artery disease, stroke, congestive heart failure, pulmonary regurgitation, multiple orthopedic problems, various cancers, and a significant decrease in life expectancy. Numerous therapies have been attempted to treat obesity, including dietary therapy, drug therapy, and more invasive procedures such as stomach stapling. However, many fail due to an inability to activate the satiety signaling pathway that tells a person when they are full. Research has now shown that many foods provided by the food industry, including those high in salt, sugar, and fat, activate a strong signaling response in the brain that keeps us eating. Summary of the Invention [Problem to be solved by the invention]

[0009] Thus, there is a need for improved forms of obesity treatment, including those that can stimulate satiety signals and / or appetite suppression signals to cause a person to stop eating or otherwise suppress appetite. [Means for solving the problem]

[0010] The present invention provides, for example, the following: (Item 1) 1. A swallowable capsule for stimulating L-cells in the intestinal track of a patient, comprising: a capsule body having a surface; the capsule body sized to be swallowed and pass through the intestinal tract of a patient; at least one pair of electrodes disposed on a surface of the capsule body for electrically stimulating the L-cells; at least one sensor coupled to the capsule body for sensing a characteristic of the intestinal track to identify a location of the capsule within the intestinal tract; a controller coupled to the at least one pair of electrodes and the at least one sensor, the controller being disposed within the capsule body and configured to receive an input signal from the at least one sensor, identify a location of the capsule within the intestinal tract based on the input, and generate a waveform that is output to the at least one pair of electrodes, the waveform configured to electrically stimulate L-cells proximate to the capsule location to secrete a polypeptide without causing peristaltic contractions of the intestinal tract; a power source coupled to the controller; A capsule comprising: (Item 2) The capsule according to item 1, wherein the secreted polypeptide is one of incretin or GLP-1. (Item 3) Item 10. The capsule of item 1, wherein the controller is configured to initiate generation of the waveform when the capsule reaches a selectable location in the intestinal tract. (Item 4) 4. The capsule of claim 3, wherein the selectable location is immediately adjacent to the small intestine. (Item 5) The capsule of claim 1, wherein the waveform is activated by contact of the capsule with the intestinal wall. 6. The capsule of claim 5, wherein contact is detected by at least one of the at least one pair of electrodes or a contact sensor or a pressure sensor disposed on a surface of the capsule body. (Item 7) 2. The capsule of claim 1, wherein the longitudinal axes of the at least one pair of electrodes are aligned with respect to the longitudinal axis of the capsule body. (Item 8) 2. The capsule of claim 1, wherein the longitudinal axes of the at least one pair of electrodes are aligned with respect to a radial axis of the capsule body. (Item 9) Item 1, wherein the at least one pair of electrodes comprises a ring-shaped electrode. (Item 10) 10. The capsule of claim 9, wherein the ring-shaped electrode is aligned coaxially with respect to a longitudinal axis of the capsule body. (Item 11) 2. The capsule of claim 1, wherein the at least one pair of electrodes has a spacing configured to minimize electrical stimulation of tissue beneath a mucosal layer of the intestinal tract. (Item 12) Item 12. The capsule of item 11, wherein the at least one pair of electrodes has a spacing configured to minimize electrical stimulation of tissue more than about 3-5 mm below the surface of the mucosal layer of the intestinal tract. (Item 13) Item 12. The capsule of item 11, wherein the spacing between the electrodes is within the range of between about 0.01 to 0.2 inches. (Item 14) Item 12. The capsule of item 11, wherein the spacing between the electrodes is within the range of between about 0.05 to 0.2 inches. (Item 15) Item 1 , the capsule of item 1 , wherein the controller comprises a signal generator. (Item 16) 16. The capsule of item 15, wherein the signal generator comprises one of a pulse generator or an H-bridge. (Item 17) Item 16. The capsule of item 15, wherein the signal generator is configured to generate a pulsed signal. (Item 18) Item 18. The capsule according to item 17, wherein the pulse signal has a frequency in the range of between about 1 and 100 Hz. (Item 19) 2. The capsule of claim 1, wherein the at least one sensor includes a pressure sensor for sensing contractions or contractile forces in the intestinal tract. (Item 20) 2. The capsule of claim 1, wherein the at least one sensor comprises a pH sensor for sensing the pH of the intestinal tract or a change in the pH of the intestinal tract as the capsule moves through the tract. (Item 21) Item 1, the capsule according to item 1, wherein the at least one sensor includes a pH sensor and a pressure sensor. (Item 22) 2. The capsule of claim 1, wherein the controller includes a sensor conditioning circuit for conditioning an input from the at least one sensor. (Item 23) 23. The capsule of claim 22, wherein the conditioning circuit includes at least one of a band pass filter, a high pass filter, or a low pass filter. (Item 24) 2. The capsule of claim 1, wherein the power source comprises a capacitor, an electric battery, a lithium battery or a lithium ion battery. (Item 25) 2. The capsule of claim 1, wherein the power source comprises a piezoelectric power source configured to generate power from movement of the capsule through the intestinal tract or mechanical interaction of the capsule with the intestinal tract or contents of the intestinal tract. (Item 26) 2. The capsule of claim 1, wherein the waveform is configured to stimulate L-cells within about 5 cm of the capsule body surface. (Item 27) 2. The capsule of claim 1, wherein the waveform is configured to stimulate L-cells within about 2 cm of the capsule body surface. (Item 28) 2. The capsule of claim 1, wherein the waveform is configured to stimulate L-cells within about 1 cm of the capsule body surface. (Item 29) Item 10. The capsule of item 1, further comprising an accelerometer for sensing movement of the capsule through the intestinal tract, the accelerometer being coupled to the controller. (Item 30) 2. The capsule of claim 1, wherein the controller is configured to generate a first waveform and a second waveform, the first waveform configured to electrically stimulate L cells proximate the capsule location to produce a polypeptide that is secreted without causing peristaltic contractions of the intestinal tract, and the second waveform configured to cause peristaltic contractions of a portion of the intestinal tract proximate the capsule to advance the capsule within the intestinal tract. (Item 31) 31. The capsule of claim 30, wherein the second waveform is activated in response to an input indicating that the rate of capsule movement through the intestinal tract is below a minimum level. (Item 32) Item 32. The capsule of item 31 , wherein the input is from an accelerometer coupled to the controller. (Item 33) 31. The capsule of claim 30, wherein the first waveform and the second waveform are generated by an algorithm stored electronically in the controller or a memory resource coupled to the controller. (Item 34) 1. A method for stimulating L cells in the intestinal track of a patient to secrete a polypeptide, comprising: ingesting a swallowable device configured to advance through the intestinal tract and electrically stimulate L-cells within the intestinal tract; delivering an electrical signal from the device to the intestinal wall proximate to the device, the signal comprising a waveform configured to electrically stimulate L cells in the intestinal tract to secrete the polypeptide; electrically stimulating the L cells to secrete the polypeptide; A method comprising: (Item 35) 35. The method of claim 34, wherein the intestinal wall is the wall of the small intestine. (Item 36) 35. The method of claim 34, wherein the peptide comprises an incretin. (Item 37) 37. The method of claim 36, wherein the incretin comprises GLP-1. (Item 38) 37. The method of claim 36, further comprising the step of modulating insulin release in the patient in response to the secreted polypeptide. (Item 39) 39. The method of claim 38, wherein said insulin release is modulated by said electrical stimulation of said L-cells resulting in an increase in plasma insulin within 30 minutes of stimulation. (Item 40) 35. The method of claim 34, further comprising controlling the patient's blood glucose level in response to the secreted polypeptide. (Item 41) 35. The method of claim 34, further comprising suppressing the appetite level of the patient in response to the secreted polypeptide. (Item 42) Item 35. The method of item 34, wherein the waveform has a substantially square waveform. (Item 43) 35. The method of claim 34, wherein the waveform is configured to stimulate the L-cells without causing substantial peristaltic contractions. (Item 44) 35. The method of claim 34, wherein the waveform comprises a first waveform and a second waveform, the first waveform being configured to stimulate the L-cells without causing substantial peristaltic contractions. (Item 45) 45. The method of claim 44, wherein the second waveform is configured to generate peristaltic contractions of intestinal tissue immediately adjacent to the device, the method further comprising the step of advancing the device within the intestinal tract using the generated peristaltic contractions. (Item 46) 47. The method of claim 45, wherein the second waveform is substantially different from the first waveform. 46. ​​The method of claim 45, wherein the second waveform is generated in response to a velocity of the device moving through the intestinal tract. (Item 48) Item 48. The method of item 47, wherein the velocity is measured using an accelerometer disposed on or in the device. (Item 49) 35. The method of claim 34, further comprising the step of determining a location of the device within the GI tract, wherein the signal is delivered in response to the location of the device within the intestinal tract. (Item 50) 50. The method of claim 49, wherein the location is the small intestine. (Item 51) 50. The method of claim 49, wherein the location is determined using a sensor. (Item 52) 52. The method of claim 51, wherein the location is identified based on at least one of sensed pH or sensed pressure exerted on the device surface by intestinal wall tissue. (Item 53) 35. The method of claim 34, wherein the ingestion of the device is coordinated with the ingestion of food. (Item 54) 54. The method of claim 53, wherein the device is ingested during a selected period before, during, or after ingestion of food. (Item 55) 55. The method of claim 54, wherein the period is selected to coordinate the stimulation of the L cells with the absorption of nutrients from food into the bloodstream. (Item 56) 35. The method of claim 34, wherein the device comprises a swallowable capsule. (Item 57) 35. The method of claim 34, wherein the device comprises a controller, at least one electrode, and a waveform generator. (Item 58) 1. A method for stimulating L-cells in the intestinal track of a patient to secrete incretins that regulate insulin release, comprising: ingesting a swallowable device configured to advance through the intestinal tract and electrically stimulate L-cells within the intestinal tract; delivering an electrical signal from the device to the intestinal wall proximate to the device, the signal comprising a waveform configured to electrically stimulate L-cells in the intestinal tract to secrete the incretin without substantially causing peristaltic contractions of the small intestine or other GI organs; electrically stimulating the L cells to secrete the incretin; modulating the release of insulin in the patient in response to the secreted incretin; A method comprising: (Item 59) 59. The method of claim 58, wherein insulin release is modulated by said electrical stimulation of said L-cells resulting in an increase in plasma insulin within 30 minutes of stimulation. (Item 60) 59. The method of claim 58, wherein the incretin comprises GLP-1. (Item 61) 59. The method of claim 58, further comprising increasing insulin sensitivity of the patient's body tissue in response to the secreted incretin. (Item 62) 59. The method of claim 58, further comprising controlling the patient's blood glucose level in response to the secreted incretin. (Item 63) 1. A method for stimulating L cells in the intestinal tract of a patient to secrete incretins that suppress appetite levels, comprising: ingesting a swallowable device configured to advance through the intestinal tract and electrically stimulate L-cells in the intestinal tract; delivering an electrical signal from the device to the intestinal wall proximate to the device, the signal comprising a waveform configured to electrically stimulate L-cells in the intestinal tract to secrete the incretin without substantially causing peristaltic contractions of the small intestine or other GI organs; electrically stimulating the L cells to secrete the incretin; suppressing the appetite level of the patient in response to the secreted incretin. A method comprising: (Item 64) 64. The method of claim 63, wherein the incretin comprises GLP-1. (Brief summary) Embodiments of the present invention provide devices and methods for stimulating L-cells in the small intestine to produce incretins and other peptides for the treatment of various diseases and conditions, including diabetes and obesity. Many embodiments provide methods and devices for the treatment of obesity, diabetes and other glucose regulation disorders by electrically stimulating L-cells to secrete glucagon-like protein (GLP) and other incretins and stimulating the production of insulin. Particular embodiments provide a swallowable capsule for electrically stimulating L-cells in the intestinal tract to secrete GLP as the capsule travels through the intestinal tract. Capsule embodiments may include two or more electrodes for providing electrical stimulation to the L-cells, a sensor for sensing the position of the capsule in the intestinal tract, a power source such as a battery for powering one or more electrical components in the capsule, a controller for controlling one or more operations of the capsule, and a signal / waveform generator for generating an electrical signal that is delivered by the electrodes to the tissue to stimulate the L-cells to produce incretins such as glucagon-like peptide-1 (GLP-1). The signal typically includes a waveform such as a square wave with selectable pulse duration and may be generated by a signal / waveform generator integrated or coupled to the controller. The signal is preferably configured to stimulate the L-cells to secrete incretins such as GLP-1, but not induce peristaltic contractions at intestinal sites near the capsule or anywhere else in the intestine. However, in some embodiments, the waveform generator may be configured to generate two waveforms, one to stimulate the L-cells without inducing peristaltic contractions, and a second to induce peristaltic contractions to advance the capsule along the intestine. In these latter embodiments, the capsule may include an accelerometer to detect when the capsule has stopped moving or is moving below a desired velocity threshold. In use, these latter embodiments may advance the capsule in patients with very slow intestinal motility, such as those with enteric neuropathy or other related conditions such as intestinal necrosis.When the controller receives an input from the accelerometer indicating that the capsule has stopped or is moving too slowly, the controller can signal the waveform generator to generate a second waveform to induce peristaltic contractions of the intestine in an area near the capsule, thereby propelling the capsule distally through the intestine. This process can be repeated as necessary, with selectable delays to account for the refractory period of the peristaltic contractions.

[0011] The electrodes typically include at least a pair of electrodes that may be positioned at various locations and orientations on the capsule surface. This may include in a longitudinal manner relative to the longitudinal or radial axis of the capsule. In a specific embodiment, the electrodes may include one or more pairs of annular electrodes positioned on the surface capsule. The electrodes may include various conductive metals known in the art, including, for example, silver-silver chloride or platinum. The spacing of the electrodes may be configured to minimize electrical stimulation of tissues below the mucosal layer of the intestinal tract. In a specific embodiment, the spacing may be configured to limit electrical stimulation of the intestinal wall to a depth of 5 mm or less.

[0012] In various embodiments, the at least one sensor may include one or more pH sensors to detect the passage of the capsule from the stomach to the small intestine, and a pressure sensor to sense peristaltic contractions of the intestine to detect when the capsule is in the intestine (independently or in combination with input from the pH sensor). The pressure sensor may also be used to detect when the intestine is in contact with the capsule (e.g., when it is being squeezed during peristaltic contractions), and therefore when to initiate a stimulation period. Particular embodiments may include both a pH sensor and a pressure sensor to identify changes in pH from the stomach to the intestine in addition to peristaltic contractions, increasing the level of accuracy in locating the sensor in the tube. Still other sensors are contemplated, such as temperature, O2, CO2, optical sensors, etc. Inputs from multiple sensors may be combined to provide a total sensory input to the controller for locating the capsule. In various embodiments, a sensor conditioning circuit (e.g., a band pass filter) may be coupled to the controller to condition the sensor signal before being input to the controller.

[0013] In an exemplary embodiment of the method of use, the swallowable capsule of the present invention may be used to stimulate secretion of various proteins, such as GLP, by L-cells to enhance insulin release and / or enhance activity in the body. In these and other related embodiments, a user may swallow the capsule before, during, or after a meal. After ingestion, the swallowable capsule passes through the stomach and into the small intestine. A sensor within the capsule may detect its relative location within the body. For example, a pH, pressure, or other relevant indicator sensor may identify when the capsule reaches the small intestine. Once in the small intestine, a controller (typically within the capsule) activates the swallowable capsule to provide electrical stimulation that causes the L-cells in the small intestine to secrete GLP-1 or other incretins (GIP, PYY, etc.). The GLP-1 and / or other incretins then induce insulin secretion and / or promote the body's use of insulin. Activation of the swallowable capsule to provide electrical stimulation may be commanded, for example, by internal instructions and / or programs within the swallowable capsule, or may be provided by external control of the swallowable capsule. The swallowable capsule is preferably taken just before or with a meal so that stimulation of secretion of GLP-1 and / or other incretins is coordinated with the absorption of nutrients from ingested food, and therefore subsequent insulin production is also coordinated with the influx of glucose, fat and other nutrients into the bloodstream. In this way, the patient's blood glucose levels can be controlled after a meal to more closely resemble those of a normal, non-diabetic individual.

[0014] Further details regarding these and other embodiments and aspects of the invention are described in more detail below with reference to the accompanying drawings. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows the distribution of L cells along the small intestine and intestinal wall. [Diagram 2] FIG. 2 is a cross-sectional view of the intestine showing the location of L cells in the intestinal wall. [Diagram 3] FIG. 3 is a schematic diagram showing the biochemical and physiological functions of L cells, including hormone secretion and intracellular signaling. [Figure 4] FIG. 4 is a side view showing an embodiment of a swallowable capsule of the present invention. [Diagram 5] FIG. 5 is a cross-sectional view illustrating the use of an embodiment of a swallowable capsule in the intestinal tract to stimulate L cells to secrete incretins. [Figure 6] FIG. 6 is a side view showing the gap between the electrodes of an embodiment of the swallowable capsule. [Figure 7] Figures 7a-d show various embodiments of electrode configurations on a capsule: Figure 7a is a side view of an embodiment of a capsule with annular electrodes; Figure 7b is a side view of an embodiment with laterally oriented electrodes; Figure 7c is a cross-sectional view of an embodiment with multiple laterally oriented electrodes; and Figure 7d is a side view of an embodiment with both annular and laterally oriented electrodes. [Figure 8] FIG. 8 is a block diagram illustrating an embodiment of an electronic structure for controlling one or more functions of the swallowable capsule. [Figure 9] 9a-d are side views illustrating the use of electrical stimulation waveforms emitted from the capsule to induce peristaltic waves to move the capsule through the intestinal tract. [Figure 10] FIG. 10 is a bar graph showing the effect of electrical stimulation on in vitro GLP-1 production by differentiated NCI-H716 cells. [Figure 11] FIG. 11 is a time course graph showing the effect of electrical stimulation on in vitro GLP-1 production by differentiated NCI-H716 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Detailed Description of the Invention The embodiments described herein provide methods and devices for stimulating cells in the small intestine to secrete glucagon-like proteins (also referred to herein as glucagon-like peptides) and other hormones and secretory compounds for the treatment of a variety of conditions, including diabetes and obesity.

[0017] Referring now to Figures 1-3, the mucosal surface of the intestinal tract, including the small intestine and large intestine, is lined with many cells, including L cells (LC) and K cells (KC). L cells include a submucosal portion SP and a luminal protruding portion LP that extends from the surface of the mucosa M and binds various molecules, including glucose. L cells and K cells secrete various gastrointestinal hormones known as incretins, including glucagon-like protein (GLP-1), glucose-dependent insulinotropic peptide GIP, and oxyntomodulin (OXM).

[0018] The hormone GIP can enhance the secretion of GLP-1. GIP is secreted by the so-called "K" cells of the proximal duodenum, under some control of enteric cholinergic neurons. In addition to K cells, L cells also secrete GLP-1 and GIP in response to exposure to glucose. GIP then acts to increase the release of GLP-1. GLP-1 in turn acts to increase insulin production, as described below. Incretins also produce other beneficial effects such as appetite suppression, weight loss, restoration of insulin sensitivity in body tissues, and preservation of pancreatic beta cells. Incretins are rapidly metabolized / degraded by the kidney and peptidases (half-life GLP-1<2 min, GIP<7 min).

[0019] Incretins are believed to play an important role in glucose control in the body, with incretins such as GLP-1 increasing insulin secretion in a glucose-dependent manner in a phenomenon known as the "incretin effect." In fact, approximately 50% or more of the insulin response to a meal is attributable to the incretin effect. This incretin effect results in a very rapid increase in plasma insulin, usually within about the first 30 minutes after ingestion of glucose. Many type 2 diabetes patients have a significant decrease in the incretin effect, including a decreased secretion of GLP-1 and a substantial decrease in the insulinotropic activity of GIP. This results in a substantial decrease in the rate and amount of insulin production in diabetic patients.

[0020] Several approaches can be contemplated to reverse the loss of incretin effect that occurs in diabetes, including type II diabetes. These include increasing the production of GIP and / or GLP-1. As mentioned above, in type II diabetes patients, GIP loses its insulinotropic activity and therefore is unable to regulate glucose-dependent insulin secretion even at supraphysiological (pharmacological) plasma levels. This loss of activity is detrimental to insulin production by pancreatic β-cells, especially after a meal. Therefore, increasing the production of GIP may not be a viable option. However, even in type II diabetes, GLP-1 is insulinotropic, albeit at significantly reduced levels. Therefore, increasing the level of GLP-1 appears to be an approach to increase insulin production in diabetic patients, including type II diabetes patients.

[0021] Thus, various embodiments of the present invention contemplate increasing the production of GLP-1 and other incretins by electrically stimulating a portion of the intestine at or substantially the same time as a meal is ingested. This can be accomplished by ingesting a swallowable capsule before, during or after a meal, which is configured to electrically stimulate a portion of the intestine to stimulate L-cells to secrete GLP-1 and other incretins, thereby increasing insulin production. The capsule is desirably swallowed in a manner coordinated with the intake of a meal (e.g., during a selected time before, during or after the intake of a meal, e.g., 1-30 minutes before or after the intake of a meal), so that the secretion of GLP-1 or other incretins is coordinated with the absorption of nutrients into the bloodstream. Coordination or timing of the capsule with the intake of a meal may also be selected to produce other effects, such as appetite suppression, as described herein.

[0022] 4-8, an embodiment of a swallowable capsule 10 for stimulating L-cells and other cells in the intestinal IT to secrete incretins includes a capsule body 20, at least two or more electrodes 40 for providing electrical stimulation to the desired cells, a controller 30 for controlling one or more operations of the capsule and generating electrical signals delivered to the tissue by the electrodes, a power source 55 for powering one or more components of the capsule, such as the controller, and at least one sensor 60 for determining the location of the capsule within the tract and / or various events and conditions within the GI tract. In various embodiments described herein, the capsule 10 may also include an accelerometer 65 for measuring the rate of movement of the capsule through the intestinal IT and for determining periods of no movement.

[0023] Capsule body 20 (herein referred to as body 20) is desirably sized and shaped to be swallowed by a user (herein referred to as a patient) and pass completely through the intestinal tract by normal peristalsis. Body 20 includes a body surface 25 and an interior cavity 21 for various components, such as controller 30. Body 20 can be made from a variety of biocompatible, inert plastics known in the art and can also include a variety of coatings, such as an enteric coating.

[0024] The electrodes 40 may comprise a variety of biocompatible conductive materials, including silver-silver chloride, platinum, or stainless steel. Still other conductive materials known in the art are contemplated, such as various conductive polymers. The electrodes 40 may also have a laminated construction with a more antiseptic material on the surface. Typically, the electrodes 40 include at least one electrode pair 50 of electrodes, which may be configured as a bipolar electrode. Multiple pairs 50 of electrodes 40 are also contemplated, including two, three, four, and even greater numbers.

[0025] The electrodes 40 may be arranged in various ways on the surface 25 of the capsule body 20, including longitudinally relative to the radius 20r of the capsule, as shown in the embodiment of FIG. 7a. FIG. 7a also shows an embodiment in which the electrodes 40 include one or more pairs 50 of annular electrodes 40r arranged on the surface capsule. Multiple pairs 50 of annular electrodes 40r may be distributed along the length of the capsule 20, with each pair being switchable by the controller 30 or other switching circuitry. Such an embodiment allows the controller 30 to switch individual electrode pairs 50 on and off to optimize stimulation of the L-cells based on various factors, such as when peristaltic contractions or squeezing are detected in one portion of the capsule but not another.

[0026] In other embodiments, the electrodes 40 may be oriented in a lengthwise manner relative to the longitudinal axis 20L of the capsule 20, as shown in the embodiment of FIG. 7b. In a preferred embodiment, the capsule 20 may include multiple pairs 50 of electrodes 40 oriented relative to the lateral axis 20L to be distributed around the capsule perimeter 20p, as shown in the embodiment of FIG. 7c. In yet other embodiments, the capsule 20 may include a combination of laterally and radially oriented electrodes, as shown in the embodiment of FIG. 7d. Such embodiments may be used to stimulate different types of cells (e.g., L-cells and K-cells), cells in different locations, or to stimulate L-cells and intestinal musculature to elicit peristaltic contractions as described herein.

[0027] The spacing or gap 45 between the individual electrodes is desirably configured to minimize electrical stimulation of tissue below the intestinal mucosal layer, as shown in the embodiment of FIG. 6. The spacing 45 may be configured to limit electrical stimulation of the intestinal wall to a depth of 5 mm or less, more preferably 3 mm or less, and even more preferably 1 mm or less. In certain embodiments, the gap 45 may be in the range of about 0.05 to about 0.2 inches, and in specific embodiments, 0.1, 0.15 inches. To achieve a shallower stimulation effect, closer spacing may be used. In certain embodiments, the spacing between the electrode pairs 50 may vary, with some pairs configured for a shallower stimulation effect and other pairs configured for a deeper stimulation effect. In the latter case, the deeper stimulation effect may be configured to stimulate the intestinal muscle tissue to elicit peristaltic contractions of the intestine as described herein.

[0028] The power source 55 typically includes a small chemical battery, such as a lithium or lithium ion battery. In a battery embodiment of the power source 55, the battery may be configured to provide a battery life of at least 5 hours or more. The controller 30 may include various power management circuits to optimize battery life. In various alternative embodiments, the power source 55 may also include a piezoelectric power source using a piezoelectric electric material configured to obtain energy from compression or deformation of the capsule due to its movement through the intestinal tract. In still other embodiments, the power source may include a thermoelectric power source, such as a Peltier effect power device configured to utilize the heat of the patient's body to generate power. In such embodiments, all or a portion of the capsule may include a thermally conductive layer or other thermally conductive element configured to conduct heat to the Peltier effect device.

[0029] In various embodiments, the at least one sensor 60 may include one or more pH sensors and pressure / force sensors. The pH sensor may be configured to detect the passage of the capsule from the stomach to the small intestine, indicated by a spike in pH as the capsule passes from the pyloric valve to the duodenum. Various miniature pH sensors known in the art may be utilized. The pressure sensor 60 may be utilized to sense peristaltic contractions of the intestine to detect when the capsule is in the intestine. The pressure sensor 60 may be used to detect when the intestine is in contact with the capsule (e.g., when it is being squeezed during a peristaltic contraction or peristaltic squeezing) and therefore when a stimulation period should commence. Various miniature solid-state pressure / force sensors may be used, such as various miniature strain gauge sensors, including various micro-electrical-mechanical systems (MEMS) based strain gauges or other related pressure / force sensors. Certain embodiments may include both pH and pressure sensors to increase the level of accuracy in locating the sensor within the tract by identifying changes in pH and peristaltic contractions from the stomach to the intestine. In various embodiments, multiple pH and pressure sensors 60 may be distributed on the capsule body surface 25 to determine when a portion of the capsule has entered the intestine, or when a portion is being squeezed by peristaltic contractions (so that electrode in that section may be switched on), or other pressure differences that do not change the position or status of the capsule.

[0030] Still other sensors are contemplated, such as temperature sensors, O2 sensors, CO2 sensors, optical sensors, acoustic sensors, etc. Additionally, inputs from multiple sensors may be combined to generate a total sensory input to the controller for determining the location of the capsule. Also, as described herein, in various embodiments, a sensor conditioning circuit 63 may be coupled to the controller 30 to condition the sensor signal 61 before being input to the controller 30.

[0031] 5, in one embodiment of a method of use, the swallowable capsule 10 of the present invention may be used to enhance insulin release and / or enhance activity in the body. Once ingested, the swallowable capsule 10 passes through the stomach and into the small intestine SI. A sensor 60 within the capsule 10 may detect its relative location within the body. For example, a pH, pressure, or other relevant indicia sensor may identify when the capsule has passed the pyloric sphincter and reached the small intestine. In the case of a pH measurement, this may be identified by the sudden increase in pH that occurs after the capsule has passed the pyloric sphincter and into the duodenum.

[0032] Once the swallowable capsule 10 enters the small intestine, it is activated to provide electrical stimulation that causes the L-cells in the small intestine to secrete GLP-1 or other incretins (GIP, PYY, etc.). The GLP-1 and / or other incretins then induce insulin secretion and / or enhance the body's use of insulin. Activation of the swallowable capsule to provide electrical stimulation may be directed by internal instructions and / or programs, for example, within a controller or other logic resource located within the swallowable capsule, or may be provided by external control of the swallowable capsule.

[0033] Since some patients (especially diabetic patients with a mostly distally located uneven distribution) tend to have more concentrated L-cells in the distal portion, in certain embodiments, the capsule controller 30 may start a timer upon reaching the small intestine so that the controller can estimate how far the capsule has traveled through the small intestine. This distance may be estimated using the mean intestinal transit time or by individual measurement of the transit time for a particular patient using methods known in the GI diagnostic art. The timer function may then be used to determine an appropriate delay in initiating stimulation. For patients with longer transit times, a longer delay may be used. In embodiments having an accelerometer, the actual speed of the capsule through the intestine may be calculated and used to determine when to initiate the stimulation signal after the capsule enters the small intestine. Additionally, in embodiments using a peristaltic contraction stimulation signal, the timing of the L-cell stimulation signal may be adjusted, as described below.

[0034] Alternatively or in addition to using a pH sensor to determine the location of the capsule, including when it enters the small intestine, the capsule 10 may also include a pressure sensor 60 to detect when the intestinal wall is squeezing the capsule, for example by peristaltic contractions. Appropriate pressure / force levels indicative of intestinal squeezing may be determined from known physiological measurements or may be established by looking for a relative increase in squeezing pressure (e.g., 2-fold, 3-fold, 5-fold, or an order of magnitude or more). Since it may be desirable for the electrodes to be in contact with or near the intestinal wall, in some embodiments, detection of squeezing by the intestinal wall may also serve as a trigger to initiate electrical stimulation of the L-cells. Such contact or proximity may help to more effectively deliver electrical current to and depolarize the L-cells to produce GLP-1. Also, in related embodiments, electrical stimulation may be stopped (either initially or after a programmed delay) upon detection of a decrease in pressure (indicative of the intestinal wall relaxing and moving away from the capsule) in order to conserve battery power while stimulation-induced release of GLP-1 or other incretins may be suboptimal. In this way, the stimulation signal from the electrodes can be turned on and off with each peristaltic contraction of the intestine (small or large intestine) until the capsule has passed through all or a selected portion of the intestine.

[0035] The swallowable capsule is preferably taken with a meal so that stimulation of L-cells (or other cells) to secrete GLP-1 and / or other incretins is coordinated with the absorption of nutrients from the meal, and thus subsequent insulin production is coordinated with the influx of glucose, fat and other nutrients into the bloodstream. In this way, insulin is delivered in a manner that mimics the physiological delivery of insulin during normal food digestion, thus achieving improved blood glucose control. This process can be further improved by monitoring blood glucose levels after a meal using standard glucose monitoring methods (e.g., a blood glucose meter) and adjusting delays or other timing of the stimulation signal. In some embodiments, the capsule can be configured to allow the user to input into the capsule the amount and type of food consumed (e.g., high carbohydrate or high fat meals, which are more likely to cause a spike in blood glucose values). This allows a software module present in or coupled to the controller 30 or other logic resource in the capsule 10 to adjust the timing and sequence of L-cell stimulation signals to titrate the level of insulin produced in response to the consumption of food. Input to the capsule may be sent by a mobile device, such as a cell phone or similar device, using BLUETOOTH or other wireless connections or protocols known in the art. In these and related embodiments, the capsule 10 may include an RF-communications chip.

[0036] Referring now to FIG. 8, an embodiment of a circuit architecture 100 for controlling one or more functions of the capsule 10 will now be described. The architecture 100 typically includes a controller 30, a sensor 60 (such as pressure and pH sensors), a sensor conditioning circuit 63, a stimulus signal source 70 (signal source 70 herein), and an H-bridge or similar device 80. The controller 30 typically includes a microcontroller, such as a microprocessor or state device, and may be coupled to one or more other electronic components of the capsule 10, as shown in the embodiment of FIG. 8. Also shown in the figure is a power supply 55 that may be coupled to one or more components of the architecture 100 (e.g., the controller 30, the sensor 60, the stimulus signal source 70, etc.) to provide power to those components. The sensor conditioning circuit 63 may include standard circuitry known in the art and may serve to condition (e.g., high-pass or low-pass filter) the input 61 received from the sensor 60. The signal source 70 includes various energy conversion circuits that convert a fixed DC voltage from a battery or other power source 55 into a programmable energy format. Suitable energy conversion circuits for the signal source 70 may include one or more of a programmable current source, a programmable voltage source, a DC-DC converter, or a DC-AC converter. The H-bridge device 80 provides signals to the electrodes 40 and may be configured (by one or more switches operable by the controller 30) to not only stop current flow completely but also to change the direction of current flow between the electrodes 40 to produce a biphasic stimulation signal (described below).

[0037] The controller 30, the stimulation signal source 70 and the H-bridge 80 collectively comprise a signal generator 110, also known as a waveform generator 110, which generates a stimulation signal 200 that is delivered to the electrodes 40 and then transmitted to the intestinal tissue (e.g., the intestinal wall) to stimulate L-cells (or other cells) to produce incretins such as GLP, which stimulates insulin production or enhances the effects of insulin. The signal 200 is preferably configured to stimulate the L-cells to produce incretins such as GLP-1, but not to induce peristaltic contractions at the site of the intestine near the capsule 200 or anywhere else in the intestinal tract. This quality can be achieved by controlling one or more of the current, voltage and / or frequency of the signal as well as the pulse duration of the pulse signal, as described herein. For purposes of stimulating L-cells (and K-cells), the signal 200 can have a voltage of about 0.1-10 V, a current of about 10 μa-2 mA, and a frequency of 1 Hz-100 Hz. The voltage, current and frequency may also be fine-tuned or otherwise modified depending on the condition being treated (e.g., diabetes, obesity, etc.), the severity of the condition (e.g., Type I vs. Type II diabetes), and other patient conditions (e.g., enteric neuropathy, etc.).

[0038] Signal 200 may have a variety of waveforms, such as, for example, a square wave, a sine wave, a sawtooth wave, a trapezoidal wave, etc. In a preferred embodiment, signal 200 may include a biphasic signal 200b, which may be generated using an H-bridge device 80 as described above. In many embodiments, including those having a square wave, signal 200 may include a pulsed signal 200p. Pulsed signal 200p may have a pulse width in the range of 10 μs to 100 ms.

[0039] As mentioned above, the signal 200 is preferably configured to stimulate L-cells (or other relevant cells such as K-cells) to produce incretins such as GLP-1, but not induce peristaltic contractions in the intestinal region near the capsule or anywhere else in the intestinal tract. However, in some embodiments, the waveform generator 110 may be configured to generate two waveforms: a first waveform 200 for stimulating L-cells without inducing peristaltic contractions, and a second waveform 210 for inducing peristaltic contractions to advance the capsule 10 along the intestinal tract. In these latter embodiments, the capsule may include an accelerometer 65 for detecting when the capsule 10 has stopped moving or is moving below a desired velocity threshold. In use, these latter embodiments may advance the capsule 10 in patients with very slow intestinal motility, such as patients with enteric neuropathy or other related conditions such as intestinal necrosis. When the controller 30 receives an input 66 from the accelerometer 65 indicating that the capsule 10 has stopped or is moving too slowly, the controller signals the waveform generator 110 to generate a second waveform 210, which induces peristaltic contractions of the intestine in the area near the capsule, thereby propelling the capsule distally through the intestine. This process can be repeated as necessary, with selectable delays to account for the refractory period of the peristaltic contractions.

[0040] 9a-9d, a discussion of embodiments of methods for propelling a capsule through the intestine by inducing peristaltic contractions is now presented. As described herein, some patients, particularly diabetic patients, have a condition known as enteric neuropathy in which the small and / or large intestine transit time of food is greatly reduced due to damage to motor neurons that innervate the intestine. As such, in certain embodiments, the controller may be configured to generate two stimulation signals, one signal having a first waveform for stimulating the L-cells without inducing peristaltic contractions, and a second signal having a second waveform for inducing peristaltic contractions to advance the capsule along the intestinal tract. As described herein, the second signal may have a higher stimulation current than the first signal, for example, in the range of 2-5 ma. In embodiments using a peristaltic stimulation signal, the capsule 10 may include an accelerometer 65 for detecting when the capsule has stopped moving or is moving below a desired velocity threshold. When the controller 30 detects that the capsule is below a desired threshold or that the capsule has been stationary for more than a desired period of time (e.g., 0.5 to 2 minutes, although longer and shorter periods are contemplated), it initiates the generation of one or more peristaltic stimulation signals to trigger peristaltic contractions to propel the capsule distally within the intestine. An appropriate delay may then be incorporated before the L-cell stimulation signal is delivered to allow peristaltic contractions to occur for the electrical refractory period of the intestine. If desired, multiple peristaltic initiation signals may be generated to trigger a series of peristaltic contractions, e.g., for patients with particularly slow transit times, or just as the capsule is entering the small intestine, to move the capsule more distally within the intestine before the L-cell stimulation signal is delivered. In use, such embodiments may advance the capsule in patients with very slow intestinal motility, such as patients with enteric neuropathy or other related conditions such as intestinal necrosis. When the controller receives input from the accelerometer indicating that the capsule has stopped or is moving too slowly, the controller generates a second waveform to induce peristaltic contractions of the intestine in a region near the capsule, which propels the capsule distally through the intestine.This process can be repeated as necessary, with a selectable delay to account for the refractory period of peristaltic contractions. EXAMPLES

[0041] (Example) Various embodiments of the present invention will now be further illustrated with reference to the following examples, although it will be understood that these examples are given for purposes of illustration and that the invention is not limited to these specific examples or their details.

[0042] Example 1 - Electrical stimulation of GLP-1 release in vitro Culture dishes were placed at 50ul / cm 2 The wells were coated on ice with Matrigel by adding 100 μl of 10 ...

[0043] In the experiments, the cell culture medium was replaced with HBSS supplemented with 0.5% FBS and any one of the following test factors:

[0044] 1. PMA (phorbol-12-myristate-13-acetate) (1 mg stock solution in 1.6 ml DMSO = 1 mM; add 1 ul per ml of medium to get a final concentration of 1 uM) 2.1.5% sucrose 3.10% glucose 4. Electrical stimulation (250uA, 5Hz, 0.1, 1.0 or 10ms AC pulse wave).

[0045] Cells were incubated for 2 hours. Test factors were added and cell supernatants were removed at various time points for analysis. PMSF (10 ul) was added to the cell supernatants, which could be frozen or used immediately. Lysis buffer was prepared by combining RIPA with 10 ul PMSF, 10 ul proteinase inhibitor, and 10 ul sodium orthoborate. 200-300 ul of RIPA lysis buffer was then added to the wells along with the cell supernatant samples. The wells were scraped with a cell scraper and the mixture was pipetted into a 1.5 ml tube, followed by pipetting again to break the cells and cell membranes. The tubes were spun down at full speed for 5 minutes and the supernatants were collected and then frozen or analyzed immediately.

[0046] GLP-1 was measured by ELISA. Streptavidin-coated wells were incubated with a biotin-conjugated antibody that specifically binds GLP-1. After incubation with lysed cell supernatants, samples were incubated with a GLP-1-binding antibody conjugated to HRP (horseradish peroxidase). Substrate conversion by HRP was then used to quantify GLP-1. The results are shown in Figures 10 and 11.

[0047] (Conclusion) The above description of various embodiments of the present invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Many modifications, variations, and improvements will be apparent to those skilled in the art. For example, the capsule can be sized for various pediatric applications. Also, the waveforms can be configured to stimulate as well as inhibit various cells in the intestinal tract. For example, the waveforms can be configured to stimulate one cell type and inhibit another cell type. In addition, various embodiments of the capsule can include telemetry for signaling to and from external monitoring and / or control devices.

[0048] Elements, features, or acts from one embodiment may be readily combined or substituted with one or more elements, features, or acts from other embodiments to form numerous additional embodiments within the scope of the present invention. Moreover, elements shown or described as being combined with other elements may, in various embodiments, exist as independent elements. Thus, the scope of the present invention is not limited to the details of the described embodiments, but is limited only by the scope of the appended claims.

Claims

1. 1. A system for stimulating L cells in the intestinal tract of a patient to secrete a polypeptide, comprising: a swallowable device configured to advance through the intestinal tract and electrically stimulate L-cells in the intestinal tract; a means for delivering an electrical signal from the device to the intestinal wall in the vicinity of the device, the signal comprising a waveform configured to electrically stimulate L-cells in the intestinal tract to secrete the polypeptide; means for electrically stimulating said L cells to secrete said polypeptide; Including, the system.

2. The system of claim 1 , wherein the intestinal wall is the wall of the small intestine.

3. The system of claim 1 , wherein the peptide comprises an incretin.

4. The system of claim 3, wherein the incretin comprises GLP-1.

5. 4. The system of claim 3, further comprising means for modulating the release of insulin in the patient in response to the secreted polypeptide.

6. 6. The system of claim 5, wherein said insulin release is regulated by said electrical stimulation of said L-cells causing an increase in plasma insulin within 30 minutes of stimulation.

7. The system of claim 1 further comprising a means for controlling blood glucose levels in the patient in response to the secreted polypeptide.

8. The system of claim 1 , further comprising a means for suppressing the appetite level of the patient in response to the secreted polypeptide.

9. The system of claim 1 , wherein the waveform has a substantially square waveform.

10. The system of claim 1 , wherein the waveforms include a first waveform and a second waveform.

11. the second waveform is configured to produce peristaltic contractions of intestinal tissue immediately adjacent the device; and The system of claim 10 , wherein the device is configured to advance within the intestinal tract using the generated peristaltic contractions.

12. The system of claim 11 , wherein the second waveform occurs when the second waveform is substantially different from the first waveform.

13. The system of claim 11 , wherein the second waveform is generated in response to a velocity of the device moving through the intestinal tract.

14. The system of claim 13 , wherein the velocity is measured using an accelerometer located on or in the device.

15. 10. The system of claim 1, further comprising a means for determining a location of the device within the GI tract, wherein the signal is delivered in response to the location of the device within the intestinal tract.

16. The system of claim 15 , wherein the location is the small intestine.

17. The system of claim 15 , wherein the location is determined using a sensor.

18. 18. The system of claim 17, wherein the location is determined based on at least one of sensed pH or sensed pressure exerted on the device surface by intestinal wall tissue.

19. The system of claim 1 , wherein ingestion of the device is coordinated with ingestion of food.

20. 20. The system of claim 19, wherein the device is ingested during a selected period before, during, or after ingestion of food.

21. 21. The system of claim 20, wherein the period is selected to coordinate the stimulation of the L cells with the absorption of nutrients from the food into the bloodstream.

22. The system of claim 1 , wherein the device comprises a swallowable capsule.

23. The system of claim 1 , wherein the device includes a controller, at least one electrode, and a waveform generator.

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