Abstract
This disclosure concerns expandable devices, specifically self-deployed devices, for adherence to a tissue, for example intestinal tissue. The disclosure also concerns expandable devices, specifically self-deployed devices for delivery of at least one active agent to, or across, a tissue.
Claims
1. A self-expandable device configured for attaching a tissue-attachable layer to a tissue, the device having a collapsed state and an expanded state, and comprising: at least one self-expandable compartment formed out of a substantially continuous, deformable film having one or more liquid-permeable sections, the compartment enclosing a gel forming material therein, the gel forming material being configured for swelling upon contact with liquid, thereby expanding the compartment to irreversibly switch the device from the collapsed state to the expanded state; and a tissue-attachable layer coating at least a portion of an external surface of the compartment, such that expansion of the device from the collapsed state to the expanded state causes expansion of the compartment to drive the tissue-attachable layer towards said tissue for attaching at least part of the tissue-attachable layer to the tissue.
2. The device of claim 1, wherein the tissue-attachable layer comprises a plurality of microneedles.
3. The device of claim 1, wherein the tissue-attachable layer is a mucoadhesive layer.
4. The device of claim 3, wherein the mucoadhesive layer comprises at least one mucoadhesive material.
5. The device of claim 3, wherein the mucoadhesive layer comprises at least one mucoadhesive material and at least one active agent.
6. The device of claim 2, wherein the microneedles are comprised of a polymeric material in which at least one active agent is embedded.
7. The device of claim 5, wherein the active agent is a pharmaceutical active agent.
8. The device of claim 5, wherein the device comprises at least one additional active substance, being different from said at least one active agent.
9. The device of claim 1, wherein said one or more sections of the deformable film differ one from the other in their liquid permeability.
10. The device of claim 1, wherein the deformable film is disintegrable.
11. (canceled)
12. The device of claim 1, wherein the deformable film comprises weak regions permitting fragmentation of the film.
13. The device of claim 1, wherein the gel forming material is disintegrable.
14. The device of claim 1, wherein, when in the collapsed state, the device is folded in a primary folded configuration and is configured to undergo unfolding during transition from the collapsed state to the expanded state.
15. (canceled)
16. The device of claim 14, wherein, when in the collapsed state, the device has a secondary, rolled configuration, whereby the folded device is further rolled about an axis thereof, and is configured to simultaneously undergo unrolling and unfolding during transition from the collapsed state to the expanded state.
17. (canceled)
18. (canceled)
19. The device of claim 1, wherein, when in the collapsed state, the device is rolled about an axis thereof, and is configured to undergo unrolling during transition from the collapsed state to the expanded state.
20. The device of claim 1, comprising a biodegradable shell, encapsulating the device in its collapsed state.
21. The device of claim 1, being an ingestible device.
22. (canceled)
23. (canceled)
24. (canceled)
25. The device of claim 1, wherein, in the collapsed state, the tissue-attachable layer is a sheet of mucoadhesive material having a non-extended configuration, with a portion of the tissue-attachable layer coating at least a region of the external surface of the compartment, and having an extended configuration in the expanded state in which the sheet extends beyond the compartment.
26. (canceled)
27. A method of attaching, through a mucous membrane, a tissue-attachable layer to a tissue of a subject in need thereof, the method comprising administering to the subject a self-expandable device of claim 1, encapsulated in a biodegradable shell.
28. A method of 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-expandable device of claim 5 encapsulated in a biodegradable shell.
29. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0132] 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:
[0133] FIGS. 1A-1G are schematic representations of a device according to several exemplary embodiments of this disclosure;
[0134] FIGS. 2A-2F are schematic representations of a sequence of operation of the device after administration to a subject;
[0135] FIG. 2G is a schematic representation of a non-symmetrical device according to an embodiment of this disclosure;
[0136] FIG. 2H is a schematic representation of a device according to this disclosure, with non-symmetrical adherence of a tissue-attachable layer to the tissue;
[0137] FIGS. 3A-3D are exemplary cross sections of the device in its expanded state;
[0138] FIGS. 3E-3F are longitudinal cross-sections through devices of FIGS. 3A and 3B, respectively;
[0139] FIGS. 3G-3H show cross sections where the device is designed to conform to a lumen or cavity with a varying cross section;
[0140] FIG. 3I shows a cross section where the device comprises compartments of different size;
[0141] FIGS. 4A-4B are exemplary cross sections of further configurations of the device in its expanded state;
[0142] FIGS. 5A-5B are schematic representations of a device according to some further embodiments of this disclosure;
[0143] FIGS. 6A-6C are schematic representations of a device according to additional embodiments of this disclosure, in which the device is configured as a sleeve: FIG. 6A being a front perspective view FIG. 6B being a top cross-sectional view across line V-V, FIG. 6C showing the device in an expanded form;
[0144] FIG. 6D-6F show various folding configurations of the device of FIGS. 6A-6B;
[0145] FIGS. 6G-6H shows the folded configuration of the device of FIG. 6E, enveloped in an enteric envelopetop view (FIG. 6G) and side view (FIG. 6H);
[0146] FIGS. 7A-7B are schematic representations of some variations of the device of FIGS. 6A-6B;
[0147] FIGS. 7C-7D shows the device of FIG. 7A or 7B, in possible primary folded configurations;
[0148] FIGS. 7E-7F show the devices of FIGS. 7C-7D, respectively, covered by an enteric envelope.
DETAILED DESCRIPTION OF EMBODIMENTS
[0149] In the following, exemplary devices according to this disclosure will be described. While the specific examples show the device as being substantially symmetric, it is to be understood that the device may also be asymmetric or of any other shape. Further, the elements of the device are shown out of scale for ease of illustration.
[0150] Shown in FIG. 1A is a self-expandable device according to an embodiment of this disclosure, in a collapsed (non-expanded) state. The device 100 includes a self-expandable compartment, generally designated 102, that is formed out of a continuous deformable film 104. In this specific example, the entire deformable film is made of liquid-permeable material; however, as noted herein it is to be understood that the deformable film may have one or more sections that are liquid-permeable (not shown), and other sections which are not liquid-permeable. At least part of the volume of the compartment is filled with gel-forming material 106. Tissue-attachable layer 108 of this embodiment, e.g. a mucoadhesive layer or a layer comprising microneedles or microhooks, substantially coats the external surface of the compartment 102 (i.e. the face of the film 104 that faces outwards from the compartment). When the device is intended for delivery of one or more active agents to the tissue, the tissue-attachable layer 108 comprises the active agent(s). In order to permit administration, for example by oral intake for deployment in the intestine, the device is encapsulated by a biodegradable (e.g. gastric degradable) capsule 110, that enables the device to pass the stomach intact and undeployed.
[0151] Another embodiment of the device is shown in FIG. 1B, in which the tissue-attachable layer coats spaces-apart zones of the external surface of the compartment.
[0152] The device can further comprise one or more additional active substances, e.g. contained within the compartment, for example intermixes with the gel-forming material 106.
[0153] In the embodiment of FIG. 1C, another device is shown for oral intake, and is designed to deliver the tissue-attachable layer to the intestine. In this example, the device 100 is shown in a collapsed and encapsulated state. In addition to capsule 110, which is designed to facilitate the swallowing of the device and intended for disintegration in the stomach, a second, inner shell 116 is an enteric envelope, that coats or encapsulates the device. The enteric envelop is configured to maintain the device in its collapsed state as long as the device is in the stomach, and disintegrates upon exposure to proper conditions in the intestine, thus enabling deployment of the device in the intestine and not in the stomach.
[0154] In another example, shown in FIG. 1D, the mucoadhesive layer 108 partially, and non-symmetrically coats a region of the compartment.
[0155] By another example, the compartment may be formed out of at least two different deformable films, 104 and 105 as seen in FIG. 1E, to cause asymmetrical deployment of the tissue-attachable layer. For example, film 104 can be made of a liquid-permeable material and film 105 may be made of non-liquid permeable film. Alternatively, films 104 and 105 can differ in their degree of liquid permeability.
[0156] In another embodiment, shown in FIGS. 1F-1G, the device is shown in a collapsed and encapsulated state, and the capsule 110 further contains anti-buoyancy elements 111 located within the enteric envelope 116. Elements 111 typically have a density higher that the density of stomach liquid, e.g. higher than about 1 g/ml, to ensure submerging of the capsule in the stomach liquid and delivery of the device to the intestine.
[0157] In the example of FIG. 1F, elements 111 are attached to an inner surface of the enteric envelope. Alternatively, elements 111 can be constituted by regions of the enteric envelope having a larger thickness than the other regions of the enteric envelope.
[0158] In the example of FIG. 1G, enteric envelope 116 defines an internal space, which is divided into main space 115 in which the folded device 102 is enveloped, and two auxiliary spaces 113 housing the anti-buoyancy elements 111.
[0159] Shown in FIGS. 2A-2E, is an exemplary sequence of operation of the devices of this disclosure. While this example shows deployment of the device in the intestine, it is to be understood that the device can be administered and deployed in any other suitable bodily lumen or cavity. For example, the device can be administered to other organs, such as urine tract, vagina, rectally, intranasally, etc. Where the target organ or cavity is relatively user-accessible, the device can be administered by utilizing a dedicated applicator (not shown), in order to insert the device into the organ or cavity.
[0160] After the device is administered, e.g. orally, the biodegradable capsule 110 passes the stomach and undergoes disintegration when exposed to suitable conditions in the intestine, thus exposing device 100. As noted, in some configurations, as shown in FIG. 2A, the biodegradable capsule 110 is degraded in the stomach and the device is encapsulated/coated with an enteric layer (coating) 116, that protects the device when passing along the stomach, and is designed to disintegrate when exposed to suitable conditions in the intestine. It is to be noted, however, that in other configurations, the layer 116 may be absent. The enteric layer typically comprises or is formed out of one or more enteric polymers.
[0161] Once the capsule 110 (or the enteric layer 116, as shown in FIG. 2A) is disintegrated, liquid in the intestine permeates the liquid-permeable sections of deformable film 104 of compartment 102, causing expansion of gel-forming material 106 contained therein. Expansion of the gel-forming material causes expansion of the compartment and deformation of film, as shown in FIG. 2B, causing the device to assume its expanded state. In the expanded state, the expansion of the gel-forming material causes application of force onto film 104, in the direction of arrow 112, forcing the tissue-attachable layer 108 to come into contact with the tissue 114 and adhering thereto. Hence, the transition of the device from its collapsed state to its expanded state drives the mucoadhesive layer associated with the compartment towards the tissue and brings it into intimate contact therewith under application of force (applied by the expanding gel-forming material).
[0162] As seen in FIGS. 2G and 2H, the mucoadhesive layer 108 does not need to symmetrically coat the deformable film and/or can adhere to the tissue in a non-symmetrical manner.
[0163] As shown in FIGS. 2C-2D, the deformable film 104 and/or the gel forming material 106 undergo disintegration and are cleared from the target site by the intestinal natural movement, leaving the tissue-attachable layer attached or adhered to the tissue. When the tissue-attachable layer 108 contains an active agent, the active agent contained within the mucoadhesive layer is thus delivered to the tissue during the time period in which the tissue-attachable layer remains adhered to the tissue, as seen in FIG. 2E.
[0164] As the tissue is routinely shed from the intestinal wall every few hours, shedding of the tissue will result also in detachment and disintegration of the tissue-attachable layer, as seen in FIG. 2F, and clearance of the tissue-attachable layer from the intestine.
[0165] By some other embodiments, in the collapsed state, the device is rolled about an axis thereof, and is configured to undergo unrolling during transition from the collapsed state to the expanded state (i.e. without folding).
[0166] In the expanded state, the device may have a circular cross-section, a polygonal cross-section, or an irregular shape cross-section. Typically, in its expanded state, the device can assume a three-dimensional (3D) shape generally conforming to the shape of at least a section of the lumen or cavity in which it expands (is deployed). In specific exemplified embodiments, the compartment assumes a substantially cylindrical shape, with a circular cross-section as shown in FIG. 3A. However, it is also possible that the device assumes different shapes having different cross-sections when in the expanded state, such as that shown in FIG. 3B. As seen in FIG. 3B, the device can assume a cylindrical shape in its expanded state, with a hollow lumen. Such a hollowed cylindrical shape prevents formation of blockage of the organ cavity when the device is in its expanded state, permitting passage of liquids or solids through the organ while the device is deployed therein and attached to the tissue.
[0167] While typically the device has a single compartment, it is also envisaged that the device can comprise two or more compartments, similar or different, as shown, for example, in FIGS. 3C-3D, which can be arranged to form a hollow lumen therebetween to permit passage of fluids and solids through the organ after expansion of the device (thus preventing blockage of the organ).
[0168] FIGS. 3E-3H show examples of cross sections of the device in a direction perpendicular to those show in FIGS. 3A-3D. FIGS. 3E and 3F correspond to FIGS. 3A and 3B, respectively. FIGS. 3F and 3G show cross sections where the device is designed to conform to a lumen or cavity with a varying cross section. The device may also be designed to conform to a cavity having a non-cylindrical form.
[0169] FIG. 3I shows a cross section of a device, in the same direction as that of FIGS. 3E-3H, comprising of compartments with different lengths.
[0170] As shown in FIGS. 4A-4B, the device can have other expanded shapes. For example, the device can comprise compartments having different sizes and configurations, resulting in three-dimensional (3D) shapes having different mechanical strengths. Further, some of the compartments can be attached to one another in one or more attachment locations, as to constrain the expansion of the device to form a desired 3D configuration. For example, while the devices shown in FIGS. 3C-3D, each compartment is attached to two adjacent compartments to form a hollow closed shape when in the expanded statein the device of FIG. 4A some of the compartments 102B are attached to two adjacent compartments, while some of the compartments 102A are attached to more than two adjacent compartments, thereby forcing the expanded device to assume an hourglass shape. Such a shape can provide increased rigidity and stability of the device. in such a configuration, not all of the compartments typically carry a tissue-attachable layer, for example compartments 102A may be utilized to provide mechanical properties to the device, while compartments 102B can carry the tissue-attachable layer (not shown) and come into contact with the tissue.
[0171] Alternatively, the compartments can be constrained by one or more constraining elements 120, forcing the compartments to assume a desired shape when in the expanded state, as seen in FIG. 4B.
[0172] Further, in order to obtain compactization of the device in its collapsed (non-expanded) state, the device may be folded in various folding configurations (i.e. primary folded configurations, not shown) and/or rolling configurations (i.e. secondary rolled configuration), to permit its unfolding (and/or unrolling) during transition from the collapsed state to the expanded state. In other words, the device may be folded to assume its collapsed state, having an overall reduced size or overall reduced volume. Once liquid permeates through the deformable film, the gel-forming material starts to swell and increase in volume. This, in turn, applies force onto the deformable film, and due to its flexibility and/or deformability, the film is unfolded to assume the device's expanded state.
[0173] In some additional embodiments, as shown in FIGS. 5A-5B, the tissue-attachable layer extends beyond the external surface of the compartment. In such embodiments, typically, an additional backing layer 118 is used, to provide support to the tissue-attachable layer.
[0174] By some embodiments, similarly to the devices in FIGS. 3C-3D, the device can assume a sleeve-like form, as shown in FIGS. 6A-7B. The device 200 of FIGS. 6A-6B has an overall cylindrical sleeve-like shape, and comprises a plurality, in this case six, self-expandable compartments, collectively designated 202, and are formed out of a continuous deformable film 204. While in this example six compartments are shown, it is to be understood that any number of compartments can be utilized, e.g. 2, 3, 4, 5, 6, 7, 8 or even more compartments.
[0175] In this example, the entire sleeve constitutes the deformable film, in which the compartments 202 are defined (as pockets made of liquid-permeable material and each enclosing a gel-forming material 206. A tissue-attachable layer 208 is located on the external surface of each compartment 202 (i.e. the face of the film 204 that faces outwards from the compartment). The tissue-attachable layer 208, as noted above, can comprise one or more active agents(s) to be delivered to a tissue.
[0176] The tissue-attachable layer 208 can be provided as patches that are applied (e.g. adhered) onto film 204 over compartments 202. For example, when the tissue-attachable layer is a mucoadhesive layer, the patch can comprise the mucoadhesive material, layered upon a backing layer (not shown) that enables adhering or attaching the patch onto the external surface of the compartment and provides support for the mucoadhesive material. Alternatively, the mucoadhesive layer can be first applied at specific locations onto film 204, followed by formation of the compartments 202 at locations corresponding to areas of the film containing the mucoadhesive layer, thus forming a multilayer film structure.
[0177] Seen in FIG. 6C is the device at its expanded form, i.e. after being exposed to liquids that cause swelling of the gel-forming material, thereby expanding the device.
[0178] FIGS. 6D-6F show various configurations for folding the device of FIGS. 6A-6C, in order to render it with a more compact form for intake. For ease of visualization, only tissue-attachable layers 208 are shown onto the film 204. When in the collapsed state shown in FIG. 6A, the device can be folded to one of the primary folded configurations shown in FIGS. 6D-6F, and encased in a biodegradable capsule (not shown). After intake and disintegration of the biodegradable capsule, exposure to liquid in the GI track causes expansion of the gel-forming material in the compartment, thereby expanding the compartment and causing at least partial concomitant expansion and unfolding into the expanded state.
[0179] Once folded, into the primary folded configuration, the folded device can be enveloped by an enteric envelope 209, as shown for example in FIGS. 6G-6H, functioning to maintain the device in its primary folded configuration until reaching proper conditions for deployment within the GI tract.
[0180] In order to obtain further compactization in the collapsed state, the device, by some embodiments, may have has a secondary, rolled configuration (not shown), whereby the folded device is further rolled about an axis thereof, and is configured to simultaneously undergo unrolling and unfolding during transition from the collapsed state to the expanded state. It is noted that an enteric envelope can envelope the device in its secondary folded configuration (not shown), instead or in addition to the enteric envelope 209 enveloping the device in its primary folded configuration. In cases where the device includes two enteric envelopes, the first and second envelopes can be configured to have the same disintegration/dissolution properties or different disintegration/dissolution properties.
[0181] FIGS. 7A-7B show alternative arrangements of the device of FIGS. 6A-6B. In the device 200 shown in FIG. 7A, each compartment 202 includes two regions coated by a layer 208 of mucoadhesive material. It is noted that while in the examples of FIGS. 7A-7B two regions are shown, a person of skill in the art would appreciate that more than two regions can be utilized over each compartment, e.g. 3, 4, 5, 6 or even more such regions, and the devices described herein are not limited by the number of such regions.
[0182] Alternatively, as seen in FIG. 7B, the device 200 can include pairs of compartments 202A,202B, the compartments in each pair being arranged consecutively along the longitudinal axis 210 of the device, and each compartment 202A,202B carrying a mucoadhesive layer 208 on its external surface. The arrangements shown in FIGS. 7A-7B permit additional folding of the device along line 212, thereby permitting the device to assume a further compacted form suitable for intake. For example, as shown FIG. 7C, the device of FIG. 7B can be flattened and then folded over line 212 to obtain a folded collapsed device. The device of FIG. 7C can be further folded, e.g. in the direction of arrows 214, to further reduce the size of the device and obtain the primary folded configuration shown in FIG. 7D. As can be seen in FIGS. 7E-7F, the devices in their primary folded configurations can be enveloped by at least one enteric envelope 209.
[0183] The devices can also comprise at least one additional active substance, being different from the 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. For example, the additional active substance can be contained in the mucoadhesive layer, to be released concomitantly or sequentially with the active agent. By another 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.
[0184] By a further example, the additional active substance can be contained within the compartment, e.g. associated with the deformable film, associated with the gel-forming material, or mixed (or dispersed) into the gel-forming material. In such cases, 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.
[0185] While the device of this example can be used to delivery at least one active agent to a target site, the device can also be devoid of active agents, or comprise only the active substances within the compartment. For example, the device can be utilized to deliver a patch to a wall of a tissue, for example for temporarily cover perforations or ulcers in the tissue.
