Deployable devices for delivery of active agents to intestinal tissue

Abstract

The disclosure concerns expandable devices, specifically self- deployed devices, for delivery of an active agent to a tissue, e.g. intestinal tissue, that have a compacted state and an expanded state. The devices (300) have at least one self-deployable unit (302) transitionable between a contracted state and a deployed state to switch the device from the compacted state to the expanded state, and at least one dosage unit (304) associated with the self-deployable unit (302). The transition of the device from the compacted state to the expanded state causes at least a surface portion of the deployable unit to drive the dosage unit towards said tissue for forming contact between the dosage unit and the tissue to deliver the active agent to the tissue.

Description

[0001] Deployable devices for delivery of active agents to intestinal tissue

[0002] TECHNOLOGICAL FIELD

[0003] The disclosure concerns expandable devices, specifically self-deployed devices, for delivery of an active agent to a tissue, e.g. intestinal tissue.

[0004] BACKGROUND ART

[0005] References considered to be relevant as background to the presently disclosed subject matter are listed below:

[0006] [1] PCT patent publication WO2016015648

[0007] [2] PCT patent publication W02008062440

[0008] [3] PCT patent publication WO2009125432

[0009] [4] PCT patent publication WO2013188819

[0010] [5] PCT patent publication WO2015026552

[0011] [6] PCT patent publication WO2015120471

[0012] [7] Anselmo et al., Nat Rev Drug Discov. 2019, 18(1), 19-40

[0013] [8] Drucker D J, Nat Rev Drug Discov. 2020, 19(4), 277-289

[0014] Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

[0015] BACKGROUND

[0016] Oral administration of active agents and pharmaceutical compositions is the preferred mode of delivery, mostly due to avoidance of pain and enhanced patient compliance. Effective delivery by oral administration of active agents and pharmaceutical compositions is hindered by improper or insufficient absorption through the intestinal tissue.

[0017] Effective and targeted delivery of various compounds and active agents to or across a tissue, for example the lining of the intestinal tract, has proven over the years to be a challenge. There is a need for administration forms that will permit direct delivery of active agents to the intestinal tissue, thereby increasing effective absorption (bio availability).

[0018] Achieving proximity between pharmaceutical compositions and a tissue lumen has shown promise in improving bio availability [7-8],

[0019] GENERAL DESCRIPTION

[0020] The present disclosure provides self-deployable devices, which can be orally administered to a subject and undergo a controlled deployment to bring one or more dosage units that contain an active agent into contact with the intestinal tissue. The devices of this disclosure are designed to hold the dosage unit(s) against the tissue for a pre-defined period of time, during which at least one active agent is absorbed from the dosage unit(s) by the tissue, improving and increasing the delivery of the active agent to the patient via the intestinal tissue.

[0021] Accordingly, by one of its aspects, there is provided a self-deployable ingestible device configured for delivery of at least one active agent to an intestinal tissue, the device having a compacted state and an extended state, and comprising at least one self-deployable unit, configured for transitioning between a contracted state and a deployed state, and thereby switch the device from the compacted state to the extended state; and at least one dosage unit that comprises said at least one active agent, the at least one dosage unit being associated with the self-deployable unit; transition of the device from the compacted state to the extended state causes at least one surface portion of the deployable unit to drive of the dosage unit towards said tissue, for forming contact between the dosage unit and the tissue to thereby deliver said active agent to the tissue.

[0022] According to another aspect of this disclosure, there is provided a self-deployable ingestible device configured for delivery of at least one active agent to an intestinal tissue, the device having a compacted state and an extended state, and comprising: at least one self-deployable unit, configured for transitioning between a contracted state and a deployed state after switching of the device from the compacted state to the extended state; and at least one dosage unit that comprises said at least one active agent, the at least one dosage unit being associated with the self-deployable unit; transition of the self-deployable unit from the contracted state to the deployed state causes at least one surface portion of the deployable unit to drive of the dosage unit towards said tissue while said device is in the extended state, for forming contact between the dosage unit and the tissue to thereby deliver said active agent to the tissue.

[0023] The disclosure provides, by a further aspect, a self-deployable ingestible device configured for delivery of at least one active agent to an intestinal tissue, the device having a compacted state and an extended state, and comprising: at least one self-deployable unit, configured for transitioning between a contracted state and a deployed state concomitantly with switching of the device from the compacted state to the extended state; and at least one dosage unit that comprises said at least one active agent, the at least one dosage unit being associated with the self-deployable unit; transition of the self-deployable unit from the contracted state to the deployed state causes at least one surface portion of the deployable unit to drive of the dosage unit towards said tissue during switching of the device into the extended state, for forming contact between the dosage unit and the tissue to thereby deliver said active agent to the tissue.

[0024] The devices of this disclosure are based on change in dimensions and / or change of geometrical configuration of one or more self-deployable units of the device. One or more dosage units are associated with these self-deployable units, such that upon change of dimensions and / or geometry of the units, the dosage units are driven towards the intestinal tissue at the target site, to bring the dosage unit into contact with the tissue. Through this contacting, the active agent is delivered from the dosage unit to the tissue.

[0025] According to some embodiments, the units are designed to maintain their deployed configuration for a pre-determined period of time, during which the units substantially continuously hold the dosage unit against the tissue, thereby enabling delivery of the active agent from the dosage unit directly to the intestinal tissue.

[0026] The devices have a compacted state and an extended state, and are configured to switch from the compacted state to the extended state after administration, once exposed to the required conditions at the target site. In the compacted state, the device has a compact configuration, and transition into the extended involves change in spatial configuration, volume, and / or dimensions, such that when at the extended state the device is physically retained at the target site for a pre-defined period of time.

[0027] Alternatively, the device can comprise one or more anchoring elements that are configured to extend outwards from the device, such that extension of the device into the extended state occurs by change of configuration the anchoring elements to temporarily anchor the device to the tissue. For example, the one or more anchoring elements can be configured as folded arms, that once unfolded at the target site due to exposure to appropriate conditions in the intestine, come into contact with the tissue and apply pressure thereonto to hold the device in location.

[0028] Transition of the device from the compacted state to the extended state typically occurs due to exposure to appropriate conditions at the target site, e.g. exposure to liquid at an appropriate pH. According to some embodiments, the device comprises a liquid expandable material, configured to switch the device from its compacted state to its expanded state when exposed to liquid. Alternatively, transition of the device from the compacted state to the extended state can occur by applying one or more external triggers.

[0029] Once the device is extended at the target site, transition of the self-deployable unit from the contracted state to the deployed state drives the dosage unit towards the intestinal tissue to bring the dosage unit into contact with the tissue, and typically continuously hold the dosage unit against the tissue for sufficient time to allow delivery of the active agent directly to the tissue as long as the self-deployable unit is in its deployed state.

[0030] Typically, the unit and / or the device are configured for disintegration after a predefined period of time to enable breakdown of the device into evacuatable fragments.

[0031] According to some embodiments, the transition of the self-deployable unit from the contracted state to the deployed state occurs substantially after switching of the device from the compacted state to the extended state.

[0032] According to other embodiments, the transition of the self-deployable unit from the contracted state to the deployed state occurs substantially simultaneously with switching of the device from the compacted state to the extended state.

[0033] According to yet other embodiments, the transition of the self-deployable unit from the contracted state to the deployed state induces the switching of the device from the compacted state to the extended state. In other words, in such embodiments, the change in dimensions or spatial configuration of the self-deployable unit causes switching of the device into its extended state.

[0034] In the extended state, the device may have a circular shape, a polygonal shape, or an irregular shape. In its extended state, the device may be designed to assume a three-dimensional (3D) shape generally conforming to the shape of at least a section of the lumen or cavity in which it extends, e.g. the intestinal tract.

[0035] In other embodiments, in the extended state, the device may have an annular or ring-like shape. In some other embodiments, the device may be configured to assume a substantially cylindrical shape when in the extended state, to define a hollow lumen. Such a hollowed cylindrical shape prevents formation of blockage of the intestine when the device is in its extended state, permitting passage of liquids or solids through the intestine.

[0036] As noted, the transition of the self-deployable unit from the contracted state to the deployed state causes at least one surface portion of the self-deployable unit to drive of the dosage unit towards the tissue. The deployment of the self-deployable unit can be manifested in various mechanisms.

[0037] By one mechanism, the deployment of the self-deployable unit can undergo volumetric change that causes change of spatial configuration of the self-deployable unit.

[0038] The self-deployable unit can be in the form of a compartment, or multiple compartments, that contains self-expandable materials that are configured to increase the volume of the compartment once in contact with liquid. The change in dimensions of such compartments can induce the device to switch from the compacted state to the extended state. Thus, by some embodiments, the self-deployable unit is in the form of an expandable compartment. According to other embodiments, such expandable compartment comprises a liquid permeable shell encasing at least one reactive material configured to react with said liquid to increase the volume of the compartment and switch the self-deployable unit from the contracted state to the deployed state. The at least one reactive material can be selected, for example, from a gel forming material, a gas generator, a foamable material, and combinations thereof.

[0039] When the self-deployable unit is in the form of an expandable compartment, the compartment can be formed out of a deformable film that has one or more liquid-permeable sections. The sections (or in some embodiments the entire deformable film) are made of liquid-permeable material. Within the context of the present disclosure, the term liquid-permeable material is meant to denote a material (compound or composition of matter) that permits diffusion or passage of liquid therethrough. For example, the liquid permeable material may be perforated or porous. According to some embodiments, the liquid-permeable material may comprise one or more compounds selected from hypromellose phthalate, cellulose acetate phthalate, hypromellose acetate succinate, cellulose acetate, cellulose acetate butyrate, ethylcellulose, polymethylmethacrylate, polyethylacrylate, polyvinyl acrylate phthalate, polyvinyl acetate, shellac, carboxymethylethylcellulose (CMEC), and any combinations thereof.

[0040] According to some embodiments, the at least one reactive material is a gelforming material. The term gel-forming material is meant to denote a compound or a composition that is capable of absorbing liquid(s), thereby forming a three-dimensional voluminous network of molecules. The gel-forming material may form a physical gel (i.e. a gel in which molecules are held in the network by physical forces) or a chemical gel (i.e. a gel in which molecules are chemically bonded one to the other to form the network structure).

[0041] According to some embodiments, the gel-forming material comprises one or more polymers. According to other embodiments, the gel-forming material may be charged or neutral. The gel-forming material is cross-linked or is cross-linkable. Without wishing to be bound by theory, the molecular weight of the gel forming material and the degree of cross-linking have significant impact on the gel’s consistency (for example, hardness or rigidity), as well as on its rheological properties (e.g. viscosity). Hence, various molecular weights and cross-linking degrees are some of the parameters that can be used to control the extent of deployment and force exerted on the dosage unit to bring it to substantially continuous contact with the tissue.

[0042] In some embodiments, the gel-forming material may be selected from gelatin, alginate, chitosan, dextran, collagen, hyaluronic-acid, polyglutamic-acid, elastin, calcium polycarbophil, acrylamides, styrene maleic anhydride, polyethylene oxide, polyacrylicacid, polyethylene glycol, carboxy methyl cellulose, polyvinyl pyrrolidone, sodium polyacrylate, hydroxypropyl methylcellulose or any combination or composition thereof. The gel-forming material can be a composition comprising at least one charged gelforming compound and at least one compound having an opposite charge, constructing a PEC (Poly Electrolyte Complex) formation upon liquid adsorption. In some embodiments, said at least one charged gel-forming compound is selected from polyvinyl acetate diethyl amino acetate (AEA), poly-lysine, chitosan, polymethacrylate (Eudragit E), poly-arginine. In other embodiments, said opposite charged compound is selected from gelatin, hyaluronic-acid, sodium polyacrylate, heparin, polyacrylic acid (Carbomer), alginate, pectin, carboxymethylcellulose.

[0043] In some other embodiments, the gel-forming material is at least one super absorbent polymer (SAP), namely a polymer (typically cross-linked) or a polymer composition, that can absorb and retain large quantities of liquids, such as water (or liquids containing water), relative to the dry mass of the polymer. Non-limiting examples of SAP are polyethylene glycol (PEG), polyglutamic acid (PGA), polyacrylamide, alginic-acid, dextran, polyacrylic acid, carboxymethylcellulose (CMC), pullulan, starch, and any combinations thereof.

[0044] Another exemplary mechanism for deployment of the self-deployable unit is utilization of shape-memory materials, typically shape-memory polymers. A shape memory polymer is a polymer or polymer composition that has at least two spatial configurations, and is transitionable between these configurations upon application of an external trigger. The transition between configurations can be obtained in various mechanism once exposed to the proper trigger, e.g. phase transition, change in the crystallinity degree of the polymer, induction of cross-linking or change in cross-linking density, induction of cross-linking cleavage, change in orientation of the polymer molecules, etc. While the external trigger can be changes in temperature, electrical trigger, irradiation triggering, etc., the shape memory polymers typically useful in the self-deployable unit of the devices of this disclosure are triggered by the environmental conditions at the target site. More specifically, the shape memory polymers can be triggered by exposure to certain chemical species at the target site, the pH at the target site and / or exposure to liquid (typically water) at the target site. The self-deployable unit can be made of or comprise deployable elements made of such shape-memory polymers, that once exposed to proper triggers at the target site in the intestine, change their spatial configuration to cause transition of the self-deployable unit from its contracted state to its deployed state.

[0045] By some embodiments, the self-deployable unit comprises one or more deployable elements made of said shape memory polymers. According to some embodiments, the self-deployable unit is made substantially out of one or more shape memory polymers.

[0046] By another example, mechanical constraint can be applied on the self-deployable unit in order to maintain it in its contracted state until exposure to deployment conditions. For example, the self-deployable device can be enveloped or encased within a constraining casing that is configured to break, disintegrate, or rupture at the target site to thereby release the self-deployable device and permit its deployment. Such a constraining casing can be an enteric envelope, that is designed to loss integrity once exposed to suitable pH conditions in the intestine.

[0047] The self-deployable device, by another example, can comprise at least one deployment element, the deployment element having a compressed state and a noncompressed state, and is biased to the non-compressed state. In the contracted state, the deployment element is held in its compressed state against its bias, for example by a liquid-disintegrable contrasting element, and once exposed to the liquid in the intestine, the disintegration of the constraining element permits the deployment element to switch into its non-compressed state to drive the self-deployable device into its deployed state. By one example, the deployment element can be an elastic element, e.g. a spring, that is held by the constraining element in a contracted state. By another example the deployment element can be an expandable stent.

[0048] Such a deployment element can be an internal element of the self-deployable device, e.g. the device can be in the form of a flexible compartment having one or more liquid-permeable portions, and the deployment element can be encased within the compartment and held thereby in the compressed state. Once exposed to liquid in the intestine, the liquid permeating into the compartment can switch the deployment element into its non-compressed state, thereby applying pressure onto the flexible compartment walls to change its spatial configuration and transition it into the deployed state.

[0049] Alternatively, the self-deployable unit can comprise one or more such deployment elements associated with an external surface thereof. In such examples, the self-deployable unit, including the deployment elements are held within a constraining casing that is configured to hold the deployment elements in their compressed state. Once one or more portions of the constraining casing is disintegrated or removed at the target site, the deployment elements can switch into their non-compressed state to drive the self-deployable unit into its deployed state. The constraining casing can also be utilized in order to induce directionality of deployment of the self-deployable unit; for example by selected disintegration of portions of the constraining casing, permitting the self-deployable unit to by deployed in a defined orientation or direction.

[0050] In another arrangement, the device comprises one or more constraining elements, and the self-deployable unit is configured as an elastic member, having said contracted state and said deployed state, the self-deployable unit being biased to the deployed state and is held in the contracted state against said bias by said one or more constraining elements when the device is in the contracted state. Once the device switches from the contracted state to the expanded state, the transition causes the constraining element(s) to cease application of constraint on the self-deployable unit, that is then permitted to switch into its deployed state.

[0051] It should be understood that the self-deployable unit can be deployed by a combination of two or more different deployment mechanisms.

[0052] As noted above, the device can comprise a plurality of self-deployable units, e.g. in the form of such compartments. In such devices, each of the compartments may comprise a different gel-forming material. In some other embodiments, all the compartments can comprise the same gel-forming material.

[0053] Depending on the active agent and / or the desired effect, the contact time between the dosage unit and the tissue can be controlled. For example, the self-deployable unit can be configured to maintain its deployed state for a pre-defined period of time, after which the dosage unit, the self-deployable unit and / or the device will degrade or lose integrity, thereby causing cease of contact between the dosage unit and the tissue.

[0054] By some embodiments, the self-deployable unit and / or the device is disintegrable. The term disintegration, or any lingual variation thereof, means to denote any type of decomposition that is caused by exposure to suitable physical, chemical or biological conditions after administration and extension / deployment. The term encompasses mechanical breakdown, chemical or physical degradation, chemical or physical decomposition, or any other type of destruction of the integrity of the device during its passage through the intestinal tract for expulsion from the body.

[0055] Alternatively, the self-deployable unit and / or the device can be designed to contract (e.g. reduce in volume) or change its spatial configuration after a pre-defined period of time, to distance the dosage unit from the tissue thereby causing said cease of contact between the dosage unit and the tissue.

[0056] According to some embodiments, the device comprises a plurality (i.e. two or more) of self-deployable units, each associated with at least one dosage unit. According to other embodiments, the device comprises a plurality of self-deployable units, each associated with one dosage unit.

[0057] By some embodiments, the device comprises a plurality of self-deployable units, at least one of which being associated with a dosage unit, for example some of the self- deployable units in said plurality being associated with a dosage unit, while others being non-associated with a dosage unit.

[0058] According to some embodiments, the device comprises two or more different self-deployable units. The self-deployable units can differ in their size, geometry, deployment mechanism, deployment timing, etc. By some embodiments, some of the self-deployment units that do not carry a dosage unit have one or more tissue-attachment means (e.g. microhooks, microneedles, mucoadhesive components, etc.) to attach the device to the tissue, for example to provide temporary anchoring of the device or directionality of extension of the device.

[0059] The dosage unit is associated with the self-deployable unit, such that transition of the unit to the deployed state causes at least one surface portion of the self-deployable unit to drive of the dosage unit towards the tissue. According to some embodiments, the surface portion is a tissue-facing surface of the self-deployable unit. According to some embodiments, the tissue-facing surface is an external surface of the self-deployed unit. According to other embodiments, the tissue-facing surface is a surface of the self-deployable unit that becomes oriented to face the tissue during transition of the self-deployable unit from the contracted state to the deployed state. By varying the size, geometry, number, etc. of the self-deployable units and / or the type of deployment mechanism, different deployment / extension rates, shapes and / or targeted delivery can be obtained, as well as obtaining symmetrical or non-symmetrical extended shape of the device. Varying the properties self-deployable units can also permit controlling the force applied by the self-deployable unit, in its deployed state, on the tissue for maintaining the dosage unit in contact with the tissue.

[0060] The dosage unit is physically connected to the self-deployable unit, i.e. associated thereto, in at least one connecting point of the self-deployable unit. The association can be direct association, namely the dosage unit being attached directly to the self-deployable unit or constitute a part of the surface potion, e.g. the tissue-facing surface. Alternatively, the dosage unit can be associated with the self-deployable unit by one or more linking elements.

[0061] According to some embodiments, the dosage unit is associated with the self-deployable unit by a linking element attached at one end thereof to the self-deployable unit and at another end thereof to the dosage unit. The linking element can be flexible or semi-flexible (e.g. a cord, a string, a strip, etc.). According to other embodiments, the dosage unit is attached, physically or chemically, to at least a segment of the surface portion (e.g. a segment of the tissue-facing surface). By some other embodiments, the dosage unit is integral with or constitutes a part of the tissue-facing surface.

[0062] The dosage unit is meant to denote any structure or composition that can contain the active agent and permit its release once in contact with the intestinal tissue.

[0063] According to some embodiments, the dosage unit is in a form of a reservoir that holds said at least one active agent (or a composition comprising it) and is configured to release the active agent therefrom during contact of the dosage unit with the tissue.

[0064] According to other embodiments, the dosage unit is in the form of a pressuresensitive element that is designed for rupturing once pressure is applied thereonto after deployment of the self-deployable unit as the dosage unit is held against the tissue (e.g. the reservoir can be in the form of a casing / envelope that holds therein the active agent or a composition thereof, the casing / envelope having at least one wall portion that is configured for rupturing under a predefined applied pressure).

[0065] According to some other embodiments, the dosage unit is in the form of a solid composition comprising or consisting of said at least one active agent, e.g. in the form of a tablet or a pill.

[0066] By some embodiments, the dosage unit can comprise a core member, i.e. a carrying member, that is coated by said at least one active agent or a composition comprising said at least one active agent.

[0067] By some other embodiments, the dosage unit can be a layer coating at least a portion of the tissue-facing surface, and constituted by the active agent, or comprising a carrying matrix in which the active agent is dispersed or embedded. For example, the dosage unit can be in the form of a gel or gel-forming matrix containing the active agent.

[0068] According to some embodiments, the dosage unit is in the form of an active layer coating at least a portion of the tissue-facing surface of the self-deployable unit. The active layer can be made of or comprise a composition containing said at least one active agent, or can consists essentially of said at least one active agent.

[0069] The dosage unit can be in the form of a layer coating one or more regions of the tissue-facing surface, a plurality of spaced-apart surface regions, or can be a continuous coating of the tissue-facing surface. In other embodiments, the dosage unit is in the form of a layer that substantially coats the entire tissue-facing surface. The dosage unit is typically in a form that is non-attachable to the tissue, and is held against the tissue in a mechanical manner by the self-deployable unit when in the deployed state. However, in some cases, the dosage unit can be tissue-attachable, e.g. by use of microneedles or microhooks, or by use of at least one mucoadhesive material.

[0070] The self-deployable unit can be associated with a single dosage unit or with a plurality of dosage units.

[0071] According to some embodiments, the self-deployable unit can comprise two or more identical dosage units. According to other embodiments, the self-deployable unit comprises two or more different dosage units, e.g. containing different active agents, different concentrations of the same active agent, different compositions to provide different release rates of the active agent from each of the dosage units, different types of dosage units, dosage units differing in their size or geometry, etc.

[0072] The active agent is typically a pharmaceutical active agent. The term pharmaceutical active agent means to denote molecules, compounds or compositions that are safe and effective for pharmaceutical use in a subject, typically mammals, and that possess the desired biological activity. The active agent can be selected, for example, from antibiotics, proteins, peptides, polypeptides, lipids, nucleic acids, hormones, steroids, antibodies, vitamins, anti-inflammatories, antihistamines, antiemetics, analgesics, chemotherapic agents, prophylactic agents, clotting factors, radiopharmaceuticals, contrasting agents, electrolytes, nutraceuticals, small molecules (of a molecular weight of less than about 1,000 Da or less than about 500 Da), etc.

[0073] In other embodiments, the active agent can be comprised of microorganisms (e.g. intestine-friendly bacteria) and / or viruses.

[0074] In other embodiments, the active agent can be a nutraceutical agent, compound or composition.

[0075] The active agent can be in the form of a salt, acid-addition salt, free base, free acid, hydrate, solvate, or prodrug.

[0076] The active agent can be suitable for administration to humans. In other embodiments, the active agent can be a veterinary active agent.

[0077] The active agent is typically present in the dosage unit in a therapeutically effective amount. The effective amount for purposes herein may be determined by such considerations as known in the art. The amount must be effective to achieve the desired therapeutic effect, depending, inter alia, on the type and severity of the disease to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, the effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, on factors such as age and gender, and others.

[0078] The pharmaceutical active agent can be selected to induce at least one effect, e.g. therapeutic effect, which is capable of inducing, enhancing, arresting or diminishing at least one effect, by way of treatment or prevention of unwanted conditions or diseases in a subject. The at least one agent (substance, molecule, element, compound, entity, or a combination thereof) may be selected amongst therapeutic agents, i.e. agents capable of inducing or modulating a therapeutic effect when administered in a therapeutically effective amount.

[0079] In other embodiments, the active agent can be a diagnostic agent, i.e. an agent that permits diagnosis of one or more conditions or disorders. A diagnostically effective amount refers to an amount of the active agent, radiopharmaceutical or diagnostic composition, which allows for efficient molecular imaging depending on the type of the imaging technique (e.g. PET, SPECT, etc.) used, the acquisition parameters of the specific imaging technique used, the area of the body scanned, the physical condition of the subject, the purpose of the test or any other factors which are apparent to the person skilled in art.

[0080] In other embodiments, the active agent can be encapsulated within various microparticulate or nanoparticulate structures, such as liposomes, microparticles, microcapsules, nanoparticles, or nanocapsules, the structures being distributed within the mucoadhesive material.

[0081] In some embodiments, the device can comprise at least one additional active substance, being different from said at least one active agent. The additional active substance can have similar pharmaceutical activity as the active agent, or have a different pharmaceutical activity to that of the active agent.

[0082] By some embodiments, the dosage unit comprises the additional active substance. In such embodiments, the active agent and the additional active substance can have a co-therapeutic effect, i.e. additional or synergistic. For example, the additional active substance can function to increase permeation or bioavailability of the active agent, or can increase or enhance the therapeutic effect or bioactivity of the active agent. By another example, the additional active substance may be selected to have an immediate or a short-term therapeutic effect, while the active agent can be selected to have a prolonged or sustained therapeutic effect.

[0083] By other embodiments, the device can comprise one or more auxiliary dosage forms comprising the additional active substance.

[0084] In other embodiments, the active agent and the additional active substance can be selected from agents having similar or identical therapeutic effects. For example, the active agent and the additional active substance can be the same, however one being contained within the dosage unit and the other within the auxiliary dosage unit, respectively. Such an arrangement can be utilized to divide the required dose of the agent, such that a portion of the agent is delivered immediately upon deployment of the self-deployable unit from the auxiliary dosage unit, and the rest will be absorbed from the dosage unit after contacting the tissue. By another example, the active agent and the additional active substance can have similar effects, with the additional active substance having an immediate effect and the active agent having a prolonged or sustained effect.

[0085] In other words, the device can be used to simultaneously administer two or more active agents, i.e. administered concurrently one after the other. Simultaneous administration may permit one agent in the combination to be administered within a certain time period (e.g. 5 minutes, 10 minutes or even a few hours) after the other, provided that the circulatory half-life concentration of the first administered agent in a combination is concurrently present in therapeutically effective amounts with the other agent administered thereafter. The time delay between administration of the agents may vary depending on the exact nature of the agents, the interaction between the individual agents, their respective half-lives, and on such other factors as easily recognized by the versed artesian.

[0086] In a further example, the active agent and the additional substance can have different effects, and the device is designed for sequential administration; meaning that a time difference exists between administering one agent and the other. Such time different may be short or may be significant, i.e. the first administered agent may no longer be present (or is present in subclinical amounts) in the bloodstream in a therapeutically effective amount when the second (or subsequent) agent is administered. The dosage unit can further comprise one or more additional components. Such additional components may be, for example, emulsifying agents (surfactants), such as poloxamers or carbomers; stabilizing agents, such as carboxymethylcellulose; suspending agents, such as cellulose, talc; acidifying agents, such as citric acid, ascorbic acid; viscosity increasing agents, such as carbopol, polyethylene oxide; effervescent agents, such as sodium bicarbonate, ammonium carbonate; solubilizing agents, such as lecithin; antimicrobial preservatives, such as sorbic acid, potassium sorbate; antioxidants, such as alpha tocopherol, butylhydroxy anisole; release modifying agents, such as Tween 80, sodium lauryl sulfate; coating agents, such as ethylcellulose, cellulose acetate; binders, such as hydroxypropyl cellulose, polyvinylpyrrolidone; stiffening agents, such as stearic acid, wax; plasticizers, such as diethyl phthalate, triethyl citrate; and others.

[0087] Typically, the devices are administered orally. Therefore, for ease of administration, the devices can be further folded into one or more folded configurations, when at the compacted state, to further reduce the size of the device. In some embodiments, the device is encapsulated in its compacted state in a self-administrable capsule, to be swallowed by the patient. In other words, the device may be folded to assume an overall reduced size or overall reduced volume when in the compacted state.

[0088] By some embodiments, transition of the device from the compacted state to the expanded state causes unfolding of the device from the folded configuration to an unfolded configuration. Namely, by some embodiments, the device undergoes substantially concomitant unfolding and extending.

[0089] When in the folded configuration, the folded device, by some embodiments, can be enveloped by an enteric envelope. According to some embodiments, the enteric envelope is formed out of an enteric film. According to such embodiments, the enteric film comprises or is composed of one or more enteric polymers. The term enteric polymer (s) means to denote polymeric material (i.e. a single polymer or a composition of polymers) that are configured to be disintegrated or solubilized by a liquid only at a defined pH range. For example, and preferably, the enteric polymers are stable (that is, maintain their physical and chemical structure) when exposed to acidic environments (for example in the stomach), and are solubilized by more alkaline liquids (such as those in the intestine).

[0090] According to some embodiments, the enteric envelope is configured to hold the device in its folded configuration, for example by forming the enteric envelope to have dimensions similar to those of the device when in its folded configuration. By some embodiments, the enteric envelope is tightly fit over the device in its folded configuration, substantially without having spaces formed between the enteric envelope and the device.

[0091] By some embodiments, the enteric film comprises one or more additives, e.g. film-forming compounds, plasticizers, stabilizers, fillers, etc.

[0092] The enteric envelope functions to maintain the device in its folded configuration after intake, until reaching proper conditions (for example, proper pH) within the GI tract that degrade the enteric envelope to permit exposure of the device and its unfolding and extension.

[0093] By some embodiments, in addition to the device, the enteric envelope encapsulates at least one anti-buoyancy element having a density higher than about 1 g / ml, to prevent the device from floating over the surface of the liquid in the stomach and improve the delivery of the encapsulated device to the intestine. The anti-buoyancy element can, in some embodiments, be constituted by one or more regions of larger thickness of the enteric envelope. By other embodiments, the anti-buoyancy element can be one or more mass units attached to the enteric envelope or positioned within the space formed by the enteric envelope. By some other embodiments, the space defined by the enteric envelope is divided into a primary space, enveloping the folded device, and one or more auxiliary spaces, containing the anti-buoyancy elements.

[0094] In order to prevent undesired or pre-mature deployment of the device, and / or in order to permit delivery of the device into the proper target site in the intestine, the device may comprise a biodegradable shell, encapsulating the device in its compacted state (or folded and compacted state). The biodegradable shell is thus selected to be degraded upon exposure to the proper biological conditions (e.g. pH, presence of certain chemical compounds, etc.). The biodegradable shell can be made of or coated by an enteric coating. For deployment in the intestine, the shell can be designed or selected such as to provide safe first passage through the stomach and biodegrade only when exposed to defined conditions in the intestine. By some embodiments, the biodegradable shell is designed to disintegrate as a function of the pH of the environment, thereby deploying in the desired part of the intestine. For example, different parts of the intestinal tract are known to have different pH values - while the stomach typically has a pH 1.5-3.5, the pH in the duodenum is typically 6, and gradually increasing to about 7.4 in the small intestine (until reaching the terminal ileum). The pH drops to 5.7 in the caecum, but again gradually increases, reaching pH 6.7 in the rectum. Hence, by utilizing an intestinal track degradable shell that degrades at defined pH values (or range of values), deployment of the device at the desired part of the intestinal track can be obtained.

[0095] The biodegradable shell can be, for example, a capsule, typically having a size that is suitable for swallowing, e.g. of about “elongated 000” or 000 or 00 capsule or less (i.e. outer diameter of about 9.97mm or less, height or locked length of about 30.0mm or less and actual volume of about 1.68ml or less).

[0096] The device may have two types of shells, one encasing the other. The outer shell in the form of a capsule, to facilitate the swallowing of the device, and is designed to be degradable in the gastric environment. The second, inner, shell may be a coating layer or an encapsulating layer, that coats / encapsulates the device, and is configured to maintain the device in its compacted (or folded and compacted) state for a predetermined period of time before deployment. For example, the inner shell can be made from an enteric material, thus preventing deployment of the device in the stomach and permitting its deployment only upon entrance to the intestine.

[0097] According to another aspect, there is provided a kit comprising a self-deployable device as described herein, encapsulated in a biodegradable shell, and instructions for use.

[0098] By yet another aspect, the disclosure provides a self-deployable ingestible device as disclosed herein, for use in delivering at least one active agent to an intestinal tissue of a subject.

[0099] By another one of its aspects, the disclosure provides a method of delivery of at least one active agent to an intestinal tissue of a subject in need thereof, the method comprising administering to the subject a self-deployable ingestible device as disclosed herein.

[0100] By a further aspect, there is provided a method of prolonged or sustained delivery of at least one active agent to a tissue of a subject in need thereof, the method comprising administering to the subject a self-deployable ingestible device as disclosed herein.

[0101] According to another aspect, there is provided the use of a self-deployable ingestible device as disclosed herein in delivery of at least one active agent to an intestinal tissue of a subject in need thereon. According to yet another aspect, there is provided a self-deployable ingestible device as disclosed herein for use in delivery of at least one active agent to an intestinal tissue of a subject in need thereon.

[0102] By some embodiments, the device is encapsulated in a biodegradable shell for administration to the subject.

[0103] Unless the context requires otherwise, the term comprise, and variations such as comprises and comprising, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.

[0104] Generally it is noted that the term ...at least one... as applied to any component of the device or arrangement of this disclosure should be read to encompass one, two, three, four, or even more different occurrences of said component in the device or arrangement.

[0105] It is appreciated that certain features of this disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of this disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0106] BRIEF DESCRIPTION OF THE DRAWINGS

[0107] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0108] Figs. 1A-1C are schematic representations of a device according to an embodiment of this disclosure in a compacted state (Figs. 1 A-1B) and an extended state (Fig. 1C).

[0109] Figs. 1D-1F show exemplary steps in deployment of the device of Figs. 1A-1C after ingestion. Figs. 2A-2C are schematic representations of a device according to another embodiment of this disclosure in a compacted state (Figs. 2A-2B) and an extended state (Fig. 2C).

[0110] Figs. 2D-2F show exemplary steps in deployment of the device of Figs. 2A-2C after ingestion.

[0111] Figs. 3A-3C are schematic representations of a device according to another embodiment of this disclosure in a compacted state (Figs. 3A-3B) and an extended state (Fig. 3C).

[0112] Figs. 3D-3F show exemplary steps in deployment of the device of Figs. 3A-3C after ingestion.

[0113] Figs. 4A-4B are schematic representations of a device according to another embodiment of this disclosure in a compacted state (Fig. 4A) and an extended state (Fig.

[0114] 4B).

[0115] DETAILED DESCRIPTION OF EMBODIMENTS

[0116] Turning first to Figs. 1A-1C, shown in an exemplary self-deployable ingestible device according to an embodiment of this disclosure. Device 100 includes a self-deployable unit 102, in this example a helical spring, to which several (in this example two) dosage units 104 are attached. Dosage units 104 typically comprise one or more active agent, e.g. pharmaceutically active agents, to be delivered by the device 100 to a desired target site at the gastrointestinal tract of a subject, once administered.

[0117] In Fig. 1A, device 100 is shown in its compacted state, namely when spring 102 is at its contracted state, therefor being in a compacted volume suitable for easy ingestion. In its contracted state, the deployment unit 102 keeps the dosage units at a defined distance d from one another. Distance d is sufficiently small to permit the device to assume a compact configuration at its compacted state, such that the device can be introduced into a cavity defined by the desired target site. For example, when the target site is the intestine, distance d is tailored to maintain the device at a dimension (at least in one of its spatial directions) that is smaller than the diameter of the intestinal tract.

[0118] Spring 102 can be made out of shape memory materials, such that it can maintain its contracted state without external mechanical constraints. Once exposed to suitable conditions at the target deployment, e.g. suitable temperature, humidity, pH, etc., spring 102 can change its geometry and switch into its extended state, as shown in Fig. 1C, thereby increasing the distance between the dosage units 104 to a distance D (D > d).

[0119] Distance D is tailored to suit the dimensions of the target site. For example, in case the target site is the intestine, distance D is at least the diameter of the intestinal tract. Hence, when the device is deployed, spring 102 drives the dosage units 104 away from one another and in the direction towards the tissue, such that when distance D is obtained - the dosage units are held against the tissue at the target site under the force applied by spring 102.

[0120] While the spring can be triggered to switch from its contracted state to its extended state by the natural conditions in the target site (e.g. the natural pH range at the target site or due to exposure of certain molecules naturally residing at the target site, for example bile salts), the device can be administered concomitantly with (or sequentially to) administration of one or more compounds or compositions functioning to modify the conditions at the target site (e.g. increase or reduce acidity, introduce required triggering molecules) to temporarily create the required deployment conditions at the target site.

[0121] Alternatively, as shown in Fig. IB, device 100 can be held, i.e. enveloped or encased, within a constraining casing 106 that is configured to break, disintegrate, or rupture at the target site to thereby release the self-deployable device and permit its deployment. Such a constraining casing can be an enteric envelope, that is designed to loss integrity once exposed to suitable pH conditions in the intestine

[0122] In addition to the device, the enteric envelope 106 can encapsulate at least one anti -buoyancy element 110 having a density higher than about 1 g / ml, to prevent the device from floating over the surface of the liquid in the stomach and improve the delivery of the encapsulated device to the intestine. The anti-buoyancy element can be constituted by one or more regions of larger thickness of the envelope, or can be one or more mass units attached to the envelope or positioned within the space formed by the envelope. The anti-buoyancy element functions to ensure that the device does not float stomach fluids, but is rather pass quickly through the stomach and delivered to intestine.

[0123] Shown in Figs. 1D-1F is an exemplary deployment sequence of device 100. Device 100, encased by envelop 106 is administered to a subject. For example, a device that is intended for deployment within the intestine 1000 will be enveloped by an enteric envelop 106 to permit safe passage of the device in its compacted state through the stomach, and permit its unharmed delivery to the intestine, as seen in Fig. ID. Once in the intestine, the envelop 106 is exposed to suitable pH conditions to initiate and promote its disintegration, to expose device 100 to the conditions at the target site, as shown in Fig. IE. Once exposed to the conditions at the target site, and / or due to the removal of the physical constrained imposed by envelop 106, deployment unit 102 changes its geometrical configuration from its contracted state (Fig. IE) to its deployed state (Fig. IF).

[0124] During such switching, the dosage units 104 that are attached to the deployment unit 102 are driven towards the intestinal tissue 1000, to bring the dosage units 104 into contact with the tissue. Deployment unit 102 is designed to maintain its deployed configuration for a pre-determined period of time, during which the dosage units 104 are substantially continuously held against the tissue by the force applied thereonto by the deployment unit 102, thereby enabling delivery of the active agent from the dosage units directly to the intestinal tissue.

[0125] Typically, the deployment unit and / or the device in its entirety are configured for disintegration after a pre-defined period of time to enable breakdown of the device into evacuatable fragments. Alternatively, the deploying unit and / or the device can be designed to contract (e.g. reduce in volume) or change its spatial configuration after a pre-defined period of time, to distance the dosage unit from the tissue thereby causing said cease of contact between the dosage unit and the tissue.

[0126] Another exemplary device is shown in Figs. 2A-2C, which show a device 200 comprising a deployment unit in the form of torsion spring 202. Dosage units 204 are arranged in a ring-like shape about torsion spring 202, with each dosage unit 204 overlapping its adjacent units. Optionally, each dosage unit 204 is detachably attached to adjacent dosage units at ends 208. In the contracted state of the deployment unit (i.e. the compacted state of the device 200), the dosage units form a closed-shape ring, as seen in Fig. 2A. Similar to device 100, in device 200 the torsion spring can be made of a shape memory material (e.g. a shape memory polymer), thereby holding its constrained configuration without the aid of further mechanical constraints. Alternatively, as shown in Fig. 2B, the device 200 can be enveloped or encased by envelop 206 to hold the device in its compacted state.

[0127] Torsion spring 202 is designed to assume a generally circular configuration at its extended state. Thus, when the torsion spring 202 switches from the contacted state, in which it defines an overall dimeter d of the compacted device, into its extended state (as seen in Fig. 2C) - the diameter defined by the torsion spring 202 increase (D>d). The force applied by spring 202 as it changes its spatial geometry, causes the dosage units 204 to be pushed apart and outwards, permitting accommodation of the spring as its changes its spatial geometry. When each dosage unit 204 is detachably attached to adjacent dosage units at ends 208, the force applied by spring 202 as it changes its spatial geometry, causes the dosage units 204 to detach from one another at ends 208, permitting accommodation of the spring as its changes its spatial geometry. As a consequence of the torsion spring 202 switch from the contacted state to its extended state, due to the increase in the overall diameter of the device, the dosage units 204 are driven by the torsion spring 202 towards the tissue and held against it for a pre-defined period of time by the spring in its extended state.

[0128] Alternatively, ends 208 can form non-detachable points of attachment between adjacent dosage units. In such cases, the dosage units can be flexible and / or folded into unfoladble configurations to form a closed, continuous ring. In such cases, the arrangement of the ring of dosage units can change its configuration along with the change in dimensions of the torsion spring, thereby accommodating the switch of the spring from the contracted to the extended state and expansion of the ring structure, hence permitting the spring to drive the dosage units in the direction of the tissue and to be held in contact with the tissue by the deployed deployment unit.

[0129] A sequence of operation of device 200 is shown in Figs. 2D-2F, similar to Figs. ID- IF with respect to device 100, in which device 200 is deployed in a tubular organ, such as the intestine 2000.

[0130] In another exemplary device, shown in Figs. 3A-3C, device 300 comprising a deployment unit in the form of a stent 302, seen in these figures in a top, cross-sectional view. The stent can be a wire stent or a mesh stent. Dosage units 304 are arranged in a ring-like shape about the stent 302, with their ends 308, optionally detachably attached similar to the arrangement in Fig. 2A. In the contracted state of the deployment unit (i.e. the compacted state of the device 300), the dosage units form a closed-shape ring, as seen in Fig. 2A. Similar to device 200, in device 300 the stent 302 can be made of a shape memory material (e.g. a shape memory polymer), thereby holding its constrained configuration without the aid of further mechanical constraints, as seen in Fig. 3A. Alternatively, as shown in Fig. 3B, the device 200 can be enveloped or encased by envelop 306 to hold the device in its compacted state. In its transition from the contracted state to the extended state, stent 302 changes its spatial configuration, expanding into the deployed state shown in Fig. 3C, thereby increasing its diameter from d to D (D>d). The force applied by stent 302 as it changes its spatial geometry, causes the dosage units 304 to pushed apart and outwards, and optionally to detach from one another at ends 308, permitting accommodation of the spring as its changes its spatial geometry. During such switch, due to the increase in the overall diameter of the device, the dosage units 304 are driven by the stent 302 towards the tissue and held against it for a pre-defined period of time by the spring in its extended state.

[0131] Alternatively, ends 308 can form non-detachable points of attachment between adjacent dosage units, in a similar manner to that described in connection with Figs. 2A-2C.

[0132] A sequence of operation of device 300 is shown in Figs. 3D-3F, similar to Figs. ID- IF with respect to device 100, in which device 300 is deployed in a tubular organ, such as the intestine 3000.

[0133] In another exemplary embodiment, shown in Figs. 4A-4B, the device 400 comprises a deployment unit 402 in the form of a flexible compartment that contains selfexpandable materials, configured to increase the volume of the compartment once in contact with liquid. The change in dimensions of such compartment induces the device to switch from the compacted state to the extended state. The expandable compartment 402 typically comprises a liquid permeable shell (or having liquid permeable sections) encasing at least one reactive material configured to react with said liquid to increase the volume of the compartment and switch the self-deployable unit from the contracted state to the deployed state. The at least one reactive material can be selected, for example, from a gel forming material, a gas generator, a foamable material, and combinations thereof.

[0134] Associated with the flexible compartments are dosage units 404, similar to those of Figs. 2A-3F, attached to one another at their ends 408 to form a ring-like structure. Once the device is administered and in the target site, liquid penetrating the flexible compartment will cause the expandable material contained thereinside to react, thereby expanding the volume of flexible compartment 402. During such expansion, the dosage units 404 are driven towards the tissue at the target site, and once forming contact - held by the expanded compartment for a pre-defined period of time to permit delivery on the active agent contained in the dosage unit to the tissue. While in the specifically embodiments exemplified herein a single deployment unit is shown, it is to be understood that each of the exemplified devices can comprise two, three, four, or more deployment units. The deployment units can be identical in their structure and properties. Alternatively, the deployment units can differ in their structure and / or at least one property. For example, each of the deployment units can be triggered to deploy in slightly different environmental conditions, or as a response to different triggers, thereby ensuring deployment of at least one deployment unit when the conditions at the target site vary. In another example, such difference in properties can provide for gradual deployment of the device as conditions in the target site change over time or to provide sequential contacting of different dosage units with the tissue at the target site as a result of sequential switching of the deployment units in a defined sequence.

[0135] According to some embodiments, the device comprises a plurality (i.e. two or more) of self-deployable units, each associated with at least one dosage unit. According to other embodiments, the device comprises a plurality of self-deployable units, each associated with one dosage unit.

[0136] By some embodiments, the device comprises a plurality of self-deployable units, at least one of which being associated with a dosage unit, for example some of the self-deployable units in said plurality being associated with a dosage unit, while others being non-associated with a dosage unit.

[0137] According to some embodiments, the device comprises two or more different self-deployable units. The self-deployable units can differ in their size, geometry, deployment mechanism, deployment timing, etc. By some embodiments, some of the self-deployment units that do not carry a dosage unit have one or more tissue-attachment means (e.g. microhooks, microneedles, mucoadhesive components, etc.) to attach the device to the tissue, for example to provide temporary anchoring of the device or directionality of extension of the device.

[0138] The dosage unit is associated with the self-deployable unit, such that transition of the unit to the deployed state causes at least one surface portion of the self-deployable unit to drive of the dosage unit towards the tissue. According to some embodiments, the surface portion is a tissue-facing surface of the self-deployable unit. According to some embodiments, the tissue-facing surface is an external surface of the self-deployed unit. According to other embodiments, the tissue-facing surface is a surface of the self- deployable unit that becomes oriented to face the tissue during transition of the self-deployable unit from the contracted state to the deployed state. By varying the size, geometry, number, etc. of the self-deployable units and / or the type of deployment mechanism, different deployment / extension rates, shapes and / or targeted delivery can be obtained, as well as obtaining symmetrical or non-symmetrical extended shape of the device. Varying the properties self-deployable units can also permit controlling the force applied by the self-deployable unit, in its deployed state, on the tissue for maintaining the dosage unit in contact with the tissue.

[0139] The dosage unit is physically connected to the deployment unit, i.e. associated thereto, in at least one connecting point of the deployment unit. The association can be direct association, namely the dosage unit being attached directly to the self-deployable unit or constitute a part of the surface potion, e.g. the tissue-facing surface. Alternatively, the dosage unit can be associated with the self-deployable unit by one or more linking elements (not shown).

[0140] The dosage unit can be any structure or composition that can contain the active agent and permit its release once in contact with the intestinal tissue. The dosage unit can be in a form of a reservoir that holds said at least one active agent (or a composition comprising it) and configured to release the active agent therefrom during contact of the dosage unit with the tissue. In other configurations, the dosage unit can be in the form of a pressure-sensitive element that is designed for rupturing once pressure is applied thereonto after deployment of the self-deployable unit as the dosage unit is held against the tissue (e.g. the reservoir can be in the form of a casing / envelope that holds therein the active agent or a composition thereof, the casing / envelope having at least one wall portion that is configured for rupturing under a predefined applied pressure).

[0141] Alternatively, the dosage unit can be in the form of a solid composition comprising or consisting of said at least one active agent, e.g. in the form of a tablet or a pill.

[0142] In other arrangements, the dosage unit can comprise a core member, i.e. a carrying member, that is coated by said at least one active agent or a composition comprising said at least one active agent.

[0143] Yet in alternative configurations, the dosage unit can be a layer coating at least a portion of the tissue-facing surface, and constituted by the active agent, or comprising a carrying matrix in which the active agent is dispersed or embedded. For example, the dosage unit can be in the form of a gel or gel-forming matrix containing the active agent. In another example, the dosage unit can be in the form of an active layer coating at least a portion of the tissue-facing surface of the self-deployable unit. The active layer can be made of or comprise a composition containing said at least one active agent, or can consists essentially of said at least one active agent. Further, the dosage unit can be in the form of a layer coating one or more regions of the tissue-facing surface, a plurality of spaced-apart surface regions, or can be a continuous coating of the tissue-facing surface.

[0144] The dosage unit is typically in a form that is non-attachable to the tissue, and is held against the tissue in a mechanical manner by the self-deployable unit when in the deployed state. However, in some cases, the dosage unit can be tissue-attachable, e.g. by use of microneedles or microhooks, or by use of at least one mucoadhesive material.

[0145] The self-deployable unit can be associated with a single dosage unit or with a plurality of dosage units, identical to one another or different in any one of the active agents, the concentrations of same active agent, the compositions of the dosage unit, the type of dosage unit, the size and geometry of the dosage unit, etc.

Claims

1. CLAIMS:

1. A self-deployable ingestible device configured for delivery of at least one active agent to an intestinal tissue, the device having a compacted state and an expanded state, and comprising:3.at least one self-deployable unit, configured for transitioning between a contracted state and a deployed state, and thereby switch the device from the compacted state to the expanded state; and4.at least one dosage unit that comprises said at least one active agent, the at least one dosage unit being associated with the self-deployable unit;5.transition of the device from the compacted state to the expanded state causes at least a surface portion of the deployable unit to drive the dosage unit towards said tissue for forming contact between the dosage unit and the tissue to thereby deliver said active agent to the tissue.

2. A self-deployable ingestible device configured for delivery of at least one active agent to an intestinal tissue, the device having a compacted state and an expanded state, and comprising:7.at least one self-deployable unit, configured for transitioning between a contracted state and a deployed state after switching of the device from the compacted state to the expanded state; and8.at least one dosage unit that comprises said at least one active agent, the at least one dosage unit being associated with the self-deployable unit;9.transition of the self-deployable unit from the contracted state to the deployed state causes at least a surface portion of the deployable unit to drive of the dosage unit towards said tissue while said device is in the expanded state, for forming contact between the dosage unit and the tissue to thereby deliver said active agent to the tissue.

3. A self-deployable ingestible device configured for delivery of at least one active agent to an intestinal tissue, the device having a compacted state and an expanded state, and comprising:11.at least one self-deployable unit, configured for transitioning between a contracted state and a deployed state concomitantly with switching of the device from the compacted state to the expanded state; and12.at least one dosage unit that comprises said at least one active agent, the at least one dosage unit being associated with the self-deployable unit; transition of the self-deployable unit from the contracted state to the deployed state causes at least a surface portion of the deployable unit to drive of the dosage unit towards said tissue during switching of the device into the expanded state, for forming contact between the dosage unit and the tissue to thereby deliver said active agent to the tissue.

4. The device of any one of claims 1 to 3, wherein said at least one surface portion is configured to hold the dosage unit in contact with the tissue for the duration / continuance of the delivery of said active agent to the tissue.

5. The device of any one of claims 1 to 4, wherein the at least one surface portion is a tissue-facing surface of the self-deployable.

6. The device of any one of claims 1 to 5, wherein the dosage unit is associated with the self-deployable unit by a linking element attached at one end thereof to the self-deployable unit and at another end thereof to the dosage unit.

7. The device of claim 6, wherein said linking element is flexible.

8. The device of any one of claims 1 to 7, wherein the dosage unit is attached to at least a segment of the surface portion.

9. The device of any one of claims 1 to 8, wherein the dosage unit is in a form of a reservoir holding said at least one active agent and configured to release the active agent therefrom during contact of the dosage unit with the tissue.

10. The device of any one of claims 1 to 9, wherein the dosage unit is in the form of a solid composition comprising or consisting of said at least one active agent.

11. The device of claim 10, wherein said solid composition is in the form of a tablet.

12. The device of any one of claims 1 to 11, wherein the dosage unit comprises a core member coated by said at least one active agent or a composition comprising said at least one active agent.

13. The device of any one of claims 1 to 9, wherein said dosage unit is tissue-attachable.

14. The device of claim 13, wherein said dosage unit comprises microneedles or microhooks.

15. The device of claim 13, wherein said dosage unit comprises at least one mucoadhesive material.

16. The device of any one of claims 1 to 5, wherein said dosage unit is in the form of an active layer coating at least a portion of the tissue-facing surface of the self-deployable unit.

17. The device of claim 16, wherein said active layer consists of said at least one active agent.

18. The device of claim 17, wherein said active layer comprises a composition comprising said at least one active agent.

19. The device of any one of claims 1 to 18, wherein said active agent is a pharmaceutical agent.

20. The device of any one of claims 1 to 18, wherein said active agent is a diagnostic agent.

21. The device of any one of claims 1 to 18, wherein said active agent is a nutraceutical agent.

22. The device of any one of claims 1 to 21, wherein the self-deployable unit is in the form of an expandable compartment.

23. The device of claim 22, wherein the expandable compartment comprises a liquid permeable shell encasing at least one reactive material configured to react with said liquid to increase the volume of the compartment and switch the self-deployable unit from the contracted state to the deployed state.

24. The device of claim 23, wherein the at least one reactive material is selected from a gel forming material, a gas generator, a foamable material, or a combination thereof.

25. The device of any one of claims 1 to 21, wherein the self-deployable unit comprises or is substantially made of one or more shape memory polymers.

26. The device of any one of claims 1 to 21, comprising one or more constraining elements, and the self-deployable unit is constrained in the contracted state by said one or more constraining elements when the device is in the compacted state, transition of the device from the compacted state to the expanded state disengages the constraining elements from the self-deployable unit to permit transition of the self-deployable unit into its deployed state.

27. The device of any one of claims 1 to 21, wherein the self-deployable device comprises at least one deployment element, the deployment element having a compressed state and a non-compressed state, and is biased to the non-compressed state, such that switching of the deployment element to the non-compressed state causes transition of the self-deployable unit into its deployed state.

28. The device of any one of claims 1 to 27, wherein the device comprises a liquid expandable material, configured to switch the device from its compacted state to its expanded state when exposed to liquid.

29. The device of any one of claims 1 to 28, wherein the device comprises at least one additional active substance, being different from said at least one active agent.

30. The device of any one of claims 1 to 29, wherein the device is bio-disintegrable.

31. The device of any one of claims 1 to 30, having one or more folded configurations when at the compacted state.

32. The device of claim 31, wherein transition of the device from the compacted state to the expanded state causes unfolding of the device from the folded configuration to an unfolded configuration.

33. A method of delivery of at least one active agent to an intestinal tissue of a subj ect in need thereof, the method comprising administering to the subject a self-deployable ingestible device of any one of claims 1 to 32.

34. The method of claim 33, wherein the device is encapsulated in a biodegradable shell for administered to the subject.

35. The self-deployable ingestible device of any one of claims 1 to 32, for use in delivering at least one active agent to an intestinal tissue of a subject.

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