AU2014200299B2 - A delivery system and process - Google Patents

Abstract

The present invention relates to a delivery system and process, and in particular to a process and device for delivering particles and/or molecules such as drugs, peptides, and/or hormones to biological tissues, or inks or dyes to a variety of materials, including paper and skin.

Description

P/00/01il Regulation 3.2 AUSTRAILIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: A delivery system and process The following statement is a full description of this invention, including the best method of performing it known to us: -lA A DELIVER RY SYSTEM AND PROCESS FIELD The present invention relates to a delivery system and prrocess, and in particular to a process and device for delivering particles and/or rolecules such as drugs., peptides, andior 5 hormones to biological tissues, or inks or dyes to a variety of materials, including paper and skin. BACKGROUND The delivery and incorporation of molecules such as drugs, hormones, peptides or dyes 10 into inert or biological materials can be achieved by a number of mechanisms. For inert materials, cost and quality of delivery is required. in. biological systems, such as animals and humans, issues of safety of delivery are also important. Delivery of drugs into animals or humans can occur either orally, by injection at the site, or systemicall Many drugs require section to achieve ithe desired terpeutic outcome. However, for some 15 conditions and diseases, the risks associated with injection can outwc.igh the benefits, Injection also requires a higher level of skill. Injecton in areas of greater sensitivity and risk, also often require sterile conditions and more involved patient care, For example, to deliver a steroid drug to the back of the eye for treatment of age-related macular degeneration requires injection into the eve with a high risk of intraocular infection and 20 retinal detachment, the most common side-effects 'associated with injecting therapeutic agents directly into the eye. It is desired to provide a delivery process and system and a delivery component for the system that alleviate one or more of the above difficulties, or at least provide a useful alternative.

SUMMARY In accordance With the present inentior, there is provided a delivery process, icluding; applying an electic field to a material to release rlecules and/or particles substantial bond within said material; arid 5 apply ng an ultrasoc signal to said niaterial to transpOrt the released moecle and/or particles through said material to a surface for delivery to an entity placed in contact with said surface, Preferably, said rnaterial includes a polymeric material or a ceramic material 10 Preferably, said polymeric material includes at least one of an electro-conductive polymer and a cross-linked polymeric go Advantageously, said cross-linked polymreric gel may be a hydrogen 15 Advantageously, said molecules may include one or more drugs for delivery to biological tissues. Advantageously, said molecules may be contained within particles substantially bound 20 within said material Advantageously, said particles may be nanoparticles, Preferably, said biological tissues include mucosal tissues, Advantageously, said biological tissues may include an eye or ocular adnexae, buccal or gingival mucosa and teeth, anal or vaginal mrucosa, or skin, Advantageously, said particles may incorporate one or more drugs, homones, and/or 30 peptides or other molecules for delivery to biological tissues.

Advantgeomlv su inoecukos i-nov fnclude ,an ink or dye- fbw pnnu06ng ar~ marking said exterarl entity 5 Advmageousy e s y inclde contreing aniensity ofsai dutrasoni sgna to determine a depth of said printing or marking in said entry. AdvaStageouslysid entiy ay include skin. Ai dvatageously, tile process m in u applying said -molecules or particlos to said inariM d all Rbind said molecules or particles witi si material prior to the appicatiOn Of silet Cirwic eld Tl present invention also provides a system having components ir executing the steps of 15 any one of the above processes, The pre tinvenidon also provides a device having cornonents for executinthe e s of any one ofth above processes 20 In accordanceo with. th-e present inveldion, there i's also pro'vidved' a deieySystem, including: a material for storing riolecules andor particles by substantial bi ending said moiec ules and/or particles to said menial means for applyIng an eletri field to said material to release said molecules 25 andor particles; and means for applying an ulirasonie sgnail to said nateria to transport the reiased rmolecdes and/or particles though sitd mateelito a sitce for delivery to an entity Preferably, said materat inchides a polymeric material or a cermic material.

4 Preferably, said polymeric materal includes at least one of an eletro-conductive pcymer and a cross-linked polymeric gel, Advantageously, said coss-inked polymeric ge may include hydrogen 5 Preferably, said means tor applying an ultrasonic signal includes at least one ultrasonic transducer attached to. said polym .veric material o eramic materiTal, Advantageously, said polymeric material may include an electro-conductive polymer and a 10 cross linked polynmeic gel, said electroconductive polymer being disposed between said cros-linked polymeric gel and said ultrasonic transducer; wherein said molecules or particles are rlase from said electro-concductve polymer and transported to a surface or said cross-linked polymeric gel for delivery to said entity. I5 Advantageoasty, saidnmoecules may include one or more drugs, hormones, peptides and/or other molecules for dlIvery to a biological tissue. Preferably, said biological tissue include a mucosal tissue, 20. Advantageously, said biological tissue may include an eye or ocular adnexae, buccal or gingival mucosa and teeth, anal or vaginal rnucosa, or skin. Preferably, said surface of said cross-linked polymenOc gel is shaped to match a correspondim' shape of a biological tissue, 25 Advantageously, said entity may include an eye, and cross-linked polymeric gel may include an onnular skirt for placement under an eyelid of said eve. Preferably, said system includes an annular delivery component defining an opening, the 30 annular delivery component inluding an annular housing attached to said annular skirt, the at least one ultrasonic tran.sducer including one or more piezoeletri transducer elements disposed about an opening of said annular housing, the opening being adapted to expose a portion of an eye during delivery of said molecules and/or particles to an annular portion of said eye disposed about said portion. 5. Advantageously, the system my include an optically transparent membrane that contacts the exposed portion of the eye during said deliver, Preferably, said material is also disposed within said housing 10 Advantageously, said annular delivery component may be disposable. Advantageously, said particles may incorporate one or more drugs, hormones, andlor peptides for delivery to biological tissues, 15 Advantageous the disposable annular dclivecry conponent may include an electrode to detect drug level. Advantagenously, the electrode nay also be adapted to deliver electrical energy to said 20 electro-conductive polymer, Preferably, the system includes a handle rotatably coupled to said disposable annular delivery component. 25 Prferably, said handle and disposable annular delivery component are -mutually coupled by coupling arus extending from said handle to corresponding openings located at substanti ally opposing sidfe of said annular delivery component Pre'ferably, the system includes a power supply for said at least one ultrasonic transducer, 30 the power supply being disposed within said handle, Preferably, said power supply is electrically coupled to said at least one ultrasonic transducer via electrodes of respective ones of said coupling arms. Advantageously, the disposable annular delivery head may include an elctroni circuit for 5 simuftaneous delivery of electrical energy to the one or more ultrasonic transducer elements and to the electro-conductive polymer. Advantageously, the amount of electrophoresis and sonophoresis can be independenty controlled by the DC and AC components in the applied signal. 10 Advantageously, said molecules may include an ink or dye o priting or marking said external entity. Advantageousl, the system may include means for controlli-ng stid ultrasonic signal to IS determine a depth of said printing or marking. Advantagceously, said external entitymay include skin. Advantageously, the system may include means for providing an electrical signal to said 21) annular delivery componenit, said electrical signal having a DC component ad an AC component, said anular delivery component including means for separating said DC component and sad A component firon said electric a signal, for generating said e i field from said DC component, and for generating said ultrasonic signal from said AC component. 25 Advantageously, said particles may be nanoparticles. I accordance with the present invention, there is also provided a delivery component for use with a delivery system, including: 30 a material for storing molecules and/or particles by substantially binding said molecules arid/or particles to said material; means for applying an electric field to said material to release said molecules and/or particles; and means for applying an ultrasonic signal to said material to transport the released molecules and/or particles through said material to a, surface of said delivery component 5 for delivery to an entity. Advantage osy said particles may be naneoparticles. BRIEF DESCRIPTION OF THE DRAWINGS Preferred embodiments of the present invention are hereinafter described, by way of 10 example only, with reference to the accompanying drawings, wherein: Figure 1 is a schematic diagram of a first preferred embodiment of a delivery :system; Figure 2 is a schematic diagram of a second preferred embodiment of a delivery system; 15 Figure 3 is a flow diagram of a prefer m-ibod iment of a delivery process; Figure 4 is a cornputer-gnerated imge of a third preferred enmodinient of a hand held delivery system or device comprising a handle component and a disposable -applicator com'Yponen t or head; Figure 5 is a cmmpter-generaed image illustrating the application of the delivery 20 device to a patient's eye in preparation for eye surgery; figure 6 is a compuem-generated image illustrating an alternative form of handle component for the delivery system; Figure 7 is an exploded perspective view of the applicator component of the delivery system; 25 Figure 8 is a perspective view of the assembled disposable applicator component; Figure 9 is schematic cross-sectional side view of the applicator component; Figure 10 is an equivalent electrical circuit diagram of the applicator component; ie 1 is a schematic diagram of an eiectrocheical cell used to measure the delivery of dye molecules from an electro-conductive polymer; 30 F,1igure 12 is a graph showing the amount of dye released as a function of tifme -wih and without ultrasonic stimultion; Figure 13 is a graph of the amount of dye released as a function of time under the influence of an electric field, with and without simutaneoas ulasonic s:imulation, Figures 14 to 16 are each fluorescence (left-hand panel) and optical phase-contrast microscopy (right-hand panel) images of sectioned rabbit eyes following intravitreal 5 injection of Avastin; the fluorescence images indicating the presence of Avastin Figures 17 to 19 are similar to Figures 14 to 16, but for non-inrasive delivery of A vastin under ultrasonc st inlation of a h;ydrogeI; Figure 20 is a schematic diagrai of an experimental arrangement or demonstrating the stimulated release of gold nanoparticks under ultrsonic stimulatior; 10 Figure 21 is a graph of photo diode output as a function of time, illustrating the enhanced transport of gold nanopartices resulting from application of an Ultrasonic signals and Figure 22' is a side view illustrating the application of the applicator component of hgures 4 to 10 to the eye of a patient, 15 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As shown in Figure 1 a delivery apparatus or system includes a storage material 102 to which an utrason"i transducer 104 is t-tached via an electrically conductive film 105. A DC voltage source 106 connected to the electrically conductive fihm 105 allows an electric 20 field to be generated in the storage raateria 102; A signal generator 108 connected tn the ultrasonic transducer 104 controls the ultrasonic signal generated by the ultrasonic transducer 104 and transmitted into the storage material 102, The storage material 102 is preferably an elecro-conductive polymer, but can alternatively 25 be a cross-linked polymeric gel material The polymeric gel material may be a hydrogen containing water, or nay not contain water, The storage material 102 can be an eectro constrictive polymer. 'he delivery system uses a delivery process as shown in Figure 3 to deliver muoleculs 30 and/or particles stored within the storage material 102 to an exposed surface 110 of the storage material 102 for delivery to an entiy 112 placed in contact with that surface 110, -9 as described below, The molecules may be drugs, hormones, and/or peptides or other floleec$ suitable for delivery to biological tissue. The molecules mnay also be coated by lipids, in wich case they are referred to as liposotnes. The particles are preferably of nanoscae dimensions to enhance their transport, and accordingly are hereinafter referred 5 to as nan-particles However t should be understood that the dhvery process and system can be applied t o larger particles if desired, providing that such particles have sufficient mobility through t e storage material 102 during use of Te process, as described belowto provide a useful flu of those parties to the delivery surface 110 In particular the delivery of nanoparticles can be used .o deliver drugs, as described in Takeuchi IH, 10 Yamamoto H, Kawashima Y (2001), MuAoadhesive nanopardiculate systeisfr pephide drug de Adv Drug Rev, 47:39-54, Processes fr forming polymer-coated nanoparticles are also described in Cui F, Qian F, Yin C (2006), Preparaton mad chwactrisation of mucoadheshe poilk er-ased nranparticles. int J Pharmn 316 654 161. 15 As shown in Figure 3, the delivery process begins at step 302 by storing within the storage material 102 molecules and/or nanoparicles to be delivered: The molecules and/or nanoparticles can be introduced into the storage material 102 using a standard syringe or can be incorporated within the storage material 102 during its formaion although it will 20 be apparent to those skilled in the art that other methods can antemativy Ie used.In any case, the molecules and/or nanoparticles can be stored within the storage material 102 while it is configured as shown in Figure or it may be so configred at a later time as described below. The molecules and/or nanoparticles have a net electrical charge which causes them to be substantially bound within the storage iaterial 102, Whether the net 25 electric charge is positive or negative depends upon the nature and type of the particular electro-onductive polymer or pointic gel used. For example, the most preferred electro-conductive polymer is polypyrrole, which has a positively charged polymer matrix that selectively binds negatively charged molecules aid/or nanoparticles The preferred polymeric gel is cross-linked hydroxyethyl methacrylate, which is capable of binding 30 either positively or negatively charged molecules or nanopartides, depending on he nature -10 of the crosslinking agent and the polarity of the polmer gel matrix. However, in addition to binding based on the charge of the molecules andO nanoparticles, polymer gels are also porous and are capable of binding by physical entrapment w.itin their pores. If an electro constrtve polyrner is used as the storage matenal 102, the electric field causes a 5 reduction in the volume of t etectr-constritive polymer, thereby further enhancing the transport of the nmolecules and/or nanoparticles from the electroAconstrictiv polymer. Having stored the molecIles and/or nanoparticles within the storage material 102, the storage material 102 can be stored for sbsequent use and may be provided to another 10 Party for use with that party's delivery system, In either case, when it is desired to deliver the stored molecules and/or nanoparticles to an entity, the storage material 102 is configured as shown in Figure I (if it is not already so conffgured). At step 304, an e lric field is estabished within the storage material 102 by way of the voltage source 106, wh typically generates DC voltages up to about +15 VDC. Atyial distance from the 15 applied DC voltage to the extenai entity 12i about 10 mm, producing an electric feld of about 150Vim In an alternative embodiment, the electric field is pulsed by an alterating voltage (typically varying between about -0,5V and +0.6V) to produce pulatile release of the stored molecules and/or nanoparticles. The aitemating voltage is preferably in the form of1 a symmetrical 3~second square wave having a frequency of about 0,3 Hz In either 20 embodiment, the el ctric I ild release the bound molecules and/or nanoparticles stored within the storage rnaterial 102, allovig them to diffuse and/or otherwise bo transported through the storage material 102. At step 306, an ultrasonic signal (typically of 40 kd-fz) is generated in the storage material 25 102 by way of the signal generator 108 typically providing a peak-to-peak voltage of 20 V to the ultrasonic transducer 104. This provides an acoustic flux of approximately 200 mW cm The ultrasonic signal greatly increases the mobility of the released molecules and/or nanoparticles (a phenomenon referred to as sonophoresis), effectively transporting them to the delivery surface 130 of the storage material 102, thus allowing 30 them to be delivered to an e tenal entity 112 contacted by the delivery surface 110 of the storage material 102.dditionally, the ultrasonic signal is transmitted through the storage material 102 to the surface of the entity 112. where it can also enhance the permeability of that surfer 5 Although the electric field has been described above as being applied prior to the application of the ultrasonc signa it will be apparent to those skilled in the art that it is not necessary that the electric field precede the application of the ultrasonic signal, but may alternatively be apphed or otherwise controlled at theme tie as the ultrasonic signal in order to control the release andor transport of the stored molectles and/or nanoparticles, 10 n a second preferred embodiment, as shown in, Figure 2, the storage material 202 is an eetro-conductive polymer, and a cross-linked polymeric gel material 204 is applied to the surface of the storage material 202 opposite to the ultrasorac transducer 104 provide a biocompatible surface for delivery to biological tissues. As with the fit preferred 15 embodinent described above, the polymeric gel material 204 may or may not contain water; In this second preferred embodiment, the molecules and/or nanoparticles released from the storage material 202 are transported through the polymeric gel 204 for delivery to an external entity 112 placed in contact with the otherwise exposed surface of the polymeric gel 204 opposite to the storage material 202. The electro-conductive 20 polymer 202 and the olymeric gel. 204 can be bonded together by a variety of methods. including use of an adhesive, treatment of the polymers 202, 204 with a plasma, use of a elcal reaction to cause cross linking of the polymers 202, 204 together, use of a chemical reaction to bond the polymers together without causing or the physical proximity and surface treatments of the polymers causing absorption of the 25 polymers to each other. It. should be understood the representation of Figure 2 is schematic and the polymeric gel material 204 is typically substantially thinner than showt The delivery process and systems can be used for a wide variety of applications, including both internal and external drug delivery, and printing, marking, or otherwise labeling 30 animate or inanimate entities.

in a third preferred embodiment, as shown in Figure 4, the delivery system is provided in the form of a handheld device 400 for the non-invasPi delivery of moleulfes to the anterior or postior segments of the eye, T molecues may include (i) anaesthetic 5 compounds, (ii) antibiotic conpounds, (iii)roidal anti-inflarnatory drugs (NSAIDs), (iv) steroid drugs, and/or (v) peptides The delivery device 400 has two major components: a reusable handle 402, and a disposable applicator hcad 404. The handle 402 is provided in two forms, only one of which is capable of being srilised in an autoclave, 10 The disposable applicator head 404 is preferably provided separately in a sterile form, packaeud irn a bubble-package 406. The applicator head 404 is g4zenerally- annular in shape and incles two opposed and radially Otwardly directed cylindrical openings into which correspondagly shaped and inwardly directed projections 408 of the handle 402 are inse to pivotally coupl th, applicator head 4f 4 to the handle 402, This arragement 15 allows the applcator head 404 to pivot about the securing projectins 408 to facilitate alignment to the 0 ee However, the applicator head 404 could aitematively be coupled to the handle by way of an articulated coupling that provides additional degrees of freedom for mating the applicator head 404 to the eye, Theapplicator head 404 contauns a storage material 708 in the form of a polyner gel ar ' electro--conductive polymer that stores the 20 desired molecules and/or nanopartie for delivery to the eye, as shownr in Figure 5. If the storage material 708 is an ecr-odxctive polymer, the voltage generated by a voltage source located within th handle 402 iaduces an electrochemical ecrostatc, and/or electro-constrictive-based release of the stored moleules and/or nanoparticles otherwise bound to the electro-conductive polymer '08 The ultrasonic energy tranmitted from the 25 applicator ead S04 to the 'ye enhances the diffusion of the molecues and/or nanoparticles, through the storage material 708 for delivery to the eve. Furthennore, the ultrasound is also transmitted to the eve itself, thereby enhancingv the permeabilit of the eve tissues during delivery, a phenomenon known as sonophoresis. The delivery of the molecules and/or nanoparticles to the anteror and posterior segments of the eye is thus 30 assisted by the ultrasound. The electrically induced release of the stored molecules and/or -13 nanoparticles fr the electrocondictive polyrer 708 allows the rate and total amount of the releasedand hence deliveed molecules and/or nanoparticles to be controlled by controlling the duration and magnitude of the electric voltage applied to the storage material 708, For example i response to pressing a 412 button on the handle 402, the 5 delivery system 400 can be configured to apply a fixed (or selected) DC or AC voltage to the storage materil 708 for a fixed (or selected) period of time, corresponding to a fixed (or selected) fluence or dosage of the delivered molecules and/or nanopartiles Additionally, the delivery of the molecules and/or nanoparticles may be slightly enhanced when retum current from the eye itself forms part of the electrical circuit, thereby assisting 10 the delivery of the molecules and/or nanoparticles (released by sonophoresis) into the eye by iontophoresis, as described in Tyle P, Agrawala P. ".Drug Delivery by Phonophoresis", Pharmaceutical Research, 6(5):355-361, 1989) ("Tyle and Agrawala"). As shown in Figures 4 to 8, the disposable applicator head 404 is generally annular in 15 shape. defining a central hole 410 of diameter II mn. The applicator head itself 404 is provided in a range of extemal diameters rnom 15 mm to 20 mm to deliver molecules andlor nanoparticlies to targeted sites on the eye, For example, a 15 mr diameter applicator head is used for delivery only to the come and limbus areas, whereas a 20 mm diameter applicator head is used to arget both the cornea/limbus areas as wel! as the insertion of the 20 extraocular muscles. It can be desirable to target the extraocular muscles to immobilise the eye in addition to anacsthetising the eye (cornea and limbus), As shown in Figre 5, the delivery device 400 is applied to the eye 502 of a patient, and can bei used to deliver an anaesthetic compound into the anterior and posterior segments of 25 tne eye 502 during eye surgery. The central opening or hole 410 through the applicator head 404 allows a surgeon to accurately align and position the applicator head 404 to be centre d with respect to the come and the ey-pupil by being able to view the comea and eye-pupil through the central opening in the applicator head 404, Although the central opening 410 is shown as passing right through the applicator head 404, it is preferred that 30 the opening be closed at the delivery end by a thin, optically transparent polymer S14 menmbrane that contacts the eye 502 during delivery (in a manner analogous to a contact lens), Figures 7 and 8 are respectively exploded and assembled views of the sMajor components 5 of thet applicator Lead 404, vomiting (for reasons of clarity) detail such as the electrical contacts to the power supply located in the device handle 402. As sho win in igure 7 the applicator head 404 inchides a piezoeecwic transducer having four piezoelectric transducer elements 702 distributed about the central hole 410 In an ahemative embodiment (not shown), only a single annularshaped piezoelectric transducer elemen is 10 used, In either embodiment, the electrical contact to the piezoelectri transducer is included within an electrically conductive housing 712, s described below A part spherical, annular metal contact ring 704 provides the support and the electrical Contat for the storae material 708 which is in comact w ith the surface of the contact rng 704, Thus the electrical contact fbr the piezoelect.e transducer i5 separate and inslated from the 1.5 electeal contact for the storage material 708 as described bow. The contact ring 704 includes two metal locating arms 706 extending orthogonally from the contact ring to ocate the storage material 708 therebetween The contact ring 704 is disposed between the piezoelectric element 702 and the storage material 708, which as described above can be either a polymeric gel or an electro-conductive polymer. A moulded polymerie gel skirt 20 710 provides the biocompatible delivery surface in contact with the eve, and the peripheral skirt is slid underneath the patients eyelid during use, as shown in Figum 22 By forming the skirt from an electrically conductive material, or by forming an electically conductive surface coating on the skirt return path for electrical curnt is provided The bottom face or delivery surface 714 of the moulded gel skirt 710 is generally concave in shape to fit the 25 anterior eve surface and as described above preferably includes a thin, optically transparent membrane of the ge located over the central opening 50 1 Finally, an electrically conductive housing 712 is provided to encase the piezoelectrie elements 702, te ring contact 704 and the electroconductive polymer 708 to provide an 30 integral applicator head 504, as shown assembled in Figure 8, As described above, the si5 applicator head 504 can be sold or otherwise provided separately from the remainder ofthe delivery devices a disposable (or possibly rechargeable) component. Figure 8 is a cross-sectional sideiew of the annlar applicator bad 404 showing how the 5 various components are electrically coupled. 'ihe electrical interface between the disposable annular applicator head and the device handle provided bytvo radially directed electrodes 902, 904 of opposite electrical polarities located within the cyindrical openings of the applicator head 404, as described above. A first electrode 902 of these two electrodes 902, 904 is cylindrical in shape and projects om the outer housing 712, to 10 wich it is electrically connected A second electode 904 of these two electrodes 902, 904 includes an outwardly directed cylindrical portion projecting from the housing 712 and a disc-shaped portion disposed between the piezoele transducers 702 on one side and an annular disc-shaped elecrical imldator 906 on the other 'These electrodes 902, 904 form electrical comections with corresponding mating electrodes at the ends of the inwardly 15 directed projections 408 of the device handle 402 The elctrodes 902, 904 simultaneously supply elctrical energy to both the piezoeleric transducers 702 and the storage material 708 as a DCbiased highdrequency AC signal. Hliglfrequency acoustic energy is transmitted through the gel into the eye in the following 20 manner: the electrodes 501, $02 connect directly across and deliver high frequency AC energy to the piezoectric transducer~s 702, which convert this electrical energy into acoustic energy., The resulting acoustic energy is then coupled through the annular disc shaped portion of the second electrode 904, t electrical insulator 906 ande an annular dise shaped intermediate electrode 908 nto th electro-conductive / nanoparticle polymer 25 708 and the cross-linked gel 710 into the patient's eye. As the piezoelectric transducers 702 are electrically insulating, they do not provide any substantial electrical path for DC current, DC electrical energy is transmitted through the gel 710 into the eye in the following 30 manner: current is conducted through the second electrode 904 through a resistor 910 into the intermediate electrode 908. Note the insudator 906 prevents an alternate current path through the transducer interace The high frequency AC component of the applied signal is dramatically reduced by a lowpass filter formed by the resistor 910 and a capacitor 912 electrically connected between the intermediate lectrode 908 and the grou-.ded housing 5 712 (electrically coupled to the patient's eye 02 as will be apparent from the equivient circuit diagram of Figure 10 The result of this fCtering effect is to substantially remove the DC or very low frequency AC component of the electrical signal applied to the second electrode 502. This DC component is hen passed through the electro-conductive / electro~ constrictive polymer 402 and through the cross-linked gel 404 into the patient's eye 502, 10 transporting nanoparticles with it by iontophoresis, as described above. The patient retur current path is via the housing 712, the current retuming via the patient' s eyelid: l this embodinwet the AC and DC components of thie electrical signal applied to the disposable annular delivery head can be independently selected or controlled by the power 15 supply located within the handle 402 to independently control the levds of electrophoresis/iontophoresis, sonophoresis and electroconstrcton (if an electroconstrction polymer is used as the storage material) in the electro-coniductive gel, Another advantage of this arrangement is the ability to detenine the condition of the 20 storage material 708 and the amount of drugs or other stored species remaining in the storage material 708, because the amount of free ions in suspension can readily be measured by the resultant current that flows when a lowdtequency AC voltage is applied to the first and second electrodes 902, 904 The amount of DC across the capacitor 912 carn be controlled by a DC offset or by the values of the R-C network, As the return current 2$ path is via the patient's eyelid, there is no need for additional electrodes to complete the patient circut. Figure 6 shows an alternative form of handle 602 for use with the applicator heads 404, and it will be apparent that a wide variety of different handle types can be used with the 30 applicator heads 404. For example, not only can handles be provided in different shapes -17 and sizes for different types of users and/or applications, but als different power supplies can be poided within these diffeent handles. For example, the simplest type of power supply might include a simple battery with an on-off button that simply connects and disconnects the battery directly to the anplicator head 404, Conversel a more complex $ power supply niglt be rechargeable and include selectable and/or programmable DC and/or AC voltages, allowing sophisticated users to select different signal magitudes, frequencies and wavefomns suited to particular applications. For example, the power supply could be pre-configured for one or more predetermined types of applicator head with particular coinatons of drugs and poi mers so that the user could select what 10 dosage of drug is be delivered and the device could power the applicator head with a suitable signal and then generate an indication (for example, an audible sinal) when the desired dosage should bave been delivered or absorbed by a particular type of biological tissue. 15 The handheld delivery devices described above provide means for non-invasve drug delivery to the eye that overcome the risks associated with injection into the eye. It provides a painless, rapid and accurate means of delivering local anaesthetic, antibiotic and/or antiinflammatories to the eye for surgery, It facilitats a safe and relatively comfortable delivery of drugs targeted for the retina that would otherwise require injectim 20 into or around the eye, or delivered systemically., exposing the patient to potential unwanted side effects, Although t.he handheld delivery device 400 described above is particularly suited for delivery of drugs and other molecules to the eye, it will be apparent that dhe delivery 25 surface 714 of the device need not be annular and can alteratively be shaped to fit the contours of other Kody parts or biological tissues to which it is desired to deliver drugs and/or other moiecus-For example, the delivery surface 714 could be shaped o fit the teeth and/or jaw bones for delivery of molecules to the buccal or gingival Iucosa and teeth, or shaped to fit the contours of the anus or vagina for delivery of molecules to the 30 anal or vagi mcosa.or shaped for transdermal deliver' oflmoleules. Additionally, the -18 delivery component or head may include an electrode to detect drug levels That electrode may be the same electrode used to deliver electrical energy to the storage matera, or may be a separate electrode, 5. Alternatively, the delivery systems described abow can be used to deliver one or more eietrically charged chemical compounds, including a dye or ink that carries an electric charge, or is contained within a particle that carries an electric charge 'the dye or ink can be deposited at a desired depth below the surface of the entty to which the dye or ink is applied, which may include almost any materiaLe and in particular may include paper, 10 plastic or skinda this application, the depth of the deposit is determined by the intensity and/or duration of the ultrasonic signal, and the release of the ink or dye can be controlled by controlling the electric field applied to the storage material When appied to skiin, the utrasonic signal also enhances the permeability of the skin, and 1 hence the transport of the ink or dye into the skin. For example, a temporary tattoo lasting for a relatively short period of time can be produced on the skin of an individual by using a relatively low power ultrasonic signal to deposit the ink or dye within the outer most epidemial layer of the cells in the skin, In contrast, a tattoo can be made to last for a relatively long period of time ("a permanent tattoo") by usiog an ultrsonic signal of .213 relatively high power to deposit the ink or dye in the dernal layer of cells in the skin Temporary tattoos can be useful for a variety of applications, including applications in the cosmetic industry, for examples Permanent tattoos an be used to provide an efficient and painless means for identifiing domestic or experimental animals In either case, a significant advantage of the processes described herein is that the ink or dye can be 25 deposited within the skin without physically penetrating the skin by any pan of the delivery device or system, This nominvasive process thus reduces the risk of infection and/or contamination.

-19 EXAMPLE 1 As shown in Figure i1, an electrochenical cell 1100 was constructed by Oiing a plasti UV cuvette 1102 with a PBS bufferThe PBS buffer (3 mi) is a phosphate buffered saline having a pH of- 74 at 25 *C and contains 0.1 M phosphate bute r J.0027 M [otassntm 5 chloride and 0.137 M sodium chloride An AgAg.C1 (saturated NaCI) reference electrode 1104 vas partially inserted into the PBS buffer, An auxiliary electrode i106 formed from stainless steel mesh of dimensions 4: 0.8 cmz was attached to one side of the cuvette, and a working electrode 1108 was attached to the Oppfsite side of the cuvette 1102. The working electrode 1108 was prepared by torming a polypyrrok film (of dimesions 0 8 x 10 08 cm) on one end of gold mylar substrate was prepared from aqueous 0,2 M pyrrole contaunng 0.1 M sulforhodamine B dye as the supporting electrolyte. The amount of polypyrrole was controlled by applying a constant current density of 1 0 mA/cn to the solution for 6 minutes. This as-prepared polypyrrole fihn was then throughJtout rinned with MilfiQ water and then dried in air, A piece of stainless steel mesh was used to make the 15 electri'ai contact to the gold mylar at another end; According to total consumed charge for the growth of polypyrroiethe amount of dye in the polypyrrole flm was estinated at - 98 pmg The workinAg electrde 1108 and an ultrasound transducer 1110 wcre respective attached 20 to the iner and outer faces of one of the walls of the plastUic V cuvette I102, as shown. The ultrasound transducer I 110 was supplied with a 15 V (peak to peak at 40 Hz) square wave AC voltage by a function generator (notshownh A, magnetic stirrer 1112 at the base of the cuvette 1. 102 rotated at -- 90 RPM, 25 The cell 1100 was placed in a MultiSpec-1501 UV-VIS spectrophotometer from Shirnadzu rt Which was used to collect UYVIS spectra from 500 nm to 800 TnI with a collection ime interval of 0. minutes. The resulting UVNIS spectra were used to determine the amount of dye released from the polypyrrole film, -20 Figure 12 s a graph showing the amount of sulforhodamine B dye in pg as a function of te in. minutes under various conditions, The line 1202 Shows the release of dye from polypyrmole with no electrical or uidrasohie stimulation; ie, by natural diffusion, In contrast, the top line 1204 represents the release of dye wit ultrasound stimulation, which 5 cleary increases the rate of release by about a factor of two. In the initial linear regime over the first few minutes, the rate of release under natural diffusion was alxt 0 2 pghuin, and with ultrasound was 0,33 pghnin. After 180 minutes, the total mount of dye released was 5.2ug and 9,9 pg, The effect of ultrasound was confirmed by an intermediate line. 1206 in which the dye was initially released under natural diffusion, and at approximate 10 50 minutes the ultrasound transducer I00 was Powered, which dranatically increased the rate of release, as shown by the arrow 1.208 in Figure 12, However, in all cases the finad amount of release dye in each Case was less than 5% of the total amount of dye in the polymer film. 15 The effect of a pulsed electric field on the release of dye was demonstrated by applying a syVmetrical. three second period square-wave AC signal ranging between -$00 mV and + n600V (vs, Ag/AgG), The lower data set 1302 in Figure 13 shows the rate of release of the dye during the electrical stimulation as described above In comparison with Figure 12, it is clear that the electrical stimulation really enhances the relase of dye from 20 polypyrrole ,with the rat of release in the first five minutes being -4.4 gt As shown by the second data set 1304 the rate of release i.s also greatly affected when the electrical simulation is combined with the ultrasound stimulation\lthough the initial ate of release indicated by the electrical stimulation alone (data se 1302) is greater than when both stimuli are applied, it will be apparent that this rate of release quickly decreases with tite, 25 whereas under combined electrical and ultrasound sinalation (data set 1304), the rate of release remains appronnately near over at last the first 400 minutes, with the rate of release ove-r 8 hours being 0. 19 pg min, and the final amount of dye reased from the polymer being about 100 gg, being approximately 50% of the total amount of dye in the polymer, 21 Considering that the poiypyrrok is a poly cationic matrix doped with anioni, dye molecules, ion exchange would occur between the dye and the unions in the PBS. Since the dye is reativeilyn bi (lt580i7), r matof the dye molecules might h~e physically entrapped in the polymer nmtix so that only a small fraction of them were released (-25%), 5 Ultrasound may increase the rate of release by opening up the pores The data shown in Figure 13 demonstrates that electrical stimulation signficantly enhances the rate and amount of release. At a reduction potential, the positive charge along the polypyrrole chain was neutalised, and the anf ici dye was released from the polymer 10 matrix, At an oxidation potential, the polypyrrole became positively charged and incorporated onions from the supporting electrolyte. Repetitive potential pulsing promoted anionic exchange and enhanced the rate of release in a short time period. EXAMPIF 2 15 As described above, the delivery system or device can be used to deliver molecules and/or nanoparticies to the eye of a patient Once delivered to the surface of the eye, the molecules andlar nanoparticles can penetrate the outer surface of the eye and diffuse to the posterior parts of the eye. For example, Figures 14 to 19 are optical miroscope images of sectioned rabbit eyes imaged by Diftrential Interference Contrast (01C) phase contrast 20 imaging and fluorescence imaging, ilHustratig the distribution of the moolonal antibody Avastinto various parts of the eye; Each of these six Figures includes two panels. comprising a left-hand panel showing a fluorescence image, and a right-hand panel showing a white light DIC phase contrast image, Figures 14 to 16 illustrate the distribution of Avastin delivered by intra vitreal injection whereas Figures 17 to 19 show 5 the distribution of Avastin delivered tom a hydrogel by sonophoresis of five Minute duration, The red colour in the fluorescence images indicates a secondary antibody bound to Avastin, Consetquently, the red colour indicates the location of Avastin in the tissues of the eye.

-22 The scctiorung procedure has caused the retioachoroid to separate from the sclera fn the eye (ut) with the intravitreal in action the vireow is visible with abundant presence (red staining) of Avasti.. The vitreous humor was not visibly stained in the eye (LE) with the Sonoactuator which indicated that no Avastin difftsed out of the retina, The ciiary body and irs are also heavily stand in the eye following intravitreal injection That is not surprising yiven the role of the vitreous in providing a source for diffusion of Avastin. However/ the cilary body does not stain well in the eye folowing delivery from the gel with ultrasound Tie passage of Avastin through the outermnost layers of cells at 10 the surface of the eye is believed to occur by the ultrasound energy racing to increase the permeablity of the layers of cells in the corea and sclera, especially in the area of the external limbus. by reversible altering the lipid structure of the cells of the cornea and sclera. After pemeating the comea and slera the Avastin reached the retina by diffusion in the uveal tract or in the potential space between the vitrecus humor and the inner 3 limiting membra"ne of the retina. The precise mechanism in the eye is not known but, Tyle and Agarwala describe related theories of the effect of ultrasound on drug permeation in the skin as being due either to cavitation effects or effects on the lipid strucutw of the stratum corneun of the skin. 20 The vitreous humor is not visible inhe " whiteiight" DIC iinages because the sections are mounted on the slides uing a 90% glycerwl solution inforder to stabilise the cover slip and the section during the conmfocal microscopy; The glycerol has a sindar refractive index to the vitreous humor. The DuC procedure relies on phase-conrast optics, and hence structures are only visible when there are differences in refractive index, Figures 47 to 19 clearly demonstrate that the Avastin has been noninvasivey delivered to the chorcil and retina - 23 EXAMPLE 3 As described above. the delivery system can also be used to deliver nanoparticles to an entity. Figure 2.0 iu k anl experimeatal arrangement for demonstrating the dlier of galdnanoparides rito an optically transparent gel 2004 under utrasonic stinulation The 5 storage niedium 2002 was formed by adding the goid namVparticles to an agarose solution heated to about 70 - 90*CThe agarose solution was then allowed to soidify by cooling in a 4T2environment. he result was a solid cylindrical gel 13 mm in diameter and 10 mm high containing a suspended dispersion of gold nanoparticles This storage material 2002 was then sandwiched between the transparent gel 2004 and an ultrasonic transducer 102 10 driven, by 20 v p-p nal@ 40 kz provided by a signal generator 108, resulting in an actustie stimulation of about 200 mWem The beam generated by a HeNe laser 2006 is directed through the tranparent gel 2004 tbe received by a photodetector 2008 in order to measure the optical transmission of te laser beam through the transparent gel 2004. and thereby intr the transport of the gold 3anopartides Into the transpareit gel 2004, A 15 standard computer system 2010 having an analog to digital converter (AD) card processed the analog signJ generated by the photodetector 2008 for subsequent analysis and display to a user, in this particular arrangement, the storage material 2002 and the transparent get 2004 were 20 both polmymeric gels forned by dissolving 0.5% agarose (w/v) in MiliIQ water. Gold nanoparticks of 1S to 20 nanometre diameter were added to the heated (70-90"C) solution of agarose in MlliQ water and the gold nanoprtiles incorporated into the storage matenal 2002 during the setting of the agarose to fonn the polymeric gel. 25 Figure 21 is a graph of the photodiode output 2102 as a function of time, initially, the optical transmission of the transparent gel 2004 was constant, At a time of around 8 minutes fmin the start of the experiment, a 40 kflz ultrasonic signal was generated by the ultrasonic transducer 102 as indicated and transmitted into the storage material 2002. In this. particular arraneient, the laser beam was positioned at a point I mm below the 30 interface between the dcear gel 204 and the storage material 2002, Afier a delay of approximately 2 minutes the transmNsion of the laser bean dropped rapidly over a period of about 8 minutes. and then began to saturate at a fixed levels At a time of around 29 minutes, the ultrasonic signal was witchd off as indicated, This data clearly demonstrates that the 40 k1 ultrasonic signal was very effective in tnlsporting the gold 5 nanoparticles into the lear gel 2004, Scanning electron mcroscopy f the clear gel 2004 revealed the presence of the gold nanopartcle confirming that they had been transported from the storage material 2002. A control experineizt was perfonned using an identical storage material without gold nanopartIes showed a constant opticl transmission that was not affected by the presence or absence of the ultrasonic signal 10 Many modifications will be apparent to those skilled in the art without departing from the scope of the present invention as hereinbefore described with reference to the accompanying drawings

Claims (41)

1. A delivery process to non-invasively deliver molecules and/or particles to an eye and/or ocular adnexae, including applying an ultrasonic signal to a polymeric material in contact with a surface of the eye and/or ocular adnexae to: . release the molecules and/or particles substantially bound within the polymeric material; . transport the released molecules and/or particles through the polymeric material to a surface of the polymeric material that is in contact with the surface of the eye and/or ocular adnexae ; and . enhance permeability of the surface of the eye and/or ocular adnexae.

2. A process according to claim 1 further including the application of an electric field to the polymeric material to enhance the rate and/or amount of release of the molecules and/or particles from the polymeric material.

3. A process according to claim 1 or 2, wherein the molecules and/or particles are substantially bound through: i) the polymeric material comprising an electrical charge and the molecules and/or particles comprising an electrical charge opposite to the electrical charge of the polymeric material; and/or ii) the molecules and/or particles being physically trapped within pores of the polymeric material.

4. A process according to any one of claims 1 to 3, wherein the molecules and/or particles substantially bound through being physically trapped within pores of the polymeric material.

5. A process according to any one of claims 1 to 4, wherein the polymeric material is a gel.

6. A process according to any one of claims I to 5, wherein the polymeric material includes agarose.

7. A process as claimed in any one of claims 1 to 5, wherein the polymeric material includes an electro-constrictive polymer.

8. A process according to any one of claims 1 to 5, wherein the polymeric material includes a cross-linked polymer.

9. A process according to any one of claims 1 to 5, wherein the polymeric material includes an electro-conductive polymer.

10. A process according to any one of claims 1 to 5, wherein the polymeric material is a hydrogel.

11. A process according to any one of claims 1 to 10, including controlling the ultrasonic signal intensity and/or duration to determine a depth of delivery of the molecules and/or particles in the eye and/or ocular adnexae.

12. A process according to any one of claims I to 11, wherein the molecules are molecules of an active agent for delivery to the eye and/or ocular adnexae, and/or the particles contain an active agent for delivery to the eye and/or ocular adnexae.

13. Aprocess according to any one of claims I to 12, wherein delivery is to the eye.

14. A process according to claim 13, wherein delivery is to one or more parts of the eye including sclera, cornea, limbus, choroid and uveal tract.

15. A process according to any one of claims 1 to 12, wherein delivery is to the ocular adnexae.

16. A process according to claim 15, wherein delivery is to the conjunctiva of the ocular adnexae.

17. A process according to any one of claims 12 to 16, wherein the active agent includes one or more drugs, hormones, antibodies, liposomes, and/or peptides.

18. A system or device having components for executing the steps of the process according to any one of claims I to 17.

19. A delivery system to non-invasively deliver molecules and/or particles to an eye and/or ocular adnexae, including: * a polymeric material for storing the molecules and/or particles, wherein the molecules and/or particles are substantially bound within the polymeric material; and a means for applying an ultrasonic signal to the polymeric material to release the molecules and/or particles and to transport the released molecules and/or particles through the polymeric material to a surface of the polymeric material that is in contact with the surface of the eye and/or ocular adnexae; and to enhance the permeability of the surface of the eye and/or ocular adnexae that is in contact with the surface of the polymeric material.

20. A system according to claim 19 further including a means for applying an electric field to enhance the rate and/or amount of release of the molecules and/or particles from the polymeric material.

21. A system according to claim 19 or 20, wherein the particles and/or molecules are substantially bound through: i) the polymeric material comprising an electrical charge and the molecules and/or particles comprising an electrical charge opposite to the electrical charge of the polymeric material; and/or ii) the molecules and/or particles being physically trapped within pores of the polymeric material.

22. A system according to any one of claims 19 to 21, wherein the particles and/or molecules are substantially bound through the molecules and/or particles being physically trapped within pores of the polymeric material.

23. A system according to any one of claims 19 to 22, wherein the polymeric material is a gel.

24. A system according to any one of claims 19 to 23, wherein the polymeric material includes agarose.

25. A system according to any one of claims 19 to 23, wherein the polymeric material includes a cross-linked polymer.

26. A system according to any one of claims 19 to 23, wherein the polymeric material includes an electro-conductive polymer.

27. A system according to any one of claims 19 to 23, wherein the polymeric material includes an electro-constrictive polymer.

28. A system according to any one of claims 19 to 23, wherein the polymeric material is a hydrogel.

29. A system according to any one of claims 19 to 28, including a means for controlling the ultrasonic signal intensity and/or duration to determine a depth of delivery of the molecules and/or particles in the eye and/or ocular adnexae.

30. A system according to any one of claims 19 to 29, wherein the molecules are molecules of an active agent for delivery to the eye and/or ocular adnexae and/or the particles contain an active agent for delivery to the eye and/or ocular adnexae.

31. A system according to any one of claims 19 to 30, wherein delivery is to the eye.

32. A system according to claim 31, wherein delivery is to one or more parts of the eye including sclera, cornea, limbus, retina, choroid and uveal tract.

33. A system according to any one of claims 19 to 30, wherein delivery is to the ocular adnexae.

34. A system according to claim 33, delivery is to the conjunctiva of the ocular adnexae.

35. A system according to any one of claims 30 to 34, wherein the active agent includes one or more drugs, hormones, antibodies, liposomes, and/or peptides.

36. A system according to any one of claims 19 to 35, wherein the means for applying an ultrasonic signal includes at least one ultrasonic transducer coupled to the polymeric material.

37. A system according to any one of claims 19 to 36, wherein the system is a hand-held device.

38. A system according to any one of claims 19 to 37, wherein the system includes a removable delivery component incorporating the polymeric material.

39. A system according to claim 38, wherein the delivery component also includes one or more ultrasonic transducers.

40. A system according to claim 38 or 39, wherein the delivery component is a single-use disposable component of the system.

41. A system according to claim 40, wherein the delivery component includes an electrode to detect levels of molecules and/or particles within the delivery component.