Improvements in methods and devices to curb appetite and/or reduce food intake

(54) Title: SMALL INTESTINE INSERT, AND, METHOD FOR GENERATING SACIETY IN AN INDIVIDUAL (30) Unionist Priority: 05/26/2006 us 60/808820 (73) Holder (s): Endosphere, Inc.

(72) Inventor (s): James Mckinley, Kenneth Binmoeller, Matt Yurek, Zhenyong Keck (74) Attorney (s): Momsen, Leonardos & CIA.

(86) International order: pct US2007012462 from

25/05/2007 (87) International Publication: wo 2007 / 139920de

06/12/2007 (57) Abstract: insertion of small intestine, and method to GENERATE SACIETY IN AN INDIVIDUAL. The present invention relates to devices and methods of operating devices that contribute to decreased appetite and / or reduced food intake. In some embodiments, the methods and devices of the present invention include as an intestinal / duodenal insert comprising an elongated member with at least one flow reduction element that can cause the stimulation of one or more biological satiety signals. Some modalities of the inserted device are anchored in the duodenal site by an anchoring member that resides in the stomach, other modalities of the device are stabilized in a targeted location by appropriate length dimensions, as well as one or more angled positions of the device that correspond to angled positions of the targeted site in the duodenum. Modalities of the device have effects due to the physical presence, as well as more active forms of intervention, including the release of bioactive materials and electrical stimulation of neurons.

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“SMALL INTESTINE INSERT, AND, METHOD FOR GENERATING SACIETY IN AN INDIVIDUAL”

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

This patent application claims priority in USC § 119 for US provisional patent application Serial No. 60 / 808,820 from Binmoeller, filed on May 26, 2006, entitled “Improvements in methods and devices for curb appetite and / or reduce food intake ”, the description of which is incorporated by reference. The patent application additionally claims priority for US patent application No. serial number 11 / 300,283 from Binmoeller, filed on December 15, 2005 and published as US patent application 2006/0178691 on August 10, 2006, the present patent application of which is partly a continuation. Patent application Serial No. 11 / 300,283 is in itself a continuation in part of US patent application No. 10 / 999,410 filed on November 30, 2004, and published as US 2005/0192614 on September 1, 2005. Patent application No. 10 / 999,410 claims priority for provisional patent application US 60 / 547,630, filed on February 26, 2004. The present patent application claims priority for each of the aforementioned patent applications, which are also incorporated herein. INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specification are hereby incorporated by reference to the same extent that if each individual patent publication or patent application were specifically and individually indicated as incorporated by the reference.

FIELD OF THE INVENTION

The invention is in the field of medical devices and methods that relate to decreased appetite and / or reduced food intake. BACKGROUND OF THE INVENTION

Obesity, defined as a body mass index (BMI) greater than 30, is a major health concern 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 many serious and life-threatening illnesses, including hypertension, diabetes, coronary artery disease, stroke, congestive heart failure, lung failure, multiple orthopedic problems, various cancers and a markedly shorter life expectancy. Intentional weight loss, however, can improve many of these medical complications associated with obesity.

Although weight loss can improve many of the medical complications associated with obesity, its management as a health concern has proved impertinent. A variety of approaches, including dietary methods, psychotherapy, behavior modification and pharmacotherapy, have each been somewhat successful, but as a whole they have failed to effectively control rapid growth in the incidence and severity of obesity seen in the United States. The severity of the problems associated with obesity has also led to the development of drastic surgical procedures. A procedure like this physically reduces the size of the stomach, so that the person cannot consume as much food as previously possible. These stomach reduction surgeries had limited success in the beginning, but it is now known that the stomach can stretch back to a larger volume over time, limiting prolonged weight loss in many individuals. Another drastic surgical procedure induces malabsorption of food by reducing the absorptive surface of the gastrointestinal (GI) tract, usually through portions that bypass the small intestine. This gastric bypass procedure was additionally combined with stomach reduction surgery. Although these surgical procedures described may be effective in inducing a reduction in food intake and / or overall weight loss in

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and with the cessation of food intake. Although higher levels of hormones, such as ghrelin, motilin and agouti-related peptide are involved in promoting appetite and starting food intake, higher levels of countless other hormones are involved in stopping food intake.

Various biological events contribute to the physiological cessation of food intake. Generally, the extent to which a meal is consumed, the food eaten and by-products of digestion interact with an arrangement of receptors throughout the GI tract to create signs of satiety. Signs of satiety communicate with the brain that an adequate amount of food has been consumed and that an organism must stop eating. Specifically, chemoreceptors of the GI tract respond to digestion products (such as sugars, fatty acids, amino acids and peptides) by stretching to the same extent and mechanoreceptors in the stomach and proximal small intestine respond to the physical presence of the food consumed. Chemoreceptors respond to digestion products by releasing hormones or other molecular signals. These released hormones and / or other molecular signals can stimulate nerve fibers to send satiety signals to the brain. The arrival of these signals in the brain can trigger a variety of neural pathways that can reduce food intake. The released hormones and / or other molecular signals can also travel to the brain on their own to help create satiety signals. Distension and mechanoreceptors usually send satiety signals to the brain by stimulating nerve fibers at the periphery of the brain signal. The present invention provides methods and devices that help to reduce food intake by providing non-surgical devices and methods that trigger the aforementioned biological events that contribute to the creation of satiety signals.

SUMMARY OF THE INVENTION

The invention relates to a device to be inserted into the small intestine, which can generally be referred to as a small intestine insert. First to be summarized are modalities that include a biodegradable material. Modalities of the insert include an elongated or central member with a proximal end, a distal end, at least an angled portion between the proximal end and the distal end, the angled portion that corresponds to at least one angled target site in the small intestine, and at least least a portion of the insert formed of a biodegradable material. Modalities may include an elongated limb initially configured to rest stably at the targeted site and then, after degradation of the biodegradable material, configured to destabilize, in such a way that it becomes unsettled from the target site, and can then be eliminated from the body through the intestinal tract.

In some embodiments, the angled portion includes biodegradable material. In some embodiments, the angled portion includes shape memory material. In some of these embodiments, the shape memory material includes either a shape memory alloy or a biodegradable shape memory polymer. In other embodiments, the angled portion includes both a shape memory alloy portion and a biodegradable portion. In some of the latter modalities, the biodegradable portion, upon degradation, is configured to facilitate destabilization and elimination of the shape memory alloy portion. In some of these embodiments, the shape memory alloy portion and the biodegradable portion are joined at a junction, the junction being configured to degrade as the biodegradable portion degrades.

In some embodiments, the target site angled in the small intestine is in the duodenum. Additionally, in some embodiments, the target site angled in the duodenum includes two angles, and the insert has two angles that correspond to two angles of the duodenum.

In some embodiments of the small intestine insert, the device includes at least one flow reduction element supported by the elongated member, the flow reduction element being configured to reduce chyme flow in the small intestine. In some of these embodiments, the flow reduction element is formed, at least in part, from a biodegradable material. In some embodiments, the flow reduction element includes either a slat, a net, a glove, a centrally mounted baffle, a peripherally mounted baffle, a foam-like material, or a fan. In the embodiments of the flow reducing elements that include a foam-like material, the foam-like material can include any of an open cell foam, a closed cell foam, or a hydrogel. In some of these embodiments, the foam-like material includes a bioactive material incorporated in it. And in some of these modalities, the foam-like material is biodegradable, and the bioactive material is released through degradation of the foam-like material. In other embodiments, the flow reduction element includes at least one releasable reservoir of one or more bioactive materials.

In some modalities with flow reduction elements, the elements reduce the flow rate of the chyme sufficiently to alter its biochemical profile. And in some of these modalities, the biochemical profile is altered enough to cause the generation of a hormonal satiety signal.

In some embodiments, the physical dimension of the insert is such that the insert stretches a portion of the small intestine when the insert is seated in it, and the distension is sufficient to cause stretching of receptors or other neurons in the small intestine to generate a satiety signal in response to it. The physical dimensions or characteristics of the insert that cause distension include any length, width, volume, density, weight, porosity, or surface properties.

Some insertion modalities include one or more releasable reservoirs containing one or more bioactive materials, the one or more reservoirs supported either directly or indirectly by the elongated limb and, additionally, include an active drug delivery mechanism also supported both directly and indirectly by the limb elongated, the active drug delivery mechanism and the one or more releasable reservoirs being in operable communication with each other.

Some embodiments of the insert include a pump as a part of the active drug delivery mechanism to deliver a bioactive material, the pump being supported by the elongated member and coupled to one or more releasable reservoirs. Pump modalities can include any of an osmotic pump, an electrically driven mechanical pump, a piezoelectric pump, a flow driven pump, or a peristaltic driven pump. Some of these modalities additionally include an energy storage element configured to supply energy to the pump. And in some of these modes, the pump is controlled by a remote device.

In other embodiments, the insert can additionally include an electronic emitter or neurostimulator configured to apply an electrical potential to a site in any small intestine or stomach, the emitter supported by the elongated member. In some of these modalities, the emitter, upon activation, stimulates a neuronal response that contributes to a satiety signal. In some embodiments, the device may additionally include an energy storage element or apparatus configured to supply power to the pump, and in some embodiments, the electronic emitter may be controlled by a remote device.

Some embodiments of the device may additionally include an anchoring member fitted to the proximal end of the elongated member, the anchoring member being configured to contribute to the stabilization of the device at the targeted site. In some of these anchored modalities, the anchoring member resides in the stomach when the elongated member is seated at the target site in the small intestine.

Seconds to be summarized are modalities of a small intestine insert that include a neurological stimulator to electrically stimulate nerves in the small intestine, such as nerves involved in the generation of satiety signals. This aspect of the invention concerns a small intestine insert that includes an elongated member including a proximal end, a distal end, at least an angled portion between the proximal end and the distal end, the angled portion that corresponds to at least one site angled target in the small intestine, where at least an angled portion of the insert corresponds to at least one angled target site in the small intestine, and a neurological stimulator, supported by the elongated limb.

In some of these embodiments, the insert includes a portion formed from a biodegradable material. Some of these modalities are initially configured to settle steadily at the targeted site, and then, after degradation of the biodegradable material, they are configured to destabilize in such a way that they become unsettled from the target site, and can be eliminated from the body through the intestinal tract.

In some embodiments, the neurological stimulator is adapted to stimulate one or more nerves in the small intestine sufficiently to generate one or more satiety signals. In some of these embodiments, the insert additionally includes an energy storage element configured to supply energy to the neurological stimulator. And in some of these modalities, the neurological stimulator is controlled by a remote device.

In some embodiments of the insert, the target site angled in the small intestine is in the duodenum. And in some embodiments, the target site angled in the duodenum includes two angles, the insert with two angles that correspond to two angles of the duodenum.

In some embodiments, the insert includes at least one flow reduction element, the element configured to reduce chyme flow in the small intestine. And in some of these embodiments, the flow reduction element is formed, at least in part, from a biodegradable material.

In some embodiments of the insert, at least a portion of the insert is formed from a biodegradable material, the elongated member initially configured to rest stably at the targeted site, and then, after degradation of the biodegradable material, configured to destabilize, in such a way that it take yourself unseated from the target site. In some of these embodiments, the angled portion of the insert includes biodegradable material. In still other embodiments, the insert may additionally include an anchoring member fitted to the proximal end of the elongated member, the anchoring member configured to contribute to the stabilization of the device at the targeted site.

Third to be summarized are modalities of a small intestine insert that include one or more releasable reservoirs containing one or more bioactive materials and an active drug release mechanism coupled to the reservoirs to transfer bioactive materials to the intraduodenal site. This aspect of the invention concerns a small intestine insert that includes an elongated member including a proximal end, a distal end, at least an angled portion between the proximal end and the distal end, the angled portion that corresponds to at least one site angled target in the small intestine, where at least an angled portion of the insert corresponds to at least one angled target site in the small intestine, and one or more releasable reservoirs containing one or more bioactive materials, the one or more reservoirs supported by the elongated member; and an active drug delivery mechanism supported by the elongated member, the active drug release mechanism and the one or more releasable reservoirs in operable communication with each other.

In some of these embodiments, the insert includes a portion formed from a biodegradable material. Some of these modalities are initially configured to settle steadily at the targeted site, and then, after degradation of the biodegradable material, they are configured to destabilize, in such a way that they become unsettled from the target site, and can be eliminated from the body through of the intestinal tract. In some of these embodiments, it is the angled portion of the device that includes the biodegradable material.

Modalities of the insert may include a drug delivery mechanism that can include either an osmotic pump, an electrically driven mechanical pump, a flow driven pump, a peristaltic driven pump, or a piezoelectric pump. Modalities may additionally include an energy storage element configured to supply power to the pump. In some embodiments, the active drug delivery mechanism is controlled by a remote device. In some of these modalities, the bioactive materials released by the active drug release mechanism are sufficient to generate a satiety signal.

In some of these modalities, the target site angled in the small intestine is in the duodenum. And in some of these modalities, the target site angled in the duodenum comprises two angles, the insert having two angles that correspond to two angles of the duodenum.

In some embodiments of the insert, the angled portion comprises a shape memory portion. In other embodiments, the angled portion includes a shape memory alloy portion and a biodegradable portion. Some modalities of the insert additionally include an electronic emitter configured to apply an electrical potential to a site in the small intestine, the site generating a neuronal response that contributes to a satiety signal.

The invention further relates to methods of generating satiety in an individual by inserting an intraduodenal device inserted in an individual. The first methods to be summarized are those that use the planned modalities, as previously described, which include a biodegradable material. Modalities used in this method include an elongated member with a proximal end, a distal end, at least an angled portion between the proximal end and the distal end, the angled portion that corresponds to at least one angled target site in the small intestine, and at least a portion of the insert formed from a biodegradable material, the elongated member initially configured to rest stably at the targeted site, and then, after the degradation of the biodegradable material, configured to destabilize, in such a way that they become unsettled from the target site. The method of using this device includes generating one or more satiety signals due to one or more effects of either the presence of the insert or an active intervention by the insert.

The method may additionally include biodegrading the biodegradable material from the insert, not settling the device at the target site, and eliminating it from the body. In some embodiments of the method, where the insert includes a portion with a shape memory alloy, biodegradation of the biodegradable material facilitates the elimination of the shape memory alloy portion.

In some embodiments of the method, where the insert additionally comprises chyme flow reduction elements, the method additionally includes decreasing the chyme passage with the flow reduction elements. In some of these modalities, reducing the passage of the chyme changes the biochemical profile of the chyme. And in some of these modalities, changing the biochemical profile of the chyme activates cells in the intestine, such as chemoreceptors, the chemoreceptors generating a neuronal signal or secreting bioactive material in response to it.

In some modalities of the method, the generation of a satiety signal includes neurons sensitive to the stretch of the intestine responding to the distension of at least a portion of the duodenum due to the presence of the insert. In some modalities of the method, the generation of a satiety signal includes cells from the intestine that secrete one or more bioactive materials in response to the presence of the insert.

In some modalities of the method, where the insert additionally comprises bioactive materials in releasable reservoirs, an active intervention by the insert includes the insert that releases one or more bioactive materials. In some of these modalities, the release of one or more bioactive materials includes the efflux or elution of the reservoir. In other modalities, where the insert additionally includes a pump in operable connection with the releasable reservoirs, and the release of one or more bioactive materials includes the pumping of the materials from the reservoir. In such modalities, the pumping can be any of an osmotic pump, an electrically driven pump, a piezoelectric structure, a flow driven pump, or a peristalsis driven pump.

In some embodiments, where bioactive materials are included in a portion of the device comprising biodegradable materials, and bioactive materials are released upon degradation of the biodegradable material. In some embodiments, biodegradable materials are included in one or more flow reducing elements of the insert that include a foam type material, such as an open cell foam, a closed cell foam, or a hydrogel.

In some modalities where the insert additionally includes a neurological stimulator supported by the elongated limb, active intervention includes stimulating one or more nerves in the duodenum with the stimulator.

The invention further relates to methods, the second to be described, of generating satiety in an individual by positioning a modality of an inserted intraduodenal device that includes a neurological stimulator in an individual. The insert modality includes an elongated member including a proximal end, a distal end, at least an angled portion between the proximal end and the distal end, the angled portion that corresponds to at least one angled target site in the small intestine, and a stimulator neurological, supported by the elongated limb; the method including stimulating nerves in the duodenum with the neurological stimulator. The method may include, more specifically, neurons sensitive to the stretch of the intestine, which responds to the presence of distention of the insert by sending a satiety signal.

The method may additionally include decreased chyme passage with flow reduction elements, such a decrease in chyme flow contributing to additionally generate satiety signals. The method may additionally include endocrine cells in the intestine responding to the neurological stimulator by either neurally mediated or direct pathway, the response including secreting one or more hormones.

Where the insert includes bioactive materials in releasable reservoirs, the method may additionally include the insert by releasing one or more bioactive materials. In some embodiments, the insert includes biodegradable materials, and the method additionally includes biodegrading the biodegradable material from the insert and eliminating the insert from the body.

The invention further relates to a third set of methods of generating satiety in an individual by positioning an inserted intraduodenal device modality that includes one or more releasable reservoirs containing one or more bioactive materials and an active drug delivery mechanism. The insert modality includes an elongated member including a proximal end, a distal end, at least an angled portion between the proximal end and the distal end, the angled portion that corresponds to at least one angled target site in the small intestine, and one or more releasable reservoirs containing one or more bioactive materials, the one or more reservoirs supported by the elongated member; and an active drug delivery mechanism supported by the elongated member, the active drug release mechanism and the one or more releasable reservoirs in operable communication with each other. One method of using this modality includes releasing one or more bioactive agents into the duodenum.

In some embodiments, the release of one or more bioactive materials includes bombing the reservoir. Pumps included in the insert mode can include any of an osmotic pump, an electrically driven pump, a piezoelectric structure, a flow driven pump, or a peristalsis driven pump.

Modalities of the method may additionally include decreased chyme passage with flow reduction elements, such decreased chyme flow contributing to additionally generate satiety signals. Modalities of the method may additionally include neurons sensitive to the stretch of the intestine responding to the physical presence of the insert. Modalities of the method may additionally include endocrine cells from the intestine that secrete one or more hormones in response to any physical presence of the insert in response to the bioactive agents released by the active drug release mechanism. The method modalities can furthermore include biodegrading the biodegradable material of the insert and eliminating the insert from the body.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a general drawing of the stomach and duodenum of the small intestine.

Figure 2 describes several exemplary mechanisms by which satiety signals can be generated.

Figure 3 is a perspective view of an embodiment of a duodenal / small intestine insert according to the present invention positioned within the stomach and small intestine.

Figure 4 is a view of the partial section of a central tube showing attached flow reduction elements and a central lumen.

Figure 5 is a view of the partial section of a central tube showing eccentrically attached flow reduction elements and a central lumen.

Figure 6 is a perspective view of an alternative embodiment showing an elongated member and illustrating attached flow reduction elements.

Figure 7 is a view of the perspective section of a central tube and an anchoring member.

Figure 8 is a perspective view of an alternative embodiment of a central tube and an anchoring member.

Figure 9 is a sectional view of a central tube of the present invention that can harbor in the small intestine for a period of time without anchoring to the stomach or pylorus.

Figure 10 illustrates a central tube attached to an expandable sleeve, the expandable sleeve allowing the expansion of particular segments of the central tube to form flow reduction elements.

Figure 11 illustrates an expandable glove in a collapsed configuration for insertion into the small intestine .

Figure 12 illustrates a mechanism for maintaining flow reduction elements formed with an expandable sleeve in a desired expanded configuration.

Figure 13 is a flowchart that shows the role of the intestinal insert in contributing to the generation of one or more signs of satiety.

Figure 14 is a perspective view of the duodenum.

Figure 15 describes a side view of the duodenum, showing the folds of the wrinkles that form the periphery of the internal space in whose modalities of the insert device are positioned.

Figure 16 describes an embodiment of the insert with flow reduction elements in the form of a simple spiral.

Figure 17 describes an embodiment of the insert with flow reduction elements in the form of a ribbed spine.

Figure 18 describes a modality of the insert with flow reduction elements in the form of a spine with nets.

Figure 19 describes an embodiment of the insert with flow reduction elements in the form of a sleeve.

Figure 20 describes a modality of the insert with flow reduction elements in the form of closed-mesh baskets, and additionally showing proximal and distal ends of the pig tail.

Figure 21 describes a modality of the insert with flow reduction elements in the form of centrally mounted outwardly extending deflector plates, and additionally showing proximal and distal ends of the pig tail.

Figure 22 describes an embodiment of the insert with flow reduction elements in the form of inwardly extending baffles mounted peripherally, and additionally showing proximal and distal ends of the pig tail.

Figure 23 describes a modality of the insert with flow reduction elements in the form of foam-like bodies, and additionally showing proximal and distal ends of the pig tail.

Figure 24 describes a modality of the insert with flow reduction elements in the form of a porous nutrient access stent.

Figure 25 describes a modality of the insert with flow reduction elements in the form of centrally mounted fans, and additionally showing proximal and distal ends of the pig tail.

Figure 26 describes a modality of the insert with bioactive material in reservoirs that passively elute.

Figure 27 describes a modality of the insert with an osmotic pump loaded with bioactive material.

Figure 28 describes a modality of the insert with a reservoir loaded with bioactive material coupled to an electrically driven pump, energy storage unit, and an external control.

Figure 29 describes a modality of the insert with electrodes for local neurostimulation, an energy storage unit, and an external control.

Figure 30 describes a modality of the central member of an insert that includes biodegradable elements and shape memory elements. Figure 30A shows the central member in an intact configuration; Figure 30B shows the central member after biodegradation.

Figure 31 describes an embodiment of the central member of an insert that includes a polymeric memory material in a biodegradable form. Figure 31A shows the central member in an intact configuration; Figure 31B shows the central member after biodegradation. DETAILED DESCRIPTION

In Situ Device Modalities

Figure 1 provides a view of the human gastrointestinal (GI) tract, including stomach 4 and small intestine duodenum 10. Important features are esophagus 2, stomach 4, antrum 7, pylorus 8, pyloric valve 11, duodenum 10, jejunum 12 and Vater ampoule (or hepatopancreatic ampoule) 13, which is formed by the union of the pancreatic duct and the common bile duct. Functionally, esophagus 2 starts at the nose or mouth at its upper end and ends at the stomach 4 at its lower end. Stomach 4 includes a camera that is characterized, in part, by the esophageal-gastric junction 6 (an opening for esophagus 2) and anthropiloric junction 5 (a passage between antrum 7 through pylorus 8 to duodenum 10 of the intestine slender). Pylorus 8 controls the discharge of contents from stomach 4 by means of a sphincter muscle, the pyloric valve 11, which allows pylorus 8 to open sufficiently to pass sufficiently digested stomach contents (that is, objects of about a cubic centimeter or any less). These gastric contents, after passing through the duodenum 10, continue in the jejunum 12 and the ileum (not shown). The duodenum 10, jejunum 12 and ileum constitute what is known as the small intestine. However, these individual portions of the alimentary canal are sometimes referred to individually as the small intestine. In the context of this invention the small intestine can refer to all or part of the duodenum, jejunum and / or ileum. The ampule of Vater 13, which provides bile and pancreatic fluids that aid digestion, is shown as a small projection on the median wall of the duodenum 10.

Modalities of the inventive device include two basic forms. Some modalities of the intestinal insert are stabilized in the intestine by means of an anchoring member that resides in the stomach and is too large to slide through the pylorus. Other modalities stably reside in the intestine not because of a separate anchoring member in the stomach, but largely because of the device as a whole adjusting in the small intestine with angled positions that adjust or correspond to angled positions of the intestine, and the device additionally having an sufficient structural integrity that it resists being moved distally because the distal location does not physically accommodate the shape of the device. Aspects of the device that are adapted to provide stabilization without anchoring to a target site in the intestine include physical dimensions of length and width, as well as angles of the device, all of which complement the target portion of the intestine. In other embodiments, the characteristics of stabilization in the intestine may include expanded portions of the device in the duodenal bulb, which is larger than the most distal portion of the duodenum and thus effectively prevents distal movement (as in figure 18, for example) . Other stabilizing or anchoring elements may include any hook, splinters or projections on the device that fits the wall of the intestine.

Some modalities of the device and associated methods of using the device are directed towards reducing the rate of transit of food through the intestine by physical mechanisms of intervening in the rate of transit of food. In other respects, modalities of the invention act by eliciting satiety signals through physiological mechanisms, or alternatively, directly providing satiety signals by means of bioactive materials or agents, or by neuronal stimulation, thereby reducing food intake behaviorally. Some modalities of the device are intended for broader medical purposes than satiety and digestive physiology only, although the features of satiety and food consumption of the modalities of the device and method are described in more detail here. In some aspects, modalities of the device may contribute to decrease food transit and / or reduce food intake due to signs of satiety generated by the intestine in direct response to the merely physical presence of the device. Such signals can, for example, be mediated by stretch response neurons or mechanoreceptors in the intestinal wall. In other modalities, signs of satiety can be mediated by hormones that are responsive to the physical presence of material in the intestine, or that are secondarily responsive to mechanoreceptors. In other modalities, the decrease in food or the longer residence time, and the consequent change in the chemical environment of the intestine, may elicit responses from chemoreceptors that reside in the intestine for both neural and hormonal signals, in such a way that it has an effect of satiety signaling network.

In still other embodiments of the invention, the device can transfer material or bioactive agents that are released over time in the intestine, the bioactive agents transferring a satiety network signal. In some embodiments, bioactive agents with a satiety signaling effect in the network are passively released from sites, such as coatings, deposits or reservoirs on the device. Bioactive materials or agents have been described in more detail earlier, but briefly and in a broad sense they can include any of hormones, drugs or cells. In some modalities, bioactive agents can be kept in osmotic pumps and released by osmotic activation. Release mechanisms, such as osmotic pumps, provide a level of control and predictability for bioactive agent release, but the mechanism remains relatively passive and without intervention devices. Other embodiments of the invention, however, may include more active mechanisms for the release or distribution of bioactive agents, as may be provided by electrically driven pumps, or by piezoelectric elements that allow or promote the release of stored bioactive agents in response to the applied current. Such devices may include force storage elements, or they may be supplied with power from external sources by wired and wireless approaches.

In still other embodiments of the invention, the device may include electrodes or conductive elements that provide electrical stimulation of nerves in the intestine, such a resulting neural activity contributing to a network effect of satiety signaling to the brain. In some modalities, neuronal activity related to satiety may additionally be mediated by endocrine mechanisms. As in the modalities of the invention with force mechanisms for the release of bioactive agent, modalities with electrical capacity may include force storage devices, or be made possible to receive energy transferred from external sources.

In other aspects of the invention, modalities of the inserted device, with or without an anchor, can provide a platform for bioactive agent delivery, neural stimulus delivery or radiation therapy delivery, for broader medical purposes than inducing satiety, or intervention food transit. For the distribution of some bioactive agents, one can consider the advantage associated with the local distribution of an agent to an intestinal site. Such advantages may include location of the dosage, lack of exposure to stomach acid as occurs in oral distribution, or decreased exposure to the metabolic machinery of the liver and kidneys to distribute iv medication, or any form of systemic distribution faces. In addition, modalities of the device can accommodate multiple medications, in some embodiments the delivery of such multiple medications can be independently controlled.

Context of the Digestive System of the Invention

The description now addresses the digestive system, the digestive process, and aspects of satiety endocrinology and neurophysiology as they relate to the modalities of the invention. The adult duodenum is about 20-25 cm long and is the smallest, widest, and most predictable placed part of the small intestine. The duodenum forms an elongated C-shaped configuration that extends between the level of the first and third lumbar vertebrae in the supine position. Susan Standanel (ed.), Gray's Anatomy, 39^The Ed., 1163-64 (2005), provides a standard reference. Returning to figure 1 for reference and additional detail of aspects of the digestive system, the first part of the duodenum, often referred to as the duodenal bulb 10a, is about 5 cm long and begins as a continuation of the duodenal end of the pylorus 8. This first part of the duodenum passes superiorly, posteriorly and laterally to 5 cm before abruptly curving inferiorly in the superior duodenal flexure 465, which marks the end of the first part of the duodenum. The second part of the duodenum, often called the vertical duodenum 10b, is about 8-10 cm long. It starts at the upper duodenal flexure 465 and runs downward in a smooth curve towards the third lumbar vertebral body. Here, it becomes abruptly median in the lower duodenal flexure 475 that marks its junction with the third part of the duodenum. The third part of the duodenum, often called the horizontal duodenum 10c, begins at the lower duodenal flexure and is about 10 cm long. It runs on the right side at the lower edge of the third lumbar vertebra, slightly angled upwards, through the left and ends in continuity with the fourth part of the duodenum in front of the abdominal aorta. The fourth part of the duodenum is about 2.5 cm long; it starts from the left side of the aorta and goes higher and laterally to the level of the upper border of the second lumbar vertebra. Then it is taken antero-inferiorly in the duodenojejunal flexure and is continuous with the jejunum. Some embodiments of the present invention take advantage of this predictable configuration of the small intestine to provide duodenal / small intestinal implants that do not require anchoring in the pylorus or stomach, as described more fully below.

The digestive process begins when foods eaten are mixed with saliva and enzymes in the mouth. Once the food is swallowed, digestion continues in the esophagus and stomach, where the food is combined with additional acids and enzymes to liquefy it. The food resides in the stomach for a while and then passes through the duodenum of the small intestine to be intermixed with bile and pancreatic juice. The mixture of the food consumed with bile and pancreatic juice makes the nutrients contained therein available for absorption by the villi and microvilli of the small intestine and other absorbent organs of the body.

The presence of partially digested food in the stomach and small intestine initiates a cascade of biological signals that creates signs of satiety and contributes to the cessation of food intake. A satiety signal like this is initiated by the release of cholecystokinin (CCK). Cells in the small intestine release CCK in response to the presence of digested foods and, in particular, in response to fat, fatty acids, small peptides and dietary amino acids. High levels of CCK reduce the size and duration of feeding and can be done through a number of different mechanisms. For example, CCK can act on CCKA receptors in the liver and the central nervous system to induce satiety signals. CCK stimulates vagal afferent fibers in both the liver and the pylorus that it projects into the tract of the solitary nucleus, an area of ​​the brain that communicates with the hypothalamus to centrally regulate food intake and feeding behavior. CCK also stimulates the release of enzymes from the pancreas and gallbladder and inhibits gastric emptying. Because CCK is a potent inhibitor of gastric emptying, some of its effects in limiting food intake can be mediated by the retention of food in the stomach.

Small intestine cells (particularly L cells) also release glucagon-like peptide 1 (GLP-1) and oxytomodulin (OXM) in response to signs of nutrient digestion. Elevated levels of GLP-1 and

OXM are associated with signs of satiety and cessation of food intake. These hormones can be satiated by the signal by activating receptors on the afferent vagal nerves in the liver and / or the GI tract and / or inhibiting gastric emptying.

Pancreatic peptide (PP) is released in proportion to the number of calories ingested and in response to gastric distention. High levels of PP have been shown to reduce food intake and body weight. PP can exert some of its anorexic effects through vagal afferent pathways to the cerebral current, as well as through more local effects, such as by suppressing the production of gastric ghrelin.

Peptide YY3-36 (PYY₃-₃₆) is another biological sign whose peripheral release can be correlated with lower food intake and / or cessation of eating. Specifically, low levels of PYY₃-₃6 were correlated with obesity, while their administration decreases caloric intake and subjective hunger scores. Intravenous administration of PYY₃.₃₆ it can reduce food intake through its effects of suppressing ghrelin expression, delaying gastric emptying, delaying various secretions from the pancreas and stomach and increasing the absorption of fluids and electrolytes from the ileum after a feeding.

Insulin and leptin are two additional biological signals that regulate satiety and eating behavior. Through parasympathetic innervation, beta cells of the endocrine pancreas release insulin in response to circulating nutrients, such as glucose and amino acids, and in response to the presence of GLP-1 and gastric inhibitory peptide (GIP). Insulin stimulates the production of leptin from adipose tissue through increased glucose metabolism. Higher levels of insulin in the brain leads to a reduction in food intake. Elevated leptin levels also decrease food intake and induce weight loss. Insulin and leptin also involved in the regulation of energy expenditure, since their administration induces greater weight loss which can be explained by the reduction in food intake alone. Both insulin and leptin act on the central nervous system to inhibit food intake and to increase energy expenditure, most likely by activating the sympathetic nervous system. The effects of insulin to decrease food intake also involve interactions with several hypothalamic neuropeptides that are also involved in regulating eating behavior, such as, for example, NPY and melanocortin ligands.

Other hormones or biological signals that are involved in suppressing or inhibiting food intake include, for example, GIP (secreted from intestinal endocrine K cells after glucose administration or food intake with a high carbohydrate content; enterostatin {produced in response to dietary fat, amylin (co-secreted with insulin from pancreatic beta cells); glucagon, peptide that releases gastrin (GRP), somatostatin, neurotensin, bombesin, calcitonin, peptide related to the calcitonin gene, neuromedin U (NMU), and ketones.

With respect to the modalities of the present invention, when the passage of partially digested or chyme food is partially impeded in the small intestine duodenum and the flow through this area is reduced (or to express the same phenomenon in another way, as the residence time increases), emptying of the stomach and duodenum will occur more slowly. This decrease, in itself, can create greater feelings of satiety and thus lead to less food intake (due to the longer retention time of the food in the stomach). Decreased food passage also provides more time for partially digested food to interact with chemoreceptors, stretch receptors and mechanoreceptors throughout the GI tract, so that the stimulation of satiety signals can be increased and / or prolonged, which can , in turn, lead to a reduction in food intake during a feeding period and / or longer periods between food intake.

In addition to keeping partially digested food in the small intestine for a long period of time, the methods and devices of the present invention can also improve and / or prolong the release of satiety signals by releasing signals in the small intestine itself. For example, in some embodiments, the methods and devices of the present invention can release nutrient products from digestion to stimulate chemoreceptors to cause the release of hormones and / or other molecular signals that contribute to the creation of satiety signals. In another embodiment, the methods and devices of the present invention can exert a small amount of pressure on the walls of the GI tract to stimulate stretching and / or mechanoreceptors to generate and send satiety signals to the brain. In another embodiment, the methods and devices of the present invention can release signals, such as, for example, nutrient by-products of food digestion, to stimulate chemoreceptors as previously described and can exert a small amount of pressure on the intestinal walls. slender, as previously described to contribute to the generation of satiety signals.

Device with flow reduction elements, and modalities with an anchoring member

The methods and devices of the present invention can contribute to weight loss and the treatment of obesity by coating portions of the walls of the small intestine, thereby blocking any nutrient intake and / or interrupting or reducing the intermixture of digestive fluids. In some embodiments, the methods and devices of the present invention may additionally include a central tube that funnels a portion of the food consumed through the small intestine without being fully digested or absorbed. In these ways, the methods and devices of the present invention can inhibit the absorption of partially digested food materials. The partially digested food materials are then passed to the large intestine for elimination with limited caloric absorption by the body.

Figure 2 describes several exemplary non-limiting mechanisms through which satiety signals can be generated. In this figure 2, a by-product of digestion, such as a fatty acid or other protein, stimulates an L cell in the small intestine to release CCK locally into the circulation. Locally released CCK can stimulate vagal afferent nerve fibers in the area to generate satiety signals to the central nervous system (CNS). CCK entering the circulation can travel to the liver to stimulate vagal afferent nerve fibers in the liver to generate satiety signals for the CNS. Circulating CCK can travel to the gallbladder and pancreas to over-regulate activities related to the digestion of these organs. Circulating CCK can also travel to the CNS itself to contribute to the creation of a satiety signal. Once satiety signals are received and integrated into the CNS, the CNS can trigger physiological effects that serve to contribute to a feeling of satisfaction and / or cessation, by decreasing or reducing food intake.

Turning now to the modalities of the invention, figure 3 shows an exemplary small intestine insert 20 prepared in accordance with the present invention that can contribute to the creation of satiety signals. Insert 20 is positioned in stomach 4 and small intestine 10. Insert 20 has a proximal portion 30 and a distal portion 40, and a central tube 50 that extends from the proximal portion 30 to the distal portion 40. One or more flow reduction elements 200 that are classified to fit in the small intestine 10 can be attached to the central tube 50. Although not required, the portion of the central tube 50 next to the Vater 13 ampoule will generally not include a flow 200, such that the introduction of bile and pancreatic fluid into the small intestine is not prevented.

In some embodiments, the central tube 50 has an anchoring member 100 close to its proximal end 52, with the anchoring member 100 protecting the proximal end 52 of the central tube 50 in the stomach 7. The anchoring member 100 is classified in such a way that it does not pass through the pylorus 8. In this way, embodiments of the present invention including an anchoring member anchors the flow reducing elements 200 in the small intestine. In some embodiments, the anchoring member can be established by one or more inflatable balloons 102 which when inflated are larger than the pylor 8. Inflatable balloons 102 can be deflated for distribution in the stomach and then inflated within the stomach. Inflatable balloons 102 can also be deflated for later removal using endoscopic techniques.

As will be described in further detail below, modalities of the flow reduction elements 200 can assume many configurations and may vary further with respect to physical characteristics, such as composition, nature of the surface, and porosity of the massifying material. Some additionally exemplary embodiments of the flow reduction elements 200 are shown in figures 16-25. In some embodiments, as shown in figure 16, the central tube or member, also referred to as an elongated member, can itself be configured in a way that reduces the flow of the chyme into the duodenum. A functional property that modalities of flow reduction elements have in common is that they lower the transit of digesting food without blocking it, and in clinically appropriate standards. The process of lowering the transit rate can also have effects on the composition of the digesting food material, such as varying its biochemical profile in relation to the metabolized nutritional compounds. Chemical receptors and duodenal nerves are sensitive to the biochemical profile of metabolites in the chyme, and participate in the coordination of the physiology of digestion and satiety and hunger in this way. As such, altering the flow rate and, thus, the biochemical profile of the chyme, modalities of the inventive insert of the small intestine contribute to the generation of signals associated with satiety. Flow reduction elements can additionally affect the composition of the digestible food material by mixing the flow reduction elements.

The length of the central tube 50 can be established depending on the desired therapeutic result. For example, the central tube 50 and one or more attached flow reduction elements 200 can be extended in one portion or through the entire duodenum 10. In some patients the central tube 50 and one or more attached flow reduction elements 200 they can extend behind the duodenum 10 and in the jejunum 12. It is predicted that different lengths of central tubes and different numbers and configurations of flow reduction elements can be used by a doctor to treat various types of body and metabolic demands. In one example, if a patient is 20% overweight, a doctor should select a central tube length 50 with flow reduction elements attached 200 that allow absorption of only 80% of the nutritional potential of a typical daily calorie intake. This reduction in caloric intake over time can lead to an appropriate amount of weight loss in the patient.

Figure 4 shows an embodiment of the invention with a central tube 50 that includes an outer wall 54 and an inner wall 56 that defines an inner space 58. The inner space 58 forms an inner lumen 59 that can be continuous from the proximal end 52 of the central tube. 50 to just shorten the distal end 53 of the central tube 50. The distal end 53 of the central tube 50 is sealed at a point 55, in such a way that the fluid introduced into the central tube 50 does not leak distally into the small intestine. In some embodiments, a valve 90 can be located substantially at the proximal end of the inner lumen 59. The valve 90 can be a self-sealing valve that has a septum 92 that can be accessed by a blunt needle or tube for introducing fluid into the inner lumen 59. The valve 90 can also be accessed in such a way that the fluid within the inner lumen 59 of the central tube 50 can be aspirated for removal. It is understood that the valve type is not limited to a septum valve only and that other types of mechanical valves can also be used in place of the described septum valve. Particular embodiments of the present invention are adapted to accept fluids in this way, such that the devices of the present invention can be implanted in a deflated configuration and later expanded into an inflated configuration.

As shown in figure 4 and as previously mentioned, one or more flow reduction elements 200 can be attached to the central tube 50. In some embodiments, the diameter of each flow reduction element 200 may be concentric with the axis of the tube central 50. In the embodiment shown in figure 4, each flow reduction element 200 has an outer wall 210, an inner wall 212, and an inner space 214. On the proximally oriented surface 220 or close to it and also on the distally oriented surface 222 or close to it, each flow reduction element 200 can be attached to the central tube 50 with the internal space 214 of the flow reduction element 200 in fluid communication with the lumen 59 of the central tube 50, such that the inner space 214 surrounds the outer wall 54 of the central tube 50. Each flow reduction element 200 can be attached to the central tube 50, for example, by adhesives, hot connections, mechanical restraint or other suitable methods.

In the form also shown in figure 4, the central tube 50 can be formed with plural inlet / outlet ports 216 which are located within the respective flow reduction elements 200. More specifically, each port 216 is formed completely through the tube wall central 51 to establish a path for fluid communication between the inner lumen 59 of the central tube 50 and the inner space 214 of the respective flow reducing elements 200. Consequently, the inner lumen 59 of the central tube 50 can be used to introduce fluid into the internal spaces 214 of the flow reduction elements 200 and to inflate the flow reduction elements 200 of a collapsed configuration, in which the insertion and removal of the elements flow reduction 200 is facilitated, for an inflated configuration shown in figure 4, in which the resistance to the passage of food is increased to induce satiety. Thus, as previously suggested, the flow reduction element or elements 200 in this embodiment acts as balloons that can be deflated and collapsed around the central tube 50 for introduction into the small intestine and then inflated to the desired diameter, once in position.

Modes of the flow reduction elements 200 can take other forms, such as spirals, ribs, fans, deflector plates, both peripherally and centrally mounted, as well as gloves, cages or mesh baskets. Modalities such as these are further described below in the section entitled “Further embodiments of the invention”, which also includes a description of the modalities with biodegradable components, mechanisms for releasing active biomaterial, and nerve stimulation characteristics, and as shown in the figures 15 -31.

In some embodiments, individual flow reduction elements 200 of the present invention can be elastic balloons or inelastic balloons. When an elastic balloon material is used to establish a flow reducing element 200, the flow reducing element 200 inflates to a diameter that depends on the volume of fluid introduced into the internal space of the flow reducing element. This mode allows the adjustment of the balloon size determined by the doctor. If the balloon is too small, for example, additional fluid can be introduced to increase the diameter of the balloon. Alternatively, if the balloon is too large, additional fluid can be removed to shrink the diameter of the balloon. It is understood that an alternative embodiment consisting of an inelastic balloon that inflates to a diameter that depends on a volume of fluid introduced into its internal space is also included in the present invention. The diameter of this type of balloon is fixed when manufactured and does not allow in situ adjustment of the balloon size. However, this type of balloon prevents possible inflation and rupture if too much fluid is introduced into the balloon.

The flow reduction elements 200 shown in figure 4 are in the form of a round sphere. However, other forms are contemplated and any form that effectively works to inhibit the passage of partially digested food in the small intestine is acceptable according to the present invention. It is understood that the ability of the small intestine insert to remain in the small intestine can be affected by the shape, orientation and stretching of the flow reduction elements 200. For example, alternative shapes, such as ovoid, elliptical, elongated ellipse and even irregular non-geometric shapes can be used in accordance with the present invention.

Figure 5 illustrates an alternative embodiment of the present invention in which one or more flow reduction elements 300 are eccentrically attached to a central tube 350. In this embodiment the axis or diameter of the flow reduction element or elements 300 is not concentric with the axis the central tube. The outer wall 302 of the flow reduction element is attached to the side of an outer wall 354 of the central tube 350. An internal space 314 of each flow reduction element 300 is eccentric relative to the axis of the central tube 350 and is in fluid communication with an inner lumen 359 of the central tube 350 by means of a respective opening 316. As was the case with the embodiment shown in figure 4, in the embodiment shown in figure 5 the inner lumen 359 can be used to introduce and remove fluid into the internal space 314 of the flow reduction element 300 to move the flow reduction element 300 between inflated and deflated configurations.

In some embodiments of the present invention, flow reduction elements 300 can be inflated with a fluid, including a liquid and / or a gas. In some embodiments, the gas may be, for example, air, nitrogen or carbon dioxide. In another embodiment, a liquid can be, for example, water or water mixed with other solutions. Any appropriate means of inflation can be modified to deliver bioactive materials or other signals that can diffuse from the insert of the present invention into the small intestine to trigger biological signals of satiety. When bioactive materials are distributed by means of inflation, the central tube and / or flow reduction elements must be permeable to bioactive materials. Porosity can be adjusted to control the rate of diffusion of bioactive materials.

In the inflation of the flow reducing elements of the present invention, it may be important for the physician to monitor the location of the flow reducing element 300 in the small intestine and the diameter of the flow reducing element relative to the diameter of the small intestine. For this purpose, the flow reduction element can be inflated with a radiopaque fluid that is visible on X-rays. When the flow reduction element contains radiopaque fluid, a physician may non-invasively view the size and arrangement of the flow reduction element (s) from outside the patient's body. This knowledge allows the physician to adjust the size and / or arrangement of the flow reducing element (s). Likewise, radiopaque marker bands 218 as shown in figure 5 can be placed around the central tube to facilitate visualization of the location of the central tube in the small intestine. The radiopaque marker bands 218 can be placed at predetermined intervals, such that the distance within the small intestine can be used as depth markers and can be measured from outside the body.

The central tube and flow reduction elements of the present invention can be flexible. In some embodiments, they can be constructed of a polymeric material that can be easily formed or extruded and distributed with the help of an endoscope by known techniques. A central tube 50 that is soft and flexible will outline the anatomy of the gastrointestinal tract and provide less irritation of the stomach and intestinal lining.

Figure 6 shows an alternative embodiment of the invention with flow reduction elements that are generally self-expanding and do not necessarily include a central lumen. These embodiments include a central rod 450 around which flow reduction elements 400 are concentrically attached and / or are eccentrically attached 410. Elements 400 and 410 can be attached to central rod 450, for example, by hot melt, adhesives or other suitable methods known in the art. These flow reduction elements 400 can be prepared from material that can be folded or collapsed to a first volume suitable for insertion with the help of an endoscope and then can self-expand to a second volume suitable to restrict the flow of partially digested food. according to the present invention. These flow reduction elements can be prepared from materials, or materials can be configured to take shape, such as, for example, a sponge, foam, hydrogel, or springs that can be compacted into a small volume and then auto-expand to a predetermined shape and volume when not restricted. Modes based on gel or sponge may include open cell or closed cell forms. In addition to having characteristics that allow such gel or sponge-based modalities to be collapsed and expandable for disposal, such modalities typically have a high surface area that is beneficial in modalities that may include bioactive agents and may additionally be useful for biodegradability purposes. . Another modality related to foam is described below in the section entitled “Further embodiments of the invention”, and shown in figure 23. Because the elements of flow reduction are self-expanding, the need for an inflation system is eliminated and this modality represents a simple mechanical design. These flow reduction elements can also be impregnated with bioactive materials or other signals that can trigger biological satiety signals.

The central rod 450 of an embodiment, such as that shown in figure 6, can be solid and without an inner lumen or internal space. In another embodiment, the central stem 450 may include a passageway for the food consumed, in such a way that the food can pass through the small intestine without being completely absorbed.

Turning now to the various anchoring members that can be used according to the present invention, figure 7 describes a member like this. In figure 7, the central tube 50 has an anchoring member 100 close to its proximal end 52. As previously established, the anchoring member 100 can be established by one or more inflatable balloons 102. These balloons 102 can be eccentrically attached to the central tube at point 104 near the proximal end 52 of the central tube 50. These balloons can be formed in many forms and are not limited to the spherical shape shown. The central tube can be formed with an opening 116 for each respective balloon 102, such that a path for fluid communication is established between the inner lumen 59 of the central tube 50 and the internal space of each balloon 106. Inner lumen 59 is used to introduce fluid into the inner space of balloon 106 and inflate balloon 102 from a first volume in a collapsed state to a second volume or inflated state.

When one or more balloons 102 of the anchoring member 100 are fully inflated, they protect the proximal end of the central tube 52 in the stomach antrum. One or more inflatable balloons 102 have a combined cross-sectional diameter larger than the diameter of the pyloric valve to prevent migration through the pylorus. Inflatable balloons 102 can be inflated and deflated by adding or removing fluid from the inner lumen of the central tube 59. The inflatable balloons 102 can be connected to the same inner lumen of the central tube 59 as one or more flow reduction elements attached to the central tube and can be inflated simultaneously with the flow reduction elements. The central tube 50 can also have more than one inner lumen, such that the inflatable balloons 102 and one or more individual flow reduction elements can be equally inflated and deflated independently.

Figure 8 illustrates another embodiment of the invention, in which an anchoring member 100 of the present invention is disposed in the pit 7. In this embodiment, a central tube 50 is attached to an inverted umbrella skeleton 160. These skeletons 160 have a ring 162 that it surrounds the central tube 50 and is supported by the supports. In the embodiment shown, ring 162 is supported by three supports 164, 165, and 166, however more or less supports can be used successfully. In the embodiment shown in figure 8, the supports are joined together in the central tube 50 at point 167 and attached to ring 162 at points 170, 171 and 172. Ring 162 of this anchor configuration can be made, for example, of material flexible plastic or flexible wire and has a diameter significantly larger than the diameter of the pyloric valve. This umbrella skeleton 160 can be collapsed around the central tube 50 for insertion into the stomach with the help of an endoscope. Once the device is released from the endoscope, the umbrella skeleton 160 can open and assume a configuration similar to that shown in figure 8. The supports 164, 165 and 166 can be made of, for example, plastic, metal or metal coated with plastic. The rim of the ring that is in contact with the walls of the den 163 can be constructed to assist in protecting the umbrella ring 162 for the walls of the den. In some embodiments, the surface may be wrinkled to increase the friction of the surface or the wall may have projections or splinters that physically attach to the lining of the stomach.

Device without an anchoring member

Figure 9 shows a central or elongated member tube 50 of the present invention that can be lodged and remain in the small intestine for a period of time without any anchoring to the stomach or pylorus. Modalities of the present invention that can lodge and remain in the small intestine for a period of time without any anchoring to the stomach or pylorus do this (i) adopting a central tube with appropriately arranged angles that mimic the contours of the small intestine; and (ii) flow reduction elements of an appropriate diameter that help keep the intestinal insert in place. In one embodiment, although not required, these flow reduction elements may have an abrasive surface or anchoring barbs that can help them adhere to the walls of the small intestine.

In figure 9, the first three parts of the duodenum, including the duodenal bulb 10A, the vertical duodenum 10B, and the horizontal duodenum 10C are shown. The flow reduction elements of the presented modality have been removed for clarity. Distal to the pylorus 8 and immediately after entering the duodenum 10, the central tube 50 can assume a curved shape of radio β between the duodenal bulb 10A and the vertical duodenum 10B, and a curved shape of radio α between the vertical duodenum 10B and duodenum horizontal 10C. In some modalities the β radio and the α radio can be between about 45 degrees and about 110 degrees. In another embodiment, the β radio and the α radio can be between about 60 degrees and about 100 degrees, in such a way that the central tube 50 curves to the next or corresponds to the inner lumen of the duodenum 10 in these locations that contain configured curvatures predictable. In another mode, the β radio and the α radio can be about 80 degrees. Although most embodiments of the present invention include lengths that require the adoption of angle β and angle a, smaller devices that adopt one or the other are also included in the scope of the present invention. In these described embodiments of the present invention, it may be advantageous for the central tube 50 to be flexible enough to conform to the angles of the shape of the small intestine to prevent entanglement. One or more flow reduction elements with a diameter around the small intestine are also included along the length of the central tube 50. In some embodiments, this diameter is about 3 cm; in other modalities this diameter is about 4 cm.

To stabilize an intestinal insert in situ without the need for an anchoring element, the central or elongated member tube 50 can be preformed with a configuration that conforms to the duodenal angulations before insertion into the body. This embodiment of the present invention can be forced in a straight configuration by a hardening rod 110 placed under the inner lumen 59 of the central tube 50 as shown. This hardening stick 110 can be placed in a separate lumen designed to house this hardening stick or can be embedded in the wall of the central tube 50. Upon insertion into the patient with the help of an endoscope, when the central tube 50 reaches the location of the abrupt curvatures in the duodenum 10, the hardening rod 110 can be removed, thus allowing the central tube 50 to assume a preformed shape.

In another embodiment that stabilizes in situ without an anchoring member, the central or elongated member tube 50 may have a memory alloy wire embedded within the wall of the central tube 51 or residing in the inner lumen 59. This alloy wire shape memory has a preset curvature configuration with a β radio and an α radio that compares or corresponds to the curvature configuration of the duodenum and is positioned on the central tube 50 at the corresponding location. Upon insertion into the patient with the help of an endoscope, when the central tube 50 reaches the location of the abrupt curvature in the duodenum 10 and the shape memory alloy wire reaches a pre-set transition temperature equal to the body temperature or about 37 ° C, the wire takes on the programmed shape and forces the central tube 50 and the wall of the central tube 51a to assume the same shape.

In another embodiment, the central or elongated member tube 50 may have a spring embedded within the wall of the central tube 51 or inner lumen 59. This spring may be pre-shaped for the anatomy of the small intestine wall. The spring is kept straight during distribution and conforms to the anatomy of the small intestine after release and such a shape allows the device to remain in place. The shape allows the device to remain on the power. In one embodiment, by virtue of its configuration that matches or corresponds to the predictable layout and configuration of the small intestine, the device can remain in place for a period of time in the small intestine without anchoring to the stomach or pylorus of the stomach.

Although the present embodiments of the present invention may remain in the small intestine for a period of time without anchoring to the stomach or pylorus, they are not intended to remain indefinitely. In some embodiments, the inserts are removed endoscopically after a predetermined period of time. In other embodiments, the inserts can be formed from one or more biodegradable materials that are eventually degraded and eliminated from the body. The rate of biodegradability of any modality of the inventive device can be adjusted by varying the biodegradable aspects of the modality, thus allowing the manufacturing route to control the residence time in the intestinal tract to a clinically appropriate level. Biodegradable composition can be varied in qualitative terms, varying the composition of the materials. The biodegradability of the devices can also be varied in quantitative terms, for example, by varying the amount of material in a location vulnerable to biodegradation. For example, by varying the thickness of a joint designed for biodegradability, the vulnerability can be varied in thickness.

Biodegradable aspects of the embodiments of the invention are further described below; all of the modalities described herein, and all of the modalities as shown in figures 3-12, and 16-31 may have portions that include biodegradable materials, both in the tube and in the central member, also referred to synonymously as elongated member 50 and / or any one of the various modalities of chimo 200 flow reduction elements. In the description that follows, some modalities are used as specifically illustrative examples that are formed entirely or in part from biodegradable materials, but, in the established manner, all modalities may include biodegradable materials, even when not specifically identified as such, including modalities with and without an anchoring member.

Arrangement of inserts and flow reduction elements

The description now goes back to considerations related to the disposition of the inventive insert, some of which include elements of flow reduction. Flow reduction elements are referenced in a generic sense with the 200 mark, but some exemplary modalities make use of different brand numbers, for their particular characteristics. Figure 10 illustrates an embodiment of the present invention where flow reduction elements can be created by expanding the portions of an expandable sleeve; this modality will be used in the context of describing an example of how to arrange a device with flow reduction elements. In the embodiment shown in figure 10, a central tube 50 is attached to an expandable sleeve 508 at the distal end of the expandable sleeve 510 next to the distal portion of a duodenal / small intestine insert of the present invention. In a distribution configuration of the presented modality, the proximal end of the opposite central tube 50 is attached to a detachable extension tube 520 which can close in a proximal portion of the central tube 50 when the flow reduction elements 530 are expanded (after the distribution). A non-limiting method of detachable attachment is the use of one or more screws 504, where the extension tube 520 screws into the central tube 50. The central tube 50 can be preformed and has a configuration that conforms to the anatomy of the duodenum 10 shown in figure 1. A central tube 50, then described, forces the expandable sleeve 508 to assume the configuration of the central tube 50. The central tube 50 it can be constructed, merely by way of example, of wire, spring, superelastic or shaped memory alloys, hollow steel tube or plastic polymers. In some embodiments, a hardening rod or guide wire 110 can also be inserted through the lumen of the central tube 50.

The expandable sleeve 508 described here is designed to expand in predefined segments to allow the formation of flow reducing elements 530. In some embodiments, the unexpanded segments 532 of expandable sleeve 508 can be coated with a polymer to prevent their expansion . In another embodiment, flow reduction elements 530 can be coated with a flexible polymer to prevent partially digested food from entering flow reduction elements 530. In another embodiment, a hardening rod or guide wire 110 can be inserted through the lumen of the central tube 50 to arrange the central tube 50 when the device is distributed in the duodenum.

The expandable sleeve 508 can, merely by way of example, be configured as any of one or more of an interlacing, a weave, a mesh or a braid that can be formed, merely by way of example, of any one or more metal, wire, tape, plastic polymer or biodegradable material.

Figure 11 illustrates the expandable sleeve 508 which consists of flow reduction elements 530 in a collapsed configuration for insertion into the small intestine. In this configuration, a force A is applied to the expandable sleeve 508 to collapse the flow reducing elements 530. The collapsed shape can be prevented by a restraining mechanism, such as, merely by way of example, a tightly wound case or cord, or by applying sustained traction to the proximal end of the expandable sleeve 508. Figure 11 also shows portions of the central tube that will remain impassable 532, a detachable extension tube 520 and a guide wire 110.

The expansion of flow reduction elements 530 in the modalities shown in figures 10 and 11 can occur passively or actively. An example of passive expansion may be the removal of a restriction mechanism to allow flow reduction elements 530 to expand to an original expanded state. Another non-limiting mechanism may be to release traction at the proximal end of an expandable sleeve 508 to allow flow reduction elements 530 to expand to an original expanded state.

The flow reduction elements 530 of the modalities shown in figures 10 and 11 can expand in a distal to proximal way, a proximal to distal way or in a central way, depending on their relative position in relation, in some modalities, to the movement expandable sleeve 508 and central tube 50 with each other. For example, if the proximal end of the lumen flow reducing element is maintained in the duodenal bulb and the central tube 50 is removed, the distal end of the lumen flow reducing element can expand first. Expansion in this direction can be advantageous because the position of the proximal end of the lumen flow reducing element remains in the duodenal bulb.

Figure 12 illustrates some embodiments of the present invention that can close the proximal end of the expandable sleeve 508 to the central tube 50 in a position to maintain the flow reduction elements in a desirable expanded configuration. The pull on the extension tube 520 retracts the central tube 50 until the wedge 52 engages the proximal end of the expandable sleeve 508. The central tube 50 may have multiple ratchet tongue wedges that can close the expandable sleeve 508 at different degrees of expansion. The extension tube can be unscrewed from the central tube 50 after disposition of the device and expansion of the expandable sleeve 508.

Biodegradable characteristics

Although the present embodiments of the present invention may remain in the small intestine for a period of time, they are not intended to remain indefinitely. In some embodiments, the inserts are removed endoscopically after a predetermined period of time. In other embodiments, the inserts can be formed or partially formed from one or more biodegradable materials that are eventually degraded and eliminated from the body. In some embodiments, the device may include some material that is biodegradable and some material that is not biodegradable. In some embodiments that include non-biodegradable materials, degradation of the biodegradable portions of the device can facilitate the interruption and eventual elimination of the non-biodegradable portions.

Biodegradable is used in a broad sense, to include any kind of disruption or disintegration of material of any kind that can occur in a biological environment, such as an environment being defined primarily by the biological host, but also by any microorganisms in the host. Other terms that biodegradability broadly encompasses include bioabsorbability and bioerodibility. Biodegradation, by the modalities of the invention, can occur, for example, by dissolution, by the effects of pH, such as the action of acids, by hydrolytic mechanisms, by hydration, by digestive effects or catalyzed by enzyme, such as divage or by physical effects of body or muscle movement. An example of biodegradation is provided by hydrolysis, dissolution, or reaction to pH, or enzymatic lysis that results in a split of the polymer backbone of an inserted device. Microorganisms, such as those that reside in the intestine, can eat or digest polymers, and also initiate mechanical, chemical or enzymatic aging. The biodegradable materials of the modalities of the invention are also biologically compatible, as well as are products of interruption of biodegradable materials, as included in the modalities of the present invention. Biodegradable materials can include organic and inorganic compounds. Some representative inorganic compounds are described below in the section related to “device characteristics to accommodate bioactive agents”; in this section, a description of biodegradable polymers is provided for inclusion as embodiments of the present invention.

As previously mentioned, some embodiments of the invention may include a portion that maintains the resilient shape, and in some embodiments, a portion of memory so that it supports the maintenance of an advantageous configuration of the device, particularly with respect to the maintenance of alpha and beta of the inventive C-shaped duodenal insert device. Metals, as well as some polymers are capable of resiliently maintaining a shape. Shape memory materials include metal alloys as well as biodegradable polymers. Elements of the shape memory alloy device are not biodegradable, but these structural alloy elements can be combined or joined with polymeric elements that are biodegradable, and upon such degradation, the alloy elements are released in a form that allows their elimination. Such modalities are shown in figures 30A and 30B, as described below. Other embodiments or the invention may include biodegradable polymer memory elements. Biodegradable memory polymers have been described in several patent applications, including US patents US 6,160,084, US 6,281,262, US 6,388,043, US 6,720,402, and published patent applications US 20050075405A1, US 20030055198A1, US 20040015187Al , US 20040110285A1, US 20050245719A1, and US 20060142794A1. Modalities of the invention can include any one or more of such shape memory materials, and in addition, such materials can be joined together in various ways as shown in figures 31A and 31B.

A variety of natural, synthetic and biosynthetic polymers are biologically degradable and can be included as materials that comprise modalities of the intestinal insert device. A polymer based on the CC backbone tends to be non-biodegradable, in which the backbone containing heteroatom of the polymers confers biodegradability. Biodegradability can be modified by polymer engineering by the careful addition of chemical bonds, such as anhydride, ester, or amide bonds, among others. The mechanism for degradation is by hydrolysis or enzymatic divation resulting in a division of the polymer backbone. Microorganisms, such as those that reside in the intestine, can eat or digest polymers, and also initiate mechanical, chemical or enzymatic aging.

Biodegradable polymers with hydrolyzable chemical bonds are suitable as materials for a biodegradable intestinal insert. In addition to being biocompatible, the material must meet other criteria, for example, be processable, sterilizable and capable of controlled stability or degradation in response to biological conditions. Degradation products often define the biocompatibility of a polymer, not necessarily the polymer itself. Polyesters based on polylactide (FLA), polyglycolide (PGA), polycaprolactone (FCL), and their copolymers have been used extensively as biomaterials. The degradation of these materials produces the corresponding hydroxy acids, making them safe for use in vivo.

Other biodegradable polymers include poly (hydroxyalkanoate) s of the PHB-PHV class, additional poly (ester) s, and natural polymers, particularly poly (saccharide) are modified, for example, starch, cellulose, and chitosan. Chitosan is derived from chitin, and is the second most abundant natural polymer in the world after cellulose. Upon deacetylation, it produces unprecedented Chitosan biomaterial, which through additional hydrolysis produces an extremely low molecular weight oligosaccharide. Chitosan is biocompatible, antibacterial and environmentally friendly polyelectrolyte, thus suitable for medical devices and as a material for controlled release in drug distribution.

Poly (ethylene oxide), PEO, a polymer with the structural repeat unit -CH₂CH₂O-, has applications in the distribution of medicine. The material known as poly (ethylene glycol), PEG, is in fact PEO, but it also has hydroxyl groups at each end of the molecule. Unlike high molecular weight PEO, where the degree of polymerization, n, should vary from 10 to 10, the range most frequently used for biomaterials is generally 12 to 200, that is, PEG 600 to PEG 9000, although degrees up to 20,000 are commercially available. Key properties that make poly (ethylene oxide) attractive as a biomaterial are biocompatibility, hydrophilicity, and versatility. The simple, water-soluble, straight polymer can be modified by chemical interaction to form water-insoluble hydrogels, but water-swellable retaining the desirable properties associated with the ethylene oxide part of the structure.

Multi-block copolymers of poly (ethylene oxide) (PEO) and poly (ethylene terephthalate) (PBT) may also be suitable for intestinally inserted devices. These materials are subjected to both hydrolysis (by means of ester bonds) and oxidation (by means of ether bonds) . The rate of degradation is influenced by the molecular weight and content of the PEO. Additionally, the copolymer with the highest water absorption degrades more quickly.

A widely used non-degradable polymer is ethylene-vinyl acetate copolymer. This copolymer has excellent biocompatibility, physical stability, biological inertia, and processability. In drug delivery application these copolymers typically contain 30-50 weight percent vinyl acetate. The ethylene vinyl acetate copolymer membrane acts as the rate-limiting barrier for drug diffusion. In the type II class of degradable polymers, the conversion of hydrophobic substituents to hydrophilic side groups is a first step in the degradation process. Polycarbonate derived from poly tyrosine (DTEco-DT carbonate), can, for example, be a suitable material for a biodegradable intestinal insert. The material can be prepared with the pendant group by means of tyrosine either as an ethyl ester (DTE) or free carboxylate (DT). By changing the ratio of DTE to DT, the balance and hydrophobic / hydrophilic rate of the degradation material in vivo can be manipulated.

Water-swellable polymer work nets can function as hydrogels at one end or as superabsorbents at the other end. Hydrogels are characterized by the pronounced affinity of their chemical structures to aqueous solutions that they swell instead of dissolving. Such polymeric work nets can vary from being mildly absorbent, typically retaining 30% by weight of water in its structure, the superabsorbent, where they often retain their weight of aqueous fluids. Several synthetic strategies have been proposed to prepare absorbent polymers including: polyelectrolyte (s) subjected to covalent crosslinking, associative polymers consisting of hydrophilic and hydrophobic components ("effective" crosslinking via hydrogen bonds), and interpenetrating polymer work networks physically producing absorbent polymers of high mechanical resistance. These approaches are not mutually exclusive, and materials may include composite gels that are critically confident in the balance between polymer-polymer and polymer-solvent interactions in various stimuli, including changes in temperature, pH, ionic strength, solvent, concentration, pressure, tension, luminous intensity, and electric or magnetic fields.

Bioactive materials

As previously established, in some embodiments, the central tube and / or flow reduction elements of the invention can be adapted to release bioactive materials or bioactive agents that trigger biological satiety signals. In some embodiments, one or more of the flow reduction elements and / or central tube may be a porous, malleable solid designed to release a signal in the gastrointestinal (GI) tract over time. In some embodiments, nutrient products from digestion are released from one or more flow reduction elements 200 and / or central or elongated member tube 50 to trigger chemoreceptors in the GI tract to release molecular signals involved in the transmission and / or creation of satiety signals .

The description now goes back to a consideration of the release of bioactive materials from the device in further reducing appetite or decreasing absorption or food intake. The term "bioactive material (s)" refers to any organic, inorganic or living agent that is biologically active or relevant; the term has been extensively described in US patent application No. 11 / 300,283, and will be described here only briefly. For example, a bioactive material can be a protein, a polypeptide, a polysaccharide (for example, heparin), an oligosaccharide, a mono- or disaccharide, a lipid, an organometallic compound, or an inorganic compound, an antimicrobial agent (including agents antibacterial and antifungal), an antiviral agent, an antitumor agent, an immunogenic agent. You can include a living senescent cell, a stem cell, a bacterium, a virus, or any part of these. A biologically active molecule, such as a hormone, a growth factor, a virus that produces growth factor, a growth factor inhibitor, a growth factor receptor, an anti-inflammatory agent, an antimetabolite, or a full or partial functional sense or antisense gene. It can also include a particle or material prepared by man that carries a biologically relevant or active material. A bioactive material can also be a digestion by-product or an agent that changes the pH of its surrounding environment.

Bioactive materials can also include drugs, such as chemical or biological compounds that can have a therapeutic effect on a biological organism. Bioactive materials can also include precursor materials that exhibit the relevant biological activity after being metabolized, disrupted (for example, cleaving molecular components), or otherwise processed and modified in the body.

Combinations, mixtures or other preparations from the previous examples can be made and still be considered bioactive materials in the meaning intended here. Aspects of the present invention directed to bioactive materials can include any or all of the previous examples.

Examples of bioactive materials included in the present invention include hormones and other compounds that transfer signals that promote satiety. Bioactive materials of the present invention can also include other naturally occurring or synthesized peptides, proteins, and steroid hormones. Bioactive agents may additionally include antitumor agents, antimicrobial agents, such as antibiotics: cephalosporins: aminoglycosides; macrolides: tetracyclines, chemotherapeutic agents, sulfonamides, urinary tract antiseptics, antibiotics for anaerobic infection, tuberculosis drugs, leprosy drugs, antifungal agents, antiviral agents, amebiasis chemotherapeutic agents, anti-myeliasis agents, anti-inflammatory agents, anti-inflammatory agents, analgesics centrally, thyroid drugs, including those used in adjunctive therapy and those used as antithyroid drugs, viral surface antigens or parts of viruses, bacterial surface antigens or parts of bacteria, parasite surface antigens that cause diseases or portions of parasites, immunoglobulins, antitoxins, and antigens that elicit an immune response, such as antigens associated with the disease or bioactive agents, such as hormones, enzymes or clotting factors.

Characteristics of the device to accommodate bioactive agents for distribution

The central tube 20 and / or flow reduction elements 200 of the present invention can have bioactive materials adhered to its surface (by means of dip coating, spray coating, spray coating and a variety of other techniques known to those skilled in the art ) or included in tanks or tanks accessible to the surface, or can be manufactured, in such a way that the materials that make up the intestinal insert include and spread such bioactive materials. The central tube and / or flow reduction elements of the present invention that diffuses bioactive materials, can be created by a number of different procedures that are referenced in US patent application Serial No. 11 / 300.283 by Binmoeller, filed on December 15, 2005 and published as a US patent application 2006/0178691 on August 10, 2006, including references to US patent No. 5,019,400 to Gombotz et at., US patent No. 6,685,957 to Bezemer et al. and US patent No. 6,685,957.

When a hydrophobic bioactive material, such as a steroid hormone is incorporated by the method described above, at least one hydrophobic antioxidant may be present. Hydrophobic antioxidants that can be used include, tocopherols (such as atocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, δ.-tocopherol, zetai-tocopherol, zeta2-tocopherol, and eta-tocopherol) and 1-ascorbic acid, 6-palmitate. Such hydrophobic antioxidants can delay the degradation of the copolymer and delay the release of the bioactive material.

When a charged polymer prepared according to the technique referenced above includes a hydrophilic bioactive material, the charged polymer may also include, in addition to a hydrophobic antioxidant, a hydrophobic molecule, such as, for example, cholesterol, ergosterol, lithocholic acid, cholic acid, dinosterol, betulin, or oleanolic acid, which can serve to slow the release rate of the copolymer agent. Such hydrophobic molecules prevent water from penetrating the charged polymer, but do not compromise the degradability of the polymer matrix. Additionally, such molecules can decrease the diffusion coefficient of the polymer matrix for the bioactive material to be released and, in this way, provide a longer release of a bioactive material from the polymer matrix.

Methods of dispersing bioactive materials in polymers and the role of lyophilization to include thermal protectors was provided in Binmoeller US Patent Application Serial No. 11 / 300,283, filed December 15, 2005, which is incorporated by reference.

Non-limiting examples of polymers that can be used in accordance with the present invention, particularly with regard to the accommodation and release of bioactive agents, include polyurethanes, polyesterurethanes, silicone, fluoropolymers, ethylene vinyl acetate, polyethylene, polypropylene, polycarbonates, trimethylenecarbonate, polyphosphazene , polyhydroxybutyrate, polyhydroxyvalerate, polydioxanone, polyiminocarbonates, polyiortoesters, ethylene vinyl alcohol copolymer, Lpolylactide, D, L-polylactide, polyglycolide, polycaprolactone, lactide and glycolide copolymers, polymethylmethacrylate, poly (n-butyl) methacrylate, polyacrylates, polymethacrylates, elastomers and mixtures thereof. Representative elastomers that can also be used include, for example, a thermoplastic elastomer material available under the trade name “CFLEX” from Concept Polymer Technologies from Largo, Fia., Polyether amide thermoplastic elastomer, fluoroelastomers, fluorsilicone elastomer, styrene rubber butadiene, butadiene-styrene rubber, polyisoprene, neoprene (polychloroprene), ethylene-propylene elastomer, chlorine polyethylene sulfonate elastomer, butyl rubber, polysulfite elastomer, polyacrylate elastomer, nitrile, rubber, polyester, styrene, ethylene, propylene, butadiene and isoprene, thermoplastic polyester elastomer and mixtures thereof.

One skilled in the art can determine the amount or concentration of bioactive material (s) to include on the surface or material of the intestinal inserts of the present invention, depending on the particular treatment goals and desired release profiles, as described in the US patent application. Serial No. 11 / 300,283 of Binmoeller, filed on December 15, 2005, which was incorporated by reference.

In some embodiments, the intestinal inserts of the present invention, or portions thereof, may include a coating or barrier to decrease the diffusion or release of bioactive materials. Typically, the barrier must be biocompatible (that is, its presence does not elicit an adverse response from the body), and can have a thickness ranging from about 50 angstroms to about 20,000 angstroms. In some embodiments, the barrier may include a polymer supplied with the polymer that defines bioactive materials.

In some embodiments, a barrier of the present invention comprises inorganic materials, which were detailed in US patent application Serial No. 11 / 300,283 by Binmoeller, filed on December 15, 2005, which was incorporated by reference. Further detailed in the patent application are several methods that can be used to deposit a barrier on the inserts of the present invention. Nitrite barrier coatings, such as, for example, titanium nitrite, titanium carbonitrite, chromium nitrite, titanium and aluminum nitrite and zirconium nitrite can be deposited on the inserts of the present invention at relatively low temperatures by deposition at vacuum in the cathodic arc. Such a method can be chosen where bioactive materials included in an insert of the present invention are sensitive to temperature. Additionally detailed in the patent application are sound methods for producing films from pure metals and alloys.

In some modalities, it is contemplated that the barrier will contain mainly inorganic material. However, other modalities may include barriers with a mixture of materials or organic and inorganic barriers of all organic materials. Some organic compounds that can be used according to the present invention include, by way of example, polyacrylonitrile, polyvinylidene chloride, nylon 6-6, perfluorpolymer, polyethylene terephthalate, polyethylene 2,6naphthalene dicarboxylate, and polycarbonate. Generally, the drug's solubility in the barrier material is less than the drug's solubility in its carrier polymer. Also, generally, the drug diffusivity in the barrier material is less than the drug diffusivity in its carrier polymer. In some embodiments, the barrier may be biodegradable. Suitable biodegradable materials that can be used to create a barrier include, by way of example, calcium phosphates, such as, for example, hydroxyapatite, carbonated hydroxyapatite, tricalcium phosphate, (3 tricalcium phosphate, octacalcium phosphate, phosphate amorphous calcium and calcium orthophosphate Certain calcium salts, such as calcium phosphate (plaster of Paris) can also be used. The biodegradability of the barrier can act as an additional mechanism to control the release of medication from the first layer support.

Active control of the release of bioactive material

Some device modalities and methods provide a more active, that is, more controlled or measured method of delivering bioactive agents, as opposed to the more passive diffusion of the drug from surfaces or deposits. These approaches are also more receptive to handling the release distribution of multiple drugs. Modalities of the inventive device may include a pump to dispense one or more bioactive agents from a reservoir or deposit. Pumps can include electrically driven pumps 72, mechanical pumps, piezo electric devices that control pores, for example, or pumps can be pumps driven osmotically 71. The distribution of the osmotic pump is relatively passive in that it does not require energy input, but is controllable , predictable and calibrable. Osmotic pumps are typically triggered or stimulated through pH difference or concentration gradients. The release of bioactive materials can be controlled by external control devices, such as by an electronic signaling device controlled by both the user and a programmable measuring / signaling device. Examples of devices that incorporate these active approaches to the delivery of bioactive materials or agents are further described below and are shown in figures 26-28.

There are advantages to a drug delivery site in the intestinal lumen that can, for example, be advantageously applied for the delivery of bioactive agents in a broader arrangement than just specific drugs to modulate digestion or appetite. Such other agents can include chemotherapeutic agents, or radioactive particles for anticancer therapy. Another type of bioactive material that can benefit from local distribution may include cells, such as stem cells or immune activated cells, for intestinal cell therapy. Advantages of the intraduodenal release site may include proximity to target sites, taking advantage of specific chemical recovery receptors in the intestine, and minimizing the systemic metabolism of drugs that occur during drug passage through organs such as the liver and kidney that occur when medications are delivered intravenously or orally.

In addition to the distribution of bioactive materials to the small intestine that can reduce food intake, the methods and devices of the present invention can also be used to deliver other bioactive materials normally taken orally. The release of bioactive materials directly into the small intestine can be advantageous because many bioactive materials, including many drugs that are usually taken orally, are degraded by severe stomach conditions before they can reach the small intestine to be absorbed. For this reason, many bioactive materials are coated with layers of protective materials. By releasing bioactive materials, including medications, directly into the small intestine, coatings to protect bioactive materials may not be necessary. This lack of need for protective coatings can be beneficial for patients due to less unnecessary substances being introduced into their systems, and is additionally beneficial as a measurement in the reduction of the process step and cost reduction.

In another aspect of the invention that takes an active rather than intervention role, modalities of the device may include an electronic emitter configured to apply an electrical potential to tissue in the stomach or duodenum. This electrical potential will trigger neuroreceptors and / or mechanoreceptors, and / or osmo-receptors, and / or chemoreceptors to send satiety signals to the brain. Exemplary modalities of the device, such as those described further below are shown in figure 29. The role of the modalities of the intestinal insert and methods associated with its use are more generally considered in the context of figure 13, as detailed in the following section.

Additional exemplary modalities of the invention

Figure 13 is a schematic flowchart of the various ways in which modalities of the device employ the physiology of the individual host, and intervenes in ways to generate a sense of satiety that ultimately reduces food intake. Modalities of the inventive device intervene in the physiology of digestion and satiety by two broad approaches, each of which imitate or explore the natural mechanisms of satiety. Modalities can employ the physiology of the host individual (1) for its mere physical presence having effects, and / or (2) for its more direct intervention or actively for the direct condition of bioactive agents or direct neural stimulation. Figure 13 and this associated description are provided as a simplified theoretical framework for understanding the invention; it is not intended to be complete in every detail; various interactions, dotted lines and blurring of distinctions are omitted due to simplicity.

First, the mere physical presence of a device has two main effects, it has distending effects and, if it has different elements of flow reduction, it prevents the flow of the chyme. Each of these two broad effects depends on the dimensions of the device and its flow reduction system, if the latter is present. First, then, the presence of the device stretches the duodenum, and such distension can be felt or detected neurally, as for example, by neurons sensitive to stretching in the duodenum. In this way, any physical dimension, aspect, or characteristic, such as, for example, any of length, width, total volume, overall conformation or topography, density, weight, or surface properties can affect the strain, or can be neurally detected in some way. Second, with regard to the physical impediment of the chyme flow, this impediment process can alter the biochemical profile of digesting the chyme, and the sense of chemoreceptors in the duodenum that draw the profile as being more fully digested. It may also be that there is neural recognition more specifically of residence time of chyme greater, to the extent that the information separates from the biochemical profile altered per se; then an effect such as this can also be related to the neural detection of distension. Neuronal pathways are in fact stimulated by distension and neuroelectric and / or neuropeptide and neurotransmitter signals can be released to local or more distant sites of action. Combined neural feedback are chemical signals, both from the metabolite profile per se, and from hormone secretion, such as CCK. Neural and chemical responses emanate from the central nervous system and other organs which, in sum, indicate that enough has been eaten and satiety is achieved. In the additional response, the central nervous system supports a cessation of eating and a decrease in digestive processes.

Second, with additional reference to figure 13, modalities of the device can intervene in an active manner, in addition to that caused by mere physical presence. Modalities of the device can safely provide (1) bioactive agents and / or (2) provide electrical stimulation of nerves that then encompass the physiology of satiety and digestion in much the same way, or through the same physiological pathways previously described. In sum, a variety of effects of the presence of the device in the duodenum result in biochemical effects or signals (such as hormonal responses and / or biochemical profile of metabolites, both in the intestine and in the bloodstream) and neural activity that involves electrical signals, all which converge physiologically to result in “satiety”, with its complement of felt satiety, felt or perceived appetite, physiological correlations and habitual behavior and responses.

Modalities of the invention, a small intestine insert, typically include an elongated member including at least an angled portion and at least one flow reduction element, to decrease chyme passage (or, in other words, increasing residence time) of the chyme) in the duodenum, although some modalities of the device do not necessarily include a flow reduction element (as illustrated in figures 26-28), and in some modalities, the central or elongated member itself can be configured to reduce flow (Figure 16, for example). These modalities typically actually have one or two angled positions that correspond to the angled target portions of the duodenum. The configuration of the angled positions of the insert, including the flow reduction elements, is such that the device stably resides in the duodenum for a period of time. Modalities of the insert may include adaptations that contribute to the generation of one or more physiological satiety signals. Modalities of the insert may include other features, such as the inclusion of biodegradable portions, a neurological stimulator, and one or more releasable reservoirs of bioactive materials that can be actively released by a bioactive material release mechanism.

The residence time of the insertion modalities at the angled site targeted in the duodenum will vary according to the configuration of the modality and according to the particulars of the biodegradable materials that comprise portions of the device. Degradation of the device by biological processes is typically what causes release or failure of the device to settle or detach from the target site, and elimination of the device through the intestinal tract. It can be understood, in this way, that the device can be configured initially to fit or be seated in the targeted angled portion of the small intestine, and then, after a period of residence and through the effects of biodegradation, then configured to be non from the target site, and eliminated from the body by defecation. Biodegradability is the characteristic of some polymers, and can be included in the polymeric portions of any modality described here and / or as illustrated in figures 3 -12, and 16 - 29. Biodegradation is a characteristic explicitly presented in the modalities shown in the figures 30 and 31.

The device's modalities elicit physiological satiety signals typically through hormonal or neurological pathways. In some modalities, the paths are stimulated by the physical presence of the device, including the total sum of a central member and elements of flow reduction, whose collective dimensions, both length, width, or total volume, or surface properties, are in a way such that neuronal elements of the intestine, such as mechanoreceptors or stretch receptors, sense of the presence of material that is interpreted as the presence of partially digested food and, thus, stimulates neuronal messages to the central nervous system that are interpreted as food satiety. In other modalities, the satiety signal can be hormonal. Flow-reducing elements slow down the passage of the chyme being processed in the duodenum, the biochemical profile of food interruption products is altered, and chemoreceptors in the duodenum respond to the altered biochemical profile in a way that transfers satiety to the central nervous system and other portions of the digestive system.

In yet other modalities, the device includes reservoirs of bioactive materials that can be released, by both passive and active mechanisms. In modalities, satiety signals are provided directly by the device, not by the endocrine pathways of the insert host. Modalities of the device may include reservoirs of material of any type, including, for example, medicament coatings that passively or passively elute with degradation of a host lining the material, and some modalities include reservoirs that are coupled with pumps. Such pumps can be mechanical, by trellis, for example, biological energy transferred by peristalsis, or electrical energy, or mechanical energy. Some modalities may include osmotic pumps, which do not require electric energy input, but instead of tapping heads in the stored energy of osmotic gradients. Modes that depend on electrical energy to be released by a pump typically include an energy storage device, such as a battery or capacitor. Some of the energized modalities include, as part of a larger system, a remote stimulator that can control the action of the pump. In some modalities, the device can provide direct neural stimulation, through electrodes that stimulate local nerves in the duodenum, which transfers a feeling of satiety to the central nervous system. As with pumps, devices that include neural stimulus characteristics may also include energy storage devices and external on / off force control devices or variables that communicate either through direct or wireless connection, such as via radio frequency signals.

Figure 14 provides a view of a portion of the human gastrointestinal tract that focuses on the duodenum of the small intestine 10, starting at the anthro-pyloric junction 5, and extending to the entrance of the jejunum 12. The ampoule of Vater 13, the site entrance of the hepato-pancreatic duct 15, which is formed by the union of the pancreatic duct (of the pancreas 9) and the common bile duct of the liver. The pylorus 8 controls the discharge of the contents of the stomach by means of a sphincter muscle, the pyloric valve 11, which allows the pylorus 8 to open loose enough to pass the digested stomach contents sufficiently. These gastric contents, after passing through the duodenum 10, continue in the jejunum 12 and the ileum. The duodenum 10, jejunum 12 and ileum constitute what is known as the small intestine, however the individual portions of the alimentary canal are also commonly referred to as the small intestine. In the context of this invention, the small intestine can refer to all or part of the duodenum, jejunum and / or ileum. Figure 15 provides a flat planar view of the duodenum 10, including the wrinkles 19, or the portion of the lining that folds internally into the duodenum that forms the periphery of the internal space in which modalities of the insert device are positioned. Also presented are the pylorus 8, the pyloric valve 11, the duodenal bulb 10A, the vertical duodenum 10B, and the horizontal duodenum 10C, the ampoule of Vater 13, and the initial portion of the jejunum 12. This figure provides visual feedback for figures 16-29 which follow, each of which describes a modality of the inserted inventive device seated at the targeted site of the duodenum.

Figure 16A describes an embodiment of insert 20 with a central tube or member 50 in the form of a simple spiral like a telephone cord; in this embodiment the flow reduction elements 200A can be understood as the individual spiral elements or segments of the extended central member 50. Figure 16B shows a detail of a proximal portion or the distal end of the device that takes the shape of a pig tail 61, as can emerge from a device disposition tube 620. Modalities of the end portion of the pig tail can provide usefulness and advantage during disposal, as well as an end point of stabilization and non-irritant when the insert is seated at the target site.

Figure 17A describes an embodiment of insert 20 with a central tube or member 50 in the form of a C-shaped spine, similar to the embodiment shown in figures 3 and 9, with flow reduction elements 200 in the form of ribs attached to the spine. Figure 17B shows the central member 50 and rib tips 200 emerging from an arrangement tube 620. Some modalities of the flow reduction elements formed by ribs 200 can be spring-type and deflected outwards, the elements reducing the flow by their presence, but also, and advantageously, stimulating the wall of the duodenum 10, thus contributing to the generation of a satiety sign and, additionally, contributing to the stabilization of the insert as it resides in the targeted and angled site of the duodenum. With respect to the latter, the portion of the duodenal bulb 10A bulges to a radius wider than the most distal portion of the duodenum and thus an expansive element at this site provides a particularly effective stabilization site.

Figure 18 describes an embodiment of insert 20 with flow reduction elements in the form of a spine with mesh. This modality can be considered similar to that presented in figure 17, but with a mesh, filter, or mesh arranged between expandable ribs. The expandable ribs provide benefit as previously described; the network provides an effect in terms of reduced chyme flow being processed through the duodenum 10. By using the mesh of varying pore size in the flow reduction elements 200, the device can be supplied in variations that decrease the flow in varying degrees. In addition, the mesh elements can be formed of materials of varying properties, such as hydrophilicity or varied hydrophobicity, which can have effects on the flow rate of the chyme. In addition, the mesh can provide an advantageous site due to its high surface area for the adsorption of bioactive materials, which can then passively elute or desorb during the period that the insert 20 resides in the duodenum.

Figure 19 describes an embodiment of the insert 20 with flow reduction elements in the form of a distally closed sleeve which is protected by a proximal portion 30A in the form of a proximally opened ring-like end cap. The glove can have pores of various dimensions, providing leakage of varying degrees and, generally, the characteristics described for the modality network presented in figure 18.

Figure 20A describes an embodiment of the insert 20 with flow reduction elements 200 in the form of closed-mesh baskets along a central member 50 and adjacent to it and additionally showing proximal and distal ends of the pig tail 61. Figure 20B shows the device that emerges from a disposition tube 620, and that expands in the emergency. The modalities of the mesh baskets are flexible and expandable, the mesh can be of varying size and composition. Typically, the basket portions themselves do not form angles, but the interconnecting central portion 50 can form and resiliently maintain predetermined angles. The composition of the baskets and the central portion may be identical and contiguous or the compositions may vary from one another. The interconnecting central portion 50, in particular, may additionally have shape memory characteristics, as provided by both the shape memory alloy and shape memory polymers. The polymeric materials comprising the baskets 200 and / or the central member 50, whether resiliently maintaining the shape, or capable of shape memory, can additionally be biodegradable.

Figure 21 describes an embodiment of the insert 20 with flow reduction elements 200 in the form of centrally mounted outwardly extending baffles, and additionally showing proximal and distal ends of the pig tail 61. The baffle plates are mounted at spatial intervals on a central member 50, which can include angled positions that are maintained by resiliently modeled materials or modeled by memory, as described in the context of the modality shown in figure 20.

Figure 22 describes an embodiment of insert 20 with flow reduction elements 200 in the form of inwardly extending baffles mounted peripherally, and additionally showing proximal and distal ends of the pig tail 61. The baffle plates are mounted at spatial intervals on a hollow central member 50 which can include angled or curved portions that are held by resiliently modeled materials or modeled by memory, as described in the context of the modality shown in figures 20 and 21. This modality differs generally of many others presented due to its hollow body aspect. The device 20 is opened both in its proximal portion 30 and in the distal portion 40. This hollow shape can confer some particular advantages in relation to the contribution of the generation of satiety signals. The shape of the device is to fill the space in the duodenum 10, and in this way it can be particularly well suited for stimulating mechanically responsive or responsive nerves by stretching the wall of the duodenum, the stimulation of such nerves generally providing a feeling of satiety. The device 20 in this form can also have a force distribution advantage over those with a more centrally arranged central member 50, as seen in most other embodiments. In addition, the surface configuration of the device 20 may vary; it can, for example, be solid or box type, substantially box type, but with holes or openings (not shown), or it can be cage type or mesh type (not shown). Each of these forms can have particular advantages. Additionally, with a more substantial physical presence, a box-type device provides a physical platform for attaching or assembling medication reservoirs, as well as pumps and circuits, as presented in another embodiment in figures 27 and

28. In addition, a box-like shape like this can provide a fitting fitting for neural stimulation electrodes, as shown in a modality shown in figure 29. This particular modality can be understood as being particularly treatable to capture kinetic energy from the body in the form of movement peristaltic with the baffles, particularly when they have a spring deflection. Such energy capture can have benefits in terms of decreasing the flow of the chyme, while reducing the likelihood of clogging or creating chyme pockets that become isolated and blocked with respect to the flow.

Figure 23 describes a modality of insert 20 with flow reduction elements 200 in the form of a foam-like body, and additionally showing proximal and distal ends of the pig tail 61. This modality, in a broad aspect, is similar to the modality shown in figure 6. Foam-type flow reduction elements 200 are compressible and expandable and are thus receptive for disposal in a target zone by means of narrow tubes or scopes. Foam-like materials can be a closed cell form or an open cell form or they can be hydrogels. Such foam-like materials serve the function of reducing flow due to the fact that they are bulky, reliable and tend to be space-filling. They also provide a high amount of surface area, which is advantageous for adsorption of bioactive agents, as provided by the modalities of the invention, which can then be passively desorbed during the residence period in the duodenum. Such foam or sponge-like materials can also be completely or partially biodegradable. Biodegradability generally serves the purpose of providing a limited residence time, as well as being a way in which it disperses bioactive agents incorporated or adsorbed into the material.

Figure 24 describes an embodiment of insert 20 with a flow reduction element 200 in the form of a stent that drips porous nutrient, open at both the proximal end 30 and the distal end

40. This modality generally differs from that shown in figure 19 in that it has greater integrity in form; on the contrary, the embodiment of figure 19 is referred to as an open sleeve and has no particular structural shape. The modality of the nutrient-dripping stent presented here has structural integrity and is more surely space filling. The material typically takes the form of a mesh, the shape with other types of intraluminal stents and can be formed of polymeric and / or metallic strands. The mesh is typically open enough to provide a trickle of liquefied nutrient-rich portions of chyme 18 processing, while maintaining the chyme volume flow in the closed channel through the stent.

Figure 25 describes an embodiment of insert 20 with flow reduction elements 200 in the form of centrally mounted fans or blades, mounted at spatial intervals on a central member 50, and additionally showing proximal and distal ends of the pig tail 61. Such paddles fan 200 can be rotatable, with varying degrees of resistance to rotation, including minimal resistance. To the extent that such flow reduction modalities 200 actually rotate according to the chyme processing flow, such movement can be beneficial in ways similar to those described in the embodiment shown in figure 22, in which chyme mixing can be a process used as an adjunct for flow reduction.

Figure 26 describes a modality of the insert 20 with bioactive material in reservoirs or deposits, or in layers, or adsorbed, or incorporated in the central- or elongated member 50, from which the bioactive agent can passively elute in the duodenum 10. This modality emphasizes the bioactive material or distribution aspect of the device's agent and is shown with no flow reduction element particularly formed other than its own physical dimension, however, it must be understood that a drug that elutes central member 50 such as this can be combined with any of the various flow reduction elements 200 shown in other figures.

Figure 27 describes an embodiment of insert 20 with an osmotic pump loaded with bioactive material 71, in the form supported by the central or elongated member 50. Osmotic pumps are well known in the art, as provided, for example, by Alm Corporation (Cupertino, CA ). The actuation of an osmotic pump can occur in several ways; for example, actuation by water by a chemical potential across an osmotic membrane and enters a salt chamber. The larger volume in the salt chamber forces an expansion membrane to deflect in a medicine reservoir. As the expansion membrane pushes the reservoir, the medication is dispensed through one or more exit ports.

Figure 28 describes a modality of insert 20 with a reservoir loaded with bioactive material 73 coupled to an electrically driven pump 72, storage and energy dispensing unit 75, all such components being supported by the central or elongated member 50, as well as external control 77 As shown in figures 26 and 27, the modality currently presented emphasizes the distribution of a bioactive agent or material to the targeted duodenal site. Any of these modalities can include more than one medication. The difference between this type of bioactive agent dispensation and that of figures 26 and 27 is that they are relatively passive, running at a predetermined course time by the particulars of the bioactive agent release mechanism. In the modality shown in figure 28, however, the release of the bioactive material is through active control of a pump, and the pump can additionally be through control of an external control that communicates with the pump either through an implanted wire or, as presented here , by wireless communication, such as radio frequency transmission. A device can include more than one unit like this, or a single unit can include more than one reservoir and pump, so more than one bioactive agent can be delivered independently of a single device 20.

Figure 29 describes a modality of the inventive insert 20 with electrodes 78 for local neurostimulation, a storage and energy distribution unit 75, such as a battery or capacitor, and an external controller 77, all such components being supported both directly and indirectly by the member central or elongated 50. This modality is illustrated in such a way as to focus on neuronal stimulation, but as explained earlier in the reference to devices that elicit medication, the neural stimulatory characteristics of the device can be combined with any of the various flow reduction elements 200. In the present modality, the electrodes can be advantageously positioned in places where the nerves are known to reside. The electrodes can target more than one nerve to stimulate, or they can target a nerve at more than one point.

Figure 30 describes an embodiment of the central member 50 of an insert 20 that includes biodegradable elements and shape memory elements. Figure 30A shows the central member in an intact configuration with apparent α and β angles; Figure 30B shows the central member after biodegradation has started. At the last point, the central member will further deteriorate, it will lose its integrity and conformation and the α and β angles will disappear as the C-shaped device definition arms disappear. As such, this represents a modality of the device that is configured first to settle on a targeted site in the intestine, and then after residence and a period of biodegradation, the device is set up to stay unsetted from the target site, such as not setting due to loss of initial conformation corresponding to the target site. In the exemplary embodiment shown here, an insert device 20 is formed from a combination of curved shaped memory alloy portions 22 and relatively straight biodegradable polymer portions. The metal portions 22 and polymer portions 24 are joined segmentally to create a full size insert with a desired full angle or curve, such as radius α and radius β shown in figure 9. The metal portions have portions that expand at both ends to provide a more substantial joining surface and to protect the host individual from tip injury or irritation, as the metal elements are loosened by biological degradation of the member 20 as a whole. Metal and polymer portions can be joined in other ways to complete an angled device, familiar to those skilled in the art.

Figure 31 describes an embodiment of the central member 50 of an insert that includes a biodegradable polymeric material; biodegradable polymers have been described extensively earlier. Figure 31A shows the central member in an intact configuration; Figure 31B shows the central member after biodegradation has started. At the last point, the central member 50 will further disintegrate, and radio angles α and radio β will no longer maintain their shape. In some embodiments, the polymeric material may be able to resiliently maintain an angle, such as radio angles α and radio β shown in figure 9, and in other embodiments, the polymer may be of a type capable of maintaining a shape memory, as previously described.

Terms and conventions

Unless otherwise defined, all technical terms used herein have the same meanings commonly understood by one skilled in the art to which this invention belongs. Various conventions and terms have also been described in related US patent application No. 11 / 300,283. Specific methods, devices, and materials are described in this patent application, but any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention.

Although modalities of the inventive device and method have been described in detail and by way of exemplary illustrations, such illustration is for the purpose of clarifying understanding only and is not intended to be limiting. Several terms have been used in the description to convey an understanding of the invention; it will be understood that the meaning of these various terms extends to the common linguistic and grammatical variations and forms of these. It will also be understood that when terminology referring to devices, equipment, or medications is used, trade names or common names of these names are provided as contemporary examples, and the invention is not limited by such a literal scope. The terminology that is introduced in a last term that can reasonably be understood as a derivative of a contemporary term or designating a subset of objects encompassed by a contemporary term will be understood as described by the now contemporary terminology. In addition, although some theoretical considerations have advanced in providing an understanding, for example, in various ways that the modalities of the invention employ the physiology of satiety, the claims of the invention are not linked to such a theory. Furthermore, any one or more features of any embodiment of the invention can be combined with any one or more other features of any other embodiment of the invention, without departing from the scope of the invention. In addition, it should be understood that the invention is not limited to the modalities that have been presented for purposes of exemplification, but is defined only by an impartial reading of the claims that are attached to the patent application, including the full range of equivalence to which each element of this is titled.