Patent Application: US-201213654324-A

Abstract:
a micro - needle array is provided that may be used to deliver a bioactive agent to a therapeutic target . the micro - needle array preferably includes a substrate , a plurality of micro - needles integral with the substrate , and a bioactive agent . at least one micro - needle preferably includes a top surface , a bottom surface , a side surface , and a cavity defined by an inner surface . the bioactive agent may be disposed on the substrate and the plurality of micro - needles . the at least one micro - needle may further include a slit connecting the cavity to an aperture , the slit extending from the top surface to the bottom surface . a plurality of micro - needles on a patch is also disclosed for transdermal drug delivery applications .

Description:
micro - needles are new medical devices with the same purpose of classic hypodermic needles but fabricated on micro - scale often in the form of arrays in various materials . during the past few decades scientists and engineers have spent considerable amount of time and resources to develop micro - needle patches for drug delivery . these devices aim to replace the hypodermic needles and consist of a patch with micro - sized needles . micro - needle patches are about the size of a postage stamp and hold hundreds of micro - sized needles , each less than a millimeter long and in different shapes . these patches generally do not induce pain since these micro - sized needles penetrate into the skin small enough and do not reach pain receptors and they can be applied without the help of a health professional [ 1 ]. the term “ biocompatible ,” as used herein , refers to a material that is substantially non - toxic in the in vivo environment of its intended use , and that is not substantially rejected by the patient &# 39 ; s physiological system . a biocompatible structure or material , when introduced into a majority of patients , will not cause an undesirably adverse , long - lived or escalating biological reaction or response . such a response is distinguished from a mild , transient inflammation which typically accompanies surgery or implantation of foreign objects into a living organism . the term “ biodegradable ,” as used herein , refers to a material that dissipates upon implantation within a body , independent of the mechanisms by which dissipation can occur , such as dissolution , degradation , absorption and excretion . the actual choice of which type of materials to use may readily be made by one of ordinary skill in the art . such materials are often referred to by different terms in the art , such as “ bioresorbable ,” “ bioabsorbable ,” or “ biodegradable ,” depending upon the mechanism by which the material dissipates . the prefix “ bio ” indicates that the erosion occurs under physiological conditions , as opposed to other erosion processes , caused for example , by high temperature , strong acids or bases , uv light or weather conditions . the term “ controlled release ,” as used herein , refers to the release of an agent at a predetermined rate . a controlled release may be constant or vary with time . a controlled release may be characterized by a drug elution profile , which shows the measured rate that the agent is removed from a device in a given solvent environment as a function of time . for example , a controlled release elution profile from a medical device may include an initial burst release associated with the deployment of the device , followed by a more gradual subsequent release . a controlled release may be a gradient release in which the concentration of the agent released varies over time or a steady state release in which the agent is released in equal amounts over a certain period of time ( with or without an initial burst release ). the term “ barrier layer ,” as used herein , is any layer that is placed over at least a portion of a bioactive agent present in or on a portion of a device of the present invention . in general , the bioactive agent will not be present in the barrier layer . any mixing of a bioactive agent with the barrier layer is unintentional and merely incidental . the barrier layer may or may not be the outer - most layer present on the device . for example , a bioactive agent may be coated onto a surface of the device , a first barrier layer placed over the bioactive agent and further barrier layers and layers containing the same or a different bioactive agent placed on the first barrier layer . the barrier layer may control the release of the bioactive agent from the device upon implantation . the term “ carrier material ,” as used herein , refers to a material that forms a mixture with bioactive agent on or in a device of the present disclosure . the carrier material may control the release of the bioactive agent from the device . the term “ bioactive agent ,” as used herein , refers to any pharmaceutically active agent that produces an intended therapeutic effect on the body to treat or prevent conditions or diseases . the term “ treatment ” or “ treating ,” as used herein , describes the management and care of a human or veterinary patient for the purpose of combating or preventing a disease , condition , or disorder and includes the administration of a bioactive agent to alleviate the symptoms or complications , or eliminate the disease , condition , or disorder . the term “ therapeutically - effective amount ,” as used herein , is the minimal amount of a bioactive agent which is necessary to impart therapeutic benefit to a human or veterinary patient . for example , a “ therapeutically effective amount ” to a human or veterinary patient is such an amount which induces , ameliorates or otherwise causes an improvement in the pathological symptoms , disease progression or physiological conditions associated with or resistance to succumbing to a disorder . as explained above , the dimensions of the micro - needles can be optimized to avoid contact with the dermis layer of the skin yet still deliver effective amounts of bioactive agents . this approach prevents the needles from activating pain receptors , thus the patient only experiences the sensation of being touched by a flat patch . this leads to other advantages ; indeed having a painless vaccination means that less people avoid vaccination . moreover the dimensions enable preparation of the micro - needles in a patch for simple administration , possibly by patients themselves and can be inserted painlessly onto the skin without specialized training . these micron - scale needles can be mass produced using low - cost methods for distribution to doctors &# 39 ; office , pharmacies and , possibly , people &# 39 ; s homes . in addition , having such small needles that most of time could dissolve through the skin would eliminate the risk of sharp hazardous waste and reduce the possibility of undesirable re - use of the device . other advantages of the micro - needle patches could include lower dosage requirements . lower doses could be particularly important because flu vaccine production capacity sometimes is limited for seasonal vaccine , and a future influenza pandemic would require much greater production of vaccine . replacing a hypodermic needle with a micro - needle patch also could significantly impact the way other vaccines are delivered , and could be particularly beneficial in developing countries . in summary , the advantages of micro - needles over conventional needles include ; i ) no painful piercing of the skin , ii ) self - application , easily distributed and sold over the counter , iii ) no sharp hazardous waste after immunization , iv ) more effective vaccinations , and v ) more cost effective than hypodermic needles . with the goal of decreasing the pain associated with drug injection and blood extraction researchers have investigated transdermal micro - needle array technologies . several different types of micro - needles have been fabricated . it is possible to find solid ( straight , bent , filtered ) and hollow micro - needles . solid needles could be used to increase drug diffusion rate by using a drug patch . hollow needles which include tapered and beveled tips ( see fig3 ) allow delivery of microliter quantities of drugs to specific locations in human body . micro - needles arrays of hollow needles can also be used together with a pump system to remove fluid from the body for analysis such as blood glucose measurements . furthermore , small enough micro - needles could even provide drug administration to individual cells and also open possibilities for stem cell research . the first micro - needle arrays reported in the literature were etched into a silicon wafer and developed for intracellular delivery in vitro by hashmi et al . [ 5 ]. these needles were inserted into cells and nematodes to increase molecular uptake and gene transfection . henry et al . [ 1 ] conducted the first study to determine if micro - needles could be used to increase transdermal drug delivery . an array of solid micro - needles was embedded in cadaver skin , which exhibited skin permeability to a small model compound . the development of micro - needles began in the late 1990s with micro - fabrication of solid needles made from silicon , using microlithography and etching technologies originally developed for the microelectronics industry . this method produced arrays of up to 400 needles designed to punch holes in the outer layer of skin to increase its permeability to small molecules applied with the patches . that work has broadened to include both solid and hollow micro - needles . these creations range in size from 1 millimeter in length to only 25 μm in diameter [ 3 ]. kaushik et al . [ 6 ] carried out a small trial to determine if micro - needles are perceived as painless by human subjects . micro - needle arrays were inserted into the skin of twelve subjects and compared to pressing a flat surface against the skin and inserting a 26 - gauge hypodermic needle into the skin surface . subjects were unable to distinguish between the painless sensation of the flat surface and the one caused by micro - needles . all subjects found the sensation caused by the hypodermic needle to be much more painful . other studies have also reported that micro - needles can be applied to human subjects in a painless manner [ 7 , 8 ]. one drawback reported in the literature was the breakage of metal needles inside the skin since metal micro - needles were not elastic but rather brittle . one solution to this problem is by changing the material from metals to polymers . it was easier , cheaper and faster to obtain the desired shape and dimensions while maintaining strength . moreover micro - needles were made of a harmless dissolving polymer that was mixed with a freeze - dried vaccine . it means that instead of the needles injecting a fluid , the needles quickly dissolve to become the fluid . this way when the patch is removed there is nothing sharp left on it and it is readily and safely disposable without hazardous outcome . biodegradable polymer micro - needles have recently been fabricated and characterized . the advantage of biodegradable polymer needles is that they can be cost - effectively produced and do not pose a problem of breakage in the skin due to biocompatibility and biodegradability [ 9 , 10 ]. in addition , coated encapsulated molecules within micro - needles can dissolve in the skin and leave no biohazardous waste thereafter [ 12 ]. fabrication of biodegradable polymer micro - needles with sharp , beveled or tapered tips is possible by using masking and etching mems processing techniques or within an in situ lens - based lithographic technique . presently , many different types of micro - needles can be found in literature : solid , hollow , with different shapes for different purposes , and with different materials . the broad range of sizes , shapes and materials must be assessed and optimized to permit production of micro - needle arrays customized for the type and volume of drug to be delivered , the time period of use , and most importantly , minimizing the pain . several micro - electro - mechanical - systems ( mems ) type micro - needle designs have been developed by using semiconductor based fabrication methods . moving away from the original expensive microelectronics - based fabrication techniques , manufacturing process chains have been developed for low cost production of micro - needles in metal and polymer materials . in these process chains , techniques to fabricate molds are utilized then polymeric micro - needles are fabricated with injection molding . the creation of the molds is done by using a master prototype for micro - needles . metallic micro - needles can also be produced through electro - deposition and glass micro - needles can be fabricated using glass drawn micropipette techniques as reported in literature [ 3 ]. multi layer structures for polymeric micro - needles are proposed by kuo & amp ; chou [ 13 ]. the fabrication process for the multi layer structure is shown in fig4 and multi - layer structure of multiple - layer fluidic structure is shown in fig5 . the first step is the deposition of sin4 layer on single crystal silicon wafer as mask material with a dry etching process . then , there are duplicate recesses on the silicon substrate are formed and each recess is shaped into the inclined sidewall structure during the etching process . a release layer and a polymeric layer are coated on top of the structure respectively . following a multiple exposure process , a multi layer structure is fabricated and a supporting layer of micro - needles is built ( fig4 b and 4 c ). a polymeric layer is coated on the exposed layer and the micro - channels are constructed . as a final step the silicon substrate is peeled off and the micro - needles are developed [ 13 ]. according to kuo & amp ; chuo [ 13 ] this technique can fabricate hollow micro - needles with sharp tips and the dimensions of 50 μm and length of 600 μm . very small micro - needles could provide highly targeted drug administration to individual cells . these are capable of very accurate dosing , complex release patterns , local delivery and biological drug stability enhancement by storing in a micro volume that can be precisely controlled . these studies suggest that micro - needles may provide a powerful new approach to transdermal drug delivery . thus , in accordance with the present invention , micro - needle arrays have been designed and fabricated using a based patch prototype with micro - milling of polymeric materials . the i ) design , ii ) process planning for prototyping , iii ) fabrication , iv ) evaluation of results , and v ) discussion and conclusions are provided herein . the micro - needle array patches described herein enable cost - effective and less painful approaches for drug delivery ( e . g ., vaccination ) thereby providing an improved drug delivery medical device . the following example is provided to illustrate certain embodiments of the invention . it is not intended to limit the invention in any way . basic needle shapes ( pyramidal , conical , cylindrical , etc .) and design parameters such as dimensions and micro - needle array density have been investigated . in parallel , a direct low cost and rapid solution to fabricate a micro - needle array manufacturing method is also provided . machining of a pyramidal shape single micro - needle object using micro - milling was initially investigated . furthermore fabrication of pyramidal shaped micro - needle array using many individual micro - needles was also performed on a polymer workpiece . in the beginning a square shaped pyramidal micro - needle structure typically 1 to 3 mm tall was selected as the basic needle shape . the aspect ratio of these micro - needles was the same of the tool which is about 3 . other shapes including squared pyramidal and circular pyramidal ( conical ) have been considered . these shapes were considered because they can be fabricated by using single edge , zero helical angle straight but tapered and specially fabricated carbide micro - tools . at first , a design with solid micro - needle array type structure was constructed . but also a design with hollow micro - needle array type structure was also considered for further development to store liquid or freeze like substance for vaccination and immunization . since hollow micro - needle structures are more fragile and delicate to fabricate , a choice of solid micro - needle structure was made for prototyping using micro - milling . typically in micro - milling tool forces are strong enough to bend , damage and break the fragile and thin micro - structures even if they are made in polymers . for these reasons initial design for basic micro - needle geometry was selected as in the order of millimeters but a further scaling down was planned to keep the micro - needle array structure small enough to be inserted into the human skin and yet not reach to the pain receptors in the dermis section of the skin tissue . a number of micro - needle array design as solid structures has been performed and these are shown in fig6 . in fig6 a , a pyramidal shape design is shown which can be fabricated using a tapered straight cutting edge engraving type micro - milling tool by following linear tool path patterns . in fig6 b , a conical solid micro - needle array design is shown which can be fabricated by using the same micro - milling tool but circular tool paths . and finally fig6 c , shows a small height , shallow , dwarf type conical solid micro - needle shape design . in this case if the density of the micro - needle array either horizontal or vertical is considered as a design parameter by selecting a shallow design such requirements can be achieved . a number of micro - needle array designs incorporating hollow structures have been developed and these are shown in fig7 . in fig7 a , a modification to the solid needle array design is introduced to create a shell type hollow structure . specifically , design of holes for delivering liquid drug to be injected has been performed . in fig7 b , straight holes in the center of the micro - needles are designed as the most logical first choice . however in the design the sharp tips of the micro - needles are removed . therefore other alternatives have been sought . one alternative is to fabricate the hole parallel to the side surface of the micro - needle as shown in fig7 c . in this case the holes are not straight but angled . this design maintains the sharp tip of the micro - needle . however it creates lower strength for the micro - needle when it is inserted into human skin . the last alternative was to design the holes off - centered in the micro - needles so that the sharp tip of the micro - needle is still maintained while the holes are straight and the hollow structure possesses some strength . there are a number of design parameters which can be varied when developing micro - needles arrays . these are the basic shape of a micro - needle , the height , the base diameter ( conical shape ) or the base dimension ( square based pyramidal shape ), horizontal and vertical spaces , and linear or circular array type . the micro - pyramidal shape array was first defined taking account of the biomedical needs and the milling limits . the arrays had to be made of biocompatible material , the height must be between 0 . 6 and 1 . 5 mm and the tip had to be both sharp and resistant to penetrate easily through the skin but not break inside . the micro - milling approach was designed to specifically address these problems , e . g ., maintenance of the sharpness and resistance of the tip , but facilitated the ability to obtain specific shapes . table 1 and fig9 summarize the design parameters . in order to fabricate micro - needle arrays , a process plan that includes the selection of the tool geometry and material , the selection of work material , the selection of micro - milling strategy and the parameters was developed and carried out at set forth below . the micro - tool was selected as a single flute straight cutting edge tungsten carbide engraving tool . this tool enabled fabrication of micro - needle features as a negative geometry of the tool tip after the material removal process . a tool geometry that is available in an engraving type straight but tapered cutting edge was utilized in fabrication of the micro - needle arrays . the characteristics of the tool geometry and geometrical parameters are shown in fig9 and table 2 . the tool tip had a flat bottom with 0 . 298 mm width . that assured creating a distance between the base features of the micro - needles . depending on the axial depth of cut taken during the micro - milling , this distance between the micro - needles within an array can be controlled . there are a number of materials that can be used for fabrication of micro - needles . the first group is polymers which are typically inexpensive , widely available , biocompatible , and possess good machinability such as acrylic , abs , peek , and pc . in addition , some metal alloys such as stainless steel and titanium alloys which are also biocompatible and possess good machinability and offer high strength and durability can be considered . a summary of the material properties and characteristics that can employed in micro - needle arrays is given in table 3 . as shown in table 3 , acrylic polymer possesses good machinability , biocompatibility and also acceptable cost . thus this material was chosen for development of initial prototypes . in alternative embodiments , the peek polymer can be employed although this polymer is a bit more costly . the machining parameters used for the micro - milling process were selected starting with some recommended values and by improving them step by step . the most important parameters affecting the machining process were spindle speed , feed rate , axial depth of cut and air cooling system pressure . all these parameters are important to control the heat generation during the machining process . heat generation is the most important phenomenon to be controlled because of very low thermal conductivity , glass transition temperature ( tg ), and low melting point temperature ( tm ) of these polymeric work materials . machining process induces temperature increases which can be very close to glass transition temperature ( even melting point temperature ) creating low quality surface finish , chip melting and smearing onto the tool or the workpiece . therefore machining parameters for micro - milling have to be optimized in order to avoid excessive temperature rises but also to maintain a desirable material removal rate . the feed rate was selected as 20 mm / min , the spindle speed was at 30000 rpm and the adoc ( for all the experiments ) was taken as 0 . 1 mm . these values resulted in good surface finish during all the experiments . in addition , an air cooling system was introduced with 80 psi air pressure and a nozzle system directing at the cutting zone . this cooling system was introduced to avoid chip and burr melting problems . an experimental set - up for micro - milling of polymers shown in fig1 has been prepared . in this experimental set - up , a 3 - axis positioning stage driven by a computer numerical control system that accepts standard part programming ( g codes ) was utilized . a precision spindle ( nsk astro - e800 ) with ceramic bearings and electrically driven up to 80 krpm was employed . a micro - tool with a straight cutting edge was attached to the spindle using with a collet type to hold the overhanging about 18 mm . a rectangular polymeric workpiece was clamped on the fixture mounted on the table of this in - house developed micro - milling machine using a micro - precision vise . the workpiece surface was segmented by using a larger diameter flat endmill to the desired size for the micro - needle array base . in addition an air cooling system was introduced by using a nozzle to cool down the temperature in the polymer and also to air blow polymeric chips and debris . a solid model for the micro - needle arrays was developed to realized the overall geometry and some challenges in machining these geometries using micro - milling processes . furthermore this model was utilized as a reference to generate the tool path and related nc part program . the first micro - needles array prototype has consisted of a pyramid shape with a square base . the tool path strategy that was utilized was a “ grill ” type profile with a z level increment of 0 . 1 mm [ fig1 ]. this strategy consisted of a zig - zag path with a stepover distance ( essentially the distance between the center of micro - needles ) on the longitudinal direction followed by the same zig - zag path in the transversal direction . the needles fabricated were 2 mm - tall , the base was a square with 0 . 7775 mm side length , and the micro - needle tips were 0 . 9075 mm apart from each other . in this case the array has 25 micro - needles arranged in 5 rows , and 5 columns . therefore the workpiece has dimensions of 5 . 426 × 5 . 426 × 5 mm including the base ( see fig1 ). it is possible to see the different steps during the experiment and the resultant profiles , where the green star and the red one are the starting and the ending point on the same z level tool path . the tool reaches to a deeper z level as the color used for the tool path turns from yellow to red . this approach was found to be problematic after the experiment . the tips of the pyramid needles were not sharp enough because of bending occurred during the last several passes of the micro - milling operation . the situation was improved by modifying the tool path strategy and the micro - needle geometry . the second prototype was also a square base pyramidal shape micro - needle array but the tool path was different in order to avoid the aforementioned problem . this new tool path strategy was a “ s ” type tool path strategy . as shown in fig1 , the micro - needle tips were sharper but some of them were broken during the last few passes of the micro - milling operation . all the dimensions were same as in the first experiment . the third prototype provided a new shape for the needles and , related to this , a new tool path strategy was introduced . these micro - needles were cone - shaped and arranged in 5 rows and 5 columns amounting to 25 micro - needles on the array as shown in fig1 . the cone - shaped micro - needles were 2 mm - tall and the base radius was 0 . 382 mm . the workpiece had dimensions of 5 . 426 × 5 . 426 × 5 mm including the base . the tool path strategy is shown in fig1 . a z level increment of 0 . 1 mm was used . as it can be seen in fig1 the cone - shaped micro - needles are sharper and well shaped than the pyramidal ones but also in this case micro - needle tips were deflected during the last few passes of the micro - milling operation . in the fourth prototype a different tool path strategy was adopted . in this case the micro - needle array was designed with a larger space between each micro - needle and with shorter needles heights ( see fig1 ). this prototype has 16 micro - needles placed in 4 rows and 4 columns . the needles were only 1 mm tall in order to obtain higher stiffness and lower tip deflection . the base radius of micro - needles was 0 . 180 mm and the distance between the tips was 1 . 420 mm . the tool path strategy was changing at every z level increment ( 0 . 1 mm ). the idea was to start machining the tip of the needles in order to obtain sharper tips and not letting them to be tall and thin to avoid deflections . in the tool path , the radius of the circular movement to obtain the cones was increased at every z level increment . before starting with this step , a roughing operation was performed to avoid breaking tools and overheating / melting problems . the roughing operation was performed using a flat end - milling tool with a “ grill ” tool path strategy ( step a , fig1 ). as described above , these different prototypes result in different processing times . beginning with the first prototype the machining times are increased due to longer tool path design . particularly the last prototype required a tool change for roughing and finishing requiring more operator &# 39 ; s time to perform it . the tool paths were improved to reduce the processing time required for completing the machining . the cost is strictly related to the processing times needed to complete the machining operations . since the work material used was the same in all experiments , the only variable affecting the cost was the number of tools used , tool life , the machine usage time , and the specialized operator &# 39 ; s time needed . as shown in fig1 , the quality of the prototype improved with each experiment , starting from the first attempt ( a good shape was obtained but burrs and chip melted together ), until the fourth prototype which is completely burrs - free and with the shape desired for the micro - needles . also the reliability of the fabrication process has been improved in the prototypes . the second prototype demonstrated some broken needles , but the needles were broken randomly during the micro - milling process making the fabrication process less reliable . the fourth micro - needle array was fabricated several times using the same micro - milling parameters and tool path strategy and the same results in dimensions , finishing and the shape were obtained consistently indicating that a reasonable reliability level was reached . micro - needle arrays based patch prototypes were developed using micro - milling technology . beginning with a simple idea , the prototype was improved in shape , fabrication strategy , dimensions and machining conditions in order to obtain the most satisfactory micro - needles patch prototype . the problems experienced during the experiments were mainly related to the tiny dimensions of the needles and the micro - machining of polymers , specially the heat generation problem . these problems were solved by modifying machining strategies and micro - milling process parameters . using this strategy , hollow micro - needles comprising a reservoir for drug storage can be developed . the skilled person will appreciate that the needles shown in the figures are useful for “ transdermal drug delivery ” of bioactive agents . where the bioactive agent is coated onto the micro - needle array , it may be advantageous to prepare the surface of the array before depositing a coating thereon . useful methods of surface preparation can include , but are not limited to cleaning ; physical modifications such as etching , drilling , cutting , or abrasion or roughing ; and chemical modifications such as solvent treatment , the application of primer coatings , the application of surfactants , plasma treatment , ion bombardment , covalent bonding and electrochemical methods such as electropolishing , striking , electroplating and electrochemical deposition . such surface preparation may serve to activate the surface and promote the deposition or adhesion of the coating on the surface . surface preparation can also selectively alter the release rate of the bioactive . any additional coating layers can similarly be processed to promote the deposition or adhesion of another layer , to further control the release of the bioactive agent , or to otherwise improve the biocompatibility of the surface of the layers . for example , plasma treating an additional coating layer before depositing a bioactive agent thereon may improve the adhesion of the bioactive agent , increase the amount of bioactive agent that can be deposited , and allow the bioactive agent to be deposited in a more uniform manner . a primer layer , or adhesion promotion layer , may also be applied to the micro - needle array . this layer may comprise , for example , silane , acrylate polymer / copolymer , acrylate carboxyl and / or hydroxyl copolymer , polyvinylpyrrolidone / vinylacetate copolymer ( pvp / va ), olefin acrylic acid copolymer , ethylene acrylic acid copolymer , epoxy polymer , polyethylene glycol , polyethylene oxide , polyvinylpyridine copolymers , polyamide polymers / copolymers polyimide polymers / copolymers , ethylene vinylacetate copolymer and / or polyether sulfones . the bioactive agent may be applied , for example , by spraying , dipping , pouring , pumping , brushing , wiping , vacuum deposition , vapor deposition , plasma deposition , electrostatic deposition , ultrasonic deposition , epitaxial growth , electrochemical deposition or any other method known to the skilled artisan . the bioactive agent may be applied as a separate layer or may be included in a layer also including a carrier material . a variety of bioactive agents may be applied to the micro - needle array in accordance with the intended use . for example , antithrombogenic agents may be applied to the array . an antithrombogenic agent is any agent that inhibits or prevents thrombus formation within a body vessel . types of antithrombotic agents include anticoagulants , antiplatelets , and fibrinolytics . examples of antithrombotics include but are not limited to anticoagulants such as thrombin , factor xa , factor viia and tissue factor inhibitors ; antiplatelets such as glycoprotein iib / iiia , thromboxane a2 , adp - induced glycoprotein iib / iiia , and phosphodiesterase inhibitors ; and fibrinolytics such as plasminogen activators , thrombin activatable fibrinolysis inhibitor ( tafi ) inhibitors , and other enzymes which cleave fibrin . further examples of antithrombotic agents include anticoagulants such as heparin , low molecular weight heparin , covalent heparin , synthetic heparin salts , coumadin , bivalirudin ( hirulog ), hirudin , argatroban , ximelagatran , dabigatran , dabigatran etexilate , d - phenalanyl - l - poly - l - arginyl , chloromethy ketone , dalteparin , enoxaparin , nadroparin , danaparoid , vapiprost , dextran , dipyridamole , omega - 3 fatty acids , vitronectin receptor antagonists , dx - 9065a , ci - 1083 , jtv - 803 , razaxaban , bay 59 - 7939 , and ly - 51 , 7717 ; antiplatelets such as eftibatide , tirofiban , orbofiban , lotrafiban , abciximab , aspirin , ticlopidine , clopidogrel , cilostazol , dipyradimole ; fibrinolytics such as alfimeprase , alteplase , anistreplase , reteplase , lanoteplase , monteplase , tenecteplase , urokinase , streptokinase , or phospholipid encapsulated microbubbles ; and other bioactive agents such as endothelial progenitor cells or endothelial cells . other bioactive agents that may be applied include antiproliferative / antimitotic agents including natural products such as vinca alkaloids ( vinblastine , vincristine , and vinorelbine ), paclitaxel , rapamycin analogs , epidipodophyllotoxins ( etoposide , teniposide ), antibiotics ( dactinomycin ( actinomycin d ) daunorubicin , doxorubicin and idarubicin ), anthracyclines , mitoxantrone , bleomycins , plicamycin ( mithramycin ) and mitomycin , enzymes ( for example , l - asparaginase which systemically metabolizes l - asparagine and deprives cells which do not have the capacity to synthesize their own asparagine ); antiplatelet agents such as ( gp ) iib / iiia inhibitors and vitronectin receptor antagonists ; antiproliferative / antimitotic alkylating agents such as nitrogen mustards ( mechlorethamine , cyclophosphamide and analogs , melphalan , chlorambucil ), ethylenimines and methylmelamines ( hexamethylmelamine and thiotepa ), alkyl sulfonates - busulfan , nirtosoureas ( carmustine ( bcnu ) and analogs , streptozocin ), trazenes - dacarbazinine ( dtic ); antiproliferative / antimitotic antimetabolites such as folic acid analogs ( methotrexate ), pyrimidine analogs ( fluorouracil , floxuridine , and cytarabine ), purine analogs and related inhibitors ( mercaptopurine , thioguanine , pentostatin and 2 - chlorodeoxyadenosine { cladribine }); platinum coordination complexes ( cisplatin , carboplatin ), procarbazine , hydroxyurea , mitotane , aminoglutethimide ; hormones ( i . e . estrogen ); anticoagulants ( heparin , synthetic heparin salts and other inhibitors of thrombin ); fibrinolytic agents ( such as tissue plasminogen activator , streptokinase and urokinase ), aspirin , dipyridamole , ticlopidine , clopidogrel , abciximab ; antimigratory ; antisecretory ( breveldin ); anti - inflammatory : such as adrenocortical steroids ( cortisol , cortisone , fludrocortisone , prednisone , prednisolone , 6 . alpha .- methylprednisolone , triamcinolone , betamethasone , and dexamethasone ), non - steroidal agents ( salicylic acid derivatives i . e . aspirin ; para - aminophenol derivatives i . e . acetaminophen ; indole and indene acetic acids ( indomethacin , sulindac , and etodalac ), heteroaryl acetic acids ( tolmetin , diclofenac , and ketorolac ), arylpropionic acids ( ibuprofen and derivatives ), anthranilic acids ( mefenamic acid , and meclofenamic acid ), enolic acids ( piroxicam , tenoxicam , phenylbutazone , and oxyphenthatrazone ), nabumetone , gold compounds ( auranofin , aurothioglucose , gold sodium thiomalate ); immunosuppressives ( cyclosporine , tacrolimus ( fk - 506 ), sirolimus ( rapamycin ), tacrolimus , everolimus , azathioprine , mycophenolate mofetil ); angiogenic agents : vascular endothelial growth factor ( vegf ), fibroblast growth factor ( fgf ); angiotensin receptor blockers ; nitric oxide and nitric oxide donors ; anti - sense oligionucleotides and combinations thereof ; cell cycle inhibitors , mtor inhibitors , and growth factor receptor signal transduction kinase inhibitors ; retenoids ; cyclin / cdk inhibitors ; endothelial progenitor cells ( epc ); angiopeptin ; pimecrolimus ; angiopeptin ; hmg co - enzyme reductase inhibitors ( statins ); metalloproteinase inhibitors ( batimastat ); protease inhibitors ; antibodies , such as epc cell marker targets , cd34 , cd133 , and ac 133 / cd133 ; liposomal biphosphate compounds ( bps ), chlodronate , alendronate , oxygen free radical scavengers such as tempamine and pea / no preserver compounds , and an inhibitor of matrix metalloproteinases , mmpi , such as batimastat . in a preferred embodiment , the bioactive agent applied to the micro - needle array is selected from the group consisting of paclitaxel , rapamycin , a rapamycin derivative , an antisense oligonucleotide , an sirna , and a mtor inhibitor . s henry , d v mcallister , m g allen and m r prausnitz , microfabricated microneedles : a novel approach to transdermal drug delivery , journal of pharmaceutical sciences , 1998 , 87 : 922 - 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