WO2023144401A1

WO2023144401A1 - Ingestible device configured for needle deployment

Info

Publication number: WO2023144401A1
Application number: PCT/EP2023/052216
Authority: WO
Inventors: Nikolaj Eusebius Jakobsen
Original assignee: Novo Nordisk A/S
Priority date: 2022-01-31
Filing date: 2023-01-31
Publication date: 2023-08-03

Abstract

An ingestible device for injecting a drug substance into a gastro-intestinal wall portion, comprising: a) a housing (110, 120, 130, 210, 220, 230), b) a reservoir (131, 231), c) a needle (190, 290) configured for injection of drug substance, the needle (190, 290) being configured for movement from a non-deployed configuration and into a deployed configuration to drive insertion of a free end of the needle (190.3, 290) into a gastro-intestinal wall portion, and d) a drive arrangement (140, 150, 240, 250) for driving drug substance from the reservoir (131, 231) through the needle. The needle (190, 290) comprises a laterally flexible portion (190.2, 290.2) operable between the non-deployed configuration wherein the laterally flexible portion (190.2, 290.2) is maintained laterally strained to the deployed configuration wherein lateral strain is at least partially released.

Description

INGESTIBLE DEVICE CONFIGURED FOR NEEDLE DEPLOYMENT

The present invention relates to ingestible devices for delivery of a drug product or therapeutic substance to a subject user by means of injection and more particular to measures for deployment of an injection needle.

BACKGROUND OF THE INVENTION

In the disclosure of the present invention reference is mostly made to the treatment of diabetes by delivery of insulin, however, this is only an exemplary use of the present invention.

May people suffer from diseases, such as diabetes, which requires them to receive injections of drugs on a regular and often daily basis. To treat their disease these people are required to perform different tasks which may be considered complicated and may be experienced as uncomfortable. Furthermore, it requires them to bring injection devices, needles and drugs with them when they leave home. It would therefore be considered a significant improvement of the treatment of such diseases if treatment could be based on oral intake of tablets or capsules.

However, such solutions are very difficult to realise since protein-based drugs will typically be degraded and digested rather than absorbed when ingested.

To provide a working solution for delivering insulin into the bloodstream through oral intake, 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). This presents several challenges among which are: (1) The drug has to be protected from degradation or digestion by the acid in the stomach. (2) The drug has to be released while being in the stomach, or in the lower gastrointestinal tract, i.e. after the stomach, which limits the window of opportunity for drug release. (3) The drug has to be delivered at the lumen wall to limit the time exposed to the degrading environment of the fluids in the stomach and in the lower gastrointestinal tract. If not released at the wall, the drug may be degraded during its travel from point of release to the wall or may pass through the lower gastrointestinal tract without being absorbed, unless being protected against the decomposing fluids.

Prior art references relating to delivery of oral dosing from a swallowable capsule includes WO 2020/160399 A1 , WO 2021/013907 A9 and US 2009043278. These references disclose injection needles that are arranged for being moved along a deployment axis from a non-deployed position into a deployed position. Further, references US 2020/376192 A1 , EP 1 980 290 A1 , WO 2021/228826 A1 , and US 2013/164371 A1 provide further examples of capsule devices having a needle or delivery member deployment wherein an actuation system typically drives the deployment of the needle or delivery member.

Having regard to the above, it is an object of the present invention to provide an ingestible device for swallowing into a lumen of a gastrointestinal tract, and which allows a needle to be deployed into tissue adjacent the ingestible device, wherein the needle deployment offers greater flexibility in arranging components needed for the needle deployment.

A further object is to provide an ingestible device having a needle deployment feature provided in a less complex manner. A still further object of the present invention is to provide an ingestible device which enables improved needle/tissue interaction.

DISCLOSURE OF THE INVENTION

In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objects or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments.

Thus, in a first aspect of the invention, an ingestible device is provided for injecting a drug substance into a gastro-intestinal wall portion of a living mammal subject, the ingestible device, comprising: a housing, a reservoir containing a drug substance, a needle associated with the reservoir and configured for injection of drug substance into the mucosal lining of a gastro-intestinal wall portion, the needle being configured for movement from a non-deployed configuration and into a deployed configuration to drive insertion of a free end of the needle into a gastro-intestinal wall portion, and a drive arrangement for driving drug substance from the reservoir through the needle, wherein the needle comprises a laterally flexible portion operable between the non-deployed configuration wherein the laterally flexible portion is maintained laterally strained to the deployed configuration wherein lateral strain is at least partially released, and wherein a needle deployment retainer is configured for releasably retaining the needle in the non-deployed configuration and configured operable for release to cause lateral strain of the laterally flexible portion to drive, or to assist driving, the needle from the non-deployed configuration to the deployed configuration.

Advantages of using the injection needle in an ingestible device according to the first aspect includes providing a greater complexity of needle movement for reaching tissue adjacent the device when the device is disposed at a target location in the Gl-tract. This may be accomplished by a simple mechanism using fewer parts. Furthermore, the solution offers improved flexibility in the distribution of components internally in an ingestible device.

In some forms the needle deployment retainer is configured for releasably retaining the needle in the non-deployed configuration and configured operable by relative movement between the needle and the needle deployment retainer so as to release retaining of the needle in the nondeployed configuration to thereby enable lateral strain of the laterally flexible portion to drive, or to assist driving, the needle from the non-deployed configuration to the deployed configuration.

In some forms the housing comprises an elongated cylindrical wall section extending along an axis and further may comprise rounded ends.

In some embodiments, a retainer mechanism is provided within or on the ingestible device, which releasably maintains the needle in the laterally flexed position where mechanical energy is deposited due to lateral straining of the needle, and wherein release of the retainer mechanism to release the needle from the laterally flexed position causes movement of the needle from the non-deployed configuration into the deployed configuration, said movement being at least partly driven by said mechanical energy deposited due to lateral straining of the needle.

In some forms, the capsule device is configured for swallowing by a patient and travelling and deploy into a lumen wall of a Gl tract of a patient, such as a lumen wall of the small intestine, a lumen wall of the large intestine or a lumen wall of the stomach, respectively.

The ingestible device may in further embodiments comprise an environmentally-sensitive mechanism configured to operate the retainer mechanism for release upon sensing a predetermined condition, such as an ambient condition at the location the ingestible device is located. The environmentally-sensitive mechanism may in certain embodiments be a Gl tract environ- mentally-sensitive mechanism. The Gl tract environmentally-sensitive mechanism maycomprise a trigger member, wherein the trigger member is characterised by at least one of the group comprising: a) the trigger member comprises a material that degrades, erodes and/or dissolves due to a change in pH in the Gl tract; b) the trigger member comprises a material that degrades, erodes and/or dissolves due to a pH in the Gl tract; c) the trigger member comprises a material that degrades, erodes and/or dissolves due to a presence of an enzyme in the Gl tract; and d) the trigger member comprises a material that degrades, erodes and/or dissolves due to a change in concentration of an enzyme in the Gl tract.

In alternative forms, the trigger arrangement may also be or include an electronic trigger.

In some forms the drive arrangement comprises an energy source configured for powering the needle for needle deployment and/or for expelling drug substance from the reservoir.

In some forms the energy source comprises at least one drive spring, such as a compression spring or a tension spring, the spring being strained or configured for being strained for powering the needle for needle deployment and/or for expelling drug substance from the reservoir.

In embodiments wherein the energy source comprises a gas generator, the gas generator may comprise a trigger arrangement configured to actuate the gas generator.

The drive arrangement may be configured for driving drug substance from the reservoir through the needle either simultaneous with, or subsequently to, the needle moving from the non-deployed configuration and into a deployed configuration.

In some configurations, at least part of the movement of the needle from the non-deployed configuration into the deployed configuration comprises insertion of the free end of the needle into the mucosal lining disposed adjacent to the ingestible device. In some forms insertion of the needle occurs by redirecting the needle for insertion of the free end of the needle into the mucosal lining In further configurations the needle is configured for movement from the non-deployed configuration to the deployed configuration entirely driven by the lateral strain stored in the laterally flexible portion in the non-deployed configuration.

In alternative configurations the needle is configured for movement from the non-deployed configuration to the deployed configuration partly driven by the lateral strain stored in the laterally flexible portion in the non-deployed configuration.

In some embodiments the drive arrangement is configured to assist driving movement of the needle as it moves from the non-deployed configuration to the deployed configuration.

In some forms the needle comprises a bend portion connecting the free end of the needle with the laterally flexible portion, wherein the bend portion defines a deflection having an angle between 135 deg. and 45 deg., such as between 120 deg. and 60 deg., such as between 105 deg. and 75 deg., and such as between 95 deg. and 85 deg. In some forms the release of the lateral strain causes the needle to move in the direction substantially parallel with the free end of the needle.

In some embodiments the housing defines a main axis wherein the needle, in the non-deployed configuration, is arranged so that the laterally flexible portion assumes a coiled configuration around the main axis, and wherein lateral strain of the laterally flexible portion acts to uncoil the laterally flexible portion as the needle moves from the non-deployed configuration to the deployed configuration.

In such embodiments, the housing may be prepared so that it comprises an exterior surface that comprises a recessed track configured to entirely accommodate, or at least partly receive, the injection needle in the non-deployed configuration.

In still further embodiments the housing comprises a needle opening, wherein the needle is configured to move through the needle opening from the non-deployed configuration to the deployed configuration, and wherein the laterally flexible portion of the needle deflects laterally due to release of lateral strain as the needle extends from the needle opening thereby redirecting the free end of the needle towards mucosal lining of a gastro-intestinal wall portion supporting the housing. In some such embodiments, the drive arrangement may comprise a piston which is configured to act on the drug substance in the reservoir to expel drug substance from the reservoir, wherein the piston is configured for movement along an expelling axis, and wherein the drive arrangement is configured to move the end of the needle opposite to the free end of the needle by movement along or parallel with the expelling axis for needle deployment.

In still further embodiments of the ingestible device at least part of the laterally flexible portion of the needle protrudes through a portion of the reservoir when the needle assumes the nondeployed configuration.

According to a second aspect of the invention, a capsule administering assembly is provided comprising an ingestible capsule, such as any of the variants of an ingestible device according to the first aspect, for delivery of a mixed drug product to a subject user, and a capsule accessory device. The ingestible capsule is operable from a first attached state where the ingestible capsule is coupled relative to the capsule accessory device, and a second detached state wherein the ingestible capsule is detached from the capsule accessory device to permit ingestion of the ingestible capsule. The capsule administering assembly comprises a first reservoir holding a first drug component (A) and a second reservoir separate from the first reservoir, the second reservoir holding a second drug component (B), and wherein the capsule administering assembly further comprises fluid communication means for establishing fluid communication between the first reservoir and the second reservoir.

The ingestible capsule comprises: a capsule housing sized to pass through the gastrointestinal tract of a patient, the capsule housing comprising a capsule housing first portion, the first reservoir arranged within the capsule housing, a drug outlet, and an expelling assembly comprising a movable wall associated with the first reservoir, the movable wall being movable relative to the capsule housing first portion to reduce the volume of the first reservoir thereby expelling drug from the first reservoir through the drug outlet.

The capsule accessory device comprises a first handling component configured for movement relative to the capsule housing first portion, wherein when the ingestible capsule assumes the first attached state, the first handling component is moveable relative to the capsule housing first portion from a first position to a second position, wherein the capsule administering assembly is configured to transfer the second drug component (B) from the second reservoir via the fluid communication means to the first reservoir upon movement of the first handling component from the first position to the second position, thereby forming said mixed drug product accommodated in the first reservoir.

In accordance with the second aspect, improved drug stability is offered compared to prior art systems. In addition, increased drug load is enabled. On the other hand, the invention according to the first aspect offers increased use of the available volume of the ingestible capsule, enabling the option of reducing the overall volume of the ingestible capsule, or improving the drug expelling performance.

In some forms the capsule accessory device comprises said second reservoir. In other embodiments, the ingestible capsule comprises both the first reservoir and the second reservoir.

In some forms, the capsule administering assembly is configured to increase the volume of the first reservoir upon movement of the first handling component from the first position to the second position thereby forcing the second drug component (B) from the second reservoir to the first reservoir. In such embodiments, the second drug component (B) may be sucked into the first reservoir for mixing the drug components.

In some embodiments the movable wall comprises a piston slidably arranged within a cylinder portion defined by the first reservoir. In other embodiments, the first reservoir may comprises a flexible wall which is configured to collapse for reducing the volume of the first reservoir.

In some embodiments, the capsule administering assembly is configured to reduce the volume of the second reservoir upon movement of the first handling component from the first position to the second position thereby forcing the second drug component (B) from the second reservoir to the first reservoir.

In some forms, the capsule accessory device further comprises a second handling component being movably arranged relative to the first handling component, wherein when the ingestible capsule assumes the attached state, the first handling component moves relative to the second handling component as the first handling component moves relative to the capsule housing first portion from said first position to said second position. In such forms, in particular embodiments, the first handling component may be configured for rotationally movement relative to the capsule housing first portion from the first position to the second position, such as a rotational only movement without axial relative movement or, alternatively, with a combined rotational and axial relative movement.

In such embodiments, the capsule housing may be provided in a form where it further comprises a capsule housing second portion that is rotationally movable relative to the capsule housing first portion.

Also, in such embodiments, the administering assembly may be so configured that, as the first handling component moves relative to the capsule housing first portion from said first position to said second position, the first handling component couples rotationally with the capsule housing second portion and the second handling component couples rotationally with the capsule housing first portion.

In further embodiments of the capsule administering assembly, wherein the movable wall defines comprises a displaceable piston, and wherein the ingestible capsule comprises a mechanism coupling the displaceable piston, the capsule housing first portion and the capsule housing second portion with each other, wherein said mechanism incorporates a helical guide structure configured to displace the piston to increase the volume of the first reservoir as the capsule housing second portion rotates relative to the capsule housing first portion. when the ingestible capsule assumes the attached state, the first handling component and the second handling component in combination define a cavity, wherein the ingestible capsule is partly of fully received in the cavity.

The first handling component and the second handling component may be configured to become mechanically separated relative to each other so as to remove the ingestible capsule from the cavity. Alternatively, the first handling component or the second handling component may provide an opening which enables the ingestible capsule accommodating the mixed drug product to be removed through the opening.

The capsule administering assembly may be formed to comprise a guide system enabling the ingestible capsule to be detached relative to the capsule accessory device subsequently to the first handling component being moved relative to the capsule housing first portion from the first position to the second position, but wherein the guide system prevents detachment relative to the capsule accessory device prior to the first handling component being moved to the second position. This prevents unintended use of the assembly.

In further embodiments the first handling component is configured for axially moving relative to the capsule housing first portion from the first position to the second position. In embodiments where first and second handling components are provided the axial movement may occur by an axial telescopic movement, e.g. by moving the first and second handling components axially towards each other.

In some forms of the capsule administering assembly, the fluid communication means comprises a fluid gate operable between a closed state wherein the fluid gate separates the first drug component (A) and the second drug component (B) from each other, and an open state wherein the fluid gate enables fluid flow from the second reservoir to the first reservoir.

In some variants the fluid communication means comprises said drug outlet. In alternative variants, the fluid communication means are formed as a drug inlet separately from said drug outlet.

In some embodiments one of the first drug component (A) and the second drug component (B) is a powder, and wherein the other of the first drug component (A) and the second drug component (B) is a liquid. In some forms wherein the drug component is provided as a powder, the powder may, prior to mixing, be accommodated in the first reservoir.

In other embodiments the first drug component (A) is a liquid and the second drug component (B) is a liquid.

The ingestible capsule may be provided so as to comprise an expelling assembly that comprises an energy source configured for exerting a load on the movable wall. Further, it may comprise a releasable trigger configured for actuation in response to one or more predetermined conditions to permit said load to move the movable wall thereby reducing the volume of the first reservoir and expelling said mixed drug product through the drug outlet.

The expelling assembly may be provided so that it is configured for accumulation of potential energy in the energy source in response to movement of the first handling component relative to at least one portion of the capsule housing and/or the second handling component. In such system, reduced risk of creep of plastic components is to be expected offering improved storage capability.

In some embodiments, the energy source is or comprises at least one spring configured as a drive spring. Exemplary springs include a compression spring, a tension spring, a torsion spring, a leaf spring or a constant-force spring. The spring may either be strained or configured for being strained for powering expulsion from the capsule device. Other non-limiting exemplary types of energy sources for the actuator include compressed gas actuators or gas generators. In some embodiments, in the pre-firing configuration, the energy source exerts a load onto the movable wall thereby biasing the movable wall for reducing the volume of the drug reservoir. In other embodiments the energy source is configured to exert a load onto the movable wall only upon triggering of a trigger member or mechanism of the capsule device.

The capsule may comprise one or more openings to allow a biologic fluid, such as gastric fluid, to enter the capsule for dissolving the dissolvable firing member(s).

According to exemplary embodiments described herein, a trigger of a capsule device may be configured to actuate the capsule device in the Gl tract of a subject, or in any other location internal to a subject, under a predetermined condition. In some embodiments, the predetermined condition includes one or more of a predetermined time after ingestion of the capsule device, a predetermined location in the Gl tract, physical contact with the Gl tract, physical manipulation in the Gl tract (e.g., compression via peristalsis), one or more characteristics of the Gl tract (e.g., pH, pressure, acidity, temperature, etc.), or combinations thereof. In some embodiments, the trigger may be a passive component configured to interact with the environment of the Gl tract to actuate the capsule device.

In some embodiments, the trigger may be a sensor that detects one or more characteristics of the Gl tract. For example, a sensor detecting contact with a Gl mucosal lining may be used to actuate the device. In embodiments where a sensor is employed, the trigger may also include an active component that moves in response to a predetermined condition being detected by the sensor. For example, a gate may be moved when contact with a Gl mucosal tract is detected. In other embodiments the trigger may employ electrical power to melt or weaken a rupturable membrane (e.g., by applying a voltage across a conductive rupturable membrane) and/or trigger a chemical reaction. Of course, any suitable active or passive trigger may be employed for a capsule device, as the present disclosure is not so limited.

In exemplary embodiments, the capsule device is configured for swallowing by a patient and travelling into a lumen of a gastrointestinal tract of a patient, such as the stomach, the small intestine or the large intestine. The capsule of the device may be shaped and sized to allow it to be swallowed by a subject, such as a human.

By the above arrangements an orally administered mixed drug substance can be delivered safely and reliably into the stomach wall or intestinal wall of a living mammal subject.

As used herein, the terms "drug", “drug substance”, “drug product” or “therapeutic substance” is meant to encompass any drug formulation or therapeutic substance 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. insulins, insulin containing drugs, GLP-1 containing drugs as well as derivatives thereof), proteins, and hormones, biologically derived or active agents, hormonal and gene-based agents, nutritional formulas and other substances in both solid, powder or liquid form. Specifically, 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.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following embodiments of the invention will be described with reference to the drawings, wherein fig. 1 is an external perspective view of an ingestible capsule 200 of a capsule administering assembly 200/300 according to a first embodiment, fig. 2a is an external perspective view of capsule accessory device 300 of the capsule administering assembly 200/300 according to the first embodiment, fig. 2b is an external perspective partly cut view of the capsule administering assembly 200/300 comprising ingestible capsule 200 accommodated within capsule accessory device 300, fig. 3 is an exploded perspective view of components of the capsule administering assembly 200/300 according to the first embodiment, fig. 4a is a perspective view of ingestible capsule 200, fig. 4b is a perspective partly cut view of ingestible capsule 200, fig. 5a is a perspective view of a needle hub 250, dissolvable firing member 280 and injection needle 290 in accordance with the first embodiment, fig. 5b is a perspective view of components of fig. 5a omitting the dissolvable firing member 280 and injection needle 290 from view, figs. 5c and 5d show a perspective view and a partly cut perspective view of a middle housing portion 220 of ingestible capsule 200, figs. 6a, 6b and 6c show respectively a perspective view, a perspective partly cut view and a cross-sectional side view of ingestible capsule 200 in a ready-to-ingest state, fig. 7 is a perspective partly cut view of capsule accessory device 300 omitting the ingestible capsule 200 from view, fig. 8a is a cross-sectional side view of capsule administering assembly 200/300 in a state prior to drug mixing, fig. 8b is a cross-sectional side view of capsule administering assembly 200/300 in a state after drug mixing, figs. 9a through 9d show a sequence of perspective views of first and second handling components 310 and 330 of capsule accessory device 300 in different states during operation, figs. 10a and 10b are cross-sectional side views of a second embodiment ingestible capsule 200’, figs. 11a-11c are three views of an increasingly curved needle according to the second embodiment during needle deployment, figs. 12a, 12b and 12c are perspective side views of a third embodiment ingestible capsule 200” during three different stages of self-orientation and needle deployment, figs. 13a and 13b are perspective side views of a fourth embodiment ingestible capsule 100 with an injection needle 190 in a non-deployed and deployed state, respectively, fig. 13c is a side view of ingestible capsule 100 in the state shown in fig. 13a, fig. 13d is a detailed perspective view of the injection needle 190 in the state shown in fig. 13a, figs. 14a and 14b are cross-sectional side views of the ingestible capsule 100 of the fourth embodiment in a ready-to-ingest state, the views rotated relative to each other by 90°, figs. 15a and 15b are cross-sectional side views of the ingestible capsule 100 of the fourth embodiment in a needle deployed state, the views rotated relative to each other by 90°, and figs. 16a and 16b are cross-sectional side views of the ingestible capsule 100 of the fourth embodiment in a state after drug expelling, the views rotated relative to each other by 90°.

In the figures like structures are mainly identified by like reference numerals. DESCRIPTION OF EXEMPLARY EMBODIMENTS

When in the following terms such as “upper” and “lower”, “right” and “left”, “horizontal” and “vertical” or similar relative expressions are used, these only refer to the appended figures and not necessarily to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only. When the term member or element is used for a given component it generally indicates that in the described embodiment the component is a unitary component, however, the same member or element may alternatively comprise a number of sub-components just as two or more of the described components could be provided as unitary components, e.g. manufactured as a single injection moulded part. The terms “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.

Different embodiments for capsule devices according to the invention may be configured for substance delivery for any drug product or therapeutic substance suitable for being delivered through a needle lumen of an injection needle. Exemplary drug products or therapeutic substances may for example be provided as a single therapeutic substance or multiple therapeutic substances which are co-formulated or delivered by sequential delivery. Further examples include a drug product which may be a mixed drug product wherein at least two drug products are to be mixed prior to drug injection.

With reference to fig. 1 a first embodiment of a drug delivery device is shown. The embodiment is designed to provide an ingestible capsule device 200 sized and shaped to be ingested by a patient and configured for subsequently become activated for drug delivery when in a target lumen of the patient so as to cause a dose of a liquid drug to be expelled through an injection needle of the capsule device 200. Fig.1 shows capsule device 200 in a state wherein the device is ready to be ingested. It is to be noted that the disclosed ingestible capsule device 200, in the following referred to as “capsule 200” is only exemplary and, in accordance with the invention, may be provided in other forms having different capsule outer shapes. The disclosed first embodiment relates to a capsule 200 suitable for being ingested by a patient to allow the capsule device to enter a lumen of the Gastro-Intestinal tract, such as the small intestine, the large intestine or the stomach, and finally to eject a liquid dose of a drug product at a target location into tissue of the lumen wall located adjacent the capsule device. In accordance with the intended location for targeted delivery into tissue of a lumen wall, the capsule device may include means for ensuring optimal tissue proximity between the injection needle and the tissue, such as a particular shape and/or mass distribution of the capsule so as to enable self-orienting, or by including other means for re-orienting the capsule so as to position the drug outlet in an orientation in order to facilitate easy and effective needle insertion into tissue. Reference is made to embodiments described further below in connection with figs. 10a through 12c, with those embodiments particularly offering improved needle/tissue interaction.

In the shown first embodiment, a mixed drug product is intended to be prepared from at least two drug products “A” and “B”. Prior to mixing, product “A” is stored within a first reservoir 231 within capsule 200 whereas product “B” is stored exterior to the capsule 200 in a capsule accessory device 300, the capsule accessory device to be described more in depth below. After the two drug components “A” and “B” have been mixed, during a drug mixing step, the mixed drug product resides in the first reservoir 231 of capsule 200. In the shown embodiment, the drug component “A” is provided initially as a lyophilized drug substance, such as a powder, whereas the drug component “B” is a reconstitution liquid, such as a diluent. In other embodiments, the drug products “A” and “B” may be provided in other forms, such as each being initially provided as a liquid, and wherein the drug products “A” and “B” prior to drug administration are mixed for being accommodated in the first reservoir 231 for subsequent swallowing of capsule 200.

The capsule 200 shown in fig. 1 includes a multi-part housing having an elongated shape extending along a central longitudinal axis, which is also referred to in the following as “the firing axis”. The elongated housing includes a cylindrical section and further include rounded end portions, i.e. a proximal end portion and a distal end portion, the latter including a drug outlet opening for the capsule 200. The drug outlet opening includes a penetrable seal, provided as an elastomeric plug 239 that is penetrable by the injection needle and which seals when not being penetrated by the injection needle. In the shown embodiment, the capsule is configured in shape and size to roughly correspond to a 00 elongated capsule. The shown multi-part housing includes a housing first portion and a housing second portion. The housing first portion is formed by proximal housing portion 210 arranged at the proximal end of the capsule 200. The housing second portion includes a generally cylindrical sleeve shaped middle housing portion 220 and a distal housing portion 230 arranged at the distal end of capsule 200. In the shown embodiment the distal housing portion 230 and the middle housing portion 220 are fixedly attached to each other by means of a permanent connection. However, the proximal housing portion 210 is mounted relative to the middle housing portion 220 so that, at least during a mixing preparation procedure for mixing separate products A and B, the proximal housing portion 210 is able to rotate relative to the middle housing portion 220 while being held axially fixed relative thereto. An injection needle 290 is movable along the firing axis in proximal and distal directions through a distal opening formed in the distal housing portion 230, i.e., protruding though elastomeric plug 239. The needle 290 is in the state shown, i.e., prior to ingestion, slightly protruding from the exterior side of the elastomeric plug 239 but in a way wherein a distal lumen opening of the injection needle is still sealingly embedded in elastomeric plug 239. In other embodiments, the free tip end of the injection needle may be completely embedded in plug 239 so as not to protrude therefrom prior to drug delivery. It is to be noted that, for the first embodiment shown in figs. 1 through 9d, the injection needle 290 is shown as a straight injection needle which is mounted to align with the longitudinal axis of the capsule. However, as will be described in connection with the second and third embodiments, the needle 290 of the first embodiment may be formed differently.

In accordance with an aspect of the present invention, the capsule 200 is configured to be accommodated within a cavity of the capsule accessory device 300 referred to above, so that the capsule accessory device 300 is used both as a packaging for storing the capsule 200 prior to use, as well as a tool for preparing the capsule 200, i.e. for providing the mixed drug product in the first reservoir 231 arranged within capsule 200. In this disclosure, the combination of capsule 200 and capsule accessory device 300 is referred to as a capsule administering assembly. A cross sectional view of a first embodiment of a capsule administering assembly 200/300 can be viewed in fig. 2b. From this view, wherein the capsule administering assembly 200/300 is depicted in its storage state, i.e. prior to drug mixing, the drug product “B” resides outside of capsule 200, more specifically in a second reservoir 332 formed as part of accessory device 300.

For the capsule administering assembly, and more specifically to the ingestible capsule, reference is made to “a first attached state” where the ingestible capsule is coupled relative to the capsule accessory device, and “a second detached state” wherein the ingestible capsule is detached from the capsule accessory device to permit ingestion of the ingestible capsule. Referring to fig. 2a the capsule accessory device 300 forms two separate grippable handling components 310 and 330, both portions being generally cylindrical, which are configured so that they can be arranged and coupled relative to each other to extend along a common axis which, when capsule device 200 is accommodated within capsule accessory device 300, is coaxial with the firing axis of capsule 200. The distal handling component 330 forms a first handling component configured to engage and cooperate with the distal housing portion 230 of capsule 200. The proximal handling component 310 forms a second handling component configured to engage and cooperate with the proximal housing portion 210 of capsule 200. It is to be noted that, although the embodiments disclosed within this disclosure each comprise two separate handling components to cooperate with a single capsule device, other embodiments according to the invention only include a single handling component which cooperates with a particular design of a capsule device.

Referring also to figs. 7 and 9a-9d, the distal handling component 330 includes a cylindrical reduced diameter portion 333 configured to be received within a cylindrical bore of proximal handling component 310 when the two handling components are positioned relative to each other as shown in figs. 2a, 7, 9c and 9d. In this state, the two handling components 310 and 330 in combination form a closed volume 301 which is sized so that the capsule 200 is snugly received within volume 301 , cf. also fig. 2b. As shown in fig. 7, the second reservoir 332 is formed in the distal handling component 330 adjoining a plug 390 made of an elastomeric material, the plug being arranged distally from the second reservoir 332. In this way the plug 390 forms one side wall of the reservoir 332.

As shown in fig. 2a, on exterior surfaces of distal handling component 330, a pair of wings 331 are formed. Likewise, on exterior surfaces of proximal handling component 310, a pair of wings 311 are formed. The wings are shaped so that a patient, or other assisting personnel, may grip capsule accessory device 300, and then, e.g. using both hands, may initially twist the distal handling component 330 and the proximal handling component 310 relative to each other, and subsequently separate the two handling components axially from each other so at to provide access to the capsule 200.

Referring to figs. 1 and 7, these views reveal that distal housing portion 230 includes a nonround keyed outer surface 237 which fits in mating relationship into a non-round keyed inner surface 337 of distal handling component 330. Similarly, proximal housing portion 210 includes a non-round keyed outer surface 217 which fits in mating relationship into a non-round keyed inner surface 317 of proximal handling component 310. Hence, when the distal handling component 330 is twisted relative to the proximal handling component 310 the distal housing portion 230 is twisted relative to the proximal housing portion 210. The pairs of cooperating surfaces 237/337 and 217/317 are formed so that the capsule end portions are axially detachable relative to the respective cooperating handling components so that, after the handling components are separated axially from each other, the capsule 200 can be removed entirely from the capsule accessory device 300.

Fig. 3 shows an exploded perspective view of all the components of the first embodiment capsule administering assembly 200/300. It is to be noted that drug component “A”, i.e. the powder, is shown schematically as a cylindrical shaped entity corresponding to the volume of first reservoir 231 when the capsule assembly administering assembly 200/300 assumes the storage state. Also note that drug component “B”, i.e. the diluent, is shown schematically as a cylindrical shaped entity corresponding to the volume of the second reservoir 332 when the capsule assembly administering assembly 200/300 assumes the storage state.

Now turning to figure 4a and 4b the capsule 200 of the first embodiment will be described more in detail. The figures show the capsule in the state wherein the mixed drug product is accommodated inside first reservoir 231 , and wherein the capsule is prepared ready to be ingested by a patient. In fig. 4b, the products “A” and “B” are schematically shown as two separate portions inside first reservoir 231. However, in real life settings, the two products will typically rapidly have become mixed or at least substantially mixed together so that a reconstituted drug product is rapidly established which fills the first reservoir 231 in a substantially uniform manner, however in some embodiments also with an amount of air present within reservoir 231 .

Inside capsule 200 the first reservoir 231 is defined by a tubular member, i.e., a cylinder, extending in the proximal direction from a distal end part of the distal housing portion 230, and so that the distal end surface of the reservoir 231 is defined by a proximally facing interior surface of distal housing portion 230. Inside the tubular member a movable needle hub 250 is arranged, the needle hub forming a piston having a ring-shaped seal 270 arranged to sealingly engage the interior cylindrical wall surface of the tubular member. In the shown embodiment, during a drug mixing preparation step, the needle hub 250 is arranged to be both axially and rotationally movable relative to the middle housing portion 220 and distal housing portion 230. During drug expelling, the needle hub 250 is arranged to be axially movable relative to the middle housing portion 220 and distal housing portion 230 but prevented from moving rotation- ally relative to portions 220/230.

The needle hub 250 and the tubular member in combination forms a piston/cylinder assembly wherein the needle hub 250, when being moved along the firing axis in the proximal direction, provides for sucking in liquid into reservoir 231 as the volume of the reservoir is increased. Oppositely, when the needle hub 250 is moved distally, thereby reducing the volume of reservoir 231 , the liquid present in the reservoir is being expelled from the first reservoir 231.

In capsule 200, a source for storing potential energy is incorporated, which in the shown embodiment is provided as a compression spring 240, arranged for being axially compressed to accumulate energy. In the shown embodiment, the compression spring 240 is formed as a helical spring which is arranged coaxially with the firing axis. The proximal end of compression spring is arranged in a distal spring seat formed as an integral part of the proximal housing portion 210. The distal end of compression spring 240 is arranged in a distal spring seat formed as an integral part of the needle hub 250. Potential energy is accumulated in compression spring 240 as the needle hub 250 is moved proximally. The needle hub 250 and compression spring 240 forms part of an drive arrangement, wherein triggering of the drive arrangement is controlled by a trigger. In the shown embodiment, triggering occurs after a certain time after capsule 200 is exposed to intestinal liquid present in the small intestine.

Referring now to fig. 5a, the needle hub 250 is generally cylindrical and part of a needle hub assembly. The needle hub assembly further includes an injection needle 290 which is fastened to the needle hub 250 so that the injection needle extends in the distal direction along the firing axis away from the needle hub. The injection needle 290 comprises a distal pointed section, a distal needle opening (non-referenced) arranged near the distal pointed section, a proximal arranged side opening (non-referenced) arranged in the vicinity of the needle hub 250 and an internal lumen extending between the distal needle opening and the side opening providing fluid communication between the two openings. The proximal side opening is located so that it provides fluid communication between reservoir 231 and the lumen of the injection needle at all stages of operation of capsule 200. The needle hub assembly further includes the ringshaped seal 270 arranged in a cylindrical channel on needle hub 250, and a pair of dissolvable firing members 280. In the state shown in figs. 4a and 4b, i.e. the ready-to-ingest state, the dissolvable firing members 280 provide a means of releasably retaining the needle hub 250 against the mechanical load provided by compression spring 240, in a start expelling position within first reservoir 231 , to prevent it from moving distally, i.e. the dissolvable firing members 280 act as a releasable trigger.

As noted above, in accordance with aspects of the invention, the triggering systems disclosed herein are only exemplary. Other trigger systems may be used in alternative embodiments, wherein the trigger is configured to actuate in response to one or more predetermined conditions.

Referring to figs. 4a and 4b, when the capsule 200 assumes the ready-to-ingest state, the injection needle 290 with its distal pointed section will be substantially accommodated within the capsule 200 so that the distal needle opening is embedded within plug 239 to prevent fluid communication through the injection needle 290.

As shown in fig. 5b, a pair of symmetrically arranged radially protruding rib systems 252 protrude radially outwards from a radially outwards facing surface of the needle hub 250. Each of the pair of rib systems 252 includes a helical segment and an axial segment. Each of the rib systems 252 is configured to cooperate with a respective one of a pair of radially inwards extending protrusions 222 arranged on a radially inwards facing surface of the middle housing portion 220 (see fig. 5d). Each protrusion 222 serves as a track follower that follows a helical segment track 252a on needle hub 250 which further leads to an axial segment track 252b, both tracks being defined by the rib system 252 of needle hub 250. When the dissolvable firing members 280 are present at location 252c, the dissolvable firing members prevent relative axial movement between the protrusions and the dissolvable firing member, thus preventing the protrusions 222 to move past location 252c in the axial segment track 252b. As shown in fig. 5c, a pair of window openings 228 are located in housing 222 so that, with the capsule in the state shown in fig. 4a and 4b, the window openings 228 provides for the dissolvable firing members 280 being exposed to intestinal liquids. However, prior to ingestion, the window openings 228 may include a layer of an enteric coating designed to pass through the stomach unaltered and disintegrate at the changed pH-level in the intestine. This will cause the dissolvable firing members 280 to become exposed to the intestinal liquids with subsequent disintegration of the dissolvable firing members 280 to allow the protrusions 222 to pass the locations 252c and continue unhindered in the axial segment track 252b.

As indicated in fig. 5b, a protrusion 255 protrudes radially inwards from a radially inwards facing surface of needle hub 250. The axial protrusion 255 is configured to be received in an axial extending groove 215 formed in the radially outwards facing surface of proximal housing portion 210, see fig. 3. The protrusion 255 and the axial extending groove 215 serve for preventing relative rotational movement between the proximal housing portion 210 and the needle hub 250 while allowing axial relative movement between the two components to occur.

For the capsule administering assembly 200/300, when the capsule 200 assumes the ready- to-mix state shown in fig. 8a (which is similar to the state shown in fig. 2b) the capsule 200 is accommodated within the accessory capsule device 300, and the drug product “B” is present in the second reservoir 332. The drug product “A” is present in the first reservoir 231. As the needle hub 250 is positioned relatively far distally, the volume of reservoir 231 is approximately half the size compared to the state wherein the drug products “A” and “B” are mixed within reservoir 231 , cf. fig. 8b. The distal opening of the injection needle 290 is positioned so that the opening is plugged within plug 390, meaning that the two reservoirs are not in fluid communication. The proximal handling component 310 and the distal handling component 330 maintains the capsule 200 accommodated within volume 301 so that the drug product portions A and B are sealed from the external environment.

Referring to figs. 5a and 5d, the protrusions 222 are located along the helical segment track 252a of needle hub 250. When the subject user takes the capsule administering assembly 200/300 into use, the proximal handling component 310 is rotated relative to the distal handling component 330. This causes the proximal housing portion 210 and the needle hub 250 to rotate relative to the middle housing portion 220 which in turn causes the protrusions 222 to move along the rib system right to the position wherein the protrusions are rotationally located within the axial track segments 252b. During rotation, due to the interaction between the rib system 252 and the protrusion 222, the needle hub 250 is moved proximally causing the injection needle to be axially withdrawn from the plug 390 and become positioned so that there is fluid communication between the second reservoir 332 and the first reservoir 231 . As the needle hub moves proximally, the size of the first reservoir 231 is increased. Hence, due to differences in hydraulic pressure, the drug product “B” is transferred from the second reservoir 332 into the first reservoir 231. As the needle hub 250 moves proximally as the handling components 310 and 330 are rotated relative to each other potential energy is accumulated in compression spring 240.

The rotation continues until the protrusions 222 reach the end of the helical part of the rib system, where after the needle hub 250 is pushed slightly distally by the compression spring 240 until the protrusions 222 arrives resting on the dissolvable firing members 280. At this point in time, the distal opening of the injection needle 290 is plugged into the plug 239, and all or a predefined portion of the drug product “B” has been transferred to reservoir 231. This causes the two drug products “A” and “B” to mix forming a mixed drug product suitable for administration. This state is shown in fig. 8b, which is also referred to as the ready-to-ingest state for the capsule device 200.

Naturally, prior to ingestion, the capsule 200 needs to be removed from the capsule accessory device 300. In the shown embodiment, as outlined in figs. 9a through 9d, the distal handling component 330 and the proximal handling component 310 includes a guide system which ensures that, a predefined sequence of movement between the two is required, preventing malfunction by unintended operation. In the shown embodiment, a system of tracks and track followers are incorporated to provide this sequence control.

The proximal handling component 310 includes a pair of oppositely arranged track followers 315 protruding radially inwards into the cylindrical bore of the proximal handling component 310. A plurality of segments of axial and round-going tracks are formed on the reduced diameter portion 333 of distal handling component 330, each segments of tracks being formed to receive and guide a respective one of the track followers 315.

Referring to fig. 9b, during assembly of the capsule administering assembly 200/300, i.e. after insertion of the capsule 200 into the opening formed in the reduced diameter portion of the distal handling component 330, a first axial track 335a ensures axial only movement for approaching the proximal handling component 310 relative to the distal handling component 330, cf. the arrow shown in fig. 9a. At this stage, a one-way snap protrusion 336 ensures that the two handling components 310 and 330 cannot be axially withdrawn relative to each other. A further one-way snap protrusion 337 serves to ensure that the assembly in the state shown in fig. 8a is maintained until the assembly is put into use.

When a deliberate rotational force is exerted between the two handling components in accordance with the arrow shown in fig. 8c, the track followers 315 are allowed to pass the one-way snap protrusions 337 and continued rotational movement in the order of 140 deg. is performed to enable the track followers 315 to pass further one-way snap protrusions 338, cf. fig. 9d. In this position, the capsule administering assembly 200/300 assumes the state shown in fig. 8b. Axial track 335d means that further manipulation between handling components 310 and 330 can only occur by axially separating the two. When the subject user intends to swallow the capsule 200, the distal and proximal handling components 330, 310 are axially withdrawn from each other as indicated by the arrow in fig. 9d and the capsule 200 can be entirely removed from the capsule accessory device 300. In this state the capsule is in the ready-to-ingest state.

As described above, subsequent to swallowing of the capsule device, the capsule 200 first moves through the stomach and enters the small intestine. Due to the enteric coating becoming dissolved only after passage of the stomach, the dissolvable firing members 280 are exposed to intestinal fluid in the small intestine. After lapse of a pre-defined time the dissolvable firing members 280 are sufficiently eroded to enable the protrusions 222 of the middle housing portion 220 to pass the locations 252c, cf. fig. 5b. This means that the needle hub 250 is allowed to move unhindered distally, forced by the potential energy accumulated in compression spring 240, causing the injection needle 290 to be shot out of the capsule 200 and into mucosal tissue at the target location. As the needle hub 250 moves further distally, the mixed drug product accommodated in the first reservoir 231 is ejected through the lumen of the injection needle to deliver the mixed drug product for a drug depot to be formed in the mucosal tissue. After delivery of the mixed drug product, the capsule 200 is allowed to pass the alimentary canal and be subsequently excreted.

With reference to figs. 10a and 10b, these depictions show a schematical presentation of a second embodiment capsule 200’ in two different states. The second embodiment capsule 200’ corresponds in most aspects to the first embodiment capsule 200 but with the injection needle 290 being of a different design. Fig.10a shows capsule 200’ in a state ready for ingestion, whereas fig. 10b shows capsule 200’ in a state close to finalization of drug delivery.

The shown second embodiment capsule 200’ may be intended to be provided to the end user in the state as shown in fig. 10a where liquid drug product A in a final injectable form is accommodated in reservoir 231 , i.e. , also during long-term storage of capsule 200’.

The injection needle 290 is configured for movement from a non-deployed configuration and into a deployed configuration to drive insertion of a free end of the needle into a gastro-intestinal wall portion. The injection needle 290 includes a laterally flexible portion 290.2 extending between the portion of the needle that is mounted relative to needle hub 250 and the free end of the needle. Prior to the assembling of capsule 200’ during manufacturing, in a needle preparation step, the part of the injection needle 290 that extends distally from needle hub 250 when disposed in capsule 200’ is bent in shape by permanent deformation so that this part of the needle assumes a curved segment 290.2 along a substantial portion of the length of the needle. The curvature of segment 290.2 of the finished needle 290, prior to assembling into capsule device 200’, and in a free state with no forces straining the needle laterally, roughly corresponds to the curved shape depicted in fig. 10b.

When the capsule 200’ is assembled, the injection needle 290 is mounted to extend inside the capsule 200’ with the needle assuming an almost linear shape inside reservoir 231 between the needle hub 250 and the elastomeric plug 239. In practical embodiments, at least for some embodiments, in the storage state, due to the lateral pre-straining of the needle and due to the plug 239 laterally constraining the portion of the needle engaged by the plug, the needle will assume a shape which resembles a slightly curved s-form shape in a manner similar to the shape of needle 290 shown in fig. 11a. Hence, the lateral flexible portion 290.2 of injection needle 290 will be maintained pre-strained laterally so that the needle is held in a substantially straight configuration with lateral bias stored in the needle segment 290.2.

During operation of capsule 200’, due to the distal driving movement of needle hub 250, the injection needle 290 will be gradually deployed to increasingly protrude through the needle opening formed by elastomeric plug 239. When the needle moves through plug 239, as the laterally non-constrained portion of the needle will cease to be laterally supported by plug 239, the released lateral strain will cause the free end of the needle to assume a curved shape and be redirected laterally towards tissue adjacent the capsule. Fig. 11b and 11c are two further views of the increasingly curved needle during needle deployment.

For the shown second embodiment, the accommodated drug in reservoir 231 will be expelled from reservoir 231 during needle deployment from the non-deployed configuration and into the deployed configuration. However, in alternative embodiments, in accordance with the particular drive and expelling arrangement of the capsule, the operational sequence may be configured different. For example, the expelling of drug through the injection needle may be designed to initiate only subsequent to partial deployment of the needle. Alternatively, the drug expelling through the injection needle may be designed to initiate only subsequent to full deployment of the needle, i.e. in a sequential configuration.

In accordance with the present invention, it is to be noted that although the second embodiment shows an injection needle which in the non-deployed configuration assumes a position aligned coaxially with the central longitudinal axis of the capsule, other embodiments may include needle configurations where the needle is disposed differently. For example, the needle, or part of the needle, may in the non-deployed configuration be oriented along an axis running in parallel with the central longitudinal axis and/or may be disposed at an angle inclined relative to the central longitudinal axis, so that the outlet opening, e.g. an elastomeric plug, is located non- centrally on the rounded endcap or even located to emerge on the cylindrical surface.

In accordance with the present invention, further embodiments of a capsule device optionally include means for automatically re-orienting at least a housing part of the capsule device so as to provide a particular needle orientation relative to tissue prior to or during needle deployment. Such re-orienting features may for example rely on re-orienting relative to gravity (as described in W02020/160399 A1) or re-orienting relative to a portion of a tissue surface located adjacent to the capsule housing part by utilizing one or more active and movable support features cooperating with tissue portions adjacent the capsule housing.

In some embodiments the automatic re-orienting may be provided as an active deployable reorienting feature that may be associated with the capsule housing and which upon movement of the active deployable orienting feature relative to the capsule housing may serve to re-orient the capsule in a desired orientation relative to a target tissue surface adjacent the capsule housing. As an example, a third embodiment capsule 200” is depicted in figs. 12a-12c which show schematical representations of a capsule device 200” in three consecutive states. The overall configuration of capsule 200” corresponds to the second embodiment capsule 200’ described above. An active re-orienting feature, in this embodiment first and second wings 260 formed as a pair is mounted relative to capsule middle housing 220, is provided, In capsule 200”, in an initial first state, each of the wings 260 wraps tightly around the capsule middle housing 220. In a second state the wings release to unwrap away from the capsule middle housing.

The first and second wings 260 may for example be made of sheets of a shape memory polymer which will unfold at a specific condition associated with the use of capsule. For example the specific condition may be an ambient condition such as temperature, PH value or a combination of the two, wherein the wings 260 unfold away from capsule middle housing 220 when the capsule reaches a target location in the Gl-tract, such as the stomach, the small intestine or the large intestine. In other embodiments, the wings may be biased towards their unfolded position and wherein an enteric coating initially serves to maintain the wings wrapped around the capsule, and subject to dissolution of the enteric coating allows the wings to unfold by release of the bias.

In the shown embodiment, each wing is formed as a trapezoidal sheet having a first side edge 260.1 which connects along a majority of the length of capsule middle housing 220. A second side edge 260.2 opposes said first side edge 260.1. A distally disposed (third) short side edge 260.3 and a proximally disposed (fourth) long side edge 260.4 are arranged opposed to each other and interconnects the first side edge 260.1 with the second side edge 260.2 so that the second side edge 260.2 is angled relative to the first edge 260.1 . The second side edge 260.2 is adapted to contact a tissue surface when the capsule 200” rests supported on the tissue surface. When the two wings have deployed, they serve as two legs arranged symmetrically on a lower part of the capsule housing with the two edges 260.2 of the wings being supported on tissue surface portion T. This causes the proximal end of the capsule housing to be arranged with longer separating distance relative to the tissue T than the first end of the capsule housing in this way re-orienting the capsule 200’ to assume a position with an angle of the capsule housing positioned relative to the adjacent tissue T at an angle a (see fig. 12c). This serves to re-orient the outlet opening formed by elastomeric plug 239 towards tissue surface T in a manner which further aids in proper tissue/needle interaction when the injection needle 290 is subsequently deployed. In the shown embodiment, the curvature of the needle 290 is arranged so that the needle deployment and the re-orienting of capsule housing by means of deployment of the wings act in synergy for needle/tissue interaction.

In the shown embodiment, the wing deployment and needle deployment occur sequentially in the stated order and with no substantial overlap timewise. The sequence may be controlled by various methods. In the shown embodiment, the dissolution of the dissolvable firing members 280 occurs with a pace so that the deployment of wings 260 has been completed prior to triggering. Other exemplary methods may include an enteric coating which covers both the wings and the window 228 and which releases the wings 260 prior to exerting the trigger to gastric juice. In still other examples, the wings serve to block entry of gastric juice through window 228 until the wings have deployed for subsequent triggering of drug expelling.

The shown second and third embodiment capsules 2007200” are intended to be supplied to the end user in a state where a liquid drug product A in a final injectable form is accommodated in reservoir 231 , i.e., also during long-term storage of capsule 2007200”. However, as described in relation with the first embodiment, capsule 2007200” according to the second and third embodiments may alternatively be provided in a form which necessitates drug mixing prior to ingestion, such as by using a capsule accessory device, such as corresponding to capsule accessory device 300 described in connection with the first embodiment. Further embodiments therefore may be provided, wherein the injection needle described in connection with the second embodiment and/or the self-orienting features described in connection with the third embodiment are included in the first embodiment.

Turning now to a fourth embodiment of a capsule device 100 according to the invention reference will be made to figs. 13a through 16b. The capsule 100 again includes an elongated capsule housing and has a deployable injection needle that is configured for deployment movement utilizing lateral strain of the injection needle to move a tip end of the needle laterally. However, the needle configuration of the fourth embodiment is markedly different from the needle configuration of the first, second and third embodiments described above.

Referring mainly to fig. 13a, which show the capsule 100 in the ready-to-ingest state, the capsule 100 includes a multi-part housing having an elongated shape extending along the firing axis. The elongated housing includes a cylindrical section 120 and rounded end portions, i.e. a proximal end portion 110 and a distal end portion 130. The shown multi-part housing is provided as a housing first portion 120/130 and a housing second portion 110. The housing first portion is formed by distal housing portion and is provided as a generally cylindrical tubular member 120 having a rounded end cap 130. The distal end wall includes a distal opening 134 allowing insertion of a needle deployment blocking member that will be described further below.

As in the previous embodiments the cylindrical section includes a plurality of liquid ingress openings 128. Arranged at the distal end portion of cylindrical section 120 is a recessed helical track 137 which extends in a circumferential direction approximately one and a half turn. The recessed helical track 137 is configured for accommodating the injection needle 190 in a nondeployed configuration with the needle 190 assuming a coiled shape and being embedded in the track 137 within the outer surface of capsule housing.

Referring to fig. 13d the injection needle 190 is shown in a view separate from other components of capsule 100, and with the injection needle assuming a laterally strained shape corresponding to the shape the needle assumes in the non-deployed configuration shown in fig. 13a. The injection needle 190 comprises a first inlet end segment 190.1 defining a straight portion, an intermediary laterally flexible segment 190.2 and a free needle tip end segment 190.3 intended for tissue interaction, i.e. configured for penetration into the mucosal tissue of a lumen wall of the Gl-tract. In the shown embodiment, also the free needle tip end segment 190.3 defines a straight portion. A lumen extends from the end segment 190.1 to the free needle tip end segment 190.3 to allow liquid communication from the reservoir of the capsule to the needle tip end. In the shown embodiment, both the first inlet end segment 190.1 and the free end segment 190.3 are bent approximately 90 deg. relative to the respective ends of intermediary laterally flexible segment 190.2. In the embodiment shown, after needle preparation with permanent deformation of the said two 90 deg. bends the intermediary laterally flexible segment assumes a straight shape which however is intended for being temporarily coiled.

As a step during assembly of capsule 100, the injection needle 190 has been arranged with the first inlet end segment 190.1 of the needle fixedly mounted relative to the housing first portion 120/130. Thereafter, the intermediary laterally flexible segment 190.2 has been coiled around the capsule housing so that the intermediary laterally flexible segment 190.2 is disposed within the recessed helical track 137 and with the free needle tip end segment 190.3 being disposed in a radially extending recess 137.3 in housing first portion 120/130 (cf. fig. 14a).

Fig. 13c is a sideview of capsule 100 in the state shown in fig. 13a. A needle deployment blocking member 180 is visible in the recessed helical track 137. The needle deployment blocking member 180, in a blocking position, serves to temporarily maintain the needle in the shape shown in fig. 13d inside track 137 with the laterally flexible segment 190.2 assuming a coiled shape wherein lateral strain is stored in the laterally flexible segment 190.2 urging to uncoil the needle from the recessed track.

In fig. 13b the capsule is shown in the state after needle deployment. This change of state is due to the needle deployment blocking member 180 has been moved into a release position allowing the laterally flexible segment 190.2 to straighten by release of stored lateral strain. As the lateral strain of laterally flexible segment 190.2 releases the laterally flexible segment 190.2 gradually unwinds and enter into a non-strained state wherein this segment is substantially straight. During the unwinding of the coiled section, the free needle tip end segment 190.3 orbits around the housing first portion 120/130 with gradually increasing radius until the free needle tip end segment 190.3 eventually engages adjacent tissue for needle penetration into the mucosal tissue at the target tissue at the intended location along the Gl-tract. Having described the needle deployment procedure of the capsule 100 of the fourth embodiment, turning now to figs. 14a through 16b the drive arrangement for the drug administration aspects of the capsule 100 will now be described.

Fig. 14a and 14b are two cross-sectional views of the capsule 100 in the non-deployed configuration, in a first cross sectional view and in a second cross-sectional view orthogonal to the first view, respectively.

Within capsule 100, the generally cylindrical member of housing first portion 120/130 defines a cylinder wall of a reservoir 131. A piston 150 having a ring-shaped peripheral seal (nonreferenced) is arranged to sealingly engage the cylinder wall, in an initial state arranged proximally within the reservoir. The piston 150 is configured for axial sliding movement in the distal direction.

Also, within capsule 100, slightly proximal from the distal end of the reservoir 131 , a fluid gate control element 160 is arranged, the fluid gate element forming a second piston. Fluid gate control element 160 comprises a proximal portion having a large diameter flange arranged for sliding engagement with the cylinder wall, i.e. with a sealing lip arranged circumferentially. Fluid gate control element 160 further comprises a reduced diameter distal rod section 162 that fits sealingly in a centrally located bore leading to distal opening 134 in a manner which allows for axial sliding movement of distal rod section 162 in the centrally located bore. The most distal portion of distal rod section 162 cooperates with needle deployment blocking member 180 so that these components travel together. Hence, fluid gate control element 160 is arranged slidingly within the cylinder wall of housing first portion 120/130 whereas needle deployment blocking member 180 is arranged slidingly within distal opening 134 when pushed in the distal direction by fluid gate control element 160.

In the state shown in figs 14a and 14b, the fluid gate control element 160 seals the reservoir 131 distally whereas the piston 150 seals the reservoir proximally. In this state, the large diameter flange of fluid gate control element 160 is arranged a short distance from the distal end wall of housing first portion 120/130.

A drug outlet passage 135, in fluid communication with the distal end portion of the reservoir 131 , is provided as a small pocket formed in proximal facing end wall of reservoir 131. As seen in fig. 14b, first inlet end segment 190.1 of injection needle is mounted in fluid communication with drug outlet passage 135.

The cylinder wall of housing first portion 120/130 defines a set of axially extending bypass channels 133 which is arranged extending in proximal direction from the distal end of reservoir 131. In the shown embodiment the bypass channels 133 are provided as four individual liquid bypass channels.

In capsule 100, a drive source is incorporated for driving forward piston 150 and fluid gate control element 160. In the shown embodiment the drive source is provided as a swellable portion of sponge material 140 which when wetted causes the sponge material to markedly swell. The sponge material 140 fits inside the generally cylindrical member of housing first portion 120/130 at a location proximally from piston 150 and is confined within the cylinder wall which extends proximally from reservoir 131 and also confined proximally by a distally facing end wall formed by housing second portion 110. As the sponge material 140 is axially sandwiched between the distally facing end wall and the piston 150 the piston is forced to move distally as the sponge material swells.

As mentioned previously a multitude of openings or channels 128 serve as fluid inlet openings which allow ingress of gastric fluid present in the Gl tract towards the sponge material 140. Although not visible in any of the figures, the openings 128 are initially covered by a pH-sensi- tive enteric coating 129 which initially blocks fluid ingress through the openings 128. As known in the art, the enteric coating may be configured to utilize the marked shift in pH level that the capsule 100 experiences when travelling from the stomach to the small intestine.

For the capsule 100 in the ready-to-ingest state, as shown in figs. 14a and 14b, fluid gate control element 160 is initially axially disposed so that the large diameter proximal flange of fluid gate control element 160, with its seal lip, is disposed proximally relative to the set of bypass channels 133. Hence, the drug product which is accommodated in the reservoir 131 is prevented from leaking from the reservoir.

Referring to fig. 14a, the needle deployment blocking member 180 forms an L-shaped member having a first radial extending portion cooperating with distal rod section 162 and a second axially extending portion that reaches axially past the radially extending recess 137.3. The second axially extending portion of needle deployment blocking member 180 forms a blocking means so that it retains the free needle tip end segment 190.3 against the lateral tension provided by laterally flexible segment 190.2 of needle 190. Hence, with the needle deployment blocking member 180 assuming the shown blocking position the needle 190 is prevented from uncoiling and, therefore, it maintains its hidden position within recessed track 137.

Subsequent to a patient or user swallowing capsule 100, upon entering the small intestine, the enteric coating 129 of the capsule 100 will begin to dissolve and gastric fluid will soon after be available through openings 128 to become sucked into sponge material 140. As the sponge material 140 swells the piston 150 will be pushed distally towards fluid gate control element 160. Hence, the hydraulic pressure of the drug product rises and eventually will cause the fluid gate control element 160 to move distally and also slaving the needle deployment blocking member 180 distally. Just prior to the fluid gate control element 160 enters into the drug release position shown in figs. 15a and 15b, the distal movement of needle deployment blocking member 180 enters into its release position where the second axially extending portion of needle deployment member 180 no longer axially blocks the radial extending recess 137.3. Hence, it no longer retains the free needle tip end segment 190.3 in its initial position, and this causes the injection needle 190 to move into its deployed configuration as shown in fig. 13b.

Increased swelling of the sponge material 140 causes the fluid gate control element 160 into a position which is shown in figs. 15a and 15b. In this position, the peripheral seal of fluid gate control element 160 has moved further distally into alignment with bypass channels 133 which allows liquid drug from reservoir 131 to bypass via the channels 133 to the distal side of fluid gate control element 160 and further via drug outlet passage 135 and injection needle 190 for expelling into mucosal tissue. The fluid gate control element 160 will discontinue its movement.

Continued swelling of sponge material 140, as depicted in figs. 16 and 16b, causes the piston 150 to move fully distally after which all the useable amount of the drug product has been expelled from reservoir 131 through the injection needle 190. After delivery of the drug product, the capsule 100 is allowed to pass the alimentary canal and be subsequently excreted.

In accordance with the present invention, the drive and expelling arrangement of the capsule device may be configured with the use of a single or a plurality of energy sources for driving the needle deployment and the expelling procedures, either simultaneously or sequentially. The energy sources may in different embodiments comprise one or more actuators or drive force sources, such as pre-strained spring, gas springs, gas-generating energy sources or other drive sources. The skilled reader will know how to suggest different drive and expelling arrangements in connection with the disclosed principles for needle deployment utilizing a lateral strained needle portion for at least partially driving lateral movement of the injection needle during needle deployment. Non-limiting examples of suitable drive arrangements for needle deployment and expelling are disclosed and set forth in references W02020/160399 A1 (fig. 52 embodiment), W02021/013907 A9 (figs.13a-14 embodiment) and US2009043278.

In the above description of exemplary embodiments, the different structures and means providing the described functionality for the different components have been described to a degree to which the concept of the present invention will be apparent to the skilled reader. The detailed construction and specification for the different components are considered the object of a normal design procedure performed by the skilled person along the lines set out in the present specification. For example, although the embodiments described in this disclosure mainly concerns capsules having an elongated capsule housing, the capsule according to the present invention is not limited to such elongated capsules but may include capsule housing shaped differently, such as oval, spherical, Gdmbdc-shaped capsules, or even otherwise formed capsule housings.

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Claims

1. An ingestible device for injecting a drug substance into a gastro-intestinal wall portion of a living mammal subject, the ingestible device (100, 200, 200’, 200”) comprising: a housing (110, 120, 130, 210, 220, 230), a reservoir (131 , 231) containing a drug substance, a needle (190, 290) associated with the reservoir (131 , 231) and configured for injection of drug substance into the mucosal lining of a gastro-intestinal wall portion, the needle (190, 290) being configured for movement from a non-deployed configuration and into a deployed configuration to drive insertion of a free end of the needle (190, 290) into a gastrointestinal wall portion, and a drive arrangement (140, 150, 240, 250) for driving drug substance from the reservoir (131 , 231) through the needle (190, 290), wherein the needle (190, 290) comprises a laterally flexible portion (190.2, 290.2) operable between the non-deployed configuration wherein the laterally flexible portion (190.2, 290.2) is maintained laterally strained to the deployed configuration wherein lateral strain is at least partially released, and wherein a needle deployment retainer (180, 239, 280) is configured for releasably retaining the needle (190, 290) in the non-deployed configuration and configured operable by relative movement between the needle (190, 290) and the needle deployment retainer (180, 239, 280) so as to release retaining of the needle (190, 290) in the non-deployed configuration to thereby enable lateral strain of the laterally flexible portion (190.2, 290.2) to drive, or to assist driving, the needle (190, 290) from the non-deployed configuration to the deployed configuration.

2. The ingestible device as in claim 1 , wherein the housing comprises an elongated cylindrical wall section (120, 220) extending along an axis and wherein the housing comprises rounded ends (110, 130, 210, 230).

3. The ingestible device as in any of claims 1-2, wherein a retainer mechanism (180, 239, 280) releasably maintains the needle (190, 290) in the laterally flexed position where mechanical energy has been deposited due to lateral straining of the needle (190, 290), and wherein release of the retainer mechanism (180, 239, 280) to release the needle (190, 290) from the laterally flexed position causes movement of the needle (190, 290) from the non- deployed configuration into the deployed configuration, said movement being at least partly driven by said mechanical energy deposited due to lateral straining of the needle (190, 290).

4. The ingestible device as in claims 3, wherein the ingestible device (100, 200, 200’, 200”) further comprises an environmentally-sensitive mechanism (129, 280) configured to operate the retainer mechanism (180, 239, 280) for release upon sensing a predetermined condition.

5. The ingestible device as in claims 4, wherein the drive arrangement is configured for driving drug substance from the reservoir (131 , 231) through the needle (190, 290) either simultaneous with, or subsequently to, the needle (190, 290) moving from the non-deployed configuration and into a deployed configuration.

6. The ingestible device as in any of claims 1-5, wherein at least part of the movement of the needle (190, 290) from the non-deployed configuration into the deployed configuration redirects the needle (190, 290) for insertion of the free end of the needle (190, 290) into the mucosal lining disposed adjacent to the ingestible device (100, 200, 200’, 200”).

7. The ingestible device as in any of claim 1-6, wherein the needle (190) is configured for movement from the non-deployed configuration to the deployed configuration entirely driven by the lateral strain stored in the laterally flexible portion (190.2) in the non-deployed configuration.

8. The ingestible device as in any of claim 1-6, wherein the needle (290) is configured for movement from the non-deployed configuration to the deployed configuration partly driven by the lateral strain stored in the laterally flexible portion (290.2) in the non-deployed configuration.

9. The ingestible device as in claim 8, wherein the drive arrangement (240, 250) is configured to assist driving movement of the needle (290) as it moves from the non-deployed configuration to the deployed configuration.

10. The ingestible device as in any of claims 1-9, wherein the needle (190) comprises a bend portion connecting the free end of the needle (190) with the laterally flexible portion (190.2), wherein the bend portion defines a deflection having an angle between 135 deg. and 45 deg., such as between 120 deg. and 60 deg., such as between 105 deg. and 75 deg., and such as between 95 deg. and 85 deg.

11. The ingestible device any of claims 1-10, wherein the housing (110, 120, 130) defines a main axis and wherein the needle (190) in the non-deployed configuration is arranged so that the laterally flexible portion (190.2) assumes a coiled configuration around the main axis, and wherein lateral strain of the laterally flexible portion (190.2) acts to uncoil the laterally flexible portion (190.2) as the needle (190) moves from the non-deployed configuration to the deployed configuration.

12. The ingestible device as in claim 11 , wherein the housing comprises an exterior surface that comprises a recessed track (137) configured to entirely accommodate, or at least partly receive, the injection needle (190) in the non-deployed configuration.

13. The ingestible device as in claim 1-10, wherein the housing (210. 220, 230) comprises a needle opening (239), wherein the needle (290) is configured to move through the needle opening (239) from the non-deployed configuration to the deployed configuration, and wherein the laterally flexible portion (290.2) of the needle (290) deflects laterally due to release of lateral strain as the needle (290) extends from the needle opening (239) thereby redirecting the free end of the needle (290) towards mucosal lining of a gastro-intestinal wall portion supporting the housing.

14. The ingestible device as in claim 13, wherein the drive arrangement (240, 250) comprises a piston (250) which is configured to act on the drug substance in the reservoir (231) to expel the drug substance from the reservoir (231), wherein the piston (250) is configured for movement along an expelling axis, and wherein the drive arrangement (231) is configured to move the end of the needle (290) opposite to the free end of the needle (290) by movement along or parallel with the expelling axis for needle deployment.

15. The ingestible device as in any of claims 13-14, wherein at least part of the laterally flexible portion (290.2) of the needle (290) protrudes through a portion of the reservoir (231) when the needle (290) assumes the non-deployed configuration.

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