Patent Application
20220001159
Embodiments described herein generally relate to articles comprising actuating components and related methods.
Insulin and other biologic drugs have transformed diabetes from a terminal diagnosis into a manageable chronic illness; however, the need to subcutaneously inject these medicines creates patient discomfort, which in turn delays initiation in treatment regimens and reduces patient compliance. The gastrointestinal (GI) tract, for example, offers an incredible opportunity for diagnosing and treating patients. The development of smart dosage systems and devices to enable this has witnessed significant growth over the preceding decade. Orally ingested drugs generally diffuse through the gastrointestinal tract tissue walls in order to enter the blood stream. Typical ingested pills or devices release their cargo into the gastrointestinal tract randomly such that the cargo (e.g., drug) transits via convection and diffusion to the tissue wall. However, many biologic drugs such as insulin cannot move through the liquid in the GI tract as they may be degraded by enzymes, even if housed in a solid formulation, and/or cannot diffuse readily through the walls of the GI tract. Accordingly, improved articles and methods are needed.
Actuating components and related methods are generally provided.
In one aspect, articles are provided. In some embodiments, the article comprises a capsule, an actuating component disposed within the capsule, the actuating component comprising a central core and three or more arms associated with and extending from the central core, having a first, pre-deployment configuration and a deployed configuration, and at least one arm having a proximal portion and a distal end and a plurality of microneedles disposed near the distal end, the plurality of microneedles comprising an active pharmaceutical agent.
In some embodiments, the plurality of microneedles, at least in the pre-deployment configuration, are oriented external to a geometric center of the capsule.
In some embodiments, the article comprises a capsule, an actuating component disposed within the capsule, the actuating component comprising a central core and three or more arms associated with and extending from the central core, having a first, pre-deployment configuration and a deployed configuration, and at least one arm having a proximal portion and a distal end and a protrusion disposed near the distal end, wherein the actuating component has a pre-deployment configuration within the capsule and a deployed configuration, different than the pre-deployment configuration, external to the capsule.
In some embodiments, the protrusion comprises a plurality of microneedles.
In some embodiments, the article comprises a core, three or more arms associated with and extending from the central core, and a plurality of microneedles disposed proximate a distal end of at least one arm.
In another aspect, methods of administering an active pharmaceutical agent to a subject are provided. In some embodiments, the method comprises administering to the subject a capsule comprising an actuating component disposed within the capsule, the actuating component having a pre-deployment configuration within the capsule, releasing the actuating component, at a location internal to the subject, such that the actuating component obtains a deployed configuration, different than the pre-deployment configuration, wherein the actuating component comprises a core and three of more arms associated with and extending from the central core, and a plurality of microneedles disposed near a distal end of at least one arm, wherein, upon obtaining the deployed configuration, the plurality of microneedles engage with a least a portion of tissue at the location internal to the subject, and exposing the tissue to the active pharmaceutical agent.
Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and/or inconsistent disclosure, the present specification shall control.
Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. In the figures:
Actuating components and related methods are generally disclosed. Certain embodiments comprise an actuating component associated with a plurality of protrusions such as (micro)needles (e.g., for administering a therapeutic agent to a subject). In some embodiments, the actuating component may be administered to a subject such that the plurality of microneedles are deployed at a location internal to the subject (e.g., in the gastrointestinal tract). The actuating component may be contained within, in some embodiments, a capsule (e.g., for oral administration to a subject). In some embodiments, the actuating component has a pre-deployment configuration in which the plurality of microneedles have a first orientation and a deployed configuration in which the plurality of microneedles have a second orientation, different than the first orientation.
The articles and actuating components described herein may be useful for, for example, as a general platform for delivery of a wide variety of pharmaceutical agents (e.g., drugs) that otherwise are generally delivered via injection directly into tissue due to degradation in the GI tract. For example, in some embodiments, the actuating components may be configured to deliver pharmaceutical agents at a desired location and/or at a desired time and/or over a desired duration to a subject. Advantageously, the actuating components described herein may offer several advantages over traditional methods for delivering pharmaceutical agents including, for example, the ability to localize to a surface of tissue located internal to a subject (e.g., tissue in the gastrointestinal tract) and/or allowing loaded pharmaceutical agents to avoid long passage through the gastrointestinal tract before diffusing into the blood stream of a subject. In some embodiments, the actuating components described herein may serve as a platform for delivering pharmaceutical agents that are otherwise susceptible to degradation by enzymes (e.g., in the gastrointestinal tract) to be absorbed at relatively higher bioavailability as compared to traditional administration methods.
The term “subject,” as used herein, refers to an individual organism such as a human or an animal. In some embodiments, the subject is a mammal (e.g., a human, a non-human primate, or a non-human mammal), a vertebrate, a laboratory animal, a domesticated animal, an agricultural animal, or a companion animal. Non-limiting examples of subjects include a human, a non-human primate, a cow, a horse, a pig, a sheep, a goat, a dog, a cat or a rodent such as a mouse, a rat, a hamster, a bird, a fish, or a guinea pig. Generally, the invention is directed toward use with humans. In some embodiments, a subject may demonstrate health benefits, e.g., upon administration of the article and/or the actuating component.
In some embodiments, the actuating component comprises a core, two or more arms associated with the core, and a plurality of microneedles disposed on at least a portion of the arms. For example, as illustrated in
Additionally, while each arm in
In certain embodiments, the actuating component has a first, pre-deployment configuration (e.g., a folded configuration). For example, as illustrated in
In some embodiments, the location internally of the subject is the small intestine, the colon, the duodenum, the ileum, the jejunum, the stomach, the rectum, the mouth, or the esophagus. As described above and herein, in some embodiments, a pharmaceutical agent may be released during and/or after penetration of the tissue located internal to the subject by at least a portion of the plurality of microneedles.
While containing structure 140 is depicted as a capsule in
In some embodiments, the capsule comprises one or more features as described in U.S. Provisional Application Ser. No. 62/672,841 filed May 17, 2018 and entitled “QUICK RELEASE CAPSULES”, the contents of which is incorporated herein by reference in its entirety for all purposes. For example, in some embodiments, the actuating component is present in a capsule having a body comprising a first compartment and a second compartment not in fluid communication with the first compartment, wherein both the first compartment and the second compartment, in a pre-deployment state of the article, are sealed from fluid communication with an environment external to the article. In some embodiments, a deployment mechanism associated with the first compartment and configured to eject, from the second compartment, the actuating component for release internally of the subject. In some embodiments, the actuating component comprises optimal combinations of materials with high and/or low elastic moduli, giving the actuating component the capacity to alter its shape and/or size once the containing structure and/or soluble retaining element is removed. For example, in some embodiments, upon removal of the containing structure (e.g., at least a portion of the containing structure dissolves, degrades, mechanically weakens, and/or mechanically separates such that the actuating component is released), the actuating component obtains a second, deployed configuration, different than the pre-deployment configuration, and external to the containing structure. For example, referring again to
In some cases, the actuating component and/or the article containing the actuating component may be administered to a subject. In some embodiments, the actuating component is administered orally, rectally, vaginally, nasally, or uretherally. In certain embodiments, upon reaching a location internal to the subject (e.g., in the gastrointestinal tract), at least a portion of the containing structure degrades such that the actuating component obtains a deployed configuration and at least a portion of the plurality of microneedles interface (e.g., contacts, penetrates) with the tissue located internal to the subject. For example, in some embodiments, the actuating component has a deployed configuration including a particular size and/or shape in a relaxed state. In certain embodiments, the actuating component may be folded from the deployed configured into a second, pre-deployment configuration. For example, in some cases, the folded/compressed actuating component may be inserted within the capsule or other containment structure in the pre-deployment configuration such that the actuating component can be administered (e.g., orally). The capsule or other containment structure can be, in some cases, configured to dissolve such that the actuating component is released at a particular location internal to the subject whereby upon release, it can reversibly revert to the deployment configuration (e.g., by elastic recoil). In some embodiments, the actuating component is configured to adopt a shape and/or size in vivo that slows or prevents further transit in a body (e.g., gastric, small intestine) cavity until a desired time (e.g., upon dissolution of the microneedles and/or the arms of the actuating component). In some embodiments, the actuating component adopts a shape and/or size configured for temporary retention (e.g., gastric residence) upon release from a capsule/container and/or retaining structure/element. In some embodiments, the actuating component is configured for adopting a shape and/or size configured for gastric deployment after being stored in its encapsulated shape and/or size for durations of less than or equal to 24 hours, less than or equal to 12 hours, less than or equal to 10 hours, less than or equal to 8 hours, less than or equal to 6 hours, less than or equal to 4 hours, less than or equal to 2 hours, less than or equal to 1 hour, less than or equal to 30 minutes, less than or equal to 15 minutes, less than or equal to 10 minutes, less than or equal to 5 minutes, less than or equal to 2 minutes, or less than or equal to 1 minute. In some embodiments, the actuating component is configured for gastric deployment for greater than or equal to 10 seconds, greater than or equal to 30 seconds, greater than or equal to 1 minute, greater than or equal to 2 minutes, greater than or equal to 5 minutes, greater than or equal to 10 minutes, greater than or equal to 15 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 2 hours, greater than or equal to 4 hours, greater than or equal to 6 hours, greater than or equal to 8 hours, greater than or equal to 10 hours, greater than or equal to 12 hours, or greater than or equal to 18 hours. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 10 seconds and less than or equal to 24 hours). Other ranges are also possible. In some embodiments, the actuating component is configured and designed such that a pharmaceutical agent is released from the actuating component (e.g., into a tissue of a subject) for at least a portion of the gastric deployment time. In some embodiments, after deployment, the actuating component is configured to exit the location internal to the subject (e.g., at least a portion of the actuating component degrades, dissolves, mechanically weakens, or mechanically breaks such that the actuating component exits the location internal to the subject).
In some embodiments, a pharmaceutical agent may be administered to a subject by administering an article comprising a containing structure (e.g., capsule) containing an actuating component and releasing the actuating component, at a location internal to the subject, such that the actuating component obtains a deployed configuration, different than the pre-deployment configuration of the actuating component. In some embodiments, upon obtaining the deployed configuration, the plurality of microneedles engage with a least a portion of tissue at the location internal to the subject and the tissue is exposed to the pharmaceutical agent.
In some embodiments, the tissue interfacing component may comprise a plurality of microneedles. In some such embodiments, the plurality of microneedles may have a particular base largest cross-sectional dimension (e.g., diameter of the base), a particular height, and/or a particular spacing.
In some embodiments, the average diameter of the base of the plurality of microneedles is greater than or equal to 100 microns, greater than or equal to 150 microns, greater than or equal to 200 microns, greater than or equal to 250 microns, greater than or equal to 300 microns, greater than or equal to 350 microns, greater than or equal to 400 microns, or greater than or equal to 450 microns. In certain embodiments, the average diameter of the base of the plurality of microneedles is less than or equal to 500 microns, less than or equal to 450 microns, less than or equal to 400 microns, less than or equal to 350 microns, less than or equal to 300 microns, less than or equal to 250 microns, less than or equal to 200 microns, or less than or equal to 150 microns. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 100 microns and less than or equal to 500 microns). Other ranges are also possible.
In certain embodiments, the average height of the plurality of microneedles (or protrusion such as a needle) is greater than or equal to 0.1 mm, greater than or equal to 0.2 mm, greater than or equal to 0.5 mm, greater than or equal to 0.7 mm, greater than or equal to 1 mm, greater than or equal to 1.2 mm, greater than or equal to 1.5 mm, greater than or equal to 2 mm, greater than or equal to 3 mm, or greater than or equal to 4 mm. In some embodiments, the average height of the plurality of microneedles/needles is less than or equal to 5 mm, less than or equal to 4 mm, less than or equal to 3 mm, less than or equal to 2.5 mm, less than or equal to 2 mm, less than or equal to 1.5 mm, less than or equal to 1.2 mm, less than or equal to 1 mm, less than or equal to 0.7 mm, less than or equal to 0.5 mm, or less than or equal to 0.2 mm. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 0.1 mm and less than or equal to 5 mm). Other ranges are also possible.
In some cases, the average spacing (e.g., spacing between adjacent microneedles in the plurality of microneedles) of the plurality of microneedles may be greater than or equal to 50 microns, greater than or equal to 100 microns, greater than or equal to 200 microns, greater than or equal to 300 microns, greater than or equal to 400 microns, greater than or equal to 500 microns, greater than or equal to 600 microns, greater than or equal to 700 microns, greater than or equal to 800 microns, greater than or equal to 900 microns, greater than or equal to 1000 microns, greater than or equal to 1100 microns, greater than or equal to 1200 microns, greater than or equal to 1300 microns, or greater than or equal to 1400 microns. In certain embodiments, the average spacing of the plurality of microneedles is less than or equal to 1500 microns, less than or equal to 1400 microns, less than or equal to 1300 microns, less than or equal to 1200 microns, less than or equal to 1100 microns, less than or equal to 1000 microns, less than or equal to 900 microns, less than or equal to 800 microns, less than or equal to 700 microns, less than or equal to 600 microns, less than or equal to 500 microns, less than or equal to 400 microns, less than or equal to 300 microns, or less than or equal to 200 microns. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 50 microns and less than or equal to 1500 microns). Other ranges are also possible.
Advantageously, in some embodiments, the plurality of microneedles dissolve relatively quickly (e.g., in less than or equal to 48 hours), reducing and/or eliminating the risk of secondary penetration by the component in undesired locations. In some embodiments, the largest cross-sectional dimension (e.g., length) of the component is designed to be delivered to whichever organ it is targeting to prevent pain and/or undesired perforation of the GI tract.
In some embodiments, the plurality of microneedles comprise a pharmaceutical agent (e.g., API) and a second material (if present), such that the pharmaceutical agent is present in the plurality of microneedles in an amount of greater than or equal to 10 wt % versus the total weight of the plurality of microneedles. In certain embodiments, the pharmaceutical agent is present in the plurality of microneedles in an amount of greater than or equal to 0.1 wt %, greater than or equal to 0.2 wt %, greater than or equal to 0.5 wt %, greater than or equal to 1 wt %, greater than or equal to 2 wt %, greater than or equal to 5 wt %, greater than or equal to 10 wt %, greater than or equal to 20 wt %, greater than or equal to 30 wt %, greater than or equal to 40 wt %, greater than or equal to 50 wt %, greater than or equal to 60 wt %, greater than or equal to 70 wt %, greater than or equal to 80 wt %, greater than or equal to 90 wt %, greater than or equal to 95 wt %, greater than or equal to 98 wt %, or greater than or equal to 99.1 wt % versus the total weight of the plurality of microneedles. In some embodiments, the pharmaceutical agent is present in the plurality of microneedles in an amount of less than or equal to 100 wt %, less than or equal to 99 wt %, less than or equal to 98 wt %, less than or equal to 95 wt %, less than or equal to 90 wt %, less than or equal to 80 wt %, less than or equal to 70 wt %, less than or equal to 60 wt %, less than or equal to 50 wt %, less than or equal to 40 wt %, less than or equal to 30 wt %, less than or equal to 20 wt %, less than or equal to 10 wt %, less than or equal to 5 wt %, less than or equal to 2 wt %, less than or equal to 1 wt %, less than or equal to 0.5 wt %, or less than or equal to 0.2 wt % versus the total weight of the plurality of microneedles. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 10 wt % and less than or equal to 100 wt %, greater than or equal to 80 wt % and less than or equal to 100 wt %). Other ranges are also possible.
In some embodiments, the central core of the actuating component comprises the same or different material as the arms of the actuating component. In certain embodiments, the core comprises a spring (e.g., comprising tempered steel and/or nitinol). For example, core may comprises a polymeric material and a spring disposed within the polymeric material.
In some embodiments, the core is configured for undergoing mechanical deformation such that the core does not permanently deform and/or break, and/or is configured to recoil after a particular amount of time such that the actuating component can be selectively retained at a location internally of a subject (e.g., until delivery of the pharmaceutical agent and/or dissolution of the plurality of microneedles and/or arms). In some embodiments, the core material has particular mechanical properties such that the core material resists brittle breakage but is sufficiently stiff such that it may withstand internal physiological mechanical, chemical, and/or biological challenges to facilitate the ability to maintain residence of the structure or at least the loaded material components of the structure for a desired time interval.
In some embodiments, the actuating component core comprises an elastic polymeric material(s). In certain embodiments, the use of an elastic polymeric material may impart favorable mechanical properties to the structure. For example, in some cases, the core (and/or the actuating component) may be configured for undergoing relatively high compressive forces (e.g., compressive forces present within the stomach and/or intestine of a subject) such that the structure does not break and/or is retained at a location internally of the subject. In certain embodiments, the actuating component and/or core may be configured for being folded (e.g., without breaking). For example, the core may be configured and/or selected for undergoing relatively high levels of bending stresses without breaking and/or without being permanently significantly deformed. In some embodiments, the core and/or the actuating component comprising the core may be configured for substantial recoil. That is to say, after mechanically deforming the core and/or the actuating component comprising the core, the actuating component may return substantially to its original configuration (e.g., the pre-deployment configuration) prior to the mechanical deformation being applied (e.g., the core may be characterized by substantially minimal creep deformation).
Appropriate screening tests may be used to determine suitable materials for use as the core. For example, the core and/or the actuating component may be tested for the capability of undergoing at least about 45 degrees, at least about 60 degrees, at least about 90 degrees, at least about 120 degrees, at least about 150 degrees, or about 180 degrees of mechanical bending deformation without breaking. In certain embodiments, the core and/or the actuating component may be configured for undergoing up to and including about 180 degrees, up to and including about 150 degrees, up to and including about 120 degrees, up to and including about 90 degrees, or up to and including about 60 degrees of mechanical bending deformation without breaking. Any and all closed ranges that have endpoints within any of the above-referenced ranges are also possible (e.g., between about 45 degrees and about 180 degrees, between about 60 degrees and about 180 degrees, between about 60 degrees and about 120 degrees, between about 90 degrees and about 180 degrees). Other ranges are also possible.
In some cases, the core and/or the actuating component may be configured for remaining in a pre-deployment configuration (e.g., at least about 45 degrees of mechanical bending deformation) for a relatively prolonged period of time—for example, in some embodiments, the core has a shelf-life in such a pre-deployment configuration of at least about 24 hours, at least about 1 week, at least about 1 month, at least about 1 year, or at least about 2 years—and still be configured for returning (i.e. recoiling) substantially to its pre-deployment configuration. In certain embodiments, the core has a shelf life in a pre-deployment configuration of up to and including about 3 years, up to and including about 2 years, up to and including about 1 year, up to and including about 1 month, or up to and including about 1 week and be configured for returning (i.e.
recoiling) substantially to its deployed configuration. Any and all closed ranges that have endpoints within any of the above-referenced ranged are also possible (e.g., between about 24 hours and about 3 years, between about 1 week and 1 year, between about 1 year and 3 years). Other ranges are also possible.
In some embodiments, the core is relatively flexible. In certain embodiments, the core may be selected such that it is configured for undergoing large angle deformation for relatively long periods of time without undergoing significant non-elastic deformation. In some such embodiments, the core may have a strength of recoil sufficient to substantially return the elastic polymeric component to its deployment configuration within less than or equal to 30 minutes, within less than or equal to 10 minutes, within less than or equal to 5 minutes, within less than or equal to 1 minute, within less than 30 seconds, within less than or equal to 15 seconds, within less than or equal to 10 seconds, within less than or equal to 5 seconds, within less than or equal to 2 seconds, or within less than or equal to 1 second after release of the mechanical deformation (e.g., as applied by the containing structure). In some embodiments, the core may have a strength of recoil sufficient to substantially return the elastic polymeric component to its deployment configuration within greater than or equal to 0.1 seconds, within greater than or equal to 1 second, within greater than or equal to 2 seconds, within greater than or equal to 5 seconds, within greater than or equal to 10 seconds, within greater than or equal to 15 seconds, within greater than or equal to 30 seconds, within greater than or equal to 1 minute, within greater than or equal to 5 minutes, or within greater than or equal to 10 minutes after release of the mechanical deformation. Combinations of the above referenced ranges are possible (e.g., less than or equal to 30 minutes and greater than or equal to 0.1 seconds). Other ranges are also possible.
The core is preferably biocompatible. The term “biocompatible,” as used in reference to a polymeric component, refers to a polymer that does not invoke a substantial adverse reaction (e.g., deleterious immune response) from an organism (e.g., a mammal), a tissue culture or a collection of cells, or invokes only a reaction that does not exceed an acceptable level. In some embodiments, the core comprises polymers, networks of polymers, and/or multi-block combinations of polymer segments, that may comprise polymers or polymer segments that are for example: polyesters—such as including but not limited to, polycaprolactone, poly(propylene fumarate), poly(glycerol sebacate), poly(lactide), poly(glycol acid), poly(lactic-glycolic acid), polybutyrate, and polyhydroxyalkanoate; polyethers—such as including but not limited to, poly(ethylene glycol) and poly(propylene oxide); polysiloxanes—such as including but not limited to, poly(dimethylsiloxane); polyamides—such as including but not limited to, poly(caprolactam); polyolefins—such as including but not limited to, polyethylene; polycarbonates—such as including but not limited to poly(propylene oxide); polyketals; polyvinyl alcohols; polyoxetanes; polyacrylates/methacrylates—such as including but not limited to, poly(methyl methacrylate) and poly(ethyl-vinyl acetate); polyanhydrides; polyvinylpyrrolidone, and polyurethanes. In some embodiments, the polymer is cross-linked. In some embodiments, the core comprises a polymer composite comprising two or more chemically similar polymers or two or more chemically distinct polymers.
According to some embodiments, the actuating component is configured to degrade, dissolve, and/or disassociate into one or more forms capable of passing through a gastrointestinal tract (e.g., after a desired period of time). In some embodiments, the arms of the actuating component may be selected such that each arm dissolves, degrades, mechanically weakens, and/or mechanically separates from the core after a particular residence time period. The term residence time period generally refers to the length of time during which the actuating component described herein is resided at a location internally of a subject as measured from the time initially present in the location internally of the subject to the time at which the device no longer resides at the location internally of the subject due to, for example, degradation, dissolution, and/or exit of at least a portion of the actuating component from the location internally of the subject. In an illustrative embodiment, the actuating component may be orally administered such that the actuating component resides at a location internally of the subject such as the small intestine and exits the small intestine (e.g., after degradation of at least a portion of the actuating component such as the arms), where the residence time period is measured as the length of time between when the actuating component initially resides in the small intestine and when the device exits the small intestine.
In some embodiments, the arms of the actuating component may comprise a degradable material. In some cases, the arms may be configured to mediate disassembly of the actuating component after, for example, delivery of a pharmaceutical agent for the residence time period (e.g., after less than or equal to 48 hours), and safe passage through the lower intestinal tract of the subject. Exit from a location such as the small intestine may be achieved through changes in the mechanical properties of each arm (e.g., via biodegradation) such that the ability to resist passage through the small intestine compromised.
In some embodiments, each arm may have a particular cross-sectional shape. In certain embodiments, the shape may be any suitable cross-sectional shape including circular, oval, triangular, irregular, trapezoidal, square or rectangular, or the like.
In some embodiments, each arm may have a particular length. In some embodiments, the average length of the arms is less than or equal to 30 mm, less than or equal to 28 mm, less than or equal to 26 mm, less than or equal to 25 mm, less than or equal to 20 mm, less than or equal to 15 mm, or less than or equal to 12 mm. In certain embodiments, the average length of the arms is greater than or equal to 10 mm, greater than or equal to 12 mm, greater than or equal to 15 mm, greater than or equal to 20 mm, greater than or equal to 25 mm, greater than or equal to 26 mm, or greater than or equal to 28 mm. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 10 mm and less than or equal to 30 mm). Other ranges are also possible.
In some embodiments, each arm may have a particular width. In some embodiments, the average width of the arms is less than or equal to 3.0 mm, less than or equal to 2.8 mm, less than or equal to 2.6 mm, less than or equal to 2.5 mm, less than or equal to 2.0 mm, less than or equal to 1.5 mm, or less than or equal to 1.2 mm. In certain embodiments, the average width of the arms is greater than or equal to 1.0 mm, greater than or equal to 1.2 mm, greater than or equal to 1.5 mm, greater than or equal to 2.0 mm, greater than or equal to 2.5 mm, greater than or equal to 2.6 mm, or greater than or equal to 2.8 mm. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 1.0 mm and less than or equal to 3.0 mm). Other ranges are also possible.
The flexural moduli of the arms may be selected to impart desirable features to the actuating component including, for example, the ability to fold and/or bend such that the actuating component can be encapsulated without breaking and/or the ability to withstand compressive forces such as those within the gastric cavity.
In some cases, the actuating component may be configured to deliver a particular amount of pharmaceutical agent per square centimeter of tissue of a subject. For example, in some embodiments, the actuating component is configured to deliver greater than or equal to 0.01 greater than or equal to 0.05 μg, greater than or equal to 0.1 μg, greater than or equal to 0.2 μg, greater than or equal to 0.5 μg, greater than or equal to 0.7 μg, greater than or equal to 1 μg, greater than or equal to 2 μg, greater than or equal to 5 μg, greater than or equal to 10 μg, greater than or equal to 25 μg, greater than or equal to 50 μg, greater than or equal to 100 μg, greater than or equal to 250 μg, greater than or equal to 500m, greater than or equal to 1000m, or greater than or equal to 2500 μg, greater than or equal to 4000 μg of pharmaceutical agent per square centimeter of tissue of the subject proximate the penetration location of the actuating component. In certain embodiments, the actuating component is configured to deliver less than or equal to 5000 μg, less than or equal to 4000 μg, less than or equal to 2500 μg, less than or equal to 1000 μg, less than or equal to 500 μg, less than or equal to 250 μg, less than or equal to 100 μg, less than or equal to 50 μg, less than or equal to 25 μg, less than or equal to 20 μg, less than or equal to 5 μg, less than or equal to 2 μg, less than or equal to 1 μg, less than or equal to 0.7 μg, less than or equal to 0.5 μg, less than or equal to 0.2 μg, less than or equal to 0.1 μg, or less than or equal to 0.05 μg of pharmaceutical agent per square centimeter of tissue. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 1 μg and less than or equal to 5000 μg). In some embodiments, the actuating component is configured to deliver greater than or equal to 1 μg and less than or equal to 5000 μg of pharmaceutical agent per square centimeter of tissue of the subject over any suitable time period (e.g., in greater than or equal to 0.1 seconds, in greater than or equal to 0.5 seconds, in greater than or equal to 1 second, in greater than or equal to 5 seconds, in greater than or equal to 30 seconds, greater than or equal to 1 minute, greater than or equal to 5 minutes, 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 4 hours, greater than or equal to 24 hours).
According to some embodiments, the components and methods described herein are compatible with one or more therapeutic, diagnostic, and/or enhancement agents, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the pharmaceutic agent, is a therapeutic, nutraceutical, prophylactic or diagnostic agent. While much of the specification describes the use of pharmaceutical agents, other agents listed herein are also possible.
Agents can include, but are not limited to, any synthetic or naturally-occurring biologically active compound or composition of matter which, when administered to a subject (e.g., a human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals, Certain such agents may include molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc., for use in therapeutic, diagnostic, and/or enhancement areas, including, but not limited to medical or veterinary treatment, prevention, diagnosis, and/or mitigation of disease or illness (e.g., HMG co-A reductase inhibitors (statins) like rosuvastatin, nonsteroidal anti-inflammatory drugs like meloxicam, selective serotonin reuptake inhibitors like escitalopram, blood thinning agents like clopidogrel, steroids like prednisone, antipsychotics like aripiprazole and risperidone, analgesics like buprenorphine, antagonists like naloxone, montelukast, and memantine, cardiac glycosides like digoxin, alpha blockers like tamsulosin, cholesterol absorption inhibitors like ezetimibe, metabolites like colchicine, antihistamines like loratadine and cetirizine, opioids like loperamide, proton-pump inhibitors like omeprazole, anti(retro)viral agents like entecavir, dolutegravir, rilpivirine, and cabotegravir, antibiotics like doxycycline, ciprofloxacin, and azithromycin, anti-malarial agents, and synthroid/levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal contraception); performance enhancement (e.g., stimulants like caffeine); and nutrition and supplements (e.g., protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineral supplements).
In certain embodiments, the active substance is one or more specific pharmaceutical agents. As used herein, the term “pharmaceutical agent” or also referred to as a “drug” refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the body of the subject to treat and/or prevent the disease, disorder, or condition. Listings of examples of known therapeutic agents can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill/Appleton & Lange; 8th edition (Sep. 21, 2000); Physician's Desk Reference (Thomson Publishing), and/or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed (2006) following its publication, Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, C. A. (ed.), Merck Publishing Group, 2005; and “Approved Drug Products with Therapeutic Equivalence and Evaluations,” published by the United States Food and Drug Administration (F.D.A.) (the “Orange Book”). Examples of drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antipsychotic agents, neuroprotective agents, anti-proliferatives, such as anti-cancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxioltyics, bacteriostatics, immunosuppressant agents, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics. Nutraceuticals can also be incorporated into the drug delivery device. These may be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or phytohormones.
In some embodiments, the pharmaceutical agent is one or more antimalarial drugs. Exemplary antimalarial drugs include quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfonamides such as sulfadoxine and sulfamethoxypyridazine, mefloquine, atovaquone, primaquine, halofantrine, doxycycline, clindamycin, artemisinin and artemisinin derivatives. In some embodiments, the antimalarial drug is artemisinin or a derivative thereof. Exemplary artemisinin derivatives include artemether, dihydroartemisinin, arteether and artesunate. In certain embodiments, the artemisinin derivative is artesunate.
In another embodiment, the pharmaceutical agent is an immunosuppressive agent. Exemplary immunosuppressive agents include glucocorticoids, cytostatics (such as alkylating agents, antimetabolites, and cytotoxic antibodies), antibodies (such as those directed against T-cell recepotors or II-2 receptors), drugs acting on immunophilins (such as cyclosporine, tacrolimus, and sirolimus) and other drugs (such as interferons, opioids, TNF binding proteins, mycophenolate, and other small molecules such as fingolimod).
In certain embodiments, the pharmaceutical agent is a hormone or derivative thereof. Non-limiting examples of hormones include insulin, growth hormone (e.g., human growth hormone), vasopressin, melatonin, thyroxine, thyrotropin-releasing hormone, glycoprotein hormones (e.g., luteinzing hormone, follicle-stimulating hormone, thyroid-stimulating hormone), eicosanoids, estrogen, progestin, testosterone, estradiol, cortisol, adrenaline, and other steroids.
In some embodiments, the pharmaceutical agent is a small molecule drug having molecular weight less than about 2500 Daltons, less than about 2000 Daltons, less than about 1500 Daltons, less than about 1000 Daltons, less than about 750 Daltons, less than about 500 Daltons, less or than about 400 Daltons. In some cases, the pharmaceutical agent is a small molecule drug having molecular weight between 200 Daltons and 400 Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltons and 2500 Daltons.
In some embodiments, the pharmaceutical agent is selected from the group consisting of active pharmaceutical agents such as insulin, nucleic acids, peptides, bacteriophage, DNA, mRNA, human growth hormone, monoclonal antibodies, adalimumab, epinephrine, GLP-1 Receptor agoinists, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, small molecule drugs, progrstin, vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, and conjugate vaccines, toxoid vaccines, influenza vaccine, shingles vaccine, prevnar pneumonia vaccine, mmr vaccine, tetanus vaccine, hepatitis vaccine, HIV vaccine Ad4-env Clade C, HIV vaccine Ad4-mGag, dna vaccines, rna vaccines, etanercept, infliximab, filgastrim, glatiramer acetate, rituximab, bevacizumab, any molecule encapsulated in a nanoparticle, epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumab pegol, ustekinumab, ixekizumab, golimumab, brodalumab, gusellu,ab, secikinumab, omalizumab, tnf-alpha inhibitors, interleukin inhibitors, vedolizumab, octreotide, teriperatide, crispr cas9, insulin glargine, insulin detemir, insulin lispro, insulin aspart, human insulin, antisense oligonucleotides, and ondansetron.
In an exemplary embodiment, the pharmaceutical agent is insulin.
In some embodiments, the tissue-interfacing component described herein comprises two or more types of pharmaceutical agents.
In certain embodiments, the pharmaceutical agent is present in the tissue interfacing component at a concentration such that, upon release from the tissue interfacing component, the pharmaceutical agent elicits a pharmaceutical response.
In some cases, the pharmaceutical agent may be present at a concentration below a minimal concentration generally associated with an active pharmaceutical agent (e.g., at a microdose concentration). For example, in some embodiments, the tissue interfacing component comprises a first pharmaceutical agent (e.g., a steroid) at a relatively low dose (e.g., without wishing to be bound by theory, low doses of pharmaceutical agents such as steroids may mediate a subject's foreign body response(s) (e.g., in response to contact by a tissue interfacing components) at a location internal to a subject). In some embodiments, the concentration of the pharmaceutical agent is a microdose less than or equal to 100 μg and/or 30 nMol. In other embodiments, however, the pharmaceutical agent is not provided in a microdose and is present in one or more amounts listed above.
In some embodiments, between 0.05 wt % to 99 wt % of the pharmaceutical agent initially contained in a plurality of microneedles is released (e.g., in vivo) between 30 minutes and 48 hours. In some embodiments, between about 0.05 wt % and about 99.0 wt % of the pharmaceutical agent is released (e.g., in vivo) from the plurality of microneedles after a certain amount of time. In some embodiments, at least about 0.05 wt %, at least about 0.1 wt %, at least about 0.5 wt %, at least about 1 wt %, at least about 5 wt %, at least about 10 wt %, at least about 20 wt %, at least about 50 wt %, at least about 75 wt %, at least about 90 wt %, at least about 95 wt %, or at least about 98 wt % of the pharmaceutical agent associated with the plurality of microneedles is released from the component (e.g., in vivo) within about 48 hours. In certain embodiments, at least about 0.05 wt %, at least about 0.1 wt %, at least about 0.5 wt %, at least about 1 wt %, at least about 5 wt %, at least about 10 wt %, at least about 20 wt %, at least about 50 wt %, at least about 75 wt %, at least about 90 wt %, at least about 95 wt %, or at least about 98 wt % of the pharmaceutical agent associated with the plurality of microneedles is released from the component (e.g., in vivo) within 30 minutes to 24 hours. For example, in some cases, at least about 90 wt % of the pharmaceutical agent associated with the plurality of microneedles is released from the component (e.g., in vivo) within 24 hours.
In certain embodiments, the configuration of the actuating component may be characterized by a largest cross-sectional dimension. In some embodiments, the largest cross-sectional dimension of the pre-deployment (i.e. first) configuration may be at least about 10% less, at least about 20% less, at least about 40% less, at least about 60% less, or at least about 80% less than the largest cross-sectional dimension of the second configuration. In certain embodiments, the largest cross-sectional dimension of the deployed (i.e. second) configuration may be at least about 10% less, at least about 20% less, at least about 40% less, at least about 60% less, or at least about 80% less than the largest cross-sectional dimension of the first configuration. Any and all closed ranges that have endpoints within any of the above referenced ranges are also possible (e.g., between about 10% and about 80%, between about 10% and about 40%, between about 20% and about 60%, between about 40% and about 80%). Other ranges are also possible.
In some embodiments, the configuration of the actuating component may be characterized by a convex hull volume of the actuating component. The term convex hull volume is known in the art and generally refers to a set of surfaces defined by the periphery of a 3-D object such that the surfaces define a particular volume. In some embodiments, the convex hull volume of the first configuration may be at least about 10% less, at least about 20% less, at least about 40% less, at least about 60% less, or at least about 80% less than the convex hull volume of the second configuration. In certain embodiments, the convex hull volume of the second configuration may be at least about 10% less, at least about 20% less, at least about 40% less, at least about 60% less, or at least about 80% less than the convex hull volume of the first configuration. Any and all closed ranges that have endpoints within any of the above referenced ranges are also possible (e.g., between about 10% and about 80%, between about 10% and about 40%, between about 20% and about 60%, between about 40% and about 80%). Other ranges are also possible.
Those skilled in the art would understand that the differences between the first configuration and the second configuration do not refer to a swelling or a shrinking of the actuating component (e.g., in the presence of a solvent), but instead refers to a change in shape and/or orientation of at least a portion of the actuating component (e.g., in the presence of a stimulus such as heat and/or mechanical pressure/compression), although some degree of swelling or shrinking may occur between the two configurations.
In some embodiments, the second configuration is constructed and arranged such that the actuating component is retained at a location internal of a subject, and the first configuration is constructed and arranged such that the actuating component may be encapsulated (e.g., for oral delivery of the actuating component within a capsule). In some cases, the second configuration is sufficiently large such that the actuating component is retained at a location internal of the subject and the first configuration is sufficiently small such that the actuating component may fit within a particular size capsule suitable for oral delivery to a subject.
In certain embodiments, the actuating component may be polymerized and/or cast in a deployment configuration, mechanically deformed such that the actuating component obtains a pre-deployment configuration, and placed in a capsule or restrained by some other containment component. The actuating component may be mechanically deformed using any suitable method including, for example, bending, twisting, folding, molding (e.g., pressing the material into a mold having a new shape), expanding (e.g., applying a tensile force to the material), compressing, and/or wrinkling the actuating component. The actuating component may maintain the pre-deployment configuration for any suitable duration prior to stimulation/release, as described herein. Advantageously, certain embodiments of the actuating components described herein may be relatively stable in the deployed and/or pre-deployment configurations such that the actuating component may be stored for long periods of time without significant degradation of mechanical properties of the core, arms, and/or microneedles. In some embodiments, the actuating component may be stable under ambient conditions (e.g., room temperature, atmospheric pressure and relative humidity) and/or physiological conditions (e.g., at or about 37° C., in physiologic fluids) for at least about 1 day, at least about 3 days, at least about 7 days, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 6 months, at least about 1 year, or at least about 2 years.
In certain embodiments, the actuating component has a shelf life of less than or equal to about 3 years, less than or equal to about 2 years, less than or equal to about 1 year, less than or equal to about 1 month, less than or equal to about 1 week, or less than or equal to about 3 days. Any and all closed ranges that have endpoints within any of the above-referenced ranged are also possible (e.g., between about 24 hours and about 3 years, between about 1 week and 1 year, between about 1 year and 3 years). Other ranges are also possible.
In some embodiments, the actuating component in the pre-deployment configuration may recoil such that the actuating component reverts to the deployed configuration. For example, in some embodiments, the actuating component in the pre-deployment configuration is contained within a capsule and delivered orally to a subject. In some such embodiments, the actuating component may travel to the stomach and the capsule may release the actuating component from the capsule, upon which the actuating component obtains (e.g., recoils to) the deployed configuration (e.g., in the absence of forces applied by the capsule or other containment structure).
As described herein, in some embodiments, the core, arms, and/or microneedles of the actuating component may be cast, molded, and/or cut to have a particular shape, size, and/or volume. In some embodiments, the core, arms, and/or microneedles are adhered via an adhesive. In certain embodiments, the core, arms, and/or microneedles are heated such that the core, arms, and/or microneedles are coupled (e.g., via bonding and/or entanglement). In some embodiments, the microneedles may be arranged such that a major axis of each microneedle is substantially perpendicular to a major plane of each arm. In some embodiments, the microneedles may be arranged such that the major axis of each microneedle is oriented at an angle of greater than or equal to 45 degrees and less than or equal to 90 degrees relative to a major plane of each arm.
In certain embodiments, the arms are arranged based on bio-inspired flower bud designs in which a number (N) of radial spokes or petals project from a central linking core. In some embodiments, these radial projections each have an internal sector angle of approximately 360°/N, where N is the total number of radial projections. In some cases, this enhances the packing volume of the encapsulated structure, thus increasing drug carrying capacity. In some embodiments, the arms are formed of a material with a relatively high elastic modulus to increase the resistance to compression and duration of gastric residence, as described herein.
Any terms as used herein related to shape, orientation, alignment, and/or geometric relationship of or between, for example, one or more articles, compositions, structures, materials and/or subcomponents thereof and/or combinations thereof and/or any other tangible or intangible elements not listed above amenable to characterization by such terms, unless otherwise defined or indicated, shall be understood to not require absolute conformance to a mathematical definition of such term, but, rather, shall be understood to indicate conformance to the mathematical definition of such term to the extent possible for the subject matter so characterized as would be understood by one skilled in the art most closely related to such subject matter. Examples of such terms related to shape, orientation, and/or geometric relationship include, but are not limited to terms descriptive of: shape—such as, round, square, circular/circle, rectangular/rectangle, triangular/triangle, cylindrical/cylinder, elipitical/elipse, (n)polygonal/(n)polygon, etc.; angular orientation—such as perpendicular, orthogonal, parallel, vertical, horizontal, collinear, etc.; contour and/or trajectory—such as, plane/planar, coplanar, hemispherical, semi-hemispherical, line/linear, hyperbolic, parabolic, flat, curved, straight, arcuate, sinusoidal, tangent/tangential, etc.; surface and/or bulk material properties and/or spatial/temporal resolution and/or distribution—such as, smooth, reflective, transparent, clear, opaque, rigid, impermeable, uniform(ly), inert, non-wettable, insoluble, steady, invariant, constant, homogeneous, etc.; as well as many others that would be apparent to those skilled in the relevant arts. As one example, a fabricated article that would described herein as being “square” would not require such article to have faces or sides that are perfectly planar or linear and that intersect at angles of exactly 90 degrees (indeed, such an article can only exist as a mathematical abstraction), but rather, the shape of such article should be interpreted as approximating a “square,” as defined mathematically, to an extent typically achievable and achieved for the recited fabrication technique as would be understood by those skilled in the art or as specifically described.
As used herein, the terms “oligomer” and “polymers” each refer to a compound of a repeating monomeric subunit. Generally speaking, an “oligomer” contains fewer monomeric units than a “polymer.” Those of skill in the art will appreciate that whether a particular compound is designated an oligomer or polymer is dependent on both the identity of the compound and the context in which it is used.
One of ordinary skill will appreciate that many oligomeric and polymeric compounds are composed of a plurality of compounds having differing numbers of monomers. Such mixtures are often designated by the average molecular weight of the oligomeric or polymeric compounds in the mixture. As used herein, the use of the singular “compound” in reference to an oligomeric or polymeric compound includes such mixtures.
As used herein, reference to any oligomeric or polymeric material without further modifiers includes said oligomeric or polymeric material having any average molecular weight. For instance, the terms “polyethylene glycol” and “polypropylene glycol,” when used without further modifiers, includes polyethylene glycols and polypropylene glycols of any average molecular weight.
The following examples are intended to illustrate certain embodiments of the present invention, but do not exemplify the full scope of the invention.
The following example describes the design and characterization of an exemplary actuating component (e.g., a luminal unfolding microinjector (LUMI)) and related articles. The actuating component in this example generally utilized the tube like geometry of the small intestine to create multiple points of contact with the tissue (
When exiting the capsule, the exemplary actuating component opened in one of two orientations: either in a plane parallel or perpendicular to the central axis of the small intestine (
Varying the arm length and unfolding angle generally affected the amount of force delivered by the actuating component core (
The milled steel center increased the unfolding impact force compared to a core made solely from mediprene. This effect was not seen if the mediprene material continued along the arm past the steel section. For example, in a 15 mm long mediprene core with a 7 mm long steel section, there existed no significant change in impact force between a device with and without the steel part (
In vivo, it was noted that devices with longer arms opened in the axial direction more frequently than devices with shorter arms (
The actuating component fit inside of a custom designed capsule with a 9 mm diameter and 26 mm length (
The unfolding arms were designed to ensure they maintained enough strength to deliver the drug payload in vivo while still dissolving in a timely manner to prevent obstruction. Fabricated from mixtures of biodegradable polyethylene oxide (PEO) and Soluplus®, the arms completely dissolved within 24 hours in vitro and in vivo (
The following example demonstrates the characterization of the penetration of tissue by the microneedle patch of the actuating component such as those described in Example 1.
Penetration experiments were performed on ex vivo human small intestine tissue as well as on ex vivo and in vivo swine tissue to determine the force and distance required to generate a full thickness perforation. Camera footage showed the needle entered the tissue after applying as low as 5 mN of force. The needle reached a displacement of over 6 mm before perforating the outermost tissue layer. Hypodermic needles of all sizes required similar amounts of force to displace the tissue 6 mm (
A novel method for microneedle fabrication utilizing API powder was developed in order to increase the drug loading for the actuating component (
The actuating component was also able to load multiple formulations and active pharmaceutical ingredients by incorporating microneedle patches made with insulin, lysozyme and alpha-glucosidase onto the actuating component (
When released in the small intestine in vivo, actuating components loaded with insulin delivered drug systemically and achieved a peak plasma concentration comparable to subcutaneous dosing. In total we delivered 0.6 mg of drug and 1 cm2 of microneedles in each experiment. In one set of experiments, we placed and released two actuating components per swine in the jejunum. This method of delivery provided a 44%±5% blood glucose drop over 60 minutes (
Over the course of 4 hours, the microneedle patch applied to the small intestine and the subcutaneously dosed insulin delivered an equivalent systemic drug uptake (
The following example demonstrates the safety and delivery design of exemplary actuating components, such as those described in Examples 1 and 2.
The experiments performed addressed the safety and efficacy of microneedle penetration in the GI tract. The tissue penetration tests performed with human and swine tissue, in combination with the “bed of needles” effect, reinforced the notion that the actuating component provided no significant risk for microneedle perforation. A comparative device containing 30 microneedles would generally require on the order of 3 N to perforate the tissue with each needle. The actuating component described in Examples 1 and 2 delivered a force on the order of 10 times less than comparative devices. Still, it was possible that a device would deliver an array of needles such that the force was unevenly distributed. In fact, literature on transdermal microneedle patch delivery demonstrated that applicators applied a disproportionate amount of force to microneedles on the corners of patches. The small intestine in particular possessed an uneven surface due to folds and villi projections, which made the tissue more susceptible to uneven force distributions. The experiments described herein showed through histology and microCT that no perforation event occurred even with an unfolding actuating component containing a single hypodermic needle on each arm.
The risk of small intestine obstruction, a medical condition sometimes requiring hospitalization and surgery, generally increases with the presence of large non-degradable objects. The actuating components described in Examples 1 and 2 were designed to dissolve and break apart into small pieces to avoid this complication. The Pillcam™, an ingestible non-dissolving capsule endoscopy system, measures 11 mm in diameter and 26 mm in length. During a study, these capsules retained for greater than 24 hours within the GI tract at a rate of 1.4%. Case reports have demonstrated that Pillcam™ retention sometimes led to GI obstruction. While this obstruction and retention rate was acceptable for devices dosed once every several years, daily dosed devices require more stringent safety limits. Many ingestible and non-degradable devices in preclinical development exhibit dimensions similar to the Pillcam™. Obstruction risk may prevent these larger devices from passing clinical trials.
An exemplary actuating component utilized the OROS osmotic pump capsule, a daily dosed and non-degrading drug delivery device, as a model for device size. One version of the OROS measured 12 mm in diameter and 5 mm in thickness with an obstruction rate of less than 1 in 50 million during commercialization. Another version of the OROS measured 9 mm in diameter and 15 mm in length. with a gastric retention rate of only 1 in 22 million. During our experiments, the actuating component left behind non-degradable pieces equivalent in size to the OROS system. After the arms degraded, the actuating component 1.5 mm thick and 12 mm in diameter core possessed dimensions smaller than the OROS pill. The capsule also broke up into smaller pieces (9 mm in diameter and 15 mm in length), comparable in size to the second OROS system. Therefore, it is expected that the rates of gastric obstruction would remain inconsequential during further translation efforts.
While certain sensations such as pain from injection do not exist in the GI tract, discomfort arises when the small intestine bloats and stretches. Because the actuating component functioned by stretching the small intestine to inject needles, discomfort may have arisen during device actuation. These feelings were not observed as deployment occurred while pigs were sedated. Pigs were monitored daily after delivering the devices, and they showed no signs of discomfort. The fast dissolution time for the arms on the order of a few hours ensured that the stretch would only occur for as long as necessary to deliver the drug payload. No changes in behavior or eating habits were observed until capsule excretion.
The exemplary actuating components generally used gastric emptying to move from the stomach to the small intestine. Gastric emptying times vary significantly between people. Emptying typically occurs in 1-4 hours, but individuals experiencing gastroparesis—common in diabetic patients-may face gastric emptying times as long as 24 hours. Ultimately, the actuating component provided a safe and effective platform technology for injecting microneedles into small intestinal tissue. It effectively delivered insulin systemically in a swine model. The actuating component could potentially deliver any drug formulation mentioned in the microneedle literature including vaccines, monoclonal antibodies, enzymes, hormones, and many other compounds which currently lack oral formulations. Clinical translation of orally delivered GI microneedle injections could lead to a paradigm shift in the delivery of macromolecules.
The following example demonstrates exemplary materials and fabrication methods that may be used to fabricate actuating components, such as those described in Examples 1-3.
Dulbecco's Phosphate-Buffered Saline (PBS) was purchased from Gibco by Life Technologies (Woburn, USA). Human insulin was obtained from Novo Nordisk (Maalov, Denmark). Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) was purchased from BASF (Ludwigshafen, Germany). The 100,000 and 200,000 molecular weight poly(ethylene oxide) (PEO), along with the sulforhodamine 101 acid chloride (Texas red) was purchased from Sigma Aldrich (Natick, USA). Polyvinylpyrrolidone, average M.W. 58,000, was obtained from Alfa Aesar (Haverhill, USA).
Polydimethylsiloxane (PDMS) Sylgard 184 was purchased from Dow Corning (Midland, USA). Female Yorkshire swine were obtained from Tufts University (Medford, USA) and excised swine tissue from the Blood Farm Slaughterhouse (West Groton, USA). Human tissue was provided within 24 h of retrieval by the National Disease Research Interchange (NDRI, Philadelphia, USA). The Blue CDI's Tissue Marking Dye® was purchased from Cancer Diagnostics (Durham, USA). Mediprene 4410-LP11L was obtained from Lubrizol (Wickliffe, USA). Eudragit L 100-55 and Eudragit S100 were obtained from Evonik (Essen, Germany). 316 stainless steel shim stock was obtained from McMaster Carr (Elmhurst, USA).
Three dimensional actuating component models were designed in Solidworks (Dassault Systemes, Velizy-Villacoublay, France) and printed out on an Objet 30 Pro 3D printer (Stratasys, Eden Prairie, USA). A negative mold was created out of PDMS (Figure S13). Stainless steel cores milled on an OtherMill V2 (Bantam Tools, Berkeley, Calif.) were encased in mediprene and added to the center core of the mold. A mixture of 25% Soluplus® and 75% PEO 200 kDa was microcompounded on an Xplore™ twin screw microcompounder (Xplore™ Instruments, Netherlands) at 50 rpm. This mixture was added to the arm sections of the mold. Using a Master-Mite model 10008 heat gun (McMaster Carr, Elmhurst, Ill.), the materials were melted. The metal core was aligned to the center of the device. Pressure was then applied to the mold and the materials were allowed to cool.
Fabricated microneedle patches were then placed on the recessed sections of the actuating component arms. The base plates of the patches were sanded down to a thickness of 1 mm and the patches were cut into 4×8 microneedle arrays of drug loaded microneedles. The arms of the device were then reheated using a heat gun, and the patches were placed into the melted sections of the arms.
Single hypodermic needle perforation testing in vivo was performed by affixing a needle to a 10 N Shimpo force gauge (Cedarhurst, USA). The force gauge was attached to an arm on a custom stage. A motor was used to move the arm downwards at a rate of 0.2 mm/s. A camera was placed on the moving stage to visualize the penetration event. The force measurements and video feed were recorded in LabVIEW (National Instruments, Austin, USA). Yorkshire swine were sedated as described in the in vivo section, and a laparotomy procedure was performed to access the small intestine. A 5 cm incision was made in the small intestine to reveal a working area of 5 cm by 1.5 cm, and the tissue was fixed so that it was held taut. The needle was then placed directly over the tissue and moved downward at the defined rate until we were able to visualize the needle on the other size of the tissue. All perforation events were correlated to a force drop. Breathing affected intraoperative measurements, and it was determined that the displacement caused by the breathing accounted for an extra 3 mm of penetration. This distance change was measured using a ruler and confirmed it by analyzing the force vs displacement curves. It was confirmed that forces during the exhaled state were equivalent to forces during the inhaled state 3 mm earlier.
Single hypodermic needle perforation testing ex vivo was performed using an Inston 5943 machine equipped with a 10 N load cell (Norwood, USA). Harvested tissue was affixed to a corkboard with a 2.5 cm diameter hole. Needles were fixed to the Instron machine's cross-head and lowered into the tissue above the hole at a rate of 0.1 mm/s until we visualized the needle on the other side of the tissue. All perforation events were correlated to a force drop.
Penetration of the microneedles attached to the actuating component were tested by performing histology and microCT on ex vivo swine tissue. MicroCT imaging was performed on a GE CT120 microCT imaging system (General Electric, Boston, USA). The devices were deployed with either sharpened metal hypodermic needles or with microneedles loaded with barium sulfate (Sigma Aldrich). The needles were also coated in a tissue marking dye (Cancer Diagnostics Inc, Durhan, USA) in order to mark the area of tissue penetration for histology.
Mixtures of either 100 kDa or 200 kDa PEO and Soluplus® were combined in an Xplore™ twin screw microcompounder (Xplore™ Instruments, Netherlands) at 50 rpm. The extruded material was captured in an Xplore™ 5.5 cm3 laboratory injection molding machine and molded in to an equilateral triangular prism with side lengths of 3.6 mm and a height of 18.55 mm. The machine exerted 3 bars of pressure for 1 second, ramped up to 4.5 bars over 1 second, and held a pressure of 4.5 bars for an additional 5 seconds. Homemade Simulated Intestinal Fluid (SIF) was made by mixing 6.8 g of KH2PO4 Potassium phosphate monobasic (Sigma Aldrich) with 0.896 g NaOH (Sigma Aldrich) in 1 L of nanopure water. The pH was confirmed to be at 6.8 using the Mettler Toledo FiveGo pH meter (Columbus, USA).
Eight 250 mL Falcon tissue culture flasks (Corning, Corning, USA) were labeled and used to house each mixture. A volume of 225 mL of SIF was inserted into each flask and stored at 37° C. in an Innova 44 incubator (Eppendorf, Hamburg, Germany) which was being shaken at 50 rpm. The 50 rpm agitation simulated the intestinal environment. The flasks containing only SIF were left in the incubator for 6 hours to allow for temperature equilibration. One extruded shape was dropped inside each flask. The shapes were photographed at the 5 min, 1.67 h and 22.5 h time points and the appearance of the arms and the SIF were noted.
Additionally, the mechanical properties of the PEO and Soluplus® mixtures were determined during the dissolution process. Using the same microcompounding and extrusion method described above, bars of the mixtures measuring 3.2 mm×12.8 mm×63.5 mm were created. Three point bend tests were performed on the bars using a uniaxial mechanical tester (Instron 5943, Norwood, USA). These bend tests were performed on bars that were not placed in any liquid bath as well as bars that were placed in a shaken and incubated mixture of SIF for 10 minutes. Bars were fixed on a three point bend fixture (Instron) with support pins placed 36 mm apart. The cross-head was moved at a rate of 10 mm/min. Maximum flexural strength was calculated from the maximum load using the following equation:
where F is the load at the fracture point, L is the length of the support span, b is the width of the bar, and d is the thickness of the bar. The maximum flexural strength for the actuating component arm was also calculated from this equation using the arm's dimensions.
Three dimensional models of the capsule pieces were created in Solidworks and printed on an Objet 30 Pro 3D printer. The two body portions of the capsule were adhered together by spray coating Eudragit S onto the piece as they were clasped together. The bottom piece of the capsule was press fit into the bottom portion of the capsule's body. A spring with a compressed length of 4.114 mm, a load of 1.343 N, and a free length of 31.750 mm (Spring CI 011EF 11S, Lee Spring, Brooklyn, USA) was then trimmed to a length of 30 mm and cut in half. Using thread (Sparkfun, Niwon, USA), one half of the springs were tied to the bottom section of the capsule, and the other half were tied to the plunger. The two spring halves were then placed inside the capsule in series. Pressure was applied on the plunger to fully compress the spring. Melted PEG was then fed through the bottom of the capsule to freeze the spring in place. Molecular weights of PEG between 3,000 and 35,000 were used (Sigma Aldrich). The change in dissolution time allowed the capsule to release the device at different time intervals. The relationship between PEG molecular weight and capsule actuation was tested in a bath of SIF heated to 37° C. Eudragit L-100 55 was then spray coated onto the bottom of the device to coat the PEG. The actuating component was then placed inside of the capsule and the cap was pressed fit onto the top of the capsule.
Microneedle patches were fabricated with insulin concentrated in the tips. Solid insulin powder was placed in PDMS female microneedle molds and forced into the microneedle tips using a spatula. Excess powder was then removed from the mold. The amount of powder added to the mold was calculated by weighing the mold before and after the addition of powder. The accuracy of weight measurements was confirmed using high performance liquid chromatography. Briefly, a 7.8×300 mm2 Insulin HMWP column (Waters Cerp, Milford, USA) was set to room temperature and an Agilent (Santa Clara, USA) HPLC machine was employed. Elution were performed at a flow rate of 0.5 mL/min for 26 minutes using a mobile phase made from 15% acetic acid (v/v), 20% acetonitrile (v/v), and 0.65 g/L L-arginine all purchased from Sigma Aldrich. The molds were then centrifuged at 3200 rcf for 10 minutes to compress the powder. Next, a 50% 58,000 molecular weight polyvinylpyrrolidone solution or 100% melted sorbitol was added to bind the powder and give mechanical structure to the microneedle patches. The mold was then centrifuged again at 3200 rcf for 10 minutes. The microneedle patches were left to dry at room temperature for 72 hours. Once dried, microneedles patches were unmolded, sanded down and mounted at the edges of the actuating component arms.
Microneedles loaded with Texas red and Texas red conjugated with dextran (3 kDa) were used to perform dissolution tests in vivo in swine prior to euthanasia and ex vivo in human small intestinal tissue. Microneedles were manually inserted for 5, 15 and 30 s and then retrieved. A microneedle patch was left to sit on top of the tissue without applying any pressure for 30 s which served as the negative control. An IVIS imaging system (Perkin Elmer, Waltham, USA) was then used to assess the Texas red and Texas red-dextran transfer onto the tissue via fluorescence. Living Image® software (Perkin Elmer, Waltham, USA) was used to quantify the radiant efficiency.
The dissolution experiment detailed above was also performed in vivo with insulin-loaded microneedles. The microneedles were imaged using an optical microscope before and after their application in the small intestine tissue to visually assess their dissolution.
An optical coherence tomography (OCT) system was used to visualize penetration of the microneedles into excised small intestine from swine. For this, various microneedle arrays were inserted ex vivo into the tissue via manual application and OCT was used to evaluate both penetration depth and dissolution. In addition, a fixture was designed in order to hold the actuating component and deploy one of its arms in a 30 degree angle into a certain point of an ex vivo swine small intestine piece in order to promptly capture the penetration event prior to microneedle degradation. In this latter case, the OCT image was captured from the outside of the wall instead of from behind the patch, allowing in turn the assessment of perforation. OCT images were processed using Image J (Open Source).
To assess the insulin microneedle formulation, the API formulation was administered to female Yorkshire swine, 35 kg to 65 kg. To deliver the actuating components, the swine were placed on a liquid diet for 24 hours before the procedure and fasted the swine overnight, the swine were then sedated them with an intramuscular injection of Telazol (tiletamine/zolazepam) (5 mg/kg), xylazine (2 mg/kg), and atropine (0.05 mg/kg) and if needed supplemental isoflurane (1 to 3% in oxygen) via a face mask. An orogastric tube or overtube was placed with guidance of a gastric endoscope and remained in the esophagus to ease the passage of the device. The overtube was fed through the stomach and into the small intestine. Encapsulated actuating components were passed through the overtube and placed into the small intestine. Non-encapsulated actuating components were inserted and actuated during a laparotomy procedure in which a 3 cm incision was used to access the small intestinal mucosa. During laparotomy experiments, the size of the small intestine was standardized to 20 mm in diameter by applying a clamp to the tissue. The microneedles delivered manually to the small intestine were also inserted during a similar laparotomy procedure in which a 3 cm incision was used to access the small intestinal mucosa, and a microneedle patch was manually inserted into the intestinal surface epithelium. Patches with an area of 1 cm2 were applied to the jejunum of the swine. Pressure was applied to the patch for 30 seconds, and then the patch was removed from the small intestine. To create the subcutaneous dose required for administration the microneedles from four patches were dissolved into 2 mL of sterile saline (Hospira, Lake Forest, USA). The mixture was then filtered through a 0.2 μm filter and 0.5 mL of the resulting solution was administered to each swine subcutaneously. Lastly, the insulin solution dosed to the jejunum was prepared by dissolving the microneedles from one patch into 10 mL of water purified using a Barnstead Nanopure system (ThermoFisher, Waltham, USA). The solution was then passed through an endoscope directly into the jejunum of the swine.
Blood samples were obtained via a central venous line at time points including but not limited to every 10 minutes for the first two hours and every 30 minutes for hours 2-4. Blood samples were tested for glucose levels using a OneTouch Ultra glucose monitor by LifeScan Inc. (Milpitas, USA). Collected plasma and blood was analyzed. Briefly, the homogenous bead assay employed two monoclonal antibodies against human insulin, creating an acceptor-bead, insulin, and donor-bead layering. This generally generated a signal which was proportional to the concentration of insulin. Additionally, blood was analyzed using ELISA. Both tests utilized antibodies specific for human insulin and neither test detected other endogenous insulins.
Specialized articles comprising the actuating components were administered to the swine to determine the capsule actuation time as well as the transit and dissolution timeline for the actuating component. These actuating components contained small pieces of metal material such as nitinol or stainless steel which allowed the device to be seen under X-ray. The swine were X-rayed over several hours in the case of the capsule actuation experiments. The swine were X-rayed over several days in the case of the transit experiments until the all of the metal components passed through the GI tract.
A geometric analysis of the unfolding event defined a minimum arm length correlated with tissue stretch from any possible orientation. It was assumed that the small intestine possessed a known diameter (d) and the tissue was not rigid. The actuating component could open up in any orientation, including: axial; parallel; or anywhere in between. An analysis of all possible orientations showed that the tissue would stretch the least in the configuration where the planes perpendicular to the central axis containing an arm's point of contact were spaced furthest apart. Therefore, the arms contacted the tissue over the greatest possible surface area. In this orientation, we noticed that the small intestine conformed to the actuating component and changed shape. The tissue transformed from a cylinder and collapsed into two parallel rectangular sheets. Because the surface area of the small intestine remained constant, the height of this newly created rectangle equaled ½ of the small intestine's perimeter. The height of this triangle, created by the actuating component's three points of contact, corresponded to 1.5 times the actuating component arm length. Therefore the arm length was generally less than πd/3 in order to force the small intestine to stretch when the actuating component opened in this configuration, although other lengths are also possible.
While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.
The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”
The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of” or, when used in the claims, “consisting of” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 62/767,710, filed Nov. 15, 2018, entitled “ACTUATING COMPONENTS AND RELATED METHODS,” which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US19/32817 | 5/17/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62767710 | Nov 2018 | US |
