Structure of intestinal tissue penetrating members

Abstract

An intestinal penetrating member (210) for drug delivery comprising: A body portion (212) having a central longitudinal axis extending between a proximal end and a distal end, a tissue penetrating end (214) extending distally from the body portion and comprising a first and second bevel surface (222) which converge at a sharp edge (220); and a solid formulation of therapeutic forming at least a portion of the intestinal penetrating member and adapted to penetrate an intestinal wall to release a therapeutic.

Description

[0001] STRUCTURE OF INTESTINAL TISSUE PENETRATING MEMBERS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 522,787 filed on June 23, 2023, entitled “Structure of intestinal tissue penetrating members, systems and related methods”, as well as US Patent Application 18 / 454,947 filed on August 24, 2023 entitled: “Drug delivery needle with enhanced penetration capability”, all of which are fully incorporated herein by reference in their entirety.

[0004] FIELD OF THE INVENTION

[0005] Embodiments described herein generally relate to the structure of intestinal tissue penetrating members, systems, and related methods and more specifically to intestinal tissue penetrating members with enhanced penetration capability as well as related systems and methods.

[0006] BACKGROUND OF THE INVENTION

[0007] Drug delivery into mucosal tissue presents many challenges. In many places in the body, mucosal tissue includes three basic layers: the epithelium, lamina propria, and the deeper sub-mucosal tissue. The lamina propria is rich in macrophages and lymphoid cells, and forms part of the barrier that protects internal tissues from external pathogenic microorganisms.

[0008] Drug delivery to the tissue of the lumen wall of the intestine, has gained significant interest in recent years due to its potential advantages in targeting specific diseases and improving therapeutic outcomes. While research in this area is ongoing, penetration of intestinal tissue and delivery of drug promises to enhance targeted delivery due to its proximity to the mucosal immune system, lymphatic vessels, and blood capillaries. Delivery of drugs to this layer allows for direct interaction with immune cells and efficient absorption into the systemic circulation, enhancing therapeutic efficacy and minimizing systemic side effects. Intestinal tissue drug delivery holds particular potential for localized therapy within the intestine. It can be utilized for the treatment of diseases such as inflammatory bowel disease (IBD), colorectal cancer, gastrointestinal infections, and other intestinal disorders. Localized delivery minimizes systemic exposure and reduces side effects associated with conventional systemic drug administration.

[0009] Submucosa drug delivery promises to provide enhanced therapeutic efficacy due to a rich blood supply and a network of lymphatic vessels, which facilitate the absorption and transportation of drugs to systemic circulation.

[0010] For therapeutics which are more typically delivered in an injectable, especially biologies, improved efficacy, patient compliance, and convenience may also be an advantage of orally administered intestinal submucosa drug delivery.

[0011] Research in the area of drug delivery to the intestinal tissue layers, such as mucosa and muscularis, is still evolving and future advancements in this field may open up new possibilities for the treatment of various disorders. However, the ability for a drug to pass the epithelium and reach the lamina propria and the sub-mucosal tissue is a challenge. For example, the mucosa in the gastrointestinal (GI) tract is covered with a continuously renewed viscous fluid which prevents needle penetration at many different angles of the needle tip with respect to the tissue. Another problem is the resilience or elasticity of the mucosa during the needle penetration process as well as the lack of counterforce to the needle penetration. Accordingly, it would be desirable to provide penetrating members, systems and methods which improve the effectiveness of penetration and delivery through the intestine wall.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention seeks to provide a drug delivery needle with enhanced penetration capability, as described in detail below. Intestinal tissue penetrating structures, systems, and related methods are generally provided. More specifically, an oral drug delivery device designed to penetrate small intestinal tissue is provided.

[0014] Forked or Franssen hollow needles are known for use as biopsy needles. However, the structure of biopsy needles is such that the biopsy needle cuts out a portion of the tissue, detaches the cut portion and removes it for testing. In the process, there is an additional step of completing the coring process such as by turning the needle. In contrast, the structure of the intestinal wall penetrating member of the invention does not core or remove any tissue. Instead, the structural design of the penetrating member is optimized to pierce the tissue with a minimum application of force and deliver a therapeutic into the intestinal wall, and more specifically, to a region of a submucosal or muscularis mucosae. The sharp edge of the penetrating member cuts the tissue in one movement of penetration, that is, makes an incision in the tissue, and pushes the drug into the incision instead of into a stretched hole. In this way, the resistance to penetration or elasticity of the tissue is overcome. In addition, the penetrating member can remain in the tissue for a period of time, such as an hour, to allow delivery of the drug into the tissue.

[0015] In one aspect, there is provided, an intestinal penetrating member for drug delivery comprising: an body portion having a central longitudinal axis extending between a proximal end and a distal end, a tissue penetrating end extending distally from the body portion and comprising a first and second bevel surface which converge at a sharp edge; and a solid formulation of therapeutic forming at least a portion of the intestinal penetrating member and adapted to penetrate an intestinal wall to release a therapeutic. In some embodiments of the present invention, a sharp edge extends between or connects two sharp distal tips which contributes to maintaining the target cutting area taut. This provides a counter force that allows the edge to cut the tissue.

[0016] In another embodiment of the present invention, there is provided an intestinal penetrating member that includes a body portion from which extends a penetrating end that includes at least two sharp distal tips, the sharp distal tips being separated from each other by an arcuate or curved trough that includes a cutting edge at least at a middle portion of the arcuate trough, wherein at least the two sharp tips are made of a drug or include a drug therein or are coated with a drug.

[0017] In yet another embodiment of the present invention, a system is provided wherein an array of penetrating members described in the various embodiments, are mounted on a substrate (e.g., extend therefrom), said substrate operably connected to an intestinal wall delivery device such as an auto- inflatable device or patch. In this way, the system is designed to target an intestinal wall, penetrate the various superficial layers and deliver therapeutics. In this embodiment, upon application of pressure per square inch of the inflatable (i.e., 1 to 5 psi) wherein a substrate forms at least a portion of an external wall of the inflatable from which the body portion of the penetrating members are connected, a therapeutic may be released at the appropriate layer. Additionally, or alternatively, one or more penetrating members can be constructed and arranged such that the required pressure applied is reduced compared with that observed for an otherwise identical devices with a different length or shape of penetrating members.

[0018] BRIEF DESCRIPTION OF THE FIGURES

[0019] The figures provided are for illustration purposes only and should be not interpreted as a limiting. The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which:

[0020] FIG. 1A, IB and 1C is a digital microscopic photograph and illustration of a sectional view depicting the various parts and layers of the small intestine.

[0021] FIG. 2A is a simplified perspective illustration of a drug delivery needle, in accordance with a non-limiting embodiment of the invention.

[0022] FIGs. 2B and 2C are simplified illustrations of the drug delivery needle from two other views.

[0023] FIG. 3 is a simplified perspective illustration of an array of the drug delivery needles, in accordance with a non-limiting embodiment of the invention.

[0024] FIG. 4A is a side-view illustration of the array of the drug delivery needles.

[0025] FIG. 4B is a sectional view of the array of the drug delivery needles, taken along lines 3B-3B in FIG. 3.

[0026] FIG. 4C is a sectional view of the array of the drug delivery needles, taken along lines 3C-3C in FIG. 3.

[0027] DETAILED DESCRIPTION

[0028] In order for the present disclosure to be more readily understood, certain terms are first defined and illustrated below. Additional definitions for the following terms and other terms are set forth throughout the specification. An illustration of the cross section of the small intestine is depicted in in FIG. 1A, B and C. Small intestine 100 has a lumen 102 in the center which runs the length of the small intestine and is surrounded by a small intestine lumen wall 101. Note that in an embodiment of the present invention, the penetrating members are on a device which travels through the length of the small intestine lumen and eventually affixes itself to the small intestine lumen wall 101. A histological transverse sectional view of the small intestine is presented in FIG. IB and FIG. 1C. The various histological layers are observed on a duodenal sample after hematoxylin and eosin stain. The mucosa 103 is the innermost layer of the small intestine and that closest to the lumen which first initially contacts the oral drug delivery device. The mucosa includes three sublayers: the epithelium 110 being a single layer of cells that line the lumen and provide a first barrier; the lamina propria 120 containing structural support as well as housing connective tissue, blood vessels and immune cells; and the muscularis mucosae 104 situated beneath the lamina propria and which facilitates folding and expansion. The submucosa 105 is located beneath the mucosa and comprised of connective tissue, blood vessels, lymphatic vessels and nerve fibers.

[0029] The present invention seeks to provide a penetrating member with enhanced penetration capability, oral drug delivery devices including the penetrating member and methods of use thereof. The penetrating member is adapted to penetrate specific layers of the small intestine wall from within the intestinal lumen, and preferably adapted to penetrate barriers in the small intestine, namely the submucosa or muscularis mucosae tissue of the small intestine and uses thereof.

[0030] As used herein, “subject” is meant to include any mammal who would benefit from treatment including but not limited to human, pig or cow. Note that most of the specific numbers provided throughout are relevant for application in human, especially in regard of dimensions.

[0031] As used throughout the description and claims, “penetrating” is meant to include any disruption or permeation of gastrointestinal tissue for example, in at least one region of a submucosa or muscularis mucosae barrier in the small intestine after being deployed intra-luminally in a subject. The term penetrating member typically includes a penetrating end having a degree of sharpness. Reference is now made to Figs. 2A-2C, which illustrate an intestinal penetrating member 210, referred to herein as “penetrating member” or “tissue penetrating member” for drug delivery to the intestinal lumen wall, in accordance with a non-limiting embodiment of the invention. Intestinal penetrating member 210, which may be referred to as a drug delivery needle, may include a body portion 212 and a tissue penetrating end 214 (herein “penetrating end”). The tissue penetrating end 214 typically has a reduced transversal cross sectional, for example a bevel-shape or taper point-shape, compared with the body portion. Body portion 212 has an elongate shape similar to a shaft and spanning along a central longitudinal axis which extends between a proximal end and a distal end. An outer perimeter o f body portion 212 may have at least one rounded comer and at least one non-rounded comer. Body portion 212 may have a square or circular cross section. Body portion 212 may have a conic or pyramidal shape.

[0032] In any of the embodiments described herein, intestinal penetrating member 210 is adapted to penetrate a layer of intestinal tissue wall to release a therapeutic, typically by disintegration of a solid formulation of therapeutic which makes up at least a portion of the penetrating members. The therapeutic may be formulated as a solid formulation of therapeutic, which forms at least a portion of the intestinal penetrating member 210. In some embodiments, the solid formulation of therapeutic forms a majority of the intestinal penetrating member. The term solid formulation is meant to suggest that it contributes to the shape of the penetrating member. Intestinal penetrating member 210 can be fabricated from various pharmaceutical excipients (e.g., sugar, polysaccharides, polymers), as will be described herein, as is described in PCT Patent Application WO 2023 / 031887 or as is known in the art. The excipients and polymers may confer desired structural, chemical and material properties to the penetrating member. In some cases, after penetrating the mucosa, the drug and the penetrating member or tip are absorbed by the intestinal tissue. Excipients and polymers may be selected to provide structural integrity (e.g., rigidity or prevention of swelling) prior to, during the penetration process or upon insertion into the intestinal wall. In some cases, excipients and polymers may be selected to provide structural integrity prior to and during the penetration process although swelling may occur upon insertion into the intestinal wall. The excipients and polymers may be selected to provide a degree of porosity of the formulation for control of drug release. The excipients and polymers may be selected to provide biodegradability to enable at least partial or complete disintegration or detachability of the penetrating member from a substrate. The plurality of penetrating members may include a dissolvable coating, or a moveable covering configured to protect the plurality of penetrating members until the portion of a surface of the drug delivery patch is actuated to the second position or the penetrating members contacts a depth of the small intestine tissue. In another example, a portion of the proximal end of the body portion of the penetrating member may degrade to release the remainder of the penetrating member from the substrate where it can degrade more slowly than the portion of the proximal end of the body portion. The formulation may additionally include further excipients such as binders, fillers, process enhancers such as lubricants and glidants. In some embodiments, the excipients do not include a disintegrant.

[0033] Various polymers and excipients may be selected for suitability of disintegration within the intestinal tissue in terms of safety, biocompatibility and efficacy. Polymers may be natural polymers or unnatural (e.g. synthetic) polymers. For example, excipients which contribute to bioavailability may be used (such as sodium caprate) or permeation enhancers such as soyabean lecithin, arginine, lysine, phenyl alanine, sodium laurate or sodium caprylate. Other excipients may include a lubricant, binder, or filler. The excipients may be a homogeneous mixture (such as with a polymer matrix) or alternatively, a coating or at least a partial layer having an enteric polymer for example, HPMCAC pH7.5. In some embodiments, the solid formulation of therapeutic described herein includes an enteric polymer (disintegrating at pH 7.5) which makes up a layer or coating on a at least a portion of penetrating member 210. In various embodiments, the tip is at least partially coated, or the tip is formulated as a separate but adjacent and distal extension of the active agent formulation. For example, a layer may include an enteric polymer which distinguished from a gastric-resistant housing which may also include an enteric polymer. For the sake of clarity, this coating would be distinguished from the gastric-resistant housing. Rather, it would provide resistance in the upper intestine upon release from the gastric-resistant housing to provide a crucial barrier against degradation and enable efficient drug delivery to the desired site of action within the intestine tissue or more specifically within the submucosa or muscularis mucosae layer of the small intestine tissue. In some embodiments, the solid formulation of therapeutic described herein includes a controlled release coating having a pore-forming agent. For example, the controlled release coating may include a low to medium-viscosity, ethyl cellulose, a pore-forming agent., and a plasticizer. Examples of pore-forming agent are known in the art and may be selected, for example, from the group consisting of polyethylene glycol, poloxamer, povidone, a saccharide, hydroxypropyl cellulose and hydroxypropyl methylcellulose. The low-viscosity ethyl cellulose and a pore-forming agent may be present in a ratio of the pore-forming agent to low-viscosity ethyl cellulose of about 9: 1 to about 4 :5. The ratio of pore-forming agent to formulation or low-medium viscosity ethyl cellulose e.g., ethyl cellulose may be about 9 : 1 to 1 : 1 or 7:4 to 4:5. Relevant ratios include 9 : 1, 8 : 2, 6 : 4, 5 : 5 and 4:5. In some cases, control release coating having a low-viscosity ethyl cellulose may further comprise a plasticizer such as TEC, DBS, PEG or triethyl citrate.

[0034] Penetrating member 210 may be a penetrating member which is a solid, controlled-release penetrating member that includes active agent loaded in microparticles contained or shaped as a microneedle. In some embodiments, the penetrating member comprises a first molding material. In some embodiments, the penetrating member comprises a mixture of a) a polymer first molding material and b) a second molding material comprising particles (e.g., rigid particles or microparticles) dispersed therein, wherein the first molding material is micro molded into the plurality of microneedles. In some embodiments, the penetrating member comprises an enteric coating or layer and a molding material comprising rigid particles dispersed therein, wherein the enteric coating is placed in the mold and a molding material with rigid particles are micro molded into the plurality of microneedles.

[0035] Further formulations may be substantially as described in PCT / IB2022 / 058299 filed on September 3, 2022, which is incorporated by reference as if fully set forth herein. In some embodiments, polymers include polymers which have been approved for use in humans by the U.S. Food and Drug Administration (FDA) for use in penetration of intestinal tissue.

[0036] In addition, methods known in the art for preparation of these solid formulations can be employed.

[0037] In some embodiments, intestinal penetrating member 210 includes a tip and / or edge which is at least partially coated by a coating comprising a water insoluble, hydrophobic, or a non-degradable polymer.

[0038] Tissue penetrating member 210 can be fabricated using one or more techniques known in the art. For example, a therapeutic formulation may be formed into the shape of the tissue penetrating member 210 using molding, compaction or other like method. Alternatively, a therapeutic may be added to a polymer or excipient formulation and formed into the penetrating member 210 using molding or other forming method known in the polymer arts. Relevant techniques required conditions and temperatures which do not produce any substantial degradation. The therapeutic may be an antibody, peptide, protein, nucleic acid or small molecule. The solid formulation can include multiple layers, for example a layer which withstands premature degradation (e.g., before an intended degradation at the target delivery location).

[0039] In some embodiments, body portion 212 has a maximum transverse dimension, for example a diameter or width, depending on the shape of the body portion, of greater than 0.1 mm, 0.25 mm, 0.5 mm, 1 mm or 2 mm. Correspondingly, a minimum transverse dimension of a penetrating member may be less than 3 mm, 2 mm, 1 mm, 0.5 mm, or any other appropriate dimension. A range involving any of the values mentioned are also possible.

[0040] A tissue penetrating end 214 extends distally from the distal end of body portion 212. The term "penetrating end" or “penetration end” refers to an object adapted to pierce a tissue and especially an intestinal tissue layer from within the lumen. In some embodiments, tissue penetrating end 214 is integral and unitary with body portion 212, such that tissue penetrating end 214 is formed as an integral and unitary portion of body portion 212. In still other embodiments, tissue penetrating end 214 and body portion 212 are formed separately and then joined together.

[0041] Tissue penetrating end 214 includes a first and second bevel 222 or surface thereof, which converge at a sharp edge 220, also referred to herein as a cutting edge. The cutting edge has sufficient sharpness to pierce at least one layer of the lumen wall. The bevel 222 surface refers to a slanted, angled or sloped edge having an acute angle (less than 90 degrees), relative to the adjoining body portion. The bevel 222 surface has a generally angled surface relative to body portion 212, although the face may have a degree of concavity.

[0042] Each of the bevel 222 surfaces extends between the body portion and the sharp edge and may be planar or concave. Each bevel 222 surface may form a bevel angle of less than 90 degrees relative to an axial plane extending from the sharp edge 220. In the case of a concave bevel surface, the bevel surface may be calculated based on a portion of a surface which forms a plane. The surface area of the first and second bevel surfaces may be the same. The surface area of the first and second bevel surfaces may be different. Although only a first and second bevel surface are portrayed in the figures provided, additional bevel surfaces may be present in the tissue penetrating end. In some embodiments, only a first and second bevel surface is present.

[0043] In some embodiments, one or both bevel 222 surfaces have a degree of concavity. For example, the first and second bevel surfaces may converge at the sharp edge, said bevel surfaces being concave, and having an arcuate depression with respect to the arcuate trough of the sharp edge and the heel of the body portion.

[0044] The sharp edge 220 has sufficient sharpness to pierce at least one or more layers of the intestinal wall from within the lumen. The location of the sharp edge is typically distal relative to body portion 212, although a tip or other part may extend beyond relative to the central longitudinal axis. The sharp edge is a geometric edge which is typically a line segment where two surfaces, in this case bevel surfaces, intersect. Sharp edge 220 may include a linear portion, functioning like a blade, which is designed for slicing or cutting. The sharp edge may have a thin but longitudinal surface area allowing for concentrated pressure, and thereby increasing its cutting efficiency for penetrating intestinal tract tissue. The sharp edge may have an axis which is transverse to the central longitudinal axis, meaning that the axis and the central longitudinal axis cross each other (i.e., they are nonparallel such that they intersect each other.) In some examples, an incident angle between the surface axis of the sharp edge and the central longitudinal axis at a location of intersection may be between 45 and 135 degrees.

[0045] The sharp edge may have an axis which is perpendicular to the central longitudinal axis. The sharp edge may have a concavity in a direction towards the central longitudinal axis. In some embodiments, a length of the sharp edge is equal to or more than a second longest dimension (e.g., diameter / width) of the body portion.

[0046] In some embodiments, penetrating member 210 may have an axial length for providing the relevant depth for drug delivery, as measured from the proximal end of the body portion to the distal end of the sharp edge or tip. In some embodiments, the axial length is at least 1 ,4mm or at least 1 ,6mm or at least 1.8mm. For some embodiments, the penetrating members may have an axial length of less than 3.0mm, less than 2.8mm, less than 2.0mm, or less than 1.7mm. For some embodiments, penetrating members may an axial length of between 1.4 and 3.0 mm. For some embodiments, penetrating members may have an axial length of between 1.4 and 2.8 mm. For some embodiments, the penetrating members may have an axial length of between 1.4 and 2.4 mm. For some embodiments, the penetrating members may have an axial length of between 1.4 and 2.2 mm. For some embodiments, the penetrating members may have an axial length of between 1.4 and 2.0 mm. For some embodiments, the penetrating members may have an axial length of between 1.4 and 1.8 mm. For some embodiments, the penetrating members may have an axial length of between 1.4 and 1.6 mm. A range involving any of the values mentioned are also possible.

[0047] The present inventors have found that a device for penetrating the relevant layers can be achieved with penetrating members extending from a surface of an inflatable device or patch, having a length as described. In some embodiments, the penetrating members extend from a surface of an inflatable patch. In some embodiments, the penetrating members extend from a surface of an inflatable patch have a length of between 1.4 to 2.8 or between 1.4 and 1.7 mm. The inflatable patch may have a pound per square inch measure of between 1 and 5psi or between 2 and 4 psi. The inventors have found that these ranges are optimal for oral administration and subsequent delivery of therapeutics via the intestinal wall.

[0048] In some embodiments, each individual intestinal penetrating member 210 comprises a portion of a therapeutically effective dose of a therapeutic agent. In some embodiments, intestinal penetrating member 210 includes a solid formulation of therapeutic which forms at least a portion of the intestinal penetrating member. Therapeutics may include an antibody (e.g., monoclonal antibody), peptide, protein, nucleic acid, small molecule or other molecules prone to enzymatic or chemical degradation when released into the lumen of the gastrointestinal tract.

[0049] The solid formulation is adapted to penetrate an intestinal tissue wall to release a therapeutic. In this case, there is no hollow portion of the penetrating member for delivery or removal purposes. In various embodiments, the solid formulation of therapeutic which forms a portion of the intestinal penetrating member 210 is non-homogeneous in with regard to a therapeutic density on a weight for weight basis within the formulation. For example, the proximal end of body portion and / or the distal end of the sharp edge and / or tip may have a lower density of therapeutic in formulation compared to the more central portion of intestinal penetrating member 210. In another example, if one were to divide intestinal penetrating member 210 into a proximal end portion making up 25% of a volume of the penetrating member and a distal end portion defined as 75% of a volume of the penetrating member, the proximal end portion may have a lower density of therapeutic in formulation on a w / w basis compared with the distal end portion.

[0050] In some embodiments, intestinal penetrating member 210 includes a body portion 212 from which extends a penetrating end 214, that includes at least two sharp distal tips 216. A tip, in general, refers to an end and / or pointed region that is sufficiently sharp to initiate penetration and located at a distal extremity. It is typically slender or tapering. Body portion 212 may taper towards the sharp distal tips.

[0051] Sharp distal tips 216 may be formulated from excipients which are disintegrable within the intestinal wall tissue environment. In this case, a sharp or cutting edge 220 may connect between two sharp tips 216. In this manner, the sharp edge 220 may interface or connect with the two sharp tips 216 and the two bevel 222 surfaces. Body portion 212 may have a triangular, square or circular cross section.

[0052] Each tip ends in a point and extend longitudinally beyond the sharp edge. The sharp distal tips 216 are separated from each other by an arcuate trough 2 18 that includes a sharp o r cutting edge 220 at least at a middle portion of the arcuate trough 218 (the area between the two leader lines of numeral 220 in Fig. 2A). The sharp edge 220 may extend completely along the entire arcuate length of arcuate trough 218, that is, from one sharp distal tip 216 to the next sharp distal tip 216. The arcuate trough 218 may have the shape of a parabola or other conical section or other arcuate shapes.

[0053] The body portion 212 of penetrating member 210 may be formed with a bevel 222 that extends from arcuate trough 218 to a heel 224. The bevel 222 may be arcuate, such as being concave, that is, having an arcuate depression with respect to arcuate trough 218 and heel 224.

[0054] The outer perimeter of body portion 212 of penetrating member 210 may be round or may have edges or a non-rounded comer. For example, in an illustrated embodiment, body portion 212 has one or more rounded corners 226, and one or more non-rounded comers. The body portion 212 may have one rounded comer 226, and one non-rounded comer, and an edge 230 of the non-rounded comer may extend up to the sharp distal tip 216.

[0055] In an embodiment of the present invention, Fig. 3 illustrates an array of the intestinal penetrating members 310 mounted on a substrate 332, which may or may not be pliable, in accordance with an embodiment of the invention. For example, the array may include at least 15, at least 20 or at least 30 intestinal penetrating members. It is to be understood that a reference to an individual intestinal penetrating member may apply to each of the plurality of intestinal penetrating members unless otherwise specified.

[0056] Each of the intestinal penetrating members 310 are mounted or operatively connected at the proximal end of the body portion and extend from the substrate. Being mounted on the substrate refers to any means for “operatively connecting” the penetrating member to the substrate and encompasses both direct structural connection and indirect function connection so long as the connecting pair is configured to work together to accomplish a common function during operation. In one or more embodiments, the intestinal penetrating members 310 are affixed to substrate 332 using a pharmaceutically acceptable excipient which form a disintegrating layer such that that penetrating members are separatable from the patch. In some embodiments, the plurality of penetrating members are configured to separate from the portion of the substrate at a specific time point.

[0057] In a further example, the substrate forms at least a portion of a surface of an intestine wall delivery device, as illustrated in FIG. 3 and 4A. In general, oral administration has the potential for the widest patient acceptance and relates to any device which includes a therapeutic and is ingested or swallowed. Intestine wall delivery device are known in the art and include, for example, a drug delivery patch which is auto inflatable and / or auto deflatable as disclosed in International Application No. PCT / 1B2023 / 058358 filed on August 22, 2023 and entitled “Auto-inflatable patch assembly for delivery of therapeutic agents to an intestinal wall” or International Application No. PCT / 1L2019 / 050906 filed on August 13, 2019 and entitled “Expandable drug delivery pill”, both of which is incorporated by reference as if fully set forth herein. For example, an intestine wall delivery device may comprise: a gastric-resistant coating; and a medication-delivery device, which (a) is pliable, (b) is disposed within the gastric-resistant coating, having a compressed shape enabled by the pliability, and includes one or more expansible chambers configured such that expansion of the one or more expansible chambers to a pressure, applies a gradually increasing force to a substrate 332 affixed to an array of intestinal penetrating members 310.

[0058] In embodiments of the present invention, there is provided orally administered devices which are designed to penetrate the intestine tissue from within the gastrointestinal tract lumen. For example, the substrate may be contained in enteric housing and have a compressed and expanded conformation.

[0059] In some embodiments, the auto-inflatable patch is configured to unfold and auto-inflate responsive to the intestinal environment and further configured to subsequently drive penetration of the distal end tip into the intestine tissue. The auto- inflatable patch is configured to inflate from a collapsed state to an inflated state. As used herein, the inflated state is a fully expanded configuration. In a fully expanded state, the substrate may form an arch shape surface. The arch shape may have a radius which is substantially similar to the radius of the small intestine.

[0060] In the inflated state, a portion of a surface of the drug delivery patch unfolds or unrolls and serves as a pliable or compliant base for the plurality of penetrating members. The plurality of penetrating members are positioned parallel to one and other. As the patch inflates, it is disposed adjacent to the small intestine lumen inner surface. In some embodiments, the penetrating members are actuated gradually towards the intestinal wall by a gradual gas generating reaction supplying pressure to the inner volume of the patch. This positioning combined with the continued inflation and penetrating members length, ensures that the patch is configured to penetrate a region of the mucosal barrier adjacent to the patch major surface after release from the housing. In some embodiments, the penetrating members are actuated gradually towards the intestinal wall by a gradual gas generating reaction supplying pressure to the inner volume of the patch. In some embodiments, two elongated surfaces are present, a portion of a surface of the drug delivery patch disposed between opposed ends as well as a minor patch surface also disposed between opposed ends however configured to face the center of the small intestine lumen (rather than the lumen wall) in the inflated state. Although it is referred to as a minor patch surface, it may be identical in size. In contradistinction from the portion of a surface of the drug delivery patch, the minor patch surface does not include penetrating members on its surface.

[0061] The drug delivery patch may be adapted to contact less than 70% of a perimeter of an intestinal lumen wall. The drug delivery patch in at least a partially inflated state, may form an arch shaped substrate having the penetrating members mounted thereon. The drug delivery patch may be adapted to inflate to a pressure of more than 1 psi, or a range of between 1 to 5 psi, or 3 to 4 psi, as measured at 37°C. In various embodiments, the oral drug delivery device includes a drug delivery patch configured to actuate penetration of the plurality of penetrating members into a submucosa or muscularis mucosae barrier at multiple locations. For example, gas generating reactants contained within the drug delivery patch may drive expansion of the patch such that the substrate converts from a pliable to a rigid state. The rigid state, in the context of the cylinder (in vitro) or intestine wall (in vivo) drives the penetration of penetrating members into the wall. In various embodiments, the oral drug delivery device described herein includes a drug delivery patch which includes two gas generating reactants disposed within a common chamber or formulation. As used herein, configured to transition between a collapsed to an inflated sate is driven by a gas generating reaction from within the patch which supplies an inflating force on the patch walls from within. In some embodiments, the gas generating reactants are contained in a chamber outside but are in communication with the drug delivery patch.

[0062] Although specifically designed for the intestine, the present invention may be applicable in similar lumens within the gastrointestinal tract or other systems in which case the gastric-resistant housing may not be necessary. In some embodiments, the devices are designed to penetrate small intestine tissue. For example, the devices may be designed to penetrate the submucosa or muscularis mucosae layer of the small intestine tissue such that a therapeutic may enter into the mucosal immune system, lymphatic vessels, and / or blood capillaries therein.

[0063] As seen in Fig. 4A, the intestinal penetrating member 410, referred to herein as a penetrating member, may have a length L, which may be, without limitation, in the range of 0.6 to 3.0 mm or in the range of 1.2 to 3.0 mm, as measured from the base to the distal most end of the penetrating member. The substrate 432 may have a thickness T, which may be, without limitation, in the range of 0.05 to 1.5 mm. Penetrating member 410 may taper towards the sharp distal tip at an angle Al, which may be, without limitation, in the range of 2 to 6°. The sharp distal tips 416 may have equal heights or unequal heights.

[0064] As seen in Fig. 4B, the arcuate trough 418 may subtend an angle A2, which may be, without limitation, in the range of 30 to 70°.

[0065] As seen in Fig. 4C, the sharp distal tip 416 may subtend an angle A3, which may be, without limitation, in the range of 10 to 30°. The bevel 422 may subtend an angle A4, which may be, without limitation, in the range of 40 to 80°.

[0066] In some embodiments, the plurality of penetrating members additionally include a hollow lumen center ending in an open distal end tip. For example, the therapeutic may be contained within the drug delivery patch in the form of a reservoir for delivery through a hollow portion of the penetrating members. The population of shapes may be homogenous of heterogenous meaning that there may be more than one shape within the general population of penetrating members.

[0067] In some embodiments, penetrating members may be formulated using shape memory polymers or shape memory alloys which may be suitable to accommodate fixation to the portion of a surface of the drug delivery patch during the compressed state when the patch is folded or rolled while providing sharpness for penetration after inflation after exposure to a change in pH increase by reverting back to a shape memory annealed form. Suitable shape memory polymers or shape memory alloys, include thermoplastics, thermosets, interpenetrating or semi-interpenetrating networks, or mixtures thereof. The polymers can be linear or branched thermoplastic elastomers with dendritic structural elements or side chains. Suitable polymer components to form a shape memory polymer include, but are not limited to, poly(vinyl alcohols), polyamides, polyester amides, polyanhydrides, polycarbonates, polyacrylates, polyalkylene terephthalates, polyalkylenes, polyalkylene glycols, polyacrylamides, polyalkylene oxides, polyortho esters, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyesters, polylactides, polyglycolides, polysiloxanes, polyurethanes, polyethers, polyether amides, polyether esters, and copolymers thereof.

[0068] In some embodiments, the degradation time of penetrating member or a portion of the penetrating members as described herein can be greater than 1 minute, 5 minutes, 30 minutes, 1 hour, 2 hours. In embodiments, the degradation time may be about or less than 5 hours, 2 hours, 1 hour, 30 minutes or even 5 minutes. The degradation time may be in a range of 1 to 120. Minutes or 30 to 90 minutes. In some embodiments, the degradation time may be in a range of any two values above. Note that the above times refer to that time from the penetration of the penetrating members into the small intestinal tissue.

[0069] In some applications, plurality of penetrating members are configured to release therapeutic in delay of more than lOmin after release from the housing. In some applications, plurality of penetrating members are configured to release a therapeutic in an extended release over about one to three hours. In some embodiments, the plurality of penetrating members are configured for exposure to the lumen environment upon at least partial biodegradation of the gastric-resistant housing.

[0070] The population of shapes may be homogenous of heterogenous meaning that there may be more than one shape within the general population of penetrating members.

[0071] The methods and devices described herein may be used to deliver various bio actives or therapeutics. In some variations, drugs that would otherwise be injected due to sensitivity to the gastrointestinal tract environment, are delivered by formulation with or delivered via penetrating members such as those described herein.

[0072] As used herein, “drug”, “bioactive”, “active agent”, “therapeutic agent”, “therapeutic”, “therapeutic agent” or “medicine” may be used interchangeably and includes any molecules which elicits a desired biological and / or pharmacological effect. Bio actives include but are not to be limited to small molecules, biologies (antibody, protein, and peptide), diagnostics, or active pharmaceutical ingredients used to treat or diagnose a patient. They can refer to any agent that, when administered, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. Generally, a therapeutic agent may refer to more than one therapeutic agent. Examples of therapeutic agents that may be suitable for use include but are not limited to chemotherapeutic agent, interferon, an antibody, an antibiotic, growth hormone, parathyroid hormone, a glucose regulating agent, an insulin compound, an incretin hormone, a GLP- 1 compound or exenatide, antiviral, protease inhibitor or an anti-seizure compound or other therapeutic agents which would otherwise chemically degrade or have limited permeability if released within the intestine lumen of the gastrointestinal tract.

[0073] In some embodiments of any of the aspects presented, an amount of the active agent to produce a desired therapeutic effect is less than an amount to produce a corresponding effect if the agent was orally delivered without enclosure in the oral drug delivery device.

[0074] A discussion will now be provided regarding therapeutics or bioactives which may be delivered by one or more embodiments of the present intestinal penetrating member.

[0075] A therapeutic may be a biologic. Examples of biologies including, but are not limited to, monoclonal antibodies, single chain antibodies, aptamers, enzymes, peptides, proteins, growth factors, hormones, fusion proteins, cytokines, therapeutic enzymes, recombinant vaccines, blood factors, anticoagulants, nucleic acid (e.g., RNA) or small molecule. Examples include antibodies (e.g., including various monoclonal antibodies such as TNF- alfa antibodies), growth hormones (e.g., IGF and other growth factor), parathyroid hormones, interferons, immuno-chemotherapeutic agents, antibiotics, antivirals, insulin and related compounds, glucagon-like peptides (e.g., GLP-1, exenatide), , anti-seizure agents (e.g., Furosemide), anti-migraine medications (e.g., sumatriptan), immune suppression agents (e.g., cyclosporine) and anti-parasitic agents (e.g., anti-malarial agents). A bioactive may be a small molecule and / or organic compound with pharmaceutical activity.

[0076] The therapeutic may be for example peptides such as for example human growth hormone, C-type natriuretic peptide, parathyroid hormone, insulin and analogues, GLP-1 analogues for example efpeglenatid, glucagon, heparin, octreotide, calcitonin, Interferon beta- 1 a, somatostatin, interferons and analogues and / or antibodies such as for example, adalimumab, epinephrine, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, progrstin, infliximab and / or vaccines such as, but not limited to polysaccharide vaccines, and conjugate vaccines, toxoid vaccines, influenza vaccine, shingles vaccine, prevnar pneumonia vaccine, mmr vaccine, tetanus vaccine, hepatitis vaccine, HPV and hepatitis A.

[0077] In general, devices described herein comprise an inflation mechanism. In some embodiments, the inflation mechanism comprises two reactants which interact and produce a gas, otherwise known as two gas generating reactants. The two reactants mix together in the presence of fluid to produce a gas. In some embodiments the inflation mechanism is structured to keep the two gas generating reactants within a common chamber. In some embodiments the inflation mechanism comprises a single formulation comprising two gas generating reactants. For example, the inflation mechanism comprises a single formulation comprising two gas generating reactants contained within a single common chamber.

[0078] In other embodiments, the inflation mechanism is structured to keep the two reactants in separate chambers. For example, the inflation mechanism may be formulated in individual formulations and contained in separated chambers divided by a divider which is fluid sensitive. In this case, the divider would disintegrate upon exposure to fluid entering the device. In other embodiments, the inflation mechanism may be substantially as described in U.S. Patent No. 17 / 892,235 filed on August 22, 2022, which is incorporated by reference as if fully set forth herein.

[0079] In general, devices described herein comprise a gastric-resistant housing. In some embodiments, the devices and methods of the present invention include a gastric-resistant housing which may contain or surrounds the patch structure in the collapsed state. The gastric-resistant housing may be shaped and dimensioned for human (e.g., adults or children) to be swallowed and pass through the stomach and pyloric valve into the intestine. In some embodiments, the housing has a diameter of less than 10 mm, similar to the size of a 000 or 00 capsule. The housing may further be made of pharmaceutically acceptable materials for decomposition and disintegrate at the target side such as the small intestine to release an inflatable patch.

[0080] In some embodiments, the gastric-resistant housing serves as a protective barrier or container for the collapsed drug delivery patch loaded within, preventing premature drug release and degradation when exposed to the acidic gastric environment in the stomach. It may be in the form of a coating or capsule from relevant polymers. It is generally configured for swallowing and to facilitate transit through a stomach and prevent premature inflation. Generally, the gastric-resistant housing is designed to withstand the harsh conditions of the gastric environment, including low pH levels and enzymatic activity, ensuring the integrity and stability of the drug formulation until it reaches the desired site of absorption or action within the body. This housing element provides an effective means to overcome the challenges associated with the gastric environment, such as potential drug degradation, reduced bioavailability, and variability in drug release kinetics.

[0081] In some embodiments, the gastric-resistant housing can be constructed using various materials and techniques known in the art. In one embodiment, the housing comprises a pH-sensitive polymer coating applied to the patch. The pH-sensitive coating is designed to remain intact and impermeable in the acidic environment of the stomach but becomes permeable and allows drug release in the more alkaline environment of the intestine or other target sites.

[0082] In some embodiments, the gastric-resistant housing may involve the use of gastric-resistant coatings. Gastric-resistant coatings typically consist of polymers that resist dissolution in the stomach but rapidly dissolve or become permeable in the intestinal environment. These coatings can be applied to the patch or incorporated within the patch matrix itself. Furthermore, the gastric- resistant housing may incorporate additional components to enhance its effectiveness. For instance, the housing can include pH modifiers or buffering agents to maintain the desired pH levels of the patch, ensuring the stability of the patch or drug formulation. It may also incorporate protective layers or barriers to further shield the patch or drug from moisture, oxygen, or other environmental factors that could compromise integrity of the system. Although several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will recognize a wide range of other means and / or structures for carrying out the operations, achieving the results, and / or obtaining one or more of the advantages described herein. Each of these variations and / or modifications is regarded as falling within the scope of the present invention. Generally speaking, those knowledgeable in the field will understand that all parameters, dimensions, materials, and configurations described here are intended to be examples, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular application or applications for which the teaching of the present invention is / are used.

[0083] Unless specifically stated to the contrary, the indefinite articles "a" and "an," as used above in the specification and in the claims, shall be interpreted to imply "at least one."

[0084] The words "and / or" as used in the specification and claims, should be interpreted to indicate "either or both" of the elements thus combined, i.e., elements that are present conjunctively in some circumstances and disjunctively in others. Other elements, whether related or unrelated to those precisely designated by the "and / or" clause, may optionally be included in addition to those specifically identified by the "and / or" clause, unless expressly stated to the contrary.

[0085] As non- limiting examples, "A and / or B" can refer to A without B (optionally including elements other than B) in one embodiment, B without A in another embodiment (optionally including elements other than A), both A and B in a third embodiment (optionally including other elements), etc. when used with open-ended language like "comprising." The words "or" and "and / or" shall be interpreted to have the same meaning as used in this specification and in the claims. For instance, "or" or "and / or" used to separate items in a list shall be read as inclusive, i.e., the inclusion of at least one, but also more than one of a number or list of components, and, optionally, other unlisted things. Only phrases that expressly state the opposite, such as "only one of," "exactly one of," or, when used in the claims, "consisting of," will denote the presence of precisely one element in a group of several. In general, the word "or" as used in this document shall only be construed as designating exclusive options (i.e., "one or the other but not both") when it is followed by terms of exclusivity like "either," "one of," "only one of," or "exactly one of." "When used in a claim, the phrase "consisting essentially of' must be understood in the context of patent law.

Claims

CLAIMS1. An intestinal penetrating member for drug delivery comprising: a body portion having a central longitudinal axis extending between a proximal end and a distal end, a tissue penetrating end extending distally from the body portion and comprising a first and second bevel surface which converge at a sharp edge; and a solid formulation of therapeutic forming at least a portion of the intestinal penetrating member and adapted to penetrate an intestinal wall to release a therapeutic.

2. The intestinal penetrating member of claim 1, wherein an axial length of the intestinal penetrating member is less than 3.0mm.

3. The intestinal penetrating member of any one of claims 1 to 2, wherein the sharp edge has an axis which is transverse to the central longitudinal axis.

4. The intestinal penetrating member of claim 3, wherein the sharp edge has an axis which is perpendicular to the central longitudinal axis.

5. The intestinal penetrating member of any one of claims 1 to 4, wherein the sharp edge has a concavity in a direction towards the central longitudinal axis.

6. The intestinal penetrating member of any one of claims 1 to 5, wherein a length of the sharp edge is equal or more than a second longest dimension of the body portion.

7. The intestinal penetrating member of any one of claims 1 to 6, wherein a first and / or second bevel surface is a concave surface extending between the body portion and the sharp edge.

8. The intestinal penetrating member of any one of claims 1 to 7, wherein a surface area of the first and second bevel surfaces are the same.

9. The intestinal penetrating member of any one of claims 1 to 8, wherein an outer perimeter of said body portion has at least one rounded comer and / or at least one non-rounded comer.

10. The intestinal penetrating member of any one of claims 1 to 9, wherein the body portion has a square or circular cross section.

11. The intestinal penetrating member of any one of claims 1 to 10, wherein the body portion has a conic or pyramidal shape.

12. The intestinal penetrating member of any one of claims 1 to 11 , wherein the sharp edge extends between two sharp distal tips.

13. The intestinal penetrating member of claim 12, wherein the sharp edge has a shape of an arcuate trough extending between two sharp distal tips.

14. The intestinal penetrating member of claim 12, wherein said body portion tapers towards saidsharp distal tips.

15. The intestinal penetrating member of claim 9, wherein an edge of said non-rounded comer extends up to one or both sharp distal tips.

16. The intestinal penetrating member of claim 12, wherein said sharp distal tips have equal heights.

17. The intestinal penetrating member of claim 12, wherein said sharp distal tips have unequal heights.

18. The intestinal penetrating member of any one of claims 1 to 17, wherein an enteric polymer forms part of a layer or coating on a penetrating member.

19. The intestinal penetrating member of any one of claims 1 to 17, wherein a tip and / or an edge is at least partially coated by a coating comprising a water insoluble, hydrophobic, or a non- degradable polymer.

20. The intestinal penetrating member of any one of claims 1 to 19, wherein the intestinal penetrating member further comprises a controlled release coating with a pore-forming agent.

21. The intestinal penetrating member of any one of claims 1 to 20, wherein the therapeutic is an antibody, peptide, protein, nucleic acid or small molecule.

22. The intestinal penetrating member of any one of claims 1 to 21, wherein a plurality of said intestinal penetrating members are mounted on a substrate.

23. The intestinal penetrating member of claim 22, wherein the substrate is operatively connected to or forms at least a portion of a surface of an intestine wall delivery device which is auto inflatable and auto deflatable.

24. The intestinal penetrating member of one of claims 22 to 23, wherein each individual intestinal penetrating member comprises a portion of a therapeutically effective dose of a therapeutic agent.

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