Patent Publication Number: US-2023134250-A1

Title: Microarray for delivery of therapeutic agent and methods of use

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. Application No. 16/513,613, filed on Jul. 16, 2019, which is a continuation of of U.S. Application No. 14/210,402, filed Mar. 13, 2014, now issued as U.S. Pat. No. 10,384,046 on Aug. 20, 2019, which claims benefit of and priority to U.S. Provisional Application No. 61/799,304, filed Mar. 15, 2013, each of which is incorporated herein by reference in their entirety. 
    
    
     TECHNICAL FIELD 
     The disclosure relates generally to a method and delivery system for sustained and/or controlled, transdermal administration of a therapeutic agent or drug or vaccine using an array of microstructures, and related features thereof. 
     BACKGROUND 
     Arrays of microneedles were proposed as a way of administering drugs through the skin in the 1970s, for example in expired U.S. Pat. No. 3,964,482. Microneedle or microstructure arrays can facilitate the passage of drugs through or into human skin and other biological membranes in circumstances where ordinary transdermal administration is inadequate. Microstructure arrays can also be used to sample fluids found in the vicinity of a biological membrane such as interstitial fluid, which is then tested for the presence of biomarkers. 
     In recent years it has become more feasible to manufacture microstructure arrays in a way that makes their widespread use financially feasible. U.S. Pat. No. 6,451,240 discloses some methods of manufacturing microneedle arrays. If the arrays are sufficiently inexpensive, for example, they may be marketed as disposable devices. A disposable device may be preferable to a reusable one in order to avoid the question of the integrity of the device being compromised by previous use and to avoid the potential need of resterilizing the device after each use and maintaining it in controlled storage. 
     Despite much initial work on fabricating microneedle arrays in silicon or metals, there are significant advantages to polymeric arrays. U.S. Pat. No. 6,451,240 discloses some methods of manufacturing polymeric microneedle arrays. Arrays made primarily of biodegradable polymers also have some advantages. U.S. Pat. No. 6,945,952 and U.S. Published Pat. Applications Nos. 2002/0082543 and 2005/0197308 have some discussion of microneedle arrays made of biodegradable polymers. A detailed description of the fabrication of a microneedle array made of polyglycolic acid is found in Jung-Hwan Park et al., “Biodegradable polymer microneedles: Fabrication, mechanics, and transdermal drug delivery,” J. of Controlled Release, 104:51-66 (2005). These biodegradable microstructure arrays (MSA) may consist of a biodegradable tip portion containing a dried active pharmaceutical ingredient (API) and excipients in a biocompatible and water soluble polymer matrix. A backing portion, which connects and supports the tips, may consist of a biocompatible, non-water soluble polymer matrix. Once the MSA penetrates into the subject’s skin, the tip portion rapidly dissolves and released the API very quickly, resulting in a fast T max . 
     A layered microstructure array has been described for hPTH delivery (U.S. Pat. No. 2011/0276028) comprising a fast dissolving drug-in-tip distal layer and a backing layer formed of an insoluble biodegradable polymer. Administration of these microstructure arrays typically lead to fast dissolution of the distal layer and corresponding fast systemic absorption of the drug. 
     Many drugs require sustained delivery for a prolonged period of time including hours, days, weeks, etc. One approach for sustained delivery uses microprojection arrays with detachable microprojections such as in U.S. Pat. No. 8,366,677 and U.S. Application No. (Attorney Docket No. 091500-0439 filed Dec. 21, 2012), which is incorporated herein by reference. 
     Therefore, there is a need for a microstructure array that provides for sustained or extended delivery of a therapeutic agent. Furthermore, there is a need to modulate or modify the drug release profile from the microstructure array in order to meet therapeutic requirements for therapeutic agents. 
     The microstructure arrays are preferably retained on or at the administration site for a period of time for a suitable or desired delivery of the therapeutic agent. One approach for maintaining the array at the delivery site uses a microneedle device that is applied to skin and adhered using a pressure sensitive adhesive surrounding the microneedle array, e.g. U.S. Pat. No. 8,267,889. This approach does not hold the microneedles closely to the skin except at the perimeter of the array where the adhesive contacts the skin and the edge of the array. U.S. Pat. No. 7,184,826 describes the use of microblades for piercing the skin to enhance delivery. To anchor the microblades, they may include a prong or barb extending from the microblades or include a partial adhesive coating. Microneedle arrays including a coating comprising a therapeutic agent coating have also been described, e.g. U.S. Pat. No. 8,057,842. 
     Thus, there is also a need in the art for microprojection arrays suitable for extended wear that provide better adhesion of the microprojection array and/or better contact of the microprojections and/or arrays. 
     The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings. 
     BRIEF SUMMARY 
     The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope. 
     In one aspect of the invention, an array of microstructures is provided comprising an approximately planar base and a plurality of microstructures. 
     In one aspect, a microstructure apparatus is provided. In an embodiment, the microstructure apparatus comprises (a) an approximately planar substrate having a first surface and a second surface opposed thereto; and (b) a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising (i) a water insoluble, biodegradable polymer, and (ii) at least one therapeutic agent, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours. In an embodiment, the water insoluble polymer is selected from polylactide, polyglycolide, and co-polymers thereof. 
     In embodiments, the polymer matrix comprises about 1-50% therapeutic agent. In other embodiments, the polymer matrix comprises about 10-50% therapeutic agent. In further embodiments, the polymer matrix comprises about 20-50% therapeutic agent. In additional embodiments, the polymer matrix comprises about 25-50% therapeutic agent. In yet further embodiments, the polymer matrix comprises about 30-50% therapeutic agent. In other embodiments, the polymer matrix comprises about 45-50% therapeutic agent. 
     In embodiments, the polymer matrix comprises about 50-99% of the water insoluble, biodegradable polymer. In other embodiments, the polymer matrix comprises about 50-90% of the water insoluble, biodegradable polymer. 
     In embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute. In other embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 0.5-10%/minute. In further embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 1-10%/minute. In additional embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 2-10%/minute. 
     In embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours. In further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours. In additional embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour. 
     In embodiments, the microstructures are detachable from the substrate. 
     In embodiments, the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine. 
     In another embodiment, the microstructure apparatus comprises (a) an approximately planar substrate having a first surface and a second surface opposed thereto; and (b) a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising (i) at least one low molecular weight polymer, (ii) at least one high molecular weight polymer, and (iii) at least one therapeutic agent; wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute; and wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours. 
     In embodiments, the polymer matrix comprises at least one water insoluble, biodegradable polymer. In further embodiments, at least one of the low molecular weight polymer or the high molecular weight polymer is the water insoluble, biodegradable polymer. In additional embodiments, the water insoluble, biodegradable polymer is selected from polylactide, polyglycolide, and co-polymers thereof. 
     In embodiments, the initial release rate is between about 0.5-10%/minute. In further embodiments, the initial release rate is between about 1-10%/minute. In additional embodiments, the initial release rate of the therapeutic agent from the polymer matrix is less than about 1-10%/minute. 
     In embodiments, the low molecular weight polymer has a molecular weight of between about 1-10 K Da. In further embodiments, the high molecular weight polymer has a molecular weight of between about 50-300 K Da. In additional embodiments, the high molecular weight polymer has a molecular weight of between about 50-70 K Da. 
     In embodiments, the low molecular weight polymer and high molecular weight polymers are present in a ratio of about 1:1-1:10. In further embodiments, the low molecular weight polymer and high molecular weight polymers are present in a ratio of about 1:1. In other embodiments, the low molecular weight polymer and high molecular weight polymers are present in a ratio of about 1:4. 
     In embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours. In further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours. In additional embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour. 
     In embodiments, the microstructures are detachable from the substrate. 
     In embodiments, the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine. 
     In another embodiment a microstructure apparatus comprises (a) an approximately planar substrate having a first surface and a second surface opposed thereto; and (b) a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising (i) at least one biodegradable polymer, (ii) a hydrophilic component, and (iii) at least one therapeutic agent; wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours. 
     In an embodiment, the biodegradable polymer is a water insoluble, biodegradable polymer. 
     In an embodiment, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 4-24 hours. In another embodiment, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 4-8 hours. In further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours. In further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours. In additional embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour. 
     In an embodiment, the polymer matrix comprises about 5%-40% of the hydrophilic component. In another embodiment, the polymer matrix comprises about 5%-10% of the hydrophilic component. In a further embodiment, the polymer matrix comprises about 5%-40% of the hydrophilic component. In yet another embodiment, the polymer matrix comprises up to about 40% of the hydrophilic component. In other embodiments, the polymer matrix comprises up to about 20% of the hydrophilic component. In further embodiments, the polymer matrix comprises up to about 10% of the hydrophilic component. 
     In embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute. In other embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 0.5-10%/minute. In further embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 1-10%/minute. In yet other embodiments, an initial release rate of the therapeutic agent from the polymer matrix is between about 2-10%/minute. 
     In embodiments the hydrophilic component is PEG-PLGA. In further embodiments, the hydrophobic polymer is selected from PLA, α-hydroxy acids, polycaprolactones, polyanhydrides, and co-polymers thereof. In additional embodiments, the α-hydroxy acid is PLGA. 
     In embodiments the microstructures are detachable from the substrate. 
     In embodiments, the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine. 
     In an embodiment, the microstructure apparatus, comprises (a) an approximately planar substrate having a first surface and a second surface opposed thereto; (b) a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising at least one polymer and at least one therapeutic agent; wherein a ratio of therapeutic agent to polymer in the matrix is low; wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute; wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours. 
     In embodiments, the ratio of therapeutic agent to polymer is between about 1:2 to 1:25. In further embodiments, the ratio of therapeutic agent to polymer is between about 1:2 to 1:20. In other embodiments, the ratio of therapeutic agent to polymer is between about 1:2 to 1:15. In yet further embodiments, the ratio of therapeutic agent to polymer is between about 1:2 to 1:10. In additional embodiments, the ratio of therapeutic agent to polymer is between about 1:2 to 1:4. 
     In an embodiment, the polymer matrix comprises at least one water insoluble, biodegradable polymer. In further embodiments, the water insoluble, biodegradable polymer is selected from polylactide, polyglycolide, and co-polymers thereof. 
     In an embodiment, the initial release rate is between about 0.5%/minute. In further embodiments, the initial release rate of the therapeutic agent from the polymer matrix is less than 10 %/minute. In additional embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours. In further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours. In additional embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours. In yet further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour. 
     In embodiments the microstructures are detachable from the substrate. 
     In embodiments, the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine. 
     In an embodiment a microstructure apparatus, comprises (a) an approximately planar substrate having a first surface and a second surface opposed thereto; and (b) a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto; wherein at least a portion of the microstructures has a distal portion dimensioned to penetrate a stratum corneum layer of a subject’s skin, and a proximal portion that is dimensioned so that it does not penetrate the skin; wherein the distal portion and proximal portion are each formed of a polymer matrix comprising (i) a biodegradable polymer, and (ii) at least one therapeutic agent. 
     In an embodiment, the apparatus further comprises a backing layer positioned between the proximal portion and the substrate, the backing layer being formed of a polymer matrix comprising (i) a biodegradable polymer, and (ii) the at least one therapeutic agent. In other embodiments, the biodegradable polymer is a water soluble biodegradable polymer. In further embodiments, the biodegradable polymer is a water insoluble biodegradable polymer. 
     In an embodiment, the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine. 
     In embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.1-24 hours. In other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.5-10 hours. In further embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.5-4 hours. In additional embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.5-4 hours. In yet other embodiments, release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.1-1 hours. In other embodiments, the microstructure array is suitable to be worn for at least 1-24 hours. 
     In another aspect, a method of making a sustained release microstructure apparatus, comprises 
     dissolving or suspending a therapeutic agent in a solvent to form a therapeutic agent solution or suspension;   dissolving at least one water insoluble, biodegradable polymer in a solvent to form a polymer solution;   mixing the therapeutic agent solution or suspension and the polymer solution or suspension to form a polymer matrix solution or suspension;   dispensing the polymer matrix solution or suspension on a mold having an array of microstructure cavities;   filling the microstructure cavities in the mold;   removing excess solution or suspension polymer matrix on the mold surface; and drying the matrix to form a plurality of microstructures;   dispensing a basement or backing layer on the mold surface;   drying the basement or backing layer.   

     In an embodiment, the method further comprises affixing the basement or backing layer to a substrate. In another embodiment, the method further comprises using a nonwoven or porous film double coated with adhesive to affix the basement or backing layer to a substrate. In a further embodiment, at least one of the solvents is selected from DMSO and acetonitrile. In other embodiments, filling the therapeutic agent is crystalline, and the method further comprises heating the plurality of microstructures to about 110° C. for about 1 hour; and storing the microstructures in a dry cabinet for about 10 days. In embodiments, the heating is performed in a convection oven. 
     In a further aspect, a method of modulating an initial release rate of a therapeutic agent from a microstructure apparatus comprising a plurality of microstructures formed of a polymer matrix comprising at least one polymer and at least one therapeutic agent, comprises:
     (a) wherein the at least one polymer comprises at least one high molecular weight polymer and at least one low molecular weight polymer, adjusting a ratio of the high molecular weight polymers to low molecular weight polymers in the polymer matrix to achieve a desired initial release rate of therapeutic agent from the polymer matrix;   (b) adjusting a ratio of therapeutic agent to polymer in the polymer matrix;   (c) adding at least one hydrophilic component to the polymer matrix; and/or   (d) selecting a solvent for preparing the polymer matrix that provides a desired initial release rate.   

     In an embodiment, (a) comprises increasing the ratio of high molecular weight polymer in the matrix to increase the initial release rate. In another embodiment, (a) comprises increasing the ratio of low molecular weight polymer in the matrix to decrease the initial release rate. In further embodiments, (b) comprises increasing the ratio of therapeutic agent in the matrix to increase the initial release rate. In additional embodiments, (b) comprises decreasing the ratio of low molecular weight polymer in the matrix to decrease the initial release rate. 
     In embodiments, (c) comprises adding the hydrophilic component as about 10-40% of the matrix to increase the initial release rate. 
     In embodiments, the hydrophilic component is PEG-PLGA. 
     In embodiments, the at least one polymer is a water insoluble, biodegradable polymer. In other embodiments, the water insoluble, biodegradable polymer is selected from polylactide, polyglycolide, and co-polymers thereof. 
     In embodiments, (d) comprises choosing one of DMSO or acetonitrile as the solvent. In other embodiments, (d) comprises choosing DMSO as the solvent to lower the initial release rate. In additional embodiments, (d) comprises choosing acetonitrile as the solvent to increase the initial release rate. 
     In another aspect, a microstructure apparatus, comprises a substrate having a first surface and a second surface opposed thereto; a plurality of microstructures extending outwardly from the first surface of the substrate; at least a portion of the microstructures comprising at least one therapeutic agent; and an adhesive coating applied to at least one of a) at least a portion of at least some of the plurality of microstructures, or b) at least a portion of the substrate first surface between the microstructures. 
     In embodiments, at least a portion of the microstructures comprise a biodegradable distal layer and at least one non-biodegradable proximal layer positioned between the distal layer and the first surface of the substrate. 
     In embodiments, at least a portion of the microstructures are biodegradable. 
     In embodiments, the therapeutic agent is a drug, a small-molecule agent, a protein or peptide, or a vaccine. 
     In embodiments, the adhesive coating comprises an adhesive selected from a medical adhesive, a tissue adhesive, or a surgical adhesive. In other embodiments, the medical adhesive is selected from acrylic adhesives, silicone based adhesives, hydrogel adhesives, and synthetic elastomer adhesives. In further embodiments, the tissue adhesive is a cyanoacrylate polymer. In yet further embodiments, the cyanoacrylate polymer is selected from n-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate. In other embodiments, the adhesive coating comprises a fibrin adhesive. In yet other embodiments, the adhesive coating comprises a bioactive film. In additional embodiments, the adhesive coating comprises a pressure sensitive adhesive. In further embodiments, the pressure sensitive adhesive is an acrylic pressure sensitive adhesive. In yet further embodiments, the adhesive coating comprises a rubber-based adhesive. 
     In embodiments, the adhesive coating is biodegradable. In other embodiments, the adhesive coating is non-continuous. In further embodiments, the adhesive coating includes a plurality of holes. In additional embodiments, the adhesive coating is porous. 
     In embodiments, the adhesive coating has a reduced adhesion over time. 
     In embodiments, the adhesive coating is applied to at least about 10-100% of the microstructures in the array. In other embodiments, at least about 10-95% of each coated microstructure has an adhesive coating. In further embodiments, the adhesive coating is applied to a distal portion of the microstructures. In additional embodiments, the adhesive coating is applied to a proximal portion of the microstructures. 
     In an embodiment, a microstructure apparatus, comprises a substrate having a first surface and a second surface opposed thereto; a plurality of microstructures extending outwardly from the first surface of the substrate; a plurality of openings extending through the substrate and positioned between at least some of the plurality of microstructures; and an adhesive coating applied to at least a portion of the substrate second surface such that the adhesive is capable of contacting a subject’s skin through the openings when placed on the skin. 
     In an embodiment, the adhesive coating is applied to all or substantially all of the substrate second surface. In other embodiments, the adhesive coating is applied the substrate second surface in the region of the openings. 
     In an embodiment, a backing layer positioned over the adhesive coating. 
     In an embodiment, at least a portion of the microstructures are at least partially biodegradable. 
     In an embodiment, the therapeutic agent is a drug, a small-molecule agent, a protein or peptide, or a vaccine. 
     In embodiments, the adhesive coating comprises an adhesive selected from a medical adhesive, a tissue adhesive, or a surgical adhesive. In other embodiments, the medical adhesive is selected from acrylic adhesives, silicone based adhesives, hydrogel adhesives, and synthetic elastomer adhesives. In further embodiments, the tissue adhesive is a cyanoacrylate polymer. In yet further embodiments, the cyanoacrylate polymer is selected from n-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate. In other embodiments, the adhesive coating comprises a fibrin adhesive. In yet other embodiments, the adhesive coating comprises a bioactive film. In additional embodiments, the adhesive coating comprises a pressure sensitive adhesive. In further embodiments, the pressure sensitive adhesive is an acrylic pressure sensitive adhesive. In yet further embodiments, the adhesive coating comprises a rubber-based adhesive. 
     In embodiments, the adhesive coating is biodegradable. In other embodiments, the adhesive coating is non-continuous. In further embodiments, the adhesive coating includes a plurality of holes. In additional embodiments, the adhesive coating is porous. 
     In embodiments, the adhesive coating has a reduced adhesion over time. 
     In embodiments, the adhesive coating is applied to at least about 10-100% of the microstructures in the array. In other embodiments, at least about 10-95% of each coated microstructure has an adhesive coating. In further embodiments, the adhesive coating is applied to a distal portion of the microstructures. In additional embodiments, the adhesive coating is applied to a proximal portion of the microstructures. 
     In another aspect, a system comprises the microstructure apparatus of any one of the combined or separate above embodiments and an applicator for applying the microstructure apparatus to a patient’s skin. 
     In another aspect, a method of delivering a therapeutic agent to a subject for an extended period of time, comprises applying a microstructure apparatus of any previous claim to a skin site of the subject; adhering the microstructure apparatus to the skin; delivering the therapeutic agent from the microstructure array to the subject; and removing the microstructure apparatus after at least about 10 minutes. 
     In an embodiment, the microstructure apparatus is removed after at least about 15 minutes. In another embodiment, the microstructure apparatus is removed after at least about 20 minutes. In a further embodiment, the microstructure apparatus is removed after at least about 30 minutes. In other embodiments, the microstructure apparatus is removed after at least about 45 minutes. In yet other embodiments, the microstructure apparatus is removed after at least about 1 hour. In further embodiments, the microstructure apparatus is removed after at least about 1-24 hours. In yet further embodiments, the microstructure apparatus is removed after at least about 1-5 days. 
     In an embodiment, at least about 10-100% of a total dose of the therapeutic agent is delivered to the subject. In other embodiments, at least about 50-100% of a total dose of the therapeutic agent is delivered to the subject. In further embodiments, at least about 60-100% of a total dose of the therapeutic agent is delivered to the subject. In additional embodiments, at least about 70-100% of a total dose of the therapeutic agent is delivered to the subject. In other embodiments, at least about 75-100% of a total dose of the therapeutic agent is delivered to the subject. In yet other embodiments, at least about 80-100% of a total dose of the therapeutic agent is delivered to the subject. In further embodiments, at least about 90-100% of a total dose of the therapeutic agent is delivered to the subject. In additional embodiments, at least about 95-100% of a total dose of the therapeutic agent is delivered to the subject. 
     In an embodiment, the method further comprises: 
     prior to applying the microstructure apparatus, positioning the microstructure apparatus on a plunger of an applicator;   actuating the applicator to release the plunger;   impacting the skin with the microstructure apparatus;   removing the applicator with the microstructure apparatus remaining on the skin site for an extended period of time.   

     In an embodiment, the method further comprises pressing the microstructure apparatus against the skin site to push the adhesive through the openings and into contact with the skin site. 
     Additional embodiments of the present microstructures, arrays, methods, and the like, will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIGS.  1 A- 1 B  are microscopic images of one exemplary sustained release microstructure array with 35% Clonidine in a PLGA polymer matrix. The image in  FIG.  1 A  is taken from the sharp side of the microstructures. The image in  FIG.  1 B  is taken from the wide side of the microstructures. 
         FIG.  2    is a microscopic image of a residual basement layer formed of a UV curable adhesive after ACN extraction. The image is taken from the sharp side of the microstructures. 
         FIG.  3    is a microscopic image of an exemplary sustained release microstructure array after exposure to a phosphate buffer at 37° C. for one week. 
         FIG.  4    is a graph of % Clonidine released from microstructures formed with 10% or 25% PLGA polymer matrices over time in minutes. The polymer matrix comprised 15%, 20%, 30%, or 44% drug load. 
         FIG.  5    is a graph of % drug released from microstructures formed using DMSO or ACN as the solvent over time in minutes. The polymer matrix comprised Clonidine or Tamsulosin at 30% or 44% drug load. 
         FIGS.  6 A- 6 C  are microscopic images of Clonidine in a PLGA film (drug load of 35%).  FIG.  6 A  shows crystallization of Clonidine.  FIG.  6 B  shows the film after heat treatment at 110° C. for one hour and storage in a dry cabinet for 10 days.  FIG.  6 C  shows a microscope glass control. 
         FIG.  7    is a graph of drug release rate in µg/hr/cm 2  for exemplary microstructure arrays prepared with a LMWP to HMWP ratio of 1:1 or a LMWP to HMWP ratio of 4:1 over time in hours. 
         FIG.  8    is a graph of drug release rate in µg/hr/cm 2  for exemplary microstructure arrays prepared with a high drug to polymer ratio or a low drug to polymer ratio over time in hours. 
         FIG.  9    is a graph of drug release rate in µg/hr/cm 2  for exemplary microstructure arrays prepared with a 0%, 10%, 20%, or 40% of a hydrophilic component over time in hours. 
         FIGS.  10 A- 10 B  are illustrations of exemplary shapes for microstructures including a funnel shape.  FIG.  10 A  depicts a microstructure having a pyramidal tip with a funnel shaped distal portion.  FIG.  10 B  depicts a microstructure having a conical tip, a cylindrical shank and a conical funnel distal portion. 
         FIGS.  11 A- 11 C  are illustrations of exemplary microstructure arrays showing drug loaded in the penetrating portion of the microstructures ( FIG.  11 A ), drug loaded in the whole or entire microstructure ( FIG.  11 B ), and drug loaded in the whole microstructure and a portion of the backing layer or substrate ( FIG.  11 C ). 
         FIGS.  12 A- 12 C  are illustrations of exemplary microstructure arrays in use.  FIG.  12 B  shows use of an exemplary microstructure array having drug loaded in the entire microstructure.  FIG.  12 A  shows use of an exemplary microstructure array having drug loaded only in the penetrating portion of the microstructures.  FIG.  12 C  shows use of an exemplary microstructure having drug loaded in the whole microstructure and a portion of the backing layer or substrate. 
         FIG.  13    is an illustration of an exemplary method of forming microstructure arrays having drug loaded in the whole microstructure and a portion of the backing layer or substrate. 
         FIG.  14    is an illustration of a microstructure with a full adhesive layer. 
         FIG.  15    is an illustration of a microstructure with a partial adhesive coating in one embodiment. 
         FIG.  16    is an illustration of a partial microstructure array with a partial adhesive coating. 
         FIGS.  17 A- 17 B  are illustrations of embodiments of microstructure array geometry. 
         FIGS.  18 A- 18 B  are side view illustrations of embodiments of microstructure array geometry. 
         FIG.  19    is an illustration of a top perspective view of an exemplary applicator device. 
     
    
    
     It will be appreciated that the thicknesses and shapes for the various microstructures have been exaggerated in the drawings to facilitate understanding of the device. The drawings are not necessarily “to scale.” 
     DETAILED DESCRIPTION 
     Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art. 
     The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g.; A.L. Lehninger,  Biochemistry  (Worth Publishers, Inc., current addition); Morrison and Boyd,  Organic Chemistry  (Allyn and Bacon, Inc., current addition); J. March,  Advanced Organic Chemistry  (McGraw Hill, current addition); Remington:  The Science and Practice of Pharmacy , A. Gennaro, Ed., 20 th  Ed.;  Goodman &amp; Gilman The Pharmacological Basis of Therapeutics , J. Griffith Hardman, L. L. Limbird, A. Gilman, 10 th  Ed. 
     Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 µm to 8 µm is stated, it is intended that 2 µm, 3 µm, 4 µm, 5 µm, 6 µm, and 7 µm are also explicitly disclosed, as well as the range of values greater than or equal to 1 µm and the range of values less than or equal to 8 µm. 
     I. Definitions 
     As used in this specification, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a “polymer” includes a single polymer as well as two or more of the same or different polymers; reference to an “excipient” includes a single excipient as well as two or more of the same or different excipients, and the like. 
     In describing and claiming the present invention, the following terminology will be used in accordance with the definitions described below. 
     “Biodegradable” refers to natural or synthetic materials that degrade enzymatically, non-enzymatically or both to produce biocompatible and/or toxicologically safe by-products which may be eliminated by normal metabolic pathways. 
     “Hydrophobic polymer” as used herein refers to polymers that are insoluble or poorly soluble in aqueous solvents. “Hydrophilic polymer” as used herein refers to polymers that are soluble or substantially soluble in aqueous solvents. 
     The terms “microprotrusion”, “microprojection”, “microstructure” or “microneedle” are used interchangeably herein to refer to elements adapted to penetrate or pierce at least a portion of the stratum corneum or other biological membranes. For example, illustrative microstructures may include, in addition to those provided herein, microblades as described in U.S. Pat. No. 6,219,574, edged microneedles as described in U.S. Pat. No. 6,652,478, and microprotrusions as described in U.S. Pat. Publication No. U.S. 2008/0269685. 
     “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. 
     “Substantially” or “essentially” means nearly totally or completely, for instance, 90-95% or greater of some given quantity. 
     “Transdermal” refers to the delivery of an agent into and/or through the skin for local and/or systemic therapy. The same inventive principles apply to administration through other biological membranes such as those which line the interior of the mouth, gastro-intestinal tract, blood-brain barrier, or other body tissues or organs or biological membranes which are exposed or accessible during surgery or during procedures such as laparoscopy or endoscopy. 
     A material that is “water-soluble” may be defined as soluble or substantially soluble in aqueous solvents, such that the material dissolves into, within or below the skin or other membrane which is substantially aqueous in nature. 
     II. Microstructure Arrays 
     A. Microstructure Array Composition 
     General features of microstructure arrays suitable for use in the instant arrays and methods are described in detail in U.S. Pat. Publication No. 2008/0269685, U.S. Pat. Publication No. 2011/0006458, and U.S. Pat. Publication No. 2011/0276028, the entire contents of which are explicitly incorporated herein by reference. 
     In one aspect, the microstructure array is a sustained release array that provides sustained release of at least one therapeutic agent from the microstructures. The array typically includes an approximately planar substrate, base or backing having a first surface and a second surface opposed thereto. At least one, but preferably a plurality of microstructures contact the first surface and are fixedly attached thereto. The microstructures typically project from the substrate at an angle. The microstructures may be attached to the substrate by any suitable means known in the art. In one, non-limiting embodiment, the microstructures are attached to the substrate using an adhesive. Suitable adhesives include, but are not limited to, acrylic adhesives, acrylate adhesives, pressure sensitive adhesives, double-sided adhesive tape, double sided adhesive coated nonwoven or porous film, and UV curable adhesives. One exemplary double-sided tape is the #1513 double-coated medical tape available from 3M. One exemplary, but non-limiting, UV curable adhesive is the 1187-M UV light-curable adhesive available from Dymax. It will be appreciated that any medical device adhesive known in the art would be suitable. The substrate, base or backing may be rigid, semi-rigid or flexible as needed based on the use of the microstructure array. 
     In another embodiment, the microstructure arrays include a proximal, backing or basement layer. In further embodiments, the microstructure arrays include a proximal backing or basement layer positioned between the microstructures and the substrate. It will be appreciated that the backing layer may also function as the substrate, base or backing such that the backing layer extends between the microstructures. In embodiments, the proximal or backing layer or portion may be designed not to penetrate the skin. 
     The substrate and/or backing layer are typically formed of one or more biocompatible and/or non-biodegradable materials. The substrate and/or backing layer may be formed of any suitable material that provides the necessary support for the microstructures. Preferably, the substrate and/or backing layer is formed of a synthetic or natural material that is biocompatible at least on the surface that may contact the patient’s skin. Suitable materials include, but are not limited to, metals, silicon and/or polymers. In an embodiment, the substrate and/or backing layer comprises one or more water insoluble polymers. Suitable polymers include, but are not limited to, polyethylene terephthalate and polyether ether ketone, polycarbonate, polyethylene, or other film forming polymers amphiphilic polyurethanes, polyether polyurethane (PEU), polyetheretherketone (PEEK), and polyamide-imide (PAI). Further suitable polymers are described in U.S. Pat. No. 7,785,301, which is incorporated herein in its entirety. In another embodiment, the backing layer and/or substrate is formed from an adhesive. One suitable adhesive is the Dymax® 1187-M UV medical device adhesive. It will be appreciated that any biocompatible adhesive is suitable for use with, in and/or as the backing layer and/or substrate. The backing layer and/or substrate may also be a nonwoven or porous film double coated with pressure sensitive adhesive. The substrate and/or backing layer may be rigid, substantially rigid or may be at least partially flexible to conform to the surface of the patient’s skin. In any case, the substrate and/or backing layer should be sufficiently strong and/or rigid to assist in or allow for the microstructures to at least partially penetrate the patient’s skin. The substrate is typically substantially planar, but may be contoured. 
     In reference to the microstructures themselves, in general, at least a portion of the microstructures have a height above the base or structure that is sufficient to pierce at least a portion of the epidermis. In embodiments, the microstructures have a height sufficient to pierce all or a portion of the stratum corneum. Typically, the microstructures have a height that penetrates into the epidermis where the density of nerve receptors is low. In embodiments, at least a portion of the microstructures have a height of at least about 50 µm or at least about 100 µm, or at least about 150 µm, or at least about 200 µm, or at least about 250 µm, or at least about 300 µm. In general, the microstructures have a height of no more than about 1 mm, no more than about 500 µm, no more than about 300 µm, no more than about 200 µm, or no more than about 150 µm. In embodiments, the microstructures have a height of between about 50 µm - 1 mm. It will be appreciated that the microstructures within an array may have different heights. The microstructures may have an aspect ratio (height to diameter at base) of at least 10:1, preferably at least about 5:1, more preferably at least about 3:1, or at least about 2:1, or at least about 1:1. As the depth of the epidermis and/or dermis layers may be different depending on the area of the body, it will be appreciated that the height of the microstructures may be adjusted depending on the administration site. 
     The microprojections may be spaced about 0-500 µm apart. In specific, but not limiting embodiments, the microprojections are spaced about 0 µm, about 50 µm, about 100 µm, about 150 µm, about 200 µm, about 250 µm, about 300 µm, about 350 µm, about 400 µm, about 450 µm, or about 500 µm apart. The space between the microprojections may be measured from the base of the microprojections (base to base) or from the tip (tip to tip). 
     One illustrative shape for the microstructures is a cone with a polygonal bottom, for example, being hexagonal or rhombus-shaped. Additional microstructure shapes include those provided, for example, in U.S. Pat. Publication No. 2004/0087992 with exemplary suitable shapes shown in  FIGS.  10 A- 10 B . In embodiments, at least a portion of the microstructure shape may be substantially cylindrical, cone-shaped, funnel-shaped, or pyramidal. In further embodiments, at least a portion of the microstructures has an asymmetrical cross-dimensional shape. Suitable asymmetric shapes include, but are not limited to, rectangular, square, oval, elliptical, circular, rhombus, triangular, polygonal, star-shaped, etc. In some embodiments, the distal layer has a cross-dimension in one direction that is smaller than the cross-dimension in the other direction. Exemplary cross-dimensional shapes with this configuration include, but are not limited to, rectangular, rhombus shaped, ellipse, and oval. The microstructures typically, but not always, have a sharp, pointed or conical distal end to ease and/or facilitate penetration. 
     In the embodiments shown in  FIGS.  10 A- 10 B , at least a portion of the microstructure has a funnel shape  40 . In embodiments, the microstructure has a funnel portion  40 , a cylindrical portion  42 , and a tip  44 . In  FIG.  10 A , the diameter of the microstructure is growing faster than linear fashion with respect to the distance from the distal end. Where microstructures are thicker towards the base, a portion of the microstructure adjacent to the base, which may be referred to herein as a “proximal portion” “backing portion”, “basement”, “foundation”, or as an “upper portion” may be designed not to penetrate the skin. 
     The proximal funnel shape allows for relatively larger volumes to be dispensed in the microstructure mold for a given total length of the microstructure. The proximal funnel shape provides a larger volume (to fill) without requiring a proportional increase in microstructure height, which results in a longer drug containing portion in the microstructure. Thus, the proximal funnel shape allows for a larger solid volume for the distal portion of the microstructure with a single fill of the mold. Other shapes may require several fill and dry cycles to achieve the same amount of solid distal portion as one fill and dry cycle for the funnel shaped microstructures. 
     While the array itself may possess any of a number of shapes, the array is generally sized to possess a diameter of from about 5 millimeters to about 25 millimeters, or from about 7 to about 20 millimeters, or from about 8 to about 16 millimeters. Exemplary diameters include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 millimeters. 
     At least a portion of the microstructures are typically formed of a polymer matrix comprising at least one therapeutic agent, active agent, or drug (collectively “agent” or “therapeutic agent” hereafter). The agent to be administered can be one or more of any of therapeutic agents, active agents or drugs known in the art, and include the broad classes of compounds such as, by way of illustration and not limitation: analeptic agents; analgesic agents; antiarthritic agents; anticancer agents, including antineoplastic drugs; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics, antifungal agents, antiviral agents and bacteriostatic and bactericidal compounds; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; anxiolytics; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular preparations including calcium channel blockers, antianginal agents, central nervous system agents, beta-blockers and antiarrhythmic agents; caustic agents; central nervous system stimulants; cough and cold preparations, including decongestants; cytokines; diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; keratolytic agents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine; nutritional agents, such as vitamins, essential amino acids and fatty acids; ophthalmic drugs such as antiglaucoma agents; pain relieving agents such as anesthetic agents; parasympatholytics; peptide drugs; proteolytic enzymes; psychostimulants; respiratory drugs, including antiasthmatic agents; sedatives; steroids, including progestogens, estrogens, corticosteroids, androgens and anabolic agents; smoking cessation agents; sympathomimetics; tissue-healing enhancing agents; tranquilizers; vasodilators including general coronary, peripheral and cerebral; vessicants; and combinations thereof. In some embodiments, the agent is a protein or a peptide. In other embodiments, the agent is a vaccine. 
     Examples of peptides and proteins which may be used with the microstructure arrays include, but are not limited to, parathyroid hormone (PTH), oxytocin, vasopressin, adrenocorticotropic hormone (ACTH), epidermal growth factor (EGF), prolactin, luteinizing hormone, follicle stimulating hormone, luliberin or luteinizing hormone releasing hormone (LHRH), insulin, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, kyotorphin, taftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor, serum thymic factor, tumor necrosis factor, colony stimulating factors, motilin, bombesin, dinorphin, neurotensin, cerulein, bradykinin, urokinase, kallikrein, substance P analogues and antagonists, angiotensin II, nerve growth factor, blood coagulation factors VII and IX, lysozyme chloride, renin, bradykinin, tyrocidin, gramicidines, growth hormones, melanocyte stimulating hormone, thyroid hormone releasing hormone, thyroid stimulating hormone, pancreozymin, cholecystokinin, human placental lactogen, human chorionic gonadotropin, protein synthesis stimulating peptide, gastric inhibitory peptide, vasoactive intestinal peptide, platelet derived growth factor, growth hormone releasing factor, bone morphogenic protein, and synthetic analogues and modifications and pharmacologically active fragments thereof. Peptidyl drugs also include synthetic analogs of LHRH, e.g., buserelin, deslorelin, fertirelin, goserelin, histrelin, leuprolide (leuprorelin), lutrelin, nafarelin, tryptorelin, and pharmacologically active salts thereof. Administration of oligonucleotides is also contemplated, and includes DNA and RNA, other naturally occurring oligonucleotides, unnatural oligonucleotides, and any combinations and/or fragments thereof. Therapeutic antibodies include Orthoclone OKT3 (muromonab CD3), ReoPro (abciximab), Rituxan (rituximab), Zenapax (daclizumab), Remicade (infliximab), Simulect (basiliximab), Synagis (palivizumab), Herceptin (trastuzumab), Mylotarg (gemtuzumab ozogamicin), CroFab, DigiFab, Campath (alemtuzumab), and Zevalin (ibritumomab tiuxetan). 
     In other embodiments, at least a portion of the distal layer comprises an agent suitable for use as a prophylactic and/or therapeutic vaccine. Examples of vaccines include, but are not limited to, vaccines to varicella, diphtheria, pertussis, hepatitis (A and/or B), Human Papillomavirus, influenza, measles, mumps, rubella, whooping cough, polio, tetanus, meningitis, shingles, etc. 
     In another embodiment, at least a portion of the distal layer comprises an agent suitable for veterinary uses. Such uses include, but are not limited to, therapeutic and diagnostic veterinary uses. 
     In embodiments, the polymer matrix comprises at least about 10-50% of the therapeutic agent. In other embodiments, the polymer matrix comprises at least about 45-50%, about 30-50%, about 25-50%, about 20-50%, or about 15-50% of the therapeutic agent. In a further embodiment, the polymer matrix comprises at least about 10-50% of at least one structural polymer. In specific, but not limiting embodiments, the polymer matrix comprises at least about 45-50%, about 30-50%, about 25-50%, about 20-50%, or about 15-50% of at least one structural polymer. In embodiments, % is weight%. 
     In one aspect, the microstructure arrays described herein provide sustained release or sustained delivery of the therapeutic agent. In this embodiment, the microstructure array typically comprises an approximately planar substrate and a plurality of microstructures contacting and being fixedly attached to a surface of the substrate. At least a portion of the microstructures are formed of a polymer matrix comprising (i) at least one water insoluble, biodegradable polymer, and (ii) at least one therapeutic agent. In one embodiment, the microstructures include a distal layer formed of the polymer matrix. The polymer matrix distal layer may be referred to as a drug-in-tip (DIT) distal layer. In another embodiment, the microstructures include a distal layer formed of the polymer matrix and a proximal or backing layer formed of a non-biodegradable polymer. At least a portion of the proximal or backing layer may be configured so that it does not penetrate the subject’s skin. 
     Suitable water insoluble, biodegradable polymers are known in the art. Exemplary water insoluble, biodegradable polymers include, but are not limited to, polylactide, α-hydroxy acids such as poly(lactic-co-glycolic acid (PLGA), polyanhydrides, an aliphatic polyester, a copolyester with aliphatic and aromatic blocks, a polyester amide, a polyester urethane, a polyethylene oxide polymer, a polyglycol, and co-polymers thereof. For co-polymers, it will further be appreciated that the ratio of the monomers may be adjusted to achieve a desired hydrophobicity and/or degradation rate. For example, lactide rich PLGA copolymers are more hydrophobic than glycolide rich PLGA copolymers. The ratio of hydrophobic:hydrophilic monomers in the polymer may be selected to achieve the desired degradation rate. In one non-limiting embodiment, the water insoluble, biodegradable polymer is PLGA. In another embodiment, the PLGA has a lactic acid/glycolic acid ratio of 75/25. 
     Microneedle arrays are typically applied for a short period of time, which is sufficient to allow the water soluble polymer matrix DIT to degrade and release the drug, typically about 5-15 minutes. However, many drugs require a sustained deliver or slow delivery for proper efficacy. Further, many conditions require continuous or sustained levels of a therapeutic agent for proper treatment. Slow release of a drug from a microprojection array may provide a suitable dose for therapy over a period of time which avoids toxicity and/or side effects. In embodiments, the microarrays described herein provide for sustained release or sustained delivery of the therapeutic agent from the polymer matrix. In embodiments sustained release provides for a slow and/or constant release of the drug over an extended period of time. Sustained release systems may be used to maintain constant drug levels over a period of time. In some embodiments, the microstructure arrays provide for release of the active agent from the polymer matrix for at least 10-15 minutes. In other embodiments, the arrays provide for release of the active agent for at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 18 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, or longer. In one embodiment, the arrays provide for release of the active agent for a period of at least about 15 minutes to about 60 hours. In further embodiments, the arrays provide for release of the active agent for a period of at least about 30 minutes to about 24 hours, about 1-48 hours, about 1-36 hours, about 1-24 hours, about1-18 hours, about 1-12 hours, about 1-10 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, about 1-2 hours, about 2-24 hours, about 2-18 hours, about 2-12 hours, about 2-10 hours, about 2-8 hours, about 2-6 hours, about 2-4 hours, about 4-24 hours, about 4-18 hours, about 4-12 hours, about 4-10 hours, about 4-8 hours, about 4-6 hours, about 6-24 hours, about 6-18 hours, about 6-12 hours, about 6-10 hours, about 6-8 hours, about 8-24 hours, about 8-18 hours, about 8-12 hours, about 8-10 hours, about 10-24 hours, about 10-18 hours, about 10-12 hours, about 12-24 hours, about 12-18 hours, about 18-24 hours, about 1-144 hours, about 1-72 hours, about 1-60, or longer. In further embodiments, the arrays provide for release of the active agent for a period of at least about 1-60 hours or longer. In specific, but not limiting embodiments, the therapeutic agent is released from the microstructure array for a period of at least about 144 hours, about 72 hours, about 24 hours, about 12 hours, about 6 hours, about 3 hours, about 2 hours, about 1 hour, or about 0.5 hours. 
     As described in Example 1, exemplary microstructure arrays comprising a drug-in-tip (DIT) distal layer comprising 35% Clonidine in PLGA and a UV adhesive backing layer on a PET substrate were formed and are shown in  FIGS.  1 A- 1 B . The DIT portions were highly degradable. As described in Example 2, a microstructure array comprising a 35% Clonidine in PLGA DIT was placed in acetonitrile (ACN) solvent to extract the DIT portion. As seen in  FIG.  2   , the DIT portion dissolved in the solvent with the UV adhesive layer remaining. 
     It has been found that type of solvent used to fabricate PLGA DIT has a significant effect on drug release rate. Without being limited as to theory, it is believed that the choice of solvent changes the morphology (crystalline/amorphous) of the drug, which affects the drug’s release rate. As described in Example 3, the effect of solvent choice on drug release rate was investigated by immersing microstructure arrays in a phosphate buffer, taking samples at specific time points and analyzing drug content in the sample by HPLC.  FIG.  5    is a graph of the % Clonidine released from the microstructure array over time in minutes. Arrays were prepared using DMSO or ACN as the solvent for 44% Tamsulosin prepared with DMSO (●), 44% Clonidine prepared with DMSO (O), 44% Clonidine prepared with ACN (▲), 30% Clonidine prepared with DMSO (Δ), and 30% Clonidine prepared with ACN (◊). As it is shown in  FIG.  5    Clonidine loaded MSA prepared from DMSO showed significantly lower drug release rate as compared to Clonidine loaded MSA prepared from ACN. For the MSA with a 44% Clonidine load, the MSA prepared with ACN had about a 15-20% increase in the percentage of drug released after 120 minutes and after 360 minutes. For the MSA with a 30% Clonidine load, the MSA prepared with ACN had about 40-45% increase in the percentage of drug released after 120 minutes and about 30-35% increase after 360 minutes. On the other hand, Tamsulosin formulated with PLGA with DMSO as solvent had almost immediate drug release, probably due to the enhanced plasticization of the drug to the polymer by the DMSO solvent. 
     The physical state of the drug (e.g. crystalline or amorphous solid solution) in PLGA DIT may have significant impact on drug release properties of the matrix. Heat treatment may be used to change physical state of drug in PLGA DIT and thus drug release profile. Heat treatment of dry PLGA DIT containing crystalline drug may lead to irreversible dissolution of crystals in solid PLGA if the samples are subjected to heating above drug melting point. To test this hypothesis PLGA films loaded with 35% Clonidine were prepared by casting from ACN (PLGA concentration in liquid casting solution was 25%) on a microscope glass. After casting and drying at 70° C. (below Clonidine melting point) Clonidine crystals had been formed in the film as it is shown in the  FIG.  6 A . A spot in the obtained films was located and marked to trace changes in the film after heat treatment. Films were heat treated in convection oven at 110° C. for 1 hour and then stored in dry cabinet for 10 days. As it is seen from  FIG.  6 B  no Clonidine crystallization was observed after heat treatment and storage. The small bright particles observed in  FIG.  6 B  correspond to microscope glass background as it is evidenced by the control photograph of microscope glass in  FIG.  6 C . 
     Addition of hydrophilic components into a hydrophobic polymer matrix can significantly change the drug release profile. In one non-limiting embodiment, the hydrophilic component is PEG-PLGA. As described in Example 5, microstructure arrays comprising Clonidine in a PLGA polymer matrix were prepared including 0%, 10%, 20%, or 40% of a PEG-PLGA hydrophilic component. The release rate of the arrays was determined by immersing the array in a phosphate buffer and taking samples at specific time points and analyzing drug content in the sample by HPLC.  FIG.  9    is a graph of the release rate of the drug in µg/hr/cm 2  for microstructure arrays comprising 0% (◊), 10% (□), 20% (O), or 40% (Δ) of the hydrophilic component over time in hours.  FIG.  9    demonstrates that the addition of hydrophilic PEG-PLGA into a PLGA matrix, the release of a protein from the MSA increases with the increase of hydrophilic component in the matrix. Addition of 10% or 20% of the hydrophilic component reduced or eliminated the initial burst of the drug. Addition of 40% of the hydrophilic component resulted in an initial burst which tapered off for about 6 hours. Addition of 10% hydrophilic component resulted in a flat release rate with no burst and sustained release for at least 24 hours. Addition of 20% of the hydrophilic component resulted in a low initial burst with a release rate of about 10-15 µg/hr/cm 2  and then a flat release rate for at least 24 hours. 
     In embodiments, the polymer matrix comprises at least about 5-40% of the hydrophilic component. In further embodiments, the polymer matrix comprises at least about 5-35%, about 5-30%, about 5-25%, about 5-20%, about 5-15%, about 5-10%, about 10-35%, about 10-30%, about 10-25%, about 10-20%, about 10-15%, about 15-35%, about 15-30%, about 15-25%, about 15-20%, about 20-30%, about 20-25%,about 25-35%, or about 25-30% of the hydrophilic component. In embodiments, % is weight%. 
     In another embodiment, the drug release rate profile may be modulated in order to meet certain therapeutic requirements for the drug. It will be appreciated that modulating the drug release rate profile may be beneficial for the sustained release microarrays described herein as well as with known microarrays such as those described in U.S. Publication No. U.S. 2008/0269685 and U.S. 2011/0276028, among others. 
     Achieving long term zero-order release of drugs from a biodegradable polymer matrix has been difficult to achieve. Release of drugs from the polymer matrix is often characterized by a rapid initial release (“burst”) in the first few hours followed by a slow, diffusion-controlled release thereafter. However, many drugs, including many peptide therapeutics, can be toxic when administered with a burst initial release rate. Further, reducing or preventing the initial burst and/or controlling the release of the drug at a constant rate allows the blood concentration of the drug to be maintained for a long period of time. In one embodiment, the release rate is modulated to provide a flat or substantially flat release for at least a period of time. In another embodiment, the release rate is flat or substantially flat for at least a period of time with no or substantially no initial burst. In a further embodiment, the release rate is less than 3 C max  - C min . 
     In embodiments, modulating the release rate comprises modulating the release rate of the drug to between about 0.05-10%/minute. It will be appreciated that modulating the release rate may refer to the overall release rate and/or to an initial release rate. In other words, one or both of the overall release rate or the initial release rate may be modulated. In other embodiments, the release rate is modulated to between about 0.5-10%/minute, about 1-10%/minute, about 2-10%/minute, about 5-10%/minute, about 0.5-20%/minute, about 1-20%/minute, about 2-20%/minute, or about 5-20%/minute. In specific, but not limiting embodiments, the release rate is modulated to about 0.05%/minute, about 0.5%/minute, about 1%/minute, about 2%/minute, about 3%/minute, about 4%/minute, about 5%/minute, about 6%/minute, about 7%/minute, about 8%/minute, about 9%/minute, about 10%/minute, or about 20%/minute. In embodiments, % is weight%. 
     In embodiments, modulating the release rate comprises modulating the release rate of the drug to between about 0.25-40 µg/hr/cm 2 . It will be appreciated that modulating the release rate may refer to the overall release rate and/or to an initial release rate. In other words, one or both of the overall release rate or the initial release rate may be modulated. In other embodiments, the release rate is modulated to between about 0.5-30 µg/hr/cm 2 , about 2-40 µg/hr/cm 2 , about 2-30 µg/hr/cm 2 , about 2-25 µg/hr/cm 2 , about 2-20 µg/hr/cm 2 , about 2-15 µg/hr/cm 2 , about 2-10 µg/hr/cm 2 , about 2-8 µg/hr/cm 2 , about 2-6 µg/hr/cm 2 , about 2-5 µg/hr/cm 2 , about 2-4 µg/hr/cm 2 , about 2-3 µg/hr/cm 2 , about 5-30 µg/hr/cm 2 , about 5-25 µg/hr/cm 2 , about 5-20 µg/hr/cm 2 , about 5-15 µg/hr/cm 2 , about 5-10 µg/hr/cm 2 , about 5-8 µg/hr/cm 2 , about 5-6 µg/hr/cm 2 , about 10-40 µg/hr/cm 2 , about 10-30 µg/hr/cm 2 , about 10-25 µg/hr/cm 2 , about 10-20 µg/hr/cm 2 , about 10-15 µg/hr/cm 2 , about 15-40 µg/hr/cm 2 , about 15-30 µg/hr/cm 2 , about 15-25 µg/hr/cm 2 , about 15-20 µg/hr/cm 2 , about 20-30 µg/hr/cm 2 , or about 20-25 µg/hr/cm 2 . In other embodiments, the release rate is modulated to below about 30 µg/hr/cm 2 , about 20 µg/hr/cm 2 , about 15 µg/hr/cm 2 , about 10 µg/hr/cm 2 , about 8 µg/hr/cm 2 , about 6 µg/hr/cm 2 , or about 5 µg/hr/cm 2 . 
     In even further embodiments, the initial release rate is adjusted or modulated to about 0.25-10 µg/hr/cm 2 , about 0.5-10 µg/hr/cm 2 , about 1-10 µg/hr/cm 2 , about 2-10 µg/hr/cm 2 , or about 1-10 µg/hr/cm 2 . 
     In one embodiment, the polymer is a mixture or blend of low molecular weight polymers (LMWP) and high molecular weight polymers (HMWP). The ratio of LMWP to HMWP can be adjusted to modify the drug release rate profile. The ratio of LMWP and HMWP may be adjusted to generate a desired release rate profile. In one preferred embodiment, the ratio of LMWP and HMWP is adjusted to provide for a constant (e.g., zero-order) release of the drug. In another preferred embodiment, the ratio of LMWP and HMWP is adjusted to provide for a no-burst release of the drug. In yet another embodiment, the ratio of LMWP and HMWP is adjusted to modify or modulate the initial release rate of the drug without significantly affecting the sustained release rate. 
     Typically LMW biodegradable polymers degrade rapidly and polymer matrices formed from LMW polymers provide a rapid release rate for drugs dissolved or suspended in the matrix. Conversely, HMW biodegradable polymers degrade more slowly and provide a slow release rate for drugs dissolved or suspended in a HMW polymer matrix. LMWP have less entanglement than HMWP which typically have a more porous structure. For blends of LMWP and HMWP, the LMWP can “plug” the free volume in the HMWP structure. 
     The polymers used may possess a variety and range of molecular weights. In one embodiment, the LMWP has a molecular weight of about 1000-10 K Da. In specific embodiments, the LMWP has a molecular weight of about 1000 Da, about 2000 Da, about 3000 Da, about 4000 Da, about 5000 Da, about 6000 Da, about 7000 Da, about 8000 Da, about 9000 Da, or about 10,000 Da. In other embodiments, the LMWP has a molecular weight of about 1000-5000 Da. In particular embodiment, the LMWP is polylactide having a molecular weight of about 1000 Da. In an embodiment, the HMWP has a molecular weight of about 50-300 K Da. In other embodiments, the HMWP has a molecular weight of about 50-70 K Da. In further embodiments, the HMWP has a molecular weight of about 200-300 K Da. In specific, but not limiting embodiments, the HMWP has a molecular weight of about 50 K Da, about 60 K Da, or about 70 K Da. 
     Adjusting the blend or proportion of LMWP and HMWP in a hydrophobic polymer matrix could significantly change the drug release profile. As described in Example 5, microstructure arrays comprising a drug in a PLGA polymer matrix were prepared including a 1:1 ratio of LMWP to HMWP or a 4:1 ratio of LMWP to HMWP. The HMWP had a molecular weight of about 76 K Da - 120 K Da. The release rate of the arrays was determined by immersing the array in a phosphate buffer and taking samples at specific time points and analyzing drug content in the sample by HPLC.  FIG.  7    is a graph of the release rate of the drug in µg/hr/cm 2  for microstructure arrays comprising LMWP/HMWP of 1:1 (Δ) and LMWP/HMWP of 4:1 (□) over time in hours. The 1:1 formulation had an initial burst of about 18-25 µg/hr/cm 2  The 4:1 formulation had little to no initial burst with an initial release rate of about 3-6 µg/hr/cm 2 . The 1:1 formulation had release of the drug for about 30 hours and the 4:1 formulation had release of the drug for at least about 56 hours. 
     The release rate of the therapeutic agent may be modulated by the ratio of drug/polymer in the DIT matrix. The initial release rate of the drug is especially sensitive to this ratio. Different release rate profiles can be achieved by changing the drug/polymer ratio. 
     As shown in  FIG.  8   , a slower initial release and flatter release rate profile is obtained with lower drug/polymer matrix ratio. The low drug/polymer ratio formulation had an initial release rate of about 5-8 µg/hr/cm 2  while the high drug/polymer ratio formulation had an initial release rate of about 18-25 µg/hr/cm 2 . 
     As described in Example 3, the effect of drug load and the ratio of drug to polymer on drug release rate was investigated by immersing microstructure arrays in a phosphate buffer, taking samples at specific time points and analyzing drug content in the sample by HPLC.  FIG.  4    is a graph of the % Clonidine released from the microstructure array over time in minutes. Arrays were prepared having 44% Clonidine/10% PLGA (◊) (including stirring), 44% Clonidine/10% PLGA (♦), 30% Clonidine/10% PLGA (□), 20% Clonidine/25% PLGA (Δ), and 15% Clonidine/25% PLGA (A). The MSA with a 44% and a 30% Clonidine drug load had about a 55% increase in the percentage of drug released after 120 minutes over the 15% Clonidine loaded MSA. The MSA with a 44% or 30% Clonidine drug load had about a 45% increase in the percentage of drug released after 240 minutes over the 15% Clonidine loaded MSA. The MSA with a 44% or 30% Clonidine drug load had about a 30% increase in the percentage of drug released after 360 minutes over the 15% Clonidine loaded MSA. The MSA with a 20% Clonidine drug load had about a 15-20% increase in the percentage of drug released after 120, 240, or 360 minutes over the 15% Clonidine loaded MSA. The MSA with a 44% and a 30% Clonidine drug load had about a 35-40% increase in the percentage of drug released after 120 minutes over the 20% Clonidine loaded MSA. The MSA with a 44% or 30% Clonidine drug load had about a 25% increase in the percentage of drug released after 240 minutes over the 20% Clonidine loaded MSA. The MSA with a 44% or 30% Clonidine drug load had about a 10-15% increase in the percentage of drug released after 360 minutes over the 20% Clonidine loaded MSA. 
     As seen in  FIG.  4   , two formulations having 44% Clonidine/10% PLGA were prepared. For one formulation (◊), the release medium was stirred. The formulation may be stirred constantly during release or at the time of sampling. A mild shake was used for the second formulation (♦). As seen in  FIG.  4   , the release medium is substantially homogeneous with no significant drug concentration gradient build up around the releasing MSA for both methods. 
     As described in Example 5, microstructure arrays comprising Clonidine in a PLGA polymer matrix with a high drug to polymer ratio and a low drug to polymer ratio were prepared. The release rate of the arrays was determined by immersing the array in a phosphate buffer and taking samples at specific time points and analyzing drug content in the sample by HPLC.  FIG.  8    is a graph of the release rate of the drug in µg/hr/cm 2  for microstructure arrays comprising High Drug/Polymer Ratio (Δ) or Low Drug/Polymer Ratio (□) over time in hours. The array with the high drug to polymer ratio formulation had an initial burst of about 18-27 µg/hr/cm 2 . The low drug to polymer ratio formulation had little to no initial burst with an initial release rate of about 5-7 µg/hr/cm 2 . The high drug to polymer ratio formulation had release of the drug for about 32 hours and the low drug to polymer ratio formulation had release of the drug for at least about 56 hours. 
     In embodiments, the ratio of the drug to the polymer may be adjusted to modulate the release rate of the drug from the polymer matrix. It will be appreciated that the ratio of drug to polymer may be lower in order to lower the release rate, especially for lowering the initial release rate. It will further be appreciated that the ratio of drug to polymer may be higher in order to increase the release rate, especially for increasing the initial release rate. In embodiments, either the ratio of the therapeutic agent to the polymer in the polymer matrix or the ratio of the polymer to the therapeutic agent in the polymer matrix is about 1:1 to about 1:25. In further embodiments, the ratio is about 1:1-1:20, about 1:1-1:15, about 1:1-1:10, about 1:1-1:6, about 1:1-1:5, about 1:1-1:4, about 1:1-1:3, about 1:1-1:2; about 1:2-1:25, about 1:2-1:20, about 1:2-1:15, about 1:2-1:10, about 1:2-1:6, about 1:2-1:5, about 1:2-1:4, about 1:2-1:3, about 1:4-1:25, about 1:4-1:20, about 1:4-1:15, about 1:4-1:10, about 1:4-1:6, about 1:4-1:5. In specific non-limiting embodiments, the ratio of the therapeutic agent to the polymer in the polymer matrix or the ratio of the polymer to the therapeutic agent in the polymer matrix is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:25, or greater. 
     It will be appreciated that the methods for modulating the release rate may be combined without limitation. Specifically, the release rate may be modulated or adjusted by any one of the combined or separate methods described herein including adding a hydrophilic component to the polymer matrix, adjusting the drug to polymer ratio in the polymer matrix, using a blend of LMWP and HMWP and/or adjusting the ratio of the polymers in the polymer matrix, the choice of solvent in preparing the polymer matrix, and/or a heat treatment. 
     In another aspect, the microstructure arrays provide an increased drug load. Many microstructure arrays include a DIT portion that penetrates the skin and a proximal or backing layer that does not penetrate the skin. The drug load is limited by the volume of the DIT (or penetrated portion) of the microstructures, among other factors. Sustained release dosage forms in particular may require a higher dose load in the microstructure array as the drug is administered over an extended period of time. In one embodiment, the dose load of microstructure arrays and/or dose delivered from the arrays is increased by modifying the method of preparing the microstructure arrays and/or modifying the microstructure array configuration. In another embodiment, the release rate profile is modified by the microstructure arrays produced by the modified method. 
     Many previous microstructure arrays provide a DIT configuration where the drug is loaded in a penetrating portion ( FIG.  11 A ). Modifying the microstructure configuration to provide drug load in the entire microstructure portion (penetrating and non-penetrating portions) as in  FIG.  11 B  or to provide drug load in the entire microstructure portion (penetrating and non-penetrating portions) as well as in at least a portion of a backing layer as in  FIG.  11 C  provides a higher volume of the microstructure array with drug loaded. 
     The configurations of  FIGS.  11 B and  11 C  also provide for a sustained release of the drug based. It will be appreciated that the configurations of  FIGS.  11 B and  11 C  may provide sustained release of a therapeutic agent for microstructure arrays for the sustained release microarrays described herein as well as with known microarrays such as those described in U.S. Publication No. U.S. 2008/0269685 and U.S. 2011/0276028 among others. 
     Further, the configurations of  FIG.  11 B  (whole MS embodiment) and 11C (whole plus MS embodiment) can be used to modulate or tailor the drug release rate. In one embodiment, the whole MS or whole plus MS configuration is used to provide sustained drug release with or without an initial burst. It will be appreciated that the whole MS or whole plus MS configurations may be used with any one or all of the methods to adjust the drug release rate as described above. 
     As shown in  FIG.  12 A , many present microstructure arrays provide for rapid delivery of drug incorporated in the portion of the microstructures that penetrate the skin. The penetrated portion may dissolve rapidly and release the drug rapidly. The array may then be removed after a period of time applied on/in the skin, e.g. 5-15 minutes. In one embodiment, the whole MS or whole plus MS configuration provide an initial release of drug from the penetrated portion of the microstructure and a sustained release from the non-penetrating portions. As seen in  FIGS.  12 B and  12 C , the microstructure array with higher drug load (whole MS as in  FIG.  12 B  or whole plus MS as in  FIG.  12 C ) is applied to the subject’s skin. The penetrated portion of the microstructure dissolves and releases the drug relatively rapidly. The array is left in place and the non-penetrated portion of the microstructures of both the whole MS and whole plus MS configurations dissolve and permeate into the skin. It will be appreciated that channels or pores formed by the administration of the microstructures into the skin will remain in the skin for a period of time after the penetrating portion has dissolved. The drug dissolved from the non-penetrating portion and/or the backing layer may thus be delivered into the stratum corneum. Depending on water back diffusion and drug permeation into the skin, the non-penetrating portion and/or backing layer may dissolve more slowly than the penetrating portion. Thus, the drug release profile may be modified to deliver the drug at a slower rate than delivered from the penetrating portion. It will be further appreciated that the penetrating portion, the non-penetrating portion and/or the backing layer may be modified to adjust the release rate, for example by the methods described above. In other embodiments, the penetrating portion is formed of a biodegradable, water soluble polymer matrix, as known in the art, and the non-penetrating portion and/or backing layer is formed of a biodegradable, water insoluble polymer matrix as described above. 
     The microstructure arrays may be formed by any suitable means as known in the art. A method of casting a microstructure array having drug loaded in the penetrating portions of the microstructures as shown in  FIG.  11 A  is described in Example 7. In one embodiment, the microstructure arrays are formed by dissolving an API and excipients in an aqueous buffer as described in Example 6. In embodiments, the excipients may be any one of or any combination of a structure-forming polymer, a sugar which can stabilize the API and/or plasticize the structure-forming polymer, a surfactant and/or an antioxidant agent. In non-limiting embodiments, the API can be polypeptides, such as human parathyroid hormone (1-34) [(hPTH(1-34)] (MW 4118), proteins such as human growth hormone (hGH) (MW~ 22000), antibodies (MW~ 150000), or a vaccine with an antigen epitope conjugated on a carrier protein formulated with or without adjuvant. Examples of the structure-forming polymers are hydrophilic, water soluble polymers, such as polysaccharides like Dextran 70, Dextran 40, Dextran 10, Hetastarch, Tetrastarch, cellulose derivatives, and other water soluble polymers like polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, copolymer of ethylene glycol and propylene glycol (Pluronic®), and/or block copolymers of PLGA-PEG. Sugars can act as a stabilizing agent for biological APIs like peptides, proteins, and antibodies, and/or can act as a plasticizer agent. Exemplary sugars include sorbitol, sucrose, trehalose, fructose, and/or dextrose. When Dextran, Hetastarch, and/or Tetrastarch are used as the structure-forming polymer in the polymer matrix, sorbitol is a preferred sugar because it can not only stabilize the API, but also plasticize the polymer matrix to make it less brittle. In some cases, a surfactant may be needed in the DIT formulation to change the surface tension and/or reduce protein adsorption and denaturation at interfaces. Exemplary surfactants include Polysorbate 20 and Polysorbate 80. Some APIs may be susceptible to oxidation either in the liquid DIT formulation or in solid DIT form. Exemplary antioxidant agents include, but are not limited to, methionine, cysteine, D-alpha tocopherol acetate, EDTA, and/or vitamin E. Exemplary liquid casting formulations containing an API are provided in Table 1 and described in Example 6. 
     Example 8 describes a casting method for forming microstructure arrays with drug loaded in the whole microstructure as shown in  FIG.  11 B . Briefly, about 70 µL of a liquid casting solution such as those described in Table 3 is dispensed on a mold having a plurality of cavities therein, covered with a flat surface to spread the formulation, and the formulation is moved into the cavities. The liquid casting solution has a solid content greater than 20% (w/w). When dried, the solids fill a greater portion of the microstructures. The cavities may be filled by pressurization or with a soluble gas such as CO 2  or CH 4 . The mold is wiped and dried using two primary drying steps. The mold is first placed in a controlled humidity chamber having elevated humidity, about 10-95% RH, for 1-30 minutes at room temperature. In one embodiment, the humidity in the chamber is controlled to 85% RH. Second, the mold is placed in an oven, such as an incubator oven, at 32° C. for about 30 minutes. A backing layer formulation is cast on the dried drug formulation to connect the drug formulations. Exemplary backing layer formulations are provided in Table 4 in Example 6. The mold with backing layer is dried in an oven for about 30-90 minutes. In one embodiment, the mold is dried in a convection oven. It will be appreciated that the oven may use any one of convection, conduction, or radiation for drying. In one embodiment, the mold is dried at an elevated temperature of about 5-50° C. In one particular embodiment, the mold is dried in a convection oven at about 45° C. 
     The whole MS microstructure arrays may also include a substrate as described above. In Example 8, a UV adhesive is dispersed on the backing layer, covered with a 5 mm sheet of polycarbonate (PC) film and cured using a UV Fusion system. The array undergoes a final drying step under vacuum (about 0.05 torr) overnight. The final drying step may be at room temperature or at an elevated temperature, e.g. 35° C. The array is demolded and die cut into 1-2 cm 2  arrays. The microstructure arrays may be sealed in a storage container. In one embodiment, the MSAs are sealed individually in a Polyfoil pouch. It will be appreciated that the pouch may be sealed under nitrogen. 
     Example 9 describes a casting method for forming microstructure arrays with drug loaded in the whole microstructure plus at least a portion of the backing layer as shown in  FIG.  11 C . Briefly, about 70 µL of a liquid casting solution such as those described in Table 3 is dispensed on a mold having a plurality of cavities therein. In one embodiment, as described in Example 9, PET polymer disk with a circular opening is placed on a silicone mold. About 50 µL of a liquid casting solution as described in Table 3 in Example 6 is dispensed on the mold, covered with a flat surface to spread the formulation, and the formulation is moved into the cavities/the cavities are filled. The cavities may be filled by pressurization or with a soluble gas such as CO 2  or CH 4 . The mold is wiped and dried using two primary drying steps. The mold is placed in an oven, such as an incubator oven, at 5-50° C. The drug is loaded in the whole microneedle and part of the backing layer. A backing layer formulation is cast on the dried drug formulation. Exemplary backing layer formulations are provided in Table 4 in Example 6. The mold is dried in an oven for about 30-120 minutes. In one embodiment, the mold is dried at an elevated temperature of about 5-50° C. In one particular embodiment, the mold is dried in a convection oven at about 45° C. The mold may be placed in a compressed dry air box for about 30 minutes with controlled air flow before being placed in the oven. 
     In another embodiment, the drug layer and backing layer may be fabricated in one step as illustrated in  FIG.  13   . In this embodiment, the mold preferably has an extended or elevated side to allow the casting of the integrated microstructure and backing layer. The mold may be formed with the sides or may include a barrier placed around the cavities on top of the mold. The casting formulation is dispensed in the mold with elevated sides and dried to form the integrated microstructure and partial backing layer having a drug loaded therein. The mold is dried as described above, and a full backing layer is cast on the partial backing layer. 
     The whole plus MS microstructure arrays may also include a substrate as described above. In Example 9, a UV adhesive is dispersed on the backing layer, covered with a 5 mm sheet of polycarbonate (PC) film and cured using a UV Fusion system. The array undergoes a final drying step under vacuum (about 0.05 torr) overnight. The final drying step may be at room temperature or at an elevated temperature, e.g. 35° C. The array is demolded and die cut into 1-2 cm 2  arrays. The microstructure arrays may be sealed in a storage container. In one embodiment, the MSAs are sealed individually in a Polyfoil pouch. It will be appreciated that the pouch may be sealed under nitrogen. 
     Microstructure arrays with a whole plus MS configuration and comprising PTH may be prepared in accord with Example 9. The MSA with the whole plus MS configuration have a significantly higher drug load than DIT microstructure arrays. The MSA with the whole plus MS configuration also have a significantly higher drug load than whole MS configured microstructure arrays. The drug load for the whole plus MS PTH arrays is expected to be about 450 µg/cm 2  for the whole plus MS configuration as compared to 45-49 µg/cm 2  for the whole MS configuration and 32 µg/cm 2  for the DIT configuration. The drug load for the whole plus MS configuration increases by about 650-900% over the whole MS configuration and by about 420% for the DIT arrays for the PTH arrays. 
     B. Extended Wear Microstructure Arrays 
     In one embodiment, the present microarrays are suitable for extended wear. Extended wear microarrays may be useful for sustained delivery of drugs or agents and/or to allow complete delivery of the drug or agent, e.g. to allow a biodegradable microstructure to degrade enough to release all or most of the drug or agent. Improving adhesion between the microarray and the subject’s skin may improve or contribute to improving drug delivery efficiency. Microarrays are typically adhered to the skin to allow delivery of drugs by an adhesive layer around the perimeter of the microarray and/or by an adhesive backing that overlies and extends beyond the edge of the microarray. These methods may be unsuitable for extended wear applications as the microstructures are not secured to the subject’s skin and the array may pull-up or detach from the skin at least in some in areas. This is especially likely for areas of the microarray that are more removed from the perimeter adhesive such as the center of the array. 
     The microarrays of the present embodiment include at least one adhesive to adhere the array to the skin for a desired period of time. Preferably, the adhesive is included as part of the microarray itself or is placed or available in the interior of microarray rather than being applied around a perimeter of the microarray. In one embodiment, the microstructure array geometry is modified to allow an adhesive to contact the skin in one or more locations in the microstructure array region or interior. In a second embodiment, an adhesive layer is included in the microstructure array construct. 
     In one embodiment, the adhesive is a medical adhesive, tissue adhesive and/or surgical adhesive. In other embodiments, the adhesive is a medical adhesive such as those used to attach medical devices to skin. Suitable medical adhesives include, but are not limited to acrylic adhesives, silicone based adhesives, hydrogel adhesives, and synthetic elastomer adhesives. In one embodiment tissue adhesive is a bioadhesive polymer. Suitable tissue adhesives include, but are not limited to, cyanoacrylate polymers. Suitable cyanoacrylate polymers include, but are not limited to, n-butyl-2-cyanoacrylate (e.g., Histoacryl®, PeriAcryl®), 2-octyl cyanoacrylate (e.g. Dermabond®, SurgiSeal), and isobutyl cyanoacrylate. In another embodiment, the adhesive is a fibrin sealant. In a further embodiment, the adhesive is a bioactive film. In a yet further embodiment, the adhesive is an acrylic pressure sensitive adhesive. In even further embodiments, the adhesive is a rubber-based adhesive. Preferably, the adhesive is nonirritating and/or non-sensitizing. The adhesive may be selected based on tack and/or peel strength as required to adhere the microstructure array to skin. In some embodiments, the adhesive is breathable. 
     It will be appreciated that the adhesive may require a further component for adhesion such as a two-part adhesive. In other embodiments, the adhesive adheres on contact with water or a moist surface. In yet further embodiments, the adhesive is activated by pressure, heat, light (UV or visible), biochemical reactions, or a combination of activation methods. In an embodiment, the adhesive is a permanent adhesive. In other embodiments, the adhesive is designed to reduce its adhesion over time. In another embodiment, the adhesive reduces adhesion over time to match the expected wear period which permits easier removal of the array. The adhesive may be absorbable or degradable, which has one advantage that the array is easily removed when the adhesive is absorbed or degraded. 
     In one embodiment, an adhesive coating is at least partially applied to at least a portion of the microstructures of the array. In embodiments, one or more adhesives are used to coat the microstructures. In other embodiments, a portion of the microstructures are coated with one adhesive and other microstructures are coated with a further adhesive. The microstructures may be alternatively coated or the coatings may be applied in a pattern. For example, stronger adhesive may be alternated with a weaker adhesive. Alternatively, an absorbable adhesive may be alternated with one that is not so that the array is easier to remove yet remains attached until removed. It will be appreciated that the coating may be applied over all or a portion of at least a portion of the microstructures in the array. 
     In embodiments, at least about 10%-100% of the microstructures in the array are at least partially coated with an adhesive. In other embodiments, at least about 25%-30%, about 25%-40%, about 25%-50%, about 25%-60%, about 25%-70%, about 25%-75%, about 25%-80%, about 25%-90%, about 25%-95%, about 30%-100%, about 30%-40%, about 30%-50%, about 30%-60%, about 30%-70%, about 30%-75%, about 30%-80%, about 30%-90%, about 30%-95%, about 40%-100%, about 40%-50%, about 40%-60%, about 40%-70%, about 40%-75%, about 40%-80%, about 40%-90%, about 40%-95%, about 50%-100%, about 50%-60%, about 50%-70%, about 50%-75%, about 50%-80%, about 50%-90%, about 50%-95%, about 60%-100%, about 60%-70%, about 60%-75%, about 60%-80%, about 60%-90%, about 60%-95%, about 70%-100%, about 70%-75%, about 70%-80%, about 70%-90%, about 70%-95%, about 80%-100%, about 80%-90%, about 80%-95%, about 90%-100%, about 90%-95%, about 90%-100%, or about 95%-100% of the microstructures in the array are coated with an adhesive. 
     As shown in  FIG.  14   , at least a portion of the microstructures  10  are coated with an adhesive coating  12 . In one embodiment where the microstructures include a DIT portion  16 , at least the DIT portion is coated with an adhesive. In other embodiments, only the backing layer, or at least a portion thereof, is coated with an adhesive. Alternatively, at least a portion of both the DIT portion  16  and the backing layer  18  are coated with an adhesive. The adhesive coating may directly contact all or a portion of the microstructures. 
     The coating may be applied directly to the microstructures or may be separated by a spacing and/or by an intermediate layer such as an intermediate polymer layer. 
     In one embodiment, the adhesive coating is porous to allow delivery of at least the drug. The adhesive may additionally contain or be configured with perforations, openings, or holes in at least a portion of the coating  14 . This embodiment may be useful for biodegradable microstructures and/or where the drug does not easily pass through the adhesive. The perforations or openings may be any size or shape suitable for the drug and/or microstructure polymer to pass through. The perforations may be formed by any suitable method. In one embodiment, the perforations are formed mechanically and/or chemically. In one non-limiting embodiment, a portion of the coating is removed to form the perforations. In yet another embodiment, the perforations are formed by masking the microstructures and spray coating or dip coating the microstructure array and removing the masking agent. In a further embodiment where the coating is applied as part of a casting method, the microstructure mold may be configured so that the resulting coating includes perforations or is otherwise non-continuous. For example, the mold may include protrusions or other features within the mold interior that the coating does not cover. The resulting coating will be non-continuous, e.g. contain perforations or openings. In other embodiments, the coating is otherwise non-continuous over at least a portion of the microstructure surface. In another embodiment, the microstructures are spot coated with the adhesive. 
     In another embodiment, only a portion of each microstructure (of the microstructures that are coated) is coated with an adhesive. In one embodiment, at least a portion of the distal end of the microstructures are coated. In another embodiment, at least a portion of the proximal end is coated. The coating may be selectively applied by any suitable means including, but not limited to, spray coating, dip coating, or be applied during formation of the microstructures. It will further be appreciated that methods used to coat microneedles with a therapeutic agent, e.g. those described in U.S. Pat. No. 8,057,842, may also be used to coat the microstructures with an adhesive. Where the microstructures are formed by casting the microstructures in a mold, the adhesive may be added at a point so that only the desired portion of the microstructure is coated. For example, where a portion of the distal tip is coated, the coating may be added to the mold prior to adding the polymer matrix, or matrices, of the microstructures. Where a portion of the proximal end is coated, the coating may be added to the mold after the polymer matrix for the distal tip is added. As shown in  FIG.  15   , the microstructure  10  includes a partial adhesive coating  12  that covers the proximal portion of the microstructure. In this embodiment, the microstructure includes a biodegradable distal tip  16  and a non-biodegradable proximal portion  18 . Only the proximal portion that is not biodegradable is covered by the adhesive coating. In this embodiment, it is not necessary to use a porous adhesive or include perforations in the coating as the biodegradable portion is not coated. It will be appreciated that a partial coating may be porous and/or include non-continuous features as described above. It will further be appreciated that only the outer portion or surface of the proximal portion  18  of the microstructures may include the coating  12 . 
     In embodiments, at least about 10%-100% of the microstructure is coated. In other embodiments, at least about 25%-30%, about 25%-40%, about 25%-50%, about 25%-60%, about 25%-70%, about 25%-75%, about 25%-80%, about 25%-90%, about 25%-95%, about 30%-100%, about 30%-40%, about 30%-50%, about 30%-60%, about 30%-70%, about 30%-75%, about 30%-80%, about 30%-90%, about 30%-95%, about 40%-100%, about 40%-50%, about 40%-60%, about 40%-70%, about 40%-75%, about 40%-80%, about 40%-90%, about 40%-95%, about 50%-100%, about 50%-60%, about 50%-70%, about 50%-75%, about 50%-80%, about 50%-90%, about 50%-95%, about 60%-100%, about 60%-70%, about 60%-75%, about 60%-80%, about 60%-90%, about 60%-95%, about 70%-100%, about 70%-75%, about 70%-80%, about 70%-90%, about 70%-95%, about 80%-100%, about 80%-90%, about 80%-95%, about 90%-100%, about 90%-95%, about 90%-100%, or about 95%-100% of the microstructure is coated with an adhesive (of the microstructures that are coated). It will be appreciated that these percentages apply both to embodiments that use a non-continuous adhesive coating and/or a partial adhesive coating. 
     In another embodiment, an adhesive coating is applied at least partially between at least a portion of the microstructures in the array. In one embodiment, the adhesive coating is applied to the substrate or backing between the microstructures. In another embodiment, as shown in  FIG.  16   , the coating is applied to the substrate or backing  20  between the microstructures  10 . In this embodiment, the coating may also be applied at least partially to the proximal portion of the microstructures  21 . In this non-limiting embodiment, the proximal portion  18  of the microstructure is non-biodegradable and the distal portion  16  including at least one agent is biodegradable. It will be appreciated that the coating may be applied only to the substrate or backing  20  between the microstructures. It will further be appreciated that the coating may be applied to the substrate or backing and all of a non-biodegradable proximal portion, where present. 
     In another embodiment, the microstructure array is layered and includes an adhesive as one layer in the array. Exemplary embodiments where the microstructure geometry includes an adhesive are shown in  FIGS.  17 A- 17 B . In this embodiment, the adhesive is included as a layer on the substrate or backing which includes at least one opening or hole that allows the adhesive to contact the subject’s skin. It will be appreciated that the number and placement of the openings may be selected to provide the desired adhesion. Placement of the openings may be selected according to a pattern to provide the desired adhesion of the microstructure array. The opening may be of any sufficient diameter for the adhesive to contact the skin. A larger diameter results in more contact between the skin and the adhesive. One skilled in the art can calculate the contact necessary, and therefore the required opening diameter, based at least one the adhesive properties of the adhesive such as adhesion strength. 
       FIG.  17 A  shows two microstructures  26  of a microstructure array  22  positioned on a substrate  20 . The substrate includes a hole or opening  24  positioned between the microstructures. An adhesive layer  28  is positioned at least partially on the substrate on the surface opposite the microstructures. The adhesive can travel through the opening to contact the subject’s skin. In one embodiment, pressure or another force is applied to the adhesive layer to move at least a portion of the adhesive through the opening to contact the skin. In another embodiment, the adhesive is sufficiently fluid to flow through the opening. In other embodiments, the adhesive may be altered to be sufficiently fluid to flow through the opening, e.g. by heating the adhesive. In yet another embodiment, the substrate layer is sufficiently thin and/or the opening is sufficiently large that the adhesive contacts the skin without flowing through the opening. The microstructure array may include a further adhesive backing layer  30  that overlies and contains the adhesive. In other embodiments, the adhesive is an adhesive tape or a double-sided adhesive coated nonwoven or porous film. 
     In another embodiment as shown in  FIG.  17 B , the adhesive  28  may be applied on the substrate  20  surface opposite the microstructures  26  as discrete portions at or near the opening(s)  24 . As above, this embodiment may include an adhesive backing  30  positioned at least over the adhesive depots. One or more adhesives may be applied to the substrate. It will be appreciated that the adhesive applied at the depots may be selected so as to provide a desired effect. For example, a stronger adhesive may be alternated with a weaker adhesive. Alternatively, an absorbable adhesive may be alternated with one that is not so that the array is easier to remove yet remains attached until removed. 
       FIGS.  18 A- 18 B  show a substrate  20  without openings ( FIG.  18 A ) and with a plurality of openings  24  ( FIG.  18 B ). 
     III. Methods of Making Microstructure Arrays 
     Before describing the methods of manufacture in detail, it is to be understood that the methods are not limited to specific solvents, materials, or device structures, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. 
     Examples of forming various microstructure arrays having different configurations are provided in Examples 1 and 4. In one exemplary method, an array is prepared by (a) filling a mold with cavities corresponding to the negative of the microstructures with a casting solution comprising a biocompatible material such as a biocompatible polymer and a solvent, (b) removing the solvent, and (c) de-molding the resulting array from the mold. The solvent may be removed by any suitable means including, but not limited, to drying the mold filled with the casting solution in an oven. The casting solution preferably contains an active agent or ingredient. In one or more embodiments, the microstructures themselves comprise the active ingredient mixed, or dispersed in a polymer matrix, as opposed to having the active ingredient present as a coating on a microstructure or microneedle made of a different, biocompatible material such as a metal. Typically, excess formulation is scraped or wiped from the mold surface prior to drying. Where the microstructures are not integral with a substrate or backing layer, the microstructures are affixed to the substrate or backing layer with an adhesive prior to de-molding. Further methods of preparing microstructure arrays are described in Examples 6-9. 
     IV. Methods of Use 
     The methods, kits, microstructure arrays and related devices described herein may be used for treating any condition. It will be appreciated that the microstructure arrays may be used with any appropriate applicator including the applicator described in U.S. Publication No. 2011/0276027 as well as those described in Attorney Docket No. 091500-0442 and 091500-0478, each of which are incorporated herein in their entirety. 
     In one aspect, a method for applying the microarrays described herein for an extended period is provided. In embodiments, the extended wear microarrays are secured to the subject’s skin for at least about 5 minutes to 24 hours. In other embodiments, the extended wear microarrays are secured to the subject’s skin for at least about 10 minutes to 24 hours, at least about 15 minutes to 24 hours, at least about 30 minutes to 24 hours, at least about 1-24 hours, at least about 1-2 hours, at least about 1-3 hours, at least about 1-4 hours, at least about 1-5 hours, at least about 1-6 hours, at least about 1-8 hours, at least about 1-10 hours, at least about 1-12 hours, at least about 2-24 hours, at least about 2-3 hours, at least about 2-4 hours, at least about 2-5 hours, at least about 2-6 hours, at least about 2-8 hours, at least about 2-10 hours, at least about 2-12 hours, at least about 3-24 hours, at least about 3-4 hours, at least about 3-5 hours, at least about 3-6 hours, at least about 3-8 hours, at least about 3-10 hours, at least about 3-12 hours, at least about 4-24 hours, at least about 4-5 hours, at least about 4-6 hours, at least about 4-8 hours, at least about 4-10 hours, at least about 4-12 hours, at least about 5-24 hours, at least about 5-6 hours, at least about 5-8 hours, at least about 5-10 hours, at least about 5-12 hours, at least about 8-10 hours, at least about 10-24 hours, at least about 10-12 hours, at least about 12-24 hours, or longer. In specific, but not limiting embodiments, the microarray is secured to the subject’s skin for at least about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, or longer. In other specific, but not limiting embodiments, the microarray is secured to the subject’s skin for at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 hours, or longer. In other embodiments, the extended wear microarrays are secured to the subject’s skin for at least about 1-30 days. In further embodiments, the microarrays are secured to the subject’s skin for at least about 1-2 days, at least about 1-3 days, at least about 1-4 days, at least about 1-5 days, at least about 1-7 days, at least about 10 days, at least about 1-14 days, at least about 1-21 days, or longer. In specific, but not limiting embodiments, the microarray is secured to the subject’s skin for at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 30 days, or longer. 
     In embodiments, the extended wear microarrays are secured to the subject’s skin until a desired portion of the total drug or agent dose is delivered. The portion of the total dose delivered may be determined by any suitable method including without limitation a residual analysis of the device as known in the art. In other embodiments, the microarray is secured to the subject’s skin until at least about 10-100% of the total dose of drug in the array is delivered. In further embodiments, the microarray is secured to the subject’s skin until at least about 10-25%, about 10-50%, about 10-55%, about 10-60%, about 10-65%, about 10-70%, about 10-75%, about 10-80%, about 10-90%, about 10-95%, or about 10-99% of the total dose of drug in the array is delivered. In yet further embodiments, the microarray is secured to the subject’s skin until at least about 25-50%, about 25-55%, about 25-60%, about 25-65%, about 25-70%, about 25-75%, about 25-80%, about 25-90%, about 25-95%, about 25-99%, about 50-55%, about 50-60%, about 50-65%, about 50-70%, about 50-75%, about 50-80%, about 50-90%, about 50-95%, about 50-99%, about 70-75%, about 70-80%, about 70-90%, about 70-95%, about 70-99%, about 75-80%, about 75-90%, about 75-95%, about 75-99%, about 80-90%, about 80-95%, about 80-99%, about 90-95%, about 90-99%, or about 95-99% of the total dose of drug in the array is delivered. In other embodiments, the microarray is secure to the subject’s skin until at least about 25%, about 30%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 95% of the total dose is delivered to the subject. 
     In another aspect, a method for administering an active agent or therapeutic agent to a subject is provided. Preferably, the active or therapeutic agent is administered dermally, transdermally, mucosally, and/or transmucosally. The method comprises providing a microprojection array or other delivery device comprising at least one active agent. Preferably, the microprojection array or other delivery device is configured to deliver at least one therapeutic agent. The agent may be coated on at least a portion of the microprojections and/or contained within at least a portion of the microstructures. The agent is delivered dermally, transdermally, mucosally, or transmucosally into contact with the skin, or more generally a membrane or body surface, of a subject. 
     In one exemplary operation, an array is placed in contact with the skin and is adhered to the skin with an adhesive disposed at least partially on the microstructures or included as part of the array. 
     The array may be applied using an applicator as known in the art. An exemplary applicator  32  is shown in  FIG.  19   . The applicator typically includes a plunger or piston where the microstructure array is positioned on a distal end of the plunger. An actuator or actuating member  34  is actuated to release the plunger. The plunger is typically held in a constrained or restrained position until released. The plunger impacts the skin and the microstructure array pierces or ruptures the skin surface. The microstructure array is removed from the plunger distal end automatically or manually. The adhesive adheres the microstructure array to the subject’s skin for a desired period of time. 
     V. Examples 
     The following examples are illustrative in nature and are in no way intended to be limiting. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C and pressure is at or near atmospheric. 
     Example 1 
     Casting Sustained Release Arrays 
     Poly(D,L-lactide-co-glycolide) (PLGA, L/G 75/25) (available from Durect Corporation (PN B6007-1P) was dissolved in acetonitrile (ACN) or dimethylsufoxide (DMSO) to a concentration of 10 wt% or 25 wt% to form a polymer solution. 
     Clonidine or Tamsulosin hydrochloride were placed in a 15 mL polypropylene tube with the PLGA polymer solution. The drug was dissolved in the PLGA polymer solution by warming the mixture in closed tubes for 10-15 minutes in a convection oven and vortexing until the drug was completely dissolved. Formulations were prepared according to Table 1.  
     
       
         
          TABLE 1
           
               
               
               
               
               
             
               
                 PLGA/drug formulations 
               
               
                 Formulation 
                 Drug 
                 %drug in solid DIT 
                 %PLGA in liquid casting solution 
                 Solvent 
               
             
            
               
                 A1 
                 Clonidine 
                 44% 
                 10% 
                 ACN 
               
               
                 A2 
                 Tamsulosin 
                 44% 
                 10% 
                 DMSO 
               
               
                 A3 
                 Clonidine 
                 44% 
                 10% 
                 DMSO 
               
               
                 A4 
                 Clonidine 
                 30% 
                 10% 
                 DMSO 
               
               
                 A5 
                 Clonidine 
                 30% 
                 25% 
                 ACN 
               
               
                 A6 
                 Clonidine 
                 44% 
                 25% 
                 ACN 
               
               
                 A7 
                 Clonidine 
                 20% 
                 25% 
                 ACN 
               
               
                 A8 
                 Clonidine 
                 15% 
                 25% 
                 ACN 
               
            
           
         
       
     
     About 75 µL of liquid drug formulation was dispensed on a silicone based mold, covered with 22 mm × 30 mm glass cover slip to spread the formulation on the mold, and then pressurized at 50 psi for 1 minute. 
     The formulation was wiped and the mold dried in a convection oven at 70° C. for 1.5 hours. 
     UV adhesive was dispensed on the drug formulation in the mold, covered with a 5 mm polyethylene terephthalate (PET) film to spread the adhesive and cured using a UV Fusion system. The UV curing dose was 1.6 J/cm 2 . After curing, the microstructure (drug in tip distal layer and UV adhesive proximal layer on PET) was die cut with an 11 mm punch. 
     The resulting microstructures were inspected under microscope. Images of intact microstructure arrays with Clonidine (35% drug in PLGA DIT) are shown in  FIGS.  1 A- 1 B . 
     Example 2 
     Dissolution of Arrays 
     Microstructure arrays (MSA) comprising 35% Clonidine in PLGA DIT were prepared in accord with Example 1 were treated with acetonitrile to extract the PLGA DIT tips and then were inspected under microscope to observe the remaining stubs, which comprised the UV adhesive layer with an image taken from the sharp side of the microstructures shown in  FIG.  2   . 
     Example 3 
     Drug Release From Microstructure Arrays 
     Microstructure arrays comprising Clonidine or Tamsulosin were prepared in accord with Example 1. The microstructure arrays were immersed in closed 20 mL scintillation vials containing 10 mL phosphate buffer (pH=7.5, 10 mM) at 37° C. under mild shaking. At specified time points, 1 mL of release medium was removed for drug content analysis by HPLC. The sample was substituted with 1 mL of fresh buffer. 
     After release experiments, the samples were inspected under a microscope. Swelling of PLGA DIT portions was observed after exposure for 1 week to phosphate buffer at 37° C. as shown in  FIG.  3   . It is theorized that the swelling of DIT after 1 week at 37° C. may be due to the void left from the release of the drug from the PLGA matrix and partial degradation of PLGA, which makes the polymer more hydrophilic. 
     The effect of Clonidine loading in PLGA DIT on cumulative drug release is shown in  FIG.  4   . Kinetic parameters, initial drug release rate (Δ%min) and time for the half drug released (t 50% ), which was calculated from the initial slope of the release curve, for the formulations shown in Table 1 are shown in Table 2. The Clonidine release rate decreased significantly with decreasing Clonidine load in the PLGA formulation.  
     
       
         
          TABLE 2
           
               
               
               
               
             
               
                 Drug Release Parameters 
               
               
                 Formulation 
                 Initial Release Rate (Δ%min) 
                 t 50%  (min) 
                 Total drug released mcg/array 
               
             
            
               
                 A1 
                 1.85 
                 27 
                 126 
               
               
                 A2 
                 9.36 
                 5 
                 139 
               
               
                 A3 
                 0.79 
                 63 
                 80.4 
               
               
                 A4 
                 0.28 
                 181 
                 32.7 
               
               
                 A5 
                 1.9 
                 27 
                 57.5 
               
               
                 A6 
                 1.9 
                 27 
                 78 
               
               
                 A7 
                 0.39 
                 128 
                 87.3 
               
               
                 A8 
                 0.24 
                 207 
                 83.5 
               
            
           
         
       
     
     The type of solvent used to fabricate the PLGA DIT had a significant effect on the drug release rate. As shown in  FIG.  5   , Clonidine loaded arrays prepared using a DMSO solvent showed a significantly lower drug release rate as compared to Clonidine loaded arrays prepared using ACN. Tamsulosin loaded arrays prepared using a DMSO solvent had almost immediate drug release, which is likely due to the enhanced plasticization of the drug to the polymer by the DMSO solvent. 
     Example 4 
     Effect of Heat Treatment on Drug Crystallization in PLGA Films 
     PLGA films loaded with 35% Clonidine were prepared by casting from ACN (PLGA concentration in liquid casting solution was 25%) on a microscope glass. The films were dried at 70° C. (which is below the melting point for Clonidine). An image of the film after casting and drying is shown in  FIG.  6 A , which shows Clonidine crystals formed in the film. 
     A spot in the films was marked to trace changes in the film. Films were heat treated in a convection oven at 110° C. for 1 hour and then stored in a dry cabinet for 10 days.  FIG.  6 B  shows no Clonidine crystallization observed after heat treatment and storage. The small, bright particles observed in the image correspond to microscope glass background as evidenced by the control photograph of a microscope glass shown in  FIG.  6 C . 
     Example 5 
     Modulating Microstructure Array Release Profiles 
     Poly(DL lactide-co-glycolide) (PLGA, L/G 75/25) (available from Durect Corporation (PN B6007-1P, IV 0.55-0.75) was used as a high molecular weight polymer (HMWP) and PLGA (L/G 75/25) from SurModics (1A, IV 0.1) was used as a low molecular weight polymer (LMWP). 
     PLGA was dissolved in acetonitrile (ACN) or dimethylsufoxide (DMSO) to a concentration of 10 wt% or 25 wt% to form a polymer solution. 
     Clonidine or Tamsulosin hydrochloride were placed in a 15 mL polypropylene tube with the PLGA polymer solution. The drug was dissolved in the PLGA polymer solution by warming the mixture in closed tubes for 10-15 minutes in a convection oven and vortexing until the drug was completely dissolved. 
     About 75 µL of liquid drug formulation was dispensed on a silicone based mold, covered with 22 mm × 30 mm glass cover slip to spread the formulation on the mold, and then pressurized at 50 psi for 1 minute. 
     The formulation was wiped and the mold dried in an oven at 32° C. for 30 minutes, then dried at 50° C. under vacuum overnight. 
     UV adhesive was dispensed on the drug formulation in the mold, covered with a 5 mL polyethylene terephthalate (PET) or polycarbonate (PC) film to spread the adhesive and cured using a UV Fusion system. The UV curing dose was 1.6 J/cm 2 . After curing, the microstructure (drug in tip distal layer and UV adhesive proximal layer on PET) was die cut with an 11 or 16 mm punch. The resulting microstructures were inspected under microscope and further vacuum dried at 35° C. overnight to remove any residual solvent. 
     A. In Vitro Release Rate 
     An in vitro release test was performed by immersing a microstructure array in a closed 20 mL scintillation vials containing 10 mL PBS buffer (pH=7.4) containing 0.1% Polysorbate 20, which was added at time=0. The vial was shaken at 100 rpm on an orbital shaking platform in an incubator at 37° C. One mL of release medium was removed at predetermined time points to quantify drug release. Fresh release medium was replenished to maintain the volume of the release medium. 
     B. Effect of LMWP/HMWP Ratio on Release Rate 
     Microstructure arrays were prepared using 1:1 LMWP/HMWP or 4:1 LMWP/HMWP for the polymer solution. An in vitro release test as above was performed with the results shown in  FIG.  7   . 
     C. Effect of Drug to Polymer Ratio on Release Rate 
     Microstructure arrays were prepared with a high drug/polymer ratio or low drug/polymer ratio. An in vitro release test as above was performed with the results shown in  FIG.  8   . 
     D. Effect of a Hydrophilic Component on Release Rate 
     Microstructure arrays were prepared in accord with the above method with the addition of 10%, 20%, or 40% of a hydrophilic PEG-PLGA component. An in vitro release test as above was performed with the results shown in  FIG.  9   . 
     Example 6 
     Casting Formulations 
     Liquid casting formulations are prepared by dissolving an active pharmaceutical ingredient (API) and excipients in an aqueous buffer as shown in Table 3.  
     
       
         
          TABLE 3
           
               
               
               
               
               
               
               
               
               
             
               
                 Liquid Casting Solution Formulations 
               
               
                 Formulation 
                 Polymer 
                 Sugar 
                 API 
                 PS20 
                 EDTA 
               
               
                   
                 Type 
                 Wt% 
                 Type 
                 Wt% 
                 Type 
                 Wt% 
                 Wt% 
                 mg/mL 
               
             
            
               
                 B1 
                 Dextran 70 
                 14 
                 Sorbitol 
                 5 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B2 
                 Dextran 70 
                 10 
                 Sorbitol 
                 4 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B3 
                 Dextran 70 
                 27 
                 Sorbitol 
                 9 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B4 
                 Dextran 70 
                 21 
                 Sorbitol 
                 7.5 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B5 
                 Tetrastarch 
                 14 
                 Sorbitol 
                 7 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B6 
                 Tetrastarch 
                 10 
                 Sorbitol 
                 5 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B7 
                 Hetastarch 
                 14 
                 Sorbitol 
                 7 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B8 
                 Hetastarch 
                 10 
                 Sorbitol 
                 5 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B9 
                 Dextran 40 
                 14 
                 Sorbitol 
                 5 
                 PTH 
                 1.8 
                 NA 
                 NA 
               
               
                 B10 
                 Dextran 70 
                 14 
                 Sorbitol 
                 5 
                 PTH 
                 2.8 
                 NA 
                 NA 
               
               
                 B11 
                 PVA 
                 14 
                 Sucrose 
                 5 
                 PTH 
                 2.8 
                 NA 
                 NA 
               
            
           
         
       
     
     Different polymeric solutions may be used for casting a basement or backing layer for the microstructure arrays. Liquid formulations for a backing layer are prepared by dissolving one or more polymers in a solvent or solvent mixture at or about room temperature with a polymer concentration of about 10-40% by weight. Liquid formulations for casting a backing layer are prepared according to Table 4.  
     
       
         
          TABLE 4
           
               
               
               
               
               
             
               
                 Liquid Backing Layer Formulations 
               
               
                 Formulation 
                 Polymer 
                 Solvent 
               
               
                   
                 Type 
                 Wt% 
                 Type 
                 Wt% 
               
             
            
               
                 C1 
                 Eudragit EPO 100 
                 20 
                 Ethanol/IPA (3:1) 
                 80 
               
               
                 C2 
                 Eudragit EPO 100 
                 30 
                 Ethanol/IPA (3:1) 
                 70 
               
               
                 C3 
                 Eudragit EPO 100/PVP (1:1) 
                 20 
                 Ethanol/IPA (3:1) 
                 80 
               
               
                 C4 
                 PLGA (75/25) 
                 10 
                 Ethyl acetate 
                 90 
               
               
                 C5 
                 PLGA (75/25) 
                 15 
                 Ethyl acetate 
                 85 
               
               
                 C6 
                 PLGA (75/25) 
                 25 
                 Acetonitrile 
                 75 
               
               
                 C7 
                 PLGA (75/25) 
                 35 
                 Acetonitrile 
                 65 
               
               
                 C8 
                 PLGA (65/35) 
                 20 
                 Acetonitrile 
                 80 
               
               
                 C9 
                 PLGA (65/35) 
                 30 
                 Acetonitrile 
                 70 
               
               
                 C10 
                 PLA 
                 20 
                 Acetonitrile 
                 80 
               
            
           
         
       
     
     Example 7 
     Casting Mircrostructure Arrays With Drug in Penetrating Portion 
     About 70 µL of liquid casting solution formulation number B1 was dispensed on a silicone mold having diamond shaped cavities (200 µm length, base width 70 µm, and 200 µm needle to needle spacing), covered with a 22 mm × 30 mm glass cover slip to spread the formulation on the mold, and then pressurized at 50 psi for 1 minute. The filled volume of liquid casting solution formulation was about 1.5-2.0 µl/cm 2  The solid content of the liquid formulations was less than 20% (w/w). 
     The formulations were wiped and the mold dried in a controlled humidity chamber with elevated humidity such as 85% RH for 1-30 minutes at room temperature. The mold was then placed in an incubator oven at 32° C. for about 30 minutes. 
     Backing layer formulation C6 was cast on the mold to connect the dried casting formulation in the cavities. The mold was dried in a compressed dry air (CDA) box for 30 minutes with controlled air flow and then in a convection oven at 45° C. for 30-90 minutes. 
     A second layer of backing layer formulation may be cast on the mold, and the mold additionally dried in a compressed dry air (CDA) box for 30 minutes with controlled air flow and then in a convection oven at 45° C. for 30-90 minutes. 
     UV adhesive was dispensed on the backing layer, covered with a small sheet of 5 mm polycarbonate (PC) film to spread the adhesive and cured using a UV Fusion system. The UV curing dose was 1.6 J/cm 2 . After curing, the microstructure array (drug in tip distal layer/PLGA backing layer/UV adhesive substrate on PC backing) was removed from the mold and die cut into 1-2 cm 2  arrays. 
     The microstructure array was dried to remove residual moisture from the drug distal layer and residual solvent from the backing layer. The mold was dried under vacuum (-0.55 torr) at 35° C. or room temperature overnight. The drug load for PTH was 32 µg/cm 2 . 
     Example 8 
     Casting Microstructure Arrays With Increased Drug Load 
     About 70 µL of liquid casting solution formulation number B3 or B4 was dispensed on a silicone mold having diamond shaped cavities (200 µm length, base width 70 µm, and 200 µm needle to needle spacing), covered with a 22 mm × 30 mm glass cover slip to spread the formulation on the mold, and then pressurized at 50 psi for 1 minute. The filled volume of liquid casting solution formulation in the mold was about 2.5-3.3 µl/cm 2  The solid content of these liquid formulations was greater than 20% (w/w) so solids can fill the cavities beyond the portion of the resulting microstructures that will penetrate skin when the distal layer is dried. 
     The formulations were wiped and the mold dried in a controlled humidity chamber with elevated humidity such as 85% RH for 1-30 minutes at room temperature. The mold was then placed in an incubator oven at 32° C. for about 30 minutes. 
     Backing layer formulation C6 was cast on the mold to connect the dried casting formulation in the cavities. The mold was dried in a CDA box for 30 minutes with controlled air flow and then in a convection oven at 45° C. for 30-90 minutes. 
     UV adhesive was dispensed on the backing layer, covered with a small sheet of 5 mm polycarbonate (PC) film to spread the adhesive and cured using a UV Fusion system. The UV curing dose was 1.6 J/cm 2 . After curing, the microstructure array (drug in tip distal layer/PLGA backing layer/UV adhesive substrate on PC backing) was removed from the mold and die cut into 1-2 cm 2  arrays. 
     The microstructure array was dried to remove residual moisture from the drug distal layer and residual solvent from the backing layer. The mold was dried under vacuum (~0.55 torr) at 35° C. or room temperature overnight. Exemplary drug loads for the drug distal layer are listed in Table 5.  
     
       
         
          TABLE 5
           
               
               
               
               
               
             
               
                 Microstructure Array Drug Load for Drug Distal Layer 
               
               
                 MSA 
                 Liquid DIT Formulation 
                 API 
                 Liquid Load Volume (µL/cm 2 ) 
                 Drug load µg/cm 2  MSA 
               
             
            
               
                 D1 
                 B3 
                 PTH 
                 3.3 
                 59 
               
               
                 D2 
                 B4 
                 PTH 
                 2.5 
                 45 
               
               
                 D3 
                 B4 
                 PTH 
                 3.3 
                 59 
               
            
           
         
       
     
     Example 9 
     Casting Microstructure Arrays With Drug in Penetrating Portion and Backing Layer 
     A PET disk with a circular opening area of about 2 cm 2  is placed on a silicone mold having diamond shaped cavities (200 µm length, base width 70 µm, and 200 µm needle to needle spacing). To this circular area, about 50 µL of liquid casting solution formulation is dispensed on a silicone mold, covered with a 22 mm × 30 mm glass cover slip to spread the formulation on the mold, and then pressurized at 50 psi for 1 minute. 
     The mold is then placed in an incubator oven at 32° C. for about 30 minutes. 
     Backing layer formulation is cast on top of the dried drug containing layer in the mold. The mold is dried in a CDA box for 30 minutes with controlled air flow and then in a convection oven at 45° C. for 30-90 minutes. 
     UV adhesive is dispensed on the backing layer, covered with a small sheet of 5 mm polycarbonate (PC) film to spread the adhesive and cured using a UV Fusion system. The UV curing dose was 1.6 J/cm 2 . After curing, the microstructure array (drug in tip distal layer and partial backing layer/PLGA backing layer/UV adhesive substrate on PC backing) is removed from the mold and is die cut into 1-2 cm 2  arrays. 
     The microstructure array is dried to remove residual moisture from the drug layer and residual solvent from the backing layer. The mold is dried under vacuum (-0.55 torr) at 35° C. or room temperature overnight. 
     Example 10 
     In Vivo Skin Penetration Efficiency and Apparent Dose Delivery Efficiency 
     Microstructure arrays (MSAs) comprising PTH were prepared in accord with Example 8. MSAs were applied to shaved skin sites of rats or pigs using a custom made applicator and held in situ (either manually by hand or with skin contact adhesive) for a period time (e.g., 1 - 5 minutes). After removing the applicator, the MSAs were kept on the animals for 5 minutes or 2 hours. 
     Residual drug remaining in the MSA was extracted by immersing the used MSA in an aqueous extraction medium for ~30 min and assayed using an appropriate analytical method, e.g. SEC-HPLC. The apparent delivered dose per unit, and delivery efficiency are then calculated as follows with the results shown in Table 6: 
     
       
         
           
             
               
                 Apparent delivered dose = Initial drug load - Residual drug 
               
             
             
               
                 %Drug delivery efficiency = 100 x Apparent delivered dose/Initial drug load 
               
             
           
         
       
     
     
       
         
          TABLE 6
           
               
               
               
               
               
             
               
                 Apparent Dose Delivered 
               
               
                 MSA 
                 API 
                 Animal 
                 Apparent Dose (µg/cm 2 ) 
               
               
                 5 min wear 
                 2 hr wear 
               
             
            
               
                 D1 
                 PTH 
                 Rat 
                 45 
                 60 
               
               
                 D2 
                 PTH 
                 Pig 
                 48 
                 64 
               
            
           
         
       
     
     For MSAs with drug loaded in the entire microneedle, the apparent dose delivered increases with increasing wear time, a phenomenon that was observed in both rats and pigs. Table 6 shows the apparent dose delivered in vivo for hPTH(1-34) MSA after 5 min and 2 hour wear times. Apparent dose delivered increased with wear time by 33% for PTH in rats and pigs. 
     Example 11 
     In Vivo Pharmacokinetics 
     Microstructure arrays (MSAs) comprising a protein are prepared in accord with Example 8. MSAs are applied to shaved skin sites of rats or pigs using a custom made applicator and held in situ (either manually by hand or with skin contact adhesive) for a period time (e.g., 1 - 5 minutes). After removing the applicator, the MSAs are kept on the animals for 5 minutes or 2 hours. The serum concentration PK profiles may be plotted by taking blood samples at predetermined times (e.g. 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours etc.) and determining the serum concentration of the API. It is expected that serum concentrations of the API will be higher for the 2 hr wear compared to the 5 min wear. The overall systemic exposure should correspond to the mean apparent doses achieved by the wear time. Thus, where the wear time for 5 min. vs. 2 hours results in a double in the mean apparent dose, the overall systemic exposure, e.g. represented by area under the curve (AUC), should also increase or even double. Increasing the MSA wear time can increase overall systemic drug delivery
     1. A microstructure apparatus, comprising: 
   an approximately planar substrate having a first surface and a second surface opposed thereto; and   a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising (i) a water insoluble, biodegradable polymer, and (ii) at least one therapeutic agent;   wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours.   
   2. The microstructure apparatus of embodiment 1, wherein the water insoluble polymer is selected from polylactide, polyglycolide, and co-polymers thereof.   3. The microstructure apparatus of the combined or separate embodiments 1-2, wherein the polymer matrix comprises about 1-50% therapeutic agent.   4. The microstructure apparatus of the combined or separate embodiments 1-3, wherein the polymer matrix comprises about 10-50% therapeutic agent.   5. The microstructure apparatus of the combined or separate embodiments 1-4, wherein the polymer matrix comprises about 20-50% therapeutic agent.   6. The microstructure apparatus of the combined or separate embodiments 1-5, wherein the polymer matrix comprises about 25-50% therapeutic agent.   7. The microstructure apparatus of the combined or separate embodiments 1-6, wherein the polymer matrix comprises about 30-50% therapeutic agent.   8. The microstructure apparatus of the combined or separate embodiments 1-7, wherein the polymer matrix comprises about 45-50% therapeutic agent.   9. The microstructure apparatus of the combined or separate embodiments 1-8, wherein the polymer matrix comprises about 50-99% of the water insoluble, biodegradable polymer.   10. The microstructure apparatus of the combined or separate embodiments 1-9, wherein the polymer matrix comprises about 50-90% of the water insoluble, biodegradable polymer.   11. The microstructure apparatus of the combined or separate embodiments 1-10, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute.   12. The microstructure apparatus of the combined or separate embodiments 1-11, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.5-10%/minute.   13. The microstructure apparatus of the combined or separate embodiments 1-12, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 1-10%/minute.   14. The microstructure apparatus of the combined or separate embodiments 1-13, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 2-10%/minute.   15. The apparatus of the combined or separate embodiments 1-14, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours.   16. The apparatus of the combined or separate embodiments 1-15, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours.   17. The apparatus of the combined or separate embodiments 1-16, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours.   18. The apparatus of the combined or separate embodiments 1-17, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours.   19. The apparatus of the combined or separate embodiments 1-18, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours.   20. The apparatus of the combined or separate embodiments 1-19, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours.   21. The apparatus of the combined or separate embodiments 1-20, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour.   22. The apparatus of the combined or separate embodiments 1-21, wherein the microstructures are detachable from the substrate.   23. The apparatus of the combined or separate embodiments 1-22, wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine.   24. A microstructure apparatus, alone or combined with any of the embodiments herein, comprising: 
   an approximately planar substrate having a first surface and a second surface opposed thereto; and   a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising (i) at least one low molecular weight polymer, (ii) at least one high molecular weight polymer, and (iii) at least one therapeutic agent;   wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute;   wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours.   
   25. The apparatus of embodiment 24, wherein the polymer matrix comprises at least one water insoluble, biodegradable polymer.   26. The apparatus of the combined or separate embodiments 24-25, wherein at least one of the low molecular weight polymer or the high molecular weight polymer is the water insoluble, biodegradable polymer.   27. The apparatus of the combined or separate embodiments 24-26, wherein the water insoluble, biodegradable polymer is selected from polylactide, polyglycolide, and co-polymers thereof.   28. The apparatus of the combined or separate embodiments 24-27, wherein the initial release rate is between about 0.5-10%/minute.   29. The apparatus of the combined or separate embodiments 24-28, wherein the initial release rate is between about 1-10%/minute.   30. The apparatus of the combined or separate embodiments 24-29, wherein the initial release rate of the therapeutic agent from the polymer matrix is less than about 1-10%/minute.   31. The apparatus of the combined or separate embodiments 24-30, wherein the low molecular weight polymer has a molecular weight of between about 1-10 K Da.   32. The apparatus of the combined or separate embodiments 24-31, wherein the high molecular weight polymer has a molecular weight of between about 50-300 K Da.   33. The apparatus of the combined or separate embodiments 24-32, wherein the high molecular weight polymer has a molecular weight of between about 50-70 K Da.   34. The apparatus of the combined or separate embodiments 24-33, wherein the low molecular weight polymer and high molecular weight polymers are present in a ratio of about 1:1-1:10.   35. The apparatus of the combined or separate embodiments 24-34, wherein the low molecular weight polymer and high molecular weight polymers are present in a ratio of about 1:1.   36. The apparatus of the combined or separate embodiments 24-35, wherein the low molecular weight polymer and high molecular weight polymers are present in a ratio of about 1:4.   37. The apparatus of the combined or separate embodiments 24-36, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours.   38. The apparatus of the combined or separate embodiments 24-37, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours.   39. The apparatus of the combined or separate embodiments 24-38, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours.   40. The apparatus of the combined or separate embodiments 24-39, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours.   41. The apparatus of the combined or separate embodiments 24-40, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours.   42. The apparatus of the combined or separate embodiments 24-41, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours.   43. The apparatus of the combined or separate embodiments 24-42, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour.   44. The apparatus of the combined or separate embodiments 24-43, wherein the microstructures are detachable from the substrate.   45. The apparatus of the combined or separate embodiments 24-44, wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine.   46. A microstructure apparatus, comprising: 
   an approximately planar substrate having a first surface and a second surface opposed thereto; and   a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising (i) at least one biodegradable polymer, (ii) a hydrophilic component, and (iii) at least one therapeutic agent;   wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours.   
   47. The apparatus of embodiment 46, wherein the biodegradable polymer is a water insoluble, biodegradable polymer.   48. The apparatus of the combined or separate embodiments 46-47, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 4-24 hours.   49. The apparatus of the combined or separate embodiments 46-48, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 4-8 hours.   50. The apparatus of the combined or separate embodiments 46-49, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours.   51. The apparatus of the combined or separate embodiments 46-50, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours.   52. The apparatus of the combined or separate embodiments 46-51, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours.   53. The apparatus of the combined or separate embodiments 46-52, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours.   54. The apparatus of the combined or separate embodiments 46-53, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours.   55. The apparatus of the combined or separate embodiments 46-54, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours.   56. The apparatus of the combined or separate embodiments 46-55, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour.   57. The apparatus of the combined or separate embodiments 46-56, wherein the polymer matrix comprises about 5%-40% of the hydrophilic component.   58. The apparatus of the combined or separate embodiments 46-57, wherein the polymer matrix comprises about 5%-10% of the hydrophilic component.   59. The apparatus of the combined or separate embodiments 46-58, wherein the polymer matrix comprises about 5%-40% of the hydrophilic component.   60. The apparatus of any the combined or separate embodiments 46-59, wherein the polymer matrix comprises up to about 40% of the hydrophilic component.   61. The apparatus of the combined or separate embodiments 46-60, wherein the polymer matrix comprises up to about 20% of the hydrophilic component.   62. The apparatus of the combined or separate embodiments 46-61, wherein the polymer matrix comprises up to about 10% of the hydrophilic component.   63. The apparatus of the combined or separate embodiments 46-62, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute.   64. The apparatus of the combined or separate embodiments 46-63, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.5-10%/minute.   65. The apparatus of the combined or separate embodiments 46-64, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 1-10%/minute.   66. The apparatus of the combined or separate embodiments 46-65, wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 2-10%/minute.   67. The apparatus of the combined or separate embodiments 46-66, wherein the hydrophilic component is PEG-PLGA.   68. The apparatus of the combined or separate embodiments 46-67, wherein the biodegradable polymer is a hydrophobic polymer selected from PLA, α-hydroxy acids, polycaprolactones, polyanhydrides, and co-polymers thereof.   69. The apparatus of the combined or separate embodiments 46-68, wherein the α-hydroxy acid is PLGA.   70. The apparatus of the combined or separate embodiments 46-69, wherein the microstructures are detachable from the substrate.   71. The apparatus of the combined or separate embodiments 46-70, wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine.   72. A microstructure apparatus, comprising: 
   an approximately planar substrate having a first surface and a second surface opposed thereto;   a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, the microstructures being formed of a polymer matrix comprising at least one polymer and at least one therapeutic agent;   wherein a ratio of therapeutic agent to polymer in the matrix is low;   wherein an initial release rate of the therapeutic agent from the polymer matrix is between about 0.05-10%/minute;   wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1-144 hours.   
   73. The apparatus of embodiment 72, wherein the ratio of therapeutic agent to polymer is between about 1:2 to 1:25.   74. The apparatus of the combined or separate embodiments 72-73, wherein the ratio of therapeutic agent to polymer is between about 1:2 to 1:20.   75. The apparatus of the combined or separate embodiments 72-74, wherein the ratio of therapeutic agent to polymer is between about 1:2 to 1:15.   76. The apparatus of the combined or separate embodiments 72-75, wherein the ratio of therapeutic agent to polymer is between about 1:2 to 1:10.   77. The apparatus of the combined or separate embodiments 72-76, wherein the ratio of therapeutic agent to polymer is between about 1:2 to 1:4.   78. The apparatus of the combined or separate embodiments 72-77, wherein the polymer matrix comprises at least one water insoluble, biodegradable polymer.   79. The apparatus of any the combined or separate embodiments 72-78, wherein the water insoluble, biodegradable polymer is selected from polylactide, polyglycolide, and co-polymers thereof.   80. The apparatus of the combined or separate embodiments 72-79, wherein the initial release rate is between about 0.5%/minute.   81. The apparatus of the combined or separate embodiments 72-80, wherein the initial release rate of the therapeutic agent from the polymer matrix is less than 10 %/minute.   82. The apparatus of the combined or separate embodiments 72-81, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 144 hours.   83. The apparatus of the combined or separate embodiments 72-82, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 72 hours.   84. The apparatus of the combined or separate embodiments 72-83, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 24 hours.   85. The apparatus of the combined or separate embodiments 72-84, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 12 hours.   86. The apparatus of the combined or separate embodiments 72-85, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 6 hours.   87. The apparatus of the combined or separate embodiments 72-86, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 3 hours.   88. The apparatus of the combined or separate embodiments 72-87, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 1 hour.   89. The apparatus of the combined or separate embodiments 72-88, wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine.   90. The apparatus of the combined or separate embodiments 72-89, wherein the microstructures are detachable from the substrate.   91. A method of making a sustained release microstructure apparatus, comprising: 
   dissolving or suspending a therapeutic agent in a solvent to form a therapeutic agent solution or suspension;   dissolving at least one water insoluble, biodegradable polymer in a solvent to form a polymer solution;   mixing the therapeutic agent solution or suspension and the polymer solution or suspension to form a polymer matrix solution or suspension;   dispensing the polymer matrix solution or suspension on a mold having an array of microstructure cavities;   filling the microstructure cavities in the mold;   removing excess solution or suspension polymer matrix on the mold surface; and drying the matrix to form a plurality of microstructures;   dispensing a basement or backing layer on the mold surface;   drying the basement or backing layer.   
   92. The method of embodiment 91, further comprising: affixing the basement or backing layer to a substrate.   93. The method of the combined or separate embodiments 91-92, further comprising: using a nonwoven or porous film double coated with adhesive to affix the basement or backing layer to a substrate.   94. The method of the combined or separate embodiments 91-93, wherein at least one of the solvents is selected from DMSO and acetonitrile.   95. The method of the combined or separate embodiments 91-94, wherein filling the microstructure cavities comprises pressurizing the mold.   96. The method of the combined or separate embodiments 91-95, wherein the therapeutic agent is crystalline, further comprising: 
   heating the plurality of microstructures to about 110° C. for about 1 hour; and   storing the microstructures in a dry cabinet for about 10 days.   
   97. The method of the combined or separate embodiments 91-96, wherein the heating is performed in a convection oven.   98. A method of modulating an initial release rate of a therapeutic agent from a microstructure apparatus comprising a plurality of microstructures formed of a polymer matrix comprising at least one polymer and at least one therapeutic agent, the method comprising: 
   (a) wherein the at least one polymer comprises at least one high molecular weight polymer and at least one low molecular weight polymer, adjusting a ratio of the high molecular weight polymers to low molecular weight polymers in the polymer matrix to achieve a desired initial release rate of therapeutic agent from the polymer matrix;   (b) adjusting a ratio of therapeutic agent to polymer in the polymer matrix;   (c) adding at least one hydrophilic component to the polymer matrix; and/or   (d) selecting a solvent for preparing the polymer matrix that provides a desired initial release rate.   
   99. The method of embodiment 98, wherein (a) comprises increasing the ratio of high molecular weight polymer in the matrix to increase the initial release rate.   100. The method of the combined or separate embodiments 98-99, wherein (a) comprises increasing the ratio of low molecular weight polymer in the matrix to decrease the initial release rate.   101. The method of the combined or separate embodiments 98-100, wherein (b) comprises increasing the ratio of therapeutic agent in the matrix to increase the initial release rate.   102. The method of the combined or separate embodiments 98-101, wherein (b) comprises decreasing the ratio of low molecular weight polymer in the matrix to decrease the initial release rate.   103. The method of the combined or separate embodiments 98-102, wherein (c) comprises adding the hydrophilic component as about 10-40% of the matrix to increase the initial release rate.   104. The method of the combined or separate embodiments 98-103, wherein the hydrophilic component is PEG-PLGA.   105. The method of the combined or separate embodiments 98-104, wherein the at least one polymer is a water insoluble, biodegradable polymer.   106. The method of the combined or separate embodiments 98-105, wherein the water insoluble, biodegradable polymer is selected from polylactide, polyglycolide, and co-polymers thereof.   107. The method of the combined or separate embodiments 98-106, wherein (d) comprises choosing one of DMSO or acetonitrile as the solvent.   108. The method of the combined or separate embodiments 98-107, wherein (d) comprises choosing DMSO as the solvent to lower the initial release rate.   109. The method of the combined or separate embodiments 98-108, wherein (d) comprises choosing acetonitrile as the solvent to increase the initial release rate.   110. A microstructure apparatus, comprising:
   an approximately planar substrate having a first surface and a second surface opposed thereto; and   a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto;   wherein at least a portion of the microstructures has a distal portion dimensioned to penetrate a stratum corneum layer of a subject’s skin, and a proximal portion that is dimensioned so that it does not penetrate the skin;   wherein the distal portion and proximal portion are each formed of a polymer matrix comprising (i) a biodegradable polymer, and (ii) at least one therapeutic agent.   
   111. The microstructure apparatus of embodiment 110, further comprising: 
   a backing layer positioned between the proximal portion and the substrate, the backing   layer being formed of a polymer matrix comprising (i) a biodegradable polymer, and (ii) the at least one therapeutic agent.   
   112. The apparatus of the combined or separate embodiments 110-111, wherein the biodegradable polymer is a water soluble biodegradable polymer.   113. The apparatus of the combined or separate embodiments 110-112, wherein the biodegradable polymer is a water insoluble biodegradable polymer.   114. The apparatus of the combined or separate embodiments 110-113, wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine. 115. The apparatus of the combined or separate embodiments 110-114, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.1-24 hours.   116. The apparatus of the combined or separate embodiments 110-115, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.5-10 hours.   117. The apparatus of any the combined or separate embodiments 110-116, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.5-4 hours.   118. The apparatus of the combined or separate embodiments 110-117, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.5-4 hours.   119. The apparatus of the combined or separate embodiments 110-118, wherein release of the therapeutic agent from the polymer matrix is sustained for a period of at least about 0.1-1 hours.   120. The apparatus of the combined or separate embodiments 110-119, where the microstructure array is suitable to be worn for at least 1-24 hours.   121. A microstructure apparatus, comprising: 
   a substrate having a first surface and a second surface opposed thereto;   a plurality of microstructures extending outwardly from the first surface of the substrate;   at least a portion of the microstructures comprising at least one therapeutic agent; and   an adhesive coating applied to at least one of a) at least a portion of at least some of the plurality of microstructures, or b) at least a portion of the substrate first surface between the microstructures.   
   122. The microstructure apparatus of embodiment 121, wherein at least a portion of the microstructures comprise a biodegradable distal layer and at least one non-biodegradable proximal layer positioned between the distal layer and the first surface of the substrate. 123. The microstructure apparatus of the combined or separate embodiments 121-122, wherein at least a portion of the microstructures are biodegradable.   124. The microstructure apparatus of the combined or separate embodiments 121-123, wherein the therapeutic agent is a drug, a small-molecule agent, a protein or peptide, or a vaccine.   125. The microstructure apparatus of the combined or separate embodiments 121-124, wherein the adhesive coating comprises an adhesive selected from a medical adhesive, a tissue adhesive, or a surgical adhesive.   126. The microstructure apparatus of the combined or separate embodiments 121-125, wherein the medical adhesive is selected from acrylic adhesives, silicone based adhesives, hydrogel adhesives, and synthetic elastomer adhesives.   127. The microstructure apparatus of the combined or separate embodiments 121-126, wherein the tissue adhesive is a cyanoacrylate polymer.   128. The microstructure apparatus of the combined or separate embodiments 121-127, wherein the cyanoacrylate polymer is selected from n-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate.   129. The microstructure apparatus of the combined or separate embodiments 121-128, wherein the adhesive coating comprises a fibrin adhesive.   130. The microstructure apparatus of the combined or separate embodiments 121-129, wherein the adhesive coating comprises a bioactive film.   131. The microstructure apparatus of the combined or separate embodiments 121-130, wherein the adhesive coating comprises a pressure sensitive adhesive.   132. The microstructure apparatus of the combined or separate embodiments 121-131, wherein the pressure sensitive adhesive is an acrylic pressure sensitive adhesive.   133. The microstructure apparatus of the combined or separate embodiments 121-132, wherein the adhesive coating comprises a rubber-based adhesive.   134. The microstructure apparatus of the combined or separate embodiments 121-133, wherein the adhesive coating is biodegradable.   135. The microstructure apparatus of the combined or separate embodiments 121-134, wherein the adhesive coating is non-continuous.   136. The microstructure apparatus of the combined or separate embodiments 121-135, wherein the adhesive coating includes a plurality of holes.   137. The microstructure apparatus of the combined or separate embodiments 121-136, wherein the adhesive coating is porous.   138. The microstructure apparatus of the combined or separate embodiments 121-137, wherein the adhesive coating has a reduced adhesion over time.   139. The microstructure apparatus of the combined or separate embodiments 121-138, wherein the adhesive coating is applied to at least about 10-100% of the microstructures in the array.   140. The microstructure apparatus of the combined or separate embodiments 121-139, wherein about 10-95% of each coated microstructure has an adhesive coating.   141. The microstructure apparatus of the combined or separate embodiments 121-140, wherein the adhesive coating is applied to a distal portion of the microstructures.   142. The microstructure apparatus of the combined or separate embodiments 121-141, wherein the adhesive coating is applied to a proximal portion of the microstructures.   143. A microstructure apparatus, comprising:
   a substrate having a first surface and a second surface opposed thereto;   a plurality of microstructures extending outwardly from the first surface of the substrate;   a plurality of openings extending through the substrate and positioned between at least some of the plurality of microstructures; and   an adhesive coating applied to at least a portion of the substrate second surface such that the adhesive is capable of contacting a subject’s skin through the openings when placed on the skin.   
   144. The microstructure apparatus of embodiment 143, wherein the adhesive coating is applied to all or substantially all of the substrate second surface.   145. The microstructure apparatus of the combined or separate embodiments 143-144, wherein the adhesive coating is applied the substrate second surface in the region of the openings.   146. The microstructure apparatus of the combined or separate embodiments 143-145, further comprising a backing layer positioned over the adhesive coating.   147. The microstructure apparatus of the combined or separate embodiments 143-146, wherein at least a portion of the microstructures are at least partially biodegradable.   148. The microstructure apparatus of the combined or separate embodiments 143-147, wherein the therapeutic agent is a drug, a small-molecule agent, a protein or peptide, or a vaccine.   149. The microstructure apparatus of the combined or separate embodiments 143-148, wherein the adhesive coating comprises an adhesive selected from a medical adhesive, a tissue adhesive, or a surgical adhesive.   150. The microstructure apparatus of the combined or separate embodiments 143-149, wherein the medical adhesive is selected from acrylic adhesives, silicone based adhesives, hydrogel adhesives, and synthetic elastomer adhesives.   151. The microstructure apparatus of the combined or separate embodiments 143-150, wherein the tissue adhesive is a cyanoacrylate polymer.   152. The microstructure apparatus of the combined or separate embodiments 143-151, wherein the cyanoacrylate polymer is selected from n-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate.   153. The microstructure apparatus of the combined or separate embodiments 143-152, wherein the adhesive coating comprises a fibrin adhesive.   154. The microstructure apparatus of the combined or separate embodiments 143-153, wherein the adhesive coating comprises a bioactive film.   155. The microstructure apparatus of the combined or separate embodiments 143-154, wherein the adhesive coating comprises a pressure sensitive adhesive.   156. The microstructure apparatus of the combined or separate embodiments 143-155, wherein the pressure sensitive adhesive is an acrylic pressure sensitive adhesive.   157. The microstructure apparatus of the combined or separate embodiments 143-156, wherein the adhesive coating comprises a rubber-based adhesive.   158. The microstructure apparatus of the combined or separate embodiments 143-157, wherein the adhesive coating is biodegradable.   159. The microstructure apparatus of the combined or separate embodiments 143-158, wherein the adhesive coating is non-continuous.   160. The microstructure apparatus of the combined or separate embodiments 143-159, wherein the adhesive coating includes a plurality of holes.   161. The microstructure apparatus of the combined or separate embodiments 143-160, wherein the adhesive coating is porous.   162. The microstructure apparatus of the combined or separate embodiments 143-161, wherein the adhesive coating has a reduced adhesion over time.   163. The microstructure apparatus of the combined or separate embodiments 143-162, wherein the adhesive coating is applied to at least about 10-100% of the microstructures in the array.   164. The microstructure apparatus of the combined or separate embodiments 143-163, wherein about 10-95% of each coated microstructure has an adhesive coating.   165. The microstructure apparatus of the combined or separate embodiments 143-164, wherein the adhesive coating is applied to a distal portion of the microstructures.   166. The microstructure apparatus of the combined or separate embodiments 143-165, wherein the adhesive coating is applied to a proximal portion of the microstructures.   167. A system comprising:
   the microstructure apparatus of the combined or separate embodiments 1-166; and   an applicator for applying the microstructure apparatus to a patient’s skin.   
   168. A method of delivering a therapeutic agent to a subject for an extended period of time, comprising: 
   applying a microstructure apparatus of any previous claim to a skin site of the subject;   adhering the microstructure apparatus to the skin;   delivering the therapeutic agent from the microstructure array to the subject; and   removing the microstructure apparatus after at least about 10 minutes.   
   169. The method of embodiment 168, wherein the microstructure apparatus is removed after at least about 15 minutes.   170. The method of the combined or separate embodiments 168-169, wherein the microstructure apparatus is removed after at least about 20 minutes.   171. The method of the combined or separate embodiments 168-170, wherein the microstructure apparatus is removed after at least about 30 minutes.   172. The method of the combined or separate embodiments 168-171, wherein the microstructure apparatus is removed after at least about 45 minutes.   173. The method of the combined or separate embodiments 168-172, wherein the microstructure apparatus is removed after at least about 1 hour.   174. The method of the combined or separate embodiments 168-173, wherein the microstructure apparatus is removed after at least about 1-24 hours.   175. The method of the combined or separate embodiments 168-174, wherein the microstructure apparatus is removed after at least about 1-5 days.   176. The method of the combined or separate embodiments 168-175, wherein at least about 10-100% of a total dose of the therapeutic agent is delivered to the subject.   177. The method of the combined or separate embodiments 168-176, wherein at least about 50-100% of a total dose of the therapeutic agent is delivered to the subject.   178. The method of the combined or separate embodiments 168-177, wherein at least about 60-100% of a total dose of the therapeutic agent is delivered to the subject.   179. The method of the combined or separate embodiments 168-178, wherein at least about 70-100% of a total dose of the therapeutic agent is delivered to the subject.   180. The method of the combined or separate embodiments 168-179, wherein at least about 75-100% of a total dose of the therapeutic agent is delivered to the subject.   181. The method of the combined or separate embodiments 168-180, wherein at least about 80-100% of a total dose of the therapeutic agent is delivered to the subject.   182. The method of the combined or separate embodiments 168-181, wherein at least about 90-100% of a total dose of the therapeutic agent is delivered to the subject.   183. The method of the combined or separate embodiments 168-182, wherein at least about 95-100% of a total dose of the therapeutic agent is delivered to the subject.   184. The method of the combined or separate embodiments 168-183, further comprising:
   prior to applying the microstructure apparatus, positioning the microstructure apparatus on a plunger of an applicator;   actuating the applicator to release the plunger;   impacting the skin with the microstructure apparatus;   removing the applicator with the microstructure apparatus remaining on the skin site for an extended period of time.   
   185. The method of the combined or separate embodiments 168-184, further comprising: pressing the microstructure apparatus against the skin site to push the adhesive through the openings and into contact with the skin site.   

     While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope. 
     All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entireties. However, where a patent, patent application, or publication containing express definitions is incorporated by reference, those express definitions should be understood to apply to the incorporated patent, patent application, or publication in which they are found, and not necessarily to the text of this application, in particular the claims of this application, in which instance, the definitions provided herein are meant to supersede.