Patent Application
20140228715
Oral administration remains the most commonly used and accepted route for the delivery of drugs. The revolution in drug-development has introduced macromolecules, including proteins (e.g., monoclonal antibodies), as therapeutics, although these are generally limited by their administration to the intravenous or subcutaneous routes.
Ultrasound has had decades of clinical success in diagnostic imaging, blood flow analysis, kidney stone disruption, and tumor and fibroid ablation. In recent years, ultrasound has been used in the clinic to transiently increase the permeability of the skin, enabling transdermal administration of drugs and sampling of extracellular analytes. Since then, ultrasound in the range of 0.02-3 MHz has been shown to improve the delivery of many macromolecules at therapeutic levels, including proteins, nanoparticles, and vaccines. Furthermore, ultrasound has been used to increase the permeability of a variety of biological barriers, such as ocular and buccal tissues and the blood-brain barrier.
A method of delivering a substance includes providing a substance at a location in a gastrointestinal (GI) tract, excluding a buccal membrane, of a biological body and applying ultrasonic waves, having a frequency between about 20 kHz and about 10 MHz, at the location.
The method may further include storing the substance in at least one reservoir; and exposing a medium within or of the GI tract to the substance. As used herein, reservoir can include a volume or a coating. For example, the reservoir can be an internal reservoir or volume of a device or a coating of a housing of a device. In an embodiment, the method includes imparting energy into the reservoir to trigger exposure of the medium to the substance. Energy can include ultrasonic waves, light, mechanical vibration, etc. Alternatively or in addition; the method may include emitting the ultrasonic waves to increase passage of the substance through a surface of the GI tract, such as gastrointestinal mucosa. Further, the method can include emitting the ultrasonic waves to facilitate passage of the substance between the at least one reservoir and the medium. For example, the substance may be an analyte released from the biological body with the ultrasonic waves emitted. In some embodiments, the substance passes from the medium into the at least one reservoir.
In an embodiment, exposing the medium to the substance includes pumping the substance between the at least one reservoir and the medium. In another embodiment, exposing the medium to the substance includes allowing the substance to diffuse between the at least one reservoir and the medium. The method may further include propelling the substance towards a surface of the GI tract with the ultrasonic waves. The method may include acoustic streaming or cavitation to enhance update of the substance by tissue of the GI tract.
In an embodiment, the method includes sensing a property of the biological body or energy presented thereto to determine proximity to the location, and applying the ultrasonic waves in response to the property sensed. The property sensed may be pH, light intensity, temperature, the absence or presence of a chemical, the absence or presence of blood, the absence or presence of a hormone, or the absence or presence of an inflamed fluid.
The ultrasonic waves can be applied in a frequency range of from about 20 kHz to about 100 kHz, or from 20 kHz to about 500 kHz, or from about 500 kHz to about 1 MHz, or from about 1 MHz to about 3 MHz, or from about 3 MHz to about 7 MHz, or from about 7 MHz to about 10 MHz. The intensity of the ultrasonic waves applied can be in a range from about 0.1 W/cm2 to about 10 W/cm2, from about 0.24 W/cm2 to about 1.4 W/cm2, from about 1.4 W/cm2 to about 10 W/cm2, from about 10 W/cm2 to about 100 W/cm2, from about 100 W/cm2 to about 500 W/cm2, or from about 500 W/cm2 to about 1000 W/cm2.
The location at which the ultrasonic waves are applied can be within an anatomic location of the GI tract, e.g., stomach, small intestine, large intestine (colon), rectum, or at a duct that enters the GI tract, such as a pancreatic duct or a common bile duct. In a preferred embodiment, the location is in a colon. Applying the ultrasonic waves may increase permeability of tissue at the location. Further, the method may include tuning the ultrasonic waves to increase or decrease enzymatic activity in the GI tract while operating therein. For example, applying the ultrasonic waves may be performed in a manner expected to decrease enzymatic activity to decrease or prevent degradation of the substance.
The substance to be delivered can include a compound having a molecular weight in a range from about 0.1 kDa to about 1000 kDa. The substance can include at least one of the following: a therapeutic compound, a bioactive compound, an imaging agent, a diagnostic agent, or combination thereof. A therapeutic compound may include a polynucleotide, small molecule, peptide, or protein. An imaging agent may include a contrast agent, e.g., a radioactive or contrast dye. In some embodiments, the substance includes a therapeutic compound that includes DNA or RNA. For example, the RNA can be small interfering RNA (siRNA) or micro-RNA (miRNA). In an embodiment, the substance includes a protein, e.g., an antibody.
In an embodiment, the substance to be delivered includes at least one of the following: liposomes, microparticles, nanoparticles, iron oxide particles, gold particles, drug crystals, polymeric particles, lipid or lipid-like particles, or combination thereof. Alternatively or in addition, the substance can include an ultrasound absorbing material.
In some embodiments, applying the ultrasonic waves includes applying the ultrasonic waves at a frequency and intensity known to treat a medical condition through direct stimulus of the ultrasonic waves. For example, the ultrasonic waves applied can include high intensity focused ultrasound (HIFU), which can treat tissue having the medical condition. Applying the ultrasonic waves can include heating, ablating, denaturing, scarring, vibrating, or combinations thereof, of tissue at the location. For example, ultrasound stimulation of tissue can include stimulation of nerves, and may include ultrasound induced vibratory stimulation.
In some embodiments, the method further includes delivering a device into the GI tract, the device including at least one ultrasound transducer and circuitry; powering the at least one ultrasound transducer and circuitry from within the device; and driving the at least one ultrasound transducer, using the circuitry, in a manner causing the at least one ultrasound transducer to emit ultrasonic waves to a medium within or of the GI tract. The device can include a housing with holes defined therethrough, and providing the substance can include exposing the substance via the holes. In an embodiment, the at least one reservoir is associated with the housing of the device.
In some embodiments, the method of delivering a substance includes propelling the device within the GI tract with the ultrasonic waves emitted or other ultrasonic waves emitted by the device.
Delivering the device can include rectally or orally introducing the device into the GI tract. Delivering the device can also include placing the device at a duct that enters the GI tract and activating the ultrasound transducer to increase passage of the substance into tissue of the duct. In an embodiment, delivering the device includes placing the device in the GI tract and activating the ultrasound transducer to increase passage of a substance into tissue of the GI tract. Also, a combination of several devices may be delivered. Further, the ultrasound device, e.g., an ingestible ultrasound pill, may be delivered in addition to another therapeutic compound that a patient ingests or consumes separately, or that a healthcare provider administers separately to the patient.
In some embodiments, the method further includes positioning the device in the GI tract, for example, by employing a positioning mechanism to hold the device stationary. The positioning mechanism can include a suture, e.g., a biodegradable suture, or an externally-placed magnet. In some embodiments, positioning the device includes causing the device to adhere to tissue of the GI tract. For example, the device can include a bioadhesive coating, and causing the device to adhere to the tissue of the GI tract can include using the bioadhesive coating. Alternatively or in addition, causing the device to adhere to the tissue of the GI tract or include releasing an adhesive from a reservoir of the device.
A device includes a housing configured to be delivered into a gastrointestinal (GI) tract of a biological body and at least one ultrasound transducer, disposed within the housing. The ultrasound transducer is configured to emit ultrasonic waves, external from the housing, within a frequency range of from about 20 kHz to about 10 MHz to a medium within or of the GI tract. Also included is circuitry, disposed within the housing and configured to drive the transducer; and a power source, disposed within the housing and configured to power the transducer and the circuitry.
In an embodiment, the device further includes at least one reservoir, e.g., volume or coating, associated with the housing and configured to store the substance to be delivered; and a mechanism, associated with the housing and configured to expose the medium to the substance. The mechanism may be configured to be activated by energy imparted into the reservoir to trigger exposure of the medium to the substance. In an embodiment, the substance is released from the reservoir by ultrasound imparted into the reservoir. Alternatively or in addition, the mechanism can include material sensitive to pH or temperature to trigger exposure of the medium to the substance. In some embodiments, the mechanism includes a pump, which may be a mechanical, chemical, osmotic pump. For example, the power source can include a deformable battery configured to serve as the pump and the power source. In an embodiment, the housing defines holes therethrough and the mechanism is configured to expose the medium to the substance via the holes. The mechanism can also be configured to utilize a concentration gradient between the reservoir and the medium external from the housing to transfer the substance by diffusion. In some embodiments, the housing is ingestible. The housing may also be implantable.
In some embodiments, the device further includes a sensor disposed within the housing and coupled to the circuitry, the sensor being configured to activate the at least one ultrasound transducer. The sensor can be a pH sensor, electromagnetic wave sensor, light sensor, temperature sensor, or chemical sensor, and may be configured to trigger release of the substance from a reservoir associated with the housing.
The ultrasound transducer of the device can be configured to operate in a frequency range of from about 20 kHz to about 100 kHz, or from about 20 kHz to about 500 kHz, or from about 500 kHz to about 1 MHz, or from about 1 MHz to about 3 MHz, or from about 3 MHz to about 7 MHz, or from about 7 MHz to about 10 MHz. The ultrasound transducer can be configured to emit ultrasonic waves to the medium at an intensity in a range from about 0.1 W/cm2 to about 10 W/cm2, from about 0.24 W/cm2 to about 1.4 W/cm2, from about 1.4 W/cm2 to about 10 W/cm2, from about 10 W/cm2 to about 100 W/cm2, from about 100 W/cm2 to about 500 W/cm2, from about 500 W/cm2 to about 1000 W/cm2.
Further, the device can be calibrated to emit ultrasonic waves to increase or decrease enzymatic activity in the body lumen. In an embodiment, the power source can be a battery configured to be recharged through a wireless connection with a device external from the body.
In some embodiments, the device is configured to be positioned in the GI tract and held stationary using a positioning mechanism, such as a suture or an externally-placed magnet. In some embodiments, the device is configured to adhere to tissue of the GI tract. For example, the device can include a bioadhesive coating, and the device can be configured to adhere to the tissue of the GI tract through the use of the bioadhesive coating. Alternatively or in addition, the device can include an adhesive releasable from a reservoir of the device.
In an embodiment, the at least one ultrasound transducer is configured to emit the ultrasonic waves in the presence of the substance to be delivered at a location of the GI tract.
In an embodiment, the device includes at least one reservoir associated with the housing, and a mechanism, associated with the housing and configured to transfer the substance between the medium and the at least one reservoir.
A method of treating inflammatory bowel disease includes providing a self-powered ultrasound device comprising at least one reservoir, each reservoir comprising a substance that includes a therapeutic molecule for treatment of inflammatory bowel disease; releasing the substance from the at least one reservoir into the gastrointestinal tract in the vicinity of target tissue for localized delivery of the substance; and emitting ultrasonic waves in a frequency range of from about 20 kHz to about 10 MHz with the ultrasound device to increase passage of the substance through a surface of the target tissue.
In an embodiment, the substance further includes nutrients. In some embodiments, emitting the ultrasonic waves further includes emitting the ultrasonic waves with the ultrasound device to increase permeability of the target tissue to the substance. The target tissue can include gastrointestinal mucosa and may include colon tissue.
The foregoing will be apparent from the following more particular description of example embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the present invention.
Ultrasound is widely used across medical disciplines. Recently, ultrasound has been approved by the Federal Drug Administration (FDA) as a tool to enhance transdermal drug delivery. Conventional ultrasound devices, which include a control unit, a probe, and an external power supply, are relatively large. Described herein are embodiments of a delivery device that includes an ingestible/implantable capsule or pill which houses an entire ultrasound apparatus. Such a stand-alone, self-powered ultrasonic device can be used for localized delivery of therapeutic macromolecules via the gastrointestinal (GI) tract. Recent technological advancements in miniaturization include high efficiency battery-power usage and novel embedding of the electronics on a microchip. An embodiment of the self-standing ultrasound pill has dimensions that can be introduced into the mouth, swallowed, and transported through the digestive tract for drug delivery applications.
Miniaturizing ultrasonic devices was noted with the introduction of the hand-held ultrasound diagnostic imaging systems by Siemens and GE in 2007. Further miniaturization of ultrasonic devices, is enabled by optimizing power transfer and efficiency. Using low output impedance amplifier circuits to replace RF amplifiers and impedance-matching circuitry increases the power transferred from the battery to the transducer to more than 95%. The first device to utilize this advancement was an implantable transducer, in dimensions of several centimeters, aimed at delivering drugs to brain tumors.
In an embodiment, a method of delivering a substance includes providing a substance to a location in the GI tract 10, excluding a buccal membrane, of a biological body and applying ultrasonic waves, having a frequency between about 20 kHz and about 10 MHz, at the location. Providing the substance and applying the ultrasound may occur simultaneously or may be offset in time, and may be adjusted according to different dosing regimens. For example, the method can include pre-administration of the substance followed by the application of the ultrasonic waves, coincident administration/application of the substance and the ultrasonic waves, and application of the ultrasonic waves followed by administration of the substance.
The method may further include storing the substance in at least one reservoir, e.g.; of device 100, and exposing a medium within or of the GI tract, e.g. fluid or tissue, to the substance. For example, the reservoir can be an internal reservoir or a coating, as described in more detail with reference to
A property of the biological body, or energy presented thereto, may be sensed to determine proximity of device 100 to the location. Ultrasonic waves may then be applied in response to the property sensed. For example, the device 100 may include a sensor that senses pH as the device 100 passes through the GI tract 10. It is generally understood that the pH varies for different locations in the GI tract. Typically, the stomach has a lower pH, e.g., pH=1.3, as compared to the small intestine, whose pH can vary along its length from pH=6, in the duodenum, to pH=7.8, in the jejunum and ileum. Other properties sensed may include light intensity, temperature, the absence or presence of a chemical, the absence or presence of blood, the absence or presence of a hormone, or the absence or presence of an inflamed fluid.
In some embodiments, providing a substance includes positioning the device 100 in the GI tract, for example, by employing a positioning mechanism to hold the device stationary. As described with references to
The device 400 further includes at least one reservoir, e.g., volume or coating, associated with the housing 402 and configured to store the substance. As shown in
In some embodiments, the housing 402 is ingestible. The housing 402 may also be implantable. As shown, the housing 402 is in the form of a pill that has a length L, e.g., from about 1 cm to about 3 cm, and a width or diameter W, e.g., from about 0.5 cm to about 1 cm.
The device 400 further can further include a sensor 422 disposed within the housing 402 and coupled to the circuitry 408, the sensor being configured to activate the at least one ultrasound transducer 404. The sensor can be a pH sensor, electromagnetic wave sensor, light sensor, temperature sensor, or chemical sensor, and may be configured to trigger release of the substance from reservoir 414.
It should be understood that the schematic diagram of
The device 500 further includes an internal reservoir or volume 512a and reservoir or coating 512b. Optionally, only one reservoir may be present. Reservoirs 512a, 512b (collectively 512a-b) are associated with the housing 502 and configured to store one or more substances. For example, a first reservoir 512a can store the substance to be delivered to the medium at the location of the GI tract and a second reservoir 512b can store another substance transferred from the medium to the reservoir, or vice versa.
As shown in
The device 500 can further include a sensor 522 disposed within the housing 502 and coupled to the circuitry 508, the sensor being configured to activate any of the ultrasound transducers 504a and 504b. The sensor 522 can be a pH sensor, electromagnetic wave sensor, light sensor, temperature sensor, or chemical sensor, and may be configured to trigger release of the substance from the reservoir 512a-b.
In the embodiments described herein, such as devices 100, 400, and 500 described with reference to
In one embodiment, the dimensions of the device are 2.7 cm in length (L) and 1 cm in width or diameter (W). Similar dimensions were previously approved by the FDA for an ingestible pill containing a camera used for diagnostic imaging of the digestive tract. As described elsewhere herein, the device can include a housing in the form of a pill and configured to house all the components needed for producing an ultrasonic signal, such as an ultrasound transducer, a power source, and circuitry connected to the power source and the transducer. The device can further include at least one reservoir and a release mechanism associated with the housing.
The hereby described technology is of a self-standing ultrasound machine in dimensions that can be introduced into the mouth, swallowed, and/or transported through the digestive tract. The technology may be used for, but not confined to:
The ultrasound device can be designed to operate at a frequency within the range of 20 kHz to 10 MHz.
The pill-shaped ultrasound device, loaded with a therapeutic substance, such as insulin, can be administered orally (and swallowed) by the patient. By sensing pH in the GI tract, a sensor in the device can activate the transducer to increase the penetration of macromolecules into the GI mucosa and/or to propel the therapeutic compound towards the mucosa and improve drug delivery. The release of the substance or drug from the internal reservoir can be triggered by pressure (using an internal pump), or by diffusion (utilizing the concentration gradient between the reservoir and the external medium). The substance or drug may be transferred through holes in the house, or holes in the transducer ceramics, and out of the pill in order to improve drug propulsion.
An ultrasound pill comprising a drug can be placed under the tongue. Upon placement, the pill can be activated to increase the permeability of mouth tissue by ultrasonic waves. Ultrasonic waves can also propel the drug from the surface of the device or transducer towards and into the tissue. This device can enable rapid delivery of a drug to into the blood stream, avoiding GI-tract metabolism, and may be used as a replacement of intravenous administration of drugs. The device can also be used for drugs focused at the oral cavity, and or for the administration of pain relievers to the mouth membrane, aside from under the tongue.
Ultrasound has been previously used to affect the activity of enzymes. The ultrasound pill can be calibrated to decrease or increase the activity of enzymes.
For example, when placing the pill under the tongue, or while traveling through the GI tract, ultrasonic waves can be used to decrease enzymatic activity thereby preventing drug degradation.
Having an inner source of ultrasonic waves, of known parameters at the source (frequency, amplitude, etc.), can be of advantage for improving ultrasound-based imaging, and or other imaging techniques.
The ability to deliver siRNA to the oral cavity and/or to the digestive tract has been a major goal. However, the susceptibility of siRNA to degradation remains a major challenge. Using ultrasound to increase the permeability and/or to propel genes (such as siRNA) into the mucosal membrane can improve siRNA therapy.
The ability to enhance the permeability of the GI membrane by ultrasound was evaluated in the porcine small intestine. Tissue specimens from animals sacrificed within 24 hours of the experiment were mounted in Franz diffusion cells (PermeGear, Hellertown, Pa.), as described below.
Through scintigraphy of the tissue and of the solution in the receiver chamber permeation enhancement was measured. For this, after each experiment, the tissue was removed from the diffusion cell 600 and washed thoroughly with PBS, to remove radio-labeled compounds that were not inside the tissue. Then, the tissue was dissolved (Souene 350, Perkin Elmer, USA), immersed in a scintillation fluid (HionicFluor, Perkin Elmer), and then measured for radiolabeled content with a scintillation counter (Tri Carb Scintillation Counter, Hewlett Packard). Similarly, the acceptor cell was measured for the radiolabeled content. All data are presented in comparison to sham samples—not treated by ultrasound.
Further penetration enhancement was evaluated using 1-MHz ultrasound across a wide range of compounds having Mw of 0.3-150 kDa. For all model compounds a significant penetration enhancement was measured.
The donor cell was loaded with PBS enriched with 14C-labeled inulin (Mw 5000, ARC)—a model compound simulating a protein drug. Ultrasound was applied at two different irradiation profiles, which simulate the clearance kinetics of medium or high-Mw compounds in the GI tract:
The donor cell was loaded with PBS enriched with 14C-labeled dextrose (Mw 70,000, ARC)—a model compound simulating a macromolecule drug. Ultrasound was applied at two different irradiation profiles, which simulate the clearance kinetics of medium or high-Mw compounds in the GI tract:
To visualize the enhanced uptake of macromolecules to the small intestine by ultrasound, Alexa Fluor 700 goat anti rabbit IgG (Mw 150,000), a monoclonal antibody, was dissolved in the donor cell and the tissue was exposed to ultrasound (1 MHz, 1.4 W/cm2) for 30 min, followed by 30 min of passive diffusion.
In the methods and devices described herein, the substance or compound to be delivered can be provided via one or more reservoirs. A reservoir can be a coating of a device, e.g., a coating applied to a housing of the device, or an internal reservoir or volume of the device. For example, the coating may be applied to the housing at a location where ultrasonic waves are emitted from the device. The reservoir can include polymeric material or material similar to the transdermal patches presently in use. The material can be sensitive to the ultrasound, as described in U.S. Appl. Ser. No. 06/936,000 entitled “Ultrasonically Modulated Polymeric Devices for Delivering Compositions” filed Nov. 28, 1986 by Joseph Kost and Robert S. Langer, now U.S. Pat. No. 4,779,806, or the material can release the substance to be delivered at a rate independent of the application of ultrasound. Many formulations are known to those skilled in the art which are safe for use internally and dissolve in the GI tract. Many biocompatible polymers can be used to form a polymeric matrix for the substance to be delivered, including both biodegradable and non-biodegradable polymers such as polyanhydrides, polylactic acid, polyglycolic acid, ethylene vinyl acetate copolymers, polypropylene, polyethylene. The release rate can also be manipulated by the form used to encapsulate the substance to be delivered. For example, the release rate from microcapsules is different from a slab containing the substance, even when made of the same material.
The methods and devices described herein can include small molecules. Examples of small molecules include organic compounds, organometallic compounds, inorganic compounds, and salts of organic, organometallic or inorganic compounds. Atoms in a small molecule are typically linked together via covalent and/or ionic bonds. The arrangement of atoms in a small organic molecule may represent a chain (e.g. a carbon-carbon chain), or may represent a ring containing carbon atoms, or, in some embodiments, a combination of carbon and heteroatoms. In some embodiments the small molecules are no more than about 5,000 daltons. For example, such small molecules can be no more than about 1000 daltons and, in some embodiments, are no more than about 750 daltons, for example, they can be less than about 500 daltons. Small molecules can be found in nature (e.g., identified, isolated, and/or purified) and/or produced synthetically (e.g., by organic synthesis and/or bio-mediated synthesis). See, e.g. Ganesan, Drug Discov. Today 7(1): 47-55 (January 2002); Lou, Drug Discov. Today, 6(24): 1288-1294 (December 2001), both of which are incorporated by reference in their entirety. Examples of naturally occurring small molecules include, but are not limited to, hormones, neurotransmitters, nucleotides, amino acids, sugars, lipids, and their derivatives.
In some embodiments, suitable dosages for small molecule substances that are administered to patients can be, for example from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, or from about 0.01 mg/kg to about 1 mg/kg body weight per treatment, e.g., per day.
Other substances that may be used with the devices described herein include polypeptides. Examples of polypeptides include any suitable L- and/or D-amino acid, for example, common α-amino acids (e.g., alanine, glycine, valine), non-α-amino acids (e.g., β-alanine, 4-aminobutyric acid, 6-aminocaproic acid, sarcosine, statine), and unusual amino acids (e.g., citrulline, homocitruline, homoserine, norleucine, norvaline, ornithine). The amino, carboxyl and/or other functional groups on a polypeptide can be free (e.g., unmodified) or protected with a suitable protecting group. Suitable protecting groups for amino and carboxyl groups, and methods for adding or removing protecting groups are known in the art. See, for example, Green and Wuts, “Protecting Groups in Organic Synthesis,” John Wiley and Sons, 1991. The functional groups of a polypeptide can also be derivatized (e.g., alkylated) using art-known methods.
An example polypeptide can include one or more modifications (e.g., amino acid linkers, acylation, acetylation, amidation, methylation, terminal modifiers (e.g., cyclizing modifications)), if desired. The polypeptide can also contain chemical modifications (e.g., N-methyl-α-amino group substitution). In addition, a polypeptide antagonist, which can be used with embodiments of the methods or devices disclosed herein, can be an analog of a known and/or naturally-occurring polypeptide, for example, a polypeptide analog having conservative amino acid residue substitution(s). These modifications can improve various properties of the polypeptide (e.g., solubility, binding), including its therapeutic efficacy.
It should be understood that the polypeptides can be linear, branched or cyclic, e.g., a peptide having a heteroatom ring structure that includes several amide bonds. In a particular embodiment, the peptide is a cyclic peptide. Such peptides can be produced by one of skill in the art using standard techniques.
The polypeptides can also encompass chimeric, or fusion, proteins that include all or a portion of a first protein operatively linked to all or a portion of a second, heterologous protein. “Operatively linked” indicates that the portions of the first protein and the heterologous protein are fused in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the first protein. For example, the fusion protein can be a GST-fusion protein in which the protein sequences are fused to the C-terminus of a GST sequence. Other types of fusion proteins include, but are not limited to, enzymatic fusion proteins, for example, β-galactosidase fusion proteins, yeast two-hybrid GAL fusion proteins, poly-His fusions, FLAG-tagged fusion proteins, GFP fusion proteins, and immunoglobulin (Ig) fusion proteins. Such fusion protein can facilitate purification (e.g., of a recombinant fusion protein). In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Therefore, in another embodiment, the fusion protein contains a heterologous signal sequence at its N-terminus.
It should be understood that fragments of proteins are intended to be compatible within the scope of embodiments of this invention.
In another embodiment, the device of the invention comprises peptidomimetic substances. For example, polysaccharides can be prepared that have the same functional groups as polypeptides. The binding moieties are the chemical atoms or groups which will react or form a complex (e.g., through hydrophobic or ionic interactions) with a target molecule, for example, a drug target. For example, the binding moieties in a peptidomimetic can be the same as those in a peptide or protein antagonist. The binding moieties can be an atom or chemical group which reacts with the receptor in the same or similar manner as the binding moiety in the peptide antagonist. Examples of binding moieties suitable for use in designing a peptidomimetic for a basic amino acid in a peptide include nitrogen containing groups, such as amines, ammoniums, guanidines and amides or phosphoniums Examples of binding moieties suitable for use in designing a peptidomimetic for an acidic amino acid include, for example, carboxyl, lower alkyl carboxylic acid ester, sulfonic acid, a lower alkyl sulfonic acid ester or a phosphorous acid or ester thereof.
The supporting structure is the chemical entity that, when bound to the binding moiety or moieties, provides the three dimensional configuration of the peptidomimetic. The supporting structure can be organic or inorganic. Examples of organic supporting structures include polysaccharides, polymers or oligomers of organic synthetic polymers (such as, polyvinyl alcohol or polylactide).
Methods and devices according to embodiments of the present invention can also include substances that are nucleic acid molecules (e.g., oligonucleotides). Suitable nucleic acid molecules include aptamers, which are capable of binding to a particular molecule of interest (e.g., a drug target) with high affinity and specificity through interactions other than classic Watson-Crick base pairing (Tuerk and Gold, Science 249:505 (1990); Ellington and Szostak, Nature 346:818 (1990)).
Aptamers, like peptides generated by phage display or monoclonal antibodies (MAbs), are capable of specifically binding to selected targets and, through binding, block their targets' ability to function. Created by an in vitro selection process from pools of random sequence oligonucleotides, aptamers have been generated for over 100 proteins including growth factors, transcription factors, enzymes, immunoglobulins, and receptors. A typical aptamer is 10-15 kDa in size (30-45 nucleotides), binds its target with sub-nanomolar affinity, and discriminates against closely related targets (e.g., will typically not bind other proteins from the same gene family). A series of structural studies have shown that aptamers are capable of using the same types of binding interactions (hydrogen bonding, electrostatic complementarity, hydrophobic contacts, steric exclusion, etc.) that drive affinity and specificity in antibody-antigen complexes.
The methods and devices described herein can be used to modulate or treat any disorder which can be treated locally or systemically.
In some embodiments, the methods and devices described herein can be used to treat any disorder which can be treated by a drug that can be administered through the GI tract. In some embodiments, the disorder is a disorder of the esophagus, including, but not limited to, esophagitis—(candidal), gastroesophageal reflux disease (gerd); laryngopharyngeal reflux (also known as extraesophageal reflux disease/eerd); rupture (Boerhaave syndrome, Mallory-Weiss syndrome); UES—(Zenker's diverticulum); LES—(Barrett's esophagus); esophageal motility disorder—(nutcracker esophagus, achalasia, diffuse esophageal spasm); esophageal stricture; and megaesophagus.
In some embodiments, the disorder is a disorder of the stomach, including but not limited to gastritis (e.g., atrophic, Menetrier's disease, gastroenteritis); peptic (i.e., gastric) ulcer (e.g., Cushing ulcer, Dieulafoy's lesion); dyspepsia; emesis; pyloric stenosis; achlorhydria; gastroparesis; gastroptosis; portal hypertensive gastropathy; gastric antral vascular ectasia; gastric dumping syndrome; HMFS (human mullular fibrilation syndrome).
In some embodiments, the disorder is a disorder of the small intestine, including but not limited to, enteritis (duodenitis, jejunitis, ileitis); peptic (duodenal) ulcer (curling's ulcer); malabsorption: celiac; tropical sprue; blind loop syndrome; Whipple's; short bowel syndrome; steatorrhea; milroy disease
In some embodiments, the disorder is a disorder of the small intestine, including but not limited to, both large intestine and small intestine enterocolitis (necrotizing); IBD (crohn's disease); vascular; abdominal angina; mesenteric ischemia; angiodysplasia; bowel obstruction: ileus; intussusception; volvulus; fecal impaction; constipation; and diarrhea (infectious).
In some embodiments, the disorder is a disorder of the small intestine, including but not limited to, accessory digestive glands disease; liverhepatitis (viral hepatitis, autoimmune hepatitis, alcoholic hepatitis); cirrhosis (PBC); fatty liver (Nash); vascular (hepatic veno-occlusive disease, portal hypertension, nutmeg liver); alcoholic liver disease; liver failure (hepatic encephalopathy, acute liver failure); liver abscess (pyogenic, amoebic); hepatorenal syndrome; peliosis hepatis; hemochromatosis; and Wilson's disease.
In some embodiments, the disorder is a disorder of the pancreas, including, but not limited to, pancreaspancreatitis (acute, chronic, hereditary); pancreatic pseudocyst; and exocrine pancreatic insufficiency.
In some embodiments, the disorder is a disorder of the large intestine, including but not limited to, appendicitis; colitis (pseudomembranous, ulcerative, ischemic, microscopic, collagenous, lymphocytic); functional colonic disease (IBS, intestinal pseudoobstruction/ogilvie syndrome); megacolon/toxic megacolon; diverticulitis; and diverticulosis.
In some embodiments, the disorder is a disorder of the large intestine, including but not limited to, gall bladder and bile ducts, cholecystitis; gallstones/cholecystolithiasis; cholesterolosis; Rokitansky-Aschoff sinuses; postcholecystectomy syndrome cholangitis (PSC, ascending); cholestasis/Mirizzi's syndrome; biliary fistula; haemobilia; and gallstones/cholelithiasis.
In some embodiments, the disorder is a disorder of the common bile duct (including choledocholithiasis, biliary dyskinesia).
Other disorders which can be treated with the methods and devices included herein include acute and chronic immune and autoimmune pathologies, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, thyroidosis, graft versus host disease, scleroderma, diabetes mellitus, Graves' disease, Beschet's disease; inflammatory diseases, such as chronic inflammatory pathologies and vascular inflammatory pathologies, including chronic inflammatory pathologies such as sarcoidosis, chronic inflammatory bowel disease, ulcerative colitis, and Crohn's pathology and vascular inflammatory pathologies, such as, but not limited to, disseminated intravascular coagulation, atherosclerosis, giant cell arteritis and Kawasaki's pathology; malignant pathologies involving tumors or other malignancies, such as, but not limited to leukemias (acute, chronic myelocytic, chronic lymphocytic and/or myelodyspastic syndrome); lymphomas (Hodgkin's and non-Hodgkin's lymphomas, such as malignant lymphomas (Burkitt's lymphoma or Mycosis fungoides)); carcinomas (such as colon carcinoma) and metastases thereof; cancer-related angiogenesis; infantile haemangiomas; and infections, including, but not limited to, sepsis syndrome, cachexia, circulatory collapse and shock resulting from acute or chronic bacterial infection, acute and chronic parasitic and/or infectious diseases, bacterial, viral or fungal, such as a HIV, AIDS (including symptoms of cachexia, autoimmune disorders, AIDS dementia complex and infections).
Other disorders which can be treated with the methods and devices included herein include acute and chronic immune and autoimmune pathologies, inflammatory diseases, infections and malignant pathologies involving, e.g., tumors or other malignancies.
The dosage administered depends upon known factors such as the pharmacokinetic characteristics of the particular administered substance(s), the age, health, and weight of the patient; nature and the extent of the symptoms and the disorder, any other treatment, and frequency of treatment. In one embodiment, a dosage of the administered substance can be, for example about 0.01 to 100.0 milligrams per kilogram (mg/kg) of body weight, per day. In one embodiment, 1.0 to 5.0, e.g., 1 to 10 mg/kg per day can be given doses 1 to 5 times a day.
In some embodiments, treatment can be provided as a daily dosage of the administered substance of 0.1 to 100.0 mg/kg, such as 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or a combination thereof, for example, using doses of every 2, 4, 6, 8, 12 or 24 hours, or any combination thereof.
In some embodiments, polypeptides and proteins are administered in the devices and methods described herein. For example, in some embodiments, antibodies are used. Antibodies include polyclonal antibodies, monoclonal antibodies, human antibodies, humanized antibodies, engineered antibodies, and chimeric antibodies. Also included are fragments, regions or derivatives thereof. Antibodies can be of any immunoglobulin class, including IgG, IgM, IgE, IgA, GILD and any subclass thereof. Fragments can include, but are not limited to, F(ab′)2 Fragments, Fab′ Fragments, Fab Fragments, Fv Fragments, and Fc Fragments, as well as single chain fragments.
The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.
While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. For example, an embodiment of an ultrasound device described herein could operate across a range of frequencies from about 20 kHz to about 50 MHz, or lower, or higher. Embodiments may also be used or modified to deliver a substance and/or apply ultrasound to a body lumen or cavity of the reproductive tract.
This application claims the benefit of U.S. Provisional Application No. 61/485,957 filed on May 13, 2011. The entire teachings of the above application are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US2012/037848 | 5/14/2012 | WO | 00 | 11/8/2013 |
| Number | Date | Country | |
|---|---|---|---|
| 61485957 | May 2011 | US |
