IONTOPHORETIC DEVICES FORDRUGDELIVERY

Ashtosh Sharma Preston Keusch

Sonal Patel Vilambi Reddy

Field of the Invention

The present invention generally relates to electrically assisted transdermal drug delivery systems.

Background

Transdermal drug delivery systems have, in recent years, become an increasingly important means of administering drugs. Such systems offer advantages clearly not achievable by other modes of administration such as, for example, oral delivery and injection. There are two types of transdermal drug delivery systems, "passive" and "active." Passive systems deliver drug through the skin of the user unaided. Active systems, on the other hand, use an external force to facilitate delivery of a drug through a patient's skin. Examples of active systems include, for example, ultrasound, electroosmosis and/or iontophoresis.

Iontophoretic delivery of a medicament is accomplished by application of a voltage to a medicament-loaded reservoir/electrode, sufficient to maintain a current between the medicament-loaded reservoir/electrode and a return electrode (another electrode) applied to a patient's skin so that an ionic form of the desired medicament is delivered to the patient.

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Conventional iontophoretic devices, such as those described in U.S. Patent Nos. 4,820,263, 4,927,408, and 5,084,008, the disclosures of which are hereby incorporated by reference, deliver a drug transdermally by iontophoresis. These devices generally comprise two electrodes, an anode and a cathode. In a typical iontophoretic device, electric current is generated by an external power supply. In a device for delivering drug from an anode, positively charged drug is delivered into the skin at the anode, with the cathode completing the electrical circuit. A schematic diagram of such a system is shown in Figure 1. Likewise, in a system for delivering drug from a cathode, negatively charged drug is delivered into the skin at the cathode, with the anode completing the electrical circuit. Such methods are useful for delivering a number of drugs for a variety of purposes, such as, for example, delivery of lidocaine for pain management.

Migraine medications are also useful in pain management. The triptans are a class of related drugs that are useful for treating migraines and correspond to the chemical structure shown in Table 1.

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Sumatriptan (IMITREX™, GlaxoSmithKline) l-[3-(2-dimethylaminoethyl)-lH-indol- 5-yl]-N-methyl-methanesulfonamide (C ₁₄ H ₂ IN ₃ O ₂ S) (MW= 295.5 Da; pKa = 9.63; logKo _/w = 0.93; logDp _H 7.4 =-1.3) corresponds to the following structure:

Sumatriptan can be used to treat migraine headaches using different dosage forms of delivery in succinate form. Sumatriptan is a selective serotonin 5-HT agonist of the 5HT _1B and 5- HTi _D receptors. There are three dosage forms used to administer IMITREX™: Oral delivery- nasal and subcutaneous injection. Each mode of delivery has deficiencies for efficacious use. The orally prescribed dosage form is slow to act and is sometimes ineffective on the first dose, requiring a supplementary dose to work effectively. Many individuals suffering from migraine also suffer from nausea, further complicating the oral administration of the drug in sufficient doses to achieve a therapeutic level of the drug in the system. Nasal delivery avoids some of the problems associated with oral delivery, but also may require multiple doses. In some patients, side-effects of nasal administration include an unpleasant aftertaste and irritation of the nasal passage and throat. Additional problems in attaining a uniform therapeutic dose with the nasal form occur if the patient has respiratory problems, such as a cough, allergy, or asthma. Injection also may require frequently dosing to attain relief. Other problems related to injection are discomfort and stress related to the procedure. Furthermore, technique can also be an issue; because although a subcutaneous injection is indicated,

Attn. Docket No. 060162/VY0026 without proper attention, mistaken intra-muscular injection can occur. The implements needed to use the injection method are also problematic as one must have available a syringe, needle and antiseptic preparation pad.

A further difficulty is related to the requirements for accuracy and precision of dosage. There are regulatory requirements related to the accuracy and precision of content of a particular drug in an individual dosage form. When a drug dosage form is a tablet, there are specific requirements related to weight variation, dissolution, content and stability. Parenteral dosage forms require concentration and stability assays. Other more complex dosage forms, such as transdermal or iontophoretic delivery devices, have similar standards.

Although iontophoretic systems have been useful in addressing problems related to drug delivery, it has proven difficult to store drug to be delivered in a complex, multicompartment reservoir/electrode. Shelf-life and storage problems can occur in iontophoresis devices such that in many cases the medicament needs to be stored separately from the reservoir/electrode until use. In some cases, the reservoir/electrode is maintained in a dry (unhydrated) condition prior to use, due to the tendency of the active electrode material to undergo physical and chemical changes during shelf storage in an aqueous medium. Thus, the need to store the several components separately has limited the use of iontophoretic devices, because in order to use the device, the reservoir/electrode needs to be charged with the medicament and hydrated immediately prior to use. Thus, in many cases, no devices are commercially available because they are unable to meet all of the needs of the potential user population.

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In some iontophoretic drug delivery devices, the user or the practitioner is required to perform some action to hydrate the reservoir/electrode and introduce the medicament to be delivered into the delivery device prior to use. Such operations that depend upon the practitioner or user to charge the medicament into the device under relatively uncontrolled conditions may result in improper dosing. Regulatory requirements for pharmaceutical products generally specify that not only medicaments contain between ninety and one hundred-ten percent of the label claim, but also that the delivery be uniform from sample to sample. One method of accurately and repeatedly loading the medicament and any required delivery enhancing excipients during the assembly process of reservoirs is described in International Patent Publication No. WO 01/91848 and corresponding U.S. Patent No. 6,496,727, both of which are incorporated herein by reference in their entirety. The device described is useful for passive transdermal drug delivery and reservoir/electrodes for iontophoretic drug delivery devices and is compatible with a mechanized assembly process, while providing a drug charged reservoir/electrode with satisfactory content uniformity.

However, the utility of many of the devices in the art is limited. What is needed are iontophoretic devices equipped with mechanical, electrical and/or electromechanical features that can maximize the efficiency and effectiveness of drug delivery and overcome some or all of the limitations as described above, especially for delivery of drugs to treat headaches such as triptans, for example.

SUMMARY

Methods and compositions for the use in the delivery of drugs, such as triptans to treat headaches are provided, including, for example, sumatriptan succinate and other triptans. In

Attn. Docket No. 060162/VY0026 certain embodiments of the disclosed devices, drug may be stored in a monolithic reservoir/electrode multicompartment reservoir/electrode where the counter-ion is Cl ^* or in a multi-compartment reservoir/electrode (MCRE) where the drug anion is not Cl ^" . Such devices comprise a hydrophilic polymeric reservoir thereby absorbing the liquid-containing drug. Further, use of a hydrophilic polymeric reservoir reduces the active area of the reservoir and the chance of a short circuit caused by a solution path on the skin and/or wetting of the patch-retaining adhesive. In various embodiments, the disclosed devices include an electrode and a hydrophilic polymeric reservoir situated in electrically conductive relation to the electrode that is ready for use immediately upon removal from its packaging with no need to load the active ingredients in the anode or return solution in the cathode. In certain other embodiments, the reservoir/electrode comprises a silver mesh electrode embedded in a solid suspension of a cation exchange resin hydrogel which is separated from the drug reservoir using a selectively permeable membrane. In such embodiments, the hydrogel advantageously reduces and/or eliminates the effect of competing ions, hi addition, the Na ⁺ ions from the resin bind strongly to the backbone of the cationic resin, thereby, increasing the fraction of the current carried by the drug (e.g., sumatriptan cation).

An electrode assembly for an electrically assisted drug delivery device is provided that includes a hermetically-sealed anode assembly comprising at least a first electrode and a donor hydrogel comprising the triptan in electrical contact with the first electrode, a second return electrode containing electrolyte. Li some embodiments, the electrode assembly is packaged within a hermetically-sealed container in the presence of an inert gas. The electrode assembly can be in any useful form, for example, and without limitation, as an

Attn. Docket No.060162/VY0026 integrated assembly containing both the anode assembly and a cathode, or as a split electrode with the anode packaged separately from the cathode.

The disclosed methods comprise delivery of a drug such as a triptan. The triptan may be in a chloride form or a non-chloride form. Novel drug reservoir conditions for the optimal delivery of sumatriptan in the succinate form are also disclosed. It has also been surprisingly found that the amount of sumatriptan delivered increases by about 67% by increasing reservoir pH from pH 4.7 to pH 6.8.

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BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Schematic of an iontophoretic drug delivery device which generally includes the designation 10. See for example, U.S. Patent No. 6,377,847. The device 10 includes an electrode assembly 12, having at least one electrode and at least one reservoir which may be combined into a single electrode assembly 12 or separately provided, along with the reservoir and electrode held or contained within a suitable structure, along with a skin adhesive and a power source 19 is provided in circuit with the electrode assembly 12 for supplying a source of electrical current. As shown, the device is divided or otherwise separated into two portions 20 and 22, with the electrode assembly 12 including two electrodes 24 and 26. One portion 20 (first) includes the electrode 24 and a reservoir 28, with the reservoir being situated adjacent and coupled to the electrode 24 and holding at least one medicament or drug 30, in ionized or ionizable forms, to be delivered iontophoretically. The other portion 22 (second) includes the electrode 26 and a reservoir 32, with the reservoir being situated adjacent to the electrode 26 and holding an electrolyte 34.

Figure 2. Schematic representation of a multi-compartment anode reservoir/electrode (MCRE)

Figure 3. Exploded view of a multi-compartment anode reservoir/electrode according to various embodiments of the present invention.

Figure 4A. Top plan view of the multi -compartment anode reservoir/electrode of Figure 3 according to various embodiments of the present invention.

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Figure 4B. Partially exploded cross-sectional side view of the multi-compartment anode reservoir/electrode of Figure 3 according to various embodiments of the present invention.

Figure 4C. Bottom plan view of the multi-compartment anode reservoir/electrode of Figure 3 according to various embodiments of the present invention.

Figure 4D. Top plan view of the electrode of the multi-compartment anode reservoir/electrode of Figure 3 according to various embodiments of the present invention.

Figure 4E. Cross-sectional side view of the multi-compartment anode reservoir/electrode of Figure 3 according to various embodiments of the present invention.

Figure 5 A. Exploded view of a monolith cathode according to various embodiments of the present invention.

Figure 5B. Top plan view of view of the monolith cathode of Figure 5A according to various embodiments of the present invention.

Figure 5C. Partially exploded cross-sectional side view of the monolith cathode of Figure 5 A according to various embodiments of the present invention.

Figure 5D. Bottom plan view of the monolith cathode of Figure 5A according to

Atto. Docket No.060162/VY0026 various embodiments of the present invention.

Figure 6. Effect of a 4-fold increase in drug load on the cumulative amount of sumatriptan delivered across porcine skin in vitro with a 6 h iontophoretic current application (0.25 mA/cm ² ) from a patch system with a PVP gel drug reservoir. Filled and hollow circles represent patch loadings of 9.7 and 39 mg, respectively (mean ± SD; n = 4).

Figure 7A and 7B. Effect of increasing formulation pH from 4.7 to 6.8 on (A) the cumulative amount of sumatriptan delivered across porcine skin in vitro and (B) the corresponding drug flux, with a 6h iontophoretic current application (0.25 mA/cm ² ) from a patch system with a PVP gel drug reservoir containing 39 mg of drug. Filled and hollow circles represent formulation pH of 4.7 and 6.8, respectively (mean ± SD; n = 4).

Figure 8. Plasma concentration profiles of sumatriptan as a function of time during subcutaneous injection (6 mg; hollow circles) and anodal iontophoresis (filled circles) in Yorkshire swine using an iontophoretic patch system with an active area of 4 cm ² and where the PVP drug reservoir contained 37 mg of sumatriptan at pH 7. Two patches were applied to each animal (total area = 8 cm ² ). A biphasic current profile was applied (dashed line, secondary y-axis), in phase 1, 1.8 mA (0.45 mA/cm ² ) for the t = 0-180 min time-period, then in phase 2, 0.8 mA (0.2 mA/cm ² ) during the t = 181-360 min time-period. (C _max , T _ma χ and AUC values were approximately 100 ng/ml ₅ 105 min, and 27, 600 ng/(ml _* min), respectively, for iontophoretic administration; cf. 194 ng/ml , 5 min, and 8480 ng/(rnl»min)for the subcutaneous injection) (mean ± SD; n = 3).

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Figure 9. Graph showing anodal delivery of zolmitriptan HCl (with PVP disk drug reservoirs) to a first swine over 6 h with the iontophoretic system in contact with skin using the shown current profile.

Figure 10. Graph showing anodal delivery of zolmitriptan HCl (with PVP disk drug reservoirs) to a second swine over 6 h with the iontophoretic system in contact with skin using the shown current profile.

DETAILED DESCRIPTION

Described herein are electrode assemblies for electrically assisted transmembrane delivery of at least one drug, such as, for example, a triptan. Although sumatriptan is the major triptan for the treatment of migraines, other useful triptans may be used. These triptans include, without limitation those that are listed in Table 1.

Table 1. Pharmacokinetics of Triptans

Tmax (hrs) Half-life (hrs) Oral bioavailability

Sumatriptan 2 (2.5)* 2.5 15%

Zolmitriptan 2 (2.5)" 3 40%

Nara triptan 2-3 (3-4)" 6 70%

Rizatriptan 1-1.5 2-3 45%

Eletriptan 1.5 (2.8)* 4-5 50%

Almotriptan 1.4-3.8 3.2-3.7 69%

Frovatriptan 2-3 25 30% (F) 20% (M)

*Tmax during migraine

It is to be understood that certain descriptions of the present invention have been simplified to illustrate only those elements and limitations that are relevant to a clear understanding of the present invention, while eliminating, for purposes of clarity, other

Attn. Docket No.060162/VY0026 elements. Those of ordinary skill in the art, upon considering the present description of the invention, will recognize that other elements and/or limitations may be desirable in order to implement the present invention. However, because such other elements and/or limitations may be readily ascertained by one of ordinary skill upon considering the present description of the invention, and are not necessary for a complete understanding of the present invention, a discussion of such elements and limitations is not provided herein. As such, it is to be understood that the description set forth herein is merely exemplary to the present invention and is not intended to limit the scope of the claims.

Other than in the examples herein, or unless otherwise expressly specified, all of the numerical ranges, amounts, values, and percentages, such as those for amounts of materials, elemental contents, times and temperatures of reaction, ratios of amounts, and others, in the following portion of the specification and attached claims may be read as if prefaced by the word "about," even though the term "about" may not expressly appear with the value, amount, or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains error necessarily resulting from the deviation found in its underlying respective testing measurements. Furthermore, when numerical ranges are set forth herein, these ranges

Attn. Docket No. 060162/VY0026 axe inclusive of the recited range end points (i.e., end points may be used). Also, it should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of "1 to 10" is intended to include all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, that is, having a minimum value equal to or greater than 1 and a maximum value equal to or less than 10.

All patents, publications, or other disclosure material referenced herein are incorporated by reference in their entirety. Any patent, publication, or other disclosure material, in whole or in part, that is incorporated by reference herein is incorporated herein only to the extent that the incorporated material does not conflict with existing definitions, statements, or other disclosure material set forth in this disclosure. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material set forth herein will only be incorporated to the extent that no conflict arises between that incorporated material and the existing disclosure material.

The articles "a," "an," and "the" are used herein to refer to one or more than one (i.e., to at least one) of the grammatical objects of the article. By way of example, "a component" means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used.

The terms "unloaded" or "unloaded reservoir," are necessarily defined by the process of loading a reservoir. In the loading process, a drug or other compound or composition is absorbed, adsorbed and/or diffused into a reservoir to reach a final content or concentration

Attn. Docket No. 060162/VY0026 of the compound or composition. An unloaded reservoir is a reservoir that lacks that compound or composition in its final content or concentration, hi one example, the unloaded drug reservoir is a hydrogel, as described in further detail below that includes water and a salt. One or more additional ingredients may be included in the unloaded reservoir. Typically, active ingredients are not present in the unloaded gel reservoir. Other additional, typically non-ionic ingredients, such as preservatives, may be included in the unloaded reservoir.

In various embodiments, the reservoir is in intimate electrical contact with an electrode, which may in certain embodiments be in the reservoir or separated from the reservoir by a semi-permeable membrane. Where the electrode and reservoir are in a combined assembly, the combination is referred to herein as a "reservoir/electrode. By the term "reservoir/electrode," it is intended that the combination of an electrode remain in close electrical contact with a drug reservoir such that the drug can be propelled from the reservoir via electrically assisted delivery.

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The term "electrically assisted delivery" refers to the facilitation of the transfer of any compound across a membrane, such as, without limitation, skin, mucous membranes and nails, by the application of an electric potential across that membrane. "Electrically assisted delivery" is intended to include, without limitation, iontophoretic, electrophoretic, electroendosmotic delivery methods, as well as any combinations thereof. By "active ingredient," it is meant, without limitation, drugs, active agents, therapeutic compounds and any other compound capable of eliciting any pharmacological effect in the recipient that is capable of transfer by electrically assisted delivery methods. A "transdermal device" or "transdermal patch" includes both active and passive transdermal devices or patches.

The reservoirs useful in practicing the methods disclosed herein can be prepared by any method that forms a structural matrix that contains water and can hold drug or electrolyte in the solution in its ionized form. Thus, in some embodiments, the anode and cathode reservoirs may comprise a hydrogel. The term "hydrogel" comprises any gel solid that has, or is capable of, imbibing a solvent such as, for example, water and/or drug. Such a hydrogel may be hydrophilic and may have varying degrees of association such as cross-linking, crystallization or self-assembling nodes and water content. Further, a hydrogel may be any pharmaceutically and cosmetically acceptable absorbent hydrogel into which active ingredients can be added in precursor solution or as solution to unloaded reservoir that can be absorbed, diffused or otherwise incorporated and that is suitable for electrically assisted drug delivery. Such hydrogels may be visco-elastic solids that are shape-retaining from the point of manufacture and during conditions of use. Suitable polymeric compositions useful in forming the hydrogel are known in the art and include, without limitation, poly vinylpyrrolidone (PVP), polyethyleneoxide, polyacrylamide, polyacrylonitrile polyvinyl

Attn. Docket No. 060162/VY0026 alcohols, modified cellulosics such as hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC), for example. The drug reservoirs may contain additional materials such as, without limitation: preservatives, such as antimicrobials; antioxidants, such as sodium metabisulfite; chelating agents, such as EDTA; humectants and other materials, either alone or in combination. In some embodiments, an unloaded reservoir may contain preservatives and salt. As used herein, the water component of the hydro gel reservoirs may be purified and meet the standard for purified water in the USP XTV.

In certain embodiments, the hydrogel has sufficient internal strength to hold its shape during its intended use and leave essentially no residue when the electrode is removed after use. As such, the cohesive strength of the hydrogel and the adhesive strength between the hydrogel and the electrode are each greater than the adhesive strength of the bonding between the hydrogel and the membrane or skin to which the electrode assembly is affixed in use.

As used herein, the term "drug" refers to any biologically active substance or combination of substances. It should be understood that the term "drug" encompasses the pharmaceutically active ion no matter what its charge neutralizing counter ion is. For example, the pharmaceutically approved drug for sumatriptan is the succinate salt where the sumatriptan is a positively charged ion and the anion is succinate ([HOOCCH ₂ CH ₂ COO] ^" ), but for iontophoretic delivery sumatriptan in the HCl form can have advantages. Although sumatriptan is the primarily prescribed triptan for the treatment of migraines, other useful triptans may be used.

In certain embodiments, a monolith reservoir/electrode is used for delivery. A monolith reservoir/electrode comprises an electrode assembly that is used to deliver an active positive drug in its chloride form. It can also deliver a negatively charged drug from the

Attn. Docket No. 060162/VY0026 return reservoir/electrode. Monolith reservoir/electrodes described herein comprise those described in US patent publication 20050228335. In another embodiment, the structure of the monolith reservoir/electrode described can be used to deliver a negatively charged drug. It is electrically coupled to a positively charged return reservoir/electrode. In another embodiment, a high capacity monolith reservoir/electrode comprises silver mesh or chlorided silver mesh and a pour-in-place reservoir.

In some embodiments, the electrode assembly includes a backing; a first silver/silver chloride electrode and a poly vinylpyrrolidone (PVP) donor hydrogel comprising a positively charged drug, such as sumatriptan in its chloride form, in electrical contact with the first electrode attached to the common backing; a second silver/silver chloride electrode and a return hydrogel in electrical contact with the second electrode attached to the backing; an electrically conductive silver/silver chloride cathode trace attached to the backing and in electrical contact with the second electrode; and a dielectric layer coating the periphery of the anode and cathode traces. The donor hydrogel may also include an amount of salt sufficient to prevent electrode corrosion during or after loading of the hydrogel reservoir. In certain embodiments, the first and second electrodes and the anode and cathode traces can be deposited as silver/silver chloride-containing ink. Also provided is a packaged electrode assembly for an electrically assisted drug delivery device. The packaged assembly includes a hermetically-sealed container and an electrode assembly sealed within the container.

A method for preparing electrode assembly for electrically-assisted delivery of the drug to a patient also is provided. The electrode assembly comprises an unloaded hydrogel reservoir in electrical contact with a silver-silver chloride electrode. The unloaded hydrogel reservoir may contain an amount of salt sufficient to prevent electrode corrosion during or

Attn. Docket No.060162/VY0026 after loading of the hydrogel reservoir. The method includes the steps of loading the unloaded hydrogel reservoir with a loading solution containing drug and packaging the assembly in a hermetically-sealed container. In one embodiment of the method, prior to the loading step, the loading solution is absorbed into an absorbent pad attached to a releasable molded sheet configured to cover the hydrogel reservoir, and the releasable liner is attached to the electrode assembly with the absorbent pad contacting the hydrogel reservoir, thereby contacting the loading solution with the hydrogel.

In various embodiments, a combination electrode assembly structured for use in association with an electrically assisted delivery device for delivery of a composition to a membrane is provided. The combination electrode assembly comprises a backing comprising a tab end structured to be received into electrical connection with at least one of a power supply and a controller of the electrically assisted delivery device and an electrode assembly securement portion; the electrode assembly securement portion including an anode electrode assembly connected to a portion thereof, the anode electrode assembly including an anode electrode and at least one anode trace electrically connected to the anode electrode, the anode trace extending from the electrical connection with the anode electrode to at least a portion of the tab end; the electrode assembly securement portion further including a cathode electrode assembly connected to a portion thereof, the cathode electrode assembly including a cathode electrode and at least one cathode trace electrically connected to the cathode electrode, the cathode trace extending from the electrical connection with the cathode electrode to at least a portion of the tab end; and, at least one hydrogel reservoir positioned for communication with at least a portion of at least one of the electrodes.

In various embodiments, the combination electrode assembly further comprises at least one of the following features: a release cover removably secured to at least a portion of

Attn. Docket No.060162/VY0026 the backing and covering at least a portion of at least one of the electrode assemblies, wherein the release cover includes at least one well structured for substantial alignment with at least a portion of at least one of the electrode assemblies, at least one non-woven fabric positioned within at least a portion of at least one of the wells of the release cover, at least one of the non- woven fabrics being connected to at least one of the portions of the wells, wherein at least one of the connections includes at least one weld, wherein the welds are substantively uniformly distributed in an area of the connection between the non-woven fabric and the well; a flexural rigidity of at least one of the electrodes is greater than a flexural rigidity of at least a portion of the backing, wherein a surface area of at least one of the electrodes is in the range of about 10 % to 70 % of a total surface area of the backing; at least one tab stiffener connected to at least a portion of the tab end, the tab end further comprising at least one tactile sensation aid selected from the group consisting of at least one notch formed in the tab and at least one wing extending from the tab end; at least one slit formed in the tab stiffener, the slit being at least partially cut to receive a knife edge during operation of the electrically assisted delivery device, and at least one sensor trace positioned distally with respect to the slit; a dielectric coating covering at least a portion of at least one of the anode electrode assembly and the cathode electrode assembly, further including the dielectric coating covering at least a portion of at least one of the traces, further including the dielectric coating covering at least a portion of a periphery of at least one of the electrodes; a surface area of at least one of the hydrogel reservoirs is greater than a surface area of the electrode in communication with the hydrogel reservoir, wherein at least one of the hydrogel reservoirs is loaded with a composition to provide a loaded hydrogel reservoir in a condition below an absorption saturation of the loaded hydrogel reservoir, also wherein at least one component in contact with the loaded hydrogel reservoir is characterized by an aqueous absorption capacity

Attn. Docket No. 060162/VY0026 less than an aqueous absorption capacity of the loaded hydrogel reservoir; a first kind of material comprising a first unloaded hydrogel reservoir in communication with the cathode electrode is substantially identical to a second kind of material of a second unloaded hydrogel reservoir in communication with the anode electrode; at least one substantially non-adhesive tab extending from the backing; a shortest distance between a surface area of the anode electrode and a surface area of the cathode electrode is in the range of about 5 mm to 25 mm to resist completing a short circuit path between the electrodes; each of the anode electrode, the cathode electrode, the anode trace, and the cathode trace being comprised of a substantially identical kind of material; during operation of the electrically assisted delivery device, one of the hydrogel reservoirs functions as a donor reservoir and another of the hydrogel reservoirs functions as a return reservoir, also including one or more indicia formed on at least one of a portion of the backing adjacent to the donor reservoir and a portion of the backing adjacent to the return reservoir; and/or at least one slit formed in at least a portion of the backing, the slit being positioned in a portion of the backing between the anode electrode and the cathode electrode.

In various other embodiments, a Multi-compartment Reservoir/Electrode (MCRE) can be used. An MCRE is useful for delivering a drug when the counter ion is not a halogen such as chloride as in the case of sumatriptan succinate, for example. Such a reservoir / electrode is shown schematically in Figure 2. This reservoir/electrode beginning from the electrode comprises a silver mesh electrode embedded in a solid suspension of a cation exchange resin hydrogel. Such a hydrogel is useful in that the effect of competing ions is eliminated. Na ⁺ ions (or H ⁺ ions in some resins) from the resin bind strongly to the backbone of the cationic resin; thereby, increasing the fraction of the current carried by the drug (e.g., sumatriptan cation). Depending on the charge of the drug (i.e., anionic or cationic) any of the

Attn. Docket No. 060162/VY0026 following ion exchange resins may be suitable for use including, but not limited to, the four main types differing in their functional groups: strongly acidic (i.e., a cation, such as Na ⁺ or H ⁺ , exchange resin comprising sulfonic acid groups, eg. sodium polystyrene sulfonate or polyAMPS); strongly basic, (i.e., an anion, such as Cl ^" or OH ^' , exchange resin comprising trimethylammonium groups, eg. polyAPTAC); weakly acidic (cation exchange resin comprising carboxylic acid groups); and weakly basic (anionic exchange resin comprising amino groups, e.g. polyethylene amine). In some embodiments, the resin is AMBERLITE™ IRP-69, (Rohm and Haas, Philadephia, PA) which is a sodium sulfonate resin.

Beneath the mesh is a size exclusion membrane with a molecular weight cutoff of about 100 Dalton and beneath the membrane is the drug reservoir. Those of skill in the art recognize that in iontophoresis all phases are in intimate electrical connection with each other, and that the drug reservoir, typically a hydrogel, is positioned so its exposed area can be in intimate electrical contact to the skin of the subject.

MCRE' s are also useful for high capacity electrotransport applications, such as when more than about 30 mA/min of charge is needed to adequately accomplish therapeutic electrotransport. In such embodiments, the return electrode can be a variation on the design previously disclosed. A silver chloride/silver electrode-for a negative electrode, a silver electrode for a positive return electrode, and both encapsulated by a salt loaded hydrogel. The hydrogel return reservoir would be of such volume that it would be in intimate contact with the skin of the subject.

An MCRE maybe manufactured and operated to achieve any and all of the following advantages:

1. Holding the drug in ionized mobile form to be electrically delivered to the skin of a

Attn. Docket No. 060162/VY0026 subject.

2. Operating at high enough current densities to deliver the required rate and profile of drug.

3. Having an electrochemical capacity to sustain the full treatment profile.

4. Having an ion exchange capacity sufficient to capture all silver ions generated (e.g., by, for example, an ion exchange resin) to prevent the silver ions from entering the drug reservoir or depositing on the skin of the subject.

5. Limiting delivery of the drug such that it is propelled out of the reservoir only through the skin of the subject.

6. Providing electrocontinuity with each active element including the reservoir with the skin of the subject.

7. Providing effective contact with the skin, such as, for example, by means of placing adhesive on bottom of a flat ring facing skin and providing a drug loaded reservoir that is slightly convex.

The patch portion of electrotransport devices designed for the delivery of a triptan, for example, can be an integrated patch. Integrated patches are useful as they are particularly convenient for operators, even though those of ordinary skill in the art recognize that split patches would also deliver drug with the same effectiveness. Integrated patches are coupled with a controller/ microprocessor /power supply. Depending upon the drug, different patch designs would be used and the controller/microprocessor /power supplies would be used at settings which are routinely optimized to maximize efficacy and safety. A patch may contain at least two reservoir/electrodes: at least one for the delivery of the drug and at least one return reservoir/electrode. If the triptan is in the chloride form, the patch may have a single monolith reservoir and at least one return reservoir/electrode, hi some embodiments, an

Attn. Docket No. 060162/VY0026 integrated anode assembly as shown in Figure 2 would be used to deliver positively charged triptan (e.g., triptan HCl). In certain embodiments, the reservoir/electrode can be a MCRE and the return electrode can be a monolithic electrode where the drug is not in the chloride form. Depending upon the charge of the drug, the reservoir /electrode may be anodic or cathodic.

In certain embodiments, the electrotransport delivery of a triptan such as sumatriptan HCl can have both active and return reservoir/ electrodes that are both of a monolithic design with the electrochemical capacity for each electrode being greater than or equal to the largest value of either the anode or cathode. The electrotransport delivery of a triptan where the accompanying cation is not Cl ^" , but is, for example, succinate, then the active reservoir /electrode would be of the MCRE type and the return reservoir /electrode would be a monolith design. The electrochemical capacity for each electrode would be greater than or equal to the largest value of either the anode or cathode.

The power supply/controller can be integrated into the patch or placed as an add-on with the appropriately wired interconnections. Such interconnect can be similar to that described in patent publication 20050228335. The placement of the controller/ power supply as in the above referenced document is not limited to placement on the plane of the skin but can be secured on top of the patch without loss of function.

The electrode assembly for delivering drugs may be manufactured by any method known in the art or as disclosed herein. For example, the MCRE assembly can be formed by laminating cylindrical annular shells or rings constructed out of closed shell low density polyethylene (LDPE) foams that are adhesively coated. These shells can be first die cut from sheet stock with release liners covering the adhesive surfaces. After removal of the release liners the shells can then be adhesively laminated.

Attn. Docket No. 060162/VY0026

In one embodiment, a MCRE may be manufactured according to the design shown in Figure 3. The design shown in Figure 3 may be used for the anode electrode and may comprise an electrode 5001 and a size exclusion membrane 5002. The electrode 5001 may be silver mesh electrode, such as a 6 Ag -10-077 silver mesh electrode from Delker Corp., Philipsburg, NJ. The size exclusion membrane 5002 may be, for example, a 50 Da, 100Da, a 200 Da cut-off, or higher cut-off membrane. The electrode 5001 and the size exclusion membrane 5002 may be laminated in a set of shells (or rings), including an upper ring 5003, a middle ring 5004, and a lower ring 5005, which may be made of foam.

The electrode 5001 may be cut into the shape shown in Figure 3. As such, its inner round portion 6001 may smaller than the openings 6002 of the shells (or rings) 5003, 5004, 5005. The electrode 5001 may also include three small rectangular tabs 6004, 6006, 6008 around the inner portion 6001 that are ninety degrees (90°) apart, and one long tab 6010 extending from the inner portion 6001 for connection to the electrical circuit. The electrode 5001 may be secured between the top ring 5003 and the middle ring 5004 by centering the inner portion 6001 of the electrode 5001 in the opening 6002 formed by the rings 5003, 5004, such that the four electrode tabs 6004, 6006, 6008, 6010 are the only part of the electrode

5001 that are sandwiched between the upper and middle rings 5003, 5004.

The membrane 5002 may be placed between the middle ring 5004 and the lower ring 5005. The electrode 5001 may then be encapsulated by dispensing an ion exchange resin as a suspension in PVP solution into an upper cavity defined by the membrane 5002 (as the lower surface of the cavity), the upper ring 5003 and the middle ring 5004. After the upper cavity is filled, it may be covered by a PET liner 5006. The bottom cavity defined by the membrane

5002 (as the upper surface of the cavity) and lower ring 5005 may be left open for placement of the active carrying drug reservoir 5007. Prior to insertion of the reservoir 5007, a number

Attn. Docket No. 060162/VY0026 of such electrode assemblies may be placed on a common release liner (not shown). When ready to fill the drug reservoir cavities (i.e., the lower cavity defined by the lower ring 5005), the assemblies may be removed from the common release liner and filled. A new single release liner 5008 maybe applied to the adhesive surface of the bottom ring 5005 prior to insertion of the reservoir 5007.

Figures 4A-C show a top plan view, a partially exploded side view, and a bottom plan view, respectively, of the electrode assembly of Figure 3 according to various embodiments. Figure 4B shows the ion exchange resin as a suspension in PVP solution 5010 in the cavity defined by the top and middle rings 5003, 5004. Figure 4D is a top view of the electrode 5001 , showing the features of the electrode in more detail.

Figure 4E is another cross-sectional view of the electrode assembly of Figure 3. In this figure, the upper, middle and lower rings 5003, 5004, 5005 are shown as an integrated housing 5012. The rings 5003, 5004, 5005 may be fabricated from an electrically insulating material, such as a closed cell LDPE polymeric foam, for example. The upper cavity 5024 defined by the membrane 5002 and the upper and middle rings 5003, 5004, is filled with a suspension in solid solution of a cation exchange resin 5010. According to various embodiments, the cation exchange resin may be AMBERLITE™ IRP-69 (available from Rohm & Haas, Perth Amboy, NJ), in crosslinked poly vinylpyrrolidone (PVP) K90 F (available from BASF, Mt. Holly, NJ). The inner dimension of the rings 5003, 5004, 5005 may be 1.13 cm in diameter, or 4 cm ² , according to various embodiments. The annular rings 5003, 5004, 5005 may be prepared from sheets of closed cell LDPE foam coated with a PIB adhesive, for example.

As shown in Figure 4D ₅ the silver mesh electrode 5001 may contain three tabs, 6004, 6006, 6008 around the inner portion 6001 of the electrode 5001. The tabs 6004, 6006, 6008

Attn. Docket No. 060162/VY0026 may be, for example, 0.5cm in length and 0.5 cm in width. The fourth, longer tab 6010 may be 3 cm in length and 0.5 cm in width. The tab 6010 may function both as an electrical lead, to be part of the external electrical circuit connecting to the controller and other electrode(s), and for securement. The size exclusion membrane 5002 between the middle ring 5004 and the lower ring 5005 may be, for example, a 3 cm x 3 cm square. Once the rings 5003-5005, the electrode 5001 and the membrane 5002 are assembled, the assembly is ready to accept the solution and suspension herein. The solid solution and suspension may each be formed from liquid solutions or suspensions respectively.

In certain embodiments, the reservoir for the MCRE can be prepared in at least two ways, for example:

(i) by cutting a hydrogel sheet prepared by crossliriking solution PVP at 24% (preserved with a PHENONIP™ (Clarient Inc., SC)), in sheet form at about 0.106 cm in thickness by electron beam irradiation using an electron accelerator of at least 1.0 MeV to form a shape retaining material, or by forming a shape retaining material by preparing a molded slab of a self assembling aqueous solution of, for example, agarose (SEACHEM GOLD™ manufactured by FMC, Philadelphia, PA) as 3.0 % solution with USP preserved water. The agarose may be heated to about 9O ⁰ C to facilitate dissolution and then solidified by cooling at room temperature. The thickness of the sheet can be about 0.106 cm or about 40 mil. The reservoir pucks can be cut by use of a circular die to 4 cm ² . Alternatively, slabs of solid agarose of thickness of about 0.012 cm or about 40 mil prepared as described above can also cut by use of a circular die to 4 cm ² .

(ii) An alternative method is to pour in place a pre-crosslinked feedmix of PVP, water and preservative into the reservoir portion of the shell and then crosslink the entire patch by

Attn. Docket No. 060162/VY0026 electron beam irradiation. In this case, an electron accelerator of at least 2.7 MeV can be used as it will simultaneously crosslink the hydrogel and the ion exchange suspension. For example, a 15 % PVP K90 F water soluble resin can be slowly dissolved by slow addition during mixing at low speed in USP purified water that contains about 0.5% of the preservative, Pheonip mixed parabens dissolved in phenoxyethanol. The PVP powder can be slowly added to the aqueous solution, where the resin is first swollen and then dissolves. The addition continues until all of the resin is added and dissolves. At this stage, the solution often contains air bubbles. The solution can be left to stand covered to fully degas, (e.g., become bubble-free to the unaided eye). At this stage, the solution is viscous and clear with a light straw color. PVP K90 F water soluble resin can then be blended with IRP - 69 cation exchange resin (Rohm and Haas, Philadelphia, PA). The powder blend can be slowly added to USP purified water while mixing at slow speed. In certain embodiments, the addition continues until all of the PVP resin is dissolved, and there is a homogenous blend of the ion exchange resin. This suspension can also be degassed and used within about 24 hours to avoid settling of the higher density ion exchange resin. The highly viscous ion exchange suspension can be loaded from the top into the cavity that has the silver mesh centered between the upper ring 5003 and the middle ring 5004.

In some embodiments, it is often advantageous to fill void through the silver mesh so it is free of air, which can be accomplished by use of high pressure dispensing of the suspension between the wall of the rings and the mesh, which displaces the air. In certain embodiments, the membrane is covered and the mesh coated to greater than 95% with the suspension to assure that the suspension is a continuous phase from membrane to mesh. After the top cavity 5024 is filled with the suspension, allowed to settle and topped off with more suspension, it can then be covered with a PET liner cover 5006.

Attn. Docket No.060162/VY 0026

Thus, in certain embodiments, the assembly as described herein can be prepared for curing. For example, in one embodiment, the partially filled patch is inverted and the PVP solution is loaded into the cylindrical opening defined by the lower ring 5005 to the membrane 5002. As described above, it is often advantageous to completely cover the membrane 5002. In some embodiments, the cavity is filled to about 0.2 cm - V/A, where V is the loading volume in cm ³ and A is the cross-sectional area of the cavity in cm ² . A release liner 5008 may then be placed over the opening (releasable side facing adhesive). In such embodiments, there preferably is enough room to both load the drug solution and allow for swelling into the unloaded reservoir after curing.

In some embodiments, the reservoir solution and ion exchange suspension patch are crosslinked by high energy electron beam irradiation, which in some embodiments, occurs not later than 24 hours post processing. A greater than 2.7 MeV electron accelerator can be used to crosslink each solution as enough energy must deposit within the patch to assure the liquids to crosslink. In some embodiments, a surface irradiation dose of about 1OkGy assures that there is sufficient crosslinking and the reservoir side has cohesive strength and tack. After curing, the circular disk fully loaded with the aliquot of drug solution is placed in the empty drug reservoir defined by the lower ring 5005. By ensuring that the surface of the disk firmly touches the membrane 5002, a reliable electrical contact can be provided. ■Furthermore, in such embodiments, the height of the reservoir is sufficient for the opposite surface to touch the surface of the skin. Those of skill in the art recognize that the method of manufacture would not alter the efficacy of the device and, in certain embodiments, the device manufactured by one method may function as an equivalent for a device manufactured by an alterative method.

In certain embodiments, a 15% PVP reservoir has enough absorption capacity to

Attn. Docket No. 060162/VY0026 imbibe greater than 400% of its weight. After crosslinking, the empty reservoirs can be loaded with drug solution. Loading can be accomplished by at least two methods:

1. Drop loading by calibrated pipette onto reservoir and waiting for absorption

2. Placing a nonwoven absorbent with absorbent capacity less then the reservoir.

3. Adding the required quantity of drug plus about 5% to the absorbent and waiting for the drug to transfer to the reservoir, as well as other methods.

These drug loading methods can be performed independent of the method of reservoir manufacture. For example, in method (i) the drug is imbibed in the circular puck before being placed in the circular cavity below the membrane 5002. In certain embodiments, the drug solution is imbibed within 24 hours. Thus, in some embodiments, the reservoir is a solid solution of drug in aqueous ionic form dissolved in the reservoir.

In certain embodiments, a high capacity return monolith reservoir/electrode can be used. Such embodiment can be manufactured in a similar fashion to the MCRE of Figure 3. For example, the return (cathode) assembly can be formed by laminating cylindrical annular shells or rings constructed out of closed shell low density polyethylene (LDPE) foams that are adhesively coated. These shells can be first die cut from sheet stock with release liner covering the adhesive surfaces. After removal of the release liners the shells can then be • adhesively laminated.

Figure 5A shows an exploded view of a monolith cathode patch 7000 according to such an embodiment. The patch 7000 may comprise an electrode 7001 between an upper cylindrical ring 7003 and a lower tabular ring 7005. The upper and lower rings 7003, 7005 may respectively define openings 7007. The rings 7003, 7005, like the rings of the electrode assembly of Figures 4A-E, may be made from closed cell LDPE polymeric foam.

The electrode 7001 may be a chlorided silver mesh, such as 6 Ag -10-077, available

Attn. Docket No.060162/VY0026 from Delker Corp. Philipsburg, NJ. In such embodiments, the silver mesh electrode 7001 may be electrolytically chlorided to an electrochemical capacity that is at least as great as the electrochemical capacity for the entire treatment. In certain embodiments, the electrode 7001 may be die cut from a chlorided sheet into a shape as shown in Figure 5 A (or similar to the shape shown in Figure 4D), such that it comprises a round inner portion 7002 that is smaller than the full opening and it has three small rectangular tabs 7004, 7006, 7008 that are ninety (90) degrees apart and one long tab 7010 for connection to the electrical circuit. The electrode 7001 can be secured between the upper ring 7003 and the lower ring 7005 by centering the inner portion 7002 of the electrode in the opening 7007 defined by the rings 7003, 7005, such that the four electrode tabs 7004, 7006, 7008, and 7010 are the only part of the electrode 7001 that are between the foam rings 7003, 7005.

Once the rings 7003, 7005 are laminated with the electrode 7001 between them, a cover 7012 can be placed over the upper ring 7003. The electrode 7001 can then be encapsulated by dispensing, for example, a 15 % PVP preserved solution containing 0.9% sodium chloride into the cavity or compartment 7016 defined by the aligned openings 7007 of the rings 7003, 7005. It is particularly useful in certain such embodiments to entirely wet the electrode 7001 with PVP feedmix. Such a feedmix can be made by the same technique described above to prepare the drug reservoir with the addition of sodium chloride USP so that it has a composition of 0.9% sodium chloride (i.e., normal saline). Such solution loaded assemblies can be crosslinked using the same equipment and techniques as those used to construct the anodes, as described herein, or any other method known in the art. In certain embodiments, it is possible for the common release liner to be replaced with a single tab release liner 7014, after crosslinking. Those of ordinary skill in the art will recognize that a high capacity monolith reservoir/electrode can also function as an active drug reservoir for a

Attn. Docket No. 060162/VY0026 negatively charged drug, by substituting the negatively charged drug for the electrolyte if high rate and duration is required.

Figures 5B-D are a top plan, a partially exploded cross-sectional side, and bottom plan views of the patch 7000 of Figure 5 A according to various embodiments. Figure 5B shows the inner portion 7002 of the electrode 7001 through the cover 7012. Figure 5C shows the reservoir 7016 disposed in the cavity defined by the rings 7003, 7005. Figure 5D shows the backside of the inner portion 7002 of the electrode 7001 as seen through the transparent release liner 7014 and the opening 7007 defined by the lower ring 7005.

Aside from silver screens or meshes or chlorided versions of the same, other electrode substrates can be used such as foils, perforated foils, screen-printed substrates, gravure- formed substrates, and combinations thereof. However, those of ordinary skill in the art recognize that each electrode will have sufficient electro-chemical capacity to propel the drugs from the active reservoir through the skin or membrane during treatment. Those of skill in the art also recognize that in certain embodiments the return electrode will have matching electrochemical capacity.

For the delivery of sumatriptan, for example, the electrochemical reaction at the anode is Ag° → Ag ⁺ + e .

For a treatment regimen of 1.8 mA of current for 3 hours followed by a current of 0.8 mA for an additional 3 hours, 468 mA min of capacity would be required. This corresponds to the conversion of 0.0314 g of Ag to Ag ⁺ . By Faradays Law, W = I*t *MW _Ag / P, where W is the weight of silver needed to partake in the electrochemical reaction, I is the current in A, t is time in s, MW _A g is the molecular weight of silver and P is Faradays constant. Thicknesses or basis weights of the above mentioned types of anodes are readily made to have greater quantities of available silver to carry on the required conversion. For the cathode, the same

Attn. Docket No.060162/VY0026 types of materials are used for the electrodes as the anode, but with quantities of silver chloride electrochemically available to react according to the formula: AgCl + e ^" → Ag° + Cl ^" . In such embodiments, the electrode forms maintain sufficient mechanical and electrical conductivity for the electrode to sustain its required capacity when used.

EXAMPLE 1

In vitro Delivery of Sumatriptan across Porcine Skin

Sumatriptan succinate was custom synthesized (Natco Pharma Limited, Hyderabad, India); ketamine, xylazine and propofol were obtained from Henry Schein Inc. (Melville, NY). Ammonium acetate (ACS reagent) was obtained from Sigma— Aldrich (St. Louis, MO); acetonitrile, acetic acid and methanol (all HPLC grade) were obtained from (GJ. Chemical, Newark, NJ). Porcine skin was obtained from Thomas D. Morris, Inc. (Reistertown, MD). The excised skin was dermatomed (~500 μm) on the same day and stored at -20 ⁰ C for a maximum period of up to 1 week. A two-compartment iontophoretic patch system was used during the studies. The electrode compartment comprised an Ag-mesh anode, a small amount of sodium chloride (0.06%) and an ion exchange resin (AMBERLITE™ IRP-69, Rohm & Haas, Perth Amboy, NJ) that trapped Ag ⁺ ions preventing them from competing with drug ions to carry current. The electrode compartment was separated from the sumatriptan succinate contained in the drug reservoir, made of agarose disks as described above by a size- selective membrane (MW cut-off 100 Da, SpectraPor; Rancho Dominguez, CA). The active surface area of the anodal patch in contact with the skin was 4 cm ² . A vertical diffusion setup was employed wherein the patch was placed on and directly in contact with the skin, which was placed on a polymeric support. A custom manufactured flow through system,

Attn. Docket No. 060162/VY0026 ensured that the drug did not accumulate in the receiver phase, which was replenished at a rate of 0.1 ml/min. A constant current of 0.25 mA/cm ² was used in all of the experiments, which is within the limits generally accepted for use in humans. An AgCl electrode was employed as the cathode. Sumatriptan succinate was dissolved in water at the appropriate concentration required for the desired patch loading and ~400 μl of the drug solution was introduced into the anodal drug reservoir (Table 2). A passive "no-current" control confirmed that there was negligible sumatriptan transport in the absence of an iontophoretic current. Unexpectedly, it was found that delivery of sumatriptan could be decreased approximately 50 percent upon replacing agarose with a PVP hydrogel. Without being bound by theory or mechanism, it could be speculated that the tortuosity of path of travel for the drug was increased by use of PVP, thereby reducing the speed that the drug could flow from the reservoir.

Attn. Docket No. 060162/VY0026

Table 2: Composition of the formulations used in the in vitro and in vivo experiments

•Agarose, 3% SeaChem Gold, FMC **PVP 12% K-90 F, BASF

Samples obtained from the in vitro experiments were assayed using reverse phase HPLC. The HPLC system comprised a 600 E Controller pump, an Autosampler Injector 717- plus, and a 486 tunable UV Detector (Waters, Milford, MA) and was equipped with a ZORBAX RX™ cl 8 column with guard and prefilter (4.6 mm internal diameter, 25 cm in length and with a 5 μm particle size) (Agilent Technologies, Palo Alto, CA). The mobile phase comprising 15% acetonitrile and 85% 0.5M ammonium acetate buffered pH 4.9 solution with 1% trifluoroacetic acid (TFA) was delivered at a flow rate of 1 ml/min. The injection volume was 50 μl. Sumatriptan was detected at 282 nm with a limit of detection at 1 μg/ml.

As shown in Fig. 6, a 4-fold increase in patch load (9.7—39 mg) produced no statistically significant difference (t-test, α = 0.05) in the cumulative amounts of sumatriptan

Attn. Docket No.060162/VY0026 delivered after current application for 6h (305.6±172.4 vs. 389.4±80.4 μg/cm). However, in a second study, the pH of the drug formulation was increased from pH 4.7 (the approximate isoelectric point of skin) to pH 6.8. Fig. 7A shows that increasing the formulation pH by two units produced a statistically significant (t-test, α = 0.05) and unexpected increase of approximately 60% in cumulative sumatriptan delivery (389.4±80.4 vs. 652.4±94.2 μg/cm ² ). hi addition, the pH of the drug reservoir remained fairly constant during current application (Table 2). Fig. 7B shows the iontophoretic flux observed under the above conditions. The flux at 6h was 109.8±14.4 and 153±25.2 2 μg/cm ² per hour at pH 4.7 and pH 6.8, respectively. At the higher pH, the steady state flux corresponds to a transport number of 0.056, meaning that ~5.6% of the charge transferred during iontophoresis is carried by the sumatriptan cation. Since there is minimal competition from cationic species, it is evident that the predominant charge carrier in the system is the chloride ion from the receptor compartment towards the anode.

EXAMPLE 2

In vivo Delivery of Sumatriptan across Porcine Skin

As in Example 1, the two-compartment iontophoretic patch system (with an active area of 4 cm ² and where PVP drug reservoirs were prepared for pucks as described above by using drug loaded PVP disks that contained 37 mg of sumatriptan at pH 7.0), coupled to a programmable power source, was used to apply the current (Table 2). Two anodal patches were applied to each animal, i.e., the total active surface area in contact with the skin was 8 cm ² . The cathode consisted of another two patches with a total surface area of 8 cm ² . All three animals received the iontophoretic treatment involving application of a biphasic current protocol. In step 1, from t = 0 to t = 180 min, the current intensity was 1.8 mA (0.45 mA/cm);

Attn. Docket No.060162/VY0026 in step 2, from t = 181 to t = 360 min, a lower current intensity of 0.8 mA (0.2 mA/crn) was applied. From t = 361 min to t = 480 min, no current was applied although the patches were left in contact with the skin to investigate elimination of the drug from the bloodstream. At i the end of the studies, the animals were euthanized. Blood samples (2 ml) were drawn at 15 min intervals from t = -15min to t = 240 min and at 30 min intervals from t = 240 min to t = 420 min and again at t = 480 min. The samples were collected into chilled 3 ml glass vacutainer tubes containing ethylenediaminetetraacetic acid tripotassium salt (K ₃ EDTA) (BD ₃ Franklin Lakes, NJ). The tubes were immediately placed on ice and centrifuged at 4 ⁰ C (160Og for 15 min). The contents were then split into two samples and stored in Nalgene cryopreserve vials (VWR, Westchester PA). The plasma samples were stored at -70 ⁰ C.

Sumatriptan was extracted by protein precipitation. The plasma samples were first allowed to thaw at room temperature. After vortexing, 100 μ 1 of sample was transferred into 2ml Eppendorf tubes. Then, 10 μ 1 of MeOH- KfeO (1:1 mixture) was added to the plasma samples containing sumatriptan. After addition of 300 μl of acetonitrile and vortexing for a few seconds, the mixture was centrifuged at 120Og for 10 min. Then, 300 μl of the resulting supernatant was transferred to 16 • 100 mm clean culture tubes and evaporated to dryness under nitrogen at 35 ⁰ C (this took approximately 20 min). The samples were then reconstituted with 100 μl of mobile phase and vortexed before being transferred to injection vials and assayed by LC/MS/MS.

Assay methods were adapted from a published method. See, Cheng, K.L. et al., J. Pharm. Biomed. Anal. 17 (1998) 339-408. The LC system comprised a LC-10 AP pump and SCL-IOM controller (Shimadzu Corporation, MD); autoinjector (Waters 717 plus autosampler, Waters Corporation, MA) and was equipped with an Inertsil ODS2 column (4.6 mm internal diameter, and 15 cm in length with 5μm particle size) (Keystone Scientific, Inc.

Attn. Docket No. 060162/VY0026

PA, USA). Perkin-Elmer API 365 and API 3000 detectors were used to detect sumatriptan.

The mobile phase (20% methanol and 80% 10 mM ammonium acetate buffered pH 4.0 solution) was delivered at a flow rate of 1 ml/min. The injection volume was 10 μl. With respect to the MS conditions, the spectrometer employed a heated ion nebulizer at 475 ⁰ C.

The product ion had a molecular weight of 251.1 Da. The limit of quantification was 0.4 ng/ml.

Fig. 8 shows sumatriptan plasma concentrations during iontophoretic current application and following subcutaneous injection (as a control) in Yorkshire swine. A biphasic current profile was employed wherein a higher current of 1.8 mA (0.45 mA/crn) was applied for 3h followed by 3h at 0.8 mA (0.2 mA/cm). Blood levels of sumatriptan rose gradually upon current application, achieving 3.4±3.1, 13.7±4.5 and 53.6±10.2 ng/ml at the 15, 30 and 60 min time points and achieved fairly constant levels, of between 90 and 100 ng/ml, during the 90 — 100 min time period. The current intensity was then decreased to 0.8 mA (0.2 mA/cm). during the 180-360 min period, and there was a concomitant decrease in drug levels in the blood. Current application was terminated at t = 360 min, at which point, sumatriptan levels fell progressively as the drug was eliminated from the bloodstream, illustrating the control afforded by iontophoresis over drug delivery kinetics.

Visual inspection of the skin at the patch application sites after sumatriptan iontophoresis (and comparison of photographs of the sites before and after iontophoresis) did not reveal any significant erythema.

EXAMPLE 3 In vivo Delivery of Zolmitriptan in Swine (Trial 1)

A two-compartment iontophoretic patch system was used, with PVP disk drug reservoirs, as described above for these clinical applications. Anodal delivery of zolmitriptan

Attn. Docket No. 060162/VY0026

HCl (with PVP disk drug reservoirs) over 6 h with the above system in contact with skin was demonstrated with the following current profile: Pulses (0.35 mA/cm ² ) at t = 0 and 180 min with lower current densities at other times (see Figure 9). Blood was withdrawn from a jugular catheter and analyzed by Bio-analysis using LC/MS/MS. The results are presented in Figure 9.

EXAMPLE 4 In vivo Delivery of Zolmitriptan in Swine (Trial 2)

A two-compartment iontophoretic patch system was used with PVP disk drug reservoirs as described above for these clinical applications. Anodal delivery of zolmitriptan HCl over 6 h with the above system in contact with skin was demonstrated with the following current profile. The current profile (electrical dose profile) was as follows: High to low current 0.35 to 0.05 mA/cm ² (see Figure 10). Blood was withdrawn from a jugular catheter and analyzed by Bio-analysis using LC/MS/MS. The results are presented in Figure 1. Although the transport profile of zolmatriptan differed from that of sumatriptan (e.g., Fig. 7), these experiments demonstrate the feasibility of using another drug besides sumatriptan for electrically assisted delivery, which is particularly advantageous where the drug is not generally permeable through skin or a membrane. As such, these surprising results demonstrate the efficacy of such systems for electrically assisted delivery of low permeability drugs.

It will be appreciated by those skilled in the art that changes could be made to the embodiments described herein without departing from the broad concept of the invention. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but is intended to cover modifications that are within the spirit and scope of the invention as defined by the claims.