Patent Application
20090182303
Obesity is a potentially life threatening condition afflicting ever increasing numbers of patients. The treatment of obesity often involves one or more of lifestyle changes, drugs and surgery. The drugs currently in use may be broadly classified as either appetite suppressants such as Sibutramine or Rimonabant, which decrease hunger and increase satiety or lipase inhibitors such as Orlistat, which impede the digestion of fats.
Anti-obesity drugs are conventionally taken orally, exposing all of the organs to the drug and thereby increasing the incidence of side effects which may be severe. For example, side effects associated with conventionally delivered drugs include heart palpitations, tachycardia, increased blood pressure, insomnia, diarrhea and nausea. In addition, a large portion of each dose of these drugs is wasted as the delivery is not directed to the digestive or nervous system target.
In one aspect the invention is directed to a method for treating obesity, comprising anchoring at a first target site within a body a first therapeutic agent delivery device including a first therapeutic agent reservoir coupled to a first outlet which, when the first device is anchored at the first target site, is positioned adjacent to a first target treatment location within a GI tract of a patient and releasing a first therapeutic agent from the first reservoir via the first outlet.
The present invention may be further understood with reference to the following description and to the appended drawings, wherein like elements are referred to with the same reference numerals. The present invention relates to devices and methods for targeted delivery of therapeutic agents such as drugs, nutritional products, etc. to the digestive system. In particular, the invention relates to delivering therapeutic agents to the digestive system to treat obesity.
The present invention provides methods and devices to improve the effectiveness of therapeutic agents and minimize their side effects by delivering controlled dosages directly to target sites in the body. For example, for the delivery of therapeutic agents for the treatment of obesity, a therapeutic agent release device is implanted in or near the digestive organs. The therapeutic agent release device comprises, for example, a therapeutic agent reservoir and a pump to dispense a therapeutic agent, wherein an outlet of the therapeutic agent reservoir is placed adjacent to or in contact with the target tissue. The therapeutic agent release device may be implanted using conventional surgical techniques or alternatively, may be implanted using minimally invasive endoscopic or laparoscopic methods, as those skilled in the art will understand. In one exemplary embodiment, the therapeutic agent release device may be implanted in the stomach or the small intestine such that an outlet of the reservoir communicates directly with the GI tract or the common bile duct (CBD) for release of controlled dosages of a therapeutic agent thereto.
A therapeutic agent release device according to the present invention may comprise a reservoir holding a therapeutic agent and a pump for supplying the therapeutic agent from the reservoir to a target site in the GI tract. As will be described in greater detail below, a single pump may be coupled to a plurality of reservoirs (e.g., via a valving arrangement) to supply separate dosages of different therapeutic agents at different times or to supply combinations of therapeutic agents, etc. Alternatively, a plurality of pumps may be coupled to a common reservoir so that each pump may supply the same therapeutic agent to different target sites as desired. Still further, a single pump may include multiple outlet conduits and a valving arrangement controllable so that the single pump may supply one or more therapeutic agents or combinations thereof to a plurality of target sites as desired. Flow control from the reservoirs may be facilitated by precision orifice selection.
Alternatively, each pump of the therapeutic agent release device may be formed as a separate unit coupled to one or more separate reservoirs. Externally communicating ports may be placed through the wall of the stomach 100 to load and refill reservoir(s) with therapeutic agents. For example, a Percutaneous Endoscopic Gastrostomy (PEG) tube may be incorporated into the system according to the invention to allow loading of the therapeutic agent through the abdominal wall. In further embodiments, pumps and reservoirs may be surgically implanted at remote sites in the body with delivery lines connected to the a desired location in an organ. For example, the pumps and/or reservoirs may be implanted under the skin or muscle and may, in alternate embodiments, be located external to the body with delivery lines connected to a desired location in an organ.
The local therapeutic agent release device of the present invention may also enable the use of novel therapeutic compounds by reducing a required total systematic dose and eliminating negative side effects, as those skilled in the art will understand. Specifically, the local delivery of therapeutic agents may enable the use of experimental compounds such as melanocortin-4 receptor agonists, ghrelin, neuopeptide Y antagonists, melanin-concentrating hormone antagonists, peptide YY, and hydrophobic detergents of pH buffering compounds. As would be understood by those skilled in the art, the therapeutic agent may be selected to inhibit the function of the bile and pancreatic lipase to reduce fat digestion and caloric intake. Furthermore, the agent may serve to neutralize bile/ lipase, coat food to prevent the digestion thereof, temporarily coat the GI tract to prevent the digestion of food, slow the process of peristalsis by temporarily paralyzing the smooth muscle of the stomach and/ or cause a sphincter such as the Pyloric Sphincter and the Sphincter of Oddi, to remain shut or reduce outflow, as those skilled in the art will understand. It will be further understood by those of skill in the art that other therapeutic agents may be delivered by the device, for example appetite suppressants, etc. In different embodiments, the therapeutic agent delivered by the device may comprise a compound that affects neural signals of the digestive organs to control feelings of hunger and satiety. For example, the therapeutic agent may target the Vagus nerve or other bundles of nerves that carry signals between the GI tract and the brain.
Embodiments of the present invention will be described with respect to the anatomy of the stomach 100 as referenced in
As those skilled in the art will understand, a material of the therapeutic agent release device 118 will be suitable to survive in the acidic environment of the stomach 100 and duodenum 102. Exemplary materials for the device include, but are not limited to: metals such as stainless steels, titanium, tantalum, cobalt alloys and nitinol and plastics such as Teflon, rubbers including neoprene, silicone, urethane, polyethylene, polypropylene, nylon, polycarbonate, polymethyl methacrylate, polyethylene terephthalate (PET) and polystyrene.
A positioning of the therapeutic agent release device 118 within the stomach 100 may correlate directly with the type of therapeutic agent being used. For example, therapeutic agents intended to impede the function of bile in the digestion of fat may be placed in the lower stomach, the pyloric antrum, the duodenal bulb or the common bile duct. Alternatively, agents targeting the vagus nerve to increase satiety may be placed in close proximity to highly innervated tissue or main nerve branches in the upper stomach or esophagus 112. The therapeutic agent release device 118 will be described in greater detail in reference to later embodiments, wherein any of the embodiments of the present invention may be implanted in the stomach 100 in the manner shown in
In operation, the therapeutic agent release device 120 may be traversed to a target portion of the stomach 100 and secured thereto via a securing means 124, wherein the securing means is one of a suture, hooks, screw, t-tacks or alternate means known in the art, as further detailed below with respect to
As shows in
In an alternate other embodiment, a pump used with the therapeutic agent release device 200 may also degrade after a predetermined period of time has elapsed since implantation in the body
The therapeutic agent release device 200 may further comprise an osmotic pump 220 such as those manufactured by Alzet, Inc. The osmotic pump 220 comprises a fluid chamber 206 surrounded by an osmotic layer 210 forming a pumping chamber 216. A flexible impenneable membrane 208 containing a high concentration of a salt may be interposed between the fluid chamber 206 and the osmotic layer 210. Additionally, the osmotic layer 210 may be separated from the outside environment by a semipermeable membrane 212. A difference in solute concentration across the semipermeable membrane 212 draws water from the GI tract into the pumping chamber 216, thus expanding the osmotic layer 210 and applying pressure to the fluid chamber 206. The applied pressure forces a therapeutic agent 204 out through the outlet 214 at a controlled rate. For example, the rate of delivery of the therapeutic agent 204 may be directly related to and controllable by the permeability of the membrane 212 and/or the properties of the osmotic layer 210, as those skilled in the art will understand.
Employment of an osmotic pump is preferred since no external power supply is needed to release the therapeutic agent 204, which is pumped out of the therapeutic agent release device 200 by harnessing the properties of the materials of the osmotic pump 220 and the surrounding environment, as described in greater detail above. Additionally, substantially large quantities of the therapeutic agent 204 may be held in the fluid chamber 206 to provide long term therapy without the need to refill the fluid chamber 206, wherein the required volume of the fluid may vary depending on a dosage required for a particular patient.
In an alternate embodiment, the osmotic pump 220 may be composed of an electroactive polymer (“EAP”), shape memory material, etc. to facilitate a release of a therapeutic agent. Specifically, this osmotic pump 220 may be actuated via known means (e.g., application of a voltage thereto, etc,) to pump a therapeutic agent. In one embodiment, the osmotic pump 220 may be actuated to slowly pump a therapeutic agent to a target site over an extended period of time, wherein the rate of flow of the therapeutic agent may be increased or decreased by a factor at any time during the pumping process.
The osmotic pump 220 is sized for ease of insertion through an endoscope (not shown) and, preferably comprises a diameter smaller than an inner diameter of a working channel of the endoscope. As would be understood by those skilled in the art, the inner diameters of standard endoscope working channels are 2.0 mm., 2.8 mm., 3.7 mm., 4.2 mm. and 6.0 mm. The size of an osmotic pump 220 which does not need to be inserted through an endoscope working channel may be substantially larger than these values but is preferably small enough to facilitate insertion through the esophagus 112—i.e., the device should be smaller than a minimum diameter of the esophagus 112, which is typically about 25 mm. However, since endoscopes passed through the esophagus 112 are typically about 12 mm. to 14 mm. in diameter, osmotic pumps that comprise a larger size must be traversed to the target site via an alternate means. One such alternative is to traverse an endoscope to a first region within the body and manipulate a guidewire along the outside thereof to a target region, as those skilled in the art will understand. The endoscope may then be removed from the body and the osmotic pump 220 may be guided to the target region via the guide wire.
In an alternate embodiment, the osmotic pump 220 may be placed percutaneously or surgically at any of a plurality of sites on or in the body. In yet another alternate embodiment, the osmotic pump 220 may traverse through a trocar or a percutaneous endoscopic gastrostomy (“PEG”) tube, as those skilled in the art will understand, wherein the size of the osmotic pump 220 is smaller than the trocar or PEG tube. Furthermore, the osmotic pump 220 may be designed with a substantially small diameter relative to the size of a guiding mechanism being employed therewith, as noted above, but may comprise a longitudinal length that may increase as the diameter is reduced. Specifically, the osmotic pump 220 may assume a coiled or folded configuration during deployment and expand to a full length when positioned at a target treatment site.
Because of the small size and smooth shape of the therapeutic agent release device 200, the seed-like osmotic pump 220 of
Different combinations of pumps and therapeutic agent reservoirs may be used to dispense therapeutic compounds according to the present invention. For example, in one embodiment the therapeutic agent may be released through the biodegradation of a polymer in which it is embedded. In this embodiment the therapeutic agent and the polymer are admixed to form a structure that degrades substantially uniformly to release the therapeutic agent at a desired rate, wherein the rate of release may be controlled by selecting an appropriate polymer. The degradable polymer may be used as a coating that produces a burst release when the polymer coating is breached.
Alternatively, as would be understood by those skilled in the art, various layers of different polymers may be employed to alter the rate of release of the therapeutic agent over time. Exemplary biodegradable polymers and polymer blends may include polyglycolide (“PGA”), poly(caprolactone), poly(dioxanone), copolymers of glycolide with trimethylene carbonate (“TMC”) and polyethylene glycol (PEG), wherein selection of a proper polymer may change the degradation rate from days to months. For example, changing the ratio of Poly(lactide) to Poly(glycolide) in a copolymer blend is known to dramatically alter the biodegradation rate thereof.
In another embodiment, the osmotic pump 220 may be designed as a rail with a plurality of separate spaces, each comprising a therapeutic agent therein, wherein the spaces may be sheathed by one of the polymer materials noted above. Accordingly, as each layer of the polymer material degrades in the body, the therapeutic agent housed in an adjacent space of the osmotic pump may be released into the body. In yet another embodiment, multiple pumps 220 may be employed in the therapeutic agent release device 200, wherein the plurality of pumps 220 may connect to one another (e.g., via a snap attachment means, etc.), thereby enabling the employment of more than one pump 220 in a particular location to affect the dosage of the therapeutic agent into the stomach.
As shown in
Once the PEG tube 402 is fluidly sealed with the stomach 100, the catheter 401 is advanced through the PEG 402 and into the stomach 100 with the balloon 400 in a deflated state. An inflation fluid 404 is supplied to the balloon 400 via the catheter 401 to inflate the balloon 400 to occupy a desired volume within the stomach 100. The inflated balloon 400 decreases the volume of food required to cause satiety, thus reducing caloric intake. In addition, if desired, the balloon 400 may be formed of a material having a desired porosity so that the inflation fluid (e.g., a therapeutic agent) leaches from the balloon 400 into the stomach 100 at a desired rate. Exemplary materials that may be rendered porous may include, but are not limited to, silicone, ePTFE, polyisobutylene (SIBS), PeBAX, PET or urethane. In this case, the inflation fluid 404 is preferably a therapeutic agent acting on digestive fluids or structures of the digestive system to reduce caloric intake. Any of the therapeutic agents described above for application in the stomach may be used. For example, a therapeutic agent 404 utilized as the inflation fluid may include a drug or ghrelin antagonist.
In an alternate embodiment, only a portion 406 of a surface of the balloon 400 may be formed to be semipermeable so that the therapeutic agent is eluted therethrough to the stomach 100. Specifically, the semipermeable portion 406 of the balloon 400 may be formed of an otherwise impermeable material treated (e.g., using laser drilling or mechanical perforation) to form small pores therein. The semi-permeable material may be produced by leaching a constituent from a multi-constituent bulk material, phase inversion processing, foam processing or other known method for forming porous materials. As would be understood by those skilled in the art, the concentration of the therapeutic agent 404 and the volume of the balloon 400 may be tailored to the needs of individual patients.
As shown in
In another embodiment of the present invention, as shown in
Implanting the therapeutic agent release device 520 in proximity to the surface of the skin facilitates refilling the therapeutic agent release device 520 which may, for example, include a selectively permeable septum 536 on an outer surface thereof facing the surface of the skin. When the supply of a therapeutic agent in the therapeutic agent release device 520 has been exhausted, a needle 540 fluidly connected to a source of therapeutic delivery agent may be inserted through the septum 536 to refill the reservoir 522. A pump or other means (not shown) in the therapeutic agent release device 520 may regulate the flow of the therapeutic delivery agent through the conduit/catheter 532 to the stomach 100 as would be understood by those skilled in the art.
In an alternate embodiment, as shown in
The therapeutic agent release device 520 may further comprise a subcutaneous pump 538 situated along a length of one or both of the conduits 532 to regulate the flow of therapeutic agent therethrough to a target site or sites in the stomach. The pump 538 may be activated, for example, by a controller outside the body to release desired doses of therapeutic agent into the body using, for example, wireless transmission, induction, etc. Accordingly, the entire length of the conduit/catheter 532 may serve as a reservoir, increasing the available quantity of therapeutic agent which may be stored therein.
The aforementioned embodiments disclose a therapeutic agent release device that may be implanted either internally in the stomach 100, attached to an external wall thereof or implanted subcutaneously and fluidly connected thereto by one or more conduits. In another embodiment, a therapeutic agent release device 620 may be implanted within tissue layers of the wall of the stomach 100. Specifically, as shown in
The therapeutic release device 620 may be implanted via the use of an injection needle 652, an elongated catheter or other means as would be understood by those skilled in the art wherein a distal tip of the injection needle is inserted to a target location in the stomach, for example, via the esophagus 112. The injection needle 652 may be guided, for example, via the employment of an optical system or other guiding system located on a distal end of an endoscope. Once a target location has been reached and the distal tip of the injection needle 652 has been inserted to a target location between the serosa 601 and the mucosa 603, the therapeutic release device 620 is inserted through the device and propelled distally by an injection device 650. After the therapeutic release device 620 has been positioned at the target location, the injection needle 652 and endoscope (not shown) may be withdrawn from the esophagus 112. It is noted that the above noted method may be used to implant the therapeutic release device 620 in any hollow organ or lumen and is not limited solely to the injection of a device into the wall of the stomach.
In another alternate embodiment, as shown in
As shown in
In yet another embodiment of the present invention, the therapeutic agent release device may deliver a therapeutic agent to multiple target sites simultaneously. As shown in
The t-tack member 724 comprises a substantially disc-shaped member 702 situated at a first end of a substantially flexible wire 704. The wire 704 comprises barbs 708 distributed along a length thereof, the barbs formed of a substantially flexible material exhibiting a predetermined rigidity. During insertion into the body (e.g., through an endoscope or catheter), the disc-shaped member 702 is bent to lie substantially parallel to a longitudinal axis of the wire 704, thus minimizing the profile of the t-tack member 724. Once a target site in the stomach is reached, the disc-shaped member 702 is positioned to lie substantially perpendicular to a longitudinal axis of the wire 704. The wire 704 is then pierced through a target portion of the wall of the stomach 100. The slot 726 of the therapeutic agent release device 720 is then threaded over the portion of the wire 704 received in the stomach. A locking cap 706 is then slidably placed over the wire 704. The locking cap 706 comprises an opening (not shown) sized and shaped to receive the wire 704 therethrough. The slidable insertion of the locking cap causes barbs 708 of the wire 704 to deflect to permit the locking cap 706 to slide therepast.
As shown in
The food sensing mechanism of the therapeutic agent release device 820 need not be connected to an external power supply. For example, they may be connected to an internal power supply such as a battery the life and size of which may vary depending on the length of time the therapeutic agent release device 820 is to remain in the body. A conduit 832 of the therapeutic agent release device 820 may serve as a restrictor for metering the therapeutic agent supplied to the stomach 100 and the device 820 may contain a refilling mechanism as described with respect to any of the earlier embodiments.
Once the bulk food sensing means 850 and/or the leads 852 detect a condition indicating that food has entered the stomach 100 (via the sensing of esophagus/tissue movement in the stomach 100), the pump of the therapeutic agent release device 820 may be activated, causing the reservoir to secrete a selected dosage of therapeutic agent into the stomach 100. The precise dosage may be controlled by the conduit 832, which serves as a restrictor.
In another embodiment of the present invention, a therapeutic agent release device 920 may during insertion into the stomach 100 via, for example, an endoscope 960, assume an elongated configuration A, facilitating the insertion of the therapeutic agent release device 920 through the esophagus 112. Once the therapeutic agent release device 920 has been inserted to a desired location, such as, for example, a location proximal to the duodenum 102, the therapeutic agent release device 920 may be deployed to a retention configuration B, in which the therapeutic agent release device 920 coils around a length of the duodenum 102. Accordingly, the therapeutic agent release device 920 may comprise a retractable coil design which automatically returns to the coiled retention configuration B upon the release of a force applied thereto to hold the therapeutic agent release device 920 in the elongated configuration A. The therapeutic agent release device 920 may be held in the elongated configuration A by any known means.
Those of skill in the art will understand that the therapeutic agent release device according to the present invention may be used to deliver different therapeutic agents to various areas of the patient's anatomy. In addition to delivering therapeutic agents to treat obesity to the stomach or duodenum, the embodiments of the invention may deliver therapeutic agents for the treatment of cancer and other diseases in the GI tract and other organs.
The present invention has been described with reference to specific exemplary embodiments. Those skilled in the art will understand that changes may be made in details, particularly in matters of shape, size, material and arrangement of parts. Accordingly, various modifications and changes may be made to the embodiments. The specifications and drawings are, therefore, to be regarded in an illustrative rather than a restrictive sense.
This application claims the priority to the U.S. Provisional Application Ser. No. 61/020,898, entitled “TARGETED THERAPEUTIC AGENT RELEASE FOR WEIGHT LOSS THERAPY” filed Jan. 14, 2008. The specification of the above-identified application is incorporated herewith by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61020898 | Jan 2008 | US |
