Patent Publication Number: US-2007118073-A1

Title: Device for manipulating a needle or abrader array and method of use

Description:
This application is a divisional application of U.S. application Ser. No. 10/163,383 filed Jun. 7, 2002 which claimed priority to previously filed provisional application Ser. No. 60/297,101 filed on Jun. 8, 2001, each of which are incorporated by reference in their entirety. 
    
    
     FIELD OF THE INVENTION  
      the invention relates to a new and useful method and apparatus for delivering a substance to a patient. The apparatus of the present invention includes a microabrader or microneedle device which includes a reservoir containing a pharmaceutically active compound for administration into a mammalian body through abrasions or perforations in the stratum corneum layer of the epidermis.  
     BACKGROUND OF THE INVENTION  
      Transdermal, or percutaneous, administration of pharmaceutical compounds is a known method of delivering drug compounds, or other agents, through the skin and into the human, or mammalian, circulatory system. The layer primarily responsible for inhibition of agents through the skin is the stratum corneum. The stratum corneum is a heterogeneous layer of flattened, relatively dry keratinised cells which limits the rate at which such agents can be administered therethrough, because of the chemical keratin-phospholipid complex it contains. Once a compound has penetrated the stratum corneum, which is approximately 15 microns thick, when dry, and expands to approximately 47 microns in thickness when fully hydrated, there remains no significant hindrance to penetration of the remaining epidermal layers. The remaining epithelial layers of the skin—the stratum granulosum, the stratum malpighii and the stratum germinativum—provide little, if any, resistance to the transmission of pharmaceutical compounds. Accordingly, once the stratum corneum has been penetrated, topically administered pharmaceutical agents are adsorbed through the lower epithelial layers and are able to enter into the circulatory system through the capillaries.  
      The prior art reports a variety of devices and methods for disrupting the stratum corneum for the purpose of delivering substances to the body. For example, breach of the stratum corneum may be achieved by puncturing as taught in U.S. Pat. No. 5,679,647 to Carson, et al. This patent teaches that narrow diameter tines, such as those found on devices used for tuberculin skin tests and allergy tests, can be coated with polynucleotides or oligonucleotides and used for delivery of such materials into the skin. The method of using such devices involves puncturing the skin with the types resulting in intracutaneous injection of the coated substance.  
      U.S. Pat. No. 5,003,987; U.S. Pat. No. 5,879,326; and U.S. Pat. No. 3,964,482 teach breaching the stratum corneum by abrasion.  
      It is, therefore, desirable to have an article of manufacture for transdermal drug delivery which can penetrate or abrade the stratum corneum using micron-sized projections, with a device for administering a pharmaceutical agent with precision and without causing undue intrusion into the lower epithelial layers, thereby minimizing patient discomfort or irritation.  
     SUMMARY OF THE INVENTION  
      A method and device for administering a substance to a mammal are provided by the present invention. The device can comprise a top or upper surface or wall, a bottom surface or wall spaced apart from said top surface or wall. The bottom surface or wall has a substantially planar outer surface from which a plurality of projecting structures extend outward. One or more side walls may join with the top and bottom walls to define in the space between them a reservoir for a substance that is to be delivered to the mammal. The device also comprises a manipulating member which is attached to at least one of the walls or surfaces of the device. The manipulating member extends outward from the surface or surfaces of attachment and is configured so as to be allow the user of the device to grip and control the device. The manipulating member may also be an extension of one or more walls or surfaces of the device and may even be molded as a single, unit body with the device. At least one passageway also extends from the reservoir to the projecting structures on the exterior of the device. The passageway or passageways may also extend through the projecting structures themselves. The device also comprises a at least one deformable member that will exert pressure on the substance contained in the reservoir and that deformable member may be one of the device walls or surface, the manipulating member or combinations thereof. In an alternate embodiment it is preferable that the device also comprise a way of retaining the substance to be delivered within the reservoir until sufficient pressure is exerted upon the substance to dispense it from the reservoir.  
      These and other aspects of the invention will become apparent to those skilled in the art in view of the following detailed description of the invention and the annexed drawings. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      The following is a brief description of the drawings in which:  
       FIG. 1  is a side view in cross section of an embodiment of the present invention showing a finger-cup attached to a microdevice which includes an array of microneedles;  
       FIG. 2  is a side view in partial cross-section of the embodiment of  FIG. 1  showing a human finger inserted into the finger-cup attached to the microdevice and an array of microneedles;  
       FIG. 3  is a cross-sectional side view of another embodiment of the present invention in which a handle extends outward from a flexible top wall of a reservoir wherein the microdevice includes an array of microabraders projecting outwardly from the planar surface of the bottom wall of the microdevice;  
       FIG. 4  is an end view in cross-section of the device of  FIG. 3 ;  
       FIG. 5  is a cross-sectional side view of another embodiment of the present invention showing the side wall of the microdevice extended to a length such that its exterior surface defines a handle and the interior region created by the joining of the top wall and bottom wall of the microdevice defines a reservoir;  
       FIG. 6  is an end view in cross-section of the embodiment of  FIG. 5 ;  
       FIG. 7  is a front view of another embodiment of the present invention showing a handle coupled to a microdevice, where the microdevice includes a top wall and a bottom wall defining a reservoir; and  
       FIG. 8  is a cross-sectional side view of the embodiment of  FIG. 7  showing a microdevice with a solid handle extending outwardly from the top wall of the microdevice.  
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      The present invention is directed to a method and device for delivering a substance through the skin of a patient. The following description of the invention primarily relates to drug delivery devices.  
      The present invention is directed to a method and apparatus for delivering a substance through the skin of a patient. One aspect of the invention is directed to a device for manipulating a microneedle or microabrading device employing micron-sized projections, to penetrate or abrade the stratum corneum. A microdevice according to the present invention is a device which has a top wall and a bottom wall separated and joined by side walls, or walls which are continues with the top wall to form a reservoir therebetween, and a substantially planar surface on the bottom wall with a plurality of projecting structures which can include either micron-sized penetrating members such as microneedles or micron-sized abrading members.  
      The projecting structures can range in length and width from less than  1  micron to several hundred microns. The projecting structures can be solid or hollow. The device may also include an axial passageway or channel from the reservoir to the projecting structures for conducting a substance from the reservoir to the projecting structures where the substance can be delivered through the stratum corneum and to the lower epithelial layers of a patient&#39;s skin. The passageway or channels maybe singular or multiple and may be located in or through one or more projections or on the substantially planar surface that houses the projections. The present invention is contemplated for use with mammalian patients.  
      In one embodiment of the invention, the microdevice has an extension to permit the manipulation of the microdevice by the user. The extension can be a stick-like elongated manipulation member such as a handle, finger-cup, or any other configuration that allows the user to control and manipulate the microdevice. The manipulation member may also contain a fluid reservoir that is either in fluid communication with an array of microneedles or microabraders or in communication with the internal reservoir containing a substance to be administered. The manipulation member is used to position the projecting structures accurately on the patient&#39;s skin to enable the user to retain control of the device. The manipulation member enables one to control the microdevice when moving the array of microneedles or abrading structures in a manner that penetrates or scores the stratum corneum while minimizing the risk of piercing the stratum corneum and penetrating into the lower epithelial layers and causing the patient excessive discomfort or irritation.  
      A substance, such as a pharmaceutical agent, is stored in a reservoir, it may also be stored in the handle. By squeezing and deforming the manipulation member, the fluid in the member impinges on the reservoir and the substance within the reservoir is forced out through the passageways or channels and delivered into and through the stratum corneum without having to increase the amount of pressure against the skin. If the handle is the reservoir the substance will be directly forced out through the passageways or channels.  
      In another embodiment of the invention, the microdevice includes a thimble-like structure or finger-cup that is comfortably and securely fitted to a fingertip. The thimble-like element of the device has an open end for inserting a finger and the projecting structure at the opposite end. A reservoir is disposed with one side in fluid communication with the projecting structures. The opposite side, or the adjacent sides may be deformable such as by including one or more membranes formed of resilient material to allow the fingertip within the thimble-like structure to deform and dispense the substance from the reservoir, by exerting pressure against the deformable material. This allows a person to accurately place the microdevice on the patient&#39;s skin and apply the necessary force to penetrate the stratum corneum and assist the percutaneous delivery of a drug composition within the reservoir, without increasing the depth to which the microneedles or abrading projections penetrate through the epithelial layer of the skin.  
      The aspects of the invention are basically attained by providing a device for administering a substance to a patient. The device comprises a top wall and a handle attached to the top wall and extending outward therefrom. The handle has a dimension sufficient to grip the device. A bottom wall is spaced apart from the top wall and has a planar outer surface. A plurality of projecting structures extend outwardly from the planar surface. Side walls join the top wall and the bottom wall. The top wall, bottom wall and side walls define a reservoir for the substance to be delivered into and through the skin of a patient.  
      The aspects of the invention are also attained by providing a device for delivering a substance through the skin of a patient. The device comprises a top wall, a finger-cup attached to the top wall and extending outward therefrom, and a bottom wall spaced apart from the top wall and having a planar outer surface. Projecting structures extend outward from the planar surface. Side walls join the top wall and the bottom wall. The top wall, bottom wall and side walls define a reservoir for the substance to be delivered to a patient.  
      The aspects of the invention are further attained by providing a method of delivering a substance through the skin of a patient. A microdevice is placed in contact with the skin of a patient. The microdevice comprises a planar surface having a plurality of projecting structures extending outwardly therefrom. A top wall is spaced apart from the planar surface. Side walls join the top wall and the planar surface to define a reservoir containing a substance. A manipulating member is attached to the top wall. A sufficient force is applied to the microdevice to cause the projecting structures to penetrate the stratum corneum layer of the skin. The substance is dispensed from the reservoir to the projecting structures and the substance is delivered below the stratum corneum layer of the skin.  
      The present invention relates to a microdevice with a structure for gripping or holding the microdevice during use. The microdevice of the present invention enables the person using the device to accurately and conveniently position and operate the microdevice, while reducing the possibility of causing penetration of the epithelial layers of the skin below the stratum corneum. By constructing a microdevice to enable greater control over its placement and operation, the stratum corneum can be abraded or pierced without the need for the application of excess pressure to the microdevice. By reducing the amount of pressure applied to the microdevice, the microneedles or microabraders of the microdevice when appropriately sized will penetrate the epithelial layer to a depth no greater than is necessary to deliver a substance below the stratum corneum without causing unintentional abrasion or penetration of the lower epithelial layers, thereby reducing patient irritation and discomfort.  
      In yet other embodiments of the invention the features of the device that are useful for delivering the substance from the reservoir are configured so that only at a predetermined pressure threshold is the delivery of the substance from the reservoir accomplished. In an embodiment with a deformable manipulating member, for example, that member will only deform, not under the forces or pressures encountered during manipulation of the device but at some higher threshold. In another example, such a pressure sensitive threshold could be set by use of a substance retaining membrane or a plug in the fluid passageway that would only rupture or be displaced at a pressure threshold greater than the pressure the substance will encounter during manipulation of the device.  
      In accordance with the invention and with respect to the drawing figures, a first embodiment of the present invention is a microdevice  10  as shown in  FIG. 1  includes a body  12  which has a top wall  20  and a bottom wall  30  spaced apart from the top wall  20  and joined by side walls  32 . The interior region created by the intersection of the top wall  20 , bottom wall  30  and side walls  32  defines a reservoir  40  for storing a substance  42  to be delivered to a patient. Typically, the substance is a pharmaceutical composition in a liquid or other flowable form such as gel or paste.  
      It is to be understood that in all of the descriptions of the figures, top and side and bottom are used for convenience and are not necessarily to be construed literally. For example, the body  12  may also be made up only one, or more, wall(s) that are a formed as a single unit body, such as for example ovoid or circular, and enclose the reservoir without distinction between top and side, or as part of another piece of the device.  
      Attached to top wall  20  and extending outwardly is a finger-cup  50  to receive and secure to the fingertip of a person using microdevice  10  to administer a substance to a patient. In preferred embodiments, finger-cup  50  is an elastic thimble-like member made of an elastic polymeric material. Finger-cup  50  is a tubular shaped member having a side wall  52  for encircling the finger of a user and an open top end  54 . A bottom end  55  of finger cup  50  is coupled to top wall  20 . In the embodiment illustrated, top wall  20  forms the bottom inner surface of finger cup  50 . In an alternative embodiment, finger cup  50  can have a bottom wall that overlies top wall  20 .  
      By securing finger-cup  50  to a finger  64 , the microdevice  10  is able to be precisely maneuvered into the desired position on the skin  56  where treatment is to be administered. For greater comfort to the person administering treatment with the microdevice, the finger-cup  50  may be formed in a manner which is specific to the fingers of a left hand or right hand or be adapted to accommodate more than one finger. It is understood that fingers may include either opposing digits or thumbs or combinations of thereof.  
      Bottom wall  30  of the microdevice  10  has an outwardly facing planar surface having outwardly extending projections  58 . The projecting structures  58  can be assembled in an array of microneedles or microabraders depending on the method desired for creating openings in the stratum corneum. The projecting structures  58  extend outwardly and generally perpendicularly from the planar surface of bottom wall  30 . Fluid conducting passageways  60  are preferably included within each projecting structure  58  in the form of axial channels that extend through each projecting structure  58 . The fluid conducting passageways  60  are open on each end to allow fluid communication between the reservoir  40  and tips  62  of the projecting structures  58 . In one embodiment, the tips  62  of the projecting structures  58  have a length to penetrate the skin slightly beneath the stratum corneum. The fluid conducting passageways  60  permit the flow of the substance  42  from the reservoir  40  through passageways  60  of projecting structures  58  to the area immediately beneath the stratum corneum. The substance delivered in this manner is then absorbed into the capillaries through the lower epithelial layers.  
      In yet another embodiment, the projecting structures are solid and the passageway, or multiple passageways, opens from the interior of the reservoir to the base of the projecting structures. The form and shape of the projecting structures can be of any design and shape that will enable them to penetrate the stratum corneum is the desire manner. Such design and configurations will be apparent to those skilled in the art.  
      Body  12  is preferably made of a suitable plastic material, but can be any material able to perform and withstand the forces encountered and be impervious and non-reactive with any materials it may encounter. Top wall  20  is preferably flexible or deformable so as to be deflected inwardly to dispense the substance contained in reservoir  40 . Bottom wall  30  is generally stiff to promote uniform penetration of projecting structures  58 . In other embodiments, bottom wall  30  is flexible to conform to the surface of the skin of the patient. In yet other embodiments one or more of the side walls are deformable.  
      In  FIG. 2 , the tip of a finger  64  is inserted into the open top end  54  of finger-cup  50 . The elasticity of the finger-cup  50  firmly secures the finger  64  within the finger-cup  50  allowing the accurate manipulation of the microdevice  10 . Once the microdevice  10  has been properly positioned on the patient&#39;s skin  56 , the tip of the finger  64  within the finger-cup  50  applies an additional amount of pressure against the top wall  20  of the microdevice  10 . When the projecting structures  58  are microneedles as shown in  FIG. 2 , application of sufficient pressure against top wall  20  of microdevice  10  causes the projecting structures  58  to penetrate the stratum corneum until the bottom wall  30  of the microdevice  10  comes in contact with the surface of the patient&#39;s skin. Provided that the length of the projecting structures  58  is greater than the thickness of the stratum corneum, the tips  62  of the projecting structures  58  will pierce the stratum corneum.  
      As used herein, penetrating refers to entering the stratum corneum without passing completely through the stratum corneum and entering into the adjacent layers. This is not to say that that the stratum corneum can not be completely penetrated to reveal the interface of the underlying layer of the skin. Piercing, on the other hand, refers to passing through the stratum corneum completely and entering into the adjacent layers below the stratum corneum.  
      The downward pressure on top wall  20  by finger  64  deflects top wall  20  inwardly as shown by phantom lines in  FIG. 2  to dispense the substance  42  from reservoir  40  through passageways  60  of each projecting structure  58 . The substance  42  stored within the reservoir  40  is discharged through the fluid conducting passageways  60  and absorbed by the patient through the epithelial layers beneath the stratum corneum.  
      The length and thickness of the projecting structures  58  are selected based on the particular substance being administered and the thickness of the stratum corneum in the location where the device is to be applied. Preferably, the projecting structures  58  penetrate the stratum corneum substantially without piercing or passing through the stratum corneum. The projecting structures  58  can have a length up to about  500  microns. Suitable projecting structures  58  have a length of about  5  to  500  microns. Preferably, the projecting structures  58  have a length of about  50  to about  300  microns, and more preferably in the range of about 75 to 250 microns, with 180 to 220 microns most preferred. In preferred embodiments, the projecting structures  58  are either hollow or solid members.  
      The method of delivering a substance through the skin of a patient using device  10  places the projecting structures  58  against skin and applies a downward pressure. In embodiments where the projecting members  58  have a length sufficient to penetrate the skin to below the stratum corneum, the downward pressure is sufficient to penetrate the skin. In other embodiments, the device  10  is moved in a back and forth or circular pattern to abrade the skin sufficiently to enable projecting structures  58  to penetrate the skin to a desired depth. A continued downward pressure flexes top wall  20  to dispense the substance in reservoir  40  for delivery through the axial passages  60  of projecting structures  58  and into the skin.  
      In one embodiment, projecting structures  58  are knife-like blades or other structures, such as pyramidal or frustoconical in shape, which are preferably perpendicular to the plane of the device and abrasive to the topmost epithelial layer and able to penetrate the stratum corneum by cutting, scoring, or abrading the surface of the stratum corneum until an opening of sufficient depth has been created for fluid to pass through. Because the microdevice  10  may need to be moved in a reciprocating manner to penetrate the stratum corneum, precise handling of microdevice  10  through the use of the attached finger-cup  50  is highly desirable. Careful use of device  10  will avoid unintentional penetration, abrasion, or piercing of the epithelial layers below the stratum corneum, and avoid unnecessary patient discomfort and irritation.  
     EMBODIMENT OF FIGS.  3  AND  4   
       FIGS. 3 and 4  show a second embodiment of a delivery device  80  of the present invention which includes a body  82  having a top wall  84 , bottom wall  86  and side walls  88  defining a reservoir  90 . A handle  92  is attached to top wall  84  and has a dimension to enable the user to grip and manipulate the device  80 . The depicted embodiment shows handle  92  being hollow and attached to the periphery of side wall  88 . In a preferred embodiment, handle  92  is made of a resilient, flexible and deformable material such as for example rubber, plastic, thin metal sheet, or combinations thereof. Handle  92  in the illustrated embodiment has a hollow cavity  93  formed by side walls  95  and a top wall  84 . In one embodiment, handle  92  has an open bottom end that is closed by the attachment to top wall  84 . In another preferred embodiment, handle  92  is closed at both ends.  
      A plurality of projecting structures  94  extend from bottom wall  86  to form an array. As in the previous embodiment, projecting structures  94  have a length and width that is sufficient to penetrate the skin to a selected depth for delivering a substance into and through the skin. In this embodiment, each projecting structure  94  includes an axial passage  96  extending from reservoir  90  to ends  99  of projecting structures  94 . The handle  92  is attached to top wall  84  in a manner which is air-tight to form hollow cavity  93 . By squeezing the handle  92  in the direction of arrows  91 , side walls  95  deflect inwardly to compress the air within handle  92  causing downward displacement of the top wall  84  as shown by the phantom lines in  FIG. 4 . The deflection of top wall  84  dispenses the contents of reservoir  90  through axial passages  96  of projections  94 . In this manner, there is no increase in the pressure applied to the skin by the microdevice  80 , thereby reducing the risk of penetration into the epithelial by the projecting structures  94 . Patients treated by the present invention can expect to experience less pain and discomfort than is normally associated with the administration of pharmaceuticals by microdevices of this nature.  
      In practice, a person is able to administer a substance, such as a pharmaceutical composition, to a patient with device  80  by grasping the handle  92  and precisely positioning the projecting structures  94  on the skin in a target area. Once the projections  94  are properly positioned on the skin of the patient, the handle  92  is used to apply gentle pressure and to move the projecting structures  94  in a generally reciprocal manner to enable projecting structures  94  to score and abrade the stratum corneum. Once projecting structures  94  have penetrated the stratum corneum, the bottom wall  86  of the microdevice  80  is, or in the case of abrader projecting structures the projecting structures themselves are held in contact with the skin of the patient. The handle  92  is squeezed to compress fluid air contained in the handle and to produce an additional amount of pressure on top wall  84  to deflect top wall  84  in a manner to reduce the volume of the reservoir  90  and to discharge the pharmaceutical composition stored within the reservoir  40  through fluid conducting passageways  96  of projecting structures  94  and into the body of the patient immediately below the stratum corneum. In this manner, the pharmaceutical composition is placed in contact with the lower epithelial layers and are able to be absorbed by the body.  
     EMBODIMENT OF FIGS.  5  AND  6   
      In another embodiment shown in  FIGS. 5 and 6 , a delivery device  100  includes a handle  102  attached to a base  104 . Base  104  includes a bottom wall  106  and side walls  108 . A plurality of projecting structures  110  arranged in an array extend from bottom wall  106 . Projecting structures  110  in the embodiment illustrated, are microneedles having an axial passage  112  that extend through bottom wall  106 . Base  104  also includes a top wall  114  coupled to side walls  108  to define a fluid reservoir  116 .  
      Handle  102  is a hollow structure formed by side walls  118  and a top wall  120  to form an internal cavity  1   19 . Handle  102  has an open bottom end  122  so that cavity  119  is in direct fluid communication with reservoir  1   16 . As in the previous embodiment, handle  102  is made of a deformable resilient material so that side walls  118  can be deflected inwardly as shown by the phantom lines in  FIG. 6  by applying an external force against the side walls  118  in the direction of arrows  124 . In this embodiment, cavity  119  can contain a substance  125  to be delivered to the patient. Deflecting side walls  118  inwardly forces the substance  125  in the direction of arrows  127  from reservoir  116  through axial passages  112  of projecting structures  11 O.  
      Operation of the device  100  of this embodiment of the invention is substantially the same as the operation of the embodiment shown in  FIG. 3 , but offers an alternative configuration suitable for instances where a larger volume reservoir is desired.  
     EMBODIMENT OF FIGS.  7  AND  8   
       FIGS. 7 and 8  show another embodiment of a delivery device  126  of the present invention including body  128  having a deformable top wall  129  spaced apart from a bottom wall  130  and side walls  132  extending between top wall  129  and bottom wall  130 . The area enclosed by top wall  129 , bottom wall  130  and side walls  132  define a reservoir  134 . A solid manipulating member  136 , such as a handle, is coupled to top wall  129 . In this embodiment, handle  136  is a solid, elongated member having a dimension to provide a surface which can be gripped by the user. By gripping handle  136 , the person administering treatment can exercise accurate control over device  126  while minimizing the possibility of causing the patient undue irritation and discomfort. Bottom wall  130  has a plurality of outwardly extending projecting structures  142  having axial passages  138  communicating with reservoir  134 . As in the previous embodiment, top wall  128  is sufficiently flexible to flex inwardly to dispense a substance  140  from reservoir  134  through axial passages  142  of projecting structures  142 .  
      Once the device is positioned properly and projecting structures  142  are embedded within the stratum corneum, handle  136  can be pressed downwardly in the direction of arrow  144  to deflect top wall  129  as shown in phantom lines of  FIG. 8 . As in the previous embodiment, device  126  can be pressed downwardly against skin  146  to cause projecting structures  142  to penetrate skin  146  to a desired depth. Alternatively, device  126  can be rubbed against skin  146  in a target site to abrade skin  146  to a depth to allow substance  140  to penetrate skin  146  below the stratum corneum.  
      In other embodiments of the invention, the substance to be delivered is physically retained within the reservoir, such as for example, by at least one rupturable membrane. This retaining membrane may be as simple as a rupturable material overlaying, or adjacent to the fluid passageway or passageways, or an enclosing bladder. Other ways of retaining the substance are also within the scope and spirit of this invention. It is also envisioned that the membrane be ruptured by internally projecting members that will pierce the membrane. Regardless of the configuration of this retaining means the material or structure used needs to be responsive to the pressure generated by the dispensing means such that at a sufficient, and generally predetermine threshold, the pressure overcomes the ability of the retaining mean to retain the substance and the substance is dispensed.  
      While several embodiments have been chosen to illustrate the invention, it will be appreciated by those skilled in the art that various changes and modifications of the device can be made without departing from the scope of the invention as defined in the appended claims.