Controlled Release Formulations and Methods of Targeted Drug Delivery within the Small Intestine Wall

Abstract

Embodiments of the invention provide solid controlled-release penetrating member for exposure to the intestinal lumen environment and delivery of an active agent across or within the small intestine lumen wall and having a tissue penetrating tip, especially advantageous for active agents typically administered by injection. Optionally, the penetrating members include a tip coat or water insoluble extension of the controlled release formulation and/or an intestine environment protective component. Methods of using the penetrating members and arrays thereof are also provided.

Claims

1. An oral device for delivery of an active agent across or within the small intestine lumen wall comprising: i. an intestine release container; ii. a solid controlled-release penetrating member comprising an active agent and having a penetrating tip at a distal end, said tip shaped and formulated to promote penetration of the intestine tissue during exposure to an intestine lumen environment and said penetrating member being operably coupled to an intestine wall deployment assembly; and iii. an intestine wall deployment assembly disposed in the intestine release container, the assembly configured to: A. position said penetrating member adjacent to the intestinal lumen wall; and B. apply a force to said penetrating member so as to penetrate the wall; wherein when the penetrating member is subject to in vitro dissolution testing employing a USP II apparatus with dissolution medium at 37° C., 30 mM buffer, pH 6.5 with fasted state simulating intestinal fluid (FaSSIF), the active agent is released from the penetrating member at a rate such that: a. the penetrating member loses less than 10% of its length or releases less than 10% of its active agent in 10 minutes; and b. the penetrating member releases at least 80% of its active agent in 120 minutes.

2. The oral device of claim 1, wherein the active agent is chemically degradable, poorly absorbed, or not well tolerated in the lumen of the gastrointestinal tract.

3. The oral device of claim 2, wherein the active agent is a peptide sequence, protein, enzyme, polysaccharide, or polynucleotide.

4. The oral device of claim 1, wherein the penetrating member loses less 5% of its length within 10 minutes.

5. The oral device of claim 1, wherein the penetrating member loses less than 5% of the active agent within 10 minutes.

6. The oral device of claim 1, wherein the penetrating member comprises a portion of a therapeutically effective dose of at least one active agent.

7. The oral device of claim 1, wherein the penetrating member has a length of less than 1000 μm measured from a proximal base to a distal tip, wherein the proximal base is operably coupled to an intestine wall deployment assembly.

8. The oral device of claim 7, wherein the penetrating member has a length of about 500 to 850 μm.

9. The oral device of claim 7, wherein the proximal base is operatively connected to a pliable substrate of an intestine wall deployment assembly.

10. The oral device of claim 7, wherein multiple penetration members are each connected to a common pliable substrate at respective bases of the multiple penetration members.

11. The oral device of claim 7, wherein the maximum diameter or length at the base of the penetrating member is between 50 and 500 μm.

12. The oral device of claim 1, wherein the penetrating member further comprises a lipophilic coating or a film-forming polymer coating having a pH threshold at about 6.5 or above.

13. The oral device of claim 1, wherein the film-forming polymer is an acrylic/methacrylic copolymer having a pH threshold at about 6.5 or above.

14. The oral device of claim 13, wherein the film-forming polymer coating comprises an enteric acrylic/methacrylic copolymer which has a pH threshold of about 7.0 and a second acrylic/methacrylic copolymer which has a pH threshold of about 6.0.

15. The oral device of claim 1, wherein the penetrating member is one of a plurality of penetration members.

16. The oral device of claim 15, wherein the plurality of penetrating members forms a microneedle array.

17. The oral device of claim 16, wherein the total amount of active agent in the plurality of penetration members is between 2 and 10 mg active agent.

18. The oral device of claim 16, wherein the total amount of active agent within the plurality of penetration members is less than an amount to produce a corresponding effect if the agent was orally delivered in a capsule without the oral device for delivery of active agent across or within a lumen of the small intestine.

19. The oral device of claim 1, wherein the penetrating member has a conical, or pyramid shape.

20. The oral device of claim 1, wherein the solid controlled-release penetrating member comprising the active agent is: i. a mixture of active agent and controlled release component; or ii. an immediate release active agent inner core and controlled release coating.

21. The oral device of claim 1, wherein the controlled release coating or controlled release component is a pH sensitive or sustained release polymer.

22. The oral device of claim 21, wherein the controlled release coating is a pH sensitive or sustained release polymer.

23. The solid tissue penetrating drug delivery member of claim 22, wherein the pH sensitive polymer is a cationic acrylic/methacrylic copolymer is non-biodegradable.

24. The oral device of claim 22, wherein the controlled release coating or controlled release mixture is further coated by an enteric acrylic/methacrylic copolymer.

25. The oral device of claim 20, wherein controlled release coating comprises a low-viscosity ethyl cellulose, a pore-forming agent, and a plasticizer.

26. The oral device of claim 1, wherein the assembly applies no force to facing intestinal walls when deployed in the lumen of the intestine and under conditions without intestinal peristalsis.

27. The oral device of claim 1, wherein the tip is at least partially coated, or the tip is formulated as a separate but adjacent and distal extension of the penetrating member, said coat comprising a water insoluble, hydrophobic, or non-degradable polymer.

28. The oral device of claim 16, wherein the microneedle array includes a range of longitudinal sizes ranging between 200-1000 μm.

29. The oral device of claim 16, wherein the microneedle array is in an amount of 100-150 microneedles per cm.sup.2.

30. The oral device of claim 1, wherein the penetrating member comprises an outer coating of an intestine environment protective component.

31. The oral device of claim 7, wherein the penetrating member comprises an outer coating of an intestine environment protective component.

32. The oral device of claim 1, wherein the intestine wall deployment assembly comprises: i. an expandable member that is associated with one or more solid controlled-release penetrating member, said expandable member having proximal and distal surfaces that face in generally opposite directions and configurable in a compacted configuration, an unconstrained configuration, and an expanded configuration; ii. a gas generating compartment in fluid communication with the expandable member and having at least a water or humidity permeable window and configured to expand a pliable expandable member from an unconstrained configuration to an expanded configuration; and iii. one or more solid controlled-release penetrating members, operably coupled to said pliable expandable member and extending from the proximal surface thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0158] The drawings are for illustration purposes only and should not introduce limitation.

[0159] FIG. 1 are schematic diagrams of the longitudinal sectional view of solid controlled-release penetrating members, according to one set of embodiments having a cylindrical shape according to the present invention.

[0160] FIG. 2 are additional schematic diagrams of the longitudinal sectional view of solid controlled-release penetrating member s, according to an additional set of embodiments having a cylindrical shape according one set of embodiments of the present invention.

[0161] FIG. 3 are schematic diagrams of the transverse sectional view of solid controlled-release penetrating members, according to an additional set of embodiments having a cylindrical shape according one set of embodiments of the present invention.

[0162] FIG. 4A and 4B are schematic diagrams of the oral device for delivery according one set of embodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0163] The present invention will be more fully understood from the following detailed description of embodiments thereof, taken together with the drawings.

[0164] Various embodiments of the invention can be used to deliver active agents or active pharmaceutical ingredients (“API”) that were previously only delivered by parenteral administration. In various embodiments, such therapeutic agents may include biotherapeutic agents (also described as biologics) or peptides.

[0165] An intestinal transmucosal drug delivery device is provided for deployment or placement at the intestinal lumen wall after oral administration or due to surgical placement and generally maintained for the duration of delivery of an active agent within or to the lumen wall so long as anchorage in the wall is maintained. Key to successful delivery of an active agent without early release into the GI tract where it made degrade is the penetrating member. This one component is required to encompass many conflicting goals including: maintenance of shape and structure without early release of active agent during exposure to intestinal lumen conditions (which include both the fluid in the lumen and mucosal tissue) such that penetration is effective during a deployment at the lumen wall; subsequent release of active agent once positioned in the intestine lumen wall while maintaining anchorage in tissue; subsequent biodegradation.

[0166] A transmucosal drug delivery device is provided for deployment in the lumen of the intestine, preferably at the upper small intestine (including but not limited to the duodenum or jejunum). The deployment, or placement, of the device as well as the mechanism by which to initiate penetration of the penetration member can be by any method known in the art including that disclosed in WO2020035857.

Penetration Member

[0167] A number of embodiments of penetration members suitable for use in accordance with the present invention are illustrated in FIGS. 1-3.

[0168] FIG. 1-3 are schematic diagrams of the longitudinal and transverse sectional view of solid controlled-release penetrating member s, according to one set of embodiments.

[0169] In one embodiment, a number of solid controlled-release penetrating members 2 is arranged on a pliable member to form an array 1 of penetrating members 2. The longitudinal sectional view of penetrating members 21-29 and 122, 127 and 129 according to the present invention are presented in FIGS. 1 and 2. Note that the penetrating members are drawn as having cylindrical shape, although conical, cylindrical, tubular, pyramid, cube, pyramid-shaped or a hook-shaped are also envisioned. Note as well that the layers are not drawn to scale and do not represent any relative measurements. In all penetrating members in FIGS. 1 and 2, during exposure to the intestinal lumen environment, there is less than 10% change in size of penetration member in any dimension at 10 minutes during an intestine lumen exposed period or less than 10% release of active agent in 10 minutes. In addition, the timing for release of active agent is between 15 minutes to 120 minutes.

[0170] In various embodiments, the solid controlled-release penetrating member includes an active agent-controlled release formulation located in the center and/or protected by outer layers or coatings. In the various embodiments described in the following figures, the active agent an active agent which chemically degrades, is poorly absorbed, and/or is not well tolerated in the GI tract. In one embodiment, such as solid controlled-release penetrating member 21, the active agent formulation 30 is a mixture or matrix with an excipient such as a polymer. In various other embodiments such as the solid controlled-release penetrating member 22, the active agent formulation 31 is an active agent inner core and the controlled release component is present as at least a partial controlled release coating 50 on the active agent inner core to form a controlled release coating. In various other embodiments, the solid controlled-release penetrating member 23 includes a molding material 32A comprising active agent loaded rigid particles 32B such as microparticles dispersed within the molding material, wherein the molding material is shaped or molded (e.g., micromolded) into a penetrating member. The choice of molding material and or excipient or polymer are chosen such that the active agent activity is preserved during the manufacturing process, during shelf life of the product to preserve stability and for optimized environment created during release.

[0171] In various embodiments, the solid controlled-release penetrating member shown in 24, 25 and 26 includes a tip shaped to promote penetration and such that it has intestine environment resistance to degradation such that during exposure to the intestinal lumen environment, the penetrating member undergoes less than 10% change in size of penetration member in any dimension at 10 minutes during an intestine lumen exposed period or less than 10% release of active agent at 10 minutes. Note that when the penetrating member is a microneedle, the tip may be especially prone to breakage. Thus, in some embodiments, the tip is enforced as exemplified the additional tip coating 40 located on the distal end of penetrating member 24 and as a partial external coating on the distal end of active formulation 33. In another example, penetrating member 25 includes an active agent formulation 34 (in this case active agent loaded microparticles contained or shaped as a penetrating member), having an adjacent and distal extension of the controlled release formulation to form an intestine resistant tip 41, for example as can be prepare by adding a tip formulation to a mold, centrifuging the formulating in mold and drying to form a tip layer or coating, and subsequently, adding a second formulation containing the active agent to fill the remaining volume of the mold. In this case, the tip is formulated as a distinct layer or coating which is slow dissolving at the tip 41 or 42 and prepared as part of a bilayer penetrating member. In this case, during exposure to the intestinal lumen, there is less than 10% change in size of penetration member in any dimension at 10 minutes during an intestine lumen exposed period or less than 10% release of active agent in 10 minutes. This approach may also include alternative shapes of molds including penetrating member 26, having tip 42 and active agent formulation 35. Thus, there are two methods, a tip coating approach which surrounds at least of portion of the tip of the active agent formulation to form a penetrating member or an adjacent formulation which forms the tip itself and resides adjacent to the active agent formulation. Both may be effective in achieving the structural integrity of the tip required for subsequent penetrating in the soft tissue of the intestine after exposure to the intestine lumen environment for an exposure period. Note that a coating or adjacent tip may be used on any active agent formulation—whether the active agent formulation is exemplified by any of 21, 22 or 23.

[0172] In additional embodiments such as penetrating member 29, an intestine environment protective component or controlled release coating 52 may surround the previous layers including the active agent formulation 38 and the tip 45 (which may be formulated as a coating as described in 40 or adjacent layer as described for tip 41), such that the intestine environment protective component or controlled release coating 52 ensures that degradation resulting from exposure to the intestinal lumen environment, does not affect the ability of the tip to subsequently penetrate the intestinal tissue and reach the target layer, the interstitial space where drug can be released and reach the blood or lymphatic system.

[0173] In alternative embodiments, such as penetrating member 27 and 28, an additional coating or layer of controlled release coating or intestine environment protective component 51 or 52, may be present under or adjacent to a tip formulation. Coating 51 and 52 may be a sustained release polymer or pH sensitive or cationic acrylic/methacrylic copolymer. For example, a film-forming polymeric material such an enteric acrylic/methacrylic copolymer which has a pH threshold of above 6.5 or about 7.0 or above may be used. In some embodiments, the tip formulation 43, 44 and 45 may be formulated as slow dissolving at the tip and prepared as part of a bilayer penetrating member or alternatively as a tip coating and may be a coating at least partially surrounding the intestine environment protective component which at least partially surrounds the active agent formulation 36. Alternatively, the active agent formulation 37 may have an intestine environment protective component 52 at least partially surrounding the active agent formulation and further including an adjacent formulation which forms tip 44, at the distal end of penetrating member 28. In these embodiments, the active agent formulation 36, 37 and 38 may be a mixture or matrix with an excipient such as a polymer as exemplified in 21, an active agent formulation having an active agent inner core and the controlled release component is present as at least a partial coating on the active agent inner core to form a controlled release coating, as exemplified in 22 or alternatively, as active agent loaded rigid particles such as microparticles dispersed within the molding material as exemplified in 23.

[0174] In some embodiments displayed in FIG. 2, in penetrating members 129, 127 and 122, there is a controlled release component 150, 152, and 154 as well as an additional layer or coating being an intestine environment protective component 151, 153 and 155. In this case, the active agent formulation 130, 131 and 132 may be a mixture or matrix with excipients or active agent loaded rigid particles (e.g., microparticles) 51 or 52. In one embodiment such as penetrating member 129, the tip may be a coating surrounding the active agent formulations or alternatively, as a separate component adjacent to and at a distal end of the active agent formulation to form a tip 140 and further coated by a controlled release component and an intestine environment protective component 151. In another embodiment, such as penetrating member 127, the tip may be a coating surrounding the controlled release component 152 or alternatively, as a separate component adjacent to and at a distal end of the controlled release component 152 which surrounds an active agent formulation 131 to form a tip 141. In this case, tip 141 is further surrounded by an intestine environment protective component 153. In yet another embodiment, tip 142 is a coating surrounding the intestine environment protective component 155 or alternatively, as a separate component adjacent to and at a distal end of the intestine environment protective component 155.

[0175] In some embodiments displayed in FIG. 3, a cross sectional view of penetrating member 129 is displayed in order to exemplify the different options for the tip in all of the embodiments. 161 is a cross sectional of penetrating member 21 which includes no tip reinforcement but additionally includes an additional intestine environment protective component not portrayed in penetrating member 21. The active agent formulation 130 is in the center and protected from early release due to exposure to the intestine environment and is surrounded by controlled release coating 150 and an intestine environment protective component 151 which provides a delayed but controlled release of active agent of between 5 minutes to 4 hours, or preferably between 15 minutes and 120 minutes. In another embodiment, 160A and 160B, the tip is reenforced to ensure effective penetration after exposure to the intestine environment. The tip may be a coating 140B surrounding the active agent formulation 130 and further coated by a controlled release coating and/or intestine environment protective component or alternatively, the layers or order of coatings may be switched, and the tip coating may be surrounding the controlled release coating and under the intestine environment protective component. In another embodiment, the tip 140A is a separate component adjacent to and at a distal end of the active agent formulation and coated by a controlled release formulation 150 and/or an intestine environment protective component 151.

[0176] Any of the above described embodiments, ensures that there is substantially no degradation nor change in shape or size of the penetrating member resulting from exposure to the intestinal lumen environment such that there is little to no effect on the ability of the tip to subsequently penetrate the intestinal tissue and reach the target layer, the interstitial space, where the active agent can be released from the penetrating member and reach the blood within less than the desired time and especially before release of the intestine wall deployment assembly disengages from the wall.

[0177] In some embodiments of any of the aspects presented, the one or more penetration members comprise an active agent and an enteric polymer having a threshold or sensitivity to degradation at a pH greater than 6.5 or about 7.0. In some embodiments, the enteric polymer forms at least a partial layer around a formulated active agent. In one example, a methyl acrylate methacrylic acid copolymer such as Eudragit® enteric polymer or more specifically a methyl acrylate-methyl methacrylate-methacrylic acid copolymer such as Eudragit® S or Eudragit® L30D55 can be used. It should be recognized to those in the art that during the coating process and curing temperature, the stability of the active agent should be preserved. It should be recognized to those in the art that these copolymers can be used alone or with a plasticizer. Such layers are normally applied using a liquid medium, and the nature of the plasticizer depends upon whether the medium is aqueous or non-aqueous. Plasticizers for use with aqueous medium include propylene glycol, triethyl citrate, acetyl triethyl citrate or Citroflex® or Citroflex® A2. Non-aqueous plasticizers include these, and diethyl and dibutyl phthalate and dibutyl sebacate. A preferred plasticizer is Triethyl citrate.

[0178] In some embodiments, two or more layers are provided. In one example, the one or more penetration members comprise: [0179] (i) at least a partial layer or coating comprising an enteric polymer which selectively degrades in the intestine wall (e.g., having a pH threshold greater than 6.5 or about 7.0); and at least a partial external coating of an intestine resistant component on the penetration member or a tip thereof (lipophilic coating).

[0180] In another embodiment, two or more layers are provided such that the penetration members comprise: [0181] (i) at least a partial layer or coating comprising an enteric polymer which selectively degrades in the intestine wall (e.g., having a pH threshold greater than 6.5 or about 7.0); and [0182] (ii) at least a tip coating of a lipophilic or water insoluble excipient.

[0183] In another embodiment, three layers or coatings are provided such that the penetration members comprise: [0184] (i) at least a partial layer or coating comprising an enteric polymer which selectively degrades in the intestine wall (e.g., having a pH threshold greater than 6.5 or about 7.0); and [0185] (ii) at least a tip coating of a lipophilic or water insoluble excipient; and [0186] (iii) at least a partial layer or coating comprising an enteric polymer which selectively degrades in the intestine wall (e.g., having a pH threshold greater than 6.5 or about 7.0); and at least a partial external coating of an intestine resistant component on the penetration member or a tip thereof (lipophilic coating).

Methods for Fabrication

[0187] A description is now provided for the fabrication process used to make various embodiments of the solid controlled-release penetrating member of the present invention. Methods for fabricating the solid controlled-release penetrating member including methods for fabricating a plurality of penetrating members and especially an array of penetrating members operably coupled to a pliable base are provided. The process and formulation were designed to meet challenges presented by the sensitivity to degradation of the preferred active agents, peptides, and proteins. In addition, the process and formulation support the operable connection of the penetrating members to a pliable base.

[0188] For preparing an array of penetrating members operably connected to a pliable base, a 3M mold can be used to produce a PDMS mold. Optionally, if a tip layer or coating is desired, a formulation for the tip can be poured prior to the active agent and centrifuged for 30 min for concentration in the tip. The active agent is then prepared with relevant excipients which are relevant to preserve activity and placed or poured into the mold. The mold is centrifuged to remove excess and then a pliable base formulation such as PVP solution can be applied on the mold and centrifuged and dried under room temperature conditions.

[0189] Once the array of penetrating members or microneedles are prepared, layers or coatings may be applied onto the core by any suitable means known to a person skilled in the art. For example, it can be applied using classical coating or dipping techniques to add a tip coating, control release coating or intestine environment protective component. Some selection in methods is necessary in order that the pliable base is not affected in terms of function.

[0190] In the masked dip coating or protective masking, for example, an array of penetrating members is dipping into the coating liquid and plate masking is used to avoid coating the pliable base.

[0191] Alternatively, a thin film dip coating method can be used where a thin coating liquid film is applied by rolling using a doctor blade C-ii, once again with control of the height of the coating and preventing the coating of the pliable base be keeping the height lower than the height of the penetrating member. As a result, when the microneedles are dipped into the thin liquid film, the coating liquid is unable to rise significantly and thus is unable to touch the base.

[0192] An additional option may be using spray coating or frozen spray coating. The solvent-based solution of coating is applied and when the target weight gain is reached, the formulation can be dried, and a further coating can be applied. Multiple coatings can thus be applied. Note that the speed of the member exiting the solution, coating solution viscosity, drying time and presence of surfactant between dips contribute to uniform coating.

[0193] An additional method may include powder layering where a dry formulation or polymer using rotor dry layering is applied and a subsequent liquid aqueous binder is applied.

[0194] In all stages of the process, drying temperatures remain under 40 degrees Celsius, optionally under vacuum conditions. Exact ratios of excipients may be varied as well as coating % and in vitro release measured for further optimization.

Intestine Wall Deployment Assembly

[0195] An exemplary intestine wall deployment assembly suitable for use in accordance with the present disclosure is illustrated in FIGS. 4A-B and illustrate an oral drug delivery device 200, for ingestion by a subject, in accordance with an application of the present invention. The oral device 200 comprises an externally located intestine release container 201 for example, an enteric capsule or alternatively present is a core which is directly coated with enteric coating.

[0196] The intestine release container 201, is configured to dissolve in the small intestine environment 202 contained within the small intestine walls 203 (e.g., a duodenum, jejunum, and/or ileum walls) and resist degradation in the gastric environment and until arriving in the lumen of the small intestine 210 of the subject. Typically, intestine release container 201 is pH-sensitive and may be configured to dissolve within 15 minutes (e.g., within 10 or 5 minutes). Typically, the intestine release container 201 has a length of at least 5 mm, no more than 30 mm, and/or between 5- and 30-mm dissolving. Typically, the intestine release container 201 has a diameter of between 3 and 6 mm or between 4 and 5 mm.

[0197] The oral drug delivery device 200 in FIG. 4A and FIG. 4B may comprises (a) an expandable member 208 having a proximal (intestinal-wall-contact) surface 204 and a distal (intestinal-lumen-facing) surface 205, which face in generally opposite directions, (b) one or more penetrating members (e.g., microneedles) 206 as described above and operably connected to a pliable base 209, and (c) a gas generating compartment having a water or humidity permeable window. The oral drug delivery device 200 (a) has a compressed shape when disposed within intestine release container 201, as shown in FIG. 4A, and (b) is configured to assume, after release from the intestine release container 201 (when it at least partially degrades, disintegrates or dissolves), an unconstrained shape and subsequently assume an expanded shape as shown in FIG. 4B, in which an expandable member 208 has an outer perimeter. FIG. 4B shows the drug delivery device 200 in expanded shape, adjacent to a wall of small intestine 203 in which penetrating members 206 are exposed for a period of time to the small intestine environment 210 during transition from the unconstrained shape, immediately after the intestine release container has at least partially degraded or dissolved, but prior to the fully expanded form wherein the penetrating members are forced into the wall of the small intestine 203. Even in the fully expanded form of the oral drug delivery device 200, the fully inner perimeter of the small intestine is not in contact with the expandable member 208 (i.e, it does not encompass the full inner volume of the lumen at any specific location), such that food and liquids may pass via 211. Typically, an expandable member 208 has elastomeric character and comprises a non-metal material, such as a plastic material (e.g., thermoplastic polyurethane or silicone). The drug delivery device 200 expands, such as by unfolding, and/or unrolling, in response to no longer being constrained by intestine release container, and/or in response to contact of drug delivery device 200 with fluid in small intestine environment 210. Preferably, the surface of the expandable member 204 does not stretch and forms a substantially flat surface such that it has a variance of height of about 5 mm or 4 mm or 3 mm or 2 mm.

[0198] For some applications, drug delivery device 200 is biodegradable along the gastrointestinal tract. For some applications, an expandable member 208 comprises an elastomer, such as polyethylene or silicone which does not biodegrade but rather passes safely through the gastrointestinal tract without sharp or rigid elements. For some applications, there are no sharp or rigid parts of the drug delivery device except for biodegradable penetration members (microneedles).

[0199] Typically, an expandable member 208 is configured such that expanded shape in FIG. 4B is generally flat when drug delivery device 200 is expanded after degradation of the intestine-release container 201. For some applications, a gas motor is configured to be initiated by complete or partial degradation of the intestine-release container (e.g., enteric layer) 201, which subsequently expands the unconstrained expanding member to assume an expanded configuration as an expanded expandable member which assumes a curved shape when constrained by wall 203 of small intestine, such as shown in FIG. 4B and is then positioned to advance the one or more penetrating members 206 into the wall of the small intestine. Typically, a gas-generating formulation that produces gas upon contact with liquid or humidity is disposed within a compartment.

[0200] The expanded expandable member 208 has proximal surface 204 of an expandable member which eventually contacts the intestinal wall 203 in expanded form, thereby bringing one or more penetrating members 206 into contact with intestinal wall 203. Typically, one or more penetrating members 206 penetrate intestinal wall 203, to release the active agent without inducing release in the lumen. In addition, one or more expandable members 208 may serve as a temporary anchor that holds the drug delivery device in place during active agent delivery. Once expanded, proximal surface 204 of an expandable member 208 establishes good (complete or nearly complete) contact with intestinal wall 203, as shown in FIG. 4B. The shape and dimensions of expandable member 208 may contribute to this good contact by preventing other, lower-contact-level orientations of the expandable member in the lumen of small intestine 203. Drug delivery device 200 and its associated small intestine tissue 203 typically remain axially stationary in the small intestine for a release period to enable release of an active agent while the penetrating members are within the tissue of the intestinal wall 203, even under contraction of the small intestine wall 203. Following delivery of the active agent, the drug delivery device 200 continues through the GI and is eventually passed from the body. The location of an expandable member 208 is generally unaffected by peristalsis and does not block liquids or food passing through the intestine.

[0201] Generally, the outer intestine release container may be sized and shaped to be swallowed and pass into the gastrointestinal tract with release in the small intestine specifically. Enteric formulations for capsules for example are known in the art. The capsule container is necessarily configured to resist degradation in the stomach and degrade in whole or in part during passage in the small intestine. In some variations, the material of the capsule container may be configured to degrade in an intestinal environment (e.g., in the small intestine) in which the pH is at least about 5.5. For example, the capsule container may be formed from a material and/or include a coating that is configured to degrade in an environment having a pH of at least 5.5, at least 6.0, at least 6.5, at least 7.0, at least 7.1.

[0202] The capsule container may be configured to dissolve in its entirety, and/or the capsule container may break apart into smaller pieces (e.g., due to dissolvable joints or seams) to facilitate release of the delivery device into the small intestine for deployment.

[0203] In general, devices described herein can comprise an expanding member coupled to the penetrating members for advancing the penetrating member into the wall of the small intestine. In some embodiments, the expandable member has proximal and distal surfaces that face in generally opposite directions. In some embodiments, the one or more penetrating members (e.g., microneedle array) extend from the proximal surface thereof.

[0204] The expanding and pliable member can be configurable in a compacted configuration, an unconstrained configuration, and an expanded configuration. In some embodiments, the expanding and pliable member is configured to be initiated by exposure to the intestinal lumen environment. In some embodiments of the present invention, the expanding and pliable member can be configurable in a compacted configuration where it is retained within the capsule in a folded state.

[0205] For examples, the expanding and pliable member can be folded to define one or more creases, which define respective inner and outer crease sides, wherein at least one of the tissues penetrating members is coupled to the patch along the inner crease sides.

[0206] In some embodiments, the pliable member can inscribe a circle having a diameter of between 2 and 10 cm when the patch is unconstrained. In some embodiments, the pliable member can inscribe a circle having a diameter of less than 8 cm, less than 6 cm, less than 5 cm minutes or about 4 cm. Combinations of the above-referenced ranges are also possible (e.g., between 2 and 5 cm).

[0207] In some embodiments, the expanded pliable member, when deployed in the lumen of the intestine without intestinal peristalsis, applies no force to facing intestinal walls along axial extents thereof. Unlike a balloon based expanded member which expands such that there is contact with most of the surfaces of the intestine wall, the expanded pliable member in this case is in surface contact in only one area of the circumference of the intestine lumen.

[0208] In some embodiments, the upper surface of the expandable member contacts an intestinal wall, thereby bringing the penetration members into contact with the intestinal wall. In some embodiments at least 50% or at least 75% or at least 80% or at least 90% of the penetration members are coupled to the proximal surface of the patch. In another embodiment, at least 50% or at least 75% or at least 80% or at least 90% of the area of the upper surface of the expandable member is in direct contact with the intestine tissue.

[0209] In some embodiments, the expandable member gradually moves from an unconstrained configuration to an expanded configuration due to gas pressure. The gas pressure resulting from the gas generating reaction is sufficient to advance the penetrating member into the wall of the small intestine.

[0210] Gas motor can be coupled to the release element and can be configured to be initiated by release of the release element which subsequently causes expansion of the expanding member for advancing the penetrating member into the wall of the small intestine. The gas generating compartment or compartments can be defined by i. a substantially water-permeable and substantially gas-impermeable, polymer layer shaped to define at least one window therethrough, and a liquid and humidity permeable and substantially gas-impermeable wetting layer, which entirely covers the at least one window and is sealed to the polymer layer around the at least one window; and ii. a gas-generating formulation that produces gas upon contact with liquid or humidity, the gas-generating formulation disposed within one or more compartments. The gas generating formulation can include sodium bicarbonate and is typically disposed in a vicinity of the at least one window which permeable to humidity or water.

[0211] In an embodiment, techniques and apparatus described in one or more of the following applications are combined with techniques and apparatus described herein: [0212] U.S. Pat. No. 8,287,902 to Gross; and/or [0213] U.S. Pat. No. 9,492,396 to Gross.

[0214] It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and sub-combinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.