CA2265678C - Electrotransport drug delivery reservoirs containing inert fillers - Google Patents

Abstract

A novel electrotransport drug delivery system (10) and therapeutic agent-containing reservoir (26, 28) for use therein are provided. An inert filler material effective to reduce the quantity of therapeutic agent otherwise present is incorporated in the reservoir (26, 28) along with the therapeutic agent t o be delivered via electrotransport. Methods for making the reservoir (26, 28) an d drug delivery system (10) are provided as well.

Description

W0 9.8l2683710H1216171819202223242526272829303233343536CA 02265678 1999-03-15PCT/US9797/22476ELECTROTRANSPORT DRUG DELIVERY RESERVOIRSCONTAINING INERT FILLERSTechnical FieldThis invention relates generally to electrotransport drug delivery. Moreparticularly, the invention relates to a method for making a new type of drugreservoir for incorporation into an electrotransport drug delivery system. Theinvention additionally relates to novel drug reservoirs and to electrotransportdrug delivery systems containing these reservoirs.Background ArtThe delivery of drugs through the skin provides many advantages;primarily, such a means of delivery is a comfortable, convenient andnoninvasive way of administering drugs. The variable rates of absorption andmetabolism encountered in oral treatment are avoided, and other inherentinconveniences -— e.g., gastrointestinal irritation and the like —— are eliminated aswell. Transdermal drug delivery also makes possible a high degree of controlover blood concentrations of any particular drug.However, many drugs are not suitable for passive transdermal drugdelivery because of their size, ionic charge characteristics and hydrophilicity.One method of overcoming this limitation in order to achieve transdermaladministration of such drugs is the use of electrical current to actively transportdrugs into the body through intact skin. The method of the invention relates tosuch an administration technique, i.e., to "electrotransport" or "iontophoretic"drug delivery.Herein the terms "electrotransport", "iontophoresis", and "iontophoretic" areused to refer to the transdermal delivery of pharmaceutically active agents bymeans of an applied electromotive force to an agent-containing reservoir. Theagent may be delivered by electromigration, electroporation, electroosmosis orany combination thereof. Electroosmosis has also been referred to aselectrohydrokinesis, electro—convection, and electrically induced osmosis. Ingeneral, electroosmosis of a species into a tissue results from the migration ofsolvent in which the species is contained, as a result of the application ofelectromotive force to the therapeutic species reservoir, i.e., solvent flow101314CA 02265678 2005-05-0451669-2induced by electromigration of other ionic species. During the electrotransportprocess, certain modifications or alterations of the skin may occur such as theformation of transiently existing pores in the ‘ skin, also referred to as"electroporation". Any electrically assisted transport of species enhanced bymodifications or alterations to the body surface (e.g., formation of pores in theskin) are also included in the term "electrotransport" as used herein. Thus. asused herein, the terms "electrotransport", "iontophoresis" and "io‘ntophoretic"refer to (1) the delivery of charged drugs or agents by electromigration. (2) thedelivery of uncharged drugs or agents by the process of electroosmosis, (3) thedelivery of charged or uncharged drugs by electroporation. (4) the delivery ofcharged drugs or agents by the combined processes of electromigration andelectroosmosis, andlor (5) the delivery of a mixture of charged and unchargeddrugs or agents by the combined processes of electromigration andelectroosmosis.Systems for delivering ionized drugs through the skin have been known for‘some time.iontophoretic delivery device which overcame one of the disadvantages of theearly devices. namely, the need to immobilize the patient near a source ofelectric current. The device was made by forming, from the electrodes and thematerial containing the drug to be delivered. a galvanic cell which itselfproduced the current necessary for iontophoretic delivery. This device allowedthe patient to move around during drug delivery and thus required substantiallyless interference with the patient's daily activities than previous iontophoreticdelivery systems.Present electrotranspon devices use at least two electrodes. Both of theseelectrodes are disposed so as to be in intimate electrical contact with someportion of the skin of the body. One electrode. called the active or donorelectrode, is the electrode from which the drug is delivered into the body. Theother electrode, called the counter or return electrode, serves .to close theelectrical circuit through the body. In conjunction with the patient's skin, thecircuit is completed by connection of the electrodes to a source of electricalenergy, e.g., a battery, and usually to circuitry capable of controlling currentpassing through the device. If the ionic substance to be driven into the body ispositively charged, then the positive electrode (the anode) will be the activeelectrode and the negative electrode (the cathode) will serve as the counterelectrode. completing the circuit. If the ionic substanoe to be delivered isBritish Patent Specification No. 410,009 (1934/5/10) describes an..._—.¢.—._..._....—....... . ..».-.._, .._.V- .—~...-_ .__..__-I\)>-—r—->—a>-—Av—A>->—-o—-$\OQ)\lC7\§lI-¥>l.r)I\.)222426272829303132CA 02265678 1999-03l-15 -2 .*1 7,.-negatively charged, then the cathodic electrode will be the active electrode and theanodic electrode will be the counter electrode.Existing electrotransport devices additionally require a reservoir or source ofthe pharmaceutically active agent, which is to be delivered or introduced into thebody. Such drug reservoirs are connected to the anode or the cathode of theelectrotransport device to provide a fixed or renewable source of one or moredesired species or agents. The reservoirs of such devices may include inert fillers,as seen for example in WO 91/16944.Thus, an electrotransport device or system, with its donor and counterelectrodes, may be thought of as an electrochemical cell having two electrodes,each electrode having an associated half cell reaction, between which electricalcurrent flows. Electrical current flowing through the conductive (e.g., metal)portions of the circuit is carried by electrons (electronic conduction), while currentflowing through the liquid-containing portions of the device (i.e., the drug reservoirin the donor electrode, the electrolyte reservoir in the counter electrode, and thepatient's body) is carried by ions (ionic conduction). Current is transferred from themetal portions to the liquid phase by means of oxidation and reduction chargetransfer reactions which typically occur at the interface between the metal portion(e.g., a metal electrode) and the liquid phase (eg, the drug solution). A detaileddescription of the electrochemical oxidation and reduction charge transfer reactionsof the type involved in electrically assisted drug transport can be found inelectrochemistry texts such as J.S. Newman, Electrochemical Svstems (PrenticeHall, 1973) and A.J. Bard and L.R. Faulkner, Methods,Fundamentals and Applications (John Wiley & Sons, 1980).ElectrochemicalGenerally, for transdermal drug delivery, it is preferred that drug flux beindependent of the concentration of drug in the reservoirs. Concentration-independent drug flux typically occurs above a threshold concentration level,accordingly, it is desirable to maintain a higher drug concentration in the drugreservoir.Y-ElCA 02265678 l999-03- 15‘-" 1' tn q‘ >3A i ' ' i no 9\\V .With respect to more costly drugs, such as peptides and proteins producedfrom genetically engineered cell lines, and/or highly potent drugs for which a verylow dosage may be efficacious, it is also desirable to minimize the amount of drugloaded into the reservoir. Although it is possible to maintain the drug concentrationabove the threshold level required for concentration-independent drug flux byreducing both the drug loading and the volume of the reservoir, there are limitationson how small the drug reservoir may be. For example,AMENDED sH.=.Er,H1314151617192022232425262728293032W0 9_8/26837CA 02265678 1999-03-15PCTlUS97l22476reducing the volume of the donor reservoir by reducing the skin contact areaincreases the potential for skin irritation, i.e., irritation caused by the appliedelectric current and/or components of the drug composition delivered to theskin. Further, if the volume of the donor reservoir is reduced by decreasing thethickness of the reservoir, the potential for electrical shorting between theelectrodes and the skin increases; thinner reservoirs also are inherently moredifficult to manufacture with precise uniformity.Thus, there is a need in the art for a method of minimizing drug loading inan electrotransport donor reservoir while nevertheless maintaining the drugconcentration above a level required for concentration-independent drug flux,without reducing reservoir size or volume. The present invention addressesthis need, and is directed to novel drug reservoirs for use in conjunction with anelectrotransport drug delivery system and methods of making these newreservoirs. In contrast to prior methods for making drug reservoirs for use inelectrotransport drug delivery systems, the present invention provides areservoir that enables smaller quantities of drug to be loaded into the system,by virtue of an inert filler material dispersed throughout the drug reservoir.Description of the inventionAccordingly, the invention in one aspect is an electrotransport device whichovercomes the above—mentioned limitations in the art.It is another aspect of the invention to provide an electrotransport device fordelivering a therapeutic agent through an animal body surface while minimizingthe quantity of therapeutic agent contained within the device.It is a further aspect of the invention to provide an electrotransport devicewhich incorporates a therapeutic agent—containing polymeric reservoir -comprising a polymeric matrix containing a therapeutic agent and an inert fillermaterial.It is still a further aspect of the invention to provide an electrotransport drugdelivery device capable of cost—effective|y delivering therapeutic agents such aspeptides, proteins, or fragments thereof.1015202530CA 02265678 2005-09-2967696—2745It is still another aspect of the invention toprovide a therapeutic agent—containing polymeric reservoirfor incorporation into an electrotransport device foreffectively delivering a therapeutic agent through an animalbody surface while minimizing the quantity of therapeuticagent contained within the reservoir.It is a further aspect of the invention to providea method for minimizing the quantity of therapeutic agent ina therapeutic agent—containing polymer reservoir forincorporation into an electrotransport device.Additional aspects, advantages and novel featuresof the invention will be set forth in part in thedescription which follows, and in part will become apparentto those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.In accordance with one aspect of this invention,there is provided an electrotransport agent delivery device(10),(24)comprising a donor electrode (22), a counter electrodeand a source of electrical power (32) to beelectrically connected to the donor and counter electrodes,wherein the donor electrode (22) is electrically connectedto a donor reservoir (26, 28) having a predetermined volume(V) and being comprised of a polymeric matrix containing apredetermined quantity (q) of a therapeutic agent to bedelivered, the polymeric matrix also containing an inertfiller material having substantially no tendency to interactwith the agent, the inert filler being present in the matrixin a form which allows electrotransport of the agent throughand from the reservoir to a patient body surface,characterized in that the agent loading in the reservoir isless than 10 wt.% of the total reservoir admixture and theinert filler material is present in the polymeric matrix in1015202530CA 02265678 2005-09-2967696-2745aan amount up to about 60 vol.% which achieves aconcentration (p) of therapeutic agent in the matrix whichexceeds q/V.In accordance with another aspect of this(26,theinvention, there is provided a donor reservoir 28) foran electrotransport agent delivery device (10),reservoir having a predetermined volume (V) and beingcomprised of a polymeric matrix containing a predeterminedquantity (q) of a therapeutic agent to be delivered, thepolymeric matrix also containing an inert filler materialhaving substantially no tendency to interact with the agent,the inert filler being present in the matrix in a form whichallows electrotransport of the agent through and from thein thatreservoir to a patient body surface, characterizedthe agent loading in the reservoir is less than 10 wt.% ofthe total reservoir admixture and the inert filler materialis present in the polymeric matrix in an amount up to about60 vol.% which achieves a concentration (p) of therapeuticagent in the matrix which exceeds q/V.In accordance with a further aspect of thisinvention, there is provided a method for minimizing thetherapeutic agent loading of a polymeric donor reservoir(26, 28) for an electrotransport delivery device (10), whilemaintaining a therapeutic agent concentration (p) of thetherapeutic agent in the reservoir above a level requiredfor concentration—independent agent flux without reducingreservoir size or volume, the reservoir containing apredetermined quantity (q) of the therapeutic agent to bedelivered, the method comprising providing the reservoirwith a therapeutic agent loading of less than 10 wt.% andplacing up to about 60 vol.% of an inert filler material ina polymer matrix, the filler material having substantiallyno tendency to interact with the therapeutic agent, tol0152025CA 02265678 2005-09-2967696-274v5bproduce a donor reservoir comprised of therapeutic agentinert filler—containing polymer matrix.Brief Description of the DrawingFigure 1 is a perspective exploded view of oneembodiment of an electrotransport drug delivery system whichmay be used in conjunction with drug formulations made usingthe inventive method.Modes for Carrying Out the InventionBefore describing the present invention in detail,it is to be understood that this invention is not limited toparticular drugs, carriers, electrotransport deliveryor the like,systems, as such may vary.It must be noted that, as used in thisspecification and the appended claims, the singular forms"a", "an" and "the" include plural referents unless thecontext clearly dictates otherwise. Thus, for example,reference to "a drug" or "a therapeutic agent" includes amixture of two or more drugs or agents, reference to "aninert filler" includes two or more such fillers, and thelike.Unless defined otherwise, all technical andscientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art towhich the invention pertains. Although any methods andmaterials similar or equivalent to those described hereincan be used in the practice for testing of the presentinvention, the preferred materials and methods are describedherein.1516171819202223242526272829303233343536WO 98/26837CA 02265678 1999-03-15PCT/US‘97I22476In describing and claiming the present invention, the following specificterminology will be used in accordance with the definitions set out below.By the terms "therapeutic agent," "drug" or "pharmaceutically active agent"as used herein is meant any chemical material or compound which induces adesired local or systemic therapeutic effect, and is capable of being deliveredby electrotransport. Examples of such substances will be set forth below.The term "inert filler material" refers to a material having substantially notendency to interact with the therapeutic agent, by which is intended to meanthat such an inert filler material will not bind, absorb, adsorb or react chemicallywith any significant quantity of therapeutic agent. The material will generally beparticulate or fibrous, or it may be comprised of a glass bead, polymeric meshorthe like, as will be explained in detail below.By “polymer matrix" is intended to refer to a solution of a polymer in anappropriate solvent, a solvent-containing polymer that has swollen byabsorption or adsorption of the solvent, a composition comprising a dispersed,solvent-containing polymer phase combined with a continuous, solvent phaseto form a viscous, colloidal composition, or other form of polymer matrix thathas the chemical and/or physical characteristics that allow the incorporation ofdrug therein and use as a reservoir in an electrotransport drug delivery system(e.g., viscosity, surfactant properties, and the like).A "hydroge|" is a polymer useful for forming the aforementioned polymericmatrices and capable of absorbing at least about 20 wt.% water.In a first embodiment, then, a novel electrotransport drug delivery device isprovided, the device effectively delivering a therapeutic agent through ananimal body surface while minimizing the quantity of therapeutic agentcontained within the drug reservoir of the device. More specifically, theelectrotransport device incorporates a therapeutic agent—containing polymerreservoir having a predetermined volume (V), the reservoir comprising apolymer matrix with a predetermined quantity (q) of a therapeutic agentdispersed therein and an amount of an inert filler material effective to achieve aconcentration (p) of the therapeutic agent in the polymer matrix which exceedsqN. This therapeutic agent—containing polymer reservoir is also novel andrepresents an additional aspect of the presently claimed invention.The inert filler material thus provides for a desired concentration of thetherapeutic agent in the drug reservoir. and thus, in turn, maintains the flux ofthe therapeutic agent. Drug concentration can be reduced withoutWO 98/2683710H131415171819202223242526272829303233343536CA 02265678 1999-03-15PCT/UVSV97/22476compromising the size of the drug reservoir.Materials suitable for use as the inert filler include, but are not limited to:glass beads; mineral filler materials, such as titanium dioxide. talc, quartzpowder, or mica; and polymer filler materials. Examples of polymer fillermaterials are: polymer meshes, such as Saati polypropylene mesh; polymerpowders having particle sizes of between about 1pm to about 150um, such asmicronized polymer waxes of polyethylene (e.g., Aqua Poly 250), polypropylene(e.g., Propyltex® 140$), polytetrafluoroethylene (e.g., Fluo 300), Fischer-Tropsch waxes (e.g., MP-22C, available from Micro Powders, lnc.), andmixtures thereof; crosslinked polymer beads, such as styrene/divinylbenzene(e.g., Amber|ite® XAD-4 1090 or Amberlite® XAD 16-1090),acrylic/divinylbenzene (e.g., Amberlite® XAD-7) (available from Rohm andHaas), or the like; cellulosic polymers, such as crosslinked dextrans (e.g.,Sephadex®) (available from Pharmacia Laboratories); polymer solids havingweight average molecular weights between about 20,000 and about 225,000,such as polyvinyl alcohol (e.g., Airvol® 103, available from Air Products;Mowiol® 4-98 Mowiol® 66-100, from Hoechst),polyvinylpyrrolidone (e.g., Povidone PVP K—29/32; international SpecialtyProducts), polyethylene oxide (Union Carbide), hydroxypropyl(Aqualon), hydroxyethyl cellulose (Union Carbide), and mixtures thereof.The drug reservoir is a polymeric matrix which generally although notnecessarily is comprised of a hydrogel. Suitable polymers useful for forminghydrogel reservoirs include: polyvinyl alcohols; polyvinyl—pyrrolidone; cellulosicpolymers, e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose, and the like;polyethylene oxides; polyanhydrides; polyvinyl pyrrolidone/vinylcopolymers, and the like; and mixtures and copolymers thereof.and availablecellulosepolyurethanes;acetateTherapeutic agents useful in connection with the novel reservoirs anddelivery devices of the invention include any pharmaceutical compound orchemical that is capable of being delivered by electrotransport. In general, thisincludes agents in all of the major therapeutic areas including, but not limited to,anti-infectives such as antibiotics and antiviral agents, analgesics includingfentanyl, sufentanil, buprenorphine and analgesic combinations, anesthetics,anorexics, antiarthritics, antiasthmatic such as terbutaline,anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals,antihistamines, anti-inflammatory agents, antimigraine preparations, antimotionagentsWO 98/268371314H1617181920212223242526272829303233343538CA 02265678 1999-03-15PCT/US7V97l22476sickness preparations such as scopolamine and ondansetron, antinauseants,antineoplastics, antiparkinsonism drugs, antipruritics,antipyretics, antispasmodics, including gastrointestinalanticholinergics, sympathomimetrics, xanthine derivatives, cardiovascularpreparations including calcium channel blockers such as nifedipine, beta-blockers, beta-agonists such as dobutamine and ritodrine, antiarrythmics,antihypertensives such as atenolol, ACE inhibitors such as rinitidine, diuretics,vasodilators, including general, coronary, peripheral and cerebral, centralnervous system stimulants, cough and cold preparations, decongestants,diagnostics, hormones such as parathyroid hormone, bisphosphoriates,hypnotics, relaxants, parasympatholytics,parasympathomimetrics. psychostimulants, sedatives andThe invention is particularly useful in conjunction with theelectrotransport delivery of proteins, peptides and fragments thereof, whethernaturally occurring, chemically synthesized or recombinantly produced.With respect to the delivery of peptides, polypeptides, proteins and othersuch species, these substances typically have a weight average molecularweight of at least about 300 daltons, and more typically have a molecularweight in the range of about 300 to 40,000 daltons. Specific examples ofpeptides and proteins in this size range include, without limitation, GHRH,GHRF, insulin, insultropin, calcitonin, octreotide, endorphin, TRH, NT-36 (N-[[(s)—4-oxo-2-azetidinyl]carbonyl]—L-histidyl-L-prolinamide), liprecin, pituitaryhormones (e.g., HGH, HMG, desmopressin acetate, etc), follicle luteoids,ocANF, growth factors such as growth factor releasing factor (GFRF), BMSH,somatostatin, bradykinin, somatotropin, platelet-derived growth factor,asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionicgonadotropin, corticotropin (ACTH), erythropoietin, epoprostenolaggregation inhibitor), glucagon, HCG, hirulog, hyaluronidase, interferon,interleukins, menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase,tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTHanalogs, ANP, ANP clearance inhibitors, angiotensin ll antagonists, antidiureticantipsychotics,and urinaryimmunosuppressives, muscleprostaglandins,tranquilizers.hormone agonists, bradykinin antagonists, CD4, ceredase, CSl's, enkephalins,FAB fragments, lgE peptide suppressors, lGF-1, neurotrophic factors, colonystimulating factors, parathyroid hormone and agonists, parathyroid hormoneantagonists, prostaglandin antagonists, pentigetide, protein C, protein S, renininhibitors, thymosin alpha-1, thrombolytics, TNF, vaccines, vasopressin(platelet -WO 98/26837101213141516171819202223242526272829303233343535CA 02265678 1999-03-15PCTIUSY97/22476antagonists analogs, alpha-1 antitrypsin (recombinant), and TGF—beta.Luteinizing hormone-releasing hormone ("LHRH") and LHRH analogs suchas goserelin, buserelin, gonadorelin, napharelin and leuprolide, representanother class of peptides and proteins in this size range that are useful inconnection with the present invention. One preferred LHRH analog isgoserelin. Goserelin is a synthetic decapeptide analogue of LHRH having thechemical structure pyro-G|u—His-Trp-Ser—Tyr—D-Ser(But)-Leu—Arg-Pro-Azgly-NH2. The drug is useful in the treatment of prostate and breast cancers and intreating certain gynecological disorders.The therapeutic agent-containing polymer reservoir is prepared byincorporating predetermined amounts of a therapeutic agent and an inert fillermaterial into a polymeric matrix. The polymeric matrix is typically, although notnecessarily, an aqueous solution, preferably containing between about 1 wt.%to 50 wt.% polymer. The inert filler typically accounts for up to about 60 vol.%-,preferably 5 to 60 vol.%, more preferably 20 to 60 vol.%, and most preferably40 to 60 vol.% of the polymer reservoir. A relatively small quantity of thetherapeutic agent, between about 0.001 wt.% to about 10 wt.%, preferably 0.01wt.% to about 3 wt.%, and more preferably about 0.1 wt.% to about 2 wt.% oftotal admixture, is all that is typically used in this invention.The incorporation of the therapeutic agent and the inert filler material intothe polymeric matrix may be accomplished by any method known in the art,such as overhead stirring, double planetary mixing, Brabender mixing,volumetric metering pump, extrusion dispensing, or the like.The therapeutic agent may be incorporated first into the polymeric matrix,followed by incorporation of the inert filler material into the therapeutic agent-containing polymeric matrix to form a therapeutic agent-containing polymericreservoir which may then be used in an electrotransport drug delivery system.Alternatively, the inert filler material may be incorporated first into the polymericmatrix, followed by addition of the therapeutic agent into the inert filler-containing polymeric matrix. The method of this invention may in the alternativeinvolve simultaneously incorporating the therapeutic agent and the inert fillermaterial into the polymeric matrix.Figure 1 illustrates a representative electrotransport delivery device thatmay be used in conjunction with the present drug reservoirs. Device 10comprises an upper housing 18, a circuit board assembly 18, a lower housing20, anode electrode 22, Cathode electrode 24, anode reservoir 26, cathodeWO 98/268371011121314161718192022232425262728293233343536CA 02265678 l999-03- 15PCT/Us’97/2247610reservoir 28 and skin—compatible adhesive 30. Upper housing 16 has lateralwings 15 which assist in holding device 10 on a patient's skin. Upper housing16 is preferably composed of an injection moidable elastomer (e.g., ethylenevinyl acetate). Printed circuit board assembly 18 comprises an integratedcircuit 19 coupled to discrete components 40 and battery 32. Circuit boardassembly 18 is attached to housing 16 by posts (not shown in FIG. 1) passingthrough openings 13a and 13b, the ends of the posts being heated/melted inorder to heat stake the circuit board assembly 18 to the housing 16. Lowerhousing 20 is attached to the upper housing 16 by means of adhesive 30, theupper surface 34 of adhesive 30 being adhered to both lower housing 20 andupper housing 16 including the bottom surfaces of wings 15.Shown (partially) on the underside of circuit board assembly 18 is a buttoncell battery 32. Other types of batteries may also be employed to power device10.The device 10 is generally comprised of battery 32, electronic circuitry19,40, electrodes 22,24, and polymeric drug reservoirs 26,28, all of which areintegrated into a self-contained unit. The outputs (not shown in FIG. 1) of thecircuit board assembly 18 make electrical contact with the electrodes 24 and 22through openings 23,23‘ in the depressions 25,25‘ formed in lower housing 20,by means of electrically conductive adhesive strips 42,42‘. Electrodes 22 and24, in turn, are in direct mechanical and electrical contact with the top sides44',44 of drug reservoirs 26 and 28. The bottom sides 46',46 of drug reservoirs26,28 contact the patient's skin through the openings 29',29 in adhesive 30.Device 10 optionally has a feature which allows the patient toself—administer a dose of drug by electrotransport. Upon depression of pushbutton switch 12, the electronic circuitry on circuit board assembly 18 delivers apredetermined DC current to the electrode/reservoirs 22,26 and 24,28 for a ‘delivery interval of predetermined length. The push button switch 12 isconveniently located on the top side of device 10 and is easily actuated throughclothing. A double press of the push button switch 12 within a short timeperiod, e.g., three seconds, is preferably used to activate the device for deliveryof drug, thereby minimizing the likelihood of inadvertent actuation of the device10. Preferably, the device transmits to the user a visual and/or audibleconfirmation of the onset of the drug delivery interval by means of LED 14becoming lit and/or an audible sound signal from, e.g., a "beeper". Drug isdelivered through the patient's skin by electrotransport, e.g., on the arm, overWO 98/2683713141516171819202223242526272829303233343536CA 02265678 1999-03-15PCT/UAST97/2247611the predetermined delivery interval.Anodic electrode 22 is preferably comprised of silver and cathodicelectrode 24 is preferably comprised of silver chloride. Both reservoirs 26 and28 are comprised of a polymeric material, generally a hydrogel, as describedabove. Electrodes 22,24 and reservoirs 26,28 are retained by lower housing20.The polymer reservoirs 26 and 28 contain drug solution and inert fillermaterial uniformly dispersed in at least one of the reservoirs 26 and 28. Drugconcentrations in the range of approximately 1 x 10‘ M to 1.0 M or more can beused, with drug concentrations in the lower portion of the range being preferred.The push button switch 12, the electronic circuitry on circuit boardassembly 18 and the battery 32 are adhesively "sea|ed" between upperhousing 16 and lower housing 20. Upper housing 16 is preferably composed ofrubber or other elastomeric material. Lower housing 20 is preferably composedof a plastic or elastomeric sheet material (e.g., polyethylene) which can beeasily molded to form depressions 25,25‘ and cut to form openings 23,23’. Theassembled device 10 is preferably water resistant (i.e., splash proof) and ismost preferably waterproof. The system has a low profile that easily conformsto the body, thereby allowing freedom of movement at, and around, the wearingsite. The reservoirs 26 and 28 are located on the skin-contacting side of thedevice 10 and are sufficiently separated to prevent accidental electrical shortingduring normal handling and use.The device 10 adheres to the patient's body surface (e.g., skin) by meansof a peripheral adhesive 30 which has upper side 34 and body-contacting side36. The adhesive side 36 has adhesive properties which assures that thedevice 10 remains in place on the body during normal user activity, and yetpermits reasonable removal after the predetermined (e.g., 24-hour) wear‘period. Upper adhesive side 34 adheres to lower housing 20 and retains theelectrodes and drug reservoirs within housing depression 2525' as well asretains lower housing 20 attached to upper housing 16.While the invention has been described in conjunction with the preferredspecific embodiments thereof, it is to be understood that the foregoingdescription as well as the examples which follow are intended to illustrate andnot limit the scope of the invention. Other aspects, advantages andmodifications within the scope of the invention will be apparent to those skilledin the art to which the invention pertains.131415Am20222324252627282930323334CA 02265678 1999-03-15WO 98/26837 PCT/US797/2247612Example 1Preparation of Cellulose Acetate lnertFiller-Containing Hvdroqel Polvmer Reservoirinto a 250 mL jacketed glass beaker was added 59.0 g of purified water,USP. A rubber stopper equipped with a powder addition funnel, thermocouplethermometer, and a stainless steel stirring shaft with a Delrin® paddle wasinserted into the mouth of the beaker. The water was stirred with an overheadstirrer while warming to 70°C. Hydroxypropyl methylcellulose (HPMC)(Methocel K—1OOMP, Dow Chemical) was added to the beaker through thepowder addition funnel and the mixture was stirred for 5-10 minutes to preparea uniform dispersion of HPMC in the hot water. Poly(vinyl alcohol), 10.0 g,(Mowiol® 66-100, Hoechst Celanese) was added to the beaker through thepowder addition funnel and the mixture was warmed to about 90°C to 95°C andheld at that temperature for 70 minutes. The poly(vinyl alcohol) solution wascooled to 75°C and 15.0 g of cellulose acetate (Aldrich Chemical) was added tothe beaker in 5.0 g aliquots through the powder addition funnel and stirred for5 to 10 minutes. The poly(vinyl alcohol) solution was cooled to 60°C and 15.0 gof AG 3-X4 (50% HCI form) (BioRad) ion exchange resin was added to thebeaker and the mixture was stirred for 5 to 10 minutes. The poly(vinyl alcohol)solution was transferred into a polypropylene syringe that had been previouslywarmed to 60°C with an aluminum heating block, and the poly(vinyl alcohol)solution was dispensed with a Multicore Solder Paste Dispenser into 2.0 cm2 x0.16 cm foam mold hydrogel reservoirs. The filled hydrogel reservoirs wereplaced into a -20°C freezer for 18 hours and then removed from the freezer andallowed to warm to 4°C over an eight—hour interval. The hydrogel containingthe cellulose acetate inert filler was subsequently used for drug delivery studies.Example 2Preparation of Acrylic/Divlnvlbenzene InertFiller-Containin<LHvdroqel Polymer ReservoirInto a 250 mL jacketed glass beaker was added 39.0 g of purified water,USP, and a rubber stopper equipped with a powder addition funnel,thermocouple thermometer, and a stainless steel stirring shaft with a Delrin®paddle was inserted into the mouth of the beaker. The water was stirred withWO 98/26837222324252627CA 02265678 1999-03-15PCTIUSY97/2247613an overhead stirrer while warming to 70°C. Hydroxypropyl methylcellulose(HPMC) (Methocel K-10OMP, Dow Chemical) was added to the beaker throughthe powder addition funnel and the mixture was stirred for 5-10 minutes toprepare a uniform dispersion of HPMC in the hot water. Poly(vinyl alcohol),10.0 g, (Mowiol 66-100, Hoechst Celanese) was added to the beaker throughthe powder addition funnel and the mixture was warmed to 90°C to 95°C andheld at that temperature for 70 minutes. The poly(vinyl alcohol) solution wascooled to 75°C and 35.0 g of acrylic/divinylbenzene crosslinked polymer beads(Amberlite® XAD—7; Rohm & Haas) was added to the beaker through thepowder addition funnel and stirred for 5 to 10 minutes. The poly(vinyl alcohol)solution was cooled to 60°C and 15.0 g of AG 3-X4 (50% HCI form) (BioRad)ion exchange resin was added to the beaker and the mixture was stirred for5 to 10 minutes. The poly(vinyl alcohol) solution was transferred into apolypropylene syringe that had been previously warmed to 60°C with analuminum heating block and the poly(vinyl alcohol) solution was dispensed witha Multicore Solder Paste Dispenser into 2.0 cm2 x 0.16 cm foam mold hydrogelreservoirs. The filled hydrogel reservoirs were placed into a —20°C freezer for18 hours and then removed from the freezer and allowed to warm to 4°C overan eight hour interval. The hydrogel containing the Amberlite® XAD—7 inertfiller was subsequently used for drug delivery studies.Example 3Preparation of inert FillerGoserelin Acetate-Containinq Polymer ReservoirsThe objective of the experiment was to determine the compatibility of agoserelin acetate solution with various filler materials listed in Table 1 and to ‘assess which materials irreversibly bind goserelin acetate.WO 98/2683714TABLE 1Filler Materials ScreenedDescription Trade Name SourcePolypropylene Mesh Saati Mesh 980/47 SaatiMicronized polyethylene Propyltex 1408 Micronwax PowdersMicronized po|ytetraf|uoro- Fluo 300 Micronethylene PowdersMicronized Fischer-Tropsch MP-22C Micronwax PowdersMicronized Polyethylene Aqua Poly 250 Micronwax PowdersTitanium dioxide Spectraspray White 50802 WarnerFranklinStyrene/divinylbenzene Amberlite® XAD-4 Rohm & HaasresinAcrylic/divinylbenzene resin Amberlite® XAD-7 Rohn & HaasStyrene/divinylbenzene Amberlite® XAD16/1090 Rohn & HaasresinCellulose type 20 Sigmace|l® SigmaDextran/epichlorohydrin Sephadex® G-25 SigmaSilica gel Nucleosil® 100-10 Phenomenex4CA02265678 1999-03-15PCT/US797/22476A 0.15 g sample of the inert filler was weighed into a polypropylene vial and2.5 mL of HPLC—grade water was added. A cap was placed on the vial and thesample was allowed to equilibrate at ambient temperature overnight to assureH12CA 02265678 1999-03-15WO 93125337 PCT/USV97/2247615that the inert filler was completely hydrated prior to the addition of the goserelinacetate solution. The vials were opened and 0.50 mL of a goserelin acetatesolution was added to the sample to provide a 1.0 mg/mL solution of goserelinacetate in contact with the inert filler. The samples were placed on a shaker atambient temperature and samples were removed after 24 hours, 72 hours,1 week, 2 weeks, and 3 weeks and the concentration of goserelin acetate insolution was determined by HPLC assay. Control samples were prepared byadding 2.5 mL of HPLC-grade water and 0.5 mL of the goserelin acetatesolution to yield a 1.0 mg/mL goserelin acetate solution. The control goserelinacetate solutions were stored at 4°C and 25°C and sampled at each timepoint.The HPLC analysis of the goserelin acetate solutions in contact with the inertfiller after three weeks are shown in Table 2.10TCA 02265678 1999-03-15PCTIUS97/22476WO 98/2683716TABLE 2Filler Material Screening Study with Goserelin AcetateFiller Material (Trade Name) Goserelin(% Control)Polypropylene Mesh (Saati Mesh 980/47) 106.4Fluo 300 (Micronized PTFE Wax) 89.9MP—22C (Micronized F—T Wax) 119.3Propyltex 1408 (Micronized PE Wax) 101.8AquaPo|y 250 (Micronized PE Wax) 89.5Magnesium Silicate (123 Talc) 70.2Titanium Dioxide (Spectraspray White 50802) 80.6Dextran/Epichlorohydrin (Sephadex G—25) 86.4Cellulose Type 20 (Sigmacell®) 70.1Cellulose Acetate 108.5Sillca gel (Nucleosil® 100-10) 51.4Poly(vinyl alcohol) (Airvol 103) 92.7The results provided in Table 2 indicate that goserelin acetate is acceptablycompatible with micronized polymeric waxes such as polyethylene and Fischer- 'Tropsch wax based on the HPLC assay of the samples. The polypropylenemesh and cellulose acetate were also acceptable inert fillers since essentiallyno loss of goserelin acetate was detected from the test solution after threeMineral fillers such as titanium dioxide (Spectraspray White 50802).silicon dioxide (Nucleosil® 100-10) and magnesium silicate (123 Talc) incontact with the goserelin acetate solution resulted in an approximately 30% to50% loss of goserelin acetate from the test solution after three weeks.Amberlite® XAD resins in contact with the goserelin acetate test solutionresulted in 0% recovery of goserelin acetate after 24 hours.weeks.

Claims (35)

CLAIMS:

1. An electrotransport agent delivery device (10), comprising a donor electrode (22), a counter electrode (24) and a source of electrical power (32) to be electrically connected to the donor and counter electrodes, wherein the donor electrode (22) is electrically connected to a donor reservoir (26, 28) having a predetermined volume (V) and being comprised of a polymeric matrix containing a predetermined quantity (q) of a therapeutic agent to be delivered, the polymeric matrix also containing an inert filler material having substantially no tendency to interact with the agent, the inert filler being present in the matrix in a form which allows electrotransport of the agent through and from the reservoir to a patient body surface, characterized in that the agent loading in the reservoir is less than 10 wt.% of the total reservoir admixture and the inert filler material is present in the polymeric matrix in an amount up to about 60 vol.% which achieves a concentration (p) of therapeutic agent in the matrix which exceeds q/V.

2. The device of claim 1, wherein the polymeric matrix is comprised of a water-swellable polymer selected from the group consisting of polyvinyl alcohols, polyvinylpyrrolidone, cellulosic polymers, polyurethanes, polyethylene oxide, polyanhydrides, polyvinyl pyrrolidone/vinyl acetate copolymers, and mixtures and copolymers thereof.

3. The device of claim 1, wherein the inert filler material has substantially no tendency to bind, absorb, adsorb or react chemically with the therapeutic agent.

4. The device of claim 1, wherein the inert filler material comprises about 5 vol.% to about 60 vol.% of the polymeric matrix.

5. The device of claim 1, wherein the inert filler material comprises about 20 vol.% to about 60 vol.% of the polymeric matrix.

6. The device of claim 1, wherein the inert filler material comprises about 40 vol.% to about 60 vol. % of the polymeric matrix.

7. The device of claim 1, wherein the inert filler is in the form of solid particles or fibers dispersed in the polymeric matrix.

8. The device of claim 7, wherein the inert filler material is selected from the group consisting of glass beads, polymer powders, polymer beads, polymer solids, cellulose polymers, mineral fillers, and mixtures thereof.

9. The device of claim 1, wherein the inert filler material is comprised of a polymer mesh.

10. The device of claim 9, wherein the polymer mesh is comprised of polypropylene.

11. The device of claim 8, wherein the inert filler is comprised of a polymer powder.

12. The device of claim 11, wherein the polymer powder comprises a micronized polymer with particle size of about 1 µm to about 50 µm.

13. The device of claim 12, wherein the micronized polymer is selected from the group consisting of polyethylene waxes, polypropylene waxes, polytetrafluoroethylene waxes, Fischer-Tropsch waxes, and mixtures thereof.

14. The device of claim 8, wherein the inert material comprises beads of a crosslinked polymeric material.

15. The device of claim 14, wherein the crosslinked polymeric material is selected from the group consisting of acrylic/divinylbenzene coploymers, styrene/divinylbenzene copolymers, and mixtures thereof.

16. The device of claim 8, wherein the inert filler is comprised of a polymer solid.

17. The device of claim 16, wherein the polymer solid is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof.

18. The device of claim 8, wherein the inert filler is comprised of a mineral filler material.

19. The device of claim 18, wherein the mineral filler material is selected from the group consisting of titanium dioxide, mica, quartz powder, talc, and mixtures thereof.

20. The device of claim 1, wherein the agent loading is within the range of about 0.01 wt.% to about 3 wt.%.

21. The device of claim 1, wherein the agent loading is within the range of about 0.1 wt.% to about 2 wt.%.

22. The device of claim 1, wherein the agent concentration within the reservoir is within the range of about 1×10 -4 M to about 1.0 M.

23. A donor reservoir (26, 28) for an electrotransport agent delivery device (10), the reservoir having a predetermined volume (V) and being comprised of a polymeric matrix containing a predetermined quantity (q) of a therapeutic agent to be delivered, the polymeric matrix also containing an inert filler material having substantially no tendency to interact with the agent, the inert filler being present in the matrix in a form which allows electrotransport of the agent through and from the reservoir to a patient body surface, characterized in that the agent loading in the reservoir is less than 10 wt.% of the total reservoir admixture and the inert filler material is present in the polymeric matrix in an amount up to about 60 vol.%
which achieves a concentration (p) of therapeutic agent in the matrix which exceeds q/V.

24. The reservoir of claim 23, wherein the polymer matrix comprises a water-swellable polymer selected from the group consisting of polyvinyl alcohols, polyvinyl pyrrolidone, cellulosic polymers, polyurethanes, polyethylene oxide, polyanhydrides, polyvinyl pyrrolidone/vinyl acetate copolymers, and mixtures and copolymers thereof.

25. The reservoir of claim 23, wherein the inert filler material has substantially no tendency to bind, absorb, adsorb or react chemically with the therapeutic agent.

26. The reservoir of claim 23, wherein the inert filler material comprises about 5 vol.% to about 60 vol.% of the polymeric matrix.

27. The reservoir of claim 23, wherein the inert filler material comprises about 20 vol.% to about 60 vol.%
of the polymeric matrix.

28. The reservoir of claim 23, wherein the inert filler material comprises about 40 vol.% to about 60 vol.%
of the polymeric matrix.

29. The reservoir of claim 23, wherein the inert filler is in the form of solid particles or fibers dispersed in the polymeric matrix.

30. The reservoir of claim 29, wherein the inert filler material is selected from the group consisting of glass beads, polymer powders, polymer beads, polymer solids, cellulose polymers, mineral fillers, and mixtures thereof.

31. The reservoir of claim 23, wherein the inert.
filler is comprised of a polymer mesh.

32. The device of claim 23, wherein the agent loading is within the range of about 0.01 wt.% to about 3 wt.%.

33. The device of claim 23, wherein the agent loading is within the range of about 0.1 wt.% to about 2 wt.%.

34. The device of claim 23 wherein the agent concentration within the reservoir is within the range of about 1×10 -4 M to about 1.0 M.

35. A method for minimizing the therapeutic agent loading of a polymeric donor reservoir (26, 28) for an electrotransport delivery device (10), while maintaining a therapeutic agent concentration (p) of the therapeutic agent in the reservoir above a level required for concentration-independent agent flux without reducing reservoir size or volume, the reservoir containing a predetermined quantity (q) of the therapeutic agent to be delivered, the method comprising providing the reservoir with a therapeutic agent loading of less than 10 wt.% and placing up to about 60 vol.% of an inert filler material in a polymer matrix, the filler material having substantially no tendency to interact with the therapeutic agent, to produce a donor reservoir comprised of therapeutic agent inert filler-containing polymer matrix.