Abstract:
A device for delivering a substance into the skin of a patient includes a housing and a plurality of microneedles for penetrating the skin. The housing includes a bottom wall with a plurality of apertures for supplying the substance to the microneedles. The housing also includes a flexible top cover member enclosing a bladder containing the substance to be delivered. The bottom wall of the housing has at least one cannula facing the bladder. Pressing on the top cover member causes the cannula to puncture the bladder and deliver the substance to the microneedles for delivery to the patient. In one embodiment, the cannula is surrounded by a flexible member to prevent piercing of the bladder until sufficient pressure is applied to the cover member to depress the flexible member.

Description:
FIELD OF THE INVENTION 
     The present invention relates to a method and delivery device for delivering a substance, such as a drug or pharmaceutical agent transdermally to a patient. More particularly, the invention is directed to a device containing a diluent for delivering a reconstituted drug transdermally to a patient. 
     BACKGROUND OF THE INVENTION 
     Various devices have been proposed for transdermally delivering pharmaceutical agents, drugs and other substances. Although the subcutaneous delivery methods using a standard cannula are effective for many applications, the pain normally induced by the cannula has prompted the development of less painful delivery methods. 
     The use of prefilled syringes and other delivery devices has increased significantly in recent years due in part to the convenience and reduced risk of contamination. Prefilled syringes are generally suitable for drug solutions that are stable for extended periods of time. The drug solution itself must be stable and the solution must not interact with the syringe barrel or other container during storage. Certain drugs are inherently unstable in solution and are normally stored as a dried or lyophilized powder that must be reconstituted prior to use. These drugs are not suitable for standard prefilled syringes. 
     A method that has received much attention in recent years is the delivery of drugs through the skin by forming micropores or cuts through the stratum corneum. By penetrating the stratum corneum and delivering the drug to the skin in or below the stratum corneum, many drugs can be effectively administered. The devices for penetrating the stratum corneum generally include a plurality of micron size needles or blades having a length to penetrate the stratum corneum without passing completely through the epidermis. Examples of these devices are disclosed in U.S. Pat. No. 5,879,326 to Godshall et al.; U.S. Pat. No. 5,250,023 to Lee et al., and WO 97/48440. 
     The skin is made up of several layers with the upper composite layer being the epithelial layer. The outermost layer of the skin is the stratum corneum which has well known barrier properties to prevent molecules and various substances from entering the body and analytes from exiting the body. The stratum corneum is a complex structure of compacted keratinized cell remnants having a thickness of about10-30 microns. 
     The natural impermeability of the stratum corneum prevents the administration of most pharmaceutical agents and other substances through the skin. Numerous methods and devices have been proposed to enhance the permeability of the skin and to increase the diffusion of various drugs through the skin so that the drugs can be utilized by the body. Typically, the delivery of drugs through the skin is enhanced by either increasing the permeability of the skin or increasing the force or energy used to direct the drug through the skin. 
     One example of a method for increasing the force for the delivery of drugs through the skin include iontophoresis. Iontophoresis generally applies an external electrical field to ionize the drug, thereby increasing the diffusion of the drug through the skin. However, it can be difficult to control the amount and rate of drug delivery using iontophoresis. Under some circumstances, iontophoresis can cause skin damage depending on the extent of ionization, the energy applied to ionize the drug and duration of the treatment. 
     Sonic, and particularly ultrasonic energy, has also been used to increase the diffusion of drugs through the skin. The sonic energy is typically generated by passing an electrical current through a piezoelectric crystal or other suitable electromechanical device. Although numerous efforts to enhance drug delivery using sonic energy have been proposed, the results generally show a low rate of drug delivery. 
     The prior methods and apparatus for the transdermal administration of drugs has exhibited limited success. Accordingly, a continuing need exists in the industry for an improved device for the administration of various drugs and other substances. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to a method and device for the transdermal delivery of a substance, such as a drug, vaccine or other pharmaceutical agent, to a patient. In particular, the invention is directed to a method and device for delivering a pharmaceutical agent to the stratum corneum of the skin to a sufficient depth where the pharmaceutical agent can be absorbed and utilized by the body. 
     Accordingly, a primary object of the invention is to provide a method and device for reconstituting a pharmaceutical agent and administering the pharmaceutical agent transdermally through the skin substantially without pain to the patient. 
     Another object of the invention is to provide a prefilled delivery device having a reservoir containing a substance and a plurality of microneedles or blades for penetrating the stratum corneum of the skin for delivering the substance to the skin. 
     A further object of the invention is to provide a device having a dried pharmaceutical agent and a reservoir containing a diluent for reconstituting the dried pharmaceutical agent and delivering the pharmaceutical agent to the patient. 
     Another object of the invention is to provide a device having a bladder containing a substance and a cannula for piercing the bladder to dispense the substance and deliver the substance to the patient. 
     A further object of the invention is to provide a device for the transdermal delivery of a substance where the apparatus includes a bladder containing the substance, a cannula to pierce the bladder and a protecting shield to prevent premature piercing of the bladder. 
     A still further object of the invention is to provide a device for the transdermal delivery of a pharmaceutical agent having a plurality of microneedles for penetrating the stratum corneum and a bladder containing the pharmaceutical agent for delivering the pharmaceutical agent to the microneedles. 
     Another object of the invention is to provide a device having a plurality of microneedles for penetrating the stratum corneum and an outer adhesive patch for adhesively attaching the apparatus to the skin of a patient. 
     Still another object of the invention is to provide a transdermal delivery device having an array of microneedles for penetrating the stratum corneum of the skin, a flexible bladder containing a substance and flexible cover that can be deflected toward the bladder to dispense the substance to the microneedles. 
     A further object of the invention is to provide a device for the transdermal delivery of a substance to a patient where the device has an array of microneedles and a dried substance on the microneedles, where the dried substance is reconstituted by dispensing a diluent from a bladder within the device. 
     These and other objects of the invention are substantially attained by providing an intradermal delivery device for introducing a substance into the skin of a patient. The device comprises a housing having a central opening and a planar member positioned in the central opening of the housing. The planar member has an inner surface and an outer surface. The outer surface has a plurality of microneedles extending therefrom, at least one opening passing through the planar member from the inner surface to the outer surface, and at least one cannula on the inner surface. A flexible cover is coupled to the housing and overlies the central opening and is spaced from the planar member to define a cavity in the housing. A bladder containing at least one substance is positioned in the cavity of the housing between the planar member and the flexible cover. The bladder is piercable by the cannula and is collapsible by pressing the flexible cover to dispense the substance through the opening to the microneedles. 
     The objects and advantages of the invention are further attained by providing an intradermal device for administering a pharmaceutical agent through the skin of a patient. The device comprises a housing having a bottom wall and at least one side wall defining a cavity. The bottom wall has a plurality of microneedles and a plurality of passages extending through the bottom wall to the microneedles. A flexible cover is coupled to the housing and encloses the cavity. The flexible cover has a generally arcuate shaped outer surface in a first position and is movable from the first position to a second position toward the bottom wall. A bladder contains a substance and the bladder is positioned in the cavity and is collapsible by applying pressure to the flexible cover to dispense the substance through the passages in the bottom wall to the microneedles. 
     Another object of the invention is to provide a method of administering a substance such as a pharmaceutical agent through the skin of a patient which comprises providing a delivery device having a housing with a bottom wall and at least one side wall defining a cavity. The bottom wall has an outer surface with a plurality of microneedles extending therefrom and has a plurality of passages extending through the bottom wall from the cavity to the microneedles. A bladder contains at least one substance and is positioned in the cavity, and a flexible cover encloses the cavity. The device contacts the skin of a patient and sufficient pressure is applied to the device to cause the microneedles to penetrate the skin a sufficient depth for delivering a substance to the patient. Sufficient pressure is applied to the flexible cover to rupture the bladder and dispense the substance to the microneedles. 
     The objects, advantages and other salient features of the invention will become apparent from the following detailed description which, taken in conjunction with the annexed drawings, discloses preferred embodiments of the invention. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The following is a brief description of the drawings in which: 
     FIG. 1 is a top view of the transdermal delivery device in accordance with a first embodiment of the invention; 
     FIG. 2 is a cross-sectional view of the transdermal delivery device of FIG. 1; 
     FIG. 3 is a perspective view of the transdermal delivery device of FIG. 1; 
     FIG. 4 is a side view in cross-section of a transdermal delivery device of FIG. 1 showing the outer cover and bladder depressed; 
     FIG. 5 is a side elevational view in cross-section of a second embodiment of the invention; 
     FIG. 6 is side elevational view in cross-section of the delivery device in a third embodiment of the invention; 
     FIG. 7 is a partial side view of the transdermal delivery device in a fourth embodiment of the invention; 
     FIG. 8 is a partial top view of the embodiment of FIG. 7; and 
     FIG. 9 is a partial cross-sectional side view of the embodiment of FIG. 7 showing the bladder pierced by the cannula. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The present invention is directed to an intraepidermal delivery device for administering a substance to a patient. More particularly, the invention is directed to a prefilled delivery device containing a drug solution or diluent for a dried drug and to a method for administering the drug solution or a reconstituted drug solution into or below the stratum corneum of the skin of a patient. Intradermal refers to one or more layers within the skin and is not limited to the dermis layer of the skin. 
     The device and method of the present invention are particularly suitable for use in administering various substances, including pharmaceutical agents, to a patient, and particularly to a human patient. As used herein, a pharmaceutical agent includes a substance having biological activity that can be delivered through the body membranes and surfaces, and particularly the skin. Examples include various drugs, such as antibiotics, antiviral agents, analgesics, anesthetics, anorexics, antiarthritics, antidepressants, antihistamines, anti-inflammatory agents, antineoplastic agents, vaccines, including DNA vaccines, adjuvants, biologics, and the like. Other substances which can be delivered intradermally to a patient include proteins, peptides and fragments thereof. The proteins and peptides can be naturally occurring, synthesized or recombinantly produced. 
     The invention is directed to a delivery device  10  having a housing  12 , a plurality of microneedles  14  and a prefilled bladder  16  as shown in FIGS. 1-4. The invention is further directed to a method of delivering a substance to a patient using the delivery device  10 . 
     Referring to FIGS. 1-4, the housing  12  of device  10  in this embodiment has a generally circular shape having a central opening  18  defining an inner wall  20 . Housing  12  is preferably made of a flexible plastic or rubber-like material that is non-reactive to the substance being delivered to the patient. In the embodiment illustrated, the microneedles  14  are integrally formed with a planar member  22  that is dimensioned to fit within the central opening  18 . Planar member  22  preferably has a shape corresponding to the shape of central opening  18  and fits securely against inner wall  20 . An outer edge  24  of planar member  22  abuts inner wall  18  to form a fluid tight seal. In one embodiment of the invention, the planar member  22  is attached to the inner wall  20  by a suitable adhesive or other suitable bonding method. As shown in FIG. 2, planar member  22  is positioned in the central opening  18  of housing with the microneedles  14  facing outwardly beyond the housing  12  to ensure complete contact with the skin of the patient as discussed hereinafter in greater detail. 
     Housing  12  in the embodiment shown in FIGS. 1-4 is sufficiently flexible to conform to the contour of the patient&#39;s skin. In other embodiments, the housing can be made of a rigid material. A bottom surface  26  of housing  12  preferably includes a pressure sensitive adhesive  28  for attaching housing  12  to the skin of a patient during use. The pressure sensitive adhesive  28  can be a suitable adhesive as known in the art that is commonly used in adhesive bandages. The adhesive layer  28  preferably encircles the central opening  18  and is able to form a substantially fluid tight seal around the central opening  18  and microneedles  14 . 
     Planar member  22  forms a bottom wall of housing  12  having the microneedles  14  facing outwardly from the housing  12 . In the embodiment illustrated, microneedles  14  are integrally formed with the planar member  22 . In alternative embodiments, a separate bottom wall can be provided and a second member having microneedles formed thereon can be superimposed. 
     As shown in FIG. 1, a flexible film  42  of a sheet material is attached to the housing  12 . Film  42  has a dimension to extend beyond the dimension of the housing  12  in opposite directions. Film  42  includes an adhesive coating for attaching delivery device  10  to the skin of a patient in a manner similar to an adhesive bandage strip. 
     Delivery device  10  is generally made from a plastic material that is non-reactive with the substance being administered. Suitable plastic materials include, for example, polyethylene, polypropylene, polyesters, polyamides and polycarbonates as known in the art. The microneedles can be made from various materials by methods as known in the art. For example, microneedles can be made from silicon, stainless steel, tungsten steel, alloys of nickel, molybdenum, chromium, cobalt, and titanium, ceramics, glass polymers and other non-reactive metals, and alloys thereof. 
     The length and thickness of the microneedles 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. In one embodiment, the microneedles penetrate the stratum corneum substantially without penetrating or passing through the epidermis. The microneedles can have a length for penetrating the skin up to about 250 microns. Suitable microneedles have a length of about 5 to 200 microns. Typically, the microneedles have a length of about 5 to about 100 microns, and generally in the range of about 10 to 40 microns. The microneedles in the illustrated embodiment have a generally conical shape. In alternative embodiments, the microneedles can be triangles, flat blades or pyramids. Typically, the microneedles are perpendicular to the plane of the device. The width of the microneedles can be about 15 to 40 gauge to obtain optimum penetration of the skin. 
     The microneedles  14  are generally formed in uniformly spaced rows and columns to form an array. The microneedle array generally has a surface area of about 0.5 to about 5.0 cm 2 . The spacing between the rows and columns can be varied depending on the substance being administered and the desired dosage. In one embodiment, the microneedles are spaced apart a distance of about 0.05 mm to about 5.0 mm. 
     In the embodiment of FIGS. 1-4, microneedles  14  include a hollow passage  30  extending axially through each microneedle  14  and planar member  22 . Passage  30  of each microneedle is dimensioned to allow fluid to pass through the microneedles to the tips  32  of the microneedles for delivery to the skin surface. 
     A generally domed shaped cover member  34  is attached to a top surface  36  of housing  12  to completely cover central opening  18  and define a cavity  38  within housing  12 . As shown in FIG. 2, cover member  34  has a dimension slightly larger than the dimension of central opening  18  and has a generally convex outer surface  40 . Cover member  34  is preferably made of a plastic sheet material that is sufficiently flexible to be flexed in a generally downward direction. In one embodiment, cover member  34  is made of material that has sufficient memory to return to its domed shape and can be depressed to snap to an inverted concave shape. 
     Flexible bladder  16  is positioned in cavity  38  of housing  12 . Bladder  16  is preferably a sealed bulbous shaped member made from a flexible material that can conform to the shape of cavity  38  and can be depressed to dispense the contents. Bladder  16  is prefilled with a desired substance before the delivery device is assembled. 
     A cannula  44  is provided on the top surface  46  of planar member  22  as shown in FIG.  2 . In the embodiment illustrated, three cannulas  44  are positioned to face toward bladder  42 , although the number used can vary as needed. Cannula  44  has a generally flat base  46  and a pointed tip  48  that is capable of piercing the bladder. Cannula  44  can be made of suitable metal or plastic having sufficient strength to pierce bladder  42 . As shown in FIG. 2, cannula  44  is a separate element that is attached to planar member  22 . In alternative embodiments, cannula  44  can be integrally formed with planar member  22 . Typically, cannula  44  has a generally conical shape, although can be any suitable shape capable of piercing bladder  16 . 
     Bladder  16  can contain a drug solution or other substance to be delivered to the patient. Preferably, bladder  16  is dimensioned to contain a premeasured dosage for the particular drug solution being administered. 
     In further embodiments, bladder  16  contains a diluent or carrier for reconstituting a substance to be delivered to the patient. The diluent can be, for example, distilled water or saline solution. In a preferred embodiment, a dried drug is provided as a coating on the outer surfaces of the microneedles. In further embodiments, the dried drug can be a coating on the top surface of planar member  22  or in passages  30 . In this embodiment, the dried or lyophilized drug or pharmaceutical agent is dissolved or dispersed in the diluent and delivered to the patient. This embodiment is particularly suitable for unstable drug solutions. 
     Delivery device  10  is produced as a complete, prefilled unit for delivery of a substance to a patient. The device can include a protective cover (not shown) over microneedles  14  to prevent damaging or contamination of the microneedles during storage and shipping. Similarly, a protective release liner (not shown) can be applied over the adhesive and the device packaged in a suitable packaging material commonly used for medical devices. 
     The primary barrier properties of the skin including the resistance to drug penetration reside in the outermost layer of the skin, referred to as the stratum corneum. The inner layers of the epidermis generally include three layers, commonly identified as the stratum granulosum, the stratum malpighii, and the stratum germinativum. Once a drug or other substance penetrates below the stratum corneum, there is substantially less resistance to permeation into the subsequent layers of the skin and eventual absorption by the body. Thus, delivery of a substance below the stratum corneum can be an effective system for administering some substances, and particularly some vaccines, to the body. The delivery device of the invention is able to deliver a substance into or below the stratum corneum where it can be utilized by the body. Preferably, the device and method of the invention pierce the stratum corneum substantially without penetrating the dermis to target the tissue layers below the stratum corneum. As used herein, the term penetrate refers to entering a layer of the skin without necessarily passing completely through. Piercing refers to passing completely through a layer of the skin. As used herein, transdermal refers to the delivery of a substance, such as a pharmaceutical, biological agent or vaccine, through one or more layers of skin. 
     In use, delivery device  10  is removed from its packaging and the release sheet, if provided, is separated to expose the adhesive layer on the bottom face of the device. Delivery device  10  is positioned on the desired location of the skin  48  and pressed in place with a gentle downward pressure until the microneedles penetrate the outermost layer of skin and the adhesive layer contacts the skin and forms a seal around the microneedle array. A gentle rubbing motion also can be applied to delivery device  10  to assist in the penetration of the skin by the microneedles  14 . Cover member  34  is then pushed downwardly in the direction of arrow  50  as shown in FIGS. 3 and 4 with sufficient pressure to cause cannula  44  to pierce bladder  16 . The pressure is applied to cover member  34  and bladder  16  to collapse the bladder and force the contents of the bladder into cavity  38  and through passages  30  to tips  32  of the microneedles  14 . Preferably, adhesive layer  28  on the bottom of housing  12  and film  42  form a seal to contain the drug solution or other substance in the target area of the microneedle array where it can penetrate the stratum corneum and be absorbed by the body. 
     Generally, the pressure applied to cover  34  is sufficient to enable a drug solution to flow to the tips of the microneedles  14  where the drug solution is available for absorption by the skin. In further embodiments, cover member  34  can be made of stiff plastic material so that when pressed, the dome shaped cover member snaps to an inverted position and retains the inverted position to maintain a constant force on the bladder. In this manner, a constant pressure can be produced to deliver the substance to the microneedles. 
     Embodiment of FIG.  5   
     FIG. 5 shows a second embodiment of the delivery device  52 . Delivery device  52  is similar to the embodiment of FIGS. 1-4 and includes a housing  54  having a central opening  56 , a bottom surface  58  and a top surface  60 . Bottom surface  58  is preferably provided with a layer of a pressure sensitive adhesive  62  that encircles central opening  56 . A flexible film  64  having an adhesive  66  is attached to top surface  60  of housing  54  for attaching delivery device  52  to the skin  68  of a patient. 
     A planar member  70  is formed with an array of microneedles  72 . Microneedles  72  are provided with an axial hollow passage  74  extending through planar member  70 . A bladder  75  contains a drug solution, diluent or other substance as in the previous embodiment. A cannula  76  is provided on the top surface of planar member  70 , and a flexible cover  78  is attached to housing  54  to enclose a cavity  80 . 
     In the embodiment of FIG. 5, an indicator device  82  is provided in housing  54  for indicating proper contact of the microneedle array with skin  68  of the patient. In the embodiment illustrated, indicator device  82  is an electrical device that contacts the skin when sufficient downward pressure is applied to delivery device  52 . Indicator device  82  includes a pair of electrodes  84  connected by leads extending from the bottom surface  62  of housing  54  to top surface  60 . Electrodes  84  are coupled to a power source  86  having a visual indicator  88 , such as, for example, a liquid crystal display or liquid crystal diode. 
     Delivery device  54  is applied to skin  68  of a patient with a downward pressure until electrodes  84  contact skin  68 . The conductivity of the patient&#39;s skin completes the electrical circuit between electrodes  84  to actuate indicator  88  thereby providing an indication that sufficient pressure is applied for microneedles  72  to penetrate the skin a sufficient depth for delivery of the drug solution. Cover member  78  is then depressed to pierce bladder  75  by cannula  76  and dispense the contents of bladder  75 . 
     In the embodiment illustrated, the indicator device is an electrical device that relies on the electrical conductivity of the skin of the patient. In further embodiments, the indicator can be a pressure sensor device or other suitable devices capable of providing an indication that sufficient pressure is applied to the microneedle array. 
     Embodiment of FIG.  6   
     FIG. 6 shows a delivery device  92  in a further embodiment of the invention. Delivery device  92  is similar to the delivery device  10  of FIGS. 1-4 except for the array of microneedles  94 . Accordingly, identical components are identified by the same reference number with the addition of a prime. 
     The microneedle array  94  is formed on a bottom surface of a planar member  96 . As in the previous embodiments, the planar member  96  is coupled to housing  12 ′ in the central opening  14 ′ to define a cavity. A plurality of passages  98  extend through the planar member  96  from the cavity to the outer face. In this embodiment, microneedles  94  are solid structures and passages  98  terminate substantially at the base of the microneedles and between adjacent microneedles  94 . 
     Delivery device  92  is used in substantially the same manner of the previous embodiments. Delivery device  92  is positioned on the skin and rubbed or pressed gently to enable microneedles  94  to penetrate the skin. Cover member  34 ′ is then pressed to cause bladder  16 ′ to be pierced by cannula  44 ′. The substance contained in the bladder  16 ′ is then dispensed and directed to passages  98  to microneedles  94 . As in the previous embodiments, bladder  16 ′ can contain a drug solution or a diluent to dissolve a dried drug in the cavity  38 ′ or on the surface of the microneedles  94 . 
     Embodiment of FIGS.  7 - 9   
     A delivery device  100  in a further embodiment is shown in FIGS. 7-9. Delivery device  100  is similar to delivery device  10  of the embodiment of FIGS. 1-4, except for a protecting shield device  102  that cooperates with a cannula  104 . Accordingly, identical components are identified by the same reference number with the addition of a prime. 
     As in the previous embodiment, delivery device  100  includes a planar member  22 ′ having an array of microneedles  14 ′ on a bottom surface of the planar member  22 ′. Microneedles  14 ′ include an axial passage  30 ′ that extends through planar member  22 ′ to cavity  38 ′. 
     The protecting member  102  is a supporting or cradle-like device that is positioned in the upper surface of planar member  22 ′ to shield cannula  104  for preventing or resisting premature rupturing and piercing of bladder  16 ′. As shown in FIGS. 6 and 7, protecting member  100  includes a base  106  having an outer edge  108  and has a height greater than a height of cannula  104 . In the embodiment illustrated, base  106  is a flat circular member, although the actual shape of the base can be varied depending on the particular needs of the device. 
     A cannula  104  is coupled to base  106  and extends in a generally upward direction away from planar member  22 ′ toward bladder  16 ′. Cannula  104  in the embodiment illustrated is a separate member coupled to base  106  by a suitable adhesive, welding or the like. In alternative embodiments, cannula  104  can be integrally formed with the base. Cannula  104  has a generally conical shape converging to a sharp tip  110  suitable for piercing bladder  16 ′. 
     A resilient arm  112  has a first end  114  coupled to the base  106  and a second end  116  extending away from the base  106 . In the embodiment of FIGS. 7-9, four arms  112  are coupled to the base  106  and extend at an incline toward the tip  110  of cannula  104 . The arms  112  are positioned such that the second free ends  116  of arms  112  assume a normal position above tip  110  of cannula  108  as shown in FIG.  7 . Arms  112  surround tip  110  of cannula  104  and support bladder  16 ′ above cannula  104  to prevent bladder  16 ′ from contacting cannula  104  during shipping and storage. In the embodiment illustrated, arms  112  are integrally formed with base  106 , although in other embodiments, the arms  112  can be separate members that are assembled together. 
     The delivery device  100  is used in a manner similar to the previous embodiments. Delivery device  100  is positioned on the skin  118  of the patient and gently rubbed and pressed against skin  118  and secured in place by the adhesive. Cover member  34 ′ is then pushed downwardly to push bladder  16 ′ toward cannula  104 . Arms  112  of protecting member  102  are sufficiently flexible that downward pressure on cover member  34 ′ and bladder  16 ′ pivots free end  116  of arms  112  toward base  106  to enable cannula  104  to pierce bladder  16 ′ as shown in FIG. 9 to dispense the contents of the bladder. 
     The delivery devices of the invention are generally intended for single use and contain a selected dose for the substance being delivered to the patient. The adhesive film is able to hold the delivery device in place with minimal discomfort for extended periods of time. The length of time the delivery device remains in contact with the skin can vary from several minutes to several hours. Various factors that determine the length of time the delivery device remains in contact with the skin include, for example, the depth of penetration, the volume of the substance being delivered, and the absorption rate of the substance. 
     While several embodiments have been shown to illustrate the present invention, it will be understood by those skilled in the art that various changes and modifications can be made therein without departing from the scope of the invention as defined in the appended claims.