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1. (WO2018225075) DEVICES FOR DELIVERY OF ACTIVE AGENTS TO A TARGET SITE
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DEVICES FOR DELIVERY OF ACTIVE AGENTS TO A TARGET SITE

TECHNOLOGICAL FIELD

The present disclosure concerns devices, i.e. medical devices, for delivery of various active agents to a target site. More specifically, this disclosure concerns devices for controlled release of an active agent upon contact with bodily fluids, e.g. blood.

BACKGROUND ART

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

- US 2006/173430

- WO 08/059266

- US 5,141,750

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

Devices for topical delivery of agents are known. Most such devices, for example devices for delivery of hemostatic agents to a topical wound are based on layered structures in which one of the layers contain the hemostatic agent, or may be in the form of a pouch that contains the hemostatic agent that releases the agent to the target site upon breach of the pouch. Such devices often have a limited flexibility and hence provide limited contact area with the target site. In addition, often such devices have limited capacity to carry and deliver a plurality of active agents.

As such devices are typically used by first-aid care providers, these devices also require to be easily applied to the site of injury and simple to use.

GENERAL DESCRIPTION

The present disclosure concerns devices, i.e. medical devices, that are designed to deliver one or more active agents to a target site in controlled and selective manner and sequence of delivery. In some designs of the devices of this disclosure, the device also have improved flexibility to maximize the contact area with the target site. The devices of this disclosure are designed to selectively control the timing and location of delivery of the active agent by providing, inter alia, a highly controllable local disintegration of one or more portions of the device in order to release the active agent contained therein in a targeted and timed manner {e.g. substantially immediate and local release of active agent from the device to the target site upon contact of the device with the target site).

For this purpose, the present disclosure provides medical devices, e.g. bandages or dressings, that comprise a plurality of cells that contain at least one active agent, and are configured for selective release of the active agent to the target site. By segmenting the devices to a plurality of cells, improved flexibility of the device is obtained, as well as isolation of various active agents one from the other prior to use. It is a further object of the present disclosure to provide an application device that permits highly localized application of active agents topically or within bodily cavities by releasing a plurality of capsules that contain said at least one active agent directly to the target site.

Thus, in a first aspect of this disclosure, there is provided a flexible device for delivery of at least one active agent to a target site, the device comprises a flexible substrate for placing onto the target site with a plurality of spaced-apart cells, each cell containing the at least one active agent and having at least one wall portion made of a film of at least one polymeric material that is at least partially disintegrable upon contact with a fluid to thereby release the active ingredient to the target site.

The term flexible or any lingual variation thereof, is meant to denote the property of pliability, being able to bend or fold without applying significant force while maintaining structural integrity. In the device of this disclosure, flexibility is rendered possible by the combination of a flexible substrate and the segmentation of the agent-carrying pouch carried by the substrate. Segmentation to a plurality of spaced-apart cells allows the device to be folded or bent along the division lines, separating between the cells, such that the device can be formed to closely follow the contours of the body part to which the device is applied and remain in contact therewith.

The cells carried by the substrate are closed cells, each being of a desired volume and shape. The cells may each have identical volume and/or shape, or may differ one from the other in one or both of their volume and shape. The cells are said to be spaced-apart one from the other, i.e. being distanced one from the other in a plane defined by the flexible substrate.

The plurality of cells include at least 2 cells. In some embodiments, the device includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or more cells, arranged in a spaced-apart manner on the substrate. The arrangement may be in an ordered form {i.e. an ordered array) or in random distribution.

At least a portion of the cells, at times each of the cells, contain therein at least one active agent to be delivered by the device to a target site. For this purpose, the cells are made of at least one polymeric material that is at least partially disintegrable upon contact with a fluid. The term disintegrable means to denote physical or chemical destruction of the polymeric material, thus causing rupture of the cell and release of the active material contained therein. The term means to encompass any type of physical or chemical disintegration, e.g. solubilization, dispersion, chemical reaction that causes disintegration of the polymer chains, swelling or gelling of the polymer, or any other suitable deterioration of the structural integrity of the cell that is caused by contact with a suitable fluid. The polymeric material is at least partially disintegrable, meaning that complete disintegration of the polymeric material is not compulsory; the polymeric material needs to be disintegrable to the extent that the release of the active agent contained within the cell is enabled.

In the device of this disclosure, the cells may be configured for selective disintegration upon contact with said fluid. Namely, cells which have not been in contact with the fluid will remain intact. Thus, when applied to the target site, only cells which are in contact with a fluid present in the target site will be disintegrated to release the active agent to the target site; adjacent cells will not be ruptured. Contrary to devices in which a single pouch is used and its entire content is delivered, the selective disintegration enables targeted delivery of the active agent(s) only to the desired target site.

In some embodiments, the polymeric material is fully disintegrable within between about 5 second and 30 minutes from contact with said fluid. In other embodiments, said polymeric material may be fully disintegrable within between about 5 second and 10 minutes from contact with said fluid. In some other embodiments, said

polymeric material is fully disintegrable within between about 5 second and 2 minutes from contact with said fluid.

The cells may also differ by their disintegration rates; namely, in some embodiments at least one portion of cells and at least another portion of cells being configured to have different disintegration rates to release said active agents therefrom at different rates. In other words, some of the cells may be made of a polymeric material, or may be structured as will be described below, to have a first disintegration rate, while other cells may be configured to have a slower disintegration rate. Such an arrangement enables the formation of a sequence of releasing of active agents from the device, for example a first active agent is released, followed by the release of another dose of said first active agent or the release of a second active agent. Such arrangements will be described in more details below.

In the context of the present disclosure, the term polymeric material (or polymer) includes homopolymers, copolymers, such as for example, block, graft, random and alternating copolymers as well as terpolymers, further including their derivatives, combinations and blends thereof. In addition to the above the term includes all geometrical configurations of such structures including linear, block, graft, random, alternating, branched structures, and combination thereof. Block copolymer is meant to encompass a polymer formed from two or more homo-polymer subunits (blocks) linearly linked by chemical bonds {i.e. the blocks are connected end-to-end). Block copolymers with two, three, four and multiple homo-polymer units are referred to as di-block, tri-block, tetra-blocks and multi-blocks respectively. The number of monomer types in a block co-polymer may be less than or equal to the number of blocks. Thus, an ABC linear tri-block consists of three monomer types, whereas an ABA linear tri-block consists of two monomer types.

The polymeric material is selected to be at least partially disintegrable when in contact with a fluid present at the target site. In some embodiments, the fluid is a bodily fluid, e.g. blood, saliva, urine, gastrointestinal fluid, cerebral fluid, etc. According to some embodiments, the fluid is blood. Thus, in some embodiments, the polymeric material is biocompatible (and/or its degradation products are biocompatible).

As a man of the art would appreciate, water is one of the primary constituents of such bodily fluids. Therefore, in some embodiments, the polymeric material is selected to be at least partially disintegrable when in contact with water, i.e. being water-soluble or water-dispersible. Typically, water soluble or dispersible polymers contain hydrophilic groups as substituents or incorporated into the backbone of the polymer chain. Examples of such water-disintegrable polymers are polysaccharide, which may or may not have a plurality of identical monomers (such as in the case of dextran) or different monomers (such as in the case of arabinogalactan). The polysaccharide may be natural or synthetic and may be branched or linear. The polysaccharide may be a chemically modified or a semi-synthetic polysaccharide, permitting association with the at least one drug moiety. Exemplary polysaccharides are starch, glycogen, cellulose, dextran, pullulan, chitosan, arabinin, arabinogalactan, galactan, galactomannan, gelatin, pectin, amilo-pectin, glycan, poly-mannan, hyaluronic acid, guar gum and any other poly sugar or synthetic combination thereof.

Other exemplary water-disintegrable polymeric materials may be comprise a polymer selected from polyethyleneoxide (PEO), polyvinylpyrrolidone (PVP), polyvinyl-alcohol (PVA), polyacrylic acid (PAA), polyacryloamides, polyoxazoline, cellulose ethers (e.g. HPMC, HPC), etc.

It is of note that the cells are made of said polymeric material, being in film form. Namely, the cells are formed out of sheets of polymeric material. The film may be a single-layered film made of said polymeric material. Alternatively, the film may comprise two or more layers of polymeric material, the layers may be the same or different in their composition, thickness, uniformity, water disintegrability, etc., as long as the multi-layered film is at least partially disintegrable to permit release of the active agent from the cell or capsule.

The polymeric material may have, by some embodiments, a molecular weight of at least 50,000 g/mole. In other embodiments, the molecular weight of the polymeric material may be between about 100,000 to 200,000 g/mole.

In some embodiments, portions of the films may be textured, e.g. embossed, micro- or nano-perforated, to modify the disintegrability of the film.

As noted herein, the cells in the plurality of cells may differ one from the other. Thus, in some embodiments, at least one portion of cells is different in at least one property from at least another portion of cells in the plurality of cells. The property may be at least one property selected from film thickness, molecular weight of the polymeric material, composition of the polymeric material, film texture, water solubility of the film, volume of cell, geometry of cell, geometry and size of disintegrable area, type of active agent contained therein, etc.

In order to maintain structural integrity of the device, the flexible substrate may be made of a material substantially non-disintegrable or non-soluble upon contact with said fluid. Thus, the substrate remains intact during use. The substrate may be made of any suitable material, e.g. a polymer, a natural fabric, a synthetic fabric, a woven flexible composite, etc. The device may further comprise additional external flexible layers, such as fabric layers, coatings, absorbing layers, and others.

As already noted, the cells are arranged in a space-apart manner. In some embodiments, the cells are spaced-apart by substantially non-disintegrable segments, thus also forming a peripheral seal around each cell. The non-disintegrable segments may have non-uniform thickness and/or density to permit flexibility and/or foldability of said segments. The segments may be perforated in order to afford further flexibility of the device. The non-disintegrable segments may be made of the same or different material as the flexible substrate.

The cells comprise at least one active agent for delivery to a target site. The active agent may be any agent, chemical or biological, that is required for delivery to the target site, and may be in any suitable form, such as a powder, a non-aqueous liquid, a nonaqueous solution, a non-aqueous suspension, crystalline form, non-aqueous gel, emulsion, or any other suitable form. It is of note that the term also means to encompass formulations and compositions comprising the active agent.

Each cell may comprise one or more active agents, each having a similar or different activity. In some embodiments, all of the cells in the plurality of cells contain the same active agent.

In other embodiments, at least one portion of the cells contain an active agent differing from the active agent contained in at least another portion of cells. For example, a first portion of cells may contain an anticoagulant, while a second portion of the cells (that is, for example, disintegrable at a slower rate) may contain an antibiotic. In another example, a first portion of cells that come into contact with the target site contain a first agent to be administered directly to the target site, while other cells that are positioned peripherally to the first portion contain a second agent to be administered to the peripheral area of the target site.

The segmentation into a plurality of cells may also permit delivering different active agents, which are instable when combined or are not compatible for prolonged storage one with the other, to the same target site - as such different agents may be contained in adjacent spaced-apart cells. Due to the segmentation, such active agents are isolated one from the other during storage of the device, and only come into contact with one another when in use. Similarly, adjacent cells may contain different agents which react with one another upon contact to produce a desired active agent in situ at the target site.

The active agent may be selected from a coagulant, an antibiotic agent, a clotting factor, a hemostatic agent, an antimicrobial agent, a disinfectant, or any other approved compound relevant for emergency use, and mixtures and/or formulations thereof. Exemplary active agents may include coagulants such as alginate, trans-4-(aminomethyl) cyclohexanecarboxylic acid (tranexamic acid), or antibiotics such as ciprofloxacin and metronidazole, and others.

At times, the disintegration of the cells needs to be accelerated, i.e. immediate release of the cell's content is desired. Therefore, such cells may be made of a highly-soluble polymeric material.

In another embodiment, the cells may contain, in addition to the active agent, a decomposable agent capable of forming a gaseous decomposition product upon contact with the fluid. In such cases, once initial disintegration of the cell occurs and the decomposable agent comes into contact with the fluid, it decomposes into voluminous gaseous decomposition products that cause abrupt rupturing of the cell and faster release of the active agent therefrom. Exemplary decomposable agents may be calcium bicarbonate (Ca(HC03)2) or other relevant exothermic material.

According to some embodiments, the device may be a bandage, a dressing, a sleeve, a pad, an elastic pad, a standalone capsule, etc.

Such dressing utilities typically comprise one or more various layers of woven or non-woven fabric, e.g. elastic fabric, integrated one with the other to form the dressing. The devices of the present disclosure may be configured for association (e.g. adhering) or integration with the dressing utility to form an active dressing utility.

The device may further comprise an adhesive on at least a portion of the device's perimeter to enable temporary fixation and/or application of pressure onto the target site.

Thus, in some embodiments, the device may be in the form of a plaster or an adhesive bandage.

In another application, the device may be configured for insertion into a body cavity or lumen, such as an artery, a vein, intestinal tract, urinary tract, vaginally, rectally, etc. In such embodiments, the device may be configured to have a tubular form, for example, a tampon. In other such embodiments, the device may be configured for insertion into a wound, e.g. stab wound, gunshot wound, etc.

Devices of this disclosure can also be used to deliver at least one active agent to a target site, e.g. a surface wound or a target site located within a body cavity, a body tissue, or a body lumen, in the form of particulate matter. In such devices, selectively disintegrable particles are delivered by the device directly to the target site, in which the particles are selectively disintegrated by the fluid, e.g. blood, coming into contact with the particles.

Thus, in another aspect, this disclosure provides an application device for delivery of at least one active agent to a target site, the device comprises at least one container holding a plurality of disintegrable carriers, each carrier comprising at least one active agent, the particle having at least one portion made of at least one polymeric material that is at least partially disintegrable upon contact with a fluid to thereby release the active ingredient to the target site; and at least one application means to extract the disintegrable carriers from the container for application onto or into the target site.

The term carriers refers to a formulation comprising the at least one polymeric material and said at least one active agent being in discrete particulate form. The carriers may be of any suitable form, e.g. capsules, particles, core-shell particles, tablets, etc., and mixtures thereof.

In some embodiments, the carriers are in the form of capsules, in which the at least one active agent is encapsulated in a shell. The shell may have at least one shell portion made of a film of said at least one polymeric material that is at least partially disintegrable upon contact with a fluid, thus enabling release of the active ingredient. In some embodiments, the entire shell is made out of said at least one polymeric material.

In other embodiments, the carriers may be in the form of particles, in which the at least one active agent is embedded or dispersed within a matrix made of said at least one

polymeric material, and the active agent is released from the particle upon disintegration of the matrix.

The carriers may have any suitable size and shape. In some embodiments, the carriers may have an average diameter of between about 3 mm and about 30 mm.

The plurality of carriers may vary between 2 and 100 carriers, 2 and 200 carriers, 2 and 500 carriers or even 2 and 1000 carriers or more.

In the application device of this disclosure, the carriers may be configured for selective disintegration upon contact with said fluid; namely, carriers which have not been in contact with the fluid will remain intact. Contrary to devices in which a mass of polymeric material is injected/applied into/onto the target site in order to deliver an active agent, the application device of this embodiment is configured to apply discrete carriers, each having a desired release profile of the active agent, depending on the extent of exposure to the fluid. Such carriers do not form a solid mass of material, that may cause damage to the tissue at the target site and/or may be problematic to remove from the target site. Thus, the application of the selectively disintegrable carriers by the device provides effective delivery of the active agent directly to the target site with minimum damage to surrounding tissues.

In some embodiments, the polymeric material is fully disintegrable within between about 5 second and 30 minutes from contact with said fluid. In other embodiments, said polymeric material may be fully disintegrable within between about 5 second and 10 minutes from contact with said fluid. In some other embodiments, said polymeric material is fully disintegrable within between about 5 second and 2 minutes from contact with said fluid.

The carriers may also differ by their disintegration rates; namely, in some embodiments at least one portion of carriers and at least another portion of carriers being configured to have different disintegration rates to release said active agents therefrom at different rates. In other words, some of the carrier may be made of a polymeric material, or may be structured as will be described below, to have a first disintegration rate, while other carriers may be configured to have a slower disintegration rate. Such an arrangement enables the formation of a sequence of releasing of active agents from the carriers, for example a first active agent is released, followed by the release of another dose of said first active agent or the release of a second active agent.

The polymeric material and active agents constituting part of the carriers are those defined hereinabove and may be selected therefrom.

Each carrier may comprise one or more active agents, each having a similar or different activity. In some embodiments, all of the carriers in the plurality of cells contain the same active agent.

In other embodiments, at least one portion of the carriers contain an active agent differing from the active agent contained in at least another portion of carriers. For example, a first portion of carriers may contain an anticoagulant, while a second portion of the carriers (that is, for example, disintegrable at a slower rate) may contain an antibiotic.

Similar to the flexible device, at times, the disintegration of the carriers needs to be accelerated, i.e. immediate release of the carriers' content is desired. Therefore, such carriers may be made of a highly-soluble polymeric material. In another embodiment, the carriers may contain, in addition to the active agent, a decomposable agent capable of forming a gaseous decomposition product upon contact with the fluid. In such cases, once initial disintegration of the carrier occurs and the decomposable agent comes into contact with the fluid, it decomposes into voluminous gaseous decomposition products that cause abrupt rupturing of the carrier and faster release of the active agent therefrom. Exemplary decomposable agents may be calcium bicarbonate (Ca(HC03)2) or other relevant exothermic material.

The container of the application device may be of any suitable shape, size and volume, and configured to hold said plurality of carriers, such that upon operation of the application means, the carriers may be extracted from the container and applied to the target site. The container may be transparent, translucent or opaque, and can be made of any suitable material, e.g. plastic, glass, metal, ceramic, composite material, etc.

In some embodiments, the container may comprise two or more sub-containers, each sub-container holding carriers containing a different active agent or a different type of carriers, the sub-container being arranged to extract carriers from each sub-container in a sequence of extraction.

In other embodiments, the container may be divided into two more compartments, each compartment holding carriers containing a different active agent or a different type of carriers, the compartments being arranged to extract carriers from each compartment in a sequence of extraction.

The application means may be of any suitable form or design; for example, a swab, a spoon, etc.

In some embodiments, the application means may be in the form of a piston that is snugly fitted within the container, and displaceable between an extended state and a retracted state and configured to extract said plurality of carriers through an opening in the container during the piston's displacement from the extended state to the retracted state. In such embodiments, the opening may have a closed state and an open state, and may be configured to switch from the open state to the closed state by the pressure applied by the piston during displacement from the extended state to the retracted state.

In other embodiments, the opening in the container may be sealed by a removable sealing member, configured for removal by a user prior to use.

The term target site refers to a body organ to which delivery of the active agent is desired. The target site may be any body organ or tissue, including but not limited to, limbs and digits, abdomen, head and neck, internal organs (e.g. liver, heart, lungs, kidney, stomach, intestines and intestinal tract, pancreas, urinary tract, etc.).

The term tissue refers to any tissue of the subject, human or non-human, including the skin and the soft tissues of the body. The term also encompasses the blood. The term organ refers to any part of the body of an animal or of a human that is capable of performing some specialized physiological function. The term may include any part of such an organ or a collection of one or more of such organs. Non-limiting examples of organs include the heart, lungs, kidney, ureter, urinary bladder, adrenal glands, pituitary gland, skin, prostate, uterus, reproductive organs, liver, gall-bladder, brain, spinal cord, stomach, intestine, appendix, pancreas, lymph nodes, breast, salivary glands, lacrimal glands, eyes, spleen, thymus, bone marrow.

In some embodiments, the delivery of the active agent is topical delivery. Hence, in such embodiments, the devices (either the flexible device or the application device) may be suitable for external application, e.g. to treat a skin injury or external muscular or vascular injury (such as wounds, cuts, punctures, large surface hemorrhaging injuries, etc.). Other topical applications may include treatment of skin lesions, burns of various degrees, skin infections, etc.

The term topical as used herein refers to the application of a device directly onto at least a portion of a subject's skin (human or non-human skin) so as to achieve a desired effect at the site of application. In some embodiments, the desired effect is achieved at the site of application without inducing one or more systemic effects. In other embodiments, the active agent delivered by the device induces at least a partial systemic effect which contributes to the induction of at least one desired effect.

The application device described herein may also be used in order to deliver the active agent into a body cavity, body lumen, body tissue or a tubular organ. For example, the application device may be used to deliver the active agent by inserting the device into a cavity, lumen, stab wound, gunshot wound, or tubular organ (e.g. a vein, an artery, a bile duct, respiratory tract, gastrointestinal tract, urinary tract, fallopian tubes, etc.) and delivering the carriers directly to the target site within the organ. Thus, in some embodiments, the application device may be configured for insertion into a body cavity or lumen.

In another aspect, there is provided a method of manufacturing a flexible device for delivery of at least one active agent to a target site (e.g. the flexible device described herein), the method comprising:

- forming a plurality of spaced-apart cells each cell having at least one wall portion made of a film of at least one polymeric material that is at least partially disintegrable upon contact with a fluid;

- filling said cells with said at least one active material; and

- sealing the cells with a flexible substrate to form the device.

According to some embodiments, the plurality of spaced-apart cells may be formed by any method known to a person of skill that enables shaping of the polymeric film into spaced-apart cells (e.g. casting, extrusion, heat-forming, vacuum-forming, etc.). Once the empty cells are obtained, the cells are filled with the active agent and then sealed by the flexible substrate to result in the flexible device.

Another aspect of this disclosure provides a method of manufacturing a device as described herein, the method comprises:

(a) bringing a flexible substrate and a film of at least one fluid disintegrable polymeric material in proximity one to the other;

(b) integrating said flexible substrate with said film to form a plurality of spaced- apart pre-cells, the pre-cells having a portion of their perimeter non-integrated,

(c) introducing at least one active agent into said pre-cells through the non- integrated portion, and

(d) sealing said pre-cells by integrating said flexible substrate with said film along said portion to thereby form said spaced-apart cells.

Thus, the method includes first preparing spaced-apart pre-cells, which have a peripheral opening (i.e. the pre-cells are not sealed in at least a portion of their periphery). The pre-cells are filled with the active agent or a composition comprising an active agent, and then the peripheral opening is sealed to form the cells. This sequence of steps, namely steps (a) to (d), may be repeated to manufacture a device comprising an array of said spaced-apart cells.

At times, step (d) of one cycle of the method may also be step (b) of the subsequent cycle of the method. Namely, sealing the pre-cells in step (d) of a first cycle may also form the next in-line pre-cells. Thus, in a single integration, both already prepared pre-cells are sealed and the next in-line pre-cells in the array are formed.

Integration means bringing the substrate and polymeric film into intimate contact and applying conditions to adhere them one to the other. Integration may, by some embodiments, be carried out by welding, such that the film and the substrate are adhered one to the other along defined welding zones. Welding may be carried out by any suitable welding technique, for example heat sealing, contact welding, high frequency welding, ultrasonic welding, laser welding, solvent welding and others.

The welding thus forms said plurality of cells that are spaced-apart by substantially non-disintegrable segments constituted by the welding zones. In some embodiments, said segments are non-uniform in thickness and/or density to permit flexibility and/or foldability of said segments after integration. In other embodiments, the method may further include a step (e), in which the non-disintegrable segments are perforated in order to permit further flexibility/foldability of said segments.

The perimeter of the cells (i.e. the interface between the cell and the non-disintegrable segments surrounding it) may have various profiles that may be obtained by modifying the parameters of the welding conditions. Such changes in profile of the interface may be utilized to control, for example, the rupturability of the cells.

In some embodiments, the film of the polymeric material may have pre-defined cell-forming sections and seal-forming sections, such that integrating is carried out by welding said film to said substrate along said seal-forming sections. In such cases, said

cell-forming sections may be formed from a disintegrable polymeric material, while the seal-forming sections may comprise or formed of a non-disintegrable material (e.g. a non-disintegrable polymeric material). The seal-forming sections may also comprise a laminate of polymeric layers having different disintegration properties.

The method may further comprise a step prior to (a) of texturing the film or the cell-forming sections of said film. Texturing may include embossing, micro- or nano-perforating the film, thereby forming weaker spots in the cell to promote faster disintegration.

The device may be utilized as a stand-alone device, or alternatively as an active component in a dressing assembly (e.g. an elastic bandage). Therefore, the methods described above may further comprise a step of associating or integrating the device with at least one fabric layer, e.g. an elastic fabric layer or any other suitable dressing fabric (for example woven cotton, gauze, etc.).

In another aspect, the present disclosure provides a method of delivering at least one active agent to a target site of a subject, comprising contacting the flexible device described herein with said target site, such that at least a portion of the plurality of cells comes into contact with a bodily fluid to cause selective disintegration of cells for releasing said active agent to said target site.

In some embodiments, contacting with said fluid causes (i) a portion of said cells to disintegrate and release a first active agent to the target site, followed by (ii) disintegration of another portion of cells for releasing a second active agent to the target site.

In other embodiments, contacting causes all of the cells that are brought into contact with the target site to disintegrate.

In another aspect, this disclosure provides a method of delivering at least one active agent to a target site, comprising bringing the application device described herein into vicinity to the target site, and extracting the carriers from the container by the application means, such that at least a portion of the plurality of carriers comes into contact with a bodily fluid to cause selective disintegration of carriers for releasing said active agent to said target site.

In some embodiments, contacting with said fluid causes (i) a portion of said carriers to disintegrate and release a first active agent to the target site, followed by (ii) disintegration of another portion of carriers for releasing a second active agent to the target site

According to some embodiments, the active agent is delivered in an effective amount to cause at least one therapeutic effect in the target site. As known, 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 condition 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.

The active agent may be used to induce at least one effect, e.g. a therapeutic effect; namely, the active agent is capable of inducing, enhancing, arresting or diminishing at least one effect, by way of treatment or prevention of unwanted conditions in a subject. The at least one agent (substance, molecule, element, compound, entity, or a combination thereof) may be selected amongst therapeutic agents, i.e. agents capable of inducing or modulating a therapeutic effect when administered in a therapeutically effective amount, and non-therapeutic agents, i.e. which by themselves do not induce or modulate a therapeutic effect but which may be combined with another agent to endow the desired therapeutic effect.

Treatment or any lingual variation thereof, as used herein, refers to the administering of a therapeutic amount of the active agent or composition comprising therein which is effective to ameliorate undesired symptoms associated with a condition in a subject, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the condition, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the condition, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the condition from occurring or a combination of two or more of the above.

Another aspect provides a method of reducing or treat hemorrhage from a wound of a subject, comprising contacting a device as described herein with the wound, at least a portion of cells in the device comprise at least one hemostatic agent or coagulant, said cells being selectively disintegrable upon contact with blood to release said hemostatic agent or coagulant to said wound.

Yet another aspect provides a method of reducing hemorrhage from a wound, comprising bringing the application device described herein into vicinity to the wound, and extracting the carriers from the container by the application means, at least a portion of carriers in the device comprise at least one hemostatic agent or coagulant, such that said at least portion of carriers selective disintegrates upon contact with blood to release for releasing said hemostatic agent or coagulant to said wound.

The term subject as used herein refers to human and non-human subjects, i.e. the devices may be utilized in treating humans or for veterinary purposes.

As used herein, the term "about" is meant to encompass deviation of +10% from the specifically mentioned value of a parameter, such as thickness, time, molecular weight, 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.

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. 1A shows a schematic cross- sectional view of a flexible device according to an embodiment of this disclosure.

Fig. IB is a schematic representation of a dressing utility comprising an exemplary flexible device according to an embodiment of this disclosure.

Figs. 2A-2C show schematic representations of flexible devices according to some embodiments of the present disclosure.

Fig. 3 shows another schematic representation of a flexible device according to this disclosure, comprising cells with variable height profiles.

Fig. 4A-4B are schematic representations of an adhesive plaster comprising the flexible device according to an embodiment of the present disclosure with a protective layer covering the device (Fig. 4 A) and with the protective layer partially removed from the device for application of the device onto a target site (Fig. 4B).

Fig. 5 shows another schematic representation of a flexible device according to this disclosure.

Figs. 6A-6C are schematic steps of a manufacturing method of a flexible device according to an embodiment of this disclosure.

Figs. 7A-7C are schematic steps of a manufacturing method of a flexible device according to another embodiment of this disclosure.

Fig. 8 shows a device according to another embodiment of this disclosure, including formed weak areas in the cells for directed disintegration of the polymeric material.

Figs. 9A and 9B show pictures of an exemplary flexible device of this disclosure: Fig. 9A shows the device prior to contact with blood, and Fig. 9B showing the blood sample being congealed after contact with the device.

Figs. 10A and 10B are schematic representations of an application device according to an embodiment of this disclosure in the application means' extended state (Fig. 10A) and retracted state (Fig. 10B).

DETAILED DESCRIPTION OF EMBODIMENTS

As noted above, the present disclosure concerns devices that are designed to deliver one or more active agents to a target site in controlled and selective manner and sequence of delivery, while having improved flexibility to maximize the contact area with the target site. Some non-limiting examples will now be described in order to demonstrate how the devices of this disclosure maybe designed and manufactured.

Fig. 1A is a schematic cross-sectional view of a flexible device 100, such as a personal bandage, that comprises an elastic woven fabric 102, onto which flexible substrate 104 is fixated. Fixation may be obtained by adhering, stitching, or any other suitable means. The flexible substrate 104, which may be made, for example, from a non-disintegrable polymeric sheet, carries a plurality of cells 106, made from a film of a polymeric material 108. The cells 106 are made of a disintegrable material, typically a water-disintegrable polymer, and contain therein at least one active compound. The cells 106 are spaced-apart by non-disintegrable segments 110, which may or may not be perforated or scored. Due to the segmentation to a plurality of cells (as well as providing, in some cases, perforated or scored non-disintegrable segments) improved flexibility of the device is obtained, as the device bendable and/or foldable along the non-disintegrable segments 110. Such flexibility enables improved contact with the target site once the device is applied thereon. For example, when applying the device onto a hemorrhaging wound of a limb (leg or arm), such flexibility allows the device to conform to the contours of the limb and improve contact therebetween.

A dressing utility 120, e.g. an elastic bandage, comprising device 100 is shown in Fig. IB. The dressing utility 120 includes at least one layer of fabric 122, onto which device 100 is integrated. The dressing utility may be packed as individual or personal dressings (e.g. pre-packaged personal bandage) or be formed as a strip (e.g. a rolled continuous strip) that can be cut by the user on-site to a desired length.

It is to be noted that although the examples provided herein show rectangular cells, having similar geometry and size, the cells may not be necessarily so. A variety of shapes and sizes of cells may be utilized, depending on various considerations, such as rupturability, method of manufacture, targets delivery site, etc.

Fig. 2A shows another schematic device, similar to that of Fig. 1A. In this device, a peripheral section of the substrate 112 may include an adhesive, such that once applied, the device is adhered to the organ to be treated. For example, the device may be a plaster that adheres to the skin.

In the device of Fig. 2B, a portion of cells 106A differs in at least one of its properties from another portion of cells 106B. The cells may differ, for example, in one or more of the film thickness, the molecular weight of the polymeric material, the composition of the polymeric material, the film texture, water solubility of the film, the volume of cell, the geometry of cell, the size of disintegrable area, the type of active material contained within the cell, and others.

Another exemplary arrangement is shown in Fig. 2C, in which a portion of cells 106'A are located at a center of the substrate, while another portion of the cells 106'B is located at the substrate's periphery. For example, cells 106'A come into contact with the target site and contain a first agent to be administered directly to the target site, while cells 106'B that are positioned peripherally and contain a second agent to be administered to the peripheral area of the target site.

Fig. 3 shows another example of a flexible device of this disclosure. In this example, the device comprises cells 106'C and 106'D, differing in their height and volume. Such variance in volume enables controlling the quantity of active agent that is contained, and subsequently released, from the cells. For example, in some instances it is desired that a first active agent contained in cell 106'C is delivered to the target site in a larger quantity than a second active agent contained in cell 106'D. The variance in height of the cells can also vary the timing of contact of each cell with the target site. Namely, as cell 106'C has a larger height (when measuring from the base of the device) than cell 106'D, cell 106'C will contact the target site first to release the active agent contained therein, and only thereafter cell 106'D, which has a smaller height, will contact the target site. This is another mechanism by which timing of release of a sequence of active agents may be obtained by the device.

Figs. 4A-4B show an exemplary adhesive plaster 130 comprising the device 100. The adhesive plaster 130 comprises a fabric carrier layer 132, onto device 100 is fixed. An adhesive is typically applied on the area not covered by device 100, to permit adhering the plaster during use over the target site. During storage a protective layer 134 covers the device and the adhesive area, as seen in Fig. 4A; before application onto the target site, the protective layer 134 is removed from the device (partial removal is seen in Fig. 4B), thus enabling exposure of device 100 and adhering plaster 130 onto the target site.

As noted above, the segmentation of the device into discrete, spaced-apart cells renders the device with improved flexibility, as shown in Fig. 5. Such flexibility enables the device to conform in shape to irregular surfaces (such as a limb) and ensure contact with the target site for targeted delivery of the active agent.

Figs. 6A-6C show a schematic illustration of a method of producing flexible devices of this disclosure. Shown in Fig. 6A is a disintegrable polymeric film 202, shaped into a plurality of spaced-apart cells. As noted above, the polymeric film may be shaped into cells as a first step of production, or may be a priori provided in a shaped form. Shaping may be carried out by any suitable method known to a person of skill. The cells are filled with at least one active agent 204, as shown in Fig. 6B, and in the next production step (Fig. 6C) the flexible substrate 206 is integrated with the polymeric film at designated integration segments 208 to seal the cells, and thereby form the device. Additional production steps may include attaching the device to other elements, such as a flexible fabric.

Another manner of manufacturing is shown schematically in Figs. 7A-7C, in which the substrate 302 is brought into proximity with the disintegrable polymeric film 304. The substrate and the film are integrated, e.g. by welding, along a portion of the pre-cell perimeter 306 to form open pre-cells 308 (Fig. 7A), into which the active agent 310 may be filled (Fig. 7B). After filling, the pre-cells are sealed by integrating the remainder of their perimeter 312, e.g. by welding, to form the cells (Fig. 7C).

The manufacturing process of the device may comprise various other stages in order to form weak areas or spots in the cell, such weak spots function as areas for initiating disintegration of the polymeric material once in contact with fluid at the target site. For example, cells may be treated by laser treatment in order to form areas of reduced thickness of the polymeric film forming the cells at various locations on the cell. As seen in Fig. 8, laser treatment, or any other suitable abrasive method, is used to form weak areas at the corners 402 of the cells. Similarly, weak spots may be formed at any location on the surface of the cell, e.g. in the center of the cell's area (not shown). It is noted that the weak spots are not necessarily obtained by locally reducing the thickness of the polymeric film, but may also be formed by other means, such as local changes in the polymeric structure or even by using a different polymeric material to form the weak spots.

Alternatively, or in addition, embossing may be used on the entire surface of the cell or at selected portions of the surface of the cell to provide further local weakening to direct the disintegration of the cell to the desired location.

A flexible device containing 1-6 cells (as shown in Fig. 9A) of polyvinyl-alcohol, each containing tranexamic acid powder as coagulation compound was used to demonstrate the effectiveness of the device in hemorrhage scenario. The test was carried

out at the Institute for Research in Military Medicine at the Hebrew University Faculty of Medicine (Jerusalem, Israel), using a swine model of controlled hemorrhagic shock. Fresh blood drawn from the animal during the study was used. The device was applied into the blood sample.

The cells that were brought into contact with the blood disintegrated within less than 30 seconds from contact with the blood, exposing the coagulation compound to the blood. Rapid formation of blood clots was observed from contact with the coagulation compound once the cells have been disintegrated (as seen in Fig. 9B).

Figs. 10A-10B show schematic representations of an application device according to an embodiment of this disclosure. Application device 500 is designed for applying a plurality of carriers 502 to a target site, e.g. a topical wound, a wound located at an internal organ, tissue or a tubular organ of a patient. The application device 500 in this non-limiting example is in a form similar to a syringe, namely having a cylindrical container 504 that holds the plurality of carriers 502. As noted above, the carriers may be of any shape or form, and typically comprise at least one active agent contained within a disintegrable polymeric shell or matrix. An application means in the form of a piston 506 is fitted within the container 504, such that the carriers are held within the container within a volume 508 that is defined between the bottom of the container 510 and a plunger member 512 of the piston 506 when the piston is in its extended state (shown in Fig. 10A). The container further includes an opening 514, in this case at the bottom of the container, which is at a closed state while containing the carriers. The opening 514 can be configured to be switchable from its closed state to its open state, for example by utilizing a mechanism that opens and closes the opening, and maintains the opening 514 in its closed state while the device is not in use. Alternatively, the opening may be configured as (or configured with) a breakable seal, that is opened by the pressure formed within the container when pressure is applied by the use onto the piston in the direction designated by arrow 516. In another possible arrangement, the opening is fitted with a removable seal, that needs to be removed by the user prior to operating the device.

For operating the device, a user bring the device 500 into vicinity with the target area. Then, the user removes the seal from opening 514 or operates the opening mechanism of the opening 514 if such exist; otherwise - the application of pressure on the piston by the user will cause transition of the opening from a closed state to an open state. Thus, application of pressure by the user on the piston 506 in the direction of arrow 516 causes reduction of the volume 508 and plunger member 512 to be pressed against the carriers 502 held within container 504. This, in turn, drives the carriers 502 through the opening 514, as seen in Fig. 10B, and hence their application onto or into the target site.

As noted above, once the carriers are applied onto the target site, the active agent is selectively released from the carriers depending on the release profile parameters determined by the nature of the polymeric material and the features of the carriers.

As a person of the art would appreciate, the devices provided in the Figures are mere exemplary devices, and it is to be understood that other devices falling within the scope of the claims are also encompassed by this disclosure.