EP1627039A2 - Dispositif gastro-intestinal ingerable - Google Patents

Dispositif gastro-intestinal ingerable

Info

Publication number
EP1627039A2
EP1627039A2 EP04725140A EP04725140A EP1627039A2 EP 1627039 A2 EP1627039 A2 EP 1627039A2 EP 04725140 A EP04725140 A EP 04725140A EP 04725140 A EP04725140 A EP 04725140A EP 1627039 A2 EP1627039 A2 EP 1627039A2
Authority
EP
European Patent Office
Prior art keywords
constituent
interest
sink
sink material
catalyst
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04725140A
Other languages
German (de)
English (en)
Other versions
EP1627039A4 (fr
Inventor
Mark M. Levy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/422,091 external-priority patent/US7611480B2/en
Application filed by Individual filed Critical Individual
Publication of EP1627039A2 publication Critical patent/EP1627039A2/fr
Publication of EP1627039A4 publication Critical patent/EP1627039A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1678—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes intracorporal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/0014—Special media to be introduced, removed or treated removed from the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/0057—Special media to be introduced, removed or treated retained by adsorption
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/0064—Special media to be introduced, removed or treated changed by biological action
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0413—Blood
    • A61M2202/0445—Proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/20—Pathogenic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/10—Trunk
    • A61M2210/1042—Alimentary tract

Definitions

  • the present invention relates to an ingestible device capable of eliminating via removal or conversion, either constructive or destructive conversion, undesirable substances from the body.
  • dialysis is used to remove soluble waste and solvent from blood
  • hemofiltration is used to remove plasma water from blood
  • hemodiafiltration is used to remove both unwanted solute (soluble waste) and plasma water from blood.
  • metabolic toxins such as mercaptans, free fatty acids, and conjugated bilirubin and endotoxins are completely bound with proteins in the bloodstream.
  • Hemoperfusion is a blood purification method that works in conjunction with activated carbon or iron exchange resins that absorb materials including the protein-bound toxins.
  • Phosphate agents can be administered orally and used as therapeutic agents, which are intended to prevent the reabsorption of food phosphates in the gastrointestinal tract.
  • peritoneal dialysis Another treatment procedure that has been used is peritoneal dialysis, wherein a sterile saline solution is injected into the peritoneal cavity and remains there for a period of time.
  • the saline solution is separated from the bloodstream by the peritoneum, which is a membrane that is semi-permeable selectively allowing only waste products to diffuse into the saline solution which is then drained out.
  • osmosis of water through the peritoneum into the saline solution allows the removal of water, excess to overall body needs.
  • This procedure is semi- invasive and carries the risk of infection. Also, such a procedure is not suitable for the removal of a variety of substances, and may not be suitable for all patients.
  • a disadvantage of various of the above-mentioned treatments is that the biological fluids of the patient have to be transferred from the body, circulated through an exterior treating device, and then returning the biological fluids back to the patient.
  • These treatments are typically done in a medical setting such as a hospital, and require the patient to travel to and from the hospital where the procedure is performed. This process can be time-consuming and disruptive to the normal activity of the daily life of the patient.
  • the wall is known to surround a compartment that contains the agent and a passageway through the wall for dispensing the agent.
  • the intestines are recipient of normal local secretions (from the intestine wall) and secretions from exocrine glands of the stomach cells, pancreas and liver (through the bile). That includes hormones, electrolytes and glycoproteins (mucus).
  • efflux and exsorption are processes where the intestine wall secretes into the intestine lumen substances in a way inverted to the intestinal absorption mechanisms (e.g., passive diffusion, facilitated diffusion and specific transport systems), including large molecules and drugs.
  • energy- dependent membrane transporters pump drugs against their concentration gradient out of the cell and back into the intestinal lumen; compared with kidney and liver, little is known about the mechanisms underlying transport into the intestinal lumen.
  • Collection of secreted or exsorpted molecules from the gut lumen can lead to reduction or elimination of their local effect on the gut wall.
  • reduction of their concentration or elimination thereof would inhibit cascades that lead to other events or eliminate digestion of certain molecules, thus leading to decrease of absorbable substances in the lumen.
  • These actions would aid in the elimination of toxic levels of substances (endogenous or exogenous), may alter the course of medical conditions or diseases, and may also be used to control levels of drugs which participate in the intestinal exorption process or avoid the absorption of certain nutrients enabling weight control or treatments of various disorders.
  • a major function of the intestine is to form a defensive barrier to prevent absorption of harmful substances from the external environment.
  • This protective function of the intestinal mucosa is effected through selective permeability.
  • Evidence indicates that permeability of the intestinal mucosa is increased in most patients with Crohn's disease and in 10% to 20% of their clinically healthy relatives. Permeability is also increased in celiac disease, leaky gut syndrome and in trauma, burns, and as a result of nonsteroidal anti-inflammatory drug treatment.
  • the major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space.
  • the tight junctions are narrow belts that circumferentially surround the upper part of the lateral surfaces of the adjacent epithelial cells to create fusion points or "kisses". They are involved in maintaining the cellular polarity and in the establishment of compositionally distinct fluid compartments in the body. Tight junctions are formed by many specific proteins and are connected with the cytoskeleton.
  • the intestinal tight junctions are highly dynamic areas and their permeability can change in response to both external and intracellular stimuli. In fact, the tight junctions play an important role in the regulation of the passive transepithelial movement of molecules.
  • a number of signalling molecules have been implicated in the regulation of tight junction function, including Ca “1””1” , protein kinase C, G proteins and phospholipase A2 and C.
  • changes in intestinal permeability are related to alteration of tight junctions as an expression of intestinal barrier damage.
  • permeability of the tight junctions can be modified by bacterial toxins, cytokines, hormones, drugs, trauma and burns.
  • Zonula occludens toxin derived from Vibrio cholerae interacts with a specific intestinal epithelial surface receptor, with subsequent activation of a complex intracellular cascade of events that regulate tight junction permeability.
  • Zonulin a novel human protein which is similar to the Vibrio cholerae derived Zonula occludens toxin, induces tight junction disassembly and subsequent increase in intestinal permeability in intestinal epithelia.
  • Zonulin likely plays a pivotal role in tight junction regulation during developmental, physiological, and pathological processes, including tissue morphogenesis, movement of fluid, macromolecules and leukocytes between the intestinal lumen and the interstitium, and inflammatory/autoimmune disorders.
  • Zonulin expression is elevated in intestinal tissues during the acute phase of Celiac disease, a clinical condition in which tight junctions are opened and permeability is increased.
  • Enteric infections have been implicated in the pathogenesis of both food intolerance and autoimmune diseases secondary to the impairment of the intestinal barrier.
  • Small intestines exposed to either pathogenic or nonpathogenic enteric bacteria secrete zonulin.
  • Such secretion is independent of intestinal origin (species) or the virulence of the microorganisms tested; secretion occurrs only on the luminal side of the small-intestinal mucosa, and is followed by a decrease in small-intestinal tissue resistance (transepithelial electrical resistance) which is secondary to the zonulin- induced tight junction disassembly evident from the disengagement of the zonula occludens 1 protein from the tight junctional complex.
  • This zonulin-driven opening of the paracellular pathway may represent a defensive mechanism, which flushes out microorganisms and contributes to the host response against bacterial colonization of the small intestine.
  • Modulation of intestinal permeability constitute an innovative method of oral drug delivery by enhancing paracellular permeability while modulating epithelial tight junctions.
  • Zonula occludens toxin and human Zonulin are considered candidates for such use.
  • Sodium salts of medium-chain fatty acids, sodium caprate (a dairy product constituent) in particular, have been used as absorption-enhancing agents to promote transmucosal drug absorption.
  • Superporous hydrogel (SPH) and SPH composite (SPHC) also may be used as peptide drug permeation enhancers.
  • Melittin is the major active ingredient in bee venom and has been widely studied for its membrane-fusion property and has been considered as a novel absorption enhancer.
  • Chitosans other absorption enhancing agents, interact with the cell membrane resulting in a structural reorganization of tight junction-associated proteins which is followed by enhanced transport through the paracellular pathway; the binding and absorption enhancing effects of chitosans on epithelial cells are mediated through their positive charges.
  • exsorption of blood molecules can also be enhanced when using such agents in conjunction with an element that selectively could bind the undesired molecules for further excretion. Also removal of excessive zonulin produced inside the intestine lumen may alter the disease course in many conditions by restoring its defensive barrier function.
  • non-absorbed polymers are designed to operate in the gastrointestinal tract and selectively bind specific target molecules. These polymers are orally administered in capsule or tablet form, pass through the stomach and into the intestines where targeted molecules bind with the polymer, pass through the intestinal tract, and are excreted from the body.
  • the neutral intracellular pH causes the compounds to ionize.
  • the accumulation of the resulting ions in the cell is believed to interfere with other intracellular stabilizing mechanisms thereby enhancing the possibility of damage.
  • these agents can produce deep clinically significant ulcers.
  • bacteria, toxins and allergens normally prevented from penetrating the gastrointestinal system can permeate into the bloodstream, where they are carried into all parts of the body, both triggering and exacerbating symptoms. Also bowel habits may be disturbed producing constipation.
  • the gain from using such agents is smaller than the damage caused thereby.
  • an ingestible device comprising: (a) a sink mechanism for generating an net influx of at least one constituent-of-interest present in a gastrointestinal tract of an individual; and (b) a confining mechanism for confining the sink mechanism in a predetermined confinement, hence directing the net influx is into the confinement.
  • the converting the at least one constituent-of-interest comprises an anabolic process. According to still further features in the described preferred embodiments the converting the at least one constituent-of-interest comprises a catabolic process.
  • the device further comprises a substance participating in the anabolic process.
  • the device further comprises a selective membrane for allowing a preferred influx of the at least one constituent-of-interest.
  • the device further comprises a power source.
  • the device further comprises a selective membrane for allowing preferred influx of the at least one constituent-of-interest.
  • the device further comprises a mixing mechanism for actively mixing a content of the predetermined confinement and/or the surroundings of the device.
  • the mixing mechanism comprises a heating device.
  • the mixing mechanism comprises a mechanical mixer and a power source for operating the mixer.
  • the mixing mechanism comprises a sound wave generator.
  • the device further comprises a flow generating mechanism for actively generating a flow of gastrointestinal fluids through the predetermined confinement.
  • the flow generating device is a pump.
  • the confining mechanism comprises a housing.
  • the housing is designed and constructed so as to prevent damage to the sink mechanism by constituents of the gastrointestinal tract.
  • the housing is designed and constructed so as to prevent damage to the gastrointestinal tract by the sink mechanism.
  • the device further comprises a substance for maintaining a predetermined pH level within the predetermined confinement.
  • the device is made detectable by at least one detection method for detecting the device in the gastrointestinal tract.
  • the device further comprises a protective cover made of a biodegradable material, the protective cover being design and constructed to degrade only when arriving to a predetermined location of the gastrointestinal tract.
  • a method of removing or converting at least one constituent-of-interest present in a gastrointestinal tract of an individual comprising providing the ingestible device of claim 1, and prompting ingestion of the ingestible device, thereby removing or converting the at least one constituent-of-interest.
  • a method of removing or converting at least one constituent-of-interest present in a gastrointestinal tract of an individual comprising (a) generating net influx of the at least one constituent-of-interest, using a sink mechanism; and (b) confining the sink mechanism and the at least one constituent-of-interest in a predetermined confinement; thereby removing or converting the at least one constituent-of-interest.
  • the net influx generated by the sink mechanism is substantially higher than a net influx generated by a concentration difference of the at least one constituent-of-interest devoid of the sink mechanism, the concentration difference being the difference between concentrations of the. at least one constituent-of-interest in and out of the predetermined confinement.
  • the method further comprises accelerating an anabolic process of the constituent-of- interest in the predetermined confinement.
  • the method further comprises providing a substance for participating in the anabolic process.
  • the method further comprises accelerating a catabolic process of the constituent-of-interest in the predetermined confinement.
  • the method further comprises oxidizing or reducing the at least one constituent-of-interest using an oxidation-reduction system. According to still further features in the described preferred embodiments the method further comprises using a selective membrane for allowing a preferred influx of the at least one constituent-of-interest. According to still further features in the described preferred embodiments the method further comprises actively mixing a content of the predetermined confinement and/or the surroundings of the device.
  • the method further comprises maintaining a predetermined pH level within the predetermined confinement.
  • the method further comprises detecting the device in the gastrointestinal tract by at least one detection method.
  • the at least one detection method is non-invasive.
  • the at least one detection method is imaging.
  • the at least one detection method is selected from the group consisting of x-ray imaging, magnetic resonance imaging, ultrasound imaging, gamma-gamma imaging and automatic tracking.
  • the sink mechanism is selected from the group consisting of a sink material and a sink device.
  • the sink material is for absorbing the at least one constituent-of-interest.
  • the sink material is for converting the at least one constituent-of-interest. According to still further features in the described preferred embodiments the sink material comprises an oxidant for oxidizing the constituent-of-interest.
  • the sink device comprises a reductant for reducing the constituent-of-interest.
  • the sink device is for converting the at least one constituent-of-interest.
  • the conversion of the at least one constituent-of-interest is selected from the group consisting of chemical conversion, mechanical conversion and electrical conversion of the at least one constituent-of-interest.
  • the confining mechanism comprises linkers linking among molecules of the sink material, thereby forming a molecular mesh structure.
  • the sink device comprises an oxidation-reduction system.
  • the generating the net influx is by absorbing the at least one constituent-of-interest.
  • the sink material is selected from the group consisting of a high affinity sink material, a low affinity sink material and a combination of a high affinity sink material and a low affinity sink material.
  • the high affinity sink material is selected from the group consisting of an antibody, whereby the constituent-of-interest is an antigen, a receptor whereby the constituent- of-interest is a ligand, a ligand whereby the constituent-of-interest is a receptor, an enzyme whereby the constituent-of-interest is an inhibitor, an inhibitor whereby the constituent-of-interest is an enzyme and a lectin whereby the constituent-of-interest is a saccharide.
  • the low affinity sink material is selected from the group consisting of a nutritional fiber, a clay and a resin.
  • At least a portion of the sink material is attached to a solid phase.
  • the sink material is water soluble.
  • the sink material is water non-soluble. According to still further features in the described preferred embodiments the sink material comprises beads.
  • the sink material comprises a polymer. According to still further features in the described preferred embodiments the sink material comprises an inert solid phase to which affinity sink molecules are attached.
  • the converting the at least one constituent-of-interest is by an anabolic process.
  • the converting the at least one constituent-of-interest comprises is by a catabolic process.
  • the sink material is a catalyst.
  • the catalyst is water soluble.
  • the catalyst is attached to a solid phase.
  • the catalyst is an anabolic catalyst for accelerating an anabolic process of the constituent- of-interest in the predetermined confinement.
  • the catalyst is a catabolic catalyst for accelerating a catabolic process of the constituent-of- interest in the predetermined confinement.
  • the catabolic catalyst is selected from the group consisting of an esterase, a peptidase, a lipase, a saccharidase, a DNAse and an RNAse.
  • the anabolic process involves at least two constituents of the gastrointestinal tract.
  • the accelerating the catabolic process catalyst is by a catabolic catalyst selected from the group consisting of an esterase, a peptidase, a lipase, a saccharidase, a DNAse and an RNAse.
  • the catalyst is selected from the group consisting of an enzyme and a chemical catalyst.
  • the sink material is a living organism.
  • the living organism is selected from the group consisting of a bacterium, a unicellular parasite, a multicellular parasite and a fungus.
  • the fungus is a yeast.
  • the sink device is an electrical sink device.
  • the oxidation-reduction system comprises electrodes and a power source.
  • the mixing is by a heating device.
  • the mixing is by a mechanical mixer and a power source for operating the mixer.
  • the mixing is by a sound wave generator.
  • the method further comprises actively generating a flow of gastrointestinal fluids through the predetermined confinement.
  • the generating flow is by a pump.
  • the confining is by a housing.
  • the housing is composed of a bioresistant material.
  • the confining is by linkers linking among molecules of the sink material, thereby forming a molecular mesh structure.
  • the housing is configured for expanding and/or contracting.
  • the at least one constituent-of-interest is selected from the group consisting of a toxin, creatinine, uric acid, a hepatic toxic metabolite, alcohol, an alcohol metabolite, an electrolyte, a therapeutic or a medicinal agent, a detergent, a renal metabolite, a poisonous substance, a nutritional substance, a biochemical compound and a heavy metal.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing a device which can be used for removing or converting a wide range of substances from Gl fluid or blood circulation surrounding the Gl tract.
  • FIG. la is a schematic cross-sectional view of an ingestible device having a sink mechanism according to a preferred embodiment of the present invention
  • FIG. lb is a schematic cross-sectional view of a sink device, according to a preferred embodiment of the present invention
  • FIGs. 2a-c are schematic illustrations of a sink mechanism, according to a preferred embodiment of the present invention
  • FIG. 3 is a schematic cross-sectional view of an alternative embodiment of the device of Figure la illustrating a housing according to a preferred embodiment of the present invention
  • FIG. 4 is a schematic cross-sectional view of an alternative embodiment of the device of Figure la, in which the housing is made expandable, according to a preferred embodiment of the present invention
  • FIG. 5 is a schematic cross-sectional view of an embodiment illustrating use of a pump or motor facilitating the active transmission of fluids through the ingestible device of the present invention
  • FIG. 6 is a schematic cross-sectional view of an alternative embodiment of the device of Figure la, which comprises multiple compartments, according to a preferred embodiment of the present invention
  • FIG. 7 is a flowchart of a method of using an ingestible device, according to a preferred embodiment of the present invention.
  • FIG. 8 is a flowchart of a method of removing or converting at least one constituent-of-interest present in a gastrointestinal tract of an individual, according to a preferred embodiment of the present invention.
  • the present invention is of an ingestible device which can be utilized to eliminate via removal and/or conversion, either constructive, e.g., anabolic, or destructive, e.g., catabolic, unwanted substances from gastrointestinal fluids and/or blood circulation surrounding the gastrointestinal tract.
  • the present invention can be used to treat individuals having gastrointestinal tract disorders caused by, for example, toxins or other molecules and individuals suffering from other ailments by (i) removing such molecules from the gastrointestinal fluids and/or the blood circulation surrounding the gastrointestinal tract; or (ii) converting such molecules into non-toxic substances.
  • the gastrointestinal (Gl) or digestive tract is the system of organs within animals which ingests, digests, and egests food, and in the process, extracts energy and nutrients.
  • the gastrointestinal tract is also a site to numerous disorders and pathologies which affect the normal functioning of this group of organs and other organs in the body.
  • an optimally functioning gastrointestinal tract is vital for the well being and long term health of both humans and animals.
  • numerous medicaments and various treatment regimens are targeted at pathologies and disorders of the gastrointestinal tract, few examples of agents which are capable of efficiently facilitating removal or conversion of gastrointestinal constituents which participate in, or result from, such pathologies and disorders exist in the art.
  • an ingestible device which can be utilized to remove or convert at least one constituent- of-interest present in the Gl tract, referred to herein as device 10.
  • device 10 the term "constituent-of-interest" when used in context with gastrointestinal tract refers to a material present in gastrointestinal fluids or in the blood circulating around the gastrointestinal tract (e.g., within the mucosal layer of intestines). Such constituents may be a small molecule, a macromolecule or a pathogenic organism.
  • the filter 10 is designed for removing or converting any one of various substances from the blood circulating around the gastrointestinal tract and the fluids present within the gastrointestinal tract.
  • the rich vascular network and length of the gastrointestinal tract provides device 10 with a long dwell time and thus efficient contact between device 10 and the gastrointestinal content as well as the capillary-rich bowel mucosa.
  • the removal of blood or gastrointestinal fluid constituents substantially produces the inverse effect of physiological gastrointestinal absorption.
  • device 10 may remove or convert any undesirable constituent present in the gasfrointestinal fluid or the blood circulating around the gastrointestinal tract.
  • undesirable constituent include, without limitation, creatinine, urea, uric acid, hepatic toxic metabolites, unwanted electrolytes, toxins, heavy metals, alcohol, alcohol metabolites, drugs, glucose, fats and any food breakdown products or ingredients which may be irritating to specific individuals (e.g., lactose, gluten or gliadin).
  • device 10 may be used for many purposes, alternatively or in combination.
  • device 10 facilitates the binding of substances which result from the breakdown of ingested foodstuff consumed in excess, including, without limiting alcohol, sugars and fats.
  • device 10 serves as a diet supplement which can be ingested prior to, during or shortly after eating.
  • device 10 may be used for treating diseases or disorders (e.g., gastrointestinal disorders) by removing constituent-of-interest from the gastrointestinal fluid or blood of mucosal capillaries. Removal of such blood constituents can be utilized to treat hepatic or renal insufficiency or other problems associated with high concentration of certain materials in the body, such as diabetes, high bilirubin, etc.
  • diseases or disorders e.g., gastrointestinal disorders
  • removal of such blood constituents can be utilized to treat hepatic or renal insufficiency or other problems associated with high concentration of certain materials in the body, such as diabetes, high bilirubin, etc.
  • device 10 may be used to avoid possible undesired or over-absorption of substances which are present in food.
  • device 10 can also be used to prevent certain materials from entering the bloodstream through this network, effectively providing a dialysis-type function.
  • the ingestion of a plurality of devices like device 10 can be used to substantially reduce the blood concentration of an undesirable substance, such as glucose, urea, uric acid, ions and the like without dialysis and/or in a short amount of time as compared to other treatment procedures.
  • an undesirable substance such as glucose, urea, uric acid, ions and the like
  • retention enemas using Kayexalate resin is used to lower potassium levels within the body.
  • Kayexalate a form of sodium polystyrene sulfanate, is a cation-exchange resin prepared in the sodium phase, and lowers serum potassium within the blood.
  • the treatment of such a condition may utilize one or more of the devices of the present invention configured capable of continuous removing potassium from the body in an effective and efficient manner.
  • the device of the present invention can be used to remove the toxin and/or convert the toxin into a non-toxic, innocuous substance.
  • the removal or conversion via constructive or destructive pathways of a variety of substances from body fluids within the gastrointestinal tract using one or more devices like device 10 may provide an alternative to conventional treatments for a variety of conditions.
  • Figure la is a schematic illustration of device 10, which, in its simplest form, comprises a sink mechanism 14, capable of generating net influx of constituent-of-interest 15, and a confining mechanism 11 for confining sink mechanism 14 in a predetermined confinement 12.
  • confining mechanism 11 and confinement 12 are designed and configured so as to facilitate collection and/or conversion of constituent-of-interest 15, hence elimination thereof from the gastrointestinal tract.
  • device 10 of the present invention can be used to systemically eliminate substances such as urea from the body.
  • the term "sink mechanism” refers to any molecule, compound, substance, aggregate of substances or device capable of absorbing and/or of converting the constituent-of-interest, so as to act as a functional sink in inducing a flux of the constituent-of-interest towards the sink mechanism.
  • sink is frequently used in the art of life sciences to describe models explaining directional gradients, wherein the direction of the gradient is said to be between a source and a sink.
  • the source of the constituent-of-interest is the body, the gastrointestinal track in particular, whereby the sink is device 10, having therein sink mechanism 14.
  • a particular feature of the present invention is the source-sink relation between device 10 and the body, the gastrointestinal fluid in particular, which is preferably characterized by continues net influx of the constituent-of-interest from the source (e.g., the gastrointestinal fluids) to the sink (i.e., device 10 containing sink mechanism 14).
  • the source e.g., the gastrointestinal fluids
  • the sink i.e., device 10 containing sink mechanism 14
  • thermodynamics an important principle in thermodynamics is the tendency of a system to exfremize various thermodynamic functions, which are expressed in terms of the thermal variables of a system, and are often related to one another via a simple Legendre transformation.
  • a variation in the particle number is conjugated to a thermodynamic quantity, called chemical potential.
  • the chemical potential is related to the change in a particular thermodynamic function (e.g., entropy, free energy, etc.).
  • entropy free energy, etc.
  • the net influx from the source to the sink is determined by the ability of the sink to dynamically change the chemical potential of its immediate surrounding, hence to maintain a net flux from the source or reservoir to the sink, which is substantially higher than the net flux that would have been generated had the sink been absent.
  • the sink is a mechanism, which continuously reduces the concentration of a certain type of molecule in its immediate surrounding, continuously keeps a sufficient concentration difference between the source or reservoir and the sink.
  • Such sink may be, for example, a solid phase with a large number of binding sites to which molecules of type A can bound, so that A transforms from its liquid state in S 2 to a solid state on the structure.
  • the concentration difference, D can be a non-decreasing function, so that FA is maintained as long as there are vacant binding sites on the structure. More generally, FA is maintained as long as the sink is operative.
  • the sink mechanism generates conditions for a significantly higher influx compared to the first example, where there is no sink. As a result, the total net number of A molecules entering S 2 , is increased.
  • the net influx generated by sink mechanism 14 is substantially higher than a net influx generated by concentration difference devoid of sink mechanism 14 as further detailed hereinabove.
  • sink mechanism 14 can mask or convert its charge, hence allowing the net influx to continue.
  • sink mechanism 14 may be either a material or a device.
  • Sink mechanism 14 can also be in the form of a plurality of sink materials and/or devices, each designed or selected to absorb or convert a particular constituent- of-interest. This embodiment is particularly useful when there is more than one type of constituent-of-interest to be eliminated from the body, or when it is desired to employ several conversion processes (either in a parallel or in a serial fashion).
  • the number of sink materials and/or devices which are included in sink mechanism 14 is not limited.
  • the different sink materials and/or devices may also be confined in different compartments of confinement 12, so as to avoid undesired. interactions between the different sink materials, devices constituents and/or converted products derived therefrom.
  • a multi compartment device is further described hereinafter with reference to Figure 6.
  • sink mechanism 14 is a sink material
  • the material may be either water soluble or water non-soluble, and it is selected so as to absorb via high or low affinity binding and/or chemically or enzymatically convert constituent 15.
  • An absorbing sink material preferably has an affinity and specificity to constituent 15, which affinity and specificity can be low affinity and specificity or high affinity and specificity.
  • Sink mechanism 14 may also be a combination of one or more sink materials of which some have high affinity and some low affinity to constituent 15.
  • the type of sink material depends on the type of constituent-of- interest to be eliminated from the body.
  • Many pairs of substances are known to have high mutual affinity.
  • antibodies are known to have high affinity to antigens.
  • the constituent-of-interest is an antigen and the sink material is its specific antibody.
  • More representative examples of pairs of substances with high affinity include without limitation, receptor-ligand, enzyme-inhibitor or enzyme-substrate and lectin- saccharide or polysaccaride.
  • the other member of the pair may be used as a sink material in accordance with the present invention.
  • low affinity sink materials include without limitation, nutritional fibers for expelling fats and various resins for expelling positive or negative ions.
  • a sink mechanism 14 in the embodiments in which a sink material (e.g., a polymer) is employed.
  • a sink material e.g., a polymer
  • FIG. 2a-c provides schematic illustrations of sink mechanism 14, according to preferred embodiments of the present invention.
  • Figure 2a shows one embodiment, in which the sink material comprises a plurality of beads 21 having an affinity moiety 23, having affinity to constituent 15, bound or inherent thereto, thereby capable of selectively binding constituent 15.
  • Figures 2b-c show another embodiment, in which the sink material comprises a molecule 25 capable of absorbing constituent 15.
  • the sink material may include submicroscopic size moieties (for example, an antibody or a receptor).
  • the sink material further comprises an inert solid phase 27 to which the moieties are attached, so as to facilitate accumulation of the sink material within device 10.
  • Suitable chemical linkers can be used to covalently attach the moieties to the solid phase.
  • submicroscopic size moieties can serve as a sink material according to the present invention also when in solution.
  • the sink material is macroscopic in nature and is a solid phase in itself, such as in the case of ion exchange resins.
  • sink mechanism According to a preferred embodiment of the present invention, sink mechanism
  • confining mechanism 11 is solid phase 27 to which the sink material is attached. In another embodiment, confining mechanism 11 comprises linkers 31 linking molecules
  • confining mechanism 11 comprises a chamber including a membrane so selected and constructed so as to confine sink material 14 therein.
  • the sink material can generate a net influx into confinement 12 by converting constituent 15. Such conversion may be constructive, e.g., catabolic, or destructive, e.g., anabolic.
  • the sink material may be a catalyst, such as an enzyme or a chemical catalyst, which accelerate a chemical reaction converting the constituent-of-interest.
  • the catalyst is preferably water soluble or bound to a solid phase, so as to optimize its interaction with constituent 15.
  • the sink material may convert constituent 15 either by an anabolic process or by a catabolic process.
  • the sink material accelerate a process in which new molecules are synthesized from constituent 15 or a portion thereof, preferably so as to form larger molecules (e.g., conjugates or polymers).
  • larger molecules e.g., conjugates or polymers.
  • confining mechanism 11 is preferably a housing, which may be partially or fully constructed of a porous material, designed to allow passage-in of certain fluidic constituents, so as to act as a membrane or a unilateral membrane in accordance with the invention.
  • membrane refers to a structure which allows the passage of predetermined fluidic constituents, while preventing the transmission of other constituents therethrough.
  • unilateral membrane refers to a structure which allows net influx but prevents efflux of predetermined fluidic constituents.
  • the synthesized molecule is not or less harmful to the organism or may not be able to be absorbed and hence can be allowed to subsequently diffuse out of device 10.
  • constituent 15 may be a toxic material which is first converted by device 10 to a non-toxic material and thereafter returns to the body of the subject.
  • the anabolic process involves two or more constituents-of-interest of the gastrointestinal tract.
  • one constituent is not harmful to the gastrointestinal tract, but yet can be sacrificed to participate in a synthesis with the harmful constituent-of-interest.
  • the anabolic process involves one constituent-of-interest of the gastrointestinal tract and an additional substance, present in confinement 12 for the purpose of participating in the anabolic process.
  • the sink material degrades constituent 15 to provide one or more remnants 15a.
  • This embodiment may be useful, for example, when constituent 15 may be degraded into non-toxic remnants.
  • non-toxic remnants may be allowed to diffuse out of device 10 into the gastrointestinal fluids.
  • Representative examples of sink material useable in context of this embodiment of the present invention include, without limitation an esterase, a peptidase, a lipase, a lactase, a diastase, a pancreatinase, a saccharidase, a DNAse and an RNAse, each of which can be in a disolved state of bound to a solid phase.
  • the utilization of enzyme immobilization technology like with calcium alginate beads or other techniques broadens the spectrum of applications.
  • Another type of conversion of the constituent-of-interest is by oxidation-reduction.
  • the sink material comprises a molecule that donates electrons (reductant)
  • the conversion of the constituent-of-interest is by reduction.
  • examples of undesired materials which can be converted by reduction include cooper, lithium, sodium , potasium .
  • the sink material comprises molecule that accepts electrons (oxidants)
  • the conversion of the constituent-of-interest is by oxidation.
  • Examples of undesired Gl constituents which can be converted via oxidation include ammonia, alcohol, glucose, iron, sulfur, fluoride, creatinine. Conversion by an oxidation-reduction reaction can also be accomplished by a sink device, as is further detailed hereinunder.
  • device 10 further comprises a selective membrane for allowing or facilitating a preferred influx of the constituent-of-interest.
  • a selective membrane for allowing or facilitating a preferred influx of the constituent-of-interest.
  • Conversion of the constituent-of-interest can also be accomplished by living organisms, such as- but not limited to, bacteria, parasites (unicellular or multicellular) and fungi (e.g., yeasts).
  • living organisms such as- but not limited to, bacteria, parasites (unicellular or multicellular) and fungi (e.g., yeasts).
  • bacteria like lactobacillus, acidophilus consume waste by producing enzymes.
  • enzymes can convert the constituent-of-interest, as further detailed hereinabove.
  • a selective membrane may be used to specify the constituent(s) which is to be converted.
  • any of the above examples can generate a sufficient net influx of constituent 15 into confinement 12 and preferably to generate condensation of constituent 15 therein. It is to be understood, that although there is a continuous net influx of constituent 15 into confinement 12, the scope of the present invention also include situations in which the net influx is eventually terminated, e.g., when all the binding sites are occupied, and there is no more taming of the concentration growth in confinement 12. Even in such cases, it is appreciated that the total net amount of constituent-of-interest entering confinement 12 is substantially larger than that of device which do not include sink mechanism 14. As stated above, sink mechanism 14 may also be embodied as a sink device.
  • sink mechanism 14 may comprise a power source 29 and electrodes 16 for generating an electric current through the device (hence through constituent-of-interest 15), so as to generate a oxidation-reduction reaction in which constituent 15 is transformed into a non-toxic substance.
  • Power source 29 may also be powered by RF, induction, magnetic or ultrasonic source provided from outside the body and/or controlled by wireless communication using, for example, suitable short distance wireless communication, such as, but not limited to, Bluetooth technology or the wireless communication implemented in the Givenlmaging peal.
  • device 10 may further comprise a heating mechanism 52 which may be used for generating heat is confinement 12 and/or the surroundings of device 10.
  • Heating mechanism 52 can be utilized to facilitate or catalyze removal of the gastrointestinal constituent.
  • heating mechanism 52 can be used to generate heat which can denature proteinaceous compounds diffusing into confinement 12 through a selective membrane as described hereinabove.
  • the heating is also useful, for example, for dilation of blood vessels deeper than mucosal blood vessels (to generate subsequent hyperemia), or for regulating bowel motility or secretion from internal glands (of the mucosa or even pancreatic endocrine secretions).
  • a miniaturized power source which generates an electrical current within device 10 may be sufficient for heating any of its components, the heating can also be a result of an exothermic chemical reaction.
  • a mixture of magnesium iron alloy and sodium chloride with water generates heat and produces magnesium hydroxide as an end product, while calcium oxide or quicklime produces heat by reacting with water.
  • polymerization of methyl methacrylate, plastic monomers or polyurethane cqan also be utilized to generate heat since such reactions are exothermic.
  • Local heat induction on the surface of the device (used alone or in combination with other features) can also be used for accelerating enzymatic reactions and for treatment of hypothermia.
  • device 10 may further comprise a mixing mechanism 54 for actively mixing a content of confinement 12 and/or the surroundings of the device.
  • a mixing mechanism 54 for actively mixing a content of confinement 12 and/or the surroundings of the device.
  • Any mixing mechanism known in the art may be used, such as, but not limited to, a mechanical mixer, a sound wave generator and a heating device, which induces turbulences within confinement 12 or at the periphery and surroundings of device 10.
  • FIG. 3-4 is a schematic illustration of device 10 in which confinement mechanism 11 comprise a housing 33, according to a preferred embodiment of the present invention.
  • device 10 may have a capsule-like shape, as shown, or may have any other shape as desired.
  • Housing 33 may be constructed of a material which is permeable or semi-permeable to bodily fluid, allowing selective entry of constituent 15 into confinement 12 and, at the same time, shielding from various materials which can disrupt or compete for the function of the sink mechanism within device 10, thus facilitating and enhancing the efficiency thereof.
  • device 10 or some of its internal components
  • a protective cover 19 of a degradable substance such as similar to an oral medication capsule that is composed of, for example, gelatin, glycerin, egg shell, starch, edible oil, fat or vegetable oil, water soluble fiber or a mixture of these materials.
  • Cover 19 can assure the stability of the material when inserted inside device 10. Once device 10 is ingested, the cover 19 is degraded, thus liberating sink mechanism 14 to interact with the contents of device 10.
  • cover 19 allows the device of the present invention to carry components which would otherwise be damaged by the harsh conditions, e.g., pH, present in predetermined regions of the gastrointestinal fract, such as the stomach, directing its main action into the small intestine below it.
  • the device can be coated with substances that may induce more mucosal permeability like zonulin or other permeation enhancers for more availability of some drugs or bigger molecules (not otherwise passively secreted into the lumen) for its further removal by the sink mechanism.
  • a permeation enhancer such as zonulin, can be co- administered with the device of the invention.
  • FIG 3 also shows a selective membrane 18, which, as stated, is preferably used for preventing constituents other that constituent 15 to enter confinement 12.
  • membrane 18 externally encapsulates housing 33, other configuration (e.g., internal membrane) are not excluded from the scope of the present invention.
  • sink mechanism 14 may be linked to a molecule to which the membrane is impermeable, so as to prevent mechanism 14 from escaping device 10.
  • the membrane hence also serves at least in part as confining mechanism 11.
  • the membrane can confine the sink material that otherwise could be irritant to the intestine mucosa, avoiding complication, but allowing its action over the constituents.
  • Membrane 18 may also be unilateral membrane to allow net influx of the constituents but prevent efflux thereof. Membrane 18 is preferably able to withstand all physiological temperatures or pH and may have a variable range of porosity. Suitable membranes include dialysis membranes that are typically used in chemistry for separation of substances on suspensions, solutions, columns, tissue cultures, etc. These membranes can be produced from various materials including regenerated cellulose, a mixture of chemically pure cellulosic esters and a polyvinylidine fluoride, which is a flouropolymer, like TeflonTM, and is resistant to most organic solvents, as well as, corrosive aqueous solutions. These membranes can also be chosen based on their chemical compatibility such that the membranes are stable in various chemical environments.
  • membrane 18 is internal and freely moves throughout confinement 12 of device 10.
  • membrane 18 is secured to housing 33 so as to cover openings which may be formed around the periphery or ends of device 10 to allow passage of bodily fluids therethrough.
  • Membrane 18 may be similar to a bag containing a substance inside, or may be one or more pieces of membrane material.
  • Housing 33 may be hard or semi-flexible, and can be of fixed dimensions or may be selectively expandable in one or more directions. Forming housing 33 of a material so that it can expand to a predetermined desired degree within the gastrointestinal tract during use, has several advantages.
  • device 10 being designed to be ingested, is favorably compact when the ingestion of the device is prompted. Subsequently, device 10 may be expanded, so as to enlarge the contact area between device 10 and the gastrointestinal fluids, hence to increase the net influx and the device's efficiency. Second, an expandable device allows more of desired constituents to engage confinement 12 hence increases the number of constituents removed from the body.
  • conversion mechanism 16 comprise bacteria (or any other mechanism which experience reproduction or multiplication)
  • housing 33 may be formed from a series of sections formed into a telescoping mechanism, which allows selective expansion of the housing.
  • housing sections 33a and 33c are telescopically engaged with a central section 33b.
  • sections 11a and lie are preferably moveable longitudinally relative to section 33b, for selective expansion of the housing 33.
  • sections 33a and 33c may be interconnected by a central section 33b formed, e.g., in an accordion configuration.
  • housing 33 Additional structures to allow selective expansion of housing 33 are also contemplated, including folded flexible sections and the like.
  • housing 33 is designed and constructed so as to prevent damage to the contents of the device (e.g., sink mechanism 14) by constituents of the gastrointestinal tract other than constituent
  • device 10 may also comprise a buffering agent such as or a suitable ion exchanger which can effectively maintain the microenvironment around sink mechanism 14 at a suitable desired pH.
  • a buffering agent such as or a suitable ion exchanger which can effectively maintain the microenvironment around sink mechanism 14 at a suitable desired pH.
  • Housing 33 may also serve for preventing damage, such as chemical or physical irritation, to the gastrointestinal tract by sink mechanism 14.
  • housing 33 is bioresistant.
  • Materials that can be used to form housing 33 of device 10 include, but are not limited to, polyurethane, polystyrene, plastics, polymers, silicon or other synthetic material, new shape memory polymers and metallic materials including, without limiting, stainless steel and Nitinol, which is a shape memory alloy that may be programmed to expand inside the gastrointestinal tract due to a change in body temperature. While device 10 can have various conventional shapes and sizes, a typical size of housing 33 is about 11 millimeters in diameter and about 30 millimeters long.
  • Device 10 can also be sized to facilitate use with children, or otherwise as desired.
  • Housing 33 of such or other dimensions may be constructed, for example, from silicone-urethane co-polymers (e.g., PurSilTM) or a ceramic multilayer film.
  • the device can be fabricated using vacuum-forming techniques or injection molding, for further information, see, e.g., http://www.polymertech.com/device.html)
  • Suitable membranes to be used with device 10 include, without limiting,
  • a typical pore size of such membrane is about 1 00 Da.
  • the device of the present invention provides numerous benefits over the simple polymers designed for absorption of gastrointestinal fluid constituents described hereinabove.
  • Use of a selective and optionally unilateral membrane and an internal confinement enables trapping and thus removal of a wide range of substances.
  • the confinement of the device since the confinement of the device is effectively shielded from gastrointestinal fluids it enables removal rather than absorption of the constituents thus minimizing the exposure of the gastrointestinal tract to these constituents. Furthermore, the shielded cavity enables use of agents which would not otherwise function if exposed to the conditions present in the gastrointestinal tract. Finally, combined use of semi-permeable and optionally unilateral membranes and agents enables selective constituent-uptake and as a result reduces the likelihood that a function of the treatment agent is reduced or completely inhibited by gastrointestinal constituents other than the targeted constituent.
  • device 10 is made detectable by at least one detection method, preferably non-invasive detection method, such as, but not limited to, x-ray imaging, magnetic resonance imaging, ultrasound imaging, gamma-camera imaging and automatic path/positioning tracking. This may be done by positioning or attaching a detectable tag 37 to device 10.
  • detection method preferably non-invasive detection method, such as, but not limited to, x-ray imaging, magnetic resonance imaging, ultrasound imaging, gamma-camera imaging and automatic path/positioning tracking. This may be done by positioning or attaching a detectable tag 37 to device 10.
  • tag 37 may also be triggered by certain activity of device 10 within the gastrointestinal tract, such as by reactivity with predetermined constituents, an indication of treatment or treatment progress, or the like. Examples of technologies which can be utilized to track device 10 within the gasfrointestinal tract are provided in, for example, U.S. Pat. No. 5,170,801.
  • FIG. 5 A further embodiment of the invention is shown in Figure 5, which is directed to a device 20, capable of actively transmission of bodily fluids therethrough, e.g., using a flow generating mechanism 30.
  • Devise 20 preferably serve a function similar to the embodiments already described above.
  • Device 20 may include a housing 22, which may again be formed of a rigid or semi-flexible shell that can tolerate all physiological degrees of pH or temperature to be encountered within the gastrointestinal tract.
  • housing 22 may be configured to have an ingress opening 24 and an egress opening 26, which may be disposed on opposing ends of device 20 as shown, or in another suitable fashion for the ingress of bodily fluids into confinement 12 formed by housing 22.
  • flow generating mechanism 30 which may be, e.g., a pump or a motor, located relative to confinement 12 of device 20 actively transmits bodily fluids from one end of device 20 through opening 24 to the other end through opening 26.
  • the active transmission of bodily fluids with the assistance of transmission mechanism 30 through confinement 12 promotes flow of the bodily fluids to pass through device 20 hence encourages the net influx of the constituent-of-interests into confinement 12.
  • Mechanism 30 can be located on the periphery of shell 22 of device 20, as shown in Figure 5, or may be located internal to device 20 as shown at 30a. In this embodiment, mechanism 30 may also provide a force to propel, rotate or otherwise cause motion of device 20 inside the body to increase tangent and transverse flows of bodily fluids near device 20, hence to substantially increase the net influx of the constituent-of-interest into confinement 12. Alternate locations of mechanism 30 are near opening 24 to increase the flow into confinement 12 and/or opening 26 for the outward flow through device 20. Yet another embodiment of the device according to the invention is shown in
  • This device which is referred to herein as device 40 may have similar characteristics to any of the devices described hereinabove, but may comprise multiple compartments 44 which contain one or more types of sink mechanisms 14. Individual internal membranes 48 may be used with each compartment 44 or a single membrane may be used similarly to that described previously. Alternatively or additionally, degradable encapsulation 50 containing sink mechanisms 14 may be utilized, for releasing sink mechanisms 14 in a predetermined region of the gastrointestinal tract.
  • the device of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more units of the device of the present invention.
  • the pack may be accompanied by instructions for administration.
  • the pack may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or food supplements, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration.
  • Such notice for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or food supplements of an approved product insert.
  • the device can be used to deliver other physical means of treatment or concomitantly to other forms of treatment.
  • Radioactive isotopes that includes radioactive isotopes, cooling, magnetic or electromagnetic fields, electric currents, vibration movements, radio-frequency waves and others that may activate or induce activation of other compounds delivered to the body (through the gastrointestinal tract or any other delivery mode).
  • examples include, but are not limited to, bone marrow and blood radiation therapy or activation of anti-cancerous drugs, bowel CA, malignant hyperthermia, or stimulation which results from various forms of physical induction
  • Figure 7 illustrates, in flowchart format, a method of using ingestible device, such as, but not limited to, devices 10, 20 or 40 of the present invention, where in a first step of the method, the ingestible device is provided and in a second step an ingestion of the device is prompted.
  • ingestible device such as, but not limited to, devices 10, 20 or 40 of the present invention
  • the method comprises the following method steps which are illustrated in the flowchart of Figure 8.
  • a net influx of the constituent-of-interest is generated using a sink mechanism
  • the sink mechanism and the constituent-of-interest are confined in a predetermined confinement.
  • the first and the second steps are performed substantially contemporaneously.
  • the constituent-of-interest may be converted, e.g., using conversion mechanism as further detailed herein above.
  • Other optional method steps include detecting of the sink mechanism and heating the confinement and/or the surroundings of the device, as is further detailed hereinabove.
  • sink mechanisms It is expected that during the life of this patent many relevant sink mechanisms will be developed and the scope of the term sink mechanisms is intended to include all such new technologies a priori.
  • the devices and methods, according to preferred embodiments of the present invention operate within the gastrointestinal (Gl) and remove undesired highly concentrated intestinal or blood substances or metabolites, and hence such devices would be suitable for treating numerous disorders.
  • Gl gastrointestinal
  • the removal of various substances from gasfrointestinal fluids using one or more devices provides an alternative to conventional treatments.
  • effective removal of unwanted Gl substances is facilitated by a device-integrated sink mechanism, which is preferably designed capable of specifically removing one or more Gl substances.
  • the device of the present invention is used to treat poisoning.
  • the device is filled with suitable chelator including resins such as Lewatit resins or AMBERLITETM (Sybron Chemicals Inc. a Bayer Company).
  • Ion Exchange Resins Rosin and Haas
  • a toxic compound such as, but not limited to, lead, mercury, cadmium aluminum and arsenic
  • the device both separates the toxic compound from Gl fluids, by the aforementioned influx, as well as converts it to a less toxic state.
  • chelator agents that may be used in this embodiment include, without limitation, EDTA, Dimercaptol (BAL), DMSA, and D-penicillamine.
  • Natural materials such as, but not limited to, phytochelatines (vegetal heavy metal chelatoors), algae (e.g. alginate), vegetal fibers (e.g. Psyllium), clays, or other natural extracts alone or in combination, may also be used to absorb certain heavy metal ions.
  • Such a material is a composite biosorbent prepared by coating chitosan (obtained by deacetylation of chitin, extracted from the shells of shrimps, crabs, and other crustaceans, insects, and fungi) onto ceramic alumina.
  • chitosan obtained by deacetylation of chitin, extracted from the shells of shrimps, crabs, and other crustaceans, insects, and fungi
  • ceramic alumina is suitable for chelating lead, mercury, cadmium, chromium and nickel.
  • the device can be utilized to reduce excessive levels of compounds which are specifically associated with certain types of disorders.
  • the device preferably comprises an ion exchange resin or a chelator agent, which are useful for reducing high levels of ammonia associated with liver and renal failure, high levels of potassium associated with hyperkalemia, cooper which its presence is indicative for Wilson's disease and excess levels of iron characterizing hemochromatosis and hemosiderosis.
  • the device can be utilized to treat individuals having renovascular hypertension.
  • Renovascular hypertension is caused by narrowing of the arteries that carry blood to the kidneys. Renovascular hypertension is a form of secondary hypertension occurring in less than 5 % of all people with hypertension and characterized by narrowing of the renal artery leading to reduced blood flow to the kidney. Symptoms usually begin before age 30 or after age 50, depending on the cause of the damage to the kidney blood vessels. Stenosis is often related to atherosclerosis but may be caused by injury to the artery that causes scarring. Reduced blood flow to the kidney leads to an excessive release of the hormone renin, a potent hormone that increases blood pressure by activating the production of angiotensin II.
  • the device is designed for removing angiotensin II from gastrointestinal fluids.
  • the device can be used to reduce symptoms of renovascular hypertension due to reduced levels of angiotensin II in the gastrointestinal fluids.
  • the device of the present invention preferably comprise antibody molecules (polyclonal, monoclonal or antibody fragments, e.g., Fab, ScFv, etc.), capable of specifically binding angiotensin II.
  • antibody molecules can be introduced in more than one way.
  • the antibody molecules are attached to particles
  • the antibody molecules are attached directly or indirectly (via a linker) to the wall lining the housing of the device.
  • the antibody molecules are left soluble within the device.
  • the density of the antibody molecules is preferably selected so as to allow efficient trapping of angiotensin II molecules within the device while at the same time not substantially hindering diffusion of gastrointestinal fluids and small molecules through the device.
  • the device can also comprise ion exchange resins and buffers capable of maintaining the pH within the device at an optimum for binding (for additional information, see, e.g., http://www.rohmhaas.com/ionexchange/).
  • the antibody utilized by the device of the present invention can be generated according to the teachings of Dagenais and Escher (E. Regul Pept. 1993 Mar 19;44(2):239-47) or commercially purchased from IBL (Hamburg, Germany http://www.ibl-hamburg.com). Treatment or renal or prerenal failure:
  • Renal or prerenal failure is typically accompanied by existence of high levels of NH , urea and creatinine in the blood.
  • the removal of these materials by the devices and methods of the present invention may be an adequate substation to the need of dialysis.
  • the device of the present invention is preferably designed suitable for removing NH , urea and creatinine from gastrointestinal fluids.
  • the device of the present invention can include a conversion mechanism of ion exchange resin, capable of converting NH 3 to NEU by ionization.
  • the urea and the creatinine may be entrapped within the confinement of the device (e.g., using a unilateral membrane) to be removed from the body through peristaltic motion of the gastrointestinal tract.
  • Suitable sink mechanism for the designed device includes natural or synthetic Zeolites, Dowex resins produced by Dow Chemical or chitosan-coated dialdehyde cellulose (chitosan DAC) for generating net influx of NH 3 , urea and/or creatinine, respectively.
  • activated charcoal or other sorbents like AST- 120 porous spherical carbonaceous material
  • the device is designed for mobilizing enzymes to the gastrointestinal tract and thus can be utilized to treat individuals having certain enzymatic deficiencies such as lactase, sucrase, and maltase that degrade the corresponding disaccharides, lactose, sucrose, and maltose into their monosaccharide components.
  • the sink mechanism of the device can include the immobilized enzyme (e.g., lactase), capable of degrading the disaccharides (e.g., lactose) in the intestinal fract thus, avoiding its accumulation that may lead to diarrhea and abdominal distention.
  • the immobilized enzyme e.g., lactase
  • the disaccharides e.g., lactose
  • Appropriate pH conditions for the enzyme optimal activity in the device can be assured using appropriate buffers.
  • the device is designed for removing of Interleukin-6 (IL-6) and thus can be utilized to treat individuals having diseases associated with its presence in the intestines.
  • IL-6 Interleukin-6
  • IL-6 is thought to contribute to the pathogenesis of many diseases, including rheumatoid arthritis and inflammatory bowel disease. It is present in very high levels in both serum and intestinal tissue of patients with Crohn's disease. Other conditions such as multiple myeloma, and a malignant tumor of the bone marrow, are accompanied by its excess/presence.
  • the sink mechanism of the device can include immobilized IL-6 antibody molecules or bacteria genetically modified capable of synthesizing IL-6 antibodies.
  • the device is designed for removing Tumor Necrosis Factor (TNF ⁇ ) and thus can be utilized to treat individuals having diseases associated with its presence in the intestines.
  • TNF ⁇ Tumor Necrosis Factor
  • elevated levels in stool samples have been shown in patients with inflammatory bowel disease.
  • Other clinical conditions such as psoriasis, rheumatoid arthritis, and asthma are typically accompanied by excess/presence of TNF.
  • the sink mechanism of the device can include immobilized TNF ⁇ antibody molecules or bacteria genetically modified capable of synthesizing TNF ⁇ antibodies.
  • the device can also be designed for removing L-asparagine and thus can be utilized to treat individuals having Acute Lymphocytic Leukemia (ALL).
  • ALL Acute Lymphocytic Leukemia
  • ALL also known as acute lymphoid leukemia and acute lymphoblastic leukemia
  • ALL results from an acquired genetic injury to the DNA of a single cell in the bone marrow.
  • the effects of ALL are uncontrolled and exaggerated growth and accumulation of lymphoblasts, which fail to function as normal blood cells, and blockade of the production of normal marrow cells, leading to a deficiency of red cells, platelets and normal white cells in the blood.
  • the tumor cells of ALL patients are unable to synthesize the normally non-essential amino acid L-asparagine; therefore, they are forced to extract it from body fluids to survive.
  • the sink mechanism of the device can include immobilized L-asparagine antibody molecules or an enzyme capable of L-asparagine degradation such as asparaginase in order to reduce the free exogenous concentration of L-asparagine without affecting the function of normal cells.
  • Treatment of gout According to a preferred embodiment of the present invention the device is designed for oxidizing urate and thus can be utilized to treat individuals having gout disease.
  • Gout is a painful rheumatic disease, resulting from deposits of needle-like crystals of uric acid in connective tissue, and / or in the joint space between two bones. These deposits lead to inflammatory arthritis, which causes swelling, redness, heat, pain, and stiffness in the joints. Gout accounts for approximately 5% of all cases of arthritis.
  • Uric acid is a substance that results from the breakdown of purines, which are part of all human tissue and are found in many foods. Normally, uric acid is dissolved in the blood and passed through the kidneys into the urine, where it is eliminated. If the body increases its production of uric acid or if the kidneys do not eliminate enough uric acid from the body, it is accumulated in the blood (a condition called hyperurieemia). Deposits of uric acid, called tophi (singular: tophus), can appear as lumps under the skin around the joints and at the rim of the ear. In addition, uric acid crystals accumulated in the kidneys and cause kidney stones.
  • the sink mechanism of the device of the present invention can include an immobilized enzyme capable of oxidizing urate (such as, urate oxidase or uricase) in order to reduce the level of uric acid.
  • an immobilized enzyme capable of oxidizing urate such as, urate oxidase or uricase
  • the device is designed for removing cholesterol from gastrointestinal fluids and the blood circulation surrounding the gastrointestinal fract and thus can be utilized to treat individuals having hypercholesterolemia.
  • Hypercholesterolemia is a condition characterized by high levels of cholesterol in the blood. While cholesterol is an essential part of a healthy body, high levels thereof increase a risk for cardiovascular disease, which can lead to stroke or heart attack. Excess level of cholesterol circulating in the blood can create plaque along the artery walls, which plaque eventually obstruct or even block the flow of blood.
  • the sink mechanism of the device of the present invention can include a bile acid binding resin or an agent capable of synthesizing the cholesterol into long fat chains, such as, Cholestyramine (Duolite AP) in order to reduce cholesterol levels in the blood.
  • a bile acid binding resin or an agent capable of synthesizing the cholesterol into long fat chains such as, Cholestyramine (Duolite AP) in order to reduce cholesterol levels in the blood.
  • the device can also be designed for reducing the absorbance of undesired molecules from the gastrointestinal fluids and thus can be utilized to treat individuals having diverse conditions limiting their diet.
  • Certain conditions require an individual to avoid or reduce specific food components from his normal diet such as low glucose diet for diabetes, low sodium diet for hypertensive patients, and low fat and carbohydrate for obese patients.
  • the carbohydrates are absorbed in the intestines as single glucose molecules after breakage of polysaccharide chains. Lipids are absorbed as fatty acids, cholesterol and monoglycerides after emulsification and dissolution in the aqueous media of the intestinal lumen in the presence of bile salts. The size of the fat globules is the limiting factor in its absorption. Before emulsification by bile salts, lipid globules have an average diameter of 100 nm, while afterwards their diameter is reduced to 5 nm.
  • the sink mechanism of the device of the present invention preferably includes enzymes capable of synthesis of polysaccharides from single glucose molecules or conjugation of fatty acids to form bigger fat globules for avoidance of normal absorption and reducing their concentration in the enterocytes and subsequent levels in blood.
  • chitosan can be used as an effective adsorbent for removing free fatty acids.
  • Other embodiments include, without limitation, exchange resins for sodium trapping or specific antibodies for known food allergens.
  • the device of the present invention preferably comprises immobilized gliadin antibody molecules or bacteria genetically modified capable of synthesizing gliadin antibodies.
  • the device is designed for reducing the levels of alcohol and acetaldehyde and thus can be utilized to reduce damaging effects of alcohol consumption.
  • ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH), followed by its oxidation to a less harmful molecule -acetate, by aldehyde dehydrogenase (ALDH).
  • ADH alcohol dehydrogenase
  • ADH aldehyde dehydrogenase
  • Acetaldehyde is a toxic metabolite that is responsible for the hepatic damage and risk factor for alimentary tract cancers.
  • the sink mechanism of the device of the present invention preferably comprises immobilized ALDH enzyme for oxidation of endogenous (bacterial produced) acetaldehyde and the one resulted from the ingested ethanol metabolism.
  • the sink mechanism may also comprise immobilized ADH enzyme in addition to ALDH, for conversion of ethanol and acetaldehyde in one device.
  • Other resins capable of absorbance of organic materials like alcohols e.g. Tenax, TA
  • the device is designed for mobilizing phenylalanine hydroxylase to the gastrointestinal tract and thus can be utilized to treat individuals having Phenylketonuria (PKU).
  • PKU is an inherited error of metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase. The absence of this enzyme results in mental retardation, organ damage, unusual posture and in cases of maternal PKU it can severely compromise pregnancy.
  • Classical PKU is an autosomal recessive disorder, caused by mutations in both alleles of the gene for phenylalanine hydroxylase, found on chromosome 12. Phenylalanine hydroxylase converts the amino acid phenylalanine to tyrosine. Mutations in both copies of the gene for this enzyme, leads to inactive or less efficient enzyme thus, the concentration of phenylalanine in the body can build up to toxic levels.
  • the sink mechanism of the device of the present invention preferably comprises a cofactor capable of performing phenylalanine enzymatic hydroxylation, such as, tetrahydrobiopterin.
  • the sink mechanism may comprise antibodies, chelators, and/or enzymatic transformation directed toward aspartame or its metabolites.
  • Aspartame an artificial sweetener widely used in the food industry
  • contraindicated in PKU patients due to produce phenylalanine as a by product, therefore its reduction or conversion is expected to reduce or eliminate its effects on PKU patients.
  • the device is designed for removing Hydroxytryptamine (5-HT or serotonin) and thus can be utilized to treat individuals having diseases associated with its presence in the intestines.
  • Hydroxytryptamine (5-HT or serotonin)
  • 5-HT Hydroxytryptamine
  • 5-HT acts as a paracrine substance to stimulate pancreatic secretion via a vagal cholinergic pathway.
  • 5-HT was suggested to have a role in Irritable Colon syndrome as well as Carcinoid Syndrome.
  • the sink mechanism of the device preferably comprises immobilized serotonin antibody molecules or bacteria genetically modified capable of synthesizing serotonin antibodies, or alternatively, an enzyme capable of serotonin conversion.
  • the is designed for reducing substance-P and thus can be utilized to treat individuals having diseases associated with its presence or high levels.
  • substance-P in the blood is a recognized indication of many disorders, such as chronic pain, fibromyalgia and depression. There is evidence of presence and localization of substance-P receptors on epithelial cells of the normal small and large intestine. Up-regulation of expression of such receptors was shown in disorders such as Crohn's disease and ulcerative colitis.
  • the sink mechanism of the device preferably comprises immobilized substance-P antibody molecules or bacteria genetically modified capable of synthesizing substance-P antibodies.
  • the sink mechanism of the device comprises bacteria genetically modified capable of synthesis of such antibodies.
  • the device is designed for reducing Zot and/or zonulin and thus can be utilized to treat individuals having diseases associated with the presence or high levels of these toxins.
  • Intestinal permeability is altered in inflammatory bowel diseases, enteral bacterium, and parasite infections, as a result of certain drug intake, food allergies or intoxication by toxins, major trauma and burns or celiac disease.
  • This increased intestinal permeability leads to severe diarrhea, increased intestinal secretions, while allowing unwanted substances to cross the intestinal barrier.
  • the pathogenesis of this condition involves the presence of Zonula occludens toxin (Zot), or up-regulation of zonulin, its eukaryotic analogue, that reversibly open the intestinal tight junctions between the cells of the intestinal epithelium (enterocytes).
  • the sink mechanism of the device of the present invention preferably comprises immobilized an anti-Zot and/or anti Zonulin antibodies or bacteria genetically modified capable of synthesizing such antibodies, or alternatively, an agent capable of inhibiting the action of these molecules (Zot and zonulin) through the sink mechanism. Reduction or eliminations of undesired drugs:
  • the device is designed for reducing specific drugs and thus can be utilized in cases such as drug overdoses, when the drug is not longer needed or when is producing unwanted side effects.
  • the sink mechanism of the device of the present invention preferably comprises natural Bentonite mineral (clay) or synthetic resin.
  • Drugs that enter the entero-hepatic circulation can also be recovered with the specific sink mechanism suitable for each case, using antibodies, chelators or transforming agents. Taking advantage of the modulation of intestinal permeability using coated devices of the present invention with modulator agents, the levels of an extended range of large molecule drugs and other substances can be reduced through a suitable sink mechanism.
  • any of the device types of the present invention described hereinabove can be packaged and identified for use in treating specific diseases and conditions. Such description can be provided by an informative leaflet packaged along with the device or printed on the packaging material. In any case, such information would preferably also include type and composition of sink mechanism, directions for use, side effects, if any, and any related information which can facilitate effective use of the device.

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Abstract

L'invention concerne un dispositif ingérable qui comprend un mécanisme d'absorption permettant de produire un flux net d'au moins un constituant d'intérêt présent dans le tractus gastro-intestinal d'un individu, et un mécanisme de confinement permettant de confiner le mécanisme d'absorption dans un confinement prédéterminé.
EP04725140A 2003-04-24 2004-04-01 Dispositif gastro-intestinal ingerable Withdrawn EP1627039A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10/422,091 US7611480B2 (en) 2003-04-24 2003-04-24 Gastrointestinal bioreactor
US10/766,861 US7459305B2 (en) 2003-04-24 2004-01-30 Ingestible gastrointestinal device
PCT/IL2004/000306 WO2004093633A2 (fr) 2003-04-24 2004-04-01 Dispositif gastro-intestinal ingerable

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EP1627039A2 true EP1627039A2 (fr) 2006-02-22
EP1627039A4 EP1627039A4 (fr) 2012-11-07

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AU (1) AU2004231368A1 (fr)
CA (1) CA2522094A1 (fr)
WO (1) WO2004093633A2 (fr)

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US20090061008A1 (en) 2007-08-30 2009-03-05 Levy Mark M Fiber/granule complex for treatment of the gi tract
CN102626338B (zh) 2008-01-14 2014-11-26 康文图斯整形外科公司 用于骨折修补的装置和方法
US20110178520A1 (en) 2010-01-15 2011-07-21 Kyle Taylor Rotary-rigid orthopaedic rod
ES2733729T3 (es) 2010-01-20 2019-12-02 Conventus Orthopaedics Inc Aparato para el acceso a huesos y para la preparación de cavidades
CN103002824B (zh) 2010-03-08 2015-07-29 康文图斯整形外科公司 用于固定骨植入物的装置及方法
US11077238B2 (en) 2013-06-07 2021-08-03 Allena Pharmaceuticals, Inc. Compositions, methods, and devices for dialysis
EP3079607A4 (fr) 2013-12-12 2017-07-26 Conventus Orthopaedics, Inc. Outils et méthodes de déplacement de tissu
WO2019010252A2 (fr) 2017-07-04 2019-01-10 Conventus Orthopaedics, Inc. Appareil et méthodes de traitement d'os

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3485235A (en) * 1967-12-04 1969-12-23 Ronald Felson Capsule for the study and treatment of the digestive tract
US5395366A (en) * 1991-05-30 1995-03-07 The State University Of New York Sampling capsule and process
US6332985B1 (en) * 1999-03-29 2001-12-25 Uop Llc Process for removing toxins from bodily fluids using zirconium or titanium microporous compositions
US20020146368A1 (en) * 2000-01-19 2002-10-10 Gavriel Meron System and method for determining the presence of a substance in-vivo

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6168948B1 (en) * 1995-06-29 2001-01-02 Affymetrix, Inc. Miniaturized genetic analysis systems and methods

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3485235A (en) * 1967-12-04 1969-12-23 Ronald Felson Capsule for the study and treatment of the digestive tract
US5395366A (en) * 1991-05-30 1995-03-07 The State University Of New York Sampling capsule and process
US6332985B1 (en) * 1999-03-29 2001-12-25 Uop Llc Process for removing toxins from bodily fluids using zirconium or titanium microporous compositions
US20020146368A1 (en) * 2000-01-19 2002-10-10 Gavriel Meron System and method for determining the presence of a substance in-vivo

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2004093633A2 *

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EP1627039A4 (fr) 2012-11-07
WO2004093633A3 (fr) 2004-12-02
WO2004093633A2 (fr) 2004-11-04
AU2004231368A1 (en) 2004-11-04
CA2522094A1 (fr) 2004-11-04

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