WO2024166100A1

WO2024166100A1 - Methods for preparing an active layer and devices comprising same

Info

Publication number: WO2024166100A1
Application number: PCT/IL2024/050138
Authority: WO
Inventors: Gil Cohen; Valery ARTAMONOV; Ilya Ruderfer
Original assignee: Epitomee Medical Ltd
Current assignee: Epitomee Medical Ltd
Priority date: 2023-02-08
Filing date: 2024-02-06
Publication date: 2024-08-15
Anticipated expiration: 2025-08-08
Also published as: EP4661854A1; CN120813340A

Abstract

The disclosure concerns methods for preparing an active layer, typically a layer comprising mucoadhesive materials and one or more pharmaceutically active compounds or nutrients, and devices comprising such active layers. The method is designed to maintain the mucoadhesive materials in non-activated form during preparation of the active layer and permit activation of the mucoadhesive materials once in vicinity of the target site.

Description

Methods for preparing an active layer and devices comprising same

TECHNOLOGICAL FIELD

The present disclosure concerns methods for preparing an active layer, typically a layer comprising mucoadhesive materials and one or more pharmaceutically active compounds or nutrients, and devices comprising such active layers.

BACKGROUND ART

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

- US 11,207,805

- US 2018/0318209

- WO 2016/079246

- US 2004/018241

Ikram et al., Adv Biomed Res 2015, 4, 239

Shidhaye et al., AAPS Pharm Sci Tech 2008, 9(3), 909-916

Jacob et al., Asian J Pharm Sci Tech 2012, 2(1), 13-22

Escalona-Rayo et al., J Pharm Innov 2020, 15, 556-568

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

BACKGROUND

Effective and targeted delivery of various compounds and active agents to or across a tissue, for example lining of the intestinal tract, has proven over the years to be a challenge. Due to mucus secretions that line various tissues for providing a hydrated environment and lubrication of biological surfaces, targeted delivery of active agents can benefit from the use of mucoadhesive components or other tissue attachment arrangements, which are capable of attaching to the tissue for a pre-defined period of time, thereby providing longer contact time between the tissue and the active agent to allow longer time of absorption of the active agent through and/or to the tissue.

While some approaches involve compositions that comprise mucoadhesive components in particulate form (e.g. capsules that comprise an active agent mixed with mucoadhesive particles, or devices that disperse the mucoadhesive particles when exposed to defined conditions), such are difficult to disperse once in vicinity of the relevant tissue, and do not provide sufficient control over the location in which the mucoadhesive is adhered to the tissue. Further, such systems often suffer from insufficient adhesion and/or insufficient residence time in the target site.

GENERAL DESCRIPTION

The present disclosure concerns a method for manufacturing an active layer that can be delivered to a target site, particularly to gastrointestinal tract or intestinal tissue, and adhered thereto by one or more mucoadhesive materials. In the methods described herein, the mucoadhesive material is in particulate form and fixated into the active layer, thereby enabling maintaining the mucoadhesive material in non-adhesive (particulate) form until the active layer is deployed in the target site. In other words, the methods described herein permit preparation of active layers, in which the mucoadhesive material is maintained in non-active (i.e. non-adhesive) form, and is activated to function to adhere the active layer only in the vicinity of the target site. By controlling various parameters of the method, an active layer can be obtained that has a defined mucoadhesive particle size, permitting fast activation and adherence of the active layer once deployed at the target site. Further, this disclosure concerns devices comprising such an active layer for delivery of one or more active agents to a target site.

Thus, by one of its aspects, the present disclosure provides a method for forming an active layer for delivery of at least one active agent to an intestinal tissue, the method comprising: a) mixing at least one non-aqueous solvent with at least one mucoadhesive material that is insoluble in said non-aqueous solvent and at least one binder soluble in said non-aqueous solvent to obtain a slurry, said mucoadhesive material being in particulate form in the slurry, b) mixing said at least one active agent into the slurry, c) applying said slurry onto at least a surface portion of a carrying substrate, and d) removing said non-aqueous solvent to obtain said active layer attached to said carrying substrate, said active layer comprises said at least one active agent and said at least one mucoadhesive material being dispersed within the binder, said at least one mucoadhesive material substantially maintains its particulate form within the active layer and having a particle size of no more than about 150pm.

In other words, in methods of this disclosure, the components of the active layer are selected according to their relative solubility in said non-aqueous solvent in order to maintain at least the mucoadhesive material (at times also the active agent, as will be further described below) in particulate form and a defined particle size. The method is aimed at preventing the mucoadhesive material from being dissolved or swelled during the preparation process of the active layer, thereby preventing its transformation into a gel form during said preparation, as well as providing an active layer that has optimal adherence functionality when deployed at the target site.

According to some embodiments, step (b) is carried out concomitantly with step (a), such that said slurry is obtained by mixing said at least one non-aqueous solvent with said at least one mucoadhesive material, said at least one binder and said at least one active agent.

By another one of its aspects, the disclosure provides an active layer for delivery of at least one active agent to a tissue, the active layer comprising at least one active agent and at least one mucoadhesive material being dispersed within at least one binder, said at least one mucoadhesive material being in particulate form having a particle size of no more than about 150 pm.

Another aspect provides a device for delivery of at least one active agent to a tissue comprising the active layer.

In the context of the methods and devices of the present disclosure, the term active layer refers to a layer that contains one or more active agents, e.g. pharmaceutically active agents or nutraceuticals, at least one mucoadhesive material, and at least one binder material, both the active agent(s) and the mucoadhesive material(s) being dispersed within the binder. The active layer is capable of adhering to a mucosal tissue for a period of time, permitting release of the active agent from the active layer to the tissue over at least a portion of said period of time.

Adherence of the active layer to the tissue is carried out by said at least one mucoadhesive material, which is a compound or composition of matter that is capable of adhering to a tissue due to its interaction with mucus present on or secreted by the tissue, e.g. one or more interactions such as electrostatic interaction, physical entanglement or interpenetration, diffusion, adsorption, mechanical interlocking, etc.

The mucoadhesive material is typically a polymer, that can be natural, semisynthetic or synthetic. Non-limiting examples of mucoadhesives are tragacanth, sodium alginate, guar gum, xanthan gum, karaya gum, gellan gum, carrageenan, soluble starches, gelatin, chitosan, cellulose derivatives (such as methylcellulose, ethylcellulose, hydroxylethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose), polyacrylic acid (PAA) polymers (such as carbomers, polycarbophil), polyhydroxyl ethylmethylacrylate, polyethyleneoxide (PEO, typically high molecular weight PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), lectins, pectin, thiolated polymers (for example chitosan-iminothiolane), poly(acrylic acid)-cysteine, poly(acrylic acid)-homocysteine, polyethylene glycol, chitosan- thioglycolic acid, chitosan-thioethylamidine, alginate-cysteine, poly(methacrylic acid)- cysteine, sodium carboxymethylcellulose-cysteine, and others.

Depending on the target site and the desired contact time between the active layer and the tissue, the mucoadhesive material can be selected to provide longer or shorter residence time on the tissue. The mucoadhesion strength can be selected to be stronger or weaker, and can be influenced, inter alia, by the molecular weight of the polymer, degree of cross-linking, chain length and flexibility, electrical charges and/or polarity, pH, concentration of the mucoadhesive in the layer, etc.

The mucoadhesive material becomes activated once in contact with water at the deployment site of the device. Once introduced into the target site, it is desirable that the active layer be adhered as quickly as possible to the tissue. The inventors of the devices and methods disclosed herein have found that when introducing the mucoadhesive material into the active layer, a particle size of no more than about 150 pm provides for optimal wetting of the mucoadhesive particles in the active layer for activating the mucoadhesive at the deployment site, as well as sufficient surface area for effective reaction with the mucosal membrane at the target site. Thus, in the active layers of this disclosure, the mucoadhesive material is in particulate form having a particle size of no more than about 150pm.

By some embodiments, the at least one mucoadhesive material has a particle size of between about 50 pm and about 150 pm. By some other embodiments, the at least one mucoadhesive material has a particle size of between about 75 pm and about 150 pm. By some other embodiments, the at least one mucoadhesive material has a particle size of between about 50 pm and about 100 pm.

The methods for manufacturing the active layer described herein are aimed at maintaining the mucoadhesive material in a particulate form during preparation of the active layer. Hence, in the methods of this disclosure, at least one mucoadhesive material in particulate form is mixed with at least one non-aqueous solvent to obtain a slurry with the solvent-soluble binder. The mucoadhesive material and the non-aqueous solvent are selected such that the mucoadhesive material is insoluble in the non-aqueous solvent, thereby substantially maintaining its particulate form in the slurry. As will be detailed below, the active agent can be added to the slurry, i.e. after mixing the solvent with the binder and mucoadhesive material, or the active agent can be added during such mixing.

The term non-aqueous solvent means to denote a solvent or a mixture of solvents that are different from water and/or substantially do not contain water. Non-aqueous solvents suitable for the process of this disclosures are solvents (or a solvent mixture) in which the binder is soluble however the mucoadhesive is insoluble.

The term soluble typically refers to solubility of a compound in a liquid of at least about 1g of compound in 100 ml of liquid, typically at least 3g/100ml. The term insoluble typically refers to solubility of a compound in a liquid of at most 0.1g compound in 100ml of liquid, e.g. at most O.Olg/lOOml. Unless otherwise specifically indicated, all solubility and insolubility values disclosed herein refer to liquids at 25°C.

By some embodiments, the non-aqueous solvent can be selected from ethanol, isopropanol, acetone, and mixtures thereof.

According to some embodiments, the non-aqueous solvent is an anhydrous nonaqueous solvent.

As noted, the slurry contains at least one binder, which functions in the active layer as a matrix component, holding the active agent and the particles of the mucoadhesive material, and attaching the active layer to the carrying substrate. The binder is typically a polymeric substance, which is soluble at least in the nonaqueous solvent, such that when mixed with the non-aqueous solvent, it forms a substantially homogenous and uniform liquid medium that suspends the particles of the mucoadhesive material, thereby obtaining the slurry, while suspending or dissolving the active agent (depending on the active agent’s solubility in the solvent) within the slurry. Once the slurry is applied onto the carrying substrate and the non-aqueous solvent is removed (e.g. evaporated), the binder functions as said matrix component in the active layer. In other words, as the binder is soluble in the non-aqueous solvent, it forms a continuous medium in the slurry, and after application of the slurry on the carrying substrate and evaporation of the solvent, the binder creates a matrix in which the active agent and the particles of the mucoadhesive material are embedded, and adheres the active layer to the carrying substrate.

According to some embodiments, the binder is soluble in said non-aqueous solvent and insoluble in said aqueous liquid.

According to other embodiments, the binder is soluble in said non-aqueous solvent and also soluble in aqueous liquids. The solubility of the binder in aqueous liquids may be pH dependent, e.g. a pH of at least about 6.

By some embodiments, the binder is hydrophilic. By some other embodiments, the binder comprises a mixture of hydrophilic polymers, hydrophobic polymers, and/or enteric polymers having solubility in water (at 25°C and at a pH range of 5 to 7). The hydrophilicity/hydrophobicity of the binder can be tailored in order to control the disintegration timing and/or rate of the active layer after attachment and delivery of the active agent to the tissue.

By some embodiments, the at least one binder is a hydrophilic polymer, e.g. selected from hydroxypropyl cellulose, povidone, and mixtures thereof.

By some other embodiments, the at least one binder is a hydrophobic polymer, e.g. selected from ethylcellulose, cellulose acetate, polyvinyl cellulose, and water insoluble polymethylmethacrylates, and mixtures thereof.

By other embodiments, the at least one binder is an enteric polymer, e.g. selected from cellulose acetate phthalate, pH-sensitive polymethacrylates (such as Eudragit® L, Eudragit® S, etc.), and hypromellose phthalate.

According to some embodiments, the at least one binder is selected from hydroxypropyl cellulose, povidone, ethylcellulose, cellulose acetate, polyvinyl cellulose, water insoluble polymethylmethacrylates, cellulose acetate phthalate, pH-sensitive polymethacrylates, hypromellose phthalate, and any mixture thereof.

Typically, albeit not exclusively, the mucoadhesive material is present in the slurry (and in the active layer) in an amount larger than the binder. According to some embodiments, the active layer comprises between about 20 wt% and about 50 wt% mucoadhesive material and between about 10 wt% and about 30 wt% of said binder.

By some embodiments, the weight ratio (weightweight) between the mucoadhesive material and the binder ranges between about 5: 1 to about 2:3.

By some embodiments, the at least one active agent is a water-soluble active agent, e.g. having solubility in water (at 25°C, pH~7) of at least about Ig/lOOml, typically at least about 3g/100ml, or even at least about 5g/100ml.

The active agent can be partially or completely soluble in the non-aqueous solvent. In such cases, the active agent is dissolved into the slurry and forms a homogenous mixture with the binder.

By some other embodiments, the at least one active agent is substantially insoluble in said non-aqueous solvent, e.g. having a solubility in said non-aqueous solvent (at 25°C, pH~7) of at most about 0. Ig/lOOml, typically at most about O.Olg/lOOml.

According to such embodiments, the active agent is in particulate form, and is dispersed in the slurry together with the mucoadhesive material particles. In such embodiments, the active agent has a particle size of no more than about 150pm, preferably no more than about 100pm.

In case where the active agent is not soluble in said non-aqueous solvent, once the slurry is applied onto the carrying substrate and the solvent removed, the particles of the active agent are substantially dispersed within the binder, together with the particles of the mucoadhesive material.

In some embodiments, the slurry and the active layer may further comprise one or more additional components.

Hence, by some embodiments, the method further comprises mixing at least one additional component into the slurry at step (a), step (b), or both steps (a) and (b) of the method.

By some other embodiments, the method further comprises a step (al), between steps (a) and (b), step (al) comprises mixing at least some of the components of the active layer into the slurry. Such additional components may be, for example, non-pharmaceutical agents, such as emulsifying agents or surfactants, e.g. poloxamers or carbomers; stabilizing agents, such as carboxymethylcellulose; suspending agents, such as cellulose, talc; acidifying agents, such as citric acid, ascorbic acid; viscosity increasing agents, such as carbopol, polyethylene oxide; effervescent agents, such as sodium bicarbonate, ammonium carbonate; solubilizing agents, such as lecithin; antimicrobial preservatives, such as sorbic acid, potassium sorbate; antioxidants, such as alpha tocopherol, butylhydroxy anisole; release modifying agents, such as Tween® 80, sodium lauryl sulfate; coating agents, such as ethylcellulose, cellulose acetate; stiffening agents, such as stearic acid, wax; and others.

The active layer is typically thin and flexible. In order to maintain flexibility and integrity of the active layer on the carrying substrate, namely when the active layer is in a dry state after removal of the non-aqueous solvent, one or more plasticizers can be used. Thus, according to some embodiments, the slurry (and the active layer) comprises at least one plasticizer, e.g. diethyl phthalate, triethyl citrate and others.

By some embodiments, the slurry (and the active layer) further comprises at least one filler in particulate form, which is substantially insoluble in water as well as in said non-aqueous solvent. As the filler is both water insoluble and insoluble in the nonaqueous solvent, it maintains its particulate form during the preparation of the active layer, as well as after exposure to water at the deployment site. Hence, the filler can be used for reducing the stickiness of the mucoadhesive material after its exposure to water at the deployment site, thereby functioning as a control measure over the adherence of the active layer to the tissue. In other words, the filler can be utilized to control the adhesion strength of the active layer to the tissue. Modifying the type, particle size, concentration of the filler, etc., are used to affect the attachment strength of the active layer to the tissue.

By some embodiments, the at least one filler has an average particle size of no more than about 50pm.

According to some embodiments, the filler is selected from microcrystalline cellulose, dicalcium phosphate, magnesium carbonate, magnesium oxide, and mixtures thereof.

Depending on the active agent and the desired delivery profile, the properties of the active layer and/or the device can be modified. For example, in case fast delivery of the active agent from the active layer is desired, one or more pore-forming agents can be added to the active layer (to the slurry) during preparation. The pore-forming agent is a compound or composition that reacts to locally form pores or holes in the active layer, to thereby increase the surface area of the layer once coming into contact with the tissue at the target site. This, in turn, permits more surface area of the active layer to be in contact with the tissue and deliver the active agent thereto. The pore-forming agent is selected to be substantially insoluble in said non-aqueous solvent, however highly soluble in, or highly reactive with, water. Hence, the pore-forming agent reacts quickly, physically or chemically, once exposed to water at the target site to form pores in the active layer.

By some embodiments, the pore-forming agent can be selected from polysaccharides and polyols, such as mannitol, polyethylene glycol, maltodextrin, etc.

In other cases, a delayed or prolonged delivery of the active agent is desired. Such delayed delivery can be obtained, for example, by selecting a mucoadhesive material in which the active agent has a relatively low diffusivity, thereby increasing the delivery time of the active agent. Another means of delaying delivery can be obtained, for example, by applying one or more functional layers onto the active layer, for example a layer with reduced diffusivity to the active agent, hence slowing down and/or prolonging the delivery of the active agent from the active layer to the tissue.

According to some embodiments, the at least one functional layer is one or more mucoadhesive layers that are substantially devoid of an active agent. Such mucoadhesive layers function to increase the distance through which the active agent needs to diffuse from the active layer to the tissue, hence causing a delay in its delivery.

The mucoadhesive layer can comprise the same mucoadhesive material(s) as in the active layer, or different mucoadhesive materials from those in the active layer.

As the active layer is relatively thin and flexible, it is supported by said carrying substrate, that provides the active layer with structural and mechanical support. The carrying substrate is an object, either made of a single material or structured as a multilayered substrate, underlying the active layer, onto which the active layer is attached and is mechanically supported thereby. Within the context of the preparation methods disclosed herein, the carrying substrate is an object onto which the slurry is applied and to which the active layer is attached.

The carrying substrate can be any suitable object, 3-dimensional or 2-dimensional, having a surface onto which the active layer is attached. The substrate can be firee- standing, or can be part of a larger object, such as a gastrointestinal device. The carrying substrate is typically made of materials that are insoluble in the non-aqueous solvent.

In some instances, mechanical support needs to be provided to the carrying substrate during formation of the active layer thereonto. Hence, according to some embodiments, the method further comprising a step (0), before step (a) or before step (b) or before step (c), step (0) comprises attaching or forming the carrying substrate onto a support element, the support element being configured to provide mechanical support to the carrying substrate during application of the slurry thereonto. In such embodiments, the method can further comprise step (d’) after step (d), of removing the carrying substrate from the support element after formation of the active layer.

According to some embodiments, the carrying substrate is a backing film. The backing film means to denote a sheet of material, typically a continuous, deformable/flexible film. The backing film can be a monolithic film i.e. a film constructed as one seamless film) or a film that is constructed out of film segments that are welded together to form a continuous structure. The backing film may be a substantially flat sheet of material, or may assume any voluminous shape or size. The backing film can be constituted by a single layer of material; alternatively, the backing film can comprise one or more layers of different materials.

According to other embodiments, the active layer is removed from the carrying substrate after its formation and then attached to a backing film. In some embodiments, portions of the active layer are removed from the carrying substrate and are attached to a backing film.

According to other embodiments, the carrying substrate with the active layer attached thereto is further attached to a backing film (i.e. the backing film is attached to the carrying substrate). In some embodiments, portions of the active layer attached to the carrying substrate are further attached to a backing film.

In some embodiments, the backing film is made of at least one water-insoluble substance, typically a water insoluble polymer, such as cellulose acetate, ethylcellulose, polyvinyl acetate, water insoluble polymethacrylates, etc.

In some other embodiments, the backing film is made of a substance that is soluble in water at a pH > ~6, for example to permit the backing film to at least partially dissolve after application at the target site (e.g. the intestine) as response to the conditions therein, e.g. cellulose acetate phthalate, pH-sensitive polymethacrylates, hypromellose phthalate, and others.

By some embodiments, the backing film is made of a mixture of at least one water insoluble polymer (e.g. cellulose acetate, ethylcellulose, polyvinyl acetate, water insoluble polymethacrylates), at least one enteric polymer (e.g. cellulose acetate phthalate, pH-sensitive polymethacrylates, hypromellose phthalate), and at least one plasticizer.

Exemplary suitable plasticizers that can be used, are, for example, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, tri ethyl citrate, acetyl tributyl citrate, diacetin, triacetin, castor oil, polyethylene glycol (e.g. PEG 200, PEG 400, PEG 600), etc.

In some embodiments, the backing film is disintegrable. Hence, after deployment of the active layer to the target site, the backing film can be relatively quickly disintegrated (e.g. mechanically, physically, and/or chemically), and can be cleared from the deployment site, to leave the active layer attached to the tissue.

Clearance of the active layer from the tissue typically occurs due to the continuous secretion of mucin by the tissue, which eventually causes loss of adherence of the layer to the tissue. Further, clearance can be assisted by shedding of tissue cells and detachment from the target site. For example, when applied to intestinal tissue, such tissue is shed every few hours, and hence an active layer that is attached thereto will clear from the target site together with the shed tissue. Hence, residence time of the active layer in the target site is typically, albeit not exclusively, determined by the nature of the tissue to which it is targeted to adhere. Alternatively, the residence time and/or detachment of the active layer from the tissue may be governed by the properties of the active layer (i.e. chemical and/or physical property).

In some embodiments, the backing film is chemically disintegrable. In other embodiments, the backing film is physically disintegrable. For example, the backing film may be tailored to disintegrate within 15 minutes to 3 hours.

By some embodiments, the carrying substrate is a multilayer substrate, comprising one or more coating layers. Such coating layers can be, for example, adherenceimproving layers to increase compatibility between the carrying substrate and the active layer to maintain the integrity of the device when at the dry state i.e. after removal of the non-aqueous solvent). Such coating layers can be utilized when the additional step (see step (e) below) comprises adhering the active layer (after it has been formed) to a surface of a delivery device (e.g. a gastrointestinal device).

Such coating layers can also function as barrier coatings that form a barrier to undesired diffusion of the active agent from the active layer to the carrying substrate thereby providing diffusion directionality of the active agent from the active layer towards the tissue. Such barrier coating may be in the form of a mucoadhesive layer that is substantially devoid of an active agent. Different coating layers can also be applied over the surface of the carrying substrate opposite the surface onto which the active layer is applied, for example for increasing mechanical support or provide sealing of the carrying substrate to solvent or water.

In the methods disclosed herein, application of the slurry can be by any suitable manner, for example by pouring, dripping, spreading, smearing, casting, templating, or any other suitable technique. Application of the slurry can be over the entire surface of the carrying substrate or over one or more surface segments thereof.

The application of the slurry can be by single application, for example, by casting or pouring of the entire layer in a single action. Alternatively, the active layer can be obtained by multiple applications of the slurry until the desired final thickness of the active layer is obtained - for example by several cycles of smearing or spreading of the slurry, allowing at least partial drying of the applied slurry in between applications.

After application of the slurry onto the carrying substrate, the non-aqueous solvent is removed to obtain the active layer attached (or adhered) to the carrying substrate. Due to the non-solubility of the mucoadhesive material in the non-aqueous solvent, the resulting active layer comprises the at least one mucoadhesive material substantially in its particulate form dispersed within the binder of the active layer, together with the at least one active agent.

By some embodiments, the carrying substrate, e.g. a backing film, is configured for attaching to a delivery arrangement, for example an ingestible device, e.g. a gastrointestinal device.

A particular example is an external surface of a gastrointestinal deployable device that is introduced into the gastrointestinal tract in a folded or compacted state, and is configured to be deployed in the target site (e.g. a location in the intestine) to assume a deployed, more voluminous state. As the carrying substrate can be attached to the gastrointestinal deployable device, deployment of the device and/or its transition from a compacted state to an expanded state, pushes the carrying substrate that carries the active layer towards the intestinal wall. Exposure of the particles of the mucoadhesive material in the active layer to the intestine fluids activates the mucoadhesive material, causing the particles to swell and/or gel, and to adhere the active layer to the intestinal wall - thus enabling delivery of the active agent from the active layer to the target site.

By some other embodiments, the carrying substrate is at least a portion of an external surface of a delivery arrangement.

By some other embodiments, the carrying substrate forms at least a portion of a delivery arrangement.

According to some embodiments, the method further comprises a step (e), after step (d), step (e) comprising adhering at least a portion of the carrying substrate to a surface of a delivery arrangement.

According to some embodiments, the method comprises a step (0), before step (a) or before step (b) or before step (c), step (0) comprises attaching or forming the carrying substrate onto a support element, the support element being configured to provide mechanical support to the carrying substrate during application of the slurry thereonto; further comprising step (d’) after step (d), of removing the carrying substrate from the support element after formation of the active layer; and further comprising a step (e), after step (d’), step (e) comprising adhering at least a portion of the carrying substrate to a surface of a backing film, to form a delivery arrangement.

According to some alternative embodiments, the method comprises step (e’) after step (d), step (e’) comprises detaching the active layer from the carrying substrate and attaching at least a portion of the active layer to at least a portion of a surface of a delivery arrangement.

According to some other alternative embodiments, the wherein the carrying substrate is a multi-layer structure, the method further comprises step (e”) after step (d), step (e”) comprises removing one or more outmost layers thereof opposite the active layer to form an attachable surface, and attaching at least a portion of the attachable surface to at least a portion of a surface of a delivery arrangement.

The term delivery arrangement refers to a system or device that is configured for introduction and delivery of the active layer to a target site of a subject.

According to some embodiments, the delivery arrangement is in the form of a patch, e.g. an ingestible patch. According to some embodiments, the delivery arrangement is an ingestible device.

According to other embodiments, the ingestible device is a gastrointestinal device.

According to some other embodiments, the gastrointestinal device is a gastrointestinal deployable device.

By other embodiments, the active layer is configured for attaching to a carrying substrate or a backing film, e.g. for providing mechanical support to the layer, thereby forming a device according to one aspect of this disclosure.

By other embodiments, the carrying substrate is configured for attaching to a delivery arrangement, e.g. a gastrointestinal (deployable) device.

By some other embodiments, the carrying substrate is at least a portion of an external surface of a delivery arrangement, e.g. a gastrointestinal (deployable) device.

According to further embodiments, the carrying substrate constitutes at least a portion of a delivery arrangement, e.g. a gastrointestinal (deployable) device.

According to yet other embodiments, the delivery arrangement constitutes a gastrointestinal device, preferably a gastrointestinal deployable device.

By some embodiments, at least a portion of the active layer is attached to at least a portion of a surface of a delivery arrangement, typically an ingestible device, e.g. a patch or a gastrointestinal (deployable) device. By other embodiments, at least a portion of a surface of a delivery arrangement carries two or more portions of an active layer, laterally spaced apart across said surface of the delivery arrangement. The devices of this disclosure, by some embodiments, can comprise one or more auxiliary functional layers applied onto the active layer, to permit various additional functionalities, such as controlled release layer, separation layers, non-mucoadhesive layers, etc. The one or more auxiliary functional layers can be continuous or can be spaced-apart layer segments.

By some embodiments, the device can comprise at least one at least one auxiliary barrier layer, configured to minimize or prevent diffusion of the active agent therethrough.

By one example, the carrying substrate comprises an auxiliary barrier layer (the auxiliary barrier layer can be sandwiched between a surface of the device and the active layer). Such barrier layer functions to ensure directionality of diffusion of the active agent and prevents its undesired diffusion in the direction of the carrying substrate. By another example, an auxiliary barrier layer can be disposed over the active layer, and configured to disintegrate upon exposure to suitable conditions at the target site, thereby minimizing or preventing undesired release of the active agent from the device before reaching and adhering to the target site.

By some embodiments, the device comprises at least one protective auxiliary layer, disposed over the active layer.

By one example, the protective auxiliary layer can be an enteric layer functioning to control the timing of the adherence of the active layer to the intestinal wall. In other words, such protective auxiliary layer prevents exposure of the active layer while intact, and is designed to disintegrate at a desired timing at the target site (e.g. once exposed to suitable pH conditions), to expose the active layer and permit the mucoadhesive material in the active layer to adhere the active layer to the intestinal wall.

By another example, the device of this disclosure comprises at least one auxiliary mucoadhesive layer, disposed over the active layer, and can be configured to control the delivery rate of the active agent from the active layer to the target site. Such auxiliary mucoadhesive layer function as additional diffusivity control - by tailoring the composition and/or thickness of the auxiliary mucoadhesive layer, controlled diffusivity of the active agent from the active layer to the target site can be obtained. Such auxiliary mucoadhesive layer can be used to provide a defined release rate or defined released dose of the active agent, once the active layer is adhered to the target site.

By yet another example, the auxiliary layer can be a separation layer, preventing adherence of the active layer to itself in case the device is folded or rolled for administration purposes, e.g. when the device is part of a gastrointestinal deployable device that undergoes deployment at the target site by change of geometrical configuration or change in dimensions.

According to some embodiments, the carrying substrate can comprise one or more liquid-permeable sections to permit transport of liquid therethrough. By some embodiments, the carrying substrate can have one or more sections that are liquid- permeable and one or more other sections that are non-permeable to liquids.

Within the context of the present disclosure, whether referring to a delivery arrangement to which the active layer is directly attached to, or to a device in which the carrying substrate is attached thereto (while carrying the active layer), or the carrying substrate being an integral part of the device, the active layer can be localized over a portion of the surface of the device or cover the entire surface of the device. The device can comprise one such active layer over a portion of its surface, or two or more active layers, laterally spaced apart from one another over the surface of the device.

The delivery arrangement or device surface to which the layer (or the carrying substrate) is attached can be an external surface of the device, or can be a surface portion that is orientable towards the tissue (for example in cases where the device is introduced into the target site in a collapsed/folded form and undergoes deployment to change its volume/spatial configuration).

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

According to some embodiments, the at least one active agent is a biopharmaceutical. The term biopharmaceutical means to denote a pharmaceutical active agent which is a macromolecule derived, extracted or produced from a biological source material. The term also mean to denote any chemically synthesized or chemically modified biomacromolecules, such as modified, synthesized or semi-synthesized peptides, DNA, RNA, tRNA, mRNA, rRNA, etc. The term also means to encompass biomacromolecules obtained by recombination and/or hybridization techniques, and/or biomacromolecules chemically modified by conjugation with polymers (e.g. PEGylation) and/or any other chemical residues. Non-limiting exemplary biopharmaceuticals are amino acids, nucleic acids, antibodies (e.g. TNFa inhibitors), proteins (e.g. interferon beta), peptides, acylated peptides, fatty acids conjugated (e.g. acylated) peptides (e.g. semaglutide, tirzepatide, retatrutide, utreglutide, efinopegdutide, cotadutide), hormones (e.g. insulin, parathyroid, growth hormones, etc.), fatty acids conjugated hormones (e.g. detemir), blood-derived components, blood factors, growth factors, interferons, enzymes, isolated cells or cell clusters, stem cells, etc. According to some embodiments, the at least one active agent is at least one fatty acid conjugated peptide, such as semaglutide, tirzepatide, retatrutide, utreglutide, efinopegdutide, detemir, and/or cotadutide.

In other embodiments, the active agent can be a microorganism (e.g. intestine- friendly bacteria) and/or virus.

In other embodiments, the active agent can be a nutraceutical compound.

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

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

According to some embodiments, the active agent is introduced into the slurry in a lyophilized state.

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

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

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

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

In such embodiments, the active agent and the additional active substance can have a co-therapeutic effect, i.e. additional or synergistic. For example, the additional active substance can function to increase bioavailability of the active agent, or can increase or enhance the therapeutic effect or bioactivity of the active agent.

In other embodiments, the active agent and the additional active substance can be selected from agents having similar or identical therapeutic effects. For example, the active agent and the additional active substance can be the same, however one portion of the active agent can be encapsulated within a sustained release coating. Such an arrangement can be utilized to divide the required dose of the active agent, such that a part of the agent is released immediately upon attachment of the active layer to the tissue, and the encapsulated part of the agent will be slowly absorbed from the active layer during a predefined period of time. By another example, the active agent and the additional active substance can have similar effects, with the additional active substance having an immediate effect and the active agent having a prolonged or sustained effect.

In other words, the active layer can be used to simultaneously administer two or more pharmaceutically active agents, i.e. administered substantially concurrently. Simultaneous administration may permit one agent in the combination to be administered within a certain time period (e.g. 5 minutes, 10 minutes or even a few hours) after the other, provided that the circulatory half-life concentration of the first administered agent in a combination is concurrently present in therapeutically effective amounts with the other agent administered thereafter. The time delay between administration of the agents may vary depending on the exact nature of the agents, the interaction between the individual agents, their respective half-lives, and on such other factors as easily recognized by the versed artesian. In a further example, the active agent and the additional substance can have different effects, and the device is designed for sequential administration; meaning that a time difference exists between administering one agent and the other. Such time different may be short or may be significant, i.e. the first administered agent may no longer be present (or is present in subclinical amounts) in the bloodstream in a therapeutically effective amount when the second (or subsequent) agent is administered.

According to some embodiments, the active layer can comprise one or more auxiliary substances, typically having no pharmaceutical activity per-se, however used to affect the stability and/or permeation of the active agent. Exemplary of such auxiliary substances are protease inhibitors for protecting protein active agents from enzymatic degradation (such as n-acetylcysteine, camostat mesylate, soybean trypsin inhibitor, aprotinin, efc.); pH modifiers (e.g. citric acid, fumaric acid, itaconic acid, tartaric acid, etc.); chelating agents (e.g. ethylenediaminetetraacetic acid, di ethylenetriaminepentaacetic acid, ethylene glycol tetraacetic acid, efc.); surfactants for preventing aggregation of proteins and/or enhance intestinal permeation of the active agent (e.g. sodium dodecyl sulfate, N-(8-[2-hydroxybenzoyl]-amino) caprylic acid, palmityl-dimethyl-ammonio-propanesulfonate, palmitoylcamitine, etc. , bile salts for increasing paracellular transport and protect against enzymatic degradation of the active agent (e.g. sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodihydrofusidate, etc. aromatic alcohols to enhance transcellular transport or for use as antioxidants (e.g. propylgallate, butylated hydroxytoluene, butylated hydroxyanisole, etc.,- piperazine derivatives for increasing permeation (e.g. 1- phenylpiperazine, l-methyl-4-phenylpiperazine, l-(4-methylphenyl)piperazine), etc.); ionic liquids for preventing protein degradation, enhance solubility or intestinal permeation, and/or reduce mucus viscosity (e.g. choline, nicotinic acid, trigonelline, c/c. ); and others.

In some embodiments, the auxiliary substance is a surfactant, which can function to disperse the active agent in the active layer and in the vicinity of the target site once the active layer is delivered to the target site, e.g. the GI tract. Depending on the active agent to be loaded into the active layer, the surfactant may be anionic, cationic, zwitterionic or non-ionic surfactant.

The surfactant(s) may be selected to modify, typically increase, the permeation of the active agent into the target site. Namely, the surfactant, according to some embodiments, is a permeation enhancer. Exemplary surfactants are polysorbates (pegylated sorbitans), and polyoxyethylene esters of saturated (hydrogenated) and unsaturated castor oil, polyethylene glycols, ethoxylated monoglycerol esters, hydroxystearate, fatty acids, fatty acid salts, ethoxylated fatty acids, ethoxylated fatty alcohols, glycoside esters of saturated and unsaturated fatty acids, mono- or polyesters of sucrose, polyglycerol esters of fatty acids, ethoxylated monoglycerides, or ethoxylated diglycerides, and salts or derivatives thereof.

According to some embodiments, the auxiliary substance is selected from caprylic acid (sodium octanoate), capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentanoic acid (EP A), docosahezaenoic acid (DHA), sodium salcaprozate (SNAC), propylgallate, sodium cholate, sodium chenodeoxycholate, sodium deoxycholate, sodium ursodeoxycholate, sodium lithocholate, sodium glycocholate, sodium taurocholate, polyethylene glycol 12-hy doxy stearate (Kolliphor® HS15, Solutol® HS15), polyethylene glycol sorbitan monolaurate (TWEEN® 20), polyoxyethylene sorbitan monopalmitate (TWEEN® 40), polyethylene glycol sorbitan monostearate (TWEEN® 60), polyethylene glycol sorbitan monooleate (TWEEN® 80), sorbitan monolaurate (SPAN® 20), sorbitan monopalmitate (SPAN® 40), sorbitan monostearate (SPAN® 60), sorbitan monooleate (SPAN® 80), sorbitan trioleate (SPAN® 85), sodium dodecyl sulfate (SDS), dioctyl sodium sulfosuccinate (DSS), caprylyl sulfobetaine (3- (decyldimethylammonio)-propane-sulfonate inner salt), oleylsarcosine, N- lauroylsarcosine sodium salt (NLS), myristyl trimethylammonium bromide (MTB), dioctyl amine lecithin, propylene glycol, polyethylene glycol, 3-[(3- cholamidopropyl)dimethylammonio]-l -propanesulfonate hydrate (CHAPS), 1-oleyl-rac- glycerol, L-limonene, D-limonene, D,L-limonene, D-a-tocopherol polyethylene glycol succinate (TPGS), poly oxy ethyl ene(4)lauryl ether (Brij® 30), polyoxyethylene lauryl ether (Brij® 35), polyethylene glycol hexadecyl ether (Brij® 52), polyoxyethylene (20) cetylether (Brij® 58), polyoxyethylene (10) oleyl ether (Brij® O10, Brij® 97), polyoxyethylene (10) cetyl ether (Brij® CIO), 2-[2-[(Z)-9- Octadecenyloxy]ethoxy]ethanol (Brij® 92), sucrose monolaurate, n-octyl-P-D- glucopyranoside (n-octylglucoside), nonaethylene glycol monododecyl ether (polyoxyethylene (9) lauryl ether), nonanoyl-N-methylglucamide (MEGA-9), saponins, 3-(Decyldimethylammonio)-propane-sulfonate, glycolic acid ethoxylate lauryl ether, or any pharmaceutically acceptable salts of the auxiliary substance above, and mixtures thereof.

According to some other embodiments, the auxiliary substance is at least one permeation enhancer selected from sodium caprate, sodium salcaprozate (SNAC), propylgallate, sodium cholate, sodium chenodeoxy cholate, polyethylene glycol 12- hydoxystearate, polyethylene glycol sorbitan monooleate (polysorbate 80), sorbitan monooleate, sodium dodecyl sulfate (SDS), dioctyl sodium sulfosuccinate (DSS), oleic acid, myristyl trimethylammonium bromide (MTB), N-lauroylsarcosine sodium salt (NLS), lecithin, propylene glycol, 3-[(3-cholamidopropyl)dimethylammonio]-l- propanesulfonate hydrate (CHAPS), 1-oleyl-rac-glycerol, polyoxyethylene (20) cetylether, and mixtures thereof.

According to yet other embodiments, the auxiliary substance is at least one permeation enhancer selected from sodium caprate, sodium salcaprozate (SNAC), propylgallate, sodium cholate, sodium chenodeoxycholate, oleic acid, dioctyl sodium sulfosuccinate (DSS), N-Lauroylsarcosie sodium salt (NLS), and mixtures thereof.

In some embodiments, the auxiliary substance is ion pairing agent. Ion-pairing agents are compounds that contain both an ionic functional group and a hydrophobic portion, such as a hydrocarbon chain. The ion pair reagent is usually an alkyl sulfonate, an alkylsulfate, or an alkylammonium salt, or perfluorinated compounds, which may be used by itself or in addition to a surfactant to change penetration properties of the active agent.

According to some other embodiments, the auxiliary substance is at least one ion pairing agent selected from 1 -octanesulfonate sodium salt, 1 -butanesulfonic acid sodium salt, 2-naphthalenesulfonic acid sodium salt, dodecyltrimethylammonium chloride, sodium 1 -hexanesulfonate, sodium 1 -pentanesulfonate, tetrabutylammonium bromide, trifluoroacetic acid, heptafluorobutyric acid, and combinations thereof.

By some embodiments, the active agent and the one or more auxiliary substances, typically with one or more surfactant and/or with one or more permeation enhancers, are co-lyophilized one with the other when introduced into the slurry.

In the context of the present disclosure, the term tissue refers to any organ surface or biological membrane that may typically be coated by mucus or mucous membrane (e.g. the mucosal epithelial tissue). For example, the tissue can be gastric tissue, intestinal tissue, rectal tissue, vaginal tissue, urine tract tissue, nasal tissue, etc.

By some embodiments, the tissue is a gastrointestinal tissue, e.g. intestinal tissue.

As used herein, the term about is meant to encompass deviation of ±10% from the specifically mentioned value of a parameter, such as temperature, pressure, concentration, etc.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases ranging/ranges between a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

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

Generally it is noted that the term ...at least one... as applied to any component of the method or device should be read to encompass one, two, three, four, or even more different occurrences of said component in a composition of the invention.

It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the disclosure. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements. The embodiments are meant to refer to both the methods and the devices described herein, unless specifically noted otherwise.

As disclosed herein, the methods involve numerous steps which may or may not be associated with other common physical-chemical processes so as to achieve the desired form of each component. Unless otherwise indicated, such method steps, if present, may be set in different sequences without affecting the workability of the method and its efficacy in achieving the desired end result. As a person skilled in the art would appreciate, a sequence of steps may be employed and changed depending on various economical aspects, material availability, raw material, environmental considerations, etc., as long as the principles of the methods and the functionality of the devices described herein are maintained.

BRIEF DESCRIPTION OF THE DRAWINGS

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

Fig- 1 shows tensile test setup for tensile test of the active layer.

Fig- 2 shows tensile test results for active layers with different particle sizes of the mucoadhesive material.

Fig- 3 shows shear force test setup.

Fig. 4 shows shear force test results for active layers with different particle sizes of the mucoadhesive material.

DETAILED DESCRIPTION OF EMBODIMENTS

As noted, in the devices and methods of this disclosure, particle size of the mucoadhesive material in the active layer was found to surprisingly play a dominant role in the performance of the device. The following experiments were carried out in order to demonstrate the effect of particle size of the mucoadhesive material on the performance of the device.

Sodium carboxymethyl cellulose (NaCMC) was used as an exemplary mucoadhesive polymer in powder form. The NaCMC powder was sieved to result in predefined particle size ranges. The sieved powder was used to assess the effect of different particle size ranges on the performance of the mucoadhesive film.

Six formulations were prepared with similar components and weight percentage (wt%), however differing in particle size of NaCMC. The mechanical properties of the formulations were tested. Samples preparation

A backing film comprising primarily of cellulose acetate and cellulose acetate derivative was used. The backing film has a thickness of about 10pm.

For the active layer, iron gluconate was used as a model active agent. Hydroxypropylcellulose was used as a binder, and NaCMC was used as the mucoadhesive material. Hydroxypropylcellulose was dissolved in ethanol (abs.) to obtain a 12% solution. NaCMC and iron gluconate were added and stirred until a homogenous slurry was obtained. The slurry was then applied onto the backing film using a K Control coater, using install bar #200 (wire diameter: 0.36 mm, wet film deposit: 200 pm). After application, the samples were left at room temperature to permit evaporation of the ethanol. The resulting dried active layers contained 35-45 wt% NaCMC, 20-30 wt% hydroxypropylcellulose binder and 35-45 wt% iron gluconate.

As noted, six different formulations were prepared, varying the NaCMC particle size, as detailed in Table 1.

Table 1: NaCMC particle size fraction

Tensile test

A tensile test is a destructive test process that measures the tensile strength of the active layer, after its adhesion to the intestine. In the test the force required to detach the active layer from the intestine is measured, together with the extent to which the active layer stretches or elongates to its breaking point.

Test procedure: A sample of pig intestine was cut and placed (inner side up) on the test apparatus base (Fig. 1, location A), wetted with ISF (Intestinal Simulating Fluid) A metal ring was placed above the intestine to fixate it in position. The test sample was glued to a plastic base using double-sided tape and immersed into ISF solution for 3 minutes, active layer side up. Following immersion, the plastic base and sample were fixed to the Instron machine (Instron 3342, with 50N load cell) rod. The Instron machine rod was manually downloaded, until the active layer came into contact with the intestine (Fig. 1, location B), and held in position for 3 minutes. The rod was then raised upwards automatically, at a constant velocity, by the Instron machine while the force was measured as a function of distance (mm).

Table 2 and Fig. 2 present the tensile test results after a wetting time of 3 minutes. As can be seen, active layers with particles size below 75 pm showed a trend in which the bigger the particle size, the higher the maximal load. The active layer with particles size>150 pm remained connected to the intestine for the entire test duration. For active layers having a particle size of 75-99 pm and higher, the maximal load plateau is the selfweight of the apparatus base (Fig. 1, location A). The plateau that can be seen in Fig. 2 for these active layers represents the time (as rod was moved at constant velocity) that the rod traveled with the apparatus base attached to it. In view of the results, it is evident that complete adhesion occurs at particle sizes over 150 pm, which can cause excessive adhesion to the tissue and possible problems with disintegration and/or evacuation of the active layer from the target site.

Table 2: Maximum load - tensile test

Shear force test

Shear force is the force acting in a parallel direction to (over the top of) a surface or cross section of a body. The shear force test simulates the force that the active layer must overcome to remain attached to the inner part of the intestine. The shear force test is designed to apply stress to a film sample so that it experiences sliding along a plane that is parallel to the direction of the applied forces.

Test procedure: A sample of pig intestine was cut and placed (inner side up) on the test apparatus base (Fig. 3, location C), wetted with ISF. The test sample was held by double-sided tape on a test rectangle and immersed into ISF solution for 3 minutes, active layer side up. Following immersion, the rectangle was placed on the intestine for 3 minutes and held in location with a ~8g weight. A pull wire connects between the rectangle (Fig. 3, location C) and the Instron machine (Fig. 3, location A), via a pully arrangement (Fig. 3, location B), that enables the rectangle with the active layer to be pulled by the Instron machine (Instron 3342, with 50N load cell) parallel to the intestine sample at a constant speed for a pre-defined distance. The force was measured as a function of distance (mm).

Table 3 and Fig. 4 present the shear force test results after a wetting time of 3 minutes. The active later with particles size >150pm showed the significantly higher maximal indicating a very strong adhesion of the active layer to the tissue. The profiles of active layers with particles size <150 pm were similar (0.11±0.04 N), showing similar maximal loads. Hence, particle size of >150pm results in excessive shear resistance, which indicate an excessive unfavorable adhesion to the tissue.

Table 3: Maximum load - shear force test

EMBODIMENTS

1. A method for forming an active layer for delivery of at least one active agent to a tissue, the method comprising:

(a) mixing at least one non-aqueous solvent with at least one mucoadhesive material that is insoluble in said non-aqueous solvent and at least one binder soluble in said non-aqueous solvent, to obtain a slurry, said mucoadhesive material being in particulate form in the slurry,

(b) mixing said at least one active agent into the slurry,

(c) applying said slurry onto at least a surface portion of a carrying substrate, and (d) removing said non-aqueous solvent to obtain said active layer being attached to said carrying substrate, said active layer comprising said at least one active agent and said at least one mucoadhesive material being dispersed within the binder, said at least one mucoadhesive material substantially maintaining its particulate form within the active layer and having a particle size of no more than about 150 pm.

2. The method of embodiment 1, wherein step (b) is carried out concomitantly with step (a), such that said slurry is obtained by mixing said at least one non-aqueous solvent with said at least one mucoadhesive material, said at least one binder and said at least one active agent.

3. The method of embodiment 1 or 2, wherein said at least one mucoadhesive material has a particle size of between about 50 pm and about 150pm.

4. The method of any one of embodiments 1 to 3, wherein said at least one mucoadhesive material is selected from tragacanth, sodium alginate, guar gum, xanthan gum, karaya gum, gellan gum, carrageenan, soluble starches, gelatin, chitosan, cellulose derivatives (such as methylcellulose, ethylcellulose, hydroxylethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose), polyacrylic acid (PAA) polymers (such as carbomers, polycarbophil), polyhydroxyl ethylmethylacrylate, polyethyleneoxide (PEO, typically high molecular weight PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), lectins, pectin, thiolated polymers (for example chitosan-iminothiolane), poly(acrylic acid)-cysteine, poly(acrylic acid)-homocysteine, polyethylene glycol, chitosan- thioglycolic acid, chitosan-thioethylamidine, alginate-cysteine, poly(methacrylic acid)- cysteine, sodium carboxymethylcellulose-cysteine, and mixtures thereof.

5. The method of any one of embodiments 1 to 4, wherein said binder is soluble in said non-aqueous solvent and insoluble in an aqueous liquid.

6. The method of any one of embodiments 1 to 4, wherein said binder is soluble in said non-aqueous solvent and soluble in aqueous liquids having a pH of between about 5 and about 7.

7. The method of any one of embodiments 1 to 4, wherein said binder is soluble both in said non-aqueous solvent and in an aqueous liquid.

8. The method of any one of embodiments 1 to 4, wherein said at least one binder is selected from hydroxypropyl cellulose, povidone, ethylcellulose, cellulose acetate, polyvinyl cellulose, water insoluble polymethylmethacrylates, cellulose acetate phthalate, pH-sensitive polymethacrylates), hypromellose phthalate, and any mixture thereof.

9. The method of any one of embodiments 1 to 8, wherein said at least one active agent is at least one water-soluble active agent.

10. The method of any one of embodiments 1 to 9, wherein said at least one active agent is substantially insoluble in said non-aqueous solvent.

11. The method of any one of embodiments 1 to 10, wherein said at least one active agent is selected from antibiotics, proteins, peptides, polypeptides, lipids, nucleic acids, hormones, steroids, antibodies, vitamins, anti-inflammatories, antihistamines, antiemetics, analgesics, chemotherapeutic agents, prophylactic agents, clotting factors, radiopharmaceuticals, contrasting agents, electrolytes, nutraceuticals, and small molecules.

12. The method of any one of embodiments 1 to 10, wherein the at least one active agent is a biopharmaceutical.

13. The method of any one of embodiments, 1 to 12, wherein the at least one active agent is introduced into the slurry in a lyophilized state.

14. The method of any one of embodiments 1 to 13, wherein the active agent is in particulate form.

15. The method of embodiment 14, wherein the active agent has a particle size of no more than about 150 pm.

16. The method of any one of embodiments 1 to 15, wherein said non-aqueous solvent is selected from ethanol, isopropanol, acetone, and mixtures thereof.

17. The method of any one of embodiments 1 to 16, wherein said non-aqueous solvent is an anhydrous non-aqueous solvent.

18. The method of any one of embodiments 1 to 17, wherein the active layer comprises between about 20 wt% and about 50 wt% mucoadhesive material and between about 10 wt% and about 30 wt% of said binder.

19. The method of any one of embodiments 1 to 18, the weight ratio (weight: weight) between the mucoadhesive material and the binder ranges between about 5 : 1 to about 2:3.

20. The method of any one of embodiments 1 to 19, wherein said at least one active agent and said at least one mucoadhesive material are substantially dispersed within the binder. 21. The method of any one of embodiments 1 to 20, further comprising adding one or more additional components to the slurry during step (a), step (b) or both steps (a) and (b).

22. The method of any one of embodiments 1 to 21, wherein the slurry further comprises at least one plasticizer.

23. The method of any one of embodiments 1 to 22, wherein the slurry further comprises at least one filler in particulate form, the filler being substantially water insoluble and substantially insoluble in said non-aqueous solvent.

24. The method of any one of embodiments, 1 to 22, wherein the slurry further comprises at least one auxiliary substance.

25. The method of embodiment 24, wherein said at least one auxiliary substance is a surfactant and/or permeation enhancer.

26. The method of embodiment 25, wherein said at least one active agent and said at least one auxiliary substance are introduced into the slurry in a co-lyophilized state.

27. The method of any one of embodiments 1 to 26, wherein the slurry further comprises at least one pore-forming agent, the pore-forming agent being substantially insoluble in said non-aqueous solvent.

28. The method of any one of embodiments 1 to 27, further comprising adding at least one additional active substance into the slurry.

29. The method of any one of embodiments 1 to 28, wherein the carrying substate is a backing film.

30. The method of embodiment 29, wherein said backing film is made of a waterinsoluble substance.

31. The method of embodiment 29 or 30, wherein the backing film is made of a mixture of at least one water insoluble polymer, at least one enteric polymer, and at least one plasticizer.

32. The method of any one of embodiments 29 to 31, wherein said backing film is configured for attaching to a delivery arrangement.

33. The method of any one of embodiments 1 to 32, wherein said carrying substrate is at least a portion of an external surface of a delivery arrangement .

34. The method of any one of embodiments 1 to 28, wherein said carrying substrate constitutes at least a portion of a delivery arrangement . 35. The method of any one of embodiments 1 to 34, further comprising step (e) after step (d), step (e) comprises adhering the carrying substrate to a surface of a delivery arrangement.

36. The method of any one of embodiments 1 to 34, further comprises step (e’) after step (d), step (e’) comprises detaching the active layer from the carrying substrate and attaching the active layer to a surface of a delivery arrangement .

37. The method of any one of embodiments 1 to 34, wherein the carrying substrate is a multi-layer structure, the method further comprises step (e”) after step (d), step (e”) comprises removing one or more outmost layers thereof opposite the active layer to form an attachable surface, and attaching the attachable surface to a surface of a delivery arrangement.

38. The method of any one of embodiments 32 to 37, wherein the delivery arrangement is a patch.

39. The method of any one of embodiments 32 to 38, wherein the delivery arrangement is an ingestible device.

40. The method of embodiment 29, wherein the ingestible device is a gastrointestinal device.

41. The method of embodiment 40, wherein the gastrointestinal device is a gastrointestinal deployable device.

42. The method of any one of embodiments 1 to 41, further comprising a step (0), before step (a) or before step (b) or before step (c), step (0) comprises attaching or forming said carrying substrate onto a support element, the support element being configured to provide mechanical support to the carrying substrate during application of the slurry thereonto; and step (d’) after step (d), of removing the carrying substrate from the support element after formation of the active layer.

43. The method of any one of embodiments 1 to 42, further comprising applying one or more functional layers onto the active layer.

44. The method of any one of embodiments 1 to 43, wherein said carrying substrate comprises one or more coating layers prior to application of the slurry thereonto.

45. An active layer for delivery of at least one active agent to a tissue, the active layer comprising at least one active agent and at least one mucoadhesive material being dispersed within at least one binder, said at least one mucoadhesive material being in particulate form having a particle size of no more than about 150 pm. 46. The active layer of embodiment 45, wherein said active agent is in particulate form.

47. The active layer of embodiment 46, wherein the active agent has a particle size of no more than about 150 pm.

48. The active layer of any one of embodiments 45 to 47, wherein said at least one active agent is at least one water-soluble active agent.

49. The active layer of any one of embodiments 45 to 48, wherein said at least one active agent is selected from antibiotics, proteins, peptides, polypeptides, lipids, nucleic acids, hormones, steroids, antibodies, vitamins, anti-inflammatories, antihistamines, antiemetics, analgesics, chemotherapic agents, prophylactic agents, clotting factors, radiopharmaceuticals, contrasting agents, electrolytes, nutraceuticals, and small molecules.

50. The active layer of any one of embodiments 45 to 48, wherein the at least one active agent is a biopharmaceutical.

51. The active layer of any one of embodiments 45 to 50, wherein said at least one mucoadhesive material is selected from tragacanth, sodium alginate, guar gum, xanthan gum, karaya gum, gellan gum, carrageenan, soluble starches, gelatin, chitosan, cellulose derivatives (such as methylcellulose, ethylcellulose, hydroxylethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (NaCMC)), polyacrylic acid (PAA) polymers (such as carbomers, polycarbophil), polyhydroxyl ethylmethylacrylate, polyethyleneoxide (PEO, typically high molecular weight PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), lectins, pectin, thiolated polymers (for example chitosan-iminothiolane), poly(acrylic acid)-cysteine, poly(acrylic acid)-homocysteine, polyethylene glycol, chitosan-thioglycolic acid, chitosan-thioethylamidine, alginate-cysteine, poly(methacrylic acid)-cysteine, sodium carboxymethylcellulose-cysteine, and mixtures thereof.

52. The active layer of any one of embodiments 45 to 51, wherein said at least one binder is selected from hydroxypropyl cellulose, povidone, ethylcellulose, cellulose acetate, polyvinyl cellulose, water insoluble polymethylmethacrylates, cellulose acetate phthalate, pH-sensitive polymethacrylates), hypromellose phthalate, and any mixture thereof. 53. The active layer of any one of embodiments 45 to 52, wherein the active layer comprises between about 20 wt% and about 50 wt% mucoadhesive material and between about 10 wt% and about 30 wt% of said binder.

54. The active layer of any one of embodiments 45 to 43, the weight ratio (weight weight) between the mucoadhesive material and the binder ranges between about 5: 1 to about 2:3.

55. The active layer of any one of embodiments 45 to 54, wherein the active layer further comprises at least one plasticizer.

56. The active layer of any one of embodiments 45 to 55, wherein the active layer further comprises at least one filler in particulate form, the filler being substantially water insoluble.

57. The active layer of any one of embodiments 45 to 56, wherein the active layer further comprises at least one pore-forming agent, the pore-forming agent being water soluble.

58. The active layer of any one of embodiments 45 to 57, wherein the active layer further comprises one or more additional non-pharmaceutically active components.

59. The active layer of any one of embodiments 45 to 58, wherein the active layer further comprising at least one additional pharmaceutically active substance.

60. The active layer of any one of embodiments 45 to 59, wherein the active layer further comprises one or more auxiliary substances.

61. The active layer of embodiment 60, wherein said at least one auxiliary substance is a surfactant and/or permeation enhancer.

62. A device for delivery of at least one active agent to a tissue, the device comprises an active layer according to any one of embodiments 45 to 61 attached to a carrying substrate.

63. The device of embodiment 62, wherein said carrying substrate is a backing film.

64. The device of embodiment 62, wherein the carrying substrate is attached to at least a portion of a backing film.

65. The device of embodiment 63 or 64, wherein said backing film is made of a waterinsoluble substance.

66. The device of any one of embodiments 63 to 65, wherein the backing film is made of a mixture of at least one water insoluble polymer, at least one enteric polymer, and at least one plasticizer. 67. The device of any one of embodiments 63 to 66, wherein the backing film is a multi-layered structure.

68. The device of any one of embodiments 63 to 66, further comprising one or more coating layers located between the backing film and the active layer.

69. The device of any one of embodiments 63 to 68, wherein said backing film is configured for attaching to a delivery arrangement.

70. The device of any one of embodiments 63 to 68, wherein said backing film is attached to a delivery arrangement.

71. The device of any one of embodiments 63 to 68, wherein said backing film constitutes at least a portion of an external surface of a delivery arrangement.

72. The device of any one of embodiments 63 to 68, wherein said backing film constitutes at least a portion of a delivery arrangement.

73. The device of any one of embodiments 63 to 68, wherein the backing film constitutes a delivery arrangement.

74. The device of embodiment 62, wherein said carrying substrate is a portion of a delivery arrangement.

75. The device of embodiment 62, wherein said carrying substate constitutes a delivery arrangement.

76. A device for delivery of at least one active agent to a tissue, the device comprises an active layer according to any one of embodiments 45 to 61, attached to at least a portion of a surface of a delivery arrangement.

77. The device of any one of embodiments 62 to 76, wherein the device is an ingestible device.

78. The device of embodiment 77, wherein the device is a gastrointestinal device.

79. The device of embodiment 78, wherein the gastrointestinal device is a deployable gastrointestinal device.

80. The device of embodiment 78 or 79, wherein the gastrointestinal device is patch.

81. The device of any one of embodiments 76 to 80, comprising a backing film between said portion of the surface of the delivery arrangement and the active layer.

82. The device of embodiment 81, wherein said backing film is made of a waterinsoluble substance. 83. The device of embodiment 82, wherein the backing film is made of a mixture of at least one water insoluble polymer, at least one enteric polymer, and at least one plasticizer.

84. The device of any one of embodiments 81 to 83, wherein the backing film is a multi-layered structure.

85. The device of any one of embodiments 62 to 84, further comprising one or more functional layers disposed over the active layer.

86. The device of embodiment 85, wherein said one or more functional layers comprise one or more mucoadhesive layers substantially devoid of said active agent.

Claims

CLAIMS:

(b) mixing said at least one active agent into the slurry,

(c) applying said slurry onto at least a surface portion of a carrying substrate, and

(d) removing said non-aqueous solvent to obtain said active layer being attached to said carrying substrate, said active layer comprising said at least one active agent and said at least one mucoadhesive material being dispersed within the binder, said at least one mucoadhesive material substantially maintaining its particulate form within the active layer and having a particle size of no more than about 150 pm.

2. The method of claim 1, wherein step (b) is carried out concomitantly with step (a), such that said slurry is obtained by mixing said at least one non-aqueous solvent with said at least one mucoadhesive material, said at least one binder and said at least one active agent.

3. The method of claim 1 or 2, wherein said at least one mucoadhesive material has a particle size of between about 50 pm and about 150pm.

4. The method of any one of claims 1 to 3, wherein said at least one mucoadhesive material is selected from tragacanth, sodium alginate, guar gum, xanthan gum, karaya gum, gellan gum, carrageenan, soluble starches, gelatin, chitosan, cellulose derivatives (such as methylcellulose, ethylcellulose, hydroxylethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose), polyacrylic acid (PAA) polymers (such as carbomers, polycarbophil), polyhydroxyl ethylmethylacrylate, polyethyleneoxide (PEO, typically high molecular weight PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), lectins, pectin, thiolated polymers (for example chitosan-iminothiolane), poly(acrylic acid)-cysteine, poly(acrylic acid)-homocysteine, polyethylene glycol, chitosan- thioglycolic acid, chitosan-thioethylamidine, alginate-cysteine, poly(methacrylic acid)- cysteine, sodium carboxymethylcellulose-cysteine, and mixtures thereof.

5. The method of any one of claims 1 to 4, wherein said binder is soluble in said non-aqueous solvent and insoluble in an aqueous liquid.

6. The method of any one of claims 1 to 4, wherein said binder is soluble in said non-aqueous solvent and soluble in aqueous liquids having a pH of between about 5 and about 7.

7. The method of any one of claims 1 to 4, wherein said binder is soluble both in said non-aqueous solvent and in an aqueous liquid.

8. The method of any one of claims 1 to 4, wherein said at least one binder is selected from hydroxypropyl cellulose, povidone, ethylcellulose, cellulose acetate, polyvinyl cellulose, water insoluble polymethylmethacrylates, cellulose acetate phthalate, pH- sensitive polymethacrylates), hypromellose phthalate, and any mixture thereof.

9. The method of any one of claims 1 to 8, wherein said at least one active agent is at least one water-soluble active agent.

10. The method of any one of claims 1 to 9, wherein said at least one active agent is substantially insoluble in said non-aqueous solvent.

11. The method of any one of claims 1 to 10, wherein said at least one active agent is selected from antibiotics, proteins, peptides, polypeptides, lipids, nucleic acids, hormones, steroids, antibodies, vitamins, anti-inflammatories, antihistamines, antiemetics, analgesics, chemotherapic agents, prophylactic agents, clotting factors, radiopharmaceuticals, contrasting agents, electrolytes, nutraceuticals, and small molecules.

12. The method of any one of claims 1 to 10, wherein the at least one active agent is a biopharmaceutical.

13. The method of any one of claims 1 to 12, wherein the active agent is in particulate form.

14. The method of any one of claims 1 to 13, wherein said non-aqueous solvent is selected from ethanol, isopropanol, acetone, and mixtures thereof.

15. The method of any one of claims 1 to 14, wherein the active layer comprises between about 20 wt% and about 50 wt% mucoadhesive material and between about 10 wt% and about 30 wt% of said binder.

16. The method of any one of claims 1 to 15, wherein said at least one active agent and said at least one mucoadhesive material are substantially dispersed within the binder.

17. The method of any one of claims 1 to 16, further comprising adding one or more additional components to the slurry during step (a), step (b) or both steps (a) and (b).

18. The method of any one of claims 1 to 17, wherein the slurry further comprises at least one plasticizer.

19. The method of any one of claims 1 to 18, wherein the slurry further comprises at least one filler in particulate form, the filler being substantially water insoluble and substantially insoluble in said non-aqueous solvent.

20. The method of any one of claims 1 to 19, wherein the slurry further comprises at least one pore-forming agent, the pore-forming agent being substantially insoluble in said non-aqueous solvent.

21. The method of any one of claims 1 to 20, wherein the carrying substate is a backing film.

22. The method of claim 21, wherein said backing film is made of a water-insoluble substance.

23. The method of claim 22, wherein the backing film is made of a mixture of at least one water insoluble polymer, at least one enteric polymer, and at least one plasticizer.

24. The method of any one of claims 21 to 23, wherein said backing film is configured for attaching to a delivery arrangement.

25. The method of any one of claims 1 to 20, wherein said carrying substrate is at least a portion of an external surface of a delivery arrangement.

26. The method of any one of claims 1 to 25, further comprising step (e) after step (d), step (e) comprises adhering the carrying substrate to a surface of a delivery arrangement.

27. The method of any one of claims 1 to 25, further comprises step (e’) after step (d), step (e’) comprises detaching the active layer from the carrying substrate and attaching the active layer to a surface of a delivery arrangement.

28. The method of any one of claims 1 to 25, wherein the carrying substrate is a multi-layer structure, the method further comprises step (e”) after step (d), step (e”) comprises removing one or more outmost layers thereof opposite the active layer to form an attachable surface, and attaching the attachable surface to a surface of a delivery arrangement.

29. The method of any one of claims 26 to 28, wherein the delivery arrangement is a patch.

30. The method of any one of claims 24 to 27, wherein the delivery arrangement is an ingestible device, optionally wherein the ingestible device is a gastrointestinal device, further optionally wherein the gastrointestinal device is a gastrointestinal deployable device.

31. The method of any one of claims 1 to 30, further comprising a step (0), before step (a) or before step (b) or before step (c), step (0) comprises attaching or forming said carrying substrate onto a support element, the support element being configured to provide mechanical support to the carrying substrate during application of the slurry thereonto; and step (d’) after step (d), of removing the carrying substrate from the support element after formation of the active layer.

32. The method of any one of claims 1 to 31, further comprising applying one or more functional layers onto the active layer.

33. An active layer for delivery of at least one active agent to a tissue, the active layer comprising at least one active agent and at least one mucoadhesive material being dispersed within at least one binder, said at least one mucoadhesive material being in particulate form having a particle size of no more than about 150 pm.

34. The active layer of claim 33, wherein said active agent is in particulate form.

35. The active layer of claim 33 or 34, wherein said at least one active agent is at least one water-soluble active agent.

36. The active layer of any one of claims 33 to 35, wherein said at least one active agent is selected from antibiotics, proteins, peptides, polypeptides, lipids, nucleic acids, hormones, steroids, antibodies, vitamins, anti-inflammatories, antihistamines, antiemetics, analgesics, chemotherapeutic agents, prophylactic agents, clotting factors, radiopharmaceuticals, contrasting agents, electrolytes, nutraceuticals, and small molecules.

37. The active layer of any one of claims 33 to 35, wherein the at least one active agent is a biopharmaceutical.

38. The active layer of any one of claims 33 to 37, wherein said at least one mucoadhesive material is selected from tragacanth, sodium alginate, guar gum, xanthan gum, karaya gum, gellan gum, carrageenan, soluble starches, gelatin, chitosan, cellulose derivatives (such as methylcellulose, ethylcellulose, hydroxylethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (NaCMC)), polyacrylic acid (PAA) polymers (such as carbomers, polycarbophil), polyhydroxyl ethylmethylacrylate, polyethyleneoxide (PEO, typically high molecular weight PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), lectins, pectin, thiolated polymers (for example chitosan-iminothiolane), poly(acrylic acid)-cysteine, poly(acrylic acid)-homocysteine, polyethylene glycol, chitosan-thioglycolic acid, chitosan-thioethylamidine, alginate-cysteine, poly(methacrylic acid)-cysteine, sodium carboxymethylcellulose-cysteine, and mixtures thereof.

39. The active layer of any one of claims 33 to 38, wherein said at least one binder is selected from hydroxypropyl cellulose, povidone, ethylcellulose, cellulose acetate, polyvinyl cellulose, water insoluble polymethylmethacrylates, cellulose acetate phthalate, pH-sensitive polymethacrylates), hypromellose phthalate, and any mixture thereof.

40. The active layer of any one of claims 33 to 39, wherein the active layer comprises between about 20 wt% and about 50 wt% mucoadhesive material and between about 10 wt% and about 30 wt% of said binder.

41. The active layer of any one of claims 33 to 40, wherein the active layer further comprises at least one plasticizer.

42. The active layer of any one of claims 33 to 41, wherein the active layer further comprises at least one filler in particulate form, the filler being substantially water insoluble.

43. The active layer of any one of claims 33 to 42, wherein the active layer further comprises at least one pore-forming agent, the pore-forming agent being water soluble.

44. The active layer of any one of claims 33 to 43, wherein the active layer further comprises one or more additional non-pharmaceutically active components.

45. A device for delivery of at least one active agent to a tissue, the device comprises an active layer according to any one of claims 33 to 44 attached to at least a portion of a surface of a delivery arrangement.

46. The device of claim 45, comprising a backing film between said portion of the surface of the delivery arrangement and the active layer.

47. The device of claim 45 or 46, wherein said backing film is made of a waterinsoluble substance.

48. The device of claim 47, wherein the backing film is made of a mixture of at least one water insoluble polymer, at least one enteric polymer, and at least one plasticizer.

49. The device of any one of claims 45 to 48, wherein the backing film is a multilayered structure.

50. The device of any one of claims 45 to 49, wherein the device is an ingestible device, optionally wherein the device is a gastrointestinal device, further optionally wherein the gastrointestinal device is a deployable gastrointestinal device.

51. The device of claim 50, wherein the gastrointestinal device is patch.

52. The device of any one of claims 45 to 51, further comprising one or more functional layers disposed over the active layer, optionally wherein said one or more functional layers comprise one or more mucoadhesive layers substantially devoid of said active agent.