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WO2024115734A1 - Dispositif de capsule à agencement d'actionneur amélioré - Google Patents

Dispositif de capsule à agencement d'actionneur amélioré Download PDF

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Publication number
WO2024115734A1
WO2024115734A1 PCT/EP2023/083920 EP2023083920W WO2024115734A1 WO 2024115734 A1 WO2024115734 A1 WO 2024115734A1 EP 2023083920 W EP2023083920 W EP 2023083920W WO 2024115734 A1 WO2024115734 A1 WO 2024115734A1
Authority
WO
WIPO (PCT)
Prior art keywords
capsule
capsule device
helical portion
penetrating member
helical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2023/083920
Other languages
English (en)
Inventor
Simon Munch Pedersen
Anders Hammelev MARSTRAND
Nökkvi Steinn SIGURDARSON
Laurits Højgaard OLESEN
Camilla SANDFELD
Jacob Pyung Hwa JEPSEN
Rolando Abaroa MARTINEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of WO2024115734A1 publication Critical patent/WO2024115734A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/10—Trunk
    • A61M2210/1042—Alimentary tract

Definitions

  • the present invention relates to ingestible devices adapted for being swallowed into a lumen of a patient and having a tissue penetrating member being shaped to penetrate tissue of a lumen wall.
  • the drug has to be delivered firstly into a lumen of the gastrointestinal tract and further into the wall of the gastrointestinal tract (lumen wall).
  • Prior art references relating to oral dosing of active agents and addressing one or more of the above challenges include WO 2020/160399 A1 , US 2020/0129441 A1 and WO 2020/157324 A1 , the first two relating specifically to self-righting capsule devices.
  • the internal configuration design offers several design challenge trade-offs.
  • an oral device e.g. for delivery of an API in form of a solid needle-shaped API, e.g. a therapeutic payload, it needs to deliver an amount of API sufficient for the intended therapy.
  • solid needle-shaped API tablets the API tablet needs to be delivered reliably into a tissue layer in a depth sufficient to enable systemic uptake.
  • the challenge is to design a device that is small enough to be swallowable, while reliably self-righting and injecting a sufficient amount of API deep enough. Furthermore, low cost and robust performance is essential.
  • Reference WO 2022/162102 A1 generally deals with such considerations and suggests to include an actuation mechanism which comprises a tension spring for energising an actuator.
  • an actuation mechanism which comprises a tension spring for energising an actuator.
  • actuation mechanism although generally optimized in most respects, obtaining further improvements will be beneficial.
  • a capsule device for swallowing into a lumen of a gastrointestinal tract which is improved with respect to all key aspects relating to swallowability, self-righting ability, payload capacity and the ability to properly deposit a tissue penetrating member, such as a member that carries a therapeutic payload, into tissue.
  • a capsule device suitable for ingestion for travelling into a lumen of the gastrointestinal tract of a patient, the lumen having a lumen wall
  • the capsule device comprises: a capsule housing comprising a compartment and an exterior tissue engaging surface defining an exit opening leading from the compartment to the exterior tissue engaging surface, a tissue penetrating member arranged along an axis and configured to be advanced axially from a proximal first position in the compartment through the exit opening to a distal second position so that at least a portion of the tissue penetrating member penetrates into the lumen wall at a target location, and an actuator arrangement configured for coupling to the tissue penetrating member, the actuator arrangement being operable between a first configuration and a second configuration, wherein the actuator arrangement comprises a drive spring which in the first configuration is strained and which releases upon actuation thereby advancing the tissue penetrating member axially from the first position through the exit opening, wherein the drive spring comprises a first helical portion and a
  • a multi-layer helical spring i.e. a nested spring, consisting of two or even more spring portions, each portion may have different spring characteristics.
  • first helical portion and the second helical portion form one continuous piece.
  • first helical portion and the second helical portion may be formed from separate members and later joined.
  • the drive spring may be designed so that it is coiled from one single piece of spring wire, or joined from two separate pieces of spring wire, to utilize the spring characteristics of both springs in one action and in a compact design. The springs can then have varying thicknesses and the characteristics can be tuned to comply with particular device design constraints.
  • the spring configuration may be designed to obtain a particular desired speed profile as the tissue penetrating member is moved from the first position to the second position. This may aid in properly penetrating the tissue layer in an effective and safe manner.
  • a hub guide may be omitted as the multi-layer helical spring may be formed to exhibit a self-centring ability, for example, wherein the second helical portion aids in self-centring of the first portion of the spring.
  • the capsule device does not include a housing guide for guiding the axial movement of the actuator.
  • the capsule housing comprises a guide for guiding one or more components of the actuator arrangement.
  • the capsule housing may be formed with guiding surfaces for guiding the second helical portion of the drive spring as it relaxes during advancement of the tissue penetrating member.
  • the actuator arrangement comprises a hub configured for interconnecting the drive spring and the tissue penetrating member.
  • the drive spring connects to the hub whereas the tissue penetrating member couples to the hub, such as by being retained relative to the hub or by being firmly gripped by the hub.
  • the actuator arrangement is configured so that the hub only interconnects the drive spring and the tissue penetrating member during the course of movement of the drive spring, e.g. during the initial release and relaxation of the drive spring.
  • the drive spring comprises a first and a second end, wherein the first end is defined by an end portion of the first helical portion opposite the transitional portion and the second end is defined by an end portion of the second helical portion opposite the transitional portion, wherein the first end is coupled to the hub and the second end is mounted relative to the capsule housing, and wherein, in the first configuration, the first end is located proximally to the second end.
  • the capsule device is configured as a self-righting capsule device, wherein when the self-righting capsule device is at least partially supported by the tissue of the lumen wall, the self-righting capsule device autonomously orients in a direction to allow the tissue penetrating member to be advanced through the exit opening and inserted into tissue at the lumen wall.
  • the actuator arrangement assuming the first configuration, as the multi-layer spring may be arranged with a centre of mass of the spring to be disposed closer to the end of the exit opening, as compared with other known solutions, improved self- orientation of the capsule device is obtained.
  • the capsule device may be configured as a monostatic body at least due to one of the shape and the mass distribution of the capsule device to provide for self-righting of the capsule device when the device is supported by a tissue surface, e.g. to autonomously orient the capsule housing so that the axis of the tissue penetrating member orients generally aligned in accordance with gravity.
  • the capsule device may in certain embodiments be configured as a self-righting capsule device having a geometric centre and a centre of mass offset from the geometric centre along the axis, wherein when the capsule device is supported by the tissue of the lumen wall while being oriented so that the centre of mass is offset laterally from the geometric centre the capsule device experiences an externally applied torque due to gravity acting to orient the capsule device with the axis oriented along the direction of gravity to enable the delivery member to interact with the lumen wall at the target location.
  • the self-righting capsule may be configured to define a monostatic body, such as a Gdmbdc or Gdmbdc-type shaped body that, when placed on a surface in any orientation other than a single stable orientation of the body, the body will tend to reorient to its single stable orientation.
  • a monostatic body such as a Gdmbdc or Gdmbdc-type shaped body that, when placed on a surface in any orientation other than a single stable orientation of the body, the body will tend to reorient to its single stable orientation.
  • the capsule device defines a geometric centre and wherein when the actuator arrangement assumes the first configuration, the drive spring has a centre of mass located distally from the geometric centre of the capsule device.
  • the capsule housing defines a distal exterior end surface portion arranged at the exit opening and a proximal exterior end surface portion opposite the distal exterior end surface portion, and wherein when the actuator arrangement assumes the first configuration the second helical portion of the drive spring has a centre of mass disposed closer to the distal exterior end surface portion than to the proximal exterior end surface portion.
  • the drive spring is configured so that the drive spring, at least during axial advancement of the tissue penetrating member from the first position through the exit opening, the first helical portion acts as a tension spring and the second helical portion acts as a compression spring.
  • the second helical portion comprises a circumferentially extending end coil portion at the end opposite the transitional portion, the end coil portion comprising a proximal facing surface being fixedly supported by a distally facing spring seat in the capsule housing.
  • the second helical portion acts as a tension spring and the first helical portion acts as a compression spring.
  • the drive spring comprises an additional loop portion that connects to the second helical portion at an end thereof opposite said transitional portion, the additional loop portion being wound radially outside relative to the second helical portion, wherein the additional loop portion forms a proximally facing loop surface being fixedly supported by a distally facing spring seat in the capsule housing.
  • the tissue penetrating member has a distal end shaped to enable insertion into tissue and a proximal end that is coupled, or being configured for coupling, to the actuator arrangement, wherein when the tissue penetrating member assumes the first position, the distal end is axially separated from the exit opening (at the tissue engaging surface) by a separating distance, thereby enabling the tissue penetrating member to be advanced towards the exit opening by an acceleration stroke corresponding to the separating distance.
  • the acceleration stroke is configured between 1 mm and 8 mm, such as between 1 and 6 mm, such as between 1.5 and 4 mm and such as between 1.5 mm and 3 mm.
  • Other accelerating strokes are also contemplated.
  • the capsule device is configured so that the axial velocity of the tissue penetrating member, when the distal end of the tissue penetrating member leaves the exit opening, is between 8 and 30 m/sec, such as between 10 and 25 m/sec, and such as between 15 and 22 m/sec.
  • Other axial velocities are also contemplated.
  • tissue penetrating member is or comprises a solid delivery member formed partly or entirely from a preparation comprising a therapeutic payload, and wherein the preparation is made from a dissolvable material that dissolves when inserted into tissue of the lumen wall to at least partially release the therapeutic payload into the blood stream.
  • the capsule device comprises: the capsule housing comprises a stop geometry associated with the capsule housing, such as within the compartment, the tissue penetrating member disposed in the compartment, the tissue penetrating member having a tissue penetrating first end, a second end opposite the first end and a radially outwards facing surface between the first end and the second end, and wherein the actuator arrangement comprises: a) a pushing portion configured for movement from a first position and into a second position, the pushing portion being configured for providing a force onto the tissue penetrating member to move the tissue penetrating member from an initial position within the capsule housing to a lodged position where at least a portion of the tissue penetration member is external to the capsule housing and at least partially lodged in tissue of the lumen wall, and b) a holder portion which, when the pushing portion assumes the first position, releasa- bly holds the tissue penetrating member by retaining engagement, such as by
  • the tissue penetrating member is effectively detached from the pushing portion at the point in time relative the moving of tissue penetrating member from the initial position within the capsule housing to the lodged position.
  • the tissue penetrating member forms part of, or comprises, a therapeutic payload
  • the solution according to the second aspect enables a larger percentage of the therapeutic payload to be available for being lodged in tissue and for subsequent release into the blood stream.
  • the tissue penetrating member assumes the initial position
  • the holder portion assumes a start position, and wherein the holder portion is moved from the start position towards the stop geometry by being displaced by slaved movement relative to the pushing portion.
  • the holder portion when assuming the start position, is in friction engagement with the pushing portion, and wherein pushing portion overcomes the friction engagement when the holder portion enters into engagement with the stop geometry.
  • the holder portion is formed as a sleeve that, when the holder portion is slaved relative to the pushing portion, interconnects the pushing portion with the tissue penetrating member.
  • the holder portion may in some embodiments comprise at least one radially resilient gripping member providing a radially inwards directed force onto the tissue penetrating member, wherein the radially resilient gripping member cooperates with the stop geometry of the capsule housing to release the radially inwards directed force upon the holder portion engaging the stop geometry.
  • the pushing portion and the holder portion are formed as a unitarily formed member formed from a deformable material and wherein the holder portion deforms when engaging the stop geometry to release the retention force.
  • the capsule housing may be so configured that is comprises an exit opening and an exterior surface portion surrounding the exit opening, the exit opening permitting the tissue penetrating member, and optionally an end portion of the pushing portion, to protrude through the exit opening, and wherein the pushing portion in its second position pushes the second end of tissue penetrating member a predefined distance from the exterior surface portion, said predefined distance selected between 1 and 5 mm, such as between 2 and 4.5 mm and such as between 2.5 and 4 mm.
  • the tissue penetrating member is a solid formed partly or entirely from a preparation comprising a therapeutic payload, wherein the tissue penetrating member is made from a dissolvable material that dissolves when inserted into tissue of the lumen wall to deliver at least a portion of the therapeutic payload into tissue.
  • an exterior portion of the tissue penetrating member defines an enclosure, and wherein a preparation comprising a therapeutic payload forms a liquid, gel or powder accommodated within the enclosure.
  • the pushing portion and/or the tissue penetrating member is configured for movement along an axis, e.g. an actuation axis.
  • the actuator arrangement comprises a hub that comprises at least one pair of a latch and a retainer portion structured to maintain the hub in a pre-actuation configuration.
  • the capsule device defines a dissolvable latch support, the dissolvable latch support being at least partially dissolved in a fluid, such as a biological fluid, a retainer portion comprised by one of the capsule housing and the hub, and a deflectable latch comprised by the other of the capsule housing and the hub.
  • the deflectable latch may be configured for lateral movement relative to the axis, and the deflectable latch defines a first surface with a blocking portion, and a support surface disposed oppositely to the first surface and configured for interacting with the dissolvable latch support.
  • the blocking portion of the deflectable latch engages the retainer portion in a latching engagement, and the support surface of the deflectable latch interacts with the dissolvable latch support to restrict movement of the deflectable latch thereby preventing release of the latching engagement.
  • the deflectable latch is allowed to move thereby releasing the latching engagement between the blocking portion of the deflectable latch and the retainer portion to allow the drive spring to actuate/fire the hub.
  • the dissolvable part is designed to simply block a mechanical activation system.
  • the mechanical activation system may be designed to rely on parts made from a suitable high-strength material, such as plastic, and do not leave any undissolved pieces that potentially could jam the mechanical activation system.
  • the deflectable latch is configured for radial movement relative to the axis.
  • the actuation axis and the hub movement is linear.
  • the actuation trajectory may be not linear, e.g. the firing trajectory of the hub may be arcuate or curved, or may include arcuate or curved trajectories.
  • the latch may be configured for lateral movement relative to the trajectory of the hub to release the hub.
  • a plurality of pairs of latch and retainer portions such as two, three, four, five or more pairs of latch and retainer portions are provided, the pairs of latch and retainer portions being disposed equally around the axis.
  • said dissolvable latch support is common to all pairs of latch and retainer portions.
  • the dissolvable latch support is arranged along the axis, wherein the at least one pair of latch and retainer portion is disposed radially outside of the dissolvable latch support.
  • one or more dissolvable latch support(s) is/are disposed, such as in a ringshaped configuration around the axis, wherein the one or more dissolvable latch supports encircle the at least one pair of latch and retainer portion.
  • the capsule device may comprise one or more openings to allow a biologic fluid, such as gastric fluid, to enter the capsule device for dissolving the dissolvable latch support(s).
  • a biologic fluid such as gastric fluid
  • the drive spring exerts a load onto the hub thereby biasing the hub along the axis.
  • the drive spring is configured to exert a load onto the hub only upon triggering of a trigger member or mechanism of the capsule device.
  • the capsule device is configured for swallowing by a patient and travelling into a lumen of a gastrointestinal tract of a patient and configured for deployment, such as the stomach, the small intestines or the large intestines.
  • the capsule of the device may be shaped and sized to allow it to be swallowed by a subject, such as a human.
  • the drug substance may e.g. be in the form of a solid, an encapsulated solid, a liquid, a gel or a powder, or any combination thereof.
  • drug drug substance
  • therapeutic agent drug
  • payload or “therapeutic payload” is meant to encompass any drug formulation capable of being delivered into or onto the specified target site.
  • the drug may be a single drug compound or a premixed or co-formulated multiple drug compound.
  • Representative drugs include pharmaceuticals such as peptides (e.g.
  • the drug may be an insulin or a GLP-1 containing drug, this including analogues thereof as well as combinations with one or more other drugs.
  • figs. 1a and 1b show cross-sectional side views of a prior art capsule device 100, the device assuming a pre-actuation configuration and an actuated configuration, respectively
  • figs. 2a, 2b and 2c each shows a cross-sectional side view of a first embodiment capsule device 200 in accordance with the invention, the device assuming a pre-actuation configuration, an intermediate configuration and an actuated configuration, respectively
  • fig. 2d shows a detailed view of a subassembly suitable for inclusion in capsule device 200, the assembly formed by a push rod 260, a holder sleeve 270 and a payload portion 230
  • figs. 3a-3c show a drive spring 240 of the first embodiment capsule device 200 in an unstrained state, in a pre-actuation strained state and an actuated released configuration, respectively.
  • assembly and “subassembly” do not imply that the described components necessarily can be assembled to provide a unitary or functional assembly or subassembly during a given assembly procedure but is merely used to describe components grouped together as being functionally more closely related.
  • an example prior art drug delivery device 100 is shown, disclosed in WO 2022/162102 A1 , and having a particular actuation configuration for deployment of a solid dose from a solid dose capsule device.
  • the shown prior art capsule device 100 is intended for being ingested by a patient to allow the capsule device to enter the stomach lumen, subsequently to orient relative to the stomach wall, and finally to deploy, by triggering, a solid dose payload for insertion at a target location in tissue of the stomach wall.
  • a solid dose payload penetrates the tissue of the subject and at least a portion of a therapeutic agent within the payload dissolves into the tissue for uptake in the blood stream of the subject.
  • the general principle for orienting the capsule relative to the stomach wall may utilize any of the principles disclosed in WO 2018/213600 A1 .
  • the state shown in figs. 1a represents a pre-actuation configuration prior to swallowing of the capsule, whereas the state shown in fig. 1 b represents an actuated configuration, i.e., corresponding to a post-delivery state.
  • the ingestible self-righting capsule device 100 comprises a first portion 100A having an average density, a second portion 100B having an average density different from the average density of the first portion 100A.
  • the capsule device 100 accommodates a payload portion 130 for carrying an agent for release internally of a subject user that ingests the article.
  • the average density of capsule device prior to deployment is larger than that of gastrointestinal fluid, enabling the capsule device to sink to the bottom of the stomach lumen.
  • the outer shape of the self-righting article is a Gbmbbc shape, i.e. a Gbmbbc-type shape that, when placed on a surface in any orientation other than a single stable orientation of the shape, the shape will tend to reorient to its single stable orientation.
  • the capsule device shown includes an upper (proximal) capsule part 110 which mates and attaches to a lower (distal) capsule part 120.
  • the upper capsule part 110 and the lower capsule part 120 together forms the capsule of the device.
  • the capsule housing parts 110/120 define a shell having an interior hollow which accommodates the payload portion 130, a hub 150 which holds and drives forward the payload portion 130, and an actuation and propulsion mechanism, in short termed an actuator arrangement, configured to actuate and drive forward the hub from a first position to a second position carrying with it the payload for drug delivery.
  • the actuator arrangement comprises an energy source in the form of a pre-strained drive spring 140, and an actuation member in the form of hub 150 which holds and drives forward the payload portion 130 for payload delivery upon release of energy from the drive spring 140.
  • the payload portion 130 is oriented along an actuation axis and configured for movement along the actuation axis.
  • the upper and lower capsule parts 110, 120 form generally rotation symmetric parts with the axis of symmetry arranged along the actuation axis.
  • the device is oriented with the actuation axis pointing vertically, and with the payload portion 130 pointing vertically downwards towards an exit opening/exit hole 124 arranged centrally in the lower capsule housing 120, the exit hole allowing the payload portion 130 to be transported through exit hole and moved outside the capsule device 100.
  • the lower capsule housing part 120 includes a tissue engaging surface 123 which is formed as a substantially flat lower outer surface surrounding the exit hole 124.
  • the distal pointed end of the payload portion 130 is situated axially a distance relative to a point on the actuation axis where the axis intersects with the tissue engaging surface 123, this distance being referred to as the separating distance. This enables the tissue penetrating member to be advanced towards the exit opening 124 by an acceleration stroke corresponding to the separating distance.
  • the upper part 110 may suitably be made from a low-density material, such as polycaprolactone (PCL), whereas the lower part 120 may be suitably made from a high-density material, such as 316L stainless steel.
  • PCL polycaprolactone
  • the overall density of the capsule device is such that the capsule device will sink to the bottom of the stomach, i.e. submerged in a fluid, such as gastric fluid present in the stomach of a patient.
  • the capsule device 100 due to the density distribution of the entire capsule device 100, and due to the outside shape of the device, when the capsule device is supported on a wall such as a tissue wall, and being subjected to gravitational forces, the capsule device 100 will tend to orient itself with the actuation axis substantially perpendicular to the surface (e.g., a surface substantially orthogonal to the force of gravity, a surface of a tissue such as the wall of the gastrointestinal tract). Hence, the capsule device tends to orient relative to the direction of gravity so that the tissue engaging surface 123 faces vertically downward.
  • the interior of the upper capsule part 110 includes a mounting structure provided as an inner sleeve 115 which extends concentrically with the actuation axis from the upper part of the upper capsule part 110 towards a proximally facing bottom surface formed in the lower capsule part 120.
  • a hub retaining structure 113 is provided as an inwardly extending round-going flange that is arranged concentrically with the actuation axis and which extends radially inwards relative to the inner sleeve 115 from the upper capsule part 110 and downwards along the actuation axis.
  • the hub retaining structure 113 serves as a retaining geometry for releasably retaining the hub 150 against the drive force emanating from a strained drive spring 140 arranged within the capsule. Referring mainly to fig.
  • the hub retainer structure 113 provides a conical retainer surface 113a wherein a surface normal to the conical retainer surface 113a points proximally and radially inwards.
  • the conical retainer surface 113a interfaces directly with the exterior rounded surface at a proximal end portion of upper capsule part 110.
  • the conical retainer surface 113a of hub retaining structure 113 forms an angle of 25 deg. relative to the actuation axis.
  • a central opening is formed at the centre thereof.
  • the central opening is dimensioned so that the hub 150 is movable axially through the central opening when the hub assumes a released state but wherein the hub 150 cannot move axially through the central opening when the hub 150 assumes a state corresponding to the actuation configuration.
  • the conical retainer surface 113 at the locations where upper edges of the conical retainer surface 113 intersect with the exterior surface of the capsule part 110, the structure defines a fluid ingress opening allowing gastric fluid to enter into contact with a fluid operated actuation mechanism.
  • payload portion 130 defines a solid delivery member formed entirely or partly from a preparation comprising the therapeutic payload.
  • the solid delivery member is formed as a thin cylindrical rod which is shaped to penetrate tissue of the lumen wall, the cylindrical rod having a tissue penetrating end, i.e. a tip portion, and a trailing end opposite the tissue penetrating end.
  • the tissue penetrating end of the rod is pointed to facilitate easy insertion into mucosal tissue of the lumen wall whereas the trailing end, in the shown embodiment, defines a truncated cylinder cut off by a 90-degree cut.
  • the hub 150 comprises an upper retaining part configured for releasably retaining the hub relative to the capsule housing and a lower interface part configured for encircling and holding the trailing end of the payload portion 130 in place.
  • the lower interface part includes a downward open bore that receives the trailing end of the payload portion 130 in a way so that the payload portion 130 is firmly attached within the bore.
  • the lower interface part further defines an annular spring seat.
  • the upper retaining part of the hub 150 forms a base portion which at a proximal end connects with two latches provided in the form of two independently deflectable latch arms 152.
  • the latch arms 152 are symmetrically arranged around the actuation axis.
  • Each latch arm extends from the upper retaining part at an angle with respect to the axis so that the arms extend inclined proximally and radially outwards from the base portion.
  • the two latch arms are thus configured in a v-shaped configuration.
  • Each latch arm 152 is resiliently movable in the radial inwards direction by a swivelling movement relative to the upper retaining part.
  • the latch arms 152 each defines a radially outwards facing latch surface configured to engage with respective portions of the conical retainer surface 113a in a latching engagement. Each of the latch arms 152 further includes a radially inwards facing latch surface configured for cooperating with a centrally disposed dissolvable latch support 195, see fig. 1a.
  • the latch arms 152 connect to the base portion of upper retaining portion by means of a hinge section allowing the two latch arms, relative to the positions they assume in fig. 1a, to become deflected radially inwards towards a collapsed position wherein the latch arms either touch each other or are positioned with a minor radial spacing between them.
  • the deflectable latch arms are allowed to release from conical retainer surface 113a thereby allowing the hub 150 to move distally relative to the capsule parts 110/120 through the central opening formed in the conical retainer surface 113a.
  • the hub 150 is moved axially from a first position to a second position as energized by the drive spring 140.
  • the dissolvable latch support 160 is formed as a generally cone-shaped member sized to be inserted between the two latch arms 152 in a wedging manner forcing the latch arms 152 in intimate contact with the conical retainer surface 113a of the hub retainer structure 113.
  • dissolvable latch support 160 different forms and compositions may be used.
  • Nonlimiting examples include pellets made from Sorbitol or Microcrystalline cellulose (MCC).
  • Other non-limiting examples include injection moulded Isomalt pellets, compressed granulate Isomalt pellets, compressed pellets made from a granulate composition of Citrate/ NaHCO3, or compressed pellets made from a granulate composition of lsomalt/Citrate/NaHCO3.
  • Such dissolvable latch support will become disintegrated when subjected to a liquid such as gastric juice of the Gl-tract.
  • a liquid such as gastric juice of the Gl-tract.
  • the prior art capsule device 100 additionally comprises a pair of sealing elements 170, 180 for maintaining the tissue penetrating member, i.e. the payload portion 130, fluidically isolated from the environment external to capsule device 100 prior to actuation.
  • an upper sealing element 170 formed as a ring of soft elastomeric material, is inserted between the lowermost annular surface of the conical retainer surface 113a and an annular proximal facing flange surface of the hub 150.
  • the lower sealing element 180 forms a fluidic gate configured to maintain the exit hole 124 fluidically blocked prior to actuation.
  • the sealing element 180 comprises an elastomeric seal member having a generally disc shaped form.
  • an outer periphery of the sealing element 180 is mounted below the lowermost winding of the drive spring 140 and clamped above an annular proximally facing surface of lower capsule part 120.
  • the central area of the sealing element 180 may comprise a fluidic gate formed to provide a self-sealing valve, such as formed by one or more thin cuts (e.g., one or more thin slits) that extend partially or completely through a thickness of the fluidic gate.
  • the sealing element 180 allows the payload portion to penetrate easily through sealing element at the time of actuation for payload delivery into tissue.
  • dissolvable latch support is located substantially flush with the proximal opening defined by conical retainer surface 113a. This serves to ensure adequate wetting of the dissolvable latch support 160 when submerged into gastric juice.
  • the drive spring 140 in prior art capsule device 100, is provided in the form of a pre-strained helical tension spring arranged coaxially with the actuation axis inside the capsule housing.
  • the drive spring in the pre-actuation configuration shown in fig. 1a, defines a wide first end mounted relative to the capsule parts 110/120 and a narrow second end mounted onto the hub 150, i.e. such that the drive spring 140 defines a large diameter portion at the first end and a narrow diameter portion at the second end, the large diameter portion being larger than the narrow diameter portion.
  • the first end is located distally to the second end.
  • the drive spring 140 is provided as a conical tapering spring which exclusively is arranged for operating in tension mode.
  • the first end of the drive spring is mounted at the extreme distal portion of the capsule, i.e. at an axial location close to the exit hole 124, and thus accommodated in a space surrounded by the lower capsule part 120.
  • the first end of drive spring 140 is seated against a first spring seat arranged in the distal end portion of the capsule device 100.
  • the first spring seat is formed by a distal end face of inner sleeve 115.
  • the distal end face of inner sleeve 115 is arranged with a slight axial spacing relative to a proximally facing surface of the lower capsule part 120.
  • a substantial portion of the lower-most winding of the drive spring 140 defines a diameter comparable with the diameter of inner sleeve 115.
  • Inner sleeve 115 is formed with a distal end face disposed with some distance relative to a proximal facing end surface of lower capsule part 120 allowing said portion of the lower-most winding of the drive spring 140 to radially overlap with the inner sleeve 115 and in this way become clamped in a circumferential slot between inner sleeve 115 and lower capsule part 120.
  • the second end of drive spring 140 is seated against a second spring seat formed by the lower interface part of the hub 150.
  • the drive spring 140 has been energized by axially tensioning the drive spring 140 between the two spring seats.
  • the hub 150 is initially under tension load from drive spring.
  • the second narrow end of the drive spring prior to final assembly and with the drive spring 140 arranged in a non-energized state with its central axis coaxially aligned with the actuation axis, the second narrow end of the drive spring would be positioned distally to the first wide end of the spring. However, during assembly wherein the drive spring 140 is increasingly strained, the second narrow end will be moved proximally relative to the first wide end to enter into the pre-actuation state shown in fig. 1a wherein the drive spring is fully energized.
  • fig. 1a shows the initial state which represents the state the capsule device assumes during storage or just after ingestion.
  • the actuator arrangement 150 assumes the preactuation configuration where the two latch arms 152 are maintained in the shown position by engagement with radially outwards facing surfaces of the dissolvable latch support 160 engaging the radially inwards facing latch surface of the latch arms.
  • the radially outwards facing latch surfaces of the latch arms are kept in engagement with the conical retainer surface 113a preventing the latch arms from sliding relative to the conical retainer surface.
  • the hub 150 cannot be moved distally even though the drive spring 140 exerts its full tensile load onto the hub 150.
  • the upper sealing element 170 engages the flange of hub 150 as well as the lower surface of hub retainer structure 113 to keep this interface fluid tight. Also, the lower sealing element 180 keeps the exit hole 124 fluid tight. The hub 150 assumes the first position.
  • the capsule device After ingestion of capsule device 100, the capsule device quickly sinks to the bottom of the stomach. Upon being supported by the stomach wall, due to the self-righting ability of the capsule device, the capsule device will quickly reorient to have its tissue interfacing surface 123 engaging the tissue stomach wall with the firing axis of the capsule device oriented virtually vertical, i.e. with the payload portion 130 pointing downwards. Dissolution of dissolvable latch support 160 has begun due to exposure to gastric fluid. This is represented in fig. 1b in connection to reference 160. The support from dissolvable latch support 160 against the latch arms 152 will cease at a specific time after swallowing.
  • the load of the drive spring 140 will cause the latch arms 152 to be gradually deflected radially inwards thereby allowing the latch arms to slide off from engagement with the conical retainer surface 113a. At some point in time the latch arms 152 will reach their collapsed position where after the hub 150 with the payload portion 130 will become released from the hub retainer structure 113. This state corresponds to the actuating configuration. As drive spring 140 exerts tension onto hub 150, the hub and the payload portion 130 are caused to travel unhindered towards the exit hole 124 with the payload portion penetrating the lower sealing element 180 and further into mucosal tissue at the target location. In the actuated configuration, as shown in fig.
  • a proximally facing housing stop surface 128 arranged at the bottom part of capsule part 120 prevents the hub 150 from moving further distally.
  • the hub 150 assumes the second position. It is seen that the second end of the spring, in the course of the delivery stroke, has been travelling distally and enter into a position axially slightly distal to the first end of the spring. Due to the tapering nature of the tension spring, the hub will have a marked tendency of self-centring to travel along the actuation axis without necessarily requiring further radial guidance relative to the capsule housing.
  • the payload portion 130 is inserted into tissue of the lumen wall where it will anchor generally in a direction along the actuation axis. As discussed above, depending on the specific design of the capsule device, the payload portion 130 may be released actively from the remaining parts of the capsule at the end of the insertion stroke. When the capsule device 100 has delivered the intended dose of the therapeutic payload the capsule will release relative to the deposited payload portion 130 which remains inside the tissue wall for release of therapeutic agent into the blood stream of the subject.
  • the device may be modified to include a mechanism for separating the payload portion 130 from the hub 150 upon the assembly of the payload portion 130 and the hub 150 arriving at the most distal position in the capsule housing.
  • Suitable non-limited principles may include the principles disclosed in WO 2020/245448 A1 wherein a ram (similar to a hub) becomes tilted at the end of the insertion stroke for detaching the tissue inserted portion of the payload portion from the ram.
  • the capsule may be held stationary for a prolonged time allowing the payload portion 130 to release a therapeutic agent into the blood stream of the subject as the capsule is held stationary relative to the tissue.
  • the remaining parts of the capsule device will travel out through the digestive system of the user and be disposed of.
  • capsule device 200 corresponds largely to the self-righting principle of the prior art device 100 described above. Also the general principle of operation is similar, i.e., the actuation trigger principle, and the actuating principle wherein a hub carrying a payload portion is arranged for being advanced along a central axis of the capsule device for payload portion deposition in a tissue wall.
  • the drive spring arrangement has been modified. Also the way the payload portion is released from the hub is different from that summarized in connection with the description of the prior art device 100.
  • the drive spring 240 is again formed as a coiled helical spring but, in accordance with the general teaching of the present invention, the spring is formed from two concentrically arranged portions with one portion being wound about a second portion and wherein one portion is configured to act as a tension spring and the other portion is configured to act as a compression spring.
  • the drive spring 240 extends as a single uninterrupted piece of spring steel between a first end coil and a second end coil.
  • a narrow proximal opening is formed in the proximal portion of upper capsule part 210.
  • a generally cylindrical space (referenced 216 in fig. 2b) is disposed adapted to accommodate a major portion of hub 250 and a portion of drive spring 240.
  • the generally cylindrical space extends from the narrow proximal opening and distally towards the lower capsule part 220.
  • four axially extending ribs 218 are distributed 90 deg. apart inside the generally cylindrical space (see fig. 2b).
  • the arrangement of the ribs 218 serves the purpose of forming guide surfaces for the drive spring and may additionally serve as guide surfaces for the hub.
  • the ribs 218 end distally with distal facing surfaces which in combination form a spring seat for cooperating with the second end coil (240a2, cf. fig. 3b) of drive spring 240.
  • the hub 250 in the first embodiment capsule device 200 may, for manufacturing and assembly reasons, be provided as a multi-component hub assembly wherein the individual components have been fixedly attached relative to each other during assembly.
  • fig. 2a which shows the capsule device 200 in the pre-actuation configuration
  • the overall design of the actuation arrangement is somewhat modified for the first embodiment device 200 as compared with the prior art device 100, in particular with regard to the form and shape of deflectable latch arms 252, the retaining structure (retainer portion 213) and the dissolvable latch support 295.
  • the latter is arranged at the most-proximal portion of the upper capsule part 210, i.e. , in a manner so that the proximal facing end surface of the dissolvable latch support 295 lies generally flush with exterior surface areas surrounding a proximal opening formed in upper capsule part 210.
  • dissolvable latch support 295 is formed as a small cylindrical member but may be formed differently, for example box-shaped, etc.
  • the retaining structure again serves the function of retaining the hub 250 in the first position against the drive force originating from strained drive spring 240 arranged within the capsule, i.e. preventing the hub from being moved from the first position to a second position.
  • the payload portion 230 is not directly engaged by the hub 250 but is carried by a distal end of pushing portion/push rod 260, the latter being fixedly attached to the hub 250.
  • the hub is provided as a hub assembly, generally referenced 250, comprises an upper retaining part 251 , configured for releasably retaining the hub assembly relative to a retainer portion 213 of the capsule housing, a lower interface part 255, and a push rod/pushing portion 260.
  • the retainer portion 213 of the capsule housing is formed in the proximal opening and is in the shown embodiment provided as two radially opposed and radially inwards extending protrusions, each protrusion defining an arc-shaped surface having a surface normal pointing radially inwards as well as proximally.
  • a pair of deflectable arms 252, i.e. latch arms extend generally axially in the proximal direction from a circular flange of the upper retaining part 251 , the two deflectable arms being arranged radially opposite to each other.
  • an open space is defined this space being designated for accommodating the dissolvable latch support 295.
  • the circular flange of upper retaining part 251 includes an annular sealing lip 290 formed by an elastomeric material and adapted in the pre-actuation configuration to sealingly engage a reduced diameter cylindrical section 217 arranged at the proximal end of generally cylindrical space 216.
  • a centrally located axial bore is formed in upper retaining part 251 , the bore being provided with an inner thread.
  • the lower interface part 255 is formed generally disc-shaped and includes a proximal facing surface adapted to engage the upper retaining part 251 and a lower distally facing flange configured to provide a hub stop surface 258 for arresting the hub assembly in an end of stroke position for the hub assembly 250.
  • a central axial opening is formed in lower interface part.
  • the push rod 260 is arranged to protrude through central openings formed in upper retaining part 251 and lower interface part 255 so that all three components are disposed with their axes of symmetry concentrically with the actuation axis.
  • a distal main portion of push rod 260 is formed as a thin elongated rod that extends distally from hub stop surface 258 towards the exit opening 224.
  • the proximal end of push rod 260 is provided with an external thread that is received into the inner thread of upper retaining part 251 to facilitate a fixed mounting.
  • the shown threaded connection is however only exemplary and may be substituted by other fastening methods.
  • the hub assembly 250 may be provided as a unitary component.
  • the first embodiment capsule device 200 additionally comprises two more sealing elements 280, 285 for maintaining the payload portion 230 fluidically isolated from the environment external to capsule device 200 prior to actuation.
  • a lower sealing element 280 forms a fluidic gate configured to maintain the exit opening 224 fluidically blocked prior to actuation.
  • the sealing element 280 comprises an elastomeric seal member having a generally disc shaped form.
  • the lower sealing element 280 is mounted within a seal retaining structure.
  • the central area of the sealing element 280 may comprise a fluidic gate formed to provide a self-sealing valve, such as formed by one or more thin cuts (e.g., one or more thin slits) that extend partially or completely through a thickness of the fluidic gate.
  • the sealing elements 280, 285 and 290 thus all cooperate to form a compartment internally in capsule device 200 that serves, prior to actuation, to maintain the payload portion 230 fluidically isolated from biological fluid externally to capsule device 200 but allows the payload portion to penetrate easily through sealing element 280 at the time of actuation for payload delivery into tissue.
  • the payload portion is not firmly attached to the push rod 260 but will engage push rod 260 by abutment, either already in the pre-actu- ation configuration, or during a part of the displacement push rod 260 experiences during actuation from the first position to the second position.
  • a holder portion provided as a holder sleeve 270 encircles both the push rod 260 and a proximal portion of the payload and which in the pre-actuation configuration attaches both to push rod 260 and to payload portion 230.
  • the holder sleeve 270 is formed with a distal portion 271 formed as a generally cylindrical sleeve with an inner diameter generally corresponding to an outer diameter of a distal portion of push rod 260.
  • the inner diameter of the cylindrical sleeve also generally corresponds to the outer diameter of the payload portion 230.
  • the holder sleeve 270 is further formed so that, at the proximal end of the cylindrical sleeve, a circular flange 277 extends radially outwards from an outer wall of the cylindrical sleeve.
  • the circular flange 277 of the holder sleeve 270 defines a proximal facing surface 279 and a distally facing sleeve stop surface 278, the latter being configured for cooperation with the housing stop surface 228.
  • the dimensions of the inner surface of the cylindrical sleeve of holder sleeve 270 is chosen so that a frictional fit between a distal end 272 of the holder sleeve 270 and the payload portion 230 is provided.
  • cooperating releasable snap geometries are formed between the push rod 260 and the holder sleeve 270.
  • the snap geometries can be seen as an inner snap geometry 274 formed on holder sleeve 270 and an outer snap geometry 264 formed on push rod 260.
  • the holder sleeve 270 is so dimensioned that the holder sleeve distal portion 272 overlaps axially with the payload portion 230 in a way so that approximately half of the axial height of the payload portion is gripped by holder sleeve distal portion 272, i.e. the distance denoted “d” in fig. 2c.
  • the axial overlap may be selected differently.
  • Non-limiting exemplary materials for the holder sleeve 270 and the push rod 260 may be selected as a relatively resilient polymeric material such as a material formed from PEEK.
  • Alternative materials for holder sleeve 270 may be formed by an elastomeric material, such as silicone rubber.
  • the payload portion 230 is formed as a small cylindrical tablet with outer dimensions of approximately 00,8 x 0,8 mm height.
  • Other dimensions and different shapes of the payload portions may be used in alternative embodiments.
  • the distal facing surface of payload portion 230 may be formed differently, such as being provided with a pointed distal spike portion pointing towards the centre of exit opening 224.
  • the payload portion may be formed as a rod-shaped portion having either a circular cross-section, or a multi-faceted cross-section, wherein the rod axial height typically is of greater magnitude than the largest lateral dimension of the rod.
  • the push rod 260 is seen suspended from the upper retaining part 251 and lower interface part 255 of hub 250.
  • the system is in this embodiment designed so that, in the pre-actuation configuration, the distal face of payload portion 230 is disposed approximately 2 mm from the tissue engaging surface 223, meaning that the assembly formed by the hub 250, the push rod 260, the holder sleeve 270 and the payload portion 230, is moved together by an acceleration stroke of approximately 2mm before the payload portion engages adjacent tissue situated below exit opening 224.
  • the push rod 260 is further dimensioned to provide an insertion depth of the distal portion of payload portion 230 in the order of approximately 4 mm relative to the tissue engaging surface 223.
  • the drive spring is provided as a single spring having the form of a dual layer helically wound spring, i.e. having first and second portions in a concentric configuration.
  • the spring 240 is shown in figs. 3a-3c with fig. 3a showing the spring in a non-strained state, fig. 3b showing the spring in a strained state corresponding to the pre-actuation configuration (cf. fig. 2a), and fig. 3c showing the spring in a partly released state corresponding to the actuated configuration (cf. fig. 2c).
  • the drive spring 240 is formed with a first helical portion 240a (having windings generally of a small diameter) and with a second helical portion 240b being wound at a generally large diameter to encircle the windings of the first helical portion 240a.
  • the first helical portion 240a is configured to act as a tension spring whereas the second helical portion 240b is configured to act as a compression spring.
  • first helical portion 240a is connected to the second helical portion 240b by means of transitional portion 240c (240ac/ 240bc) which in all states is located distally to both the remaining portion of the first helical portion 240a and remaining portion of the second helical portion 240b.
  • transitional portion 240c 240ac/ 240bc
  • the spring is provided as a unitary component made by winding a single continuous piece of spring steel but in other embodiments, the first helical portion and the second helical portion may be provided as individual components that are mounted relative to each other at the transitional portion.
  • a free first end loop is formed at a proximal end 240a1 thereof, this end loop being adapted to be retained in the recessed annular area of the hub 250.
  • a free second end loop, opposite to the first end loop, is formed at a proximal end 240b1 of the second helical portion 240b.
  • the first helical portion 240a which is designated for use as a tension spring is close wound whereas the second helical portion 240b which is designated for use as a compression spring is open wound.
  • the first coil end 240a1 which has been mounted on the hub 250, is brought axially in proximal direction into the upper capsule part 210.
  • the second helical portion 240b of drive spring 240 is axially compressed whereas the first helical portion 240a is axially tensed.
  • the proximal movement of hub 250 is advanced until the blocking portions 253 of deflectable arms 252 engage a proximal inclined surface of a respective one the retainer portions 213. In this position, the deflectable arms 252 slide outwards in full engagement with the retainer portion. This makes room radially between the deflectable arms 252 to enable the dissolvable latch support 295 to be position radially between the deflectable arms whereby the actuator arrangement enters into a stable armed state where the drive spring 240 is fully energized.
  • fig. 2a shows the capsule in an initial state representing the state the capsule device assumes during storage or just after ingestion.
  • the hub 250 assumes the pre-actuation configuration where the two deflectable arms 252 are maintained in the shown position by engagement with the radially outwards facing surface of the dissolvable latch support 295 engaging the radially inwards facing surface 252a of the deflectable arms 252.
  • the blocking portions 253 engage a proximal surface of a respective one the retainer portions 213 preventing the deflectable arms from moving radially inwards and sliding relative to the retainer portions.
  • the hub 250 cannot be moved distally even though the drive spring 240 exerts its full load onto the hub 250.
  • the upper sealing element 290 engages the reduced diameter cylindrical section 217 arranged at the proximal end of generally cylindrical space 216 to keep this interface fluid tight. Also, the lower sealing element 280 keeps the exit opening 224 fluid-tight.
  • the capsule device After ingestion of capsule device 200, the capsule device quickly sinks to the bottom of the stomach. Upon being supported by the stomach wall, due to the self-righting ability of the capsule device, the capsule device will quickly reorient to have its tissue interfacing surface 223 engaging the tissue stomach wall with the actuation axis of the capsule device oriented virtually vertical, i.e. with the payload portion 230 and the push rod 260 pointing downwards. Dissolution of dissolvable latch support 295 has begun due to exposure to gastric fluid. This is represented in fig. 2b in connection with reference 295. The support from dissolvable latch support 295 against the deflectable arms 252 will cease at a specific time after swallowing.
  • the load of the drive spring 240 will cause the deflectable arms 252 to be gradually deflected radially inwards thereby allowing the arms to slide off from engagement with the retainer portions 213. At some point in time the deflectable arms 252 will reach their radially collapsed position whereafter the hub 250 with the push rod 260, the holder sleeve 270 and the payload portion 230 will become released from the capsule housing. This state corresponds to the actuating configuration (not shown).
  • the target insertion depth of the distal face of the payload portion is designed to be approximately 4 mm into mucosal tissue.
  • further exemplary insertion depths may be selected between 2 to 6 mm, such as between 2.5 mm and 4.5 mm. Other insertion depths may also be defined.
  • the payload portion 230 is inserted into tissue of the lumen wall where it will anchor generally in a direction along the actuation axis.
  • the payload portion 230 may be released actively from the remaining parts of the capsule at the end of the insertion stroke.
  • the capsule device 200 when the capsule device 200 has delivered the intended dose, the capsule will release relative to the deposited payload portion 230 which remains inside the tissue wall for release of therapeutic agent into the blood stream of the subject.
  • capsule devices for lumen insertion in general, wherein a capsule device is positioned into a body lumen for deployment of a delivery member, or other tissue interfacing components, such as monitoring devices.
  • Non-limiting examples of capsule devices in accordance with aspects of the present invention may, apart from the stomach administered devices discussed above, include capsule devices for intestinal delivery of a drug by delivery into the tissue wall of an intestinal lumen, such as a lumen of the small intestines or a lumen of the large intestines.

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Abstract

L'invention concerne un dispositif de capsule (200) approprié pour une ingestion dans une lumière du tractus gastro-intestinal d'un patient, le dispositif de capsule (200) étant configuré sous la forme d'une capsule à redressement automatique comprenant : a) un boîtier de capsule (210, 220) comprenant un compartiment et une ouverture de sortie (224), b) un élément de pénétration de tissu (230, 260, 270), et c) un agencement d'actionneur (240, 250) configuré pour déplacer l'élément de pénétration de tissu (230, 260, 270) dans la paroi de lumière à un emplacement cible. L'agencement d'actionneur (240, 250) comprend un ressort d'entraînement (240) avec une première (240a) et une seconde partie hélicoïdale (240b) enroulée autour d'au moins une partie de la première partie hélicoïdale (240a), une partie de transition de la seconde partie hélicoïdale (240b) étant reliée à une partie de transition de la première partie hélicoïdale (240a). L'une des parties hélicoïdales (240a, b) agit comme un ressort de tension et l'autre comme ressort de compression.
PCT/EP2023/083920 2022-12-01 2023-12-01 Dispositif de capsule à agencement d'actionneur amélioré Ceased WO2024115734A1 (fr)

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Citations (7)

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Publication number Priority date Publication date Assignee Title
EP1398052A2 (fr) * 1999-12-21 2004-03-17 Phaeton Research Ltd Dispositif ingerable pouvant delivrer des substances en un site particulier du canal alimentaire
WO2018213600A1 (fr) 2017-05-17 2018-11-22 Massachusetts Institute Of Technology Systèmes à redressement automatique, et composants et procédés associés
WO2020160399A1 (fr) 2019-02-01 2020-08-06 Massachusetts Institute Of Technology Systèmes et procédés pour injection de liquide
WO2020157324A1 (fr) 2019-02-01 2020-08-06 Novo Nordisk A/S Dispositif médical ayant un mécanisme d'actionnement
WO2020245448A1 (fr) 2019-06-07 2020-12-10 Novo Nordisk A/S Dispositif ingérable avec détachement d'élément de distribution
WO2022162102A1 (fr) 2021-01-28 2022-08-04 Novo Nordisk A/S Dispositif médical à mécanisme d'actionnement amélioré
US20220249814A1 (en) * 2018-11-19 2022-08-11 Progenity, Inc. Methods and devices for treating a disease with biotherapeutics

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Publication number Priority date Publication date Assignee Title
EP1398052A2 (fr) * 1999-12-21 2004-03-17 Phaeton Research Ltd Dispositif ingerable pouvant delivrer des substances en un site particulier du canal alimentaire
WO2018213600A1 (fr) 2017-05-17 2018-11-22 Massachusetts Institute Of Technology Systèmes à redressement automatique, et composants et procédés associés
US20200129441A1 (en) 2017-05-17 2020-04-30 Massachusetts Intitute Of Technology Self-righting systems and related components and methods
US20220249814A1 (en) * 2018-11-19 2022-08-11 Progenity, Inc. Methods and devices for treating a disease with biotherapeutics
WO2020160399A1 (fr) 2019-02-01 2020-08-06 Massachusetts Institute Of Technology Systèmes et procédés pour injection de liquide
WO2020157324A1 (fr) 2019-02-01 2020-08-06 Novo Nordisk A/S Dispositif médical ayant un mécanisme d'actionnement
WO2020245448A1 (fr) 2019-06-07 2020-12-10 Novo Nordisk A/S Dispositif ingérable avec détachement d'élément de distribution
WO2022162102A1 (fr) 2021-01-28 2022-08-04 Novo Nordisk A/S Dispositif médical à mécanisme d'actionnement amélioré

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Title
ABRAMSON ALEX ET AL: "Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors", NATURE BIOTECHNOLOGY, NATURE PUBLISHING GROUP US, NEW YORK, vol. 40, no. 1, 30 August 2021 (2021-08-30), pages 103 - 109, XP037667058, ISSN: 1087-0156, [retrieved on 20210830], DOI: 10.1038/S41587-021-01024-0 *

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