WO2013114276A2

WO2013114276A2 - Devices for delivering a fluid via a flexible biological barrier

Info

Publication number: WO2013114276A2
Application number: PCT/IB2013/050756
Authority: WO
Inventors: Yotam Levin; Yehoshua Yeshurun
Original assignee: Nanopass Technologies Ltd.
Priority date: 2012-01-31
Filing date: 2013-01-29
Publication date: 2013-08-08
Also published as: WO2013114276A3

Abstract

A device for delivering a fluid via a flexible biological barrier includes a housing with a contact surface and a relief surface that is operationally connected to the contact surface, one or more hollow needles that protrude from the relief surface, and one or more components for facilitating sliding of the contact surface along the barrier to insert the needle(s) into the barrier. Preferably, the housing also includes a top surface to which the component(s) is/are operationally connected. Exemplary components include flanges and grooves for inserting handles, and flaps that are folded down after the insertion to secure the device to the barrier.

Description

DEVICES FOR DELIVERING A FLUID VIA A FLEXIBLE BIOLOGICAL

BARRIER

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to systems for delivering fluids through a flexible biological barrier and, in particular, systems employing needles such as microneedles for such purpose.

Intradermal drug delivery is known to be advantageous for a range of different medications and treatments, such as immunization, immunomodulation, gene delivery, dermatology, allergy, hypersensitivity and cosmetics. Conventionally, intradermal drug delivery has been performed by a skilled medical professional using a hypodermic needle positioned bevel-up at a shallow angle relative to the skin surface. Care is required to achieve the correct depth of penetration to ensure successful injection within the dermal layers rather than subcutaneously. The bevel-up needle orientation is needed in order to facilitate positive engagement of the needle with the skin surface at such shallow angles and is anyway the standard practice with any acute angle hypodermic needle insertion (including for example for venipuncture into deeper layers). The use of hypodermic needles for intradermal delivery is known to be painful, since nerve endings in the dermal layer are typically severed by the relatively large needles used.

Much interest has been shown in development of drug delivery devices which do not require skilled operation, for example, for self-administration of drugs by patients. One approach is that of a "mini-needle" device with an actuator which selectively deploys or retracts the needle so as to penetrate to a limited depth within the dermal layers. Examples of such a device are commercially available from Becton, Dickinson & Co. (USA) and are described in US Patents 6,843,781, 6,776,776, 6,689,1 18, 6,569,143, 6,569,123 and 6,494,865. The needle cannula of such devices typically projects between 1 and 2 millimeters, thereby defining the depth of penetration of the delivery system. Since the already-reduced-length bevel of the needle tip itself has a length of at least 0.8 mm, devices based on conventional needle structures of this type (i.e., a hollow metal cylinder with a beveled point) cannot readily be used for sealed fluid delivery to penetration depths less than 1 mm. As an alternative to conventional needle structures, many attempts have been made to develop "microneedle" structures using various micromachining technologies and various materials. An early example of the "microneedle" approach may be found in US Patent. 3,964,482 to Gerstel et ah, issued in 1976, which discloses a drug delivery device for percutaneously administering a drug by use of microneedles (projections) of dimensions up to 10 microns to puncture the stratum corneum, thereby allowing the drug to reach the epidermis. The device has multiple needles projecting outwardly from one surface and, in one implementation, delivers a drug from a reservoir via central bores of the microneedles.

In the three decades after Gerstel et al., many microneedle devices were proposed, but at the start of the twenty-first century none had yet achieved commercial success as a widespread clinical product due to a number of practical problems. A first major problem of many microneedle designs relates to mechanical weakness of the microneedles which tend to fracture on contact with the skin, particularly when exposed to shear forces due to lateral movement. A second problem relates to blockage of the bores of hollow microneedles due to punching-out of a plug of tissue during insertion through the skin. Additionally, many needle designs have relatively thin walls causing fragility, and a blunt interface, requiring excessive penetration forces to overcome skin elasticity. These problems were effectively addressed by a microneedle structure disclosed in co-assigned US Patent 6,533,949, which is hereby incorporated by reference for all purposes as if fully set forth herein. The aforementioned microneedle structures also help to overcome a further problem of microneedle devices, namely, that of ensuring effective penetration of the highly elastic skin barrier. Various structures and techniques for employing the aforementioned microneedle structure to achieve enhanced penetration are disclosed in co-assigned US Patent 7,588,552, which is also hereby incorporated by reference for all purposes as if fully set forth herein.

A still further problem which hampered use of microneedles, particularly for intradermal delivery of fluids, is the risk of leakage of fluid around the microneedles. Specifically, injection of fluids through the hollow microneedles typically generates a back-pressure which tends to expel the microneedles from their incisions. Attempts to prevent expulsion of the microneedles by application of downward force (i.e., towards the skin) on the microneedle device compresses the underlying tissue. This compression increases the 0uid impedance opposing injection of the fluid, thereby also interfering with delivery of the fluid to the target tissue. Further, in many designs the fluid flow channels extend all the way to the tip, causing a structural dependence between those two elements. This limits the ability to increase flow channel size to allow greater flow without blunting the microneedle and greatly increasing the force required to achieve penetration, and the reaction forces exerted on the structures by the skin.

Co-assigned US Patent 7,998,119, which is also hereby incorporated by reference for all purposes as if fully set forth herein, addressed this problem in the manner illustrated in Figures 1 and 2 that illustrate a generic device 10 for delivering a fluid via a flexible biological barrier 14. Device 10 employs a microneedle structure wherein a final position of one or more hollow microneedles 12 inserted into biological barrier 14 is generally sideways projecting from device 10 instead of the conventional downwards projecting arrangement. More particularly, the microneedle preferably projects from a relief surface 16 which is distinct from a primary biological-barrier contact surface 18 of device 10, and typically angled upwards away from the biological barrier. This avoids the aforementioned problems of tissue pressure impeding fluid injection by ensuring that the fluid flow vector for injection is towards a non-compressed region of tissue. Furthermore, this configuration tends to provide an anchoring effect which locks the delivery configuration into the skin, thereby avoiding the aforementioned problems of leakage around the needles or ejection of the needles by back-pressure.

To insert microneedle(s) 12 into biological barrier 14 for delivery of a fluid, contact surface 18 is brought into contact with biological barrier 14 and moved in a motion having a component parallel to the surface of flexible biological barrier 14 (i.e. a sliding motion) so as to generate a boundary region 20 between a stretched portion 22 of the flexible biological barrier and a non-stretched portion 24 of the flexible biological barrier. Typically concurrently with at least part of this movement, and most preferably as a direct result of this movement, the hollow microneedle(s) 12 is/are caused to penetrate into flexible biological barrier 14 such that, at the end of the motion, hollow microneedle(s) 12 extend(s) into flexible biological barrier 14 from boundary region 20 in a direction towards non-stretched portion 24. A quantity of fluid is then injected through the bore 28 of hollow microneedle 12 towards non- stretched portion 24. Hollow microneedle(s) 12 is/are preferably mechanically associated with contact surface 18 such that hollow rnicroneedle(s) 12 penetrate(s) into flexible biological barrier 14 as a result of moving contact surface 18. For maximum reliability and minimum manufacturing cost, device 10 is formed with no moving parts, with all required elements in rigid mechanical relation. At least part of contact surface 18 is preferably provided by an edge 26 of a block 16, 18 of material, and microneedle(s) 12 is/are preferably deployed on a face 16 of the block bordered by edge 26. As mentioned before, face 16 is preferably a "relief face", i.e., a surface which does not fully come in contact with biological barrier 14 when device 19 is first brought in contact with barrier 14. To achieve this, face 16 is preferably angled up relative to the plane of face 18. The angle between faces 16 and 18, measured internally to the block, is preferably no more than about 150°, and more preferably no more than about 130°. In one particularly preferred implementation, edge 26 is formed between substantially orthogonal faces 16 and 18. Edge 26 is not necessarily, or even preferably, a sharp intersection of the planes of faces 16 and 18. For example, edge 26 may be rounded by a suitable radius of curvature.

US 7,998,119 describes several specific embodiments of generic device 10. These embodiments are intended for brief use, to inject a predetermined quantity of therapeutic fluid into a patient. Some therapeutic agents, however, such as insulin, must be delivered over an extended period of time.

Passive transdermal technology, such as a conventional transdermal patch, may be relatively convenient for the user and may permit relatively uniform drug release over time. However, some drugs, such as highly charged or polar drugs, peptides, proteins and other large molecule active agents, may not penetrate the stratum corneum for effective delivery. Furthermore, a relatively long start-up time may be required before the drug takes effect. Thereafter, the drug release may be relatively continuous, which may be undesirable in some cases. Also, a substantial portion of the drug payload may be undeliverable and may remain in the patch once the patch is removed.

Active transdermal systems also are known. Chiang et al., in US Patent

7,828,771, teach several embodiments of a transdermal patch pump device, one of which (700) is illustrated in Figure 3. The housing 722 of device 700 has a sufficiently slim profile that device 700 can be worn conveniently by a patient for as long as is needed to slowly deliver a fluid therapeutic agent 704 such as insulin from a reservoir 724 to the patient's skin via a hollow needle 706. A health worker slides device 700 along the patient's skin to engage needle 706 with the patient's skin and then tapes device 700 in place. Device 700 includes an electrochemical activator 702 for causing therapeutic agent 704 to flow through needle 706 at the desired rate, and so is an autonomous device, but it also is known to use separate infusion pumps to deliver fluid therapeutic agents to similar devices via flexible tubing that connects the pumps to the devices. The type of needle 706 used by Chiang et al. is not indicated, but Connelly et al., in US 6,689,100, teach a similar device equipped with an array of microneedles.

US 7,998,1 19 teaches several accessories, for its specific embodiments of device 10, for facilitating the insertion of microneedle(s) 12 into the skin of a patient. These accessories are not suitable for use with slim-profile active transdermal devices. It would be highly advantageous to have an active transdermal device that is adapted for easy application to a patient.

SUMMARY OF THE INVENTION

According to the present invention there is provided a device for delivering a fluid via a flexible biological barrier, including: (a) a housing that includes: (i) a contact surface, and (ii) a relief surface operationally connected to the contact surface; (b) at least one hollow needle protruding from the relief surface; and (c) at least one component for facilitating manual sliding of the contact surface along the biological barrier to insert the at least one needle into the biological barrier.

Preferably, the needle(s) is/are microneedles.

Preferably, the housing also includes a top surface to which the components) is/are operationally connected.

One preferred class of such components is one or more flanges for reversibly receiving a handle that is used to urge the sliding. In one such embodiment, the components are two flanges on opposite sides of the top surface, preferably oriented substantially perpendicular to the relief surface. In another such embodiment, thecornponent is one flange, adjacent and parallel to the relief surface.

Another prefered component is a groove for receiving a handle that is used to urge the sliding.

Another preferred class of such components is a class of components that are grasped directly by the user to urge thesliding. In one such embodiment, the components are two flaps on opposite sides of the top surface and oriented substantially perpendicular to the relief surface. Preferably, each flap includes an adhesive patch for securing the device to the biological barrier subsequent to the insertion of the needle(s). Another such embodiment is similar, with flaps that protrude from the top surface past the relief surface, but also includes a bridge that connects the protruding portions of the flaps and that is spaced apart from the top surface to provide a window through which the needle(s) are visible after the needie(s) has/have been inserted in the biological barrier.

According to the present invention there is provided a kit for delivering a fluid via a flexible biological barrier including: (a) a device, for delivering the fluid, that includes: (i) a housing having a front end and a rear end, and (ii) at least one needle protruding from the front end; and (b) a flexible bandage that is sufficeintly longer than a distance between the front end and the rear end of the housing to secure the device to the flexible biological barrier via a first adhesive portion of the bandage that extends beyond the front end of the housing and a second adhesive portion of the bandage that extends beyond the rear end of the housing.

Preferably, the kit also includes a liner that is reversibly secured to the side of the bandage opposite the adhesive portions. BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are herein described, by way of example only, with reference to the accompanying drawings, wherein:

FIGs. 1 and 2 illustrate a generic prior art device for delivering a fluid via a flexible biological barrier;

FIG. 3 illustrates a prior art transdermal patch pump device;

FIGs. 4A and 4B illustrate a generic active transdermal patch device prior to its modification according to the present invention;

FIGs. 5A and 5B show a first embodiment of an active transdermal patch device of the present invention;

FIGs. 6A and 6B show a second embodiment of an active transdermal patch device of the present invention;

FIG. 7 shows a third embodiment of an active transdermal patch device of the present invention; FIGs. 8A and 8B show a fourth embodiment of an active transdermal patch device of the present invention;

FIGs. 9A-9C show a fifth embodiment of an active transdermal patch device of the present invention;

FIG. 10 shows a sixth embodiment of an active transdermal patch device of the present invention;

FIGs. 11A-11C show the use of a modified bandage for emplacement of an unmodified active transdermal patch device;

FIG. 12 shows a variant of the bandage of FIGs. 1 1 A-l 1C.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The principles and operation of an active device for delivering fluids through a flexible biological barrier, such as the skin of a patient, according to the present invention may be better understood with reference to the drawings and the accompanying description.

Referring again to the drawings, Figures 4A (perspective) and 4B (cross section) illustrates a generic active transdermal patch device 100 prior to its modification according to the present invention. Device 100 is based on a housing 102 that includes a contact surface 104 that corresponds to contact surface 18 of Figures 1 and 2, a top surface 106, and a relief surface 108 that corresponds to relief surface 16 of Figures 1 and 2. An array 110 of hollow microneedles protrudes from relief surface 108. Housing 102 encloses a channel 112 that conveys a fluid from tubing 114 to microneedles 110.

Figures 5 A and 5B show, in perspective view, an embodiment 120 of the present invention in which top surface 106 is provided with two flanges 122 that are shaped to receive a handle 124. A user of embodiment 120 inserts handle 124 between flanges 122 and uses handle 124 to assist in sliding embodiment 120 along a flexible biological barrier such as the skin of a patient to insert microneedles 110 into the barrier.

Figures 6A and 6B show, in perspective view, an embodiment 130 of the present invention in which top surface 106 is provided with a flange 132, adjacent to relief surface 108, that is shaped to receive a handle 134. A user of embodiment 130 inserts handle 134 behind flange 132 and uses handle 134 to assist in sliding embodiment 130 along a flexible biological barrier such as the skin of a patient to insert microneedles 110 into the barrier.

Figure 7 shows, in perspective view, an embodiment 140 of the present invention in which top surface 106 is provided with a rectangular groove 142 for the insertion of a matching handle (not shown). A user of embodiment 140 inserts the handle into groove 142 and uses the handle to assist in sliding embodiment 140 along a flexible biological barrier such as the skin of a patient to insert microneedles 110 into the barrier.

Figure 8A is a perspective view of an embodiment 150 of the present invention in which top surface 106 is provided with two flaps 152 on the sides of top surface 152. At the tip of each flap 152 is an adhesive patch 154. A user of embodiment 150 holds flaps 152 to slide embodiment 150 along a flexible biological barrier such as the skin of a patient to insert microneedles 110 into the barrier. Then the user folds flaps 152 down, as shown in perspective view in Figure 8B, to place adhesive patches 154 in contact with the barrier. Adhesive patches 154 then hold embodiment 150 in place on the barrier.

Figures 9A-9C show an embodiment 160 of the present invention that is similar to embodiment 150, except that flaps 162 of embodiment 160 are joined in front of relief surface 108 by a bridge 166 in a manner that provides a window 168 through which the insertion point of microneedles 110 in the flexible biological barrier may be observed subsequent to the insertion of microneedles 110 into the barrier. Figures 9 A (side view) and 9B (perspective view) show embodiment 160 prior to the insertion of microneedles 110 into the barrier. A user of embodiment 160 holds flaps 162 to slide embodiment 160 along the barrier to insert microneedles 110 into the barrier. Then the user folds flaps 162 down, as shown in perspective view in Figure 9C, to place adhesive patches 164 in contact with the barrier. Adhesive patches 164 then hold embodiment 160 in place on the barrier.

It is not even necessary to add components to top surface 106 to obtain an active transdermal patch device that can be applied easily to a patient. Figure 10 is a perspective view of an embodiment 200 of the present invention in which housing 102 has a "wasp-waist" shape that can be grasped easily by a user of embodiment 200 to slide embodiment 200 along a flexible biological barrier such as the skin of a patient to insert microneedles 110 into the barrier. In the embodiments discussed so far, housings 102 of various active transdermal patch devices have been modified to facilitate the insertion of the needles of the devices in a 0exible biological barrier such as the skin of a patient. Figures 1 1A-11C illustrate the use of a specially modified bandage 172 to insert the needles 170 of an unmodified active transdermal patch device 172 into a flexible biological barrier 160 and then keep device 172 secured in place on barrier 160. The housing 164 of device 162 has a front end 166 from which one or more needles 170 protrude and, on the opposite side of housing 164, a rear end 168. Bandage 172 has a front end 174 partly covered with adhesive 178 and a rear end 176 partly covered with adhesive 180.

Figure 11A shows device 162 ready to be applied to barrier 160. Rear end 176 of bandage 172 has been secured to barrier 160 immediately behind device 162 via adhesive 180.

Figure 11 B shows the use of bandage 172 to slide device 162 leftward as drawn in order to insert needle(s) 170 into barrier 160. Bandage 172 is folded leftward to contact housing 164 near rear end 168 and manual pressure is applied to bandage 172 in the direction shown by the arrow to urge device 162 leftward in a manner that inserts needle(s) 170 into barrier 170.

When needle(s) 170 have been fully inserted into barrier 160, front end 174 of bandage 172 is folded down so that adhesive 178 contacts barrier 160 to secure front end 174 to barrier 160. Bandage 172 now holds device 162 in place, as shown in Figure 11C.

Figure 12 shows an alternative embodiment of bandage 172 that includes, on its side opposite adhesive regions 178 and 180, a semi-rigid liner 182 that is secured to bandage 172 with an adhesive that is weaker than adhesives 178 and 180. The user of bandage 172 holds bandage 172 by liner 182 when using bandage 172 to apply device 1.62 to barrier 160 and then peels liner 182 off of bandage 172.

While the invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications and other applications of the invention may be made. Therefore, the claimed invention as recited in the claims that follow is not limited to the embodiments described herein.

Claims

WHAT IS CLAIMED IS:

1. A device for delivering a fluid via a flexible biological barrier, comprising:

(a) a housing that includes:

(i) a contact surface, and

(ii) a relief surface operationally connected to said contact surface;

(b) at least one hollow needle protruding from said relief surface; and

(c) at least one component for facilitating manual sliding of said contact surface along the biological barrier to insert said at least one needle into the biological barrier.

2. The device of claim 1 , wherein said needle is a microneedle.

The device of claim 1 , wherein said housing also includes: a top surface whereto said at least one component is operationally connected.

4. The device of claim 3, wherein said at least one component includes at least one flange for reversibly receiving a handle that is used to urge said sliding.

5. The device of claim 4, including two said flanges on opposite sides of said top surface.

6. The device of claim. 5, wherein said flanges are oriented substantially perpendicular to said relief surface.

7. The device of claim 4, including one said flange adjacent and parallel to said relief surface.

8. The device of claim 3, wherein said at least one component includes a groove for receiving a handle that is used to urge said sliding.

9. The device of claim 3, wherein said one component is grasped directly by a user to urge said sliding.

10. The device of claim 3, wherein said at least one component includes two flaps, on opposite sides of said top surface, oriented substantially perpendicular to said relief surface.

1 1. The device of claim 10, wherein each said flap includes an adhesive patch for securing the device to the biological barrier subsequent to said inserting.

12. The device of claim 1 1 , wherein a portion of each said flap protrudes from said top surface past said relief surface, the device further comprising:

(d) a bridge connecting said portions of said flaps that protrude past said relief surface, said bridge being spaced apart from said top surface to provide a window wherethrough said at least one needle is visible subsequent to said inserting.

13. A kit for delivering a fluid via a flexible biological barrier comprising:

(a) a device, for delivering the fluid, that includes:

(i) a housing having a front end and a rear end, and

(ii) at least one needle protruding from said front end; and

(b) a flexible bandage that is sufficeintly longer than a distance between said front end and said rear end of said housing to secure said device to the flexible biological barrier via a first adhesive portion of said bandage that extends beyond said front end of said, housing and a second adhesive portion of said bandage that extends beyond said rear end of said housing.

14. The kit of claim 13, further comprising:

(c) a liner reversibly secured to a side of said bandage opposite said adhesive portions.