CA2265673C - Polymeric foam reservoirs for an electrotransport delivery device - Google Patents

Abstract

A method is provided for preparing a novel therapeutic agent-containing reservoir (26, 28) for use in conjunction with an electrotransport drug delivery system (10). A polymeric matrix is foamed in a selected atmosphere and then cross-linked to form a polymeric closed-cell foam matrix reservoir (26, 28).
The method enables relatively smaller quantities of therapeutic agent to be loaded into the electrotransport system (10) and is especially useful for the transdermal delivery of more costly drugs, such as peptides and proteins produced from genetically engineered cell lines, and/or highly potent drugs for which a small dosage is efficacious. Reservoirs (26, 28) prepared according to this method and electrotransport devices (10) containing such reservoirs are also provided.

Description

W0 98l2676010H1314151617181920222324' 252627282930CA 02265673 1999-03-llPCT/US97l22474POLYMERIC FOAM RESERVOIRS FOR ANELECTROTRANSPORT DELIVERY DEVICETechnical FieldThis invention relates generally to electrotransport drug delivery.More particularly, the invention relates to a novel method of making a newtype of drug reservoir for incorporation into an electrotransport drug deliverysystem. The invention additionally relates to new drug reservoirs, and toelectrotransport drug 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 absorptionand metabolism encountered in oral treatment are avoided, and otherinherent inconveniences -- e.g., gastrointestinal irritation and the like --are eliminated as well. Transdermal drug delivery also makes possible ahigh degree of control over 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 activelytransport drugs into the body through intact skin. The method of the inventionrelates to such an administration technique, i.e., to "electrotransport" or"iontophoretic" drug delivery.Herein the terms "electrotransport", "iontophoresis", and "iontophoretic"are used to refer to the transdermal delivery of pharmaceutically active agentsby means of an applied electromotive force to an agent—containing reservoir.WO 98/2676010V121314151617181920222324252627282930CA 02265673 1999-03-llPCT/US97/22474The agent may be delivered by electromigration, electroporation,electroosmosis or any combination thereof. Electroosmosis has also beenreferred to as electrohydrokinesis, electro-convection, and electrically inducedosmosis. In general, electroosmosis of a species into a tissue results fromthe migration of solvent in which the species is contained, as a result ofthe application of electromotive force to the therapeutic species reservoir,i.e., solvent flow induced by electromigration of other ionic species. Duringthe electrotransport process, certain modifications or alterations of the skinmay occur such as the formation of transiently existing pores in the skin,also referred to as "electroporation". Any electrically assisted transportof species enhanced by modifications or alterations to the body surface(e.g., formation of pores in the skin) are also included in the term"electrotransport" as used herein. Thus, as used herein, the terms"electrotransport", "iontophoresis" and "iontophoretic" refer to (1) the deliveryof charged drugs or agents by electromigration, (2) the delivery of unchargeddrugs or agents by the process of electroosmosis, (3) the delivery of chargedor uncharged drugs by electroporation, (4) the delivery of charged drugs oragents by the combined processes of electromigration and electroosmosis,and/or (5) the delivery of a mixture of charged and uncharged drugs or agentsby the combined processes of electromigration and electroosmosis.Systems for delivering ionized drugs through the skin have beenknown for some time. British Patent Specification No. 410,009 (1934)describes an iontophoretic delivery device which overcame one of thedisadvantages of the early devices, namely, the need to immobilize thepatient near a source of electric current. The device was made by forming,from the electrodes and the material containing the drug to be delivered,a galvanic cell which itself produced the current necessary for iontophoreticdelivery. This device allowed the patient to move around during drug deliveryand thus required substantially less interference with the patient's dailyactivities than previous iontophoretic delivery systems.WO 98/26760-A10N1213141516181920222324252627282930CA 02265673 1999-03-llPCT/US97I22474ln present electrotransport devices, at least two electrodes are used.Both of these electrodes are disposed so as to be in intimate electricalcontact with some portion of the skin of the body. One electrode, called theactive or donor electrode, is the electrode from which the drug is deliveredinto the body. The other electrode, called the counter or return electrode,serves to close the electrical circuit through the body. In conjunction with thepatient's skin, the circuit is completed by connection of the electrodes to asource of electrical energy, e.g., a battery, and usually to circuitry capable ofcontrolling current passing through the device. If the ionic substance to bedriven into the body is positively charged, then the positive electrode (theanode) will be the active electrode and the negative electrode (the cathode)will serve as the counter electrode, completing the circuit. If the ionicsubstance to be delivered is negatively charged, then the cathodic electrodewill be the active electrode and the anodic electrode will be the counterelectrode.Existing electrotransport devices additionally require a reservoir orsource of the pharmaceutically active agent which is to be delivered orintroduced into the body. Such drug reservoirs are connected to the anodeor the cathode of the electrotransport device to provide a fixed or renewablesource of one or more desired species or agents.Thus, an electrotransport device or system, with its donor andcounter electrodes, may be thought of as an electrochemical cell havingtwo electrodes, each electrode having an associated half cell reaction,between which electrical current flows. Electrical current flowing throughthe conductive (e.g., metal) portions of the circuit is carried by electrons(electronic conduction), while current flowing through the liquid—containingportions of the device (i.e., the drug reservoir in the donor electrode,the electrolyte reservoir in the counter electrode, and the patient's body)is carried by ions (ionic conduction). Current is transferred from the metalportions to the liquid phase by means of oxidation and reduction chargeWO 98/2676010H121314151617181920222324252627282930CA 02265673 1999-03-llPCT/US97I22474transfer reactions which typically occur at the interface between the metalportion (e.g., a metal electrode) and the liquid phase (e.g., the drug solution).A detailed description of the electrochemical oxidation and reduction chargetransfer reactions of the type involved in electrically assisted drugtransport can be found in electrochemistry texts such as J.S. Newman,Electrochemical Systems (Prentice Hall, 1973) and A.J. Bard and L.R.Faulkner, Electrochemical Methods, Fundamentals and Applications(John Wiley & Sons, 1980).The present invention is directed to novel polymeric foam matrix drugreservoirs for use in conjunction with an electrotransport drug delivery systemand methods of making these new reservoirs. In contrast to methods formaking prior drug reservoirs for use in such systems and in contrast to priordrug reservoirs, the present method provides a reservoir that enables smallerquantities of drug to be loaded into the system. This is an importantconsideration with respect to more costly drugs, such as peptides andproteins produced from genetically engineered cell lines, and/or highly potentdrugs for which a small dosage is efficacious. With such drugs, it is desirableto decrease the amount of drug loaded into the reservoir.Typically, for drug delivery using transdermal drug delivery devices it ispreferred that drug flux is independent of the concentration of drug in thereservoirs. Decreasing drug loading has the effect of decreasing theconcentration of drug in the reservoir to a point where drug flux becomesdependent on reservoir drug concentration. Thus, it is desirable to maintainhigher drug concentration in the drug reservoir.Although it is possible to reduce both the drug loading and the volumeof the reservoir, thereby maintain the drug concentration above a levelrequired for concentration-independent drug flux, there are limits on howsmall the drug reservoir may be. For example, if the volume of the donorreservoir is reduced by decreasing the skin contact area the potential for skinirritation, i.e., irritation caused by the applied electric current and/or the drugW0 98l2676010H121314161718192022232425262728CA 02265673 1999-03-llPCT/US97l22474being delivered, increases. If the volume of the donor reservoir is reduced bydecreasing the thickness of the reservoir, the potential for electrical shortingbetween the electrodes and the skin increases. In addition, thinner reservoirsare inherently more difficult to manufacture with precise uniformity.Thus, there is a need for a method of reducing electrotransport donorreservoir drug loading without reducing reservoir size or volume.Description of the InventionAccordingly, it is a primary aspect of the invention to provide amethod for preparing a novel drug reservoir for use in conjunction with anelectrotransport drug delivery system, which overcomes the above—mentionedlimitations in the art.It is another aspect of the invention to provide a method for making anovel therapeutic agent-containing polymeric foam reservoir having apredetermined volume for use in electrotransport drug delivery, which methodinvolves foaming a polymeric matrix that contains a cross-linkable polymer.It is still another aspect of the invention to provide such a methodwhich involves foaming an admixture of a therapeutic agent and a polymericmatrix that contains a cross-linkable polymer.It is a further aspect of the invention to provide such a method whichinvolves the incorporation of air, carbon dioxide, oxygen, nitrogen, noblegases, or other gas or gases into a polymeric matrix such that the resultingtherapeutic agent-containing polymeric reservoir has a relatively high surfacearea with respect to the amount of polymeric matrix used.It is still a further aspect of the invention to provide a method forpreparing a therapeutic agent-containing polymeric foam reservoir capable oftransdermally delivering peptides, proteins, or fragments thereof.WO 98/2676010?1213141516171819202223242526272829CA 02265673 1999-03-llPCT/US97/22474It is still another aspect of the invention to provide an electrotransportdrug delivery device capable of cost-effectively delivering peptides, proteins,or fragments thereof.Additional aspects, advantages and novel features of the invention willbe set forth in part in the description which follows, and in part will becomeapparent to those skilled in the art upon examination of the following, or maybe learned by practice of the invention.in one embodiment of the invention, then, a method is provided formaking a therapeutic agent-containing polymeric reservoir having apredetermined volume for incorporation into an electrotransport agent deliverysystem adapted to deliver the therapeutic agent by electrotransport throughan animal body surface. The method comprises placing a predeterminedamount of the therapeutic agent in a polymer matrix to produce adrug—containing polymer matrix, foaming the polymer matrix with a gas,and cross linking the foamed matrix to produce a polymeric closed cell foamreservoir matrix having a predetermined pore volume. Once the foamedmatrix is hydrated with a liquid solvent used to solubilize the therapeuticagent, the closed foam cells contain the gas and are substantially free ofthe therapeutic agent and the liquid solvent.in a preferred embodiment of the invention, a method is providedfor preparing a drug reservoir to be incorporated in an electrotransportdrug delivery device, the method comprising foaming a polymeric mixtureof polyvinyl alcohol by rapidly stirring the mixture in a selected atmosphereto produce a polymeric foam. A therapeutic agent is added to the polymericfoam, and the drug—containing foam is frozen and then allowed to warm toambient temperature. Alternatively, the polymeric foam may be frozen andthawed, and a therapeutic agent added to the polymeric foam at a later time,but prior to its use in conjunction with the electrotransport drug deliverydevice.WO 98/2676010M1213141516171819202223242526272829CA 02265673 1999-03-llPCT/US97/22474In another embodiment of the invention, a therapeutic agent—containingpolymeric reservoir having a predetermined volume is provided whichcomprises a chemically cross-linked polymeric closed-cell foam matrixcontaining a predetermined amount of the therapeutic agent and apredetermined volume percent of closed foam cells.In still another embodiment of the invention, a therapeutic agent-containing polymeric reservoir having a predetermined volume is providedwhich comprises a polymeric closed-cell foam matrix cross—linked byexposure to actinic radiation and which contains a predetermined amount ofthe therapeutic agent and a predetermined volume percent of closed foamcells.In a further embodiment of the invention, an electrotransport drugdelivery system is provided which incorporates the aforementioned polymericfoam reservoir. The system contains a donor electrode, a counter electrode,a source of electrical power, and the polymeric reservoir containing thetherapeutic agent to be delivered, typically present as part of the donorelectrode.Brief Description of the DrawingFIG. 1 is a perspective exploded view of one embodiment of anelectrotransport drug delivery system which may be used in conjunction withdrug formulations made using the inventive method.Modes for Carrying Out the InventionBefore describing the present invention in detail, it is to be understoodthat this invention is not limited to particular drugs, carriers, electrotransportdelivery systems, or the like, as such may vary.WO 98/2676010V1213141516171920222324252627282930CA 02265673 1999-03-llPCT/US97/22474It must be noted that, as used in this specification and the appendedclaims, the singular forms "a", "an" and "the" include plural referents unlessthe context clearly dictates othenivise. Thus, for example, reference to "adrug" or "a therapeutic agent" includes a mixture of two or more drugs oragents, reference to "a polymer" includes two or more polymers, and the like.Unless defined othen/vise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although any methods and materialssimilar or equivalent to those described herein can be used in the practice fortesting of the present invention, the preferred materials and methods aredescribed herein.In 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 activeagent" as used herein is meant any chemical material or compound whichinduces a desired local or systemic therapeutic effect, and is capable of beingdelivered by electrotransport. Examples of such substances will be set forthbelow.The term "solvent—containing polymer" refers to a polymer that cancontain by absorption and/or adsorption an amount of any liquid solventcapable of dissolving a therapeutic agent of interest and/or the salt form ofthe agent in an amount sufficient to allow ions to pass while current is appliedto a drug reservoir containing such polymer that is incorporated into anelectrotransport drug delivery device. Preferably, the polymer will be capableof containing at least about 20 wt.% of the solvent. A particularly preferredsolvent is water due, at least in part, to its excellent biocompatibility. A"hydrogel" is a solvent—containing polymer capable of absorbing at least about20 wt.% of water.By "polymer matrix" is intended to refer to a solution of a polymer in anappropriate solvent, a solvent—containing polymer that has swollen byWO 98126760H12131415161718202223242526272829CA 02265673 1999-03-llPCT/US97/22474absorption or adsorption of the solvent, a composition comprising adispersed, solvent—containing polymer phase combined with a continuous,solvent phase to form a viscous, colloidal composition, or other form ofpolymer matrix that has the chemical and/or physical characteristics that allowthe formation of a foamed polymeric matrix therefrom, e.g., viscosity,surfactant properties, and the like.By "foaming a polymer matrix" is intended to mean a process wherebya plurality of gas-containing pockets or "cells" is introduced throughout apolymer matrix, thereby producing a "foamed polymer matrix." A "closed-cellpolymer foam" is a foamed polymer matrix in which gas-containing cells arediscrete and the gas phase of each cell is independent of that of the othercells.The method of the invention involves foaming a therapeutic agent-containing polymeric matrix and cross linking the foamed matrix. Thepolymeric matrix is typically, although not necessarily, an aqueous solution,preferably containing between about 1 wt.% to 50 wt.% polymer. Relativelysmall quantities of the therapeutic agent, between about 0.001 wt.% to about10 wt.%, preferably 0.01 wt.% to about 3 wt.%, and more preferably about0.1 wt.% to about 2 wt.% of total admixture, is all that is typically required.Alternatively, the therapeutic agent may be incorporated into the foamedpolymeric matrix after the foaming process is complete.Suitable polymers that may be used to prepare a foamed polymericmatrix and cross linked to provide the foamed reservoir include polyvinylalcohols, polyvinyl pyrrolidones, cellulosic polymers, e.g., hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,carboxymethyl cellulose, and the like, polyurethanes, polyethylene oxides,polyanhydrides, polyvinyl pyrrolidone/vinyl acetate copolymers, mixtures ofthese polymers and copolymers, and the like. One preferred polymer ispolyvinyl alcohol.W0 98l2676010M1213141516171819202223242526272829CA 02265673 1999-03-llPCT/US97l224741 OFoaming a polymer matrix may be accomplished by any chemical orphysical method known in the art. Typically, cellular polymers may be madeby extrusion, spraying, frothing, compression molding, injection molding,sintering, leaching, or the like. Foam formation may be accomplished bystirring a polymer solution with a high speed, high shear mixing apparatusand/or by an apparatus that injects gas into a solution of the polymer.See Perkins et al. (1983) National Technical Conference, Am. Assoc.Textile Chemists and Colorists, pp. 147-151, for a schematic diagram ofa foam generating device.In one preferred method, foaming is accomplished by rapidly stirringa solution of the polymer in a selected atmosphere of air, carbon dioxide,oxygen, nitrogen, noble gases, other gas or gases, or mixtures thereof.The stirring causes gas from the selected atmosphere to be incorporated intothe matrix, forming bubbles within the matrix. The gas bubbles act as an inertfiller, increasing the surface area of the matrix without introducing thedrawbacks of common "inert" fillers, such as glass beads, titanium dioxide,quartz powder, polymer powders, etc., to which therapeutically active agentsmay bind.Another preferred method of preparing a foamed polymer matrix isby decompression expansion. In this method, a solution of a volatileblowing agent in molten polymer is formed in an extruder under pressure.The solution is forced through an orifice onto a receiving substrate at ambienttemperature and pressure. The volatile blowing agent evaporates andcauses the polymer to expand. Dimensional stability is achieved uponcooling or other cross-linking method as described below.Yet another preferred method for foaming a polymeric matrix that isparticularly preferred when the polymer matrix comprises polyvinyl alcohol,is by a frothing process because it can be performed at ambient temperature.The frothing process involves dispersing a gas in a fluid that has surfaceWO 98/2676010V1213141516171819202223242526272829CA 02265673 1999-03-llPCT/US97l224741 1properties suitable for producing a foam. The foam can be permanentlystabilized by cross-linking as described below.Optionally, foam formation-enhancing additives can be added to thepolymeric matrix prior to the foaming process. Examples of such additivesinclude anionic surfactants, e.g., sodium lauryl sulfate, nonionic surfactants,e.g., ethyoxylated linear alcohols and ethoxylated alkyl phenols, and soaps,e.g., ammonium stearate.A technical consideration in a foam system is that the foam must havea workable viscosity. High viscosity polymeric matrices are generally moredifficult to foam and form foams having high viscosity. The viscosity of a foamprepared from a low viscosity polymeric matrix depends on the blow ratio.The volume of the polymeric foamed matrix is also a function of blowratio as well as the cell size of the foamed matrix. The blow ratio relates tothe ratio of the volume of the final foam product to the volume of thepolymeric matrix. Thus, a blow ratio of 1 indicates a doubling in volume(ratio = 1:1), with the total volume of the cell being about 50 vol.% of thepolymeric matrix, while a blow ratio of 7 represents an 8-fold increase involume, with the total volume of the cells being 87.5% of the polymeric matrix.Accordingly, polymeric matrices can be prepared in which the total cellvolume, i.e., the volume occupied by the gas component of the polymericfoamed matrix, is in the range of about 25 vol.% to about 90 vol.%.The drug-containing polymeric foam is then cross—linked to produce atherapeutic agent-containing closed-cell polymeric foam. Cross-linking maybe accomplished by any method known in the art. In particular, cross—|inkingmay be accomplished by freezing and thawing the matrix, by exposing thematrix to electromagnetic radiation or by incorporating a chemical cross-linking agent in the matrix.Preferably, if the polymeric matrix is prepared from polyvinyl alcohol,the foamed polymeric matrix is cross—linked by freezing and thawing theWO 98/2676010Y121314151617181920222324252627282930CA 02265673 1999-03-llPCT/US97l224741 2matrix. The foamed polymeric matrix is frozen at a temperature in the rangeof -10°C to —35°C, typically around -20°C, for hold-time of at least about15 seconds to about 24 hours, preferably about 30 seconds to 12 hours,more preferably about 30 seconds to 2 hours. The foam is then allowedto warm to a thaw temperature in the range of about -5°C to about 20°C,i.e., ambient temperature, preferably -5°C to about 5°C, more preferably-5°C to 0°C, at which point it may be incorporated directly into anelectrotransport drug delivery system. The dwell-time at the thawtemperature ranges can be as long as 24 hours, preferably in the range ofabout 1 to 12 hours, more preferably about 1 hourto six hours. In general,the extent of cross-linking increases in direct proportion with the thawtemperature and the dwell—time at that temperature. Optionally, thefreeze/thaw cycle may be repeated at least once and as many as 10 ormore times. Preferably, the freeze/thaw cycle is repeated between about1 and 5 times. This freeze/thaw cycle allows the polymeric matrix to formphysical cross-links without the need for chemical cross-linking agents suchas formaldehyde, glyoxal and butyraldehyde, which are known skin irritantsand may be difficult to remove from the foamed polymer matrix. Additionalcycles of freezing and thawing typically yields a foam with greater densityand structural rigidity. The preparation of polyvinyl alcohol matrices byfreeze/thaw cycling has been described in, e.g., U.S. Patent Nos. 4,524,064,4,664,857 and 4,925,603 to Nambu, 4,734,097 to Tanabe et al., 4,808,353to Nambu et al., 4,988,771 to lkada et al., and 5,141,973 to Kobayashi et al.Alternatively, the foamed polymeric matrix may be cross—linked byexposure to electromagnetic radiation, such as electron beam radiation,gamma radiation, ultraviolet radiation, and the like. Typically, a polymersolution is prepared and foamed as described above and then exposed toelectromagnetic radiation by methods well known in the art to cross-link thepolymer and trap the gas bubbles in a closed cell structure. Since manydrugs may be degraded by exposure to most forms of electromagneticWO 98/2676010?121314151617181920222324252627282930CA 02265673 1999-03-llPCT/US97/224741 3radiation, it is preferred that the therapeutic agent is added to the polymericmatrix after the cross linking process is complete. The therapeutic agent maybe incorporated into the cross-linked polymeric matrix by impregnation,absorption or the like.An additional means for cross-linking the foamed polymeric matrix isby incorporating a chemical cross-linking agent into the matrix. Examplesof cross-linking agents include aldehydes, epoxides, borax, diisocyanates,and the like, and mixtures thereof; the specific cross-linking agent will dependon the polymer used to prepare the foamed polymeric matrix. For example,cellulosic polymers can be cross-linked using formaldehyde or variousN-methylol compounds, e.g., hydantoins, triazones, and the like, in thepresence of a strong acid, diepoxides, e.g., vinylcyclohexene dioxide,butadiene dioxide, diglycidyl ether, and the like, in the presence of strongbases, and aziridine compounds, e.g., tris(1—aziridinyl)phosphine oxide andtris(aziridiny|)triazine. Polyurethanes may be cross-linked using aromaticisocyanates such as toluene diisocyanate and 4,4'diphenylmethanediisocyanate and aliphatic isocyanates such as isophorone diisocyanate,hydrogenated 4,4'—diphenylmethane diisocyanate, trimerized hexamethylenediisocyanate. A sufficient amount of cross-linking agent is used to producethe desired extent of cross-linking and density of the foamed polymerixmatrix, but preferably less than that which would result in any unconsumedmaterial. However, if excess cross-linking agent is present after foamedpolymeric matrix formation, it is preferably removed using a simple washingstep.The method of the invention alternatively may involve foaming apolymeric mixture, without the therapeutic agent to be delivered. Forexample, rapid stirring of the mixture (which is typically, again, an aqueoussolution) in a selected atmosphere of air, carbon dioxide, oxygen, nitrogen,noble gases, other gas or gases, or mixtures thereof may be used to producea polymeric foam. Then, the therapeutic agent is added to the polymericWO 98/2676010H121314151617181920222324252627282930CA 02265673 1999-03-llPCT/US97/224741 4foam by impregnation, absorption, or the like, and the therapeutic agent-containing foam is cross~linked as described above to produce a cross-linkedpolymeric matrix.Alternatively, the therapeutic agent may be incorporated into the cross-linked polymeric matrix, again, by impregnation, absorption or the like. Theresulting therapeutic agent—containing matrix may then be used as a drugreservoir in an electrotransport drug delivery system.As noted above, drugs, therapeutic or active agents useful inconnection with the present invention include any pharmaceutical compoundor chemical that is capable of being delivered by electrotransport. In general,this includes agents in all of the major therapeutic areas including, but notlimited to, anti-infectives such as antibiotics and antiviral agents, analgesicsincluding fentanyl, sufentanil, buprenorphine and analgesic combinations,anesthetics, anorexics, antiarthritics, antiasthmatic agents such asterbutaline, anticonvulsants, antidepressants, antidiabetic agents,antidiarrheals, antihistamines, anti-inflammatory agents, antimigrainepreparations, antimotion sickness preparations such as scopolamine andondansetron, antinauseants, antineoplastics, antiparkinsonism drugs,antipruritics, antipsychotics, antipyretics, antispasmodics, includinggastrointestinal and urinary anticholinergics, sympathomimetrics, xanthinederivatives, cardiovascular preparations including calcium channel blockerssuch as nifedipine, beta—b|ockers, beta-agonists such as dobutamine andritodrine, antiarrythmics, antihypertensives such as atenolol, ACE inhibitorssuch as rinitidine, diuretics, vasodilators, including general, coronary,peripheral and cerebral, central nervous system stimulants, cough and coldpreparations, decongestants, diagnostics, hormones such as parathyroidhormone, bisphosphoriates, hypnotlcs, immunosuppressives, musclerelaxants, parasympatholytics, parasympathomimetrics, prostaglandins,psychostimulants, sedatives and tranquilizers. The invention is particularlyuseful in conjunction with the electrotransport delivery of proteins, peptidesWO 98/2676010M141516181920222324252627282930CA 02265673 1999-03-llPCT/US97l224741 5and fragments thereof, whether naturally occurring, chemically synthesized orrecombinantly produced.With respect to the delivery of peptides, polypeptides, proteins andother such species, these substances typically have a molecular weight ofat least about 300 daltons, and more typically have a molecular weight of atleast about 300 to 40,000 daltons. Specific examples of peptides andproteins in this size range include, without limitation, GHRH, GHRF, insulin,insultropin, calcitonin, octreotide, endorphin, TRH, NT-36 (chemical name:N—[[(s)-4-oxo-2-azetidinyl]carbony|]-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, epoprostenol (plateletaggregation inhibitor), glucagon, HCG, hirulog, hyaluronidase, interferon,interleukins, menotropins (urofollitropin (FSH) and LH), oxytocin,streptokinase, tissue plasminogen activator, urokinase, vasopressin,desmopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensinII antagonists, antidiuretic hormone agonists, bradykinin antagonists, CD4,ceredase, CSl's, enkephalins, FAB fragments, lgE peptide suppressors,|GF—1, neurotrophic factors, colony stimulating factors, parathyroid hormoneand agonists, parathyroid hormone antagonists, prostaglandin antagonists,pentigetide, protein C, protein S, renin inhibitors, thymosin alpha-1,thrombolytics, TNF, vaccines, vasopressin antagonists analogs, alpha-1antitrypsin (recombinant), and TGF-beta.Luteinizing hormone-releasing hormone ("LHRH") and LHRH analogssuch as goserelin, buserelin, gonadorelin, napharelin and leuprolide,represent another class of peptides and proteins in this size range that areuseful in connection with the present invention. One preferred LHRH analogis goserelin. Goserelin is a synthetic decapeptide analogue of LHRH havingCA 02265673 2005-08-0563189-6451516232425262728293016the chemical structure pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg—Pro-Azgly-NH2. The drug is useful in the treatment of prostate and breast cancersand in certain gynecological conditions.It will be appreciated by those working in the field that the presentmethod can be used in conjunction with a «wide variety of electrotransportdrug delivery systems, as the method is not limited in any way in this regard.For examples of electrotransport drug delivery systems, reference may behad to U.S. Patent Nos. 5,147,296 to Theeuwes et al., 5,080,646 toTheeuwes et al., 5,169,382 to Theeuwes et al., and 5,169,383 to Gyory et al.FIG. 1 illustrates a representative electrotransport delivery device thatmay be used in conjunction with the present drug reservoirs. Device 10comprises an upper housing 16, a circuit board assembly 18, a lower housing20, anode electrode 22, cathode electrode 24, anode reservoir 26, cathodereservoir 28, and skin-compatible adhesive 30. Upper housing 16 has lateralwings 15 which assist in holding device 10 on a patient's skin. Upper housing.16 is preferably composed of an injection moldable 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,the upper surface 34 of adhesive 30 being adhered to both lower housing20 and upper housing 16 including the bottom surfaces of wings 15.Shown (partially) on the underside of circuit board assembly 18 is abutton cell battery 32. Other types of batteries may also be employed topower device 10.Device 10 is generally comprised of battery 32, electronic circuitry19,40, electrodes 22,24, and polymeric foam matrix drug reservoirs 26,28,W0 9812676010H1213141617181920212223242526272829CA 02265673 1999-03-llPCTIUS97/224741 7all of which are integrated into a self-contained unit. The outputs (not shownin FIG. 1) of the circuit board assembly 18 make electrical contact with theelectrodes 24 and 22 through openings 23,23’ in the depressions 25,25‘formed in lower housing 20, by means of electrically conductive adhesivestrips 42,42’. Electrodes 22 and 24, in turn, are in direct mechanical andelectrical contact with the top sides 44',44 of drug reservoirs 26 and 28.The bottom sides 46',46 of drug reservoirs 26,28 contact the patient's skinthrough 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 deliversa predetermined DC current to the electrode/reservoirs 22,26 and 24,28 for adelivery interval of predetermined length. The push button switch 12 isconveniently located on the top side of device 10 and is easily actuatedthrough clothing. A double press of the push button switch 12 within a shorttime period, e.g., three seconds, is preferably used to activate the device fordelivery of drug, thereby minimizing the likelihood of inadvertent actuation ofthe device 10. Preferably, the device transmits to the user a visual and/oraudible confirmation of the onset of the drug delivery interval by means oflight-emitting diode ("LED") 14 becoming lit and/or an audible sound signalfrom, e.g., a "beeper". Drug is delivered through the patient's skin byelectrotransport. e.g., on the arm, over the predetermined delivery interval.Anodic electrode 22 is preferably comprised of silver and cathodicelectrode 24 is preferably comprised of silver chloride. Both reservoirs 26and 28 are comprised of foamed polymeric materials as described above.Electrodes 22,24 and reservoirs 26,28 are retained by lower housing 20.The polymeric foam matrix reservoirs 26 and 28 contain drug solutionuniformly dispersed in at least one of reservoirs 26 and 28. Drugconcentrations in the range of approximately 1 x 10'“ M to 1.0 M or more can....«»........4..-......:..«..... ...u..t..... , WO 98/2676010H1213141516171819202223242526272829CA 02265673 1999-03-llPCT/US97l224741 8be used, with drug concentrations in the lower portion of the range beingpreferred.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 composedof rubber or other elastomeric material. Lower housing 20 is preferablycomposed of a plastic or elastomeric sheet material (e.g., polyethylene) whichcan be easily molded to form depressions 25,25‘ and cut to form openings23,23‘. The assembled device 10 is preferably water resistant (i.e., splashproof) and is most preferably waterproof. The system has a low profile thateasily conforms to the body, thereby allowing freedom of movement at, andaround, the wearing site. The reservoirs 26 and 28 are located on the skin-contacting side of the device 10 and are sufficiently separated to preventaccidental electrical shorting during normal handling and use.The device 10 adheres to the patient's body surface (e.g., skin) bymeans of a peripheral adhesive 30 which has upper side 34 and body-contacting side 36. The adhesive side 36 has adhesive properties whichassures that the device 10 remains in place on the body during normal useractivity, and yet permits reasonable removal after the predetermined (e.g.,24-hour) wear period. Upper adhesive side 34 adheres to lower housing 20and retains the electrodes and polymeric foam matrix drug reservoirs withinhousing depression 25,25‘ as well as retains lower housing 20 attached toupper 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 thoseskilled in the art to which the invention pertains.WO 98/2676010T121314151617181920CA 02265673 1999-03-llPCT/US97/224741 9Example 1Preparation of 10 wt.% Polvvinvl AlcoholPolvmeric Foam ReservoirA commercial grade of polyvinyl alcohol (average degree ofpolymerization = 5100; average molecular weight = 224 kDa; degree ofhydrolysis = 99.7 mol.%) was purified by extraction with three portionsdeionized water and one portion isopropyl alcohol. A 10 wt.% solution ofpolyvinyl alcohol was prepared by heating a mixture of 10.0 gm of the purifiedpolyvinyl alcohol in 90.0 gm of deionized water at 90°C for approximately70 minutes. The polyvinyl alcohol solution was allowed to cool to ambienttemperature and a 20.0 gm aliquot of the solution was transferred into abeaker. The solution was stirred vigorously with a pitched turbine blade(Caframo mixer) at a rate of about 2000 rpm. Approximately 50 mL of a whitefoam was obtained after about one hour of stirring.The foam was poured into cylindrical ethylene vinyl acetate molds havinga dimension of 8 cm2 by 0.16 cm, and frozen in an environmental chamber atabout —20°C for about 24 hours. The frozen foam was then removed from theenvironmental chamber and allowed to warm to ambient temperature. Theresulting cross—linked polymer matrix was soft and spongy, and maintainedacceptable structural integrity for at least two weeks at ambient temperature.CA 02265673 l999-03- 11WO 98/26760 PCT/US97l22474201 Example 22 Preparation of a 10 wt.% Polvvinvl Alcohol3 Polymeric Foam Reservoir Cross-linked Using4 Freeze—Thaw Cycling5 A polyvinyl alcohol foam prepared and poured into a mold as described inCDExample 1 was cross-linked by exposure to 3 cycles of freezing at —20°C for7 2 hours and warming "to 5°C for 30 minutes. The polyvinyl alcohol foam wass cross-linked and had a greater cross-link density than with a single 24-hour(0exposure at -20°C as described in Example 1 and resulted in a more10 structurally rigid foam.1112 Example 313 Preparation of Citrate—buffered14 15 wt.% Polvvinvl Alcohol Polvmeric Foam Reservoir15 The methods described in Examples 1 and 2 are used to make polymeric15 foam reservoirs using a solution containing 15 wt.% polyvinyl alcohol,17 0.24 wt.% citric acid, 0.37 wt.°/o trisodium citrate and 0.1 wt.% sodium1a chloride instead of a 10 wt.% solution of polyvinyl alcohol.1920 Example 421 Preparation of 15 wt.% Polvvinvl Alcohol22 Polymeric Foam Reservoir23 Containing Goserelin Acetate24 The methods described in Examples 1 and 2 are used to25 make polymeric foam reservoirs using a solution containing 15 wt.% polyvinyl26 alcohol and 1.5 mM goserelin instead of a 10 wt.% solution of polyvinyl27 alcohol.WO 98/2676010H1314151617181920222324252627282930CA 02265673 1999-03-llPCT/US97/224742 1Example 5Preparation of 15 wt.% Polvvinvl AlcoholPolvmeric Foam ReservoirContaining Fentanvl HydrochlorideThe methods described in Examples 1 and 2 are used to makepolymeric foam reservoirs using a solution containing 15 wt.% polyvinylalcohol, 1.74 wt.% fentanyl hydrochloride and 0.17 wt.% urocanic acid insteadof a 10 wt.% solution of polyvinyl alcohol.Example 6Electrotransport Studies Using aPolvmeric Foam ReservoirContaining GoserelinPermeation Cell Assembly:Electrotransport studies can be conducted using two-compartmentpolycarbonate permeation cells designed to evenly support drug—containingfoamed polymeric matrices. A silver chloride extruded laminate is overlaid onan electrode support and sealed to the receptor compartment using double-sided adhesive tape. Human cadaver epidermis (abdomen, 2 cm2) isadhered to the grid support on the receptor cell using adhesive tape, with thestratum corneum facing the donor compartment.The drug—containing polymeric foam reservoir containing goserelinprepared as described in Example 4 is seated into the anode housingsconsisting of a silver electrode and a foam mold. This assembled donorcompartment is overlaid onto the epidermis and the electrode support issecured to complete the permeation cell.Preparation of Human Epidermis:Heat—stripped human epidermis is used for the electrotransport studies.The epidermis is separated from the dermal layer by immersing the tissue inwater at 60°C for 90 seconds.CA 02265673 l999-03- 11WO 98/26760 PCT/US97l2247422Preparation of Solutions:_:2 The receptor solution consists of full strength, 0.15 M Dulbecco'sphosphate buffered saline ("DPBS"), pH 7.4.Analytical Methods:(.0A5 In vitro delivery samples are analyzed as follows: a 1 mL sample is6 transferred to a polypropylene scintillation vial and 10 mL Ready Safe®7 scintillation cocktail was added to the vial. The vial is shaken gently anda placed in the liquid scintillation counter.10 Example 711 Electrotransport Studies Using a12 Polvmeric Foam Reservoir13 Containinq Fentanyl Hydrochloride14 The methods of Example 6 substituting the polymeric foam reservoir15 containing fentanyl hydrochloride as described in Example 5 are used to16 study the electrotransport delivery of fentanyl hydrochloride.

Claims (22)

CLAIMS:

1. A method of making a therapeutic agent-containing polymeric reservoir having a predetermined volume, the reservoir being for incorporation into an electrotransport agent delivery system adapted to deliver the therapeutic agent by electrotransport through an animal body surface, comprising:
(a) placing a predetermined amount of the therapeutic agent in a polymer matrix to produce an agent-containing polymer matrix;
(b) foaming the polymer matrix with a gas to produce a polymeric foam matrix; and (c) cross-linking the polymeric foam matrix to produce a polymeric closed-cell foam matrix reservoir having a predetermined pore volume, the matrix, upon hydration with a liquid solvent used to solubilize the therapeutic agent, having closed foam cells containing the gas and being substantially free of the therapeutic agent and the liquid solvent.

2. The method of claim 1, wherein the closed cells comprise 25 to 90 vol.% of the polymeric foam matrix.

3. The method of claim 1 or 2, wherein the polymeric foam matrix is cross-linked using electromagnetic radiation, a chemical cross-linking agent or a freeze/thaw cycle.

4. The method according to any one of claims 1 to 3, wherein the polymeric foam matrix comprises a polymer selected from the group consisting of polyvinyl alcohols, polyvinyl pyrrolidones, cellulosic polymers, polyurethanes, polyethylene oxides, polyanhydrides, polyvinyl pyrrolidone/vinyl acetate copolymers, and mixtures thereof.

5. The method according to any one of claims 1 to 4, wherein the cross-linking of the polymeric foam matrix is accomplished by freezing and thawing the matrix.

6. The method of claim 5, wherein the polymeric foam matrix comprises polyvinyl alcohol.

7. The method according to any one of claims 1 to 4, wherein the cross-linking is accomplished by means of a chemical cross-linking agent.

8. The method of claim 7, wherein the chemical cross-linking agent is selected from the group consisting of aldehydes, epoxides, borax, diisocyanates, and mixtures thereof.

9. The method according to any one of claims 1 to 8, wherein the therapeutic agent is a protein, a polypeptide, or a fragment thereof.

10. The method according to any one of claims 1 to 9, wherein the gas is selected from the group consisting of air, carbon dioxide, oxygen, nitrogen, noble gases, and mixtures thereof.

11. The method according to any one of claims 1 to 10, wherein the therapeutic agent is added to the polymer matrix before, during or after the foaming of the polymer matrix.

12. A therapeutic agent-containing polymeric reservoir for an electrotransport therapeutic agent delivery system, the reservoir having a predetermined volume, the reservoir comprising a cross-linked polymeric closed-cell foam matrix containing a predetermined amount of the therapeutic agent and a predetermined volume percent of closed foam cells, the matrix, upon hydration with a liquid solvent used to solubilize the therapeutic agent, having foam cells containing a gas and being substantially free of the therapeutic agent and the liquid solvent.

13. The reservoir of claim 12, wherein the closed cells comprise 25 to 90 vol.% of the polymeric foam matrix.

14. The reservoir of claim 12 or 13, wherein the polymeric foam matrix is electromagnetic radiation cross-linked, chemically cross-linked or freeze/thaw cross-linked.

15. The reservoir according to any one of claims 12 to 14, wherein the polymeric foam matrix comprises an electron beam cross-linked polymer selected from the group consisting of polyvinyl alcohols, polyvinyl pyrrolidones, cellulosic polymers, polyurethanes, polyethylene oxides, polyanhydrides, polyvinyl pyrrolidone/vinyl acetate copolymers, and mixtures thereof.

16. The reservoir according to any one of claims 12 to 14, wherein the polymeric foam matrix comprises a chemically cross-linked polymer selected from the group consisting of polyvinyl alcohols, polyvinyl pyrrolidones, cellulosic polymers, polyurethanes, polyethylene oxides, polyanhydrides, polyvinyl pyrrolidone/vinyl acetate copolymers, and mixtures thereof.

17. The reservoir according to any one of claims 12 to 14, wherein the polymeric foam matrix comprises a freeze/thaw cross-linked polyvinyl alcohol.

18. The reservoir according to any one of claims 12 to 17, wherein the therapeutic agent is a drug.

19. The reservoir according to any one of claims 12 to 17, wherein the therapeutic agent is a protein, a polypeptide, or a fragment thereof.

20. The reservoir according to any one of claims 12 to 19, wherein the gas is selected from the group consisting of air, carbon dioxide, oxygen, nitrogen, noble gases, and mixtures thereof.

21. An electrotransport delivery device comprising the reservoir as defined in any one of claims 12 to 20.

22. An electrotransport device for delivering a therapeutic agent through an animal body surface, the device comprising a donor electrode, a counter electrode, and a source of electrical power adapted to be electrically connected to the donor electrode and the counter electrode, the donor electrode being electrically connected to the therapeutic agent-containing reservoir as defined in any one of claims 12 to 20.