HUMIDITY CONTROLLING ABSORBER FOR ELECTROTRANSPORT DRUG

DELIVERY DEVICES

TECHNICAL FIELD [0001] The subject matter described herein relates to electrotransport drug delivery devices. In particular, a method for protecting such devices from corrosion and degradation due to high relative humidity while being stored inside a hermetically sealed pouch before therapeutic use. BACKGROUND [0002] Electrotransport devices are commonly used for transdermal delivery of drugs. The term "transdermal" delivery broadly describes the delivery of a therapeutic agent through the body surface, such as skin, mucous membrane, sclera or nails into the systemic circulation. In transdermal delivery the body surface often poses the greatest barrier of drug permeation into the body. In order to enable or increase the delivery of the drug through this physical barrier that prevents the drug from entering the body, one approach is to actively force the drug molecule across this barrier. This can be achieved by applying an electrical force.

"Electrotransport" as used herein refers to actively delivering therapeutic agents through the body surface aided by utilizing an electrical force. More specifically, electrotransport includes the electrically induced or enhanced transport of at least one therapeutic agent, which may be charged, uncharged, or a combination thereof across a physical surface of the body. [0003] One type of electrotransport process, iontophoresis, involves the electrically induced transport of ionic species of therapeutic agents from a device reservoir across for instance the skin into the blood circulation of the body. Necessary components of iontophoretic devices entail at least two electrodes that complete an electrical circuit with the current of drug ions and counter-ions passing from one electrode through the body to an electrode of opposing polarity. Therefore, the electrodes must be in electric contact with some portion of body surface, through which the drug ions are to be delivered.

[0004] The "donor" electrode is directly attached to a reservoir containing the drug agent and drives the agent from the reservoir into the body. The reservoir in turn partially contacts an area of the body surface through which the drug is to be delivered. Furthermore, iontophoretic devices could utilize multiple reservoirs or sources of the drug agents with multiple donor electrodes. Such reservoirs are electrically connected with and positioned between the donor electrodes and the body surface forming close physical contact with the donor electrodes.

Examples of such reservoirs include a pouch or cavity, a porous sponge or pad, and a hydrophilic polymer or a gel matrix.

[0005] In addition, the electrode or electrodes of opposite polarity that close the electric circuit through the body are generally in contact with electrolytic reservoirs. These reservoirs act as a source and sink for counter-ions that form part of the ionic current flowing through the body during operation of the device.

[0006] Finally, in order to drive a flux of ions into and through the body an electrical power source is needed to connect to the electrodes with its voltage and current regulated by an electronic controller. The electronics of the device has various electrical components and controls the amplitude, polarity, and timing of the electronic voltage and current in order to closely regulate the amount and time of delivery of the drug agent.

[0007] Commonly, hydrogels are utilized as matrix material of the reservoirs, because many ionic drug species are easily solvable or absorbed in water. One characteristic of hydrogels is that they absorb and maintain a large volume of water. Hydrogels also possess excellent biocompatibility with skin and mucosal membranes reducing the risk of skin irritation and sensitization during the operation of the iontophoretic device. Generally, in electrotransport drug delivery devices the formulation of therapeutic agents contains some amount of water. [0008] However, in integrated electrotransport drug delivery devices the close proximity of water-containing reservoirs and the device electronics poses significant challenges. The IONSYS™ product is such an integrated electrotransport delivery device worn on the skin of the patient during delivery. In such integrated systems all the system components are encased in a single -part housing including the hydrogel-containing reservoirs as well as all of the electronic parts, such as the battery, printed circuit board (PCB), and electronic switch. In order to assure that the hydrogels are sufficiently hydrated before therapeutic usage, the device is sealed inside a foil pouch in its final manufacturing step and then shipped inside this pouch to the site, where it is administered to the patient. Shipping and storing the device in a hermetically sealed pouch prevents significant water leakage from reservoirs of the system. Yet, storing such devices in sealed pouches still present stability challenges, as during storage inside the pouch the entire system is exposed to high relative humidity (RH) values of close to 100% at varying temperatures.

[0009] Condensation inside such a closed system occurs when the ambient temperature drops below the dew point temperature assuming no significant fluctuations in external

pressure, which can be ruled out under conditions commonly experienced by packaged medical devices. The water molecules are then forced to condensate on vapor-exposed system walls in form of water droplets or taking up by water-absorbing materials of the device. When RH inside the package reaches a value larger than 90% and package temperature lies between 10° and 40° Celsius, temperature drops of 1° to 3° Celsius already move the temperature below the dew point resulting in water condensation.

[0010] Hence, at high RH as present in the package pouch of an integrated electrotransport drug delivery device, small changes in ambient temperature yield moisture condensation on the device. When wet surroundings threaten electronic systems, reducing the level of moisture, or hermetically sealing the electronics typically mitigates this threat.

[0011] Attempts have been made to reduce the moisture vapor concentration inside the package by packing desiccants inside the pouch with the delivery system. This approach has two major problems. First, the desiccant can delay the condensation problem only for a relatively short time. Once the desiccant is saturated with water, water continues to evaporate from the hydrogels causing the relative humidity inside the pouch to climb back to the high levels that are reached without the desiccant present. Upon cooling to below the dew point, the water vapor condenses onto the PCB and other surfaces of the packaged system instead of being absorbed by the now saturated desiccant. Eventually, the system reaches a liquid- vapor equilibrium that possesses no driving force for water vapor to preferentially return to the hydrogel. This leaves the gels deprived of water that has been absorbed by the desiccant or condensed elsewhere inside the pouch. Therefore, increasing the amount of desiccant to extent the time before saturation occurs will only accelerate the loss of water from the hydrogels leading to other problems such as agent precipitation of the gel formulation, potentially altering drug release performance. [0012] Information relevant to these attempts can be found in U.S. Patent Nos. 4,192,773, 5,035,731, 5,037,459, 5,936,178, 6,649,086, 6,652,775, 6,660,295 and 6,899,822, and Patent Application Publication Nos. 2006/0097223 and 2007/0007490.

[0013] Hermetically sealing the system electronics provides another option. However, this option is far from optimal for an integrated electrotransport drug delivery device. Not only will the cost of manufacturing of the system significantly increase due to the additional production step of applying for instance a conformal layer to the PCB surface, but the applications of such a layer to certain electronic parts, i.e. the inductive transducer, on the PCB also may alter their

electronic characteristics, in case of the transducer its resonance frequency, in an unpredictable way. Hence, sealing of the electronics is not only impractical, but yields undesirable consequences.

[0014] The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those skilled in the art upon reading of the specification and a study of the drawings.

SUMMARY OF THE DISCLOSURE [0015] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0016] The present application provides for an improved package of a humidity-controlling absorber and an electrotransport drug delivery device. The absorber controls the humidity in the enclosed environment of the package and at varying temperatures in such a way to limit the loss of water from the water-containing reservoir of the electrotransport drug delivery device in order to assure operability of the device after retrieval from the package. In particular, a high relative humidity environment normally present inside the package is regulated to maintain functionality of the electrotransport drug delivery device.

[0017] Furthermore, the absorber reduces moisture condensation and provides a reservoir to preferentially absorb condensed water. This reduces the time that components of the electrotransport device are exposed to condensed water, leading to improved stability and longer shelf life of the device. The absorber controls relative humidity at varying temperatures during storage of the electrotransport drug delivery device in such a way to protect the device electronics from moisture condensation, yet maintaining operability of the device by limiting its loss of water. [0018] In one embodiment, the package includes an electrotransport device for delivery of a therapeutic agent through a body surface of a patient, an absorber and a water- vapor tight container enclosing the electrotransport device and the absorber. Furthermore, the electrotransport device has two electrodes, with one of the electrodes in electrical contact with a water-containing reservoir that contains a therapeutic agent to be delivered by electrotransport. The device also includes an electrical circuit having a plurality of electronic components, and the circuit electrically connects the two electrodes. The advantage of the

absorber is that is controls relative humidity inside the package to limit loss of water from the water-containing reservoir of the electrotransport device.

[0019] In one embodiment, the absorber controls the relative humidity inside the package to be above 70% and less 99% to limit the water loss from the water-containing reservoir of the electrotransport drug delivery device.

[0020] In another embodiment, due to the absorber controlling the relative humidity inside the package the weight loss in water of the reservoir of the electrotransport device is limited to less than 20% of the total amount in water present in the reservoir at the time of packaging the electrotransport device. [0021] In a further embodiment of the package, the humidity-controlling absorber contains a hygroscopic substance, water and a carrier. The absorber is optionally contained inside a gas- permeable container.

[0022] Accordingly, it is an aspect of this application to provide an improved method of reducing moisture condensation on electronic components of an electrotransport drug delivery device that experiences a high relative humidity environment inside a package container. This method entails providing an electrotransport device that has two electrodes, with one of the electrodes in electrical contact with a water-containing reservoir that contains a therapeutic agent to be delivered by electrotransport. The device also includes an electrical circuit having a plurality of electronic components, and the circuit electrically connects the two electrodes. The next step in the method is to provide an absorber to control relative humidity inside the package to limit loss of water from the water-containing reservoir of the electrotransport device. The following step includes enclosing the electrotransport device and the absorber inside a water-vapor-tight container. In doing so one reduces moisture condensation by allowing the enclosure water vapor to transfer between the water-containing reservoir and the absorber.

[0023] It is another aspect of this application to provide an improved method of storing an electrotransport drug delivery device exposed to a high relative humidity environment during storage. One step in this method is providing an electrotransport device that has two electrodes, with one of the electrodes in electrical contact with a water-containing reservoir that contains a therapeutic agent to be delivered by electrotransport. The device also includes an electrical circuit having a plurality of electronic components, and the circuit electrically connects the two electrodes. The next step in the method is to provide an absorber that contains a hygroscopic

substance, water, and a carrier. In the following step the electrotransport drug delivery device and the absorber are enclosed inside a water-vapor-tight container wherein the relative humidity is maintained below saturation, allowing moisture exchange between the electrotransport device and the absorber. [0024] The current application also describes a method of manufacturing an improved package of an electrotransport drug delivery device. This method entails providing an electrotransport device that has two electrodes, with one of the electrodes in electrical contact with a water-containing reservoir that contains a therapeutic agent to be delivered by electrotransport. The device also includes an electrical circuit having a plurality of electronic components, and the circuit electrically connects the two electrodes. The next step in the method is to dissolve a hygroscopic substance into water forming a near-saturated solution. Subsequently, the solution is absorbed by a carrier, with the carrier and the electrotransport drug delivery device then being placed inside a water- vapor-tight container. [0025] It is yet another aspect of this application to provide an improved package of an electrical system having a hydrogel. The package includes an electrical system having a hydrogel and an absorber that controls the relative humidity inside the package to stay below saturation level at a particular temperature.

[0026] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the disclosure, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which:

[0028] FIG. 1 is schematic illustrating the moisture sorption mechanism inside the embodiment of a package containing an humidity-controlling absorber and a electrotransport drug delivery device; [0029] FIG. 2 is a side sectional schematic of a electrotransport drug delivery device; [0030] FIG. 3 is a graph illustrating the change in relative humidity over the duration of storage for an package of a electrotransport drug delivery device with and without a humidity- controlling absorber;

[0031] FIG. 4 is a photograph that shows water condensation on the surface of a IONSYS™ printed circuit board;

[0032] FIG. 5 is a graph displaying distribution in percentages of four distinct states of moisture condensation for separate components of the IONSYS™ device; [0033] FIG. 6 is a graph displaying the change in water activity of hydrogels due to decreasing water content;

[0034] FIG. 7 is a graph indicating the weight increase of two absorber samples upon injection of 1 ,2-dimethoxy ethane (DME) into the closed package containing the samples;

[0035] FIG. 8 is a histogram of multiple 5mg 1 ,2-dimethoxyethane (DME) injections; [0036] FIG. 9 is a photograph of an exemplary formulation of the humidity-controlling absorber;

[0037] FIG. 10 is a graph that illustrates the weight change of two exemplary embodiments of the absorber during storage at a temperature of 25° Celsius;

[0038] FIG. 11 is a graph illustrating the change in relative humidity at different temperature over the duration of storage for an package of a electrotransport drug delivery device with a humidity-controlling absorber;

[0039] FIG. 12 is a graph that illustrates the change in water activity of an exemplary absorber during storage as a function of absorbed water amount in addition to initial water- containing absorber solution; [0040] FIG. 13 is a graph displaying distribution in percentages of four distinct states of moisture condensation for separate components of the IONSYS™ device packaged with an absorber;

[0041] FIG. 14 is a graph illustrating the change in relative humidity over the duration of storage for an package of a electrotransport drug delivery device with a humidity-controlling absorber;

[0042] FIG. 15 is a graph that illustrates the change in water activity of an exemplary absorber during storage as a function of total water amount contained in absorber;

[0043] FIG. 16 is an exemplary manufacturing flowchart of one embodiment of the absorber; and [0044] FIG. 17 is a graph that illustrates the moisture uptake of salt solutions with varying water activity in a 98.5% RH environment.

[0045] FIG. 18 is a graph that illustrates the rate of weight change of absorber with time in an embodiment of a system of the present invention. DETAILED DESCRIPTION

[0046] The following detailed description should be read with reference to the drawings, in which like elements in different drawings are identically numbered. The drawings, which are not necessarily to scale, depict selected exemplary embodiments for the purpose of explanation only and are not intended to limit the scope of the invention. The detailed description illustrates by way of example, not by way of limitation, the principles of the invention. This description will clearly enable one skilled in the art to make and use the invention, and describes several embodiments, adaptations, variations, alternatives and uses of the invention, including what is presently believed to be the best mode of carrying out the invention. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting. [0047] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

[0048] Further, all publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. [0049] For purposes of this application, reference to the term "package" or "packaging" will be understood to also include reference to "storage" or "storing" and vice versa.

[0050] Finally, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "an active agent" includes two or more such agents; reference to "a hydrogel" includes two or more such hydrogels and the like. Definitions

[0051] Water activity (a _w ) is a measurement of the energy status of the water in a system, and is defined as the vapor pressure of water divided by that of pure water at the same temperature and pressure. Additionally, the vapor-fluid interface of pure water is assumed to be planar. Pure distilled water has therefore a water activity of exactly one. In a multi- component system the water activity of each component when measured separately from each other might be very different. Materials with a _w of less than 1 possess reduced water- vapor pressure compared to pure water. In the presence of pure water such materials would therefore

act as a sink for water attracting water molecules from the vapor phase, whereas the pure water phase would slowly shrink by yielding water molecules to the vapor phase. The same would hold true for two or more materials with different water activities. Water contained in materials with higher water activities would migrate to materials that possess lower individual water activities. An underlying assumption of this diffusion model is that the materials can exchange water molecules via a common pathway such as the vapor phase. The larger the difference between each respective value of water activity (resulting in a gradient), the higher the diffusion rate at which water molecules are moving from one material to the other assuming there exists no other factor that would block the free exchange of water molecules. [0052] Equilibrium relative humidity (ERH) is referred to when comparing water activities to relative humidity in a system. The equilibrium relative humidity of a material equals its water activity (a _w ) multiplied by 100%.

[0053] Relative humidity (RH) of a closed system is defined as the ratio of the partial pressure of water vapor in the system to the saturated vapor pressure of pure water at a given temperature and pressure. Relative humidity is expressed as a percentage. The vapor phase in a multi-component system will be between the smallest and largest ERH value of its individual components. Fluctuations in temperature and pressure that the system experiences will affect the water activity values of its components, ultimately changing the relative humidity of the vapor phase and the diffusion rate of water molecules. Saturation of water- vapor phase in a system is obtained when the relative humidity reaches 100%. The saturation point is often referred to as the dew point, and the temperature at the saturation point as the dew temperature. Decreasing the temperature below the dew temperature will cause water vapor to condense into water (dew) in the system. A high relative humidity indicates that the dew temperature is close to the ambient system temperature. [0054] Steady state in relative humidity as used herein is defined as phase during which the relative humidity inside the closed systems undergoes only minor changes over an extended period of time, such as months. This state is distinct from the equilibrium state of the system, when the relative humidity stays constant, assuming a constant ambient temperature and pressure. Once a system reaches an intermediate steady state, its RH continues to slowly drift towards its equilibrium value. Oftentimes, a system might reach its equilibrium state only after a very prolonged period of time. In a multi-component system the water activity of each component will not stay constant over time, but rather approach each other as the water

pressure increases from absorbing water molecules, while it decreases when yielding water molecules to other parts of the system. Equilibrium is reached when the ambient relative humidity of the system equals the equilibrium relative humidity values of all its components. [0055] Carbon tetrachloride (CTC) activity is a standard test for activated charcoal (ASTM D3467) as a measure of the sorbent qualities of the material. This test uses carbon tetrachloride vapor as the challenge gas for adsorption by the charcoal. The weight amount of carbon tetrachloride adsorbs per 100 g of charcoal is known as the carbon tetrachloride activity. The ASTM method can yield different CTC activities if performed on either raw carbon or dry- formulated carbon. Generally its CTC activity is an indicator of how well the specific charcoal material absorbs other organic vapors. The higher its CTC activity value the greater the ability of the material to adsorb large quantities of organic vapors. Experiments shown proof that a lower bound on the estimate for carbon 1 ,2-dimethoxyethane (CDME) activity can be obtained by dividing the CTC activity by a factor of 3.27 ± 0.2. Hence, a CTC activity of 45 g per 100 g yields an estimate of CDME activity to be at least 14 g per 100 g of dry- formulated charcoal. Wetting the charcoal will reduce the capacity of the formulation to absorb tetrachloride and 1 ,2-dimethoxyethane, respectively.

[0056] As discussed in the Background section, current approaches for protecting the electronic circuitry of an electrotransport drug delivery device from high relative humidity in an enclosed environment such as a storage pouch are problematic. The presence of water as part of the device is essential for its operability, yet can lead to deterioration and corrosion of its electronic components, and ultimately to device failure due to electronic malfunctioning. [0057] The present invention provides an improved package of an electrotransport drug delivery device and a method for limiting loss of water and corrosion thereof. The improvement contains providing an electrotransport drug delivery device with a humidity- controlling absorber into the package enclosing both the device and the absorber. The absorber controls the relative humidity inside the package such that it not only decreases the amount and duration of moisture condensing on the surface of the device electronics, but also limits the amount of water loss from water-containing reservoirs of the device as exemplified in FIG. 1. The resultant package provides improved protection against dehydration of the electrotransport device as well as corrosion of its electronic components, thereby increasing the shelf life of such devices.

[0058] Furthermore, despite high relative humidity commonly present in the package, condensation is averted through the combined effects of sorption moisture as well as of organic volatiles. Preferably, the absorber included in the package not only slowly absorbs moisture from the headspace vapor of the package to keep the ambient air from condensing, but also organic volatiles that are gassing for instance from the batteries of the electrotransport device to prevent those volatiles from participating in the condensation process. [0059] Reference is now made to FIG. 2 depicting an exemplary embodiment of an electrotransport drug delivery device that can be used in accordance with the present disclosure. [0060] Generally, the packaged electrotransport drug delivery device 10 includes at least two separate electrode assemblies, labeled first and second, respectively. The device is self- contained and can have essentially any convenient size or shape, whether square, oval, circular, or tailored for a specific location on the body. The device furthermore can be flexible and easily conform to a body surface. At least one of the electrode assemblies contains a therapeutic agent that is to be delivered through a body surface of the patient. The electrode assemblies are electronically connected via an electrical circuit 18. The electronic circuit is relatively thin and preferably has electrical pathways printed, painted or otherwise deposited on a thin substrate or board. In addition to a power source, the circuit may also include one or more of the following components which control the level, waveform shape, polarity, timing and other physical properties of the electronic current applied by the device, including for example, control circuitry such as a current controller, an on/off switch, and/or a microprocessor adapted to control the current output of the power source over time. [0061] The electrode assemblies can be physically separated form one another by an electrical isolator, and form therewith a single self-contained unit. Typically, the electrode assembly is composed of an electrode 22, 24 and an adjacent reservoir 26, 28 that either contains the therapeutic agent and/or an electrolyte. Electrodes may contain metal foils, or a polymer matrix loaded with metal powder, powdered graphite, carbon fibers, or any other suitable electrically conductive material. The reservoirs can be polymeric matrices or gel matrices adapted to hold a liquid solvent. Aqueous-based or polar solvents, especially water, are generally preferred for delivering agents across a body surface. When using an aqueous- based solvent, the matrix of reservoirs preferably has a water retaining material and contains

most preferably a hydrophilic polymer, such as a hydrogel. Natural or synthetic polymer matrices may be employed.

[0062] In a typical embodiment of a electrotransport device, the agent reservoir or reservoirs contain neutral, ionized, or ionizable supply of the agent or multiple agents to be delivered, while it can also contain a suitable electrolyte such as, for example, sodium chloride, potassium chloride or mixtures thereof. The reservoirs of the electrotransport drug delivery device must be placed in agent transmitting relation to the body surface of the patient 36, through which the agent is delivered. Usually this means the device is placed in intimate contact with the patient's skin as one possible body surface. Practice of this application is not to be limited to any particular therapeutic agent. Generally, the combined body surface contacting area of the electrode assemblies can range from about 1 cm ² to about 200 cm ² , but typically will range from about 5 cm ² to about 50 cm ² . This is typically the total surface area through which water will be exchanged between device reservoirs and the package headspace during storage. [0063] After manufacturing the electrotransport drug delivery device is packaged within a water- vapor-tight container that also includes the absorber. The container could be made from a foil pouch large enough in size to hold the device and the absorber. The pouch material is selected from materials known in the art. It is preferred that the pouch material is self-sealable, light in weight, and acts as a barrier to the water vapor contained within the pouch. For example, suitable pouch materials are disclosed in U.S. Pat. Nos. 5,077,104 and 5,268,209, which are hereby incorporated in their entirety by reference.

[0064] In an exemplary system of a individually packaged IONSYS™ device without absorber relative humidity increases to about 99% within one to two days (FIG. 3). Furthermore, since water activities of hydrogels are relatively temperature independent (Table 1), the relative humidity stabilizes at this high value for the storage duration of the electrotransport device.

[0065] Without the absorber even small temperature fluctuations on the order of 1° to 3° Celsius will cause water to condensate inside the device package as described in the Background section. Since the packaged device can be expected to repeatedly experience such temperature changes during transportation and storage, the water-containing reservoir of the device will continue to lose water through moisture condensation outside the reservoir. Changes in temperature will act as a pump forcing increasingly larger amount of water to

condensate inside the pouch while leaving the device reservoir. FIG. 4 shows condensed moisture droplets on the PCB surface of IONS YS™, an integrated electrotransport drug delivery device, immediately after removing the system from the pouch following a 1-week storage. As part of moisture condensation studies a visual inspection of the PCB and housings of the device was performed. After 3 months stored at 40° Celsius significant amounts of condensation on certain areas of the board, including around the switch (12) and underneath the transducer (40) were seen. Fine droplets are usually present over most of the board. FIG. 5 summarizes the results of the inspection with the legend of observed moisture on various device parts as follows: 1) moisture pooling was evident with likely effect on device functionality; 2) moisture droplets were observed, but no pooling (may affect device after extended storage); 3) surface film condensation was observed; and 4) no moisture was evident. Similar data was observed when stored at 25° Celsius.

[0066] The present invention provides an absorber with a water activity different to the water activity of the electrotransport device. The driving mechanism by which the absorber regulates the relative humidity inside the package is due to the difference in the water activity of the absorber and the water-containing reservoir of the electrotransport device. The advantage of providing a gradient in water activity between the absorber and the reservoir of the electrotransport device is that it forces condensed water back into the headspace vapor of the package. [0067] As explained above, with the absorber acting as a moisture sink, the difference in water activity of the absorber and reservoir of the electrotransport device will continue to pump out water from the reservoir to the absorber. This water movement only stops, once the water activity of the device reservoir approaches the water activity of the water accumulating absorber. As the absorber moves away from saturation, i.e. becomes more dilute, its water activity will increase since the ratio of absorber composition to retained water is decreasing (becomes more like pure water, which has an a _w value of 1). The rate of absorption will decrease as the absorber's a _w increases and it will continue to absorb until its a _w value matches that of the reservoir. On the other hand, the water activity of the device reservoir losing water to the absorber will drop in value until equilibrium is attained. At equilibrium the water activity gradient between the absorber and the device reservoir vanishes. Since it is advantageous to maintain a water activity gradient to reduce moisture condensation, a preferred embodiment prolongs the time at which the package reaches equilibrium beyond the storage duration.

[0068] In the exemplary embodiment with the electrotransport device reservoirs containing hydrogels, for all practical reason the water activity of gels for the storage duration can be assumed constant, since only a significant water loss (larger than 40% in weight change) will result in a significant drop in water activity of the gels (larger than 0.01) (FIG. 6). Yet, a 40% water loss to the hydrogels of the device would drastically alter their physical characteristics, yielding the device inoperable.

[0069] In the case of an electrotransport device utilizing hydrogels, whose water activity remains larger than 0.99 during storage, the preferred embodiment of the package includes an absorber that regulates relative humidity inside the package such that RH increases to at least 90% in the first 10 to 20 days of storage, while maintaining a water activity of less than 0.985 due to water absorption over the entire length of storage and at a temperature in the range of 10° to 40° Celsius.

[0070] In a preferred embodiment, the absorber contains an aqueous solution in which one or multiple hydrophilic inorganic or organic compounds are dissolved. Aqueous solutions of an inorganic compound, in particular hygroscopic salts, are preferred. Examples of hygroscopic salts include NaOH, LiBr, ZnBr ₂ , KOH, LiCl, CaBr ₂ , LiI, CaCl ₂ , MgCl ₂ , NaI, Ca(NO ₃ ) ₂ , Mg(NOs) ₂ , NaBr, KI, SrCl ₂ , NaNO ₃ , NaCl, NH ₄ Cl, KBr, (NH ₄ ) ₂ SO ₄ , KCl, Sr(NOs) ₂ , BaCl ₂ , CsI, KNO3, K ₂ SO ₄ and the like. Saturated aqueous solutions of hygroscopic salts are preferred, since upon diluting the solution the water activity remains constant until the saturation point is reached. This allows for the absorber to uptake moisture without change in its water activity. Examples of organic compounds include polyvalent alcohols, such as glycerin and ethylene glycol, organic salts such as sodium acetate and magnesium acetate, and oxalic acid. One benefit of aqueous solutions of hygroscopic substances is that their water activities are well tabulated. In addition, their use allows for tight control of the water activity of the absorber. This can be achieved by adjusting the concentration of the compound or mixing multiple compounds resulting in aqueous solutions with different water activities [0071] In another preferred embodiment, the absorber is made of the nearly saturated salt solution from potassium sulfate containing 2.5% to 3.9% of the total weight of the absorber and water in the range of 25% to 31% of total absorber weight with a water activity of about 0.97, while the water activity of the water-containing reservoir of the electrotransport device is about 0.99. The small gradient in water activity between the absorber and the reservoir is advantageous, since it limits the water flow from the reservoir to the absorber. With a larger

difference in water activities, the reservoir of the electrotransport device would lose water faster to the absorber reducing the self-life of the package.

[0072] Measurements of the water uptake of various saturated solutions of hygroscopic salt with different water activities in a 98.5% RH environment (FIG. 17) yields insight into a preferable minimum value for the water activity of the absorber when packaged with a electrotransport device containing hydrogel reservoirs. A preferred embodiment including the IONSYS™ device contains an absorber having a hydroscopic salt with a water activity larger than about 0.7. [0073] Initially upon enclosure the RH of the system will dramatically change in a couple of days with water vapor saturating the headspace environment inside pouch before reaching a steady state. At this point, the system as a whole in the package is at a steady state, rather than true equilibrium. That the device is at a steady state under which a constant flow of moisture occurs from the water-containing reservoir to the headspace to the absorber occurs the majority of the time during the duration of storage, more than 95% of the time. For example, when the device is in storage in a storage room or in the clinic or hospital, the device is at a steady state. [0074] The RH depending on the ambient temperature and pressure should preferable reach a steady state within 7-8 days with an RH below, but close to the ERH of the electrotransport device. [0075] Hence, in a preferred embodiment the absorber contains excess water. The advantage of excess water is that upon packaging the absorber with the electrotransport device, the interior of the package and the headspace of the package quickly humidifies by moisture from the absorber and the water-containing reservoir of the electrotransport device. By providing excess water in the absorber the loss of water from the device reservoir is mitigated. This initial dip in water content of the absorber occurs before a steady state in relative humidity is reached inside the package (as can be seen in FIG. 18). The graph of FIG. 18, about an the embodiment using K ₂ SO ₄ for controlling humidity in a package of an iontophoretic device, shows that initially the rate of weight change in the absorber is negative (indicating an initial loss of water by the absorber), before becoming positive (indicating the absorption of water). It is noted that the smooth curve is obtained by curve fitting the data points. The actual data points showed the rate becoming positive after a few days.

[0076] Another preferred embodiment of the absorber included in the package is in solid form to prevent the absorber from spilling, leaking or seeping inside the package and thereby

damaging the electrotransport drug delivery device or the package material. For this reason the absorber includes a carrier that can hold the excess water. As noted above, another preferred embodiment of the absorber contains hygroscopic salts in the form of saturated solutions. Adding the hygroscopic salts to a carrier agent then solidifies the solution. A preferred carrier should be porous enough to allow for free exchange of moisture from and to the absorber. In addition, the carrier should be able to hold the hygroscopic salt and excess water. [0077] The carrier may be a cellulose, silica gel, clay, carbon, carbohydrate or protein gelling agent, hydrocolloid like carrageenan or alginate, gum like konjac, hydrophilic polymer like acrylate or polyvinyl alcohol, diatomaceous earth, molecular sieves, zeolites, organic polymers or any other material that will stabilize, solidify, encapsulate or absorb the hygroscopic salt solution into a solid state. This solid-form absorber may then be sealed into a suitable container in accordance with the disclosure and placed inside the package of the electrotransport drug delivery device. [0078] In a preferred embodiment of the present disclosure, the absorber may be contained within a gas-permeable container designed to be compatible with the package of the electrotransport drug delivery device for ease of handling the absorber. The container interface must allow for sufficient vapor permeability between the solidified absorber and the headspace, i.e. the atmosphere, within the package, while securely containing the absorber. Typical containers can take the form of thermo-formed felt material, a canister, or perforated rigid or semi-rigid vessel, or a sachet made with a micro-perforated polyester/paper/polyethylene structure or a woven or non-woven material. The absorber preferably is in stable and solid-form, free-standing or in a gas-permeable container. [0079] The amount of water the absorber can hold while acting both as a water source and sink to maintain RH inside the package depends on the initial composition of the absorber including the initial excess water content. Once the water activity of the diluted absorber equals the water activity of the now less water-containing reservoir of the electrotransport drug delivery device, the absorber stops acting as the primary water source and sink for controlling RH in the closed package container. [0080] Once the package including the absorber and electrotransport device reaches a steady state with minimal changes in RH at fairly ambient constant temperature and pressures, the package RH will stay constant over extended time periods on the order of weeks to months. Now moisture condensing due to temperature drops below the dew point will readily be forced

back into the vapor phase of the package headspace due to the gradient in water activity of the moisture droplets equaling close to 1 and the lower a _w value of the absorber. At this point, the water volume within the electrotransport device will be a fraction of the water initially contained in the device when placed inside the package with the absorber. The net loss of water from the device will closely equal the net gain of water retained by the absorber with little amount of water evaporated into the package headspace and without any significant condensation inside the package.

Table 1- Water Activities of Absorbers and Gels after 6 months of storage

n: number of samples

[0081] While the RH inside the package of the absorber and electrotransport device is larger than the ERH of the absorber, water will continue to leave the hydrogel reservoir and/or from water droplets that previously condensed on surfaces elsewhere inside the package container into the package headspace. Simultaneously, water molecules will leave the headspace and be taken up by the absorber. There will be a net influx of water to the absorber. Preferably utilizing an absorber with an ERH value close to the ERH value of the electrotransport drug delivery device will limit the loss of water from the device to the absorber due to a the smaller flux rate of water. [0082] If the RH inside the package container falls below the ERH of the absorber, water molecules will be emitted not only by the device reservoir and/or condensed water inside the package, but also from the absorber in order to counter the drop in RH and maintain its previous level. In this case, the absorber acts as an additional water source thereby preventing excessive water loss from the water-containing reservoir of the electrotransport device. [0083] Overall, insuring stability and operability of the electrotransport device for its shelf life the water loss from the device is capped to no more than 20% in weight during storage. Since the intended shelf life of such devices should be at least 6 months long, in the case of the IONSYS™ system this equates to a total water loss of less than 200mg at end of IONS YS™ 6-

month shelf life. Water losses during the manufacturing process further restrict the water loss to be less than 100 mg during storage.

[0084] Keeping the relative humidity inside the package pouch within the range of 85% to 96% would suffice to limit the water loss to less 10% in the total amount of water originally contained in the electrotransport hydrogels. In the case of the IONSYS™ system this loss is less than the required lOOmg for 6 months of packaging the IONSYS™ device with the absorber at ambient temperature and pressures usually experienced during storage. [0085] In another preferred embodiment, the electrotransport device is stored with an absorber that absorbs volatile organic or acidic vapors in addition to water vapor that will further improve the shelf life of the electrotransport drug delivery device inside the package. [0086] During storage organic or acidic vapors leak from components of the device and force water vapor from the headspace to condense on various surfaces inside the package. Removing leaked vapors will eliminate this effect resulting in less moisture condensation and in turn reduce or prevent corrosion of the device. For example, 1 ,2-dimethoxyethane (DME), a solvent used as an electrolyte in the lithium battery 32 of the IONSYS™ device, was shown to slowly leak from the battery 32 and cause increased water condensation inside the package, and in part on the PCB of the device. In general, any organic volatile compound present in parts of the device can potentially contribute to the overall vapor pressure, effectively forcing water to condensate. [0087] Additionally, reducing the exposure time of the electronic components to acidic vapors will eliminate another possible cause of their corrosion. Despite the operating temperatures of the system (10°-40° Celsius) being relatively "benign", the electronic components of the electrotransport device are actually situated in a harsh environment. The acidic vapor enhances the chemical reactivity of moisture condensing on various surfaces of the electrotransport drug delivery device, increasing the rate of corrosion of metallic components of the device and subsequent device failures. Additionally, dissolving ions in the condensate can lead to electric current flow on the PCB due to a voltage applied by a power source, e.g. the battery 32, during storage of the device, causing malfunctioning of the device. [0088] The list of organic and acidic volatiles that may be present in an electrical system in an electrotransport device includes, but is not limited to acetone, methylacrylate, methyl or isopropyl cellosolve, acetic acid, 1 ,2-dimethoxyethane, dimethylformamide, butanol, methoxy isopropyl alcohol, heptane, methyl methacrylate, propylene glycol, toluene, methacrylic acid,

2-hexanone, xylene, 3-methyl hexanone, styrene, trimethyl benzene, propylene carbonate, alpha-methylstyrene, 2-ethoxyethoxy-ethanol, decane, undecane, 2-methylbutanoic acid, (2,4)- di-tert-butylphenol, butylated hydroxytoluene, difluoroethane, propene, methanol, acetaldehyde, isobutylene, methylformate, acetone, t-butanol, 2-methylpropanal, propanol, 2- methylpentane, methacrolein, cyclohexane, butanal, methyl ethyl ketone, ethylacetate, trimethylsilanol, tetrahydrofuran, butanol, 2-pentanone, heptane, (l,4)-dioxane, dichloromethane, dimethylcyclopentane, cyclotetradecene, hexadecene, and carbon tetrachloride. [0089] In another preferred embodiment, the absorber possesses a dual mode of action: controlling relative humidity inside the package centered on about 95-97% and absorbing 1,2- dimethoxyethane outgassed by components of the electrotransport device. Preferably, the absorber includes activated charcoal that not only acts as a carrier, but also absorbs organic and acid volatiles. Since batteries employed in electrotransport devices generally outgas on the order of 3 mg in 6 months at 40° Celsius, the absorber designed for a 6-month shelf-life has at least a DME activity of 14g per lOOg of dry- formulated activated carbon. This translates into the activated carbon of the absorber material to have at least a CTC activity of larger than 45 g per lOOg of the dry-formulated carbon material and larger than 5 Ig per lOOg of raw carbon. [0090] Experiments demonstrated the sorption capabilities of DME by Ig of wet formulation of absorber material containing a 7:3 ratio of activated carbon to water with a CTC activity of 51 g per lOOg for the raw carbon. When a large amount of DME was injected into a sorption chamber at 25° Celsius and relative humidity of about 98.5% with the absorber material suspended in a sachet from a microbalance, the weight increase of the sachet was measured to be about 17 mg (FIG. 7). To confirm the capacity of the formulation to absorb DME, 5 mg aliquots of DME were sequentially injected on formulation samples. Up to 15 mg 100% of DME was retained in the absorber, with the subsequent injection only yielding 50% DME absorption (FIG. 8). This confirms that a preferred embodiment including an absorber that contains water and activated charcoal, the charcoal should preferably have a CTC activity larger than 45 g per 100 g for the dry formulated absorber material. [0091] In an alternative preferred embodiment of the disclosure, the so lid- form absorber can be formed into a tablet through inclusion of an appropriate carrier that binds the composition together. The binder could be any of a known number of binders, such as polyvinyl-pyrollidone, a cellulose ether resin, a thermoplastic polymer or a wax, and can be a

separate element from the carrier that for example could be silica gel. If the binder serves as the carrier itself, adequate amounts are needed to stabilize and solidify the absorber. [0092] This tableted absorber can be used with or without it being contained within an enclosure. It could be contained as noted above, or coated with a vapor permeable coating for increased durability. Appropriate coatings would include powdered polymers such as polyethylene or polytetrafluoroethylene, coated dry or in suspension followed by heat curing. Alternatively, the tableted absorber could be resin coated with polyvinylpyrollidone or a cellulose ether followed again by a drying and curing step. The coating needs to allow for a free moisture exchange with the water vapor of headspace inside the package to not impede on the absorber controlling the relative humidity inside the package.

[0093] In an alternative embodiment of the present disclosure, the absorber may also include an antimicrobial preservative, which will control growth of microorganisms within the package. Further, by choosing an antimicrobial agent that is compatible with the container or package and the electrotransport drug delivery device, it can be ensured that the operability of the device is not interfered with. Example 1

[0094] In an exemplary embodiment of the disclosure, a packet of absorber material is placed inside the packaging with a electrotransport drug delivery device such as the IONSYS™ device as described in U.S. Pat. No. 6,881,208. The two hydrogels of the IONSYS™ reservoirs contains hydrolyzed polyvinyl alcohol. After manufacture the

IONSYS™ hydrogels contain 464 mg of water and 486 mg of water, respectively, for a total nominal weight of 950 mg of water before being hermetically sealed with the absorber inside a foil pouch for transportation and storage. An IONSYS™ hydrogel reservoir is about 2.7 cm2 in area and about 2.4 mm in thickness. It is evident that the hydrogel contains mostly water. The exact size of the hydrogel reservoir is not critical for the purpose of controlling humidity as long as it can contain a lot of water and allows moisture migration over time. The absorber material contains activated charcoal or carbon (Calgon Carbon Corporation, Type 3115) onto which a potassium sulfate solution has been sprayed. The solution is subsequently fully absorbed by the activated carbon. Excess water of the formulation is prevented from evaporating. The absorber material (FIG. 9) is then placed inside a sachet pouch of spun- bonded and uncoated medical grade polyethylene having a thickness of 6.5 mils. The sachet pouch allows air to pass through and acts as a microbial barrier. The formulation weighs about

Ig and possesses the following composition: 690mg of activated carbon, 33mg of potassium sulfate, and 280 mg of excess water. The carbon tetrachloride activity for the raw carbon is larger than 51 and for the formulated material is larger than 45. The size of the sachet pouch can be variable as long as it fit inside the foil pouch containing the IONSYS™ device. Generally, the sachet is of size 85x35mm with a thickness of about 2mm. The surface of the sachet is extremely breathable to allow maximal airflow into the sachet.

[0095] In this example the moisture uptake of the absorber averages about 25.5 mg of water from the IONSYS™ hydrogels at 6 months and 25° Celsius during storage. This is well below the above noted 100 mg threshold. The absorber draws water from the atmosphere during storage of the IONSYS™ system inside the package pouch. This helps maintain the relative humidity and reduce the water on the PCB and other electronic components of the IONSYS™ system. The rate of moisture sorption is proportional to net weight gain of the absorber (FIG. 10). Each individual data point is an IONSYS™ system at various times after placing and sealing the system inside the pouch at initial time equal zero. The systems were sealed in pouches after the initial weighing. Each system was weighed at each time point and then placed back in their pouches to await the next time point.

[0096] As a desired feature of this example, the absorber yielded some moisture (negative weight gain = weight loss) to the headspace of the pouch after 7-day packaging, because the initial relative humidity in the pouch measured less than 97%. The absorbed moisture increased over time, moving up to 6-16 mg net weight gain at three months. The absorber could gain as much as 32 mg at 6 months well below the limit of 100 mg total derived from the stability specification.

[0097] At 40° Celsius, compared to 25° Celsius, the absorption mechanism accelerated, and the amount of water absorbed is about 0.47 mg per day (greater than at 25° Celsius), but still well within the 20% allowable loss on stability. Consequently, the absorbers gained about 85 mg at 6 months at the end of the proposed shelf life of the IONSYS™ device. [0098] At 22°-24° Celsius, using this example (FIG. 3) it takes about 7 to 8 days for the relative humidity inside the package including the absorber and electrotransport device to reach a steady state at around 95%. The relative humidity at the steady state increases with increasing ambient temperature (FIG. 11), yielding a RH of 98.5% at 40° Celsius.

[0099] In this example the absorber can absorb up to 150 mg of water before reaching a water activity of 0.98 equaling the water activity of the hydrogels (FIG. 12). This occurs well past the 6 month of intended duration of storage for the package.

[0100] An additional purpose of the activated charcoal in this example besides acting as a carrier for the potassium sulfate salt and water is the sorption of 1 ,2-dimethoxy ethane (DME). Sorption of DME reduces the instance of water condensation due to DME evolution from the battery of the IONSYS™ system. The presence of DME has been shown to enhance the water condensation on the printed circuit board. Removal of DME, therefore, would help reduce the incidence of moisture on the PCBs. The activated charcoal portion of the formulation is designed to absorb DME to prevent its condensation with water vapor on the board surface. The absorber in this example effectively scavenges all DME gassing form the battery and other components of the electrotransport device. No DME was found in the headspace after 6 month of storage. The only significant organic species detected in the headspace, propene, is a non- reactive hydrocarbon (Table 3).

Table 3 -Absorption of Organic Species during storage in IONSYS™ pouches at 25° C

(nd = none detected)

[0101] Finally, no significant moisture condensation occurred in this example as confirmed by visually inspecting of moisture condensation on the IONSYS™ device after 3 months of storage with the absorber at 40° Celsius. No water was present on any of the surfaces as shown in FIG. 13. Again, similar results were obtained when stored with absorber at 25° Celsius.

Example 2

[0102] Another exemplary embodiment is identical to Example 1 except for the following:

The total weight of the absorber formulation lies in the range of 0.9 g to 1.Ig. Independent of

the total formulation weight, the weight of potassium sulfate falls in the range of 25 mg to 39 mg with the weight of the water content measuring between 250 mg to 310 mg. Example 3

[0103] In another example of the disclosure, the absorber material contains activated carbon, activated iron powder, diatomaceous earth, water and sodium chloride. Sodium chloride and diatomaceous earth is dissolved in water prior before being sprayed onto a mixture of iron powder, sodium chloride and activated carbon. The absorber material is placed inside a sachet pouch made of polyethylene, paper and polyethylene terephthalate. The sachet pouch allows air to pass through and acts as a microbial barrier. The formulation weighs 720 mg and possesses the following composition: 16mg of sodium chloride, and 56 mg of excess water. Typically, the sachet is of size 40x20mm with a thickness of about 2 mm. [0104] In this example the container material interferes with the ability of water to freely exit through pores of the sachet resulting in an a _w of 0.898 versus an a _w of 0.945 of the sole absorber containing sodium chloride without the sachet. [0105] The initial increase in relative humidity after placing the absorber and the

IONSYS™ device inside the package slows down after 10 days of storage, while it continues to steadily increase to 93 % without approaching a steady state after 90 days of storage at 25° Celsius (FIG. 14). [0106] In this example, the absorber includes 16 mg of sodium chloride and initially contains 56 mg of water upon placement in the package container. During storage the absorber can absorb up to about 450 to 500 mg yielding a water activity of about 0.93 that is close to the water activity of the hydrogels having lost at point an equal amount of water of about 450 to 500 mg (FIG. 15). Example 4 [0107] An additional example is a variation of Example 3 by allowing the total weight of the absorber formulation to fall in the range of 576 mg to 864 mg. Furthermore, the sodium chloride weighs between 7.2 mg to 12.3 mg, whereas a value between 44.6 mg to 67 ' .1 mg is chosen for the water content. All three weight parameters can be varied independently from each other. [0108] The rate of water absorbed by the absorber of Example 1 and Example 3 packaged with IONSYS™ device are shown in FIG. 10. A lower absorption is preferred, since it will

reduce the water loss from the hydrogels of IONSYS™ device. Table 2 lists the gain in weight of the absorber measured at various times during storage.

Table 2 - Actual and predicted absorber weight change

Absorber Weight Change (mg), 25 ⁰ C

Absorber T=3 T=6 T=9 T=12 T=15 T=I 8

Example 1 Predicted 11 .3 25 .2 40.4 51.7 66.7 79.3

Example 2 Actual 11 .3 25 .5 40.8 52.5

Example 3 Actual 49 .3 78 .8 103.7 167.9 ^# predicted, T: length of storage time in months.

Manufacturing Process

[0109] An exemplary manufacturing process of the absorber includes the following steps as summarized in FIG. 16: First, a measured amount of absorber salt, for instance potassium sulfate or sodium chloride, and any optional water-soluble component, i.e. diatomaceous earth, are dissolved in a measured volume of water creating a saturated solution. Second, any excess salt and other insoluble absorber material, i.e. iron powder, and activated charcoal carbon are weighed and mixed resulting in a solid-phase carrier. The charcoal has a carbon tetrachloride (CTC) activity larger than 5 Ig/ 10Og with a CTC larger than 45g/100g for the dry-formulated material. Charcoal is a natural product prepared by burning charred coconut husks. The water is of purity grade obtained from reverse osmosis. The solution is then spray-mixed onto the solid carrier, before transferred to the primary packaging machine, where the sachets are formed. The content weight is controlled to range from 0.9g to 1.Ig averaging around Ig per sachet. Preventing dry-out or heating during manufacturing ensures that the absorber is contains excess water when placed inside the package container. Optionally, additional water can be sprayed onto the absorber so that the absorber is saturated with water. The amount of water is controlled to be within +/- 3% of the initially measured volume. Final packaging includes placing the absorber and electrotransport drug delivery device inside a water- vapor tight container. Various controls are incorporated along the manufacturing process to insure quality of the product. The checks can optionally include measuring conductivity of the formulation, which directly is indicative of the salt content in the formulation. Another possible check is Loss of Drying (LOD), wherein a 1Og sample of the formulation is dried at

150° Celsius for 4 hours to remove all water contained in the sample. The weight loss of the sample after drying is equal to the initial amount of water present in the sample. [0110] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.