DEVICES FOR TOPICAL DELIVERY OF ACTIVE AGENTS TO A TARGET SITE

Abstract

Provided are devices, i.e. medical devices, for topical delivery of various active agents to a target site. More specifically, provided are devices for controlled release of an active agent to a skin portion upon contact with an aqueous fluid, such as perspiration, exudate or external applied water-based fluids.

Claims

1. A flexible device for topical delivery of at least one active agent to a target site, the device comprises a flexible substrate for placing onto a skin portion and having a plurality of spaced-apart cells, each cell in said plurality containing 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 an aqueous fluid to thereby release the active agent to the target site.

2. The device of claim 1, wherein said aqueous fluid is selected from the group consisting of perspiration, exudate, and lacrimal fluid.

3.-4. (canceled)

5. The device of claim 1, wherein the aqueous fluid is a water-based fluid applied externally onto the device during and/or after application to the skin portion.

6. The device of claim 1, wherein the cells in said plurality of cells are configured for selective disintegration upon contact with said aqueous fluid.

7. The device of claim 6, wherein at least one portion of cells being different in at least one property from at least another portion of cells in said plurality of cells, said property being 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, size of disintegrable wall portion, and type of active agent contained therein.

8. (canceled)

9. The device of claim 1, wherein said polymeric material is selected from polysaccharide, polyethyleneoxide (PEO), polyvinyl-pyrrolidone (PVP), polyvinyl-alcohol (PVA), polyacrylic acid (PAA), polyacryloamides, polyoxazoline, cellulose ethers.

10.-12. (canceled)

13. The device of claim 1, wherein said at least one active agent is selected from an anti-inflammatory agent, a pain-relief agent, wound healing promoting agents, an analgesic, an antihistamine, an opioid or opioid derivative, growth hormone, a cannabinoid, an antifungal agent, an antiviral agent, an antiseptic, an antimicrobial agent, an antibiotic, and a disinfectant.

14.-15. (canceled)

16. The device of claim 1, wherein all of the cells in said plurality of cells contain the same active agent and the cells differ in their disintegration rate, such that the difference in the integration rate forms a sequence of disintegration of the cells with a defined time interval between disintegration of subsequent cells in said sequence, the time interval being defined by the difference in the disintegration rate.

17.-20. (canceled)

21. The device of claim 1, wherein said polymeric material is fully disintegrable within between about 5 second and 30 minutes from contact with said perspiration or exudate.

22.-25. (canceled)

26. The device of claim 1, wherein said flexible substrate being made of a material substantially non-disintegrable upon contact with aqueous fluid.

27.-28. (canceled)

29. The device of claim 1, being a bandage, a dressing, or a sleeve.

30. The device of claim 29, further comprising an adhesive on at least a portion of the device's perimeter.

31. (canceled)

32. The device of claim 1, being configured for insertion into a body cavity or lumen.

33.-36. (canceled)

37. A method of manufacturing a device of claim 1, the method comprising: (a) bringing a flexible substrate and a film of at least one aqueous 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.

38. The method of claim 37, wherein steps (a) to (d) are repeated to manufacture a device comprising an array of spaced-apart cells.

39. (canceled)

40. The method of claim 37, wherein said integrating forms a plurality of cells that are spaced apart by substantially non-disintegrable segments.

41. (canceled)

42. The method of claim 37, wherein said film having 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.

43. The method of claim 42, wherein said cell-forming sections are formed from a disintegrable polymeric material.

44. The method of claim 42, wherein said seal-forming sections comprise or formed of a non-disintegrable polymeric material, or said seal-forming sections comprise a laminate of polymeric layers having different disintegration properties.

45. (canceled)

46. The method of claim 37, wherein the cells are spaced apart by substantially non-disintegrable segments constituted by integrated seal-forming sections, said segments being non-uniform in thickness and/or density to permit flexibility and/or foldability of said segments after integration.

47. (canceled)

48. The method of claim 37, further comprising a step prior to (a) of texturing said film or cell-forming sections of said film.

49. (canceled)

50. The method of claim 37, further comprising associating the device with at least one fabric layer.

51. (canceled)

52. A method of topically delivering at least one active agent to a target site, comprising contacting a flexible device of claim 1 with a skin portion of a patient, such that at least a portion of the plurality of cells comes into contact with an aqueous fluid to cause selective disintegration of cells for topically releasing said active agent to said target site.

53. The method of claim 52, wherein contacting with said aqueous fluid (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.

54.-63. (canceled)

64. The method of claim 52, wherein said active agent is selected from the group consisting of an active agent for treating skin infection, an active agent for treating a skin burn, an anti-inflammatory, an active agent for treating pain, an active agent for treating a skin ulcer or a pressure ulcer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0094] 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:

[0095] FIG. 1A shows a schematic cross-sectional view of a flexible device according to an embodiment of this disclosure.

[0096] FIG. 1B is a schematic representation of a dressing utility comprising an exemplary flexible device according to an embodiment of this disclosure.

[0097] FIGS. 2A-2C show schematic representations of flexible devices according to some embodiments of the present disclosure.

[0098] FIG. 3 shows another schematic representation of a flexible device according to this disclosure, comprising cells with variable height profiles.

[0099] 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. 4A) and with the protective layer partially removed from the device for application of the device onto a target site (FIG. 4B).

[0100] FIG. 5 shows another schematic representation of a flexible device according to this disclosure.

[0101] FIGS. 6A-6C are schematic steps of a manufacturing method of a flexible device according to an embodiment of this disclosure.

[0102] FIGS. 7A-7C are schematic steps of a manufacturing method of a flexible device according to another embodiment of this disclosure.

[0103] 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.

DETAILED DESCRIPTION OF EMBODIMENTS

[0104] As noted above, the present disclosure concerns devices that are designed to topically 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 skin portion to which the device is applied. Some non-limiting examples will now be described in order to demonstrate how the devices of this disclosure maybe designed and manufactured.

[0105] 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 perspiration- or exudate-disintegrable material, typically a perspiration- or exudate-disintegrable polymer (at times a lacrimal fluid 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 skin portion onto which the device is applied. For example, when applying the device onto a limb (leg or arm), such flexibility allows the device to conform to the contours of the limb and improve contact therebetween for effective topical delivery of the active agent to the target site.

[0106] A dressing utility 120, e.g. an elastic bandage, comprising device 100 is shown in FIG. 1B. 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.

[0107] 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.

[0108] 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 skin. For example, the device may be a plaster that adheres to the skin or a patch to be applied to an eye.

[0109] 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 agent contained within the cell, and others.

[0110] 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 a target site on the skin (e.g. a burn), while cells 106′B that are positioned peripherally and contain a second agent to be administered to the peripheral area of the target site (e.g. the skin tissue surrounding the burn area).

[0111] 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.

[0112] 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 a skin portion. During storage a protective layer 134 covers the device and the adhesive area, as seen in FIG. 4A; before application onto the skin, 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 skin.

[0113] 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 skin for maximizing contact with the skin and hence improving topical delivery of the active agent to the target site.

[0114] 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.

[0115] 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).

[0116] 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 perspiration, exudate or lacrimal fluid at the skin portion onto which the device is applied. 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.

[0117] 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.

[0118] 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.