Patent Document

CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 61/084,585, filed on 29 Jul. 2008, which is incorporated in its entirety by this reference. 
    
    
     TECHNICAL FIELD 
     This invention relates generally to the drug delivery field, and more specifically to an improved system and method for transdermal drug delivery and the method of making this improved system. 
     BACKGROUND 
     Over 10% of the population has a phobia of needles, which has created a growing $6 billion market for drug delivery through the skin. Although some drugs (most notably nicotine and birth control) are available for skin delivery, most drugs are large molecules that will not pass through the skin on their own. Penetration through the stratum corneum, or outermost layer of the skin, is a significant challenge of transdermal drug delivery, particularly for macromolecules (MW&gt;1 kDa). Conventional approaches to transdermal drug delivery of macromolecules include iontophoresis, microneedles, electrical microporation, lasers, and ultrasound. However, there are several key factors that are preventing them from being widely commercially used. Transdermal delivery systems such as radiofrequency micro-ablation, ultrasound, lasers, and electrical microporation require expensive, heavy, and bulky electronics that are impractical for common, everyday use. Additionally microneedles often require a high-speed injector device, have a low penetration rate, and frequently break causing the delivery system to fail and leaving shards in the skin. Thus, there is a need for an improved system and method for transdermal drug delivery. This invention provides such an improved and useful system and method for transdermal drug delivery and a method of making this improved system. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIGS. 1-3  are representations of the system of the first preferred embodiment of the invention; 
         FIG. 4  is an image of a skin sample with micropores (stained with Masson&#39;s trichrome, Scale=200 μm); 
         FIG. 5  is a representation of transdermal drug delivery enabled by the system of the preferred embodiment of the invention; 
         FIGS. 6 and 7  are representations of variations of the first embodiment in  FIGS. 1-3 ; 
         FIG. 8  is a representation of the method of making the system of the variation of the first preferred embodiment in  FIG. 7 ; 
         FIGS. 9 ,  10 , and  11  are representations of the system of the second, third, and fourth preferred embodiments of the invention, respectively; 
         FIG. 12  is a representation of the method of making the system of the preferred embodiment of the invention; 
         FIG. 13  is a representation of the mask used in the method of making the system of the preferred embodiment of the invention; 
         FIG. 14  is a drawing of the method of adding a chemical to the system of the preferred embodiment of the invention; and 
         FIG. 15  is a drawing of an alternate method of adding a chemical to the system of the preferred embodiment of the invention. 
     
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The following description of preferred embodiments of the invention is not intended to limit the invention to these embodiments, but rather to enable any person skilled in the art to make and use this invention. 
     As shown in  FIGS. 1 and 2 , the system  10  of the preferred embodiments includes a chemical  16 , a series of chemical delivery elements  14  that hold and deliver the chemical  16 , and a base  12  that contains the chemical delivery elements  14 . When the base  12  is coupled to an outer layer of skin of a patient, the chemical delivery elements  14  are activated and function to deliver the chemical  16  to the outer layer of skin of the patient (the stratum corneum). The chemical  16  functions to create a series of micropores  18 , as shown in  FIGS. 3 and 4 , in the outer layer of skin of the patient. Because nerve endings do not reach the outer layer of skin, the patient does not feel pain from the creation of the micropores  18 . The system  10  of the preferred embodiment is preferably designed to enable transdermal drug delivery, and more specifically, to create a series of micropores  18  in an outer layer of skin of the patient. The micropores  18  preferably increase skin permeability of the patient, enabling a drug  22  (shown in  FIG. 5 ) to reach the body of the patient. The system  10  of the preferred embodiments, however, may be alternatively used in any suitable environment and for any suitable reason. 
     1. The System 
     As shown in  FIGS. 3-5 , the chemical  16  of the preferred embodiments functions to create a series of micropores  18  in the outer layer of skin (the stratum corneum) of the patient, which preferably increase skin permeability of the patient and enable a drug  22  to reach the body of the patient. The chemical  16  is preferably an agent that does not pose a threat if it is taken up by the vasculature and/or deposited in another location in the body of the patient. The chemical  16  is preferably one of several suitable agents such as acids, bases, lipid, and/or enzymes, but may alternatively be any other suitable chemical to dissolves, or otherwise breaks down, the skin and to create micropores  18  in outer layer or stratum corneum of the skin. In a first variation, the chemical  16  is preferably 10N potassium hydroxide (10N KOH), but may alternatively be any other concentration up to approximately 10N of potassium hydroxide. Although 10N KOH is relatively strong, the combination of the small volume held by each chemical delivery element and the small area of skin that the chemical  16  is contacting enables the chemical  16  to form precise micropores  18  in the superficial layers of the skin. In addition, as the chemical  16  diffuses through the skin and creates the micropores, the chemical  16  is subsequently diluted and loses its original ability to break down tissue such as vaculature or nerves once it has gone past the superficial layers of the skin. In alternative variations, the chemical  16  is preferably an acid such as Hydrochloric acid (HCl), a base such as Sodium hydroxide (NaOH), an enzyme such as papain, bromelain, actinidin, ficin, or any other suitable agent such as Esters. 
     As shown in  FIG. 5 , the micropores  18  created by the chemical are preferably spaced such that they produce microscale, invisible channels into the skin through which drug molecules may diffuse or pass. The creation of the micropores  18  by the chemical  16  is preferably pain free and invisible to the eye. The micropores  18  are preferably in the range of approximately 10 μm to 300 μm in diameter, but may alternatively be of any appropriate size to allow a macromolecular drug (preferably greater than 1 kDa) to diffuse through the outer layer of skin, while at the same time small enough such that the skin of the patient can naturally heal and/or close the pores. 
     As shown in  FIG. 1 , the series of chemical delivery elements  14  of the preferred embodiments functions to hold and deliver the chemical  16  to the outer layer of skin of the patient. The series of chemical delivery elements  14  preferably function to focus a series of small volumes of a chemical  16  to a portion of the outer layer of skin of the patient. Each chemical delivery element  14  is preferably on the order of 100 μm by 100 μm, but may alternatively have any other suitable dimension. The dimensions of the chemical delivery element  14  may also be specific to the drug  22  that is to be delivered by the system. To prevent overlap of the created micropores  18  because of diffusion of the chemical  16  through the skin, each chemical delivery element  14  is preferably spaced at least 50 μm (center to center) from one another. In the preferred embodiments, each chemical delivery element  14  is preferably spaced about 500 μm (center to center) from one another, but may alternatively have any other suitable spacing. Each chemical delivery element  14  preferably holds a volume of 0.5 to 2.5 nL of the chemical  16 , but may alternatively hold any other suitable amount of chemical appropriate to create the desired micropores  18  while accommodating for variation in thicknesses of the superficial layers of skin. The series of chemical delivery elements  14  preferably holds a total volume of the chemical  16  of about 1 μL, but may alternatively hold a volume approximately of the range from 0.1 μL to 100 μL. However, the series of chemical deliver elements  14  may hold any other total volume suitable for creating miropores over the area necessary to transmit an appropriate dosage of transdermal drug  22 . 
     The series of chemical delivery elements  14  is preferably one of several variations. In a first variation, as shown in  FIGS. 2 and 3 , the series of chemical delivery elements  14  is a series of wells that function to hold a volume of the chemical  16 . Each well is preferably cube-shaped, 100 μm×100 μm horizontally and about 250 microns deep, but may alternatively have any suitable geometry of any suitable dimension. The material of the series of wells is preferably the same material a material that may be made temporarily hydrophilic and is otherwise hydrophobic. The material is preferably a polymer such as Polydimethylsiloxane (PDMS), which is a hydrophobic material that can be made temporarily (less than 30 minutes) hydrophilic when exposed to oxygen plasma. This property enables the wells to be loaded with the chemical  16 . A vacuum may be used to facilitate filling the wells with the chemical  16 . When the hydrophobic property of the material of the wells returns, it will form a tight interface between the chemical  16  and the wells, such that the chemical does not spill outside of the well. The hydrophobic property of the material also facilitates the deposition of chemical  16  onto the skin upon application to the skin. Alternatively, a vacuum may be used to fill the wells without using oxygen plasma. However, any other suitable method for loading the delivery elements  14  with the chemical  16  may be used. 
     In a second variation, as shown in  FIG. 6 , the series of chemical delivery elements  14  is a series of columns  26  that function to hold the chemical  16  such that when the base  12  is coupled to the outer layer of skin of the patient, the columns  26  function to deliver the chemical  16  to the outer layer of skin of the patient by “stamping” the chemical  16  onto the skin. In a third variation, as shown in  FIG. 7 , the series of chemical delivery elements  14  is a series of electrode sites  38 , electrochemically coated with a polymer having the chemical  16 . When the base  12  is coupled to the outer layer of skin of the patient, the chemical  16  will preferably leech out of the polymer coating into the outer layer of skin of the patient. The coating is preferably a thin coating, preferably on the order of 50 μm, but may alternatively be any other suitable thickness. The series of chemical delivery elements of this variation is preferably fabricated as shown in  FIG. 8 , but may alternatively be fabricated in any other suitable fashion. Although the series of chemical delivery elements  14  is preferably one of these three variations, the series of chemical delivery elements  14  may be any suitable element to hold and deliver a chemical  16 . 
     As shown in  FIGS. 1 and 2 , the base  12  of the preferred embodiments includes the series of chemical delivery elements  14  and functions to couple to an outer layer of skin of a patient. When coupled to the skin of the patient, base  12  functions to activate the delivery elements  14  to deliver the chemical  16 . The base  12  is preferably of the same material as the chemical delivery elements  14  and is preferably made of a polymer such as Polydimethylsiloxane (PDMS), but may alternatively be made of any suitable material. The material of the base  12  is preferably inert and non-toxic, such that it is biocompatible. The base  12  is preferably removably fixable to the skin. The base  12  preferably includes an adhesive that is removably fixable to the skin, but may alternatively be removably fixable to the skin in any other suitable fashion. The base  12  preferably has dimensions of about 5 cm×5 cm×1 cm, and more preferably has dimensions of less than 2 cm×2 cm×0.5 cm, but may alternatively have any other dimension suitable to enable the appropriate dose of drug  22  to be delivered transdermally to the body. 
     As shown in  FIG. 9 , the system  10  of the second embodiment is nearly identical to the system  10  of the first embodiment. The difference between the two embodiments, however, is that the system  10  of the second embodiment further includes a chemical reservoir  14 ′. In this embodiment, the chemical reservoir  14 ′ preferably includes an additional volume of the chemical  16 , which can ensure that the system  10  includes enough volume of the chemical  16  to create appropriately sized micropores  18 . The chemical reservoir  14 ′ preferably holds an additional total volume of chemical  16  of about 30 to 50 μL, but may alternatively hold any other suitable total volume. 
     As shown in  FIG. 10 , the system  10  of the third embodiment is nearly identical to the system  10  of the first embodiment. The difference between the two embodiments, however, is that the system  10  of the third embodiment further includes a hydration reservoir  32 . In this embodiment, the hydration reservoir  32  preferably maintains the hydration level of the chemical  16 , which can prevent dehydration of the chemical  16  after the system has been packaged and while it is being stored. This arrangement may be quite useful in certain environments, such as to increase the “shelf life” of the system  10 . 
     As shown in  FIG. 5 , the system  10  of the preferred embodiments also includes a drug delivery element  20 . The drug delivery element  20  functions to hold a drug  22  and functions to deliver a drug  22  to the micropores  18  created in the outer layer of skin of the patient. The drug delivery element  20  is preferably any suitable drug infused patch that functions to hold a drug  22  and functions to deliver a drug  22  to the skin. The drug  22  is preferably any suitable drug and more preferably any suitable macromolecular drug that functions to enter a patient&#39;s body through a series of micropores  18  created by the system  10 . One specific example of a suitable drug is botulinum toxin, or Botox. Other examples of suitable drugs include Enoxaparin (Lovenox), Caspofungin (Cancidas), Etanercept (Enbrel), Somatostatin (Sandostatin), or any other high molecular weight pharmaceuticals. The drug  22  may further include a buffer to neutralize the chemical  16  in the body of the patient before the drug  22  enters the body of the patient. 
     As shown in  FIG. 11 , the system  10  of the fourth embodiment is nearly identical to the system  10  of the first embodiment. The difference between the two embodiments, however, is that the system  10  of the fourth embodiment further includes a drug reservoir  34 , that functions to store and deliver drug  22 , and at least one pillar  36  that functions to simultaneously lift the base  12  off of the surface of the skin and compress the drug reservoir  34  such that the drug  22  exits the drug reservoir  34 . In this embodiment, the chemical  16  is preferably applied to the skin to create the series of micropores  18 . The pillars  36  are then activated such that they lift the base  12  off of the surface of the skin and compress the drug reservoir  34 . The pillars are preferably activated by gas expansion. The gas expansion may be activated by the user, but may also be an automatic gas expansion that expands at a rate that allows the chemical delivery elements  14  to administer the appropriate amount of the chemical  16  for the appropriate length of time before fully lifting the base  12  off the surface of the skin. However, the pillars may alternatively be activated by any other suitable mechanism. Once the base  12  is lifted off the surface of the skin, and the drug  22  exits the drug reservoir  34 , the drug  22  preferably seeps below the lifted patch and enters the micropores  18  in the skin. The drug  22  in this embodiment preferably includes a buffer to neutralize the chemical  16  in the body of the patient before the drug  22  enters the body of the patient. The system  10  may alternatively include a drug reservoir  34  that supplies the drug  22  to the micropores  18  in any other suitable arrangement. 
     2. Method of Making the System 
     The system  10  of the preferred embodiment is preferably micro-machined using standard microfabrication techniques, but may alternatively be fabricated in any other suitable fashion. As shown in  FIG. 12 , the method of the preferred embodiments includes the steps of providing a wafer S 100 , building up the mold material S 102 , masking a portion of the mold material S 104 , removing a portion of the mold material S 106 , adding the base material to the mold S 108 , and removing the base  12 , which has a series of chemical delivery elements  14 , from the mold S 110 . The method is preferably designed for the manufacture of system  10  for transdermal drug delivery. The method, however, may be alternatively used in any suitable environment and for any suitable reason. 
     One specific example of the method of the preferred embodiments uses photolithography or photolithographic patterning to create the mold. In Step S 100 , a bare silicon wafer is first cleaned in acetone and isopropyl alcohol (IPA) to remove any organics or surface impurities. AP300 is then preferably spun onto a clean four-inch wafer at 500 rpm for 5 seconds, followed immediately by 4000 rpm for 30 seconds. AP300 functions to improve SU8 adhesion. In Step S 102 , the mold material, SU8-2075 (Microchem Corp.), is preferably spun onto the wafer. The thickness of the mold material is preferably of 250 μm, but may alternatively be any other suitable thickness. The mold material is preferably SU-8, but may alternatively be any other suitable material, which functions well with the chosen material for the base  12 . The spread cycle in this variation preferably lasts 12 seconds at 500 rpms (a=100 rpm/s) while the spin cycle is preferably 1,200 rpm spin for 30 seconds (a=300 rpm/s). After settling for 30 minutes, the wafer is preferably soft baked initially at 65° C. for 7 minutes followed immediately by a second bake at 95° C. bake for 45 minutes. Deep edge bead removal is then preferably performed by washing the edge of the wafer with ACS soaked 10 mm brush while the wafer was spinning at 500 rpm. The edge is then preferably cleaned with developer while the wafer is preferably spun at 500 rpm. In Step S 104 , a mask  24  is preferably applied to the surface of the wafer using a glass sheet. As shown in  FIG. 13 , a specific example of the mask  24  is a square grid of 25 by 25 chemical delivery elements over a 1.4 cm×1.4 cm area. Each chemical delivery element is 100 μm width and 100 μm height with 500 μm spacing (center-to-center). The mask  24  may alternatively have any other suitable geometry with any other suitable dimensions. The mask  24 , on the mold material, is then preferably exposed for 15 seconds with 60 second pauses, repeated 5 times for an approximate total exposure of approximately 450 mJ/cm2 and put through a post exposure bake at 65° C. for 5 minutes, immediately followed by at 95° C. for 15 minutes. In Step S 106 , the excess mold material is removed by soaking the wafer in developer for 17 minutes with agitation, and, after removing the wafer, it is preferably sprayed by a developer for 10 seconds, then IPA for 10 seconds, followed by a rinse with diH 2 O. After air-drying the wafer, it is preferably hard baked at 150° C. for 5 minutes to prepare the mold. The patterned SU-8 layer then preferably serves as a mold for the base  12 , as shown in step S 108  in  FIG. 12 . The mold is then preferably incubated in a chamber with 1 ml of methyltrichlorosilane for 30 minutes at room temperature. The material for the base  12  is then preferably prepared by mixing pre-polymer and curing agent in a 10:1 ratio. The mixture is degassed in a vacuum changer to remove bubbles for 30 minutes, and then poured onto the wafer without forming bubbles. The wafer is then baked at 80° C. for 30 minutes. However, any other suitable process may be used to create a mold and the base  12 . 
     As shown in  FIG. 14 , the base  12 , removed from the mold, is preferably plasma oxidized, making it hydrophilic (Step S 200 ). Step S 202  shows the chemical  16  deposited over the surface of the base  12  and chemical delivery elements  14 . In S 204 , a vacuum is preferably applied to fill the chemical delivery elements with the chemical  16 . As shown in  FIG. 15 , the system  10  may alternatively be filled with the chemical  16  by use of a channel system  28  such that the chemical  16  may be inserted into the base  12  from the opposite side of the chemical delivery elements  14 . In this variation, oxygen plasma may be similarly used to make the chemical delivery elements  14  and channel system  28  to be hydrophilic and a vacuum is then preferably applied to fill the channel system  28  and the chemical delivery elements  14  with the chemical  16 . Once the chemical  16  is inserted into the base  12 , and the chemical delivery elements  14  are filled with the chemical  16 , the channel system  28  is preferably sealed with any suitable cap or sealant  30 . In both variations, a vacuum may be used alone to fill the chemical delivery elements  14  (and the channel system  28 ) without the assistance of oxygen plasma. However, any other suitable type of method or catalyst for filling the chemical delivery elements  14  with chemical  16  may be used. 
     Although omitted for conciseness, the preferred embodiments include every combination and permutation of the various bases  12 , chemical delivery elements  14 , chemicals  16 , drug delivery elements  20 , drugs  22 , and methods of making these elements. 
     As a person skilled in the art will recognize from the previous detailed description and from the figures and claims, modifications and changes can be made to the preferred embodiments of the invention without departing from the scope of this invention defined in the following claim.

Technology Category: 1