Devices and methods for enhanced microneedle penetration of biological barriers

Abstract

Microneedle devices and methods of use thereof are provided for the enhanced transport of molecules, including drugs and biological molecules, across tissue by improving the interaction of microneedles and a deformable, elastic biological barrier, such as human skin. The devices and methods act to (1) limit the elasticity, (2) adapt to the elasticity, (3) utilize alternate ways of creating the holes for the microneedles to penetrate the biological barrier, other than the simply direct pressure of the microneedle substrate to the barrier surface, or (4) any combination of these methods. In preferred embodiments for limiting the elasticity of skin, the microneedle device includes features suitable for stretching, pulling, or pinching the skin to present a more rigid, less deformable, surface in the area to which the microneedles are applied (i.e. penetrate). In a preferred embodiments for adapting the device to the elasticity of skin, the device comprising one or more extensions interposed between the substrate and the base end of at least a portion of the microneedles.

1 . A device for transport of material or energy across or into an elastic biological barrier comprising: 
 a microneedle having a tip end and a base end,    a substrate connected to the base end of the microneedle, and    a means for improving penetration of the biological barrier by the microneedle.    
     
     
         2 . The device of  claim 1  wherein the biological barrier is human or other mammalian skin.  
     
     
         3 . The device of  claim 1  wherein the means comprises one or more extensions 
 (i) interposed between the substrate and the base end of the microneedle, or    (ii) extending from the side of the substrate distal to the base end of the microneedle.    
     
     
         4 . The device of  claim 3  wherein the extension is between about 500 μm and about 10 mm in height.  
     
     
         5 . The device of  claim 3  wherein the extension has a cross-sectional dimension of at least about 200 μm.  
     
     
         6 . The device of  claim 3  wherein the extension includes an array of microneedles extending therefrom.  
     
     
         7 . The device of  claim 3  wherein the extension is composed of a material which is different from the material forming the microneedles.  
     
     
         8 . The device of  claim 3  wherein the microneedle is hollow and wherein the extension includes at least one aperture in communication with the bore of the microneedle.  
     
     
         9 . The device of  claim 3  further comprising a rigid surface positioned apart from an array of the microneedles and oriented to contact an elastic biological barrier substantially at the same time as the microneedles when the microneedles are applied to the barrier.  
     
     
         10 . The device of  claim 1  wherein the substrate is curved.  
     
     
         11 . The device of  claim 1  comprising a plurality of microneedles of varying lengths.  
     
     
         12 . The device of  claim 11  comprising four or more microneedles wherein the tip ends of the microneedles collectively define a curvilinear surface.  
     
     
         13 . The device of  claim 1  comprising a plurality of hollow microneedles in a linear array, wherein the substrate is mounted on a holder having one or more apertures through the holder in communication with the microneedles.  
     
     
         14 . The device of  claim 1  wherein the substrate is flexible.  
     
     
         15 . The device of  claim 14  wherein the substrate is deformable by fluid pressure or mechanical means.  
     
     
         16 . The device of  claim 15  wherein the substrate is mounted onto a flexible membrane bubble.  
     
     
         17 . The device of  claim 16  further comprising a second membrane bubble positioned to define a chamber between the flexible membrane bubble and the second membrane bubble.  
     
     
         18 . The device of  claim 17  wherein the chamber contains molecules which flow through the microneedle.  
     
     
         19 . The device of  claim 18  wherein the molecules are drug molecules.  
     
     
         20 . The device of  claim 1  wherein the means reduces the elasticity of the biological barrier.  
     
     
         21 . The device of  claim 20  wherein the means physically manipulates the biological barrier to present a more rigid surface in the area of the biological barrier to be penetrated by the microneedle.  
     
     
         22 . The device of  claim 21  wherein the manipulation is selected from the group consisting of stretching, pulling, pinching, and a combination thereof.  
     
     
         23 . The device of  claim 22  wherein the manipulation includes pulling by reducing the atmospheric pressure over the area of the biological barrier to be penetrated by the microneedles.  
     
     
         24 . The device of  claim 23  further comprising a body portion defining a first vacuum region and a second vacuum region, wherein an array of microneedles separates the first and second regions.  
     
     
         25 . The device of  claim 24  wherein the body portion comprises an annular ring which holds the microneedles.  
     
     
         26 . The device of  claim 25  wherein the microneedle is hollow and wherein the body portion further comprises a means for attachment to a syringe, a conduit for connection to a vacuum pump, or both.  
     
     
         27 . The device of  claim 22  wherein the means comprises a stretching cone or expandable ring around the microneedles.  
     
     
         28 . The device of  claim 22  wherein the means comprises a body portion from which a plurality of stretching elements are pivotally attached.  
     
     
         29 . The device of  claim 28  wherein the stretching elements have ends provided with a non-slip feature for engagement with the biological barrier.  
     
     
         30 . The device of  claim 22  wherein the means comprises jaws for pinching a portion of the biological barrier for contact with the microneedles.  
     
     
         31 . The device of  claim 21  wherein the means comprises an adhesive film applied over the area of the biological barrier to be penetrated by the microneedle.  
     
     
         32 . The device of  claim 2  wherein the means for improving penetration creates holes in the stratum corneum, wherein the microneedle can be inserted into the holes.  
     
     
         33 . The device of  claim 32  wherein the means for creating holes is selected from the group consisting of thermal ablation, high pressure fluid puncturing, cryoablation, and application of degradation agents.  
     
     
         34 . The device of  claim 1  wherein the means for improving penetration accelerates the tips of the microneedles into the biological barrier, accelerates the biological barrier into contact with the tips of the microneedles, or a combination thereof.  
     
     
         35 . The device of  claim 34  wherein the means for accelerating the tip of the microneedle comprises releasing a spring or gas under compression.  
     
     
         36 . The device of  claim 1  wherein a lubricating material is incorporated into or coated onto the microneedle.  
     
     
         37 . The device of  claim 1  further comprising a collar to limit the depth of microneedle penetration.  
     
     
         38 . The device of  claim 1  further comprising a means for attaching the device to the skin of a patient, wherein the means is not the microneedle.  
     
     
         39 . The device of  claim 38  wherein the means is an adhesive film.  
     
     
         40 . The device of  claim 38  wherein the means is an arm band.  
     
     
         41 . The device of  claim 1  wherein the microneedle is hollow and wherein the device further comprises a reservoir selectably in communication with the hollow microneedle.  
     
     
         42 . The device of  claim 1  wherein the means for enhancing penetration comprises an apparatus for vibrating the microneedle.  
     
     
         43 . The device of  claim 42  wherein the apparatus comprises a piezoelectric transducer or an electromechanical actuator.  
     
     
         44 . A kit of parts for use in transport of material or energy across or into an elastic biological barrier, comprising 
 (i) a device comprising one or more microneedles having a tip end and a base end, and a substrate connected to the base end of the microneedle, and    (ii) an adhesive film or barrier-tightening chemical, either of which can be applied over an area of the biological barrier to be penetrated by the microneedle.    
     
     
         45 . A method for transport of material or energy across or into an elastic biological barrier, comprising using the device of  claim 1.