11111
`
`11111
`
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`US 20090 182306A1
`
`ill Oil lii
`
`Fill
`
`1101
`
`VOl
`
`liii
`
`11111
`
`1111
`
`Hill
`
`111111
`
`11111111
`
`1111
`
`19 United States
`12 Patent Application Publication
`Lee et al
`
`10 Pub No Us 2009/0182306 Al
`43 Pub Date
`Jul 16 2009
`
`54 MICRONEEDLE DEVICES AND METHODS
`OF DRUG DELWERY OR FLUID
`WITHDRAWAL
`
`60 Provisional application No 61/023066 filed on Jan
`application No 60/832479
`23 2008 provisional
`filed on Jul 21 2006
`
`75 Inventors
`
`Jeong Woo Lee Atlanta GA US
`Prausnitz Atlanta GA
`Mark
`US
`
`Correspnndence Address
`BRENNAN LLP
`SUTHERLAND ASBILL
`999 PEACHTREE STREET N.E
`ATLANTA GA 30309 US
`
`73 Assignee
`
`Georgia Tech Research
`Corporation Atlanta GA US
`
`21 Appl.Nn
`
`12/357195
`
`22 Filed
`
`Jan 21 2009
`
`Related U.S Application Data
`63 Continuation-in-part of application No PCT/U507/
`74123 filed on Jul 23 2007
`
`Publication Classification
`
`51 Int.Cl
`A6IMS/OO
`B29C 39/42
`52 U.S Cl
`57
`
`2006.01
`2006.01
`
`604/506 604/272 264/101
`
`ABSTRACT
`
`and.use
`devices and methods of manufacture
`Microneedle
`thereof are provided The devices may be used in controlled
`biological barrier such as
`delivery of drug across or into
`from biological barriet
`In one
`skin or fluid withdrawal
`base substrate which comprises
`case the device includes
`swellable matrix material and one or
`drug dispersed in
`from the base
`more microneedles
`extending
`wherein the one or more microneedles
`water-
`comprise
`soluble or water-swellable material wherein the one or more
`microneedles will dissolve or swell
`following insertion into
`transport pathway for the
`the biological barrier providing
`drug to pass from the base substrate into the biological barrier
`
`substrate
`
`32
`
`36
`
`38
`
`34
`
`38
`
`EXHIBIT
`
`Jfi3-J
`
`

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`Patent Application Publication
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`Jul 16 2009 Sheet
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`FIG.1
`
`FIG
`
`20
`
`FIG
`
`32
`
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`
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`
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`38
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`38
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`

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`FIG 4A
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`40
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`FIG 4B
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`FIG 4C
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`16/18
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`40
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`16
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`

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`FIG 5A
`
`Kr-10
`
`40
`
`/////////////2S/
`
`FIG 5B1271/VVC
`
`FIG 5C
`F-i L.LL
`
`77//
`
`FIG._SD
`
`16118
`
`/7/7
`
`1%
`
`FIG._5E
`
`

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`Patent Application Publication
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`48
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`CD
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`

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`Patent Application Publication
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`Jul 16 2009 Sheet
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`of
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`US 2009/0182306 Al
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`CD
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`Patent Application Publication
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`Jul 16 2009 Sheet
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`of
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`US 2009/0182306 Al
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`40x1 0-6
`
`30x10
`
`Oxi
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`100
`
`80
`
`60
`
`40
`
`20
`
`-D
`-o
`
`FIG 8A
`
`Time hour
`IOwt% base
`
`30wt%base
`
`FIG 8B
`
`lOwt% loading in base
`is mg
`total amount
`
`Day
`
`

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`Patent Application Publication
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`Jul 16 2009 Sheet
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`of
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`US 2009/0182306 Al
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`1.0
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`0.8
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`0.6
`
`4-
`
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`
`72
`
`96
`
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`
`144
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`
`lime ii
`
`FIG
`
`

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`Patent Application Publication
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`Jul 16 2009 Sheet
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`of
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`102
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`104
`
`FIG 10
`
`108
`
`100
`
`106
`
`110
`
`106
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`vvvv.v
`
`108
`
`FIG 11
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`

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`50
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`40
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`Cl
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`I-I
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`Ct
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`30
`
`20
`
`Ct
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`10
`
`CD
`
`10
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`15
`
`20
`
`25
`
`Time Hour
`FIG 12
`
`

`

`US 2009/0182306 Al
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`Jul 16 2009
`
`MICRONEEILE DEVICES AND METHODS
`OF DRUG DELIVERY OR FLUID
`WITHDRAWAL
`
`TO RELATED
`CROSS-REFERENCE
`APPLICATIONS
`
`is
`
`This application
`continuation-in-part of Inter
`national Application No PCT/USO7/074123
`filed Jul 23
`to U.S Provisional Application
`2007 which claims benefit
`No 60/832479 filed Jul 21 2006 This application
`also
`to U.S Provisional Application No 61/023
`claims benefit
`066 filed Jan 23 2008 These applications are incorporated
`herein by reference
`
`STATEMENT REGARDING FEDERALLY
`SPONSORED RESEARCH OR DEVELOPMENT
`
`This invention was made with U.S government sup
`port under Contract No 8R01EB00260
`awarded by the
`Institutes of Health The U.S government
`has cer
`National
`thin rights in the invention
`
`BACKGROUND OF THE INVENTION
`
`This invention is generally in the field of devices and
`methods for the controlled transport of molecules across skin
`or other tissue barriers such as for drug delivery or sampling
`of biological fluids
`Numerous drugs and therapeutic agents have been
`developed in the battle against disease and illness
`frequent
`and efficient
`use of these drugs
`limitation to the effective
`is how to transport
`however
`the drugs
`is their delivery that
`across biological barriers in the body e.g the skin the oral
`the blood-brain barrier which nonnally do not
`mucosa
`useful or opti
`transport drugs at rates that are therapeutically
`mal
`
`been
`have
`Transdermal
`drug delivery systems
`shown to be an effective alternative drug pathway for local or
`systemic drug delivery Although these systems provide
`numerous advantages to oral drug delivery mutes develop
`ment oftransdermal delivery devices has been limited by the
`dilThsion of drugs across the stratum comeum of the skin
`To address these problems microneedles have been
`variety of different fabrication pro
`developed employing
`and
`and may be classified
`cesses
`strategies
`application
`according to the drug delivery strategy One concept uses
`microneedles
`to break the stratum corneum to create path
`ways through which
`drug may enter and thereafter applying
`drug reservoir Another concept uses
`patch to the skin as
`hollow microneedles
`as micro ducts for the flow of drug in
`liquid formulations
`approach
`another
`uses coated
`microneedles
`to deliver small amounts of drug loaded onto
`the microneedle
`surface While each of these approaches
`provides improved drug delivery across the stratum corneum
`remains
`need for improved
`there still
`transdermal
`drug
`delivery devices The first
`two approaches may be limiting in
`their requirement of an additional
`feature or step for drug
`delivery while the third approach may be limiting in the
`amount of drug that may be loaded onto the surface of the
`need to
`coated microneedles Accordingly there remains
`provide improved microneedle
`devices and methods particu
`larly for simple and effective transdermal delivery of wide
`ranges and/or relatively large volumes of drug
`In addition it would be desirable to have micron
`eedle array devices providing bolus and/or sustained delivery
`
`Still
`
`of macromolecular
`drug with
`relatively large range of
`dose It would also be desirable to provide
`
`device with the drug in
`
`stable encapsulated
`
`therapeutic
`microneedle
`
`form
`
`Microneedles
`
`also have been proposed for mini
`fluids from patients
`mally-invasive withdrawal
`of biological
`for diagnostic purposes Some of these devices include mul
`tiple parts which may be fragile costly to produce and/or
`to use properly It would be desirable to provide
`improved devices which can be made relatively inexpensively
`and which are relatively simple to use and effective
`
`difficult
`
`SUMMARY OF THE INVENTION
`
`Microneedle
`devices and methods of use thereof are
`the micron
`provided along with methods of manufacturing
`eedle devices The devices and methods address one or more
`of the drawbacks associated with prior microneedle devices
`00101
`In one aspect
`for sustained
`device is provided
`delivery of drug across or into
`biological barrier In one
`base substrate which com
`embodiment the device includes
`drug dispersed in swellable matrix material and one
`prises
`from the base substrate
`or more microneedles
`extending
`wherein the one or more microneedles
`comprise
`water-
`soluble or water-swellable material wherein the one or more
`microneedles will dissolve or swell
`following insertion into
`
`transport pathway for the
`the biological barrier providing
`drug to pass from the base substrate into the biological barrier
`and wherein the base substrate is adapted to swell following
`insertion of the one or more microneedles
`into the biological
`barrier The one or more microneedles may further
`include
`drug dispersed in the water-soluble or water-swellable mate
`rial
`
`or water
`
`In one embodiment
`the water-soluble
`swellable material of the microneedles
`polysac
`comprises
`derivative thereof The water-soluble or water
`charide or
`cellulose derivative The
`swellable material may comprise
`or water-swellable material may become
`water-soluble
`hydrogel upon insertion into the biological barrier In certain
`embodiments the water-soluble or water-swellable material
`may include carboxymethyl cellulose hydroxypropylmethyl
`cellulose amylopectin starch derivatives hyaluronic acid or
`combination
`thereof
`The matrix material of the base substrate may be
`polymeric such as
`or biodegradable poly
`bioeompatible
`mer The polymeric matrix material may comprise
`water-
`soluble or water-swellable material which may be the same
`from the water-soluble or swellable material of
`as or different
`the one or more microneedles
`The one or more microneedles may each be solid or
`hollow In one embodiment
`each have
`the microneedles
`length between about 10 pm and about 1500
`In one
`embodiment the mieroneedles each have maximum width
`between about 10 pm and about 500 p.m The mieroneedles
`may have
`pyramidal shape
`In one
`embodiment
`the mieroneedle
`device
`includes
`backing layer attached to the base substrate distal
`to the one or more microneedles In one case the backing
`layer has an annular region which surrounds the one or more
`mieroneedles This annular region may include an adhesive
`substance for contacting
`patients skin or other tissue
`for
`In particular embodiment mieroneedle
`array
`base substrate com
`drug delivery is provided that
`includes
`prising first drug dispersed in swellable polymeric matrix
`plurality of mieroneedles extending from the base
`material
`
`

`

`US 2009/0 182306 Al
`
`Jul 16 2009
`
`substrate wherein the plurality of microneedles comprises
`second
`water-soluble or water-swellable material in which
`drug may be dispersed wherein tbe plurality of microneedles
`biological bather
`will dissolve following insertion into
`transport pathway for the first and second drugs to
`providing
`pass into tbe biological barrier and wberein the base substrate
`following insertion of the one or more
`is adapted to swell
`microneedles into the biological barrier The first drug and the
`second drug may be the same drug or different drugs In
`certain variations of this embodiment
`the water-soluble or
`water-swellable material of the plurality ofmicroneedles may
`comprise
`carboxymethyl
`cellulose hydroxypropylmethyl
`cellulose amylopectin starch derivatives hyaluronic acid or
`In certain variations of this embodi
`combination
`thereof
`ment the polymeric matrix material of the base substrate may
`comprise
`carboxymethyl
`cellulose hydroxypropylmethyl
`combination
`cellulose amylopectin starch derivatives or
`thereof In one embodiment of these microneedle devices the
`peptide or protein In one embodiment the drug is
`drug is
`vaccine In one embodiment
`small molecule
`the drug is
`with molecular mass less than 2000 Da or in some cases
`less than 1000 Da or 500 Da In an embodiment an adhesive
`on at
`substance
`portion of the
`coating is provided
`the micron
`
`surface of the base substrate betweenlamong
`eedles
`
`least
`
`eedles
`
`barrier
`
`In another aspect method is provided for deliver
`drug across or into the skin or another biological bather
`ing
`the method includes the steps of
`In one embodiment
`inserting the one or more microneedles of the device into the
`biological barrier to create one or more holes in the biological
`ii dissolving
`or swelling the one or more micron
`in the biological barrier and Hi transporting the drug
`from the swellable base substrate through the holes and into
`the biological bather
`In one particular embodiment
`the
`method further
`includes dissolving or swelling the one or
`more microneedles to release the drug from the one or more
`certain embodi
`microneedles into the biological barrier In
`ment the drug from the microneedles is substantially released
`few seconds
`to about one hour
`period from about
`within
`into the bio
`after insertion of the one or more microneedles
`
`logical barrier In another particular embodiment the drug
`from the base substrate is substantially
`released within
`period from about one hour to about three days after insertion
`of the one or more microneedles
`
`into the biological barrier
`
`In one embodiment the one or more microneedles
`of the device further
`include
`dispersed in the water-
`drug
`coated onto the one
`soluble or water-swellable material
`or more microneedles or iii
`dispersed in the water-soluble
`or water-swellable material and coated onto the one or more
`microneedles
`In the latter case the drug dispersed in the
`water-soluble or water-swellable material may be the same as
`from the drug coated onto the microneedle
`or different
`
`the method includes
`In still another embodiment
`microneedle device that includes
`the steps of
`providing
`base substrate which comprises
`drug dispersed in
`swellable polymeric matrix material and ii
`plurality of
`microneedles extending from the base substrate
`inserting
`into the biological bather to create
`the microneedles
`rality of holes in the biological barrier
`permitting aqueous
`fluids from the biological
`bather
`to flow through the holes to
`hydrate and swell
`the base substrate thereby creating fluid
`pathways within the base substrate for diffusion of the drug
`within the base substrate and
`allowing the drug to diffuse
`from the base substrate through the holes and into the bio
`
`plu
`
`eedle device that
`
`includes
`
`the one or more
`certain embodiment
`In
`logical barrier
`microneedles may remain partially intact during the hydrat
`ing and swelling of the base substrate
`method is provided
`In yet another aspect
`fluid from or through
`biological barrier In one
`extracting
`the method includes
`embodiment
`providing micron
`base substrate which com
`polymeric material and ii
`one
`water-swellable
`prises
`more microneedles extending from the base substrate which
`water-soluble or water
`one or more microneedles comprise
`inserting the one or more micron
`swellable material
`eedles into the biological barrier to create
`corresponding
`withdraw
`one or more holes in the biological barrier and
`ing fluid from the biological barrier through the one or more
`holes and into the base substrate For example the biological
`barrier may comprise the skin or sclera of
`human and the
`fluid or vitreous humor and
`fluid may comprise interstitial
`solutes therein In certain embodiments the method further
`comprises analyzing the composition of the fluid or
`thereof
`
`for
`
`part
`
`In still
`
`for
`
`in
`
`rial
`
`comprises
`
`method is provided
`another aspect
`In one embodiment
`microneedle
`device
`making
`the
`method includes
`providing an inverse mold for at least one
`microneedle the mold having base surface in which
`are
`each
`located one or more concavities
`in the shape of
`microneedle
`providing microneedle structural material
`fluidized form which
`water-soluble
`or
`or vacuum or
`-swellable material
`using centrifugation
`other pressure source to force the fluidized structural mate
`into the one or more concavities
`hardening the struc
`tural material into the form of one or more microneedles
`base substrate connected to the one or more
`forming
`microneedles wherein the base substrate comprises
`drug
`polymeric matrix material which may be
`dispersed in
`swellable polymeric matrix material and
`releasing the one
`or more microneedles from the inverse mold In one embodi
`ment the base substrate and the one or more microneedles are
`formed together
`in one step by hardening of the fluidized
`In one embodiment the fluidized struc
`structural material
`solvent and the hardening
`further comprises
`certain
`step further comprises evaporating the solvent
`the inverse mold comprises
`embodiment
`plurality of the
`the one or more micron
`In one embodiment
`concavities
`eedles do not comprise
`
`tural material
`
`In
`
`drug
`
`BRIEF DESCRIPTION
`
`OF THE DRAWINGS
`
`FIG is
`side view of micron
`cross-sectional
`eedle device according to one embodiment
`FIG is
`side view of micron
`cross-sectional
`eedle device according to another embodiment
`FIG is
`side view of micron
`cross-sectional
`eedle patch device according to one embodiment
`FIG illustrates method for using an embodiment
`of the microneedle
`device according to one embodiment
`FIG illustrates method for using an embodiment
`of the microneedle
`device according to another embodiment
`FIG illustrates
`process for the fabrication of
`microneedle device according to one embodiment
`FIG illustrates
`process for the fabrication of
`microneedle device according to another embodiment
`FIGS 8A-B are graphs of in vitro release profiles
`with Franz cell
`FIG is
`flux as cumulative
`graph of transdermal
`amount of sulforhodamine
`released overtime with micron-
`
`

`

`Us 2009/0182306 Al
`
`J111 16 2009
`
`inserted into human cadaver skin the patch
`carboxymethylcellulose matrix or amylopec
`
`eedle patches
`having either
`tin matrix
`FIGS 10-11 are cross-sectional
`micron
`for containing
`eedle device that includes
`separate reservoir
`FIG 10 and releasing
`is intended to wet and
`fluid that
`the base substrate FIG 11 according to one embodi
`swell
`ment
`
`views
`
`graph showing concentration of human
`FIG 12 is
`growth hormone present in serum overtime with microneedle
`patches inserted into the skin of hairless rats shown in com
`parison to the subcutaneous injection of human growth hor
`mnne intn hairless rats the patch having either carboxymeth
`ylcellulose micmneëdles or microneedles
`comprising both
`and
`
`carboxymethylcellulose
`
`disaccharide
`
`DETAILED DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`Microneedle
`
`devices for the delivery of drugs across
`are provided which advan
`or into
`biological tissue/barrier
`tageously may overcome limitations and deficiencies associ
`ated with prior art dcvices
`The devices may provide sus
`from
`volume
`tained
`release
`that
`drug
`storage
`limited to the volume of the micron
`advantageously is not
`simple construction which is easy to use In
`eedles alone in
`the microneedle
`one embodiment
`device is in the form of
`transdermal patch In one aspect
`the single-use microneedles
`beneficially leave behind no sharp and rigid needles for dis
`posal or concern about unauthorized re-use Methods for thc
`manufacture and use of microneedle
`devices are also pro
`vided
`
`As used herein the terms comprise comprising
`include and including are intended to be open non-
`limiting terms unless the contrary is expressly indicated
`
`Microneedle Devices
`
`In one aspect microneedle
`device is provided for
`sustained release of drug across or into
`biological barrier
`The biological barrier may be
`tissue of
`biological
`patient
`human or other
`in need of the drug The patient may be
`mammal for example The microneedle devide may facilitate
`transport of one or more drugs through
`barrier layer such as
`the stratum corneum and into underlying dermal tissues The
`term biological barrier may include essentially any cells
`tissues or organs including the skin or parts thereof mucosal
`vascular
`tissues
`tissues lymphatic vessels ocular
`tissues
`e.g cornea conjunctiva
`sclera and cell membranes The
`tissue may be in humans or other types of animals
`biological
`particularly mammals as well as in plants insects or other
`fungi and embryos
`organisms including bacteria
`yeast
`Human skin and ocular
`tissues may be of particular use with
`the present devices and methods
`In one embodiment the device includes
`base substrate which comprises
`drug dispersed in matrix
`material and one or more microneedles extending from the
`swellable base substrate wherein the one or more micron
`eedles include or consist essentially of
`water-soluble or
`water-swellable material and wherein
`one or more
`microneedles will dissolve or swell
`following insertion into
`
`swellable
`
`the
`
`transport pathway for the
`the biological barrier providing
`drug to pass from the base substrate into the biological barrier
`polymer The drug transport
`The matrix material may be
`may be by diffusion alone or enhanced by an active mecha
`
`nism known in the art such as electric fields or ultrasound
`FIG shows one embodiment of microneedle
`device 10
`which
`substrate 12 and
`includes
`swellable
`base
`three
`14 extending from the base substrate The base
`
`microneedles
`
`substrate 12 includes drug 16 dispersed in polymeric matrix
`material 18 The microneedles
`14 include
`water-soluble or
`-swellable material 15 In various embodiments the one or
`more microneedles maybe solid or hollow may have
`length
`between about 10 pm and about 1500 pm and may have
`maximum width between about 10 pm and about 500 pm In
`preferred embodiment the one or more microneedles taper
`sharp tip which may have
`pyramidal shape In pre
`to
`ferred embodiment
`the microneedle
`an aspect
`has
`between about 1.5 and 2.5 more particularly between about
`1.8 and 2.2 or about 2.0 This range of aspect
`ratio may be
`particularly useful for CMC certain polysaccharides
`or other
`mechanically weak biomaterials
`
`ratio
`
`the one or more micron
`In another embodiment
`drug which may be dispersed in all
`eedles further include
`of or portion of the water-soluble or water-swellable mate
`rial The drug provided in the base substrate may be the same
`in the one or more
`from the drug provided
`as or different
`microneedles FIG shows one embodiment of micron
`eedle device 20 which includes
`swellable base substrate 12
`and three microneedles 24 extending from the base substrate
`The base substrate 12 includes drug 16 dispersed in matrix
`material 18 The matrix material may be polymeric The
`micronecdles 24 include drug molecules 26 dispersed in the
`water-soluble or -swellable material 15 In one embodiment
`dose ofa drug for
`the one ormore microneedles may provide
`immediate release e.g by dissolving rapidly upon insertion
`into the biological tissue while the base substrate provides
`sustaining or maintenance dose of the same drug e.g due to
`time needed
`for the drug to diffuse from base
`the greater
`substrate through the holcs in the biological tissuc Altcma
`different drug for the same
`tively the second drug could be
`or different indication as that of the first drug
`In one embodiment microneedle
`array device is
`provided for drug delivery The array device may be part of
`base sub
`transdennal patch The array device may include
`first drug dispersed in swellable matrix
`strate comprising
`plurality of microneedles extending from the base
`material
`substrate wherein the plurality of microneedles
`comprise
`water-soluble
`or water-swellable or otherwise dissolvable
`material in which
`second drug is dispersed wherein the
`plurality of microneedles will dissolve and/or swell following
`
`transport path
`biological bather providing
`insertion into
`way for the first and second drugs to pass into the biological
`barrier The matrix material may be polymeric The first drug
`and the second drug may be the same drug or they may be
`different from one another
`
`In various embodiments the device may include
`features for inserting the one or more microneedles
`into
`biological tissue This feature may be include mechanical or
`electrical parts or alternatively may include
`rigid or pliable
`structure for manually pressing the microneedle
`into and the
`skin or other
`base substrate structure against
`tissues For
`example the device may include
`backing layer attached to
`to the one or more microneedles In
`the base substrate distal
`one case the backing layermay have an annular region which
`surmunds the one or more microneedles wherein the annular
`an adhesive substance
`region includes
`for contacting
`patients skin Alternatively or in addition an adhesive sub
`thin film on the surface of the
`stance is provided e.g. in
`
`

`

`US 2009/0 182306 Al
`
`Jul 16 2009
`
`base substrate e.g between some or all of the microneedles
`preferred embodiment the backing layer is substantially
`In
`to the drug in the base substrate to water vapor
`impervious
`and/or to physiological fluids from tbe biological barrier The
`backing layer may stretch or deform to accommodate swell
`ing/expansion of base substrate during use For example it
`film FIG
`may include
`one
`an elastomeric
`illustrates
`embodiment of microneedle patch device 30 which includes
`swellable base substrate 32 from which an array of micron
`eedles 34 extend The base substrate includes
`drug for
`release The device 30 further includes backing layer 36 with
`adhesive 38 for securing the patch to
`skin surface during
`drug delivery Suitable adhesive substances such as pressure
`are well known in the art of adhesive
`sensitive adhesives
`bandages and transdermal drug delivery patches
`Microneedles
`and Base Substrate
`
`The one or more microneedles cxtend from thc base
`of biocom
`substrate The microneedle
`
`is formed/constructed
`
`patible materials that will degrade and/or dissolve or swell
`the biological barrier e.g in physiological
`in
`fluids present
`the site of insertion of the micron
`the biological barrier at
`eedle The materials of construction
`and the dimensions of
`the microneedle are selected to provide among other things
`the mechanical strength to remain substantially
`intact while
`being inserted into the skin or into other biological barrier
`
`in
`
`In one embodiment the material of construction of
`water soluble material As used
`the microneedle
`includes
`herein water soluble material is one that dissolves hydro
`lyzes or otherwise breaks down or disintegrates in water or in
`fluid such as blood
`contact with an aqueous physiological
`fluid mucus etc over
`period of time
`tears interstitial
`biological barrier The period of
`following insertion into
`time may be rapid e.g less than 10 seconds less than
`minute less than minutes less than 10 minutes less than 30
`minutes less than
`hour less than
`hours less than
`hours
`certain embodi
`less than 12 hours or less than 24 hours In
`ment the water soluble material comprises
`polymer In onc
`polysaccharide or derivative thereof
`case it
`
`is
`
`comprises
`
`In another embodiment the material ofconstruction
`of the microneedle
`includes
`water-swellable material
`.ks
`refers to materials which
`used herein water-swellable
`imbibe aqueous fluids that are in contact
`therewith causing
`In one embodiment
`the materials to expand
`the material
`hydrogel Hydrogels may be uncrosslioked or
`crosslinked
`Uncrosslioked
`are able to absorb
`hydrogels
`water but may not dissolve due to the presence of hydropho
`bic and hydrophilic regions Covalently
`crosslinked hydro
`gels may include networks of hydrophilic polymers includ
`ing water-soluble polymers The material may be initially dry
`and then become
`hydrogel upon insertion into the biological
`certain embodiment the material
`barrier In
`cross-linked
`is
`polymer In vanous embodiments the water-swellable mate
`polyacrylic acid known in the art
`rial may comprise
`In onc embodimcnt
`the microneedlc
`material and
`combination
`of
`water-swellable
`water-
`soluble material The combination may be for example
`mixture of the materials or
`layered structure comprising at
`least one layer of the water-soluble material being provided
`on top of at least one layer of the water-swellable material
`The base substrate may be made of the same water
`swellable materials described herein for forming the micron
`eedles or it may comprise one of the water-soluble materials
`listed that would swell without extensive dissolution
`under
`
`includcs
`
`conditions used Alternatively the base sub
`the particular
`strate may be made of
`different swellable material
`The water-soluble and/or water-swellable materials
`may comprise
`polysaccharide or derivative thereof In one
`embodiment the material
`cellulose deriva
`is biocompatible
`tive In certain embodiments the water soluble material may
`be selected from carboxymcthyl
`ccllulosc hydroxypropylm
`ethyl cellulose amylopdctin starch derivatives
`combination
`acid or
`thereof
`
`hyaluronic
`
`polysaccharide
`
`The water-soluble and/or water-swellable materials
`such as alginate amy
`also may comprise
`lose amylopectin carrageenan
`carboxymethyl
`cellulose
`dextrao gcllan guar gum polysaccharide
`conjugate vac
`cines hydroxyethyl cellulose hydroxypropyl
`cellulose
`hyaluronic acid starch derivatives
`xantan xyloglucan chi
`tosan-based hydrogel peptidoglycan and progeoglycans
`The water-soluble and/or water-swellable materials
`also may comprise
`galac
`glucosamine
`sucrose
`lactose
`fructose
`galactose
`tosamine muramic acid glucruronate gluconate focose and
`trehalose
`
`carbohydrate
`
`such as glucose maltose
`
`The water-soluble and/or water-swellable materials
`also may comprise
`synthetic polymer
`such as polyvinyl
`alcohol polyvinlypyrrolidine polyethyleoeglycol and pqly
`In other cases the water-soluble or
`oxyethylene derivatives
`-swellable material may comprise
`polyvinyl amine or polyL-lysine
`The water-soluble and/or water-swellable materials
`may include or consist of water-soluble or biodegradable
`polymer Examples of suitable biodegradable polymers may
`include polylactides polyglycolides polylactide-co-gly
`
`polypeptide such
`
`as
`
`polycarpolactones
`
`polyvaleric
`polyorethanes
`
`acids
`
`colides polyanhydrides polyorthoesters polyetheresters
`polyesteramides polybutyric
`acids polyhydroxyalkanoates
`degradable
`copolymers thereof and blends thereof Alter
`and/or water swellable material
`natively the water-soluble
`may be
`non-degradable polymer Examples of non-degrad
`able polymers include polyacrylates polymers of ethylene-
`and other acyl substituted cellulose acetates
`vinyl acetates
`polystyrenes polyvinyl chlo
`non-degradable polyurethanes
`ride polyvinyl fluoride polyvinyl imidazole chlorosulpho
`nate polyolefios polyethylene oxide blends and copolymers
`In certain embodiments hydrogel materials such as
`thereof
`cellulose CMC hydroxypropylmethyl cel
`carboxymethyl
`lulose HPMC amylopectin starch derivatives
`hyaluronic
`thereof may be used as the water-
`acid or
`soluble and/or water-swellable material
`
`combination
`
`and
`
`In
`
`preferred embodiment the microneedles
`the base substrate comprise carboxymethyl
`cellulose
`The base substrate includes one or more drugs The
`drug may be located throughout
`the base substrate material or
`thereof The drug may be dis
`provided in sub-component
`persed in the polymer As used herein the phrase dispersed
`in the polymer refers to various forms of the drug including
`where the drug is dissolved where the drug is
`separate solid
`or liquid phase or where the drug is encapsulated into
`is within the polymer matrix For
`further material
`that
`or nanoparticles of drug may be
`instance microparticlcs
`or nanoencapsulated within another
`microencapsulated
`release controlling substance e.g hiocompatible polymer
`such as
`or amphiphilic polymer and these
`hydrophobic
`microparticles or nanoparticles may be dispersed within the
`polymer matrix material of the base substrate
`
`

`

`Us 2009/0182306 Al
`
`Jul 16 2009
`
`100521
`
`Advantageously
`the base substrate simultaneously
`platform for the microneedles and storage reser
`serves as
`voir for the drug Beneficially the drug may be stored in
`substantially dry solid form encapsulated by the matrix
`material The drug and polymeric matrix may be
`solid
`solution In one embodiment the drug may comprise between
`about 0.1% and about 70% such as between 1% and 50%
`and 10% by weight
`and 25% or between
`e.g between
`of the base substrate and microneedles Higher or lower load
`ings may be used depending upon the particular drug and
`particular polymeric matrix material used
`In one embodiment
`the swellable
`base substrate
`comprises material that swells when exposed to fluid and
`will not substantially dissolve in that fluid under the intended
`operating conditions In certain embodiments the base sub
`strate comprises
`polymer being sufficiently
`crosslinked
`prevent dissolving but weakly
`enough
`crosslinked
`crosslinked to permit swelling In certain embodiments the
`very low solu
`base substrate comprises material that has
`bility in the fluid such that only
`small portion of the base
`substrate material dissolves In certain embodiments the
`small amount of
`microneedles
`are designed such that only
`fluid enters the base substrate which limits solubilization of
`
`to
`
`the base substrate material
`
`the
`
`combination of
`The base substrate may include
`water swellable material and
`water soluble material The
`combination may be for example mixture of the materials
`least one layer of the
`layered structure comprising at
`or
`least one
`water-soluble material beiog provided adjacent at
`layer ofthe water-swellable material The base substrate may
`be made ofthe same material as that forming the microneedle
`or it may be made of different material
`variety of different fluids may be used to swell
`base substrate In some embodiments the fluid comprises
`fluid from the tissue into which
`the microneedles
`were
`fluid or sweat The fluid may be
`inserted including interstitial
`In other embodiments the fluid may be provided
`aqueous
`from source other than tissue The fluid that dissolves the
`microneedles may be the same fluid that swells the base
`substrate or it may be different fluid In some embodiments
`fluid may be stored in separate reservoir of the microneedie
`device as illustrated in FIG 10 In this embodiment
`reser
`voir 102 of the fluid is contained between the backing 100 and
`membrane 104 The membrane 104 may separate the fluid in
`the reservoir 102 from the swellable matrix material of base
`substrate 106 In certain embodiments pressure applied to the
`backing 100 such as when