AU2004202073B2 - Microfabricated devices for the delivery of molecules into a carrier fluid - Google Patents

Description

Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD

PATENT

APPLICANT:

Invention Title: Microchips, Inc.

Microfabricated Devices for the Delivery of Molecules into a Carrier Fluid The following statement is a full description of this invention, including the best method of performing it known to me: MICROFABRICATED DEVICES FOR THE DEL IVERY OF MOLECULES INTO A CARRIER FLUID Background Of The Invention This invention relates generally to miniaturized devices for controlled delivery of chemical molecules into a carrier fluid.

Accurate delivery of small, precise quantities at one or more chemicals into a carrier fluid is of great importance in many different fields of science and industry. Examples in medicine include the delivery of drugs to patients using intravenous methods, by pulmonary or inhalation methods, or by the release of drugs from vascular stent devices. Examples in diagnostics include releasing reagents into fluids to conduct DNA or genetic analyses, combinatorial chemistry, or the detection of a specific molecule in an environmental sample. Other applications involving the delivery of chemicals into a carrier fluid include the release of fragrances and therapeutic aromas from devices into air and the release of flavoring agents into a liquid to produce beverage products.

U.S. Patent No. 5,547,470 to Johnson, et at.. discloses automated devices for intravenous drug delivery in which plural pumping channels independently infuse drugs and fluid. These devices and delivery methods require that the drugs be carefully pre-mixed and stored in a liquid form. A liquid form can, however, reduce the stability of some drugs and therefore can cause undesirable variability of the drug concentration. It would be desirable to more accurately and reliably measure the amount of drug introduced into the intravenous carrier fluid, as well as to store the drug in a more stable form, for example as a solid.

U.S. Patent No. 5,972,027 to Johnson discloses the use of porous metallic stents as vascular drug delivery devices. The devices reportedly deliver a drug from the porous structure of the stout to the surrounding tissue.

Such devices, however, are limited in the number of drugs that they can deliver and are severely limited in the control of both the rate and time of drug delivery, as the delivery rate is governed by the porous structure, i.e. the WO 01/35928 PCTn..soo/31529 drug is passively released. It would be advantageous to provide active and more precise control over the time and rate of delivery of a one or more of variety of drugs from the stents into, for example, the bloodstream passing through the implanted stent.

-Microchip deliver devices, described in U.S. Patents No. 5,797,898 and No. 6,123,361 to Santini et al., provide a means to control both the rate and rime of release of a variety of molecules, such as drugs, in either a continuous or pulsatile maniner. The devices fuxrther provide a means for storing the chemicals in their most stable form. These patents describe, for 1 0 example, implanting the microchip devices by themselves into a patient for delivery of drug. It would be advantageous, however, to adapt the precise control of molecule release provided by these microchip devices into a variety of other applications.

It will be seen that the preferred embodiments of the present invention variously provide devices and methods for. the accurate and reliable delivery 'of nmolecules into a carrier f luid, such as drug into an intravenously delivered fluid; Provide devices and methods for conveniently storing molecules in a stable form for release into a carrier fluid; and IProvide stenting devices having precise control over the time and rate of delivery of drugs.

Summary of the Invention Apparati and methods are provided for thc delivery of molecules to a site via a carrier fluid.' The apparati include microchip devices which have reservoirs containing the molecules for release. The apparati and m ethods provide for active or passive controlled release of the molecules. The microchip devices include a substrate, at least two reservoirs in the substrate containing the molecules for release, and a reservoir cap Positioned on, or within a portion of, the reservoir and over the molecules, so that the molecules are controllably released from the device by diffusion through or upon disintegration or rupture of the reseroir caps. Each of the reservoirs of a single microchip can contain differient molecules and/or different amounts and concentrations, which can be released independently.

The filled reservoirs can be capped with materials that passively or actively disintegrate. Passive release reservoir caps can be fabricated using materials that allow the molecules to diffuse passively out of the reservoir over time.

Active release reservoir caps can be fabricated using materials that disintegrate upon application of electrical, mechanical, or thermal energy.

Release from an active device van be controlled by a preprogramnmed microprocessor, remote control, or by biosensors.

The carrier fluids into which the molecules are released can be, for example, environments such as intravenous infusions, beverage mixtures, vascular fluids, and gaseous phases. In a preferred embodiment, the microchip device releases molecules that are contained within the reservoirs into a fluid that is delivered to a patient intravenously.

In another embodiment, the microchip device is integrated into a stent for the delivery of drugs, such as anti-restenosis drugs or such as pravastatin or other hypertension medications.

In yet another embodiment, the microchip delivers molecules, which can be in the form of, but not limited to aerosols, vapors, gases, or a mixture thereof, into a stream for either therapeutic or aesthetic purposes.

In general, the microchip provides a method for storing molecular species in their most stable form, which can be a solid, liquid, gcl, or gas.

Upon either passive or active reservoir opening, the one or more types of molecules are released into the carrier fluid in either a pulsatile or continuous manner. These methods will provide fine control over the amount of the molecules delivered as well as the time and rate at which delivery occurs.

Additionally, the molecular delivery device will extend the shelf-life (i.e.

stability) of the molecules offering new potential applications.

Brief Description of the Drawings Figure I is a perspective view of a typical microchip device for chemical delivery.

Figures 2a-e arc cross-sectional schematic views of various embodiments of devices having substrates formed from two fabricated substrate portions which have been joined together.

Figures 3a-c are cross-sectional views showing the active release of molecules from a microchip device into a carrier liquid.

Figures 4a-c are cross-sectional views showing the active release of molecules into a carrier gas.

Figures 5a-c are cross-sectional views showing a reservoir cap of a microchip device being ruptured by direct application of a mechanical force.

Figures 6a-b are cross-sectional views showing a reservoir cap of a microchip device being ruptured by application of ultrasound.

Figures 7a-c are cross-sectional views showing the passive release of molecules from a microchip device into a carrier liquid.

Figures ga-b are cross-sectional views of two embodiments of intravenous drug delivery system having integrated drug delivery microchips that release drug into a fluid delivered intravenously. Figure 8c is a perspective view of an intravenous drug delivery system including a multi-chambered interface console and a communications and digital control station.

Figures 9a-c illustrate one embodiment of a stent-microchip, drug delivery device, showing a perspective view (Fig. 9a), and two sectional views (Pigs. 9b and 9c).

Figures I On-c illustrate one embodiment of an inhalation device (a metered dose inhaler) having a microchip drug delivery device incorporated therein.

Figures I11 a-d illustrat one embodiment of a fragrance delivery system.

Figure 12 illustrates one embodiment of a system for the introduction of additives to beverages.

Detailed Description Of The Invention 1. DELIVERY AIPPARATUS AND SYSTEMS The delivery system includes one or more microchip devices, as described, for example, herein and in U. S, Patents No. 5,797,898 and No.

6,123,861 to Sarntini et al., which are hereby incorporated by reference in their entirety. See, for example, Figure 1, which illustrates a typical microchip device 10 with substrate 12, reservoirs 16, and reservoir caps 14.

The microchip device is integrated with an apparatus providing active and passive release of molecules into a carrier fluid. The apparatus may include a quantity of the carier fluid or the carrier fluid may be external to the apparatus.

A. Microchin Devices The microchip devices typically include a substratc having a plurality ofrreservoirs containing a release system that includes the molecules to be released. The microchip devices in some embodiments fur-ther includes one or more reservoir caps covering the reservoir openings. The reservoir caps can be designed and formed from a material which is selectively permeable to the molecules, which disintegrates to release the molecules, which ruptures to release the molecules, or a combination thereof. Active release systems may further include control circuitry endsa power source.

1. The Substrate The substrate contains the etched, molded, or machined reservoirs and serves as the support for the microchip. Any material that can serve as a support, is suitable for etching, molding, or machining, and is impermeable to the molecules to be delivered and to the surrounding fluids, for example, water, organic solvents, blood, electrolytes or other solutions, may be used as a substrate. Examples of substrate materials include ceramics, semiconductors, and degradable and non-degradable polymers. For drug delivery applications outside of the body, such as drug release into a gaseous stream in an inhaler, it is preferred that the substrate itself is non-toxic, but it is not required. For in v/vo applications such as stent drug delivery into vascular fluids, a sterile, biocompatible material is preferred. Nevertheless, toxic or otherwise non-biocompatible materials may be encapsulated in a biocompatible material, such as poly(ethylene glycol) or tetrafluoroethylenelike materials, before use.

For applications outside of drug delivery, such as diagnostics or fragrance delivery, substrate biocompatibility may be much less of an issue.

One example of a strong, non-degradable, easily etched substrate that is impermeable to the molecules to be delivered and the surrounding fluids is silicon. An example of a class of strong, biocompatible materials are the poly(anhydride-cu-imides) described in Uhrich et at, "Synthesis and characterization of degradable poly(anhydride-co-imides)", Macromolecules, 28:2184-93 (1995).

The substrate can be formed of only one material or can be a composite or multi-laminate material, several layers of the same or different substrate materials that are bonded together. Multi-portion substrates can include any number of layers of ceramics, semiconductors, metals, polymers, or other substrate materials. Two or more complete microchip devices also can be bonded together to form multi-portion substrate devices, as illustrated for example in Figures 2a-e. Figure 2a, for comparison, shows a "single" substrate device 200, which has substrate 210, in which reservoirs 220 are filled with molecules to be released 240.

Reservoirs 220 arc covered by reservoir caps 230 and sealed with backing plate 250 or other type of seal. Figure 2b shows device 300 having a substrate formed of a top substrate portion 310a bonded to bottom substrate portion 310b. Reservoirs 320a, in top substrate portion 310a are in communication with reservoirs 320b in bottom substrate portion 310b.

Reservoirs 320a/320b are filled with molecules to be released 340 and are covered by reservoir caps 330 and sealed with backing plate 350 or other type of seal. Figure 2c shows device 400 having a substrate formed of a top substrate portion 410a bonded to bottom substrate portion 410b. Top substrate portion 410a has reservoir 420a which is in communication with reservoir 420b in bottom substrate portion 41Db. Reservoir 420b is much larger than reservoir 420a and reservoirs 420a/420b contain molecules to be released 440. Reservoirs 420a1420b are filled wit molecules to be released 440 and are covered by reservoir cap 430 and sealed with backing plate 450 or other type of seal. Figure 4d shows device 500 having a substrate formed of a top substrate portion 510a bonded to bottom substrate portion 510b.

Top substrate portion 510a has reservoir 5209 which contains first molecules to be released 540a. Bottom substrate portion 510b has reservoir 520b which contains second molecules to be released 540b. First molecules to be released 540a can be the same or different from second molecules to be released 540b. Reservoir 520a is covered by reservoir cap 530a and sealed by reservoir cap 530b (Conned of an anode material) and partially by bottom substrate portion 510b. Reservoir 520b is covered by internal reservoir cap 530b and scaled with backing plate 550 or other type of seal. Cathodes 560a and 560b are positioned to form an electric potential with anode reservoir cap 530b. In one embodiment of the device shown in Figure 2d, second molecules to be released 540b are first released from reservoir 520b, through or following the disintegration of reservoir cap 530b, into reservoir 520a, wherein the second molecules mix with first molecules to be released 540a before the mixture of molecules is released from reservoir 520a through or following the disintegration of' reservoir cap 530a. Figure 2e shows another reservoir shape configuration in cross-section. Substrate portions 310n/410a/510a can be formed from the same or different materials and can have the same or different thicknesses as substrate portions 310b/410b/510h.

These substrate portions can be bonded or attached together after they have been individually processed etched), or they may be formed before they have any reservoirs or other features etched or micro-machined into them (such as in SOl substrates).

2. Release System The molecules to be delivered may be inserted into the reservoirs in their pure form, as a liquid solution or gel, or they may be encapsulated within or by a release system. As used herein, "release system" includes both the situation where the molecules are in pure form, as either a solid or liquid, or are in a matrix farmed of degradable material or a material which releases incorporated molecules by diffusion out of or disintegration of the matrix. The molecules can be sometimes contained in a release system because the degradation, dissolution, or diffusion properties of the release system provide a method for controlling the release rate of the molecules.

The molecules can be homogeneously or heterogeneously distributed within the release system. Selection of the release system is dependent on the desired rate of release of the molecules. Both non-degradable and degradable release systems can be used for delivery of molecules. Suitabic release systems include polymers and polymeric matrices, non-polymeric matrices, or inorganic and organic excipients and diluents such as, but not limited to, calcium carbonate and sugar. Release systems may be natural or synthetic, although synthetic release systems typically are preferred due to the better characterization of release profiles.

The release system is selected based on the period over which release is desired. In the case of applications outside of the body, the release times may range from a fraction of a second to several months. In contrast, release times for in vivo applications, such as stent drug delivery, generally are within the range of several minutes to a year. In some cases, continuous (constant) release from a reservoir may be most useful. In other cases, a pulse (bulk) release from a reservoir may provide more effective results. A single pulse from one reservoir can be transformed into pulsatile release by using multiple reservoirs. It is also possible to incorporate several layers of a release system and other materials into a single reservoir to achieve pulsatile delivery from a single reservoir. Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of molecules through it over an extended period of time. In addition, continuous release can be simulated by releasing several pulses of molecules in quick succession.

The release system material can be selected so that molecules of various molecular weights are released from a reservoir by diffusion out of or through the material or by degradation of the material. In one embodiment for the technology outside of the body, the degradation or disintegration of the release system may occur by increasing its equilibrium vapor pressure causing the release system to evaporate, thereby releasing the molecules. This can be achieved by actively increasing the temperature of the release system with thin film resistors or passively through chemical interactions with the carrier liquids and/or gases. In the case of in vivo applications, it may be preferred that biodegradable polymers, bioerodible hydrogels, and protein delivery systems are used for the release of molecules by diffusion, degradation, or dissolution. In general, these materials degrade or dissolve either by enzymatic hydrolysis or exposure to water, or by surface or bulk erosion. Representative synthetic, biodegradable polymers include: poly(amides) such as poly(amino acids) and poly(peptides); poly(esters) such as poly(lactic acid), poly(glycolic acid), poly(lactic-coglycolic acid), and poly(caprolactone); poly(anhydrides); poly(orthoesters); poly(carbonates); and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof. Representative synthetic, non-degradable polymers include: poly(ethers) such as poly(ethylene oxide), poly(ethylene glycol), and poly(tetramethylene oxide); vinyl polymers poly(acrylates) and poly(methacrylates) such as methyl, ethyl, other alkyl, hydroxyethyl methacrylate, acrylic and methacrylic acids, and others such as poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate); poly(urethanes); cellulose and its derivatives such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various cellulose acetates; poly(siloxanes); and any chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof.

3. Reservoir Caps passive release by disintelraion or diffiion In the passive timed release drug delivery devices, the reservoir caps are formed from a material that degrades or dissolves over time, or does not degrade or dissolve, but is permeable to the molecules to be delivered. These materials are preferably polymeric materials. Materials can be selected for use as reservoir caps to give a variety of degradation rates, dissolution rates, or permeabilities to enable the release of molecules from different reservoirs at different times and, in some cases, different rates. To obtain different release times (amounts of release time delay), caps can be formed of different polymers, the same polymer with different degrees of crosslinking, or a UV polymerizable polymer. In the latter case, varying the exposure of this polymer to UV light results in varying degrees of crosslinkirig and gives the cap material different diffusion properties or degradation or dissolution rates. Another way to obtain different release times is by using one polymer, but varying the thickness of that polymer. Thicker films of some polymers result in delayed release time. Any combination of polymer, degree of crosslinking, or polymer thickness can be modified to obtain a specific release time or rate. In one embodiment, the release system containing the molecules to be delivered is covered by a degradable cap material that is nearly impermeable to the molecules. The time of release of the molecules from the reservoir will be limited by the time necessary for the cap material to degrade or dissolve. In another embodiment, the cap material is non-degradable and is permeable to the molecules to be delivered. The physical properties of the material used, its degree of crosslinking, and its thickness will determine the time necessary for the molecules to diffuse through the cap material. If diffusion out of the release system is limiting, the cap material delays the onset of release. If diffusion through the cap material is limiting, the cap material determines the release rate of the molecules in addition to delaying the onset of release.

0iiD active Wrela by diita ion In one embodiment of the active timed release devices, the reservoir caps consist of a thin film of conductive material that is deposited over the reservoir, patterned to a desired geometry, and serves as an anode. Cathodes are also fabricated on the device with their size and placement dependent on the device's application and method of electric potential control. The anode is defined as the electrode where oxidation occurs. Any conductive material capable of dissolving into solution or forming soluble ions or oxidation compounds upon application of an electric current or potential (electrochemical dissolution) can be used for the fabrication of the anodes and cathodes. In addition, materials that normally form insoluble ions or oxidation products in response to an electric potential can be used if, for example, local pH changes near the anode cause these oxidation products to become soluble. Examples of suitable reservoir cap materials include metals such as copper, gold, silver, and zinc, and so-me polymers, as described, for examnple, in Kwon el at, "Electrically erodible polymer gel for controlled release of drugs", Nature, D~4:291-93 (1991); and Bac et al., "Pulsatile drug release by electric stimulus", A CS Symposium Series, 545: 98-110 (1994).

(iii) relea by' rum ure In another embodiment, the reservoir cap is positioned on the reservoir over the molecules, which are released from the reservoir upon heating or cooling the device, or a portion thereof; to rupture the reservoir cap. As used herein, the tem "rupture" includes fracture or some other farm of mechanical failure, as well as a lass of structural integrity due to a phase change, melting, in response to a change in temperature, unless a specific one of these mechanisms is indicated.

In a preferred embodiment, heating or cooling causes the molecules in the reservoir to thermally expand increase mn volume)- At a given temperature the release system completely fills the volume of the reservoir. Upon heating to temperature T2, the release system begins to expand and applies a force on the reservoir cap. Once this force exceeds the fracture strength of the cap, the reservoir cap fractures and the molecules are released. In a variation of this embodiment, the molecules can vaporize or undergo a reaction, thereby elevating the pressure within the reservoir sufficiently to cause the reservoir cap to rupture due to the mechanical stress.

Prior to the application of heat, the pressure within the reservoir is lower than that needed to rupture the reservoir cap. The addition of heat increases the equilibrium pressure within the reservoir and the forces acting on the cap material increase. Further increases in temperature cause the pressure to continue to increase until the internal pressure overcomes the fracture strength of the reservoir cap. Typically the thermal expansion, vaporization, or reaction is induced by heating the molecules in the reservoir, e.g. above ambient temperatures. In certain applications, however, the thermal expansion or reaction can be induced by cooling the molecules in the reservoir. Water, for example, expands upon freezing. If a material that thermally contracts upon cooling is used as the reservoir cap over aqueous molecules, then the mechanical failure should be fur-ther enhanced by sufficient cooling.

In one embodiment, the reservoir cap is muptured by physical (i.e.

structural) or chemical changes in the reservoir cap material itself, for example, a change caused by a temperature change. For example, the reservoir cap can be made of or include a material that expands when heated.

When the reservoir cap is secured in a fixed position and heated, the reservoir cap expands until it cracks or muptures due to the increase in volume. This embodiment permits heating oft.e reservoir cap with minimal or no heating of the reservoir contents, a feature that is particularly important when the reservoir contains heat-sensitive molecules, such as protein drugs, which can denature upon exposure to excessive hear.

In another embodiment using an active release mechanism, the reservoir cap material is melted undergoes a phase change) using resistive heating. for in viva applications, the reservoir cap preferably is composed of biocompatible copolymers, such as organic hydroxy acid derivatives lactides and lactones), which can offer a range of selectable melting temperatures (see PCT WO 98/26814). Particular melting temperatures, for example between about 2 0 *C and about 12 0 C above normal body temperature, can be selected for the reservoir caps by proper selection of starting monomer ratios and the resulting molecular weight of the copolymer. This type of reservoir opening mechanism offers at least two delivery schemes. A first scheme is based on individual reservoir caps having various melting temperatures. By heating the device, or portion thereof, to a constant temperature, only specific reservoir caps melt, opening the rescrvoir and exposing the molecules. The application of different temperature profiles therefore provides for the selective molecular release. A second scheme, shown in Figure 13, focuses on all caps having a fixed composition and a uniform mnelting temperature. The cap is a solid phase at temperature TI. Locally heating individual reservoir caps to temperature T2 causes the reservoir cap to become molten. The fluidized reservoir cap is then mobile, which facilitates the opening of the reservoir and release of molecules. In the case of In vitro applications, similar active schemes are possible with less stringent compositional and temperature requirements.

In the passive release embodiments, reservoir cap rupture is triggered by environmental temperature changes, for example, due to the placement of the device onto or into thc body of a human or other animal. The passive mechanism, differs from the active mechanism in that rupture of the reservoir cap of the active device is triggered by a directly applied temperature change rather than an environmfenital one.

In one embodiment of passive devices, the reservoir cap is thermally stimulated to enhance degradation. For example, the kinetics of reservoir cap degradation can be very slow at room temperature and the cap can be considered chemically stable. However, the kinetics of degradation are significantly increased by increasing the temperature of the cap material, by in viva implantation. The absolute rate of degradation can be selected by controlling the composition of the reservoir cap material. For example, the degradation rate of biocompatible copolymers lactones and lactides) can be between several hours and several years, preferably between two days and one year at a temperature of 37 depending on the specific molar ratios of the primary structural units. By using an array of reservoir caps, each having a different composition, complex molecular release profiles can bc achieved once the device reaches a critical temperature defined by its environment.

In another embodiment of passive devices, all reservoir caps have constant disintegration rates temperature independent) and the release profile is controlled by selection of the physical dimensions of the reservoir cap material. By fixing the rate of disintegration, the time for cap disintegration is dependent on the thickness of the reservoir cap material.

For example, in an embodiment in which all reservoir caps have identical compositions, molecular release can be controlled by varying the thickness of the cap.

In both the active and passive devices, the reservoir cap is formed of a material having a yield or tensile strength beyond which the material fails by fracture or a material that undergoes a phase change (for example, melts) with selected changes in temperature.. The material preferably is selected from metals, such as copper, gold, silver, platinum, and zinc; glasses; ceramics; semiconductors; and brittle polymers, such as semicrystalline polyesters. Preferably the reservoir cap is in the farm of a thin film, a film having a thickness between about 0. 1 jim and I 4im. However, because the thickness depends on the particular material and the mechanism of rupture electrochemical vs. mechanical breakdown), thicker reservoir caps, having a thickness between I gm and 100 pm or more, may work better for some materials, such as certain brittle materials.

The reservoir cap optionally can be coated with an overcoat material to structurally reinforce the rupturable material layer until the overcoat material has been substantially removed by dissolving, eroding, biodegrading, oxidizing, or otherwise degrading, such as upon exposure to water in vivo or in vitro. Representative suitable degradable materials include synthetic or natural biodegradable polymers.

Reservoir caps in either passive or active embodiments can be formed of a material that functions as a permeable or semi-permeable membrane depending on the temperature.

In one preferred embodiment of the active release device, a resistor is integrated into the reservoir or mounted near the reservoir, which upon application of an electric current through the resistor, heats the contents of the reservoir, the cap material, or both. In typical embodiments, resistors are located at the bottom or along the inside walls of the reservoirs, or they may be located on or near the reservoir caps covering the small reservoir openings. The resistor generalliy is a thin-film resistor, which can be integrated with the reservoir during the manufacturing process. Such resistors can be made of metals such as platinum or gold, ceramics, semiconductors, and some polymers. Methods for fabricating these resistors are described, for example, in Wogersien et at "Fabrication of Thin Film Resistors and Silicon Microstructures Using a Frequency Doubled Nd:YAG- Laser," Proc. SPIE-Int Soc. Opt Eng., 3680:1105-12 (1999); Bliattacharya Tummala, "Next Generation Integral Passives: Materials, Processes, and Integration of Resistors and Capacitors on PWB Substrates," J1 Mater. Sci Mater. Electron. 1j(3):253-68 (2000); and Vladimirsky et at., "Thin Metal Film Thermal Micro-Sensors," Proc. SPIE-Int Soc. Opt. Eng., 2640:184-92 (1995). Alternatively, small chip resistors can be surface mounted on the device in close proximity to the reservoir or reservoir cap.

4. Molecules To Be Delivered Any natural or synthetic, organic or inorganic molecule or mixture thereof can be delivered. In one embodiment, the microchip is used to deliver drugs systemically to a patient by releasing the drugs into a fluid delivered intravenously. As used herein, the termn "drug" includes therapeutic, prophy lactic, and diagnostic agents, unless otherwise indicated.

Drug molecules to be released during intravenous drug delivery applications include, but are not limited to, antibiotics, chemotherapeutic agents, in vivo diagnostic agents contrast agents), sugars, vitamins, toxin antidotes, anti-inflamnmatory agents, pain killers, and medications useful for renal procedures such as dialysis heparin). In another embodiment, the microchip releases molecules into a fluid stream for therapeutic or aesthetic purposes. For example, the molecules to be released into liquid or gaseous fluids may include, but are not limited to, aromatherapy hydrosols, various fragrances, colorants, and artificial and natural sweeteners. The field of analytical chemistry represents yet another embodiment in which a small (milligramn to nanogram) amount of one or more molecules is required.

Effective example molecules are pH buffering agents, diagnostic agents, and reagents in complex reactions such as the polymerase chain reaction or other nucleic acid amplification procedures.

One embodiment for in vivo molecular release is stent drug delivery into vascular fluids. Possible molecules to be released include anti-restinosis compounds, proteins, nucleic acids, polysaccharides and synthetic organic molecules, having a bioactive effect, for example, anesthetics, vaccincs, chemotherapeutic agents, hormones, pain killers, metabolites, sugars, immunomodulators, antioxidants, ion channel regulators, and antibiotics.

The drugs can be in the fonn of a single drug or drug mixtures and can inciude pharmaceutically acceptable carriers, B. Other Systemt or Apuaratu Componlents The delivery system or apparatus for releasing molecules into a earrier fluid can further include a variety of other components depending on the particular application.

1. Mixing Chambers, Mixer;, and Pumps In a preferred embodiment for some applications, such as in the intravenous (IV) drug administration system described below, the system further includes a mixing chamber in which the carrier fluid and released drug are combined. As used herein, unless otherwise indicated, a "Lixjg chamber" can be essentially any structure in which a carrier fluid can be temporarily contained, through which the carrier fluid can flow, while the molecules from the microchip device can contact the carrier fluid. A mixing chamber can be located adjacent the microchip device or downstream in a system in which the carrier fluid flows past a surface of the microchip device from which molecules are released. The carrier fluid and the drug mix locally by diff-usion driven by concentration gradients or due to the reduction in the chemical potential of the fluid.

To speed the mixing process, a mixer mixing device) optionally may be incorporated into the mixing chamber of the apparatus in order to use turbulence or convective transport to ensure a homogenous mixture.

Dynamic and static mixers suitable for use in these devices are known in the art.

Carrier fluid can be provided at one or more surfaces of the microchip device in a static or flowing manner. Flow can be produced, for example, by gravity, capillary action, or through the use of one or more pumps. For embodiments utilizing a pump, the pump can be located separate from the apparatus or can be provided in the apparatus or system, for example in the mixing chamber. Pumps suitable for use in these devices are known in the art. See, U.S. Patent No. 5,709,534 to O'Leary and U.S.

Patent No- 5,056,992 to Simons. in some embodiments, a pump can produce sufficient turbulence to mix the drug and carrier fluid, such that a separate mixer is not needed.

In the IV application described herein, the drug solution can enter the patient by gravity feed methods or alternatively one or more pumps can be integrated with the apparatus to pump the solution into the patient.

2. Stents In one embodiment, the microchip device is incorporated into a stent.

Stents are currently used in a range of medical applications, normally to prevent reocclusion of a vessel. Examples include cardiovascular and gastroenterology stets. Generally these sents are non-degradable. Ureteric and urethral stents are used to relieve obstruction in a variety of benign, malignant and post-traumatic conditions such as the presence of stones and/or stone fragments, or other ureteral obstructions such as those associated with ureteral stricture, carcinoma of abdominal organs, retroperitoneal fibrosis or ureteral trauma, or in association with Extracorporeal Shock Wave Lithotripsy. The stent may be placed using endoscopic surgical techniques or percutaneously. Examples of state of the art stents include the double pigtail ureteral stent Bard, Inc., Covington, GA), SpiraStent (Urosurge, Coralville, IA), and the Cook Urological Ureteral and Urethral Stents (Cook Urological, Spencer, IN).

Bioabsorbable stents are particularly desirable in applications such as urological applications, since a second procedure is not required to remove the stent. Furthermore, one of the main problems in using metallic steats in cardiovascular applications is the subsequent restenosis caused by excessive

I

growth of the endothelial wall, which is believed due, at least in part, to irritation caused by the metallic stent on the vessel wall (see Behrend, American J. Cardiol. p. 45, TCT Abstracts (Oct. 1998); Unverdorben, et aL, American J. Cardiol. p. 46, TCT Abstracts (Oct. 1998)). A bioabsorbable stent made from, or coated with a appropriate materials should produce reduced or no irritation. Bioabsorbable stents can be fabricated using methods known in the art, lbr example the methods and procedures described in U.S. Patent Nos. 5,792,106; 5,769,883; 5,766,710; 5,670,161; 5,629,077; 5,551,954; 5,500,013; 5,464,450; 5,443,458; 5,306,286; 5,059,211, and 5,085,629. See also Tanquay, Cardiology Clinics, 22:699-713 (1994), and Talja, Endourology, 1:391-97 (1997).

Integration of microchip devices into stents is described in further detail in the "Applications" section below.

II. CARRIER FLUID The molecules contained in the reservoirs of the microchip device can be released into a variety of carrier fluids, depending on the particular application. The carrier fluid can be essentially of any composition in a fluid form. As used herein, the term "fluid" includes, but is not limited to, liquids, gases, supercritical fluid, solutions, suspensions, gels, and pastes.

Representative examples of suitable carrier fluids for medical applications include natural biological fluids and other physiologically acceptably fluids such as water, saline solution, sugar solution, blood plasma, and whole blood, as well as oxygen, air, nitrogen, and inhalation propellants, The choice of carrier fluid depends on the particular medical application, for example, stein applications, intravenous delivery systems, implantable delivery systems, or systems for respiratory pulmonary) administration.

Representative examples of suitable carrier fluids for use in fragrance release systems include water, organic solvents (such as ethanol or isopropyl alcohol), aqueous solutions, and mixtures of any of these.

Representative examples of suitable carrier fluids for use in beverage additive systems include beverages or beverage bases of any type, such as water (both carbonated and non-carbonated), sugar solutions, and solutions of artificial sweeteners.

Essentially any chemidcal fluid can be used as the carrier fluid in an analytical or diagnostic system depending on the specific fluid being analyzed. Examples include, but are not limited to, environmental samples of air or water, industrial or laboratory process sampling analysis? fluid samples to be screened in quality contral assessments for food, beverage, and drug manufacturing, and combinatoritJ screening fluids.

III. OPERATION AND MOLECULE RELEASE One preferred embodiment is the active release of molecules into a liquid carrier from a microchip that releases molecules in response to electrochenmical stimulation, which is shown in Figure 3. The application of an electrical potential (see Figure 3a) causes the cap material to dissolve (see Figure 3b) providing for the release of the molecules into the liquid flowing adjacent to the reservoir opening as shown in Figure 3c. In a preferred embodiment, the electric current is modulated, rather than maintained at a constant value.

Another embodiment includes the release of the molecular species into a flowing gaseous phase (see Figs. 4a-4c). The application of heat to the release system can cause it to expand and apply pressure to the cap material (temperature T I temperature T2). At some critical temperature and applied pressure, the cap will fracture exposing and releasing the molecules into the flowing gases that surround the device (temperature T2 temperature T3).

An alternative embodiment of an active release device uses the rupture of the membrane by a mechanical force as the release mechanism.

See U.S. Patent No. 5,167,625 to Jacobsen et al., which describes rupturing means that may be modified or adapted to the devices described herein. One non-limiting example is the rupturing of caps by forccful contact of the cap surface with an array of cantilevers that are fabricated using similar MEv MS techniques or any other machining techniques (see Figure Ultrasonic waves are an alternative method capable of rupturing the cap material in order to expose the release system and release the molecules (see Figure Actuation of piezoelectric elements on or near the reservoir produces sonic waves that rupture the cap material. The piezoelectric elements can be composed of any material having crystal structure that is non-centrosymetric. Preferred piezoelectric materials are ceramics, such as HiaTiO 3 LiNbO 3 and mnO (Chiang, "Physical Ceramics", John Wiley Sons, mac, New York~ pp- 37-66 (1997)), and polymers, such as polyvinylidene (Hunter Lafontaine, "A Comparison of Muscle with Artificial Actuators," Technical Digest of the 1992 Solid State Sensor and Actuator Workshop, pp. 178-85 (1992)). These actuators can be fabricated in the form of thin films using standard techniques such as ion sputtering (Tjhen, et at, "Properties of Piezoelectric Thin Films for Micromechanical Devices and Systems", Proceedings IEEE Micro Electro Mechanical Systems, pp. 114-19 (199 and sol-gel processing as described, for example, in Klein, "Sol-Gel Optics: Processing and Applications", Kluwer Academic Publishers, 1994). The ultrasonic energy can be supplied by components located on the delivery device, in the carrier fluid, or outside of the delivery device. Methods for selecting which reservoirs are exposed include, for example, wave interference using secondary ultrasonic waves.

The secondary waves can act to destructively interfere with the primary ultrasonic waves thus restricting the application of energy to only a selected set of reservoirs.

Additional embodiments involve the passive release of molecules into the carrier fluid. One general example of this application is the degradation of the release system when placed into or exposed to the carrier fluid. The chemical nature of the fluid, acid versus basic or polar versus non-polar, may cause the cap material to degrade or dissolve (see Figure 6b).

Once the cap material is completely dissolved, the molecules will be released into the liquid flowing adjacent to the reservoir opening (see Figure 6c).

The fluid carn be any liquid or any gas that causes the disintegration of the release systemi or the cap material.

IV. METHODS FOR MANUFACTURE OR ASSEMBLY The microchip devices can be madec, for example, using techniques known in the art, particularly the methods described in U.S. Patent No.

6,123,861 to Santini et al., which is incorporated by reference. Although the fabrication methods described in the patent use microfabrication and microelectronic processing techniques, it is understood that fabrication of active and passive microchip chemical delivery devices is not limited to materials such as semiconductors or processes typically used in microelectronics manufacturing. For example, other materials, such as metals, ceramics, and polymers, can be used in the devices. Similarly, other fabrication processes, such as plating, casting, or molding, can also be used to make them.

In one embodiment, reservoirs also can be formed using silicon-oninsulator (SOT) techniques, such as is described in S. Renard, "Industrial MEMS on S01," .1 Micromeck Microeng. LOQ:245-249 (2000). SO[ methods can be useflully adapted to form reservoirs having complex reservoir shapes, for example, as shown in Figures 2b, 2c, and 2e. SOl wafers behave essentially as two substrate portions that have been bonded on an atomic or molecular-scale before any reservoirs have been etched into either portion.

S01 substrates easily allow the reservoirs (or reservoir sections) on either side of the insuilator layer to be etched independently, enabling the reservoirs on either side of the insulator layer to have different shapes. The reservoir (portions) on either side of the insulator layer then can be connected to form a single reservoir having a complex geometry by removing the insulator layer between the two reservoirs using methods such as reactive ion etching.

laser, ultrasound, or wet chemical etching.

The other system components are provided from known sources or can be easily fabricated or adapted from known devices and methods.

The microchip devices can be integrated into other system or device components assembly of the system or apparatus) using techniques known in the art, such as by using adhesives and mechanical means such as fasteners, depending on the particular application.

IV. APPLICATIONS The microchip delivery systems can be used to release molecules into a variety of carrier fluids in a wide variety of forms. Representative examples include drug delivery into a fluid to be introduced or administered to a patient, such as intravenously or to the respiratory system; drug delivery from implanted systems including stents or micropumps; analytical or diagnostic chemistry; fragrance release systems; and beverage additive systems.

It is understood that the number, geometry, and placement of each reservoir, reservoir cap, or other object resistors (heaters), electrodes, or channels) in or near each reservoir can be modified for a particular application. For simplicity, only one reservoir is shown in some Figures.

However, it is understood that a microchip component or device would contain at least two, and preferably many more, reservoirs. Detailed below are some of the many useful applications.

A. Intravenous Drugt Delivery Systemn An intravenous (IV) drug delivery system is provided that includes one or more mnicrochip chemical delivery devices that release molecules into a physiologically acceptably carrier fluid for intravenous administration.

As illustrated in Figure Sa., the IV system 100 includes console 108 which is connected to a catheter 106 extending hiorn a container 102 bag or bottle) of a carrier fluid 104. The cardier fluid flows from container 102 via catheter 106 (or other flexible hollow tubing) to console 108. In console 108, the carrier fluid 104 flows past one or more sufices of the microchip device 112, maixes with released molecules ins mixing chamber 130 using mixer 114 (optional) and then flows to the patient through a second catheter 116 (or other flexible hollow tubing) into the patient.

Another embodiment of the system is shown in Figure Sb. Thbis IV system 120 includes microchip devices 12,2a and 122b provided within container 126 of the carrier fluid 104. Carrier fluid 104 in mixing chamber 130 is mixed with released drug molecules using mixer 124 (optional). The resulting mixture flows from container 126, through tubing 128 to the Patient. If an active microchip device is used in this way, the control electronics and power source preferably are integrated wit the microchip device itself.

In a preferred embodimnent, shown in Figure 8rc, the IV system 150 includes a console 156 that contains "plug in" cartridges 152 comprising one or more drug-containing microchip devices, control eiectronics 154, and a container of IV carrier fluid 158.

In one embodiment the IV system includes an electronic control system which can be programmed to send a signal, to the microchip devices to release one or more drugs from one or more of the reservoirs of the microchip devices, thereby releasing the drugs into the carrier fluid as it passes by microchip devices and making a drug solution that is delivered into the patient. The electronic control systems can be connected to the console or to the microchip devices by cables or can transmit signals to the console or to the microchip devices by wireless conmmunicaion means known in the art. Such an IV system may also include a digital readout that would display the critical drug delivery parameters such as the drug name, the release frequency, the release rate, the amount of drug left in the microchip, and the time at which the microchip will need to be replaced with a ful one. The electronics also allow the physician to program in the type of release pattern desired, either pulsatile release or continuous release.

The inclusion of a microprocessor, memory, and a timer into the electronic control systems also can help decrease the potential for drug overdoses or the administration of the wrong drugs to patients. Safety protocols can be stored in the memory and continuously checked by the microprocessor to prohibit the release of too much drug to a patient over a particular time interval, and/or (ii) the simultaneous release of two or more incompatible drugs. In addition, the microchip can store in memory the exact amount of drug delivered, its time of delivery, and the amount of drug remaining in the microchip. This information can be transmitted using wireless technology for implants) or using standard computer connections for external, in-line, or IV systems) to the physician or to a central monitoring system on a real-time basis. This allows the physician to remotely monitor the patient's condition.

One advantage provided by these embodiments is the ability to store drugs in the microchip in its most stable form liquid, gel, or crystalline or powdered solid) until release into solution and delivery to the patient is desired. This can drastically increase the shelf-life stability) of many drugs, particularly protein or biologic drugs, for which the stability is limited once dissolved in solution.

Another advantage is the reduction of medical errors. For example, numerous medical errors can result from traditional IV bags that are inadvertently filled with the incorrect amount of drug or bags that are mislabeled. Microchip "cartridges" as described herein can be labeled with a bar code indicating the type and amount of drug in the microchip. Once the microchip cartridge is plugged into the IV system or console, the IV system can detect the type and amount of drug and display it on the digital readout, which allows a physician or nurse to easily verify' that the correct medication and dosage is delivered to the patient. It is understood that the microchip could also be placed at other locations between the carrier fluid container and the patient.

Thc body of the console preferably is made of a molded plastic. All parts in contact with the carrier fluid and/or the drug preferably arc formed from or coated with a biocompatible material, preferably one, such as poly(teirafluoroethylene) or a similar material, that does not interact with the fluids or released drugs. The mixing chamber and fluid connections should be leak-proof.

B. Drur Delyiver Stent One embodiment of a microchip device for the release of molecules into a carrier fluid involves integrating one or more drug delivery microchips into/onto a stent, such as a vascular stent. The drug-containing microchips preferably are provided on one or more surfaces of the stent, for example as illustrated in Figures 9a-c. The microchip devices can be present in the stent during implantation and steaK expansion, or the microchip devices can be attached to the inside of the stent in a separate procedure immediately following stent implantation and expansion. If the microchips are small enough, implantation and attachment of a microchip to a stent can be completed using the same catheter technology used in the implantation of stents. In a preferred embodiment, the microchips of the stcnt-microchip device arc programmed or activated by remote or wireless means to deliver drugs directly from the stent.

One preferred application of the stent-microchip device is the local delivery of anti-restenosis drugs to an artery that has recently undergone an angioplasty procedure. In another embodiment, the stent-microchip devices are used to systemically deliver one or more drugs to a patient via blood flowing through the stent. In another embodiment, stents can be designed and fabricated to have drug reservoirs and caps as part of the stent itself, that is, not as a separate microchip device, but rather as part of a monolithic stern device. It is understood that both systemic and local delivery of any drug is possible using the microchip technology in combination with stents.

The microchip-stent drug delivery devices are not limited to arterial and vascular applications. Microchips integrated with stenting technology can serve to deliver drugs within a variety of other channels in the body of humans and animals. Representative examples include the gastrointestinal tract, respiratory passages, reproductive and urinary tracts, renal vessels, cerebrospinal fluid passages, and sinuses.

C. Dru Inhalation Devie In another embodiment, microchip devices are used to release molecules into a gaseous carrier fluid, air, for subsequent inhalation by a patient. In one system, for example, a drug-containing microchip device is integrated into a metered dose inhaler (MDI) to provide a simple method for accurately controlling the molecular dose that is to be delivered. The microchip device also provides a controlled environment (within the reservoirs) that can function to extend the stability of the stored drug.

Many different styles of metered dose applicators appropriate for use with the drug-filled microchips are described in the art such as, for example, U.S. Patent No. 6,1i6,234 to Genova el ali. Figures l Os-c illustrate one embodiment of a schematic flow diagram of the drug delivery mechanism in a microchip metcred dose inhaler. The drug-filled microchips are located on the inner wall of a replaceable cartridge on the open end of the applicator.

Upon triggering an electrical signal from the power circuitry to the microchip(s) through a switch or timer, the doses can be released into a gas stream using various release techniques, such as the methods described in Figures 4 through 6. Once the reservoir cap has disintegrated or ruptured, a stream of gas flowing over the opened reservoir transports the drug molecules from the reservoirs to the patient. The carrier gas can be provided to the microchip device upon release of a pressurized gas or upon inhalation by the patient. The drug molecules can come out of reservoirs in the MDI by any of several mechianisms, including vaporization, formation of an aerosol, atomization, or by Bernoulli's principle. In an alternative embodiment, the molecules are released by diffi~on or vaporization from the opened reservoirs into a static volume of the gas, which subsequently is inhaled by the patient, in a second step.

The dosage of the drug can be accurately measured by triggering release from a select number of reservoirs having a precise quantity of the drug. Each dosage can be composed of the molecules released by one or more reservoirs.

In preferred embodiments, the microchip-inhalation device advantageously provides reservoirs that are sealed until the patient activates the required molecular dose. Therefore, potentially harsh environments encountered during packaging, use, or storage will not affect the stability and concentration of each dose within the reservoir. The microchip devices can be contained, for example, within a replaceable cartridge located within the flow path of the cardier gas.

D. Franrmnce Delivery System In another embodiment, a system is provided for the delivery of Fragrance molecules into a gaseous carrier fluid, typically air. These systems include a fragrance-containing microchip device that can be integrated into a variety Of aparati for the delivery of one or more fragrance. The fragrance molecules can be, for example, Perfumes. aromatherapy agents, chemicals for room deodorizing or odor masking, and molecules to produce or simulate a variety of odors and aromas for any purpose. The fragrance molecules may be released into the surrounding environment using methods previously described in Figures 4 through 6.

In one application, the microchip device is integrated into an article of jewelry or other personal accessory to release perfume molecules. The fragrance release can be initiated either manually by the user or programmed for continuous or pulsatile release through communication and control systems located within the accessories. The signals for activating the reservoirs may be generated by control circuitry that may be located directly within the accessory or on another accessory, such as a watch. The remote communications system can produce radio frequency signals that serve to activate one or more reservoirs. See Figure 1 ls which shows pulsatile release of fragrance from fragrance-containing microchip devices 190 integrated into a necklace 192, wherein the release is triggered by signals transitted fromi a watch 194 having an integrated signal transmitter. The microchip devices may be surface mounted onto the necklace, for example using adhesives, and may be placed at various locations around the necklace.

Figures I1I b-IlI d show details of the activation process by local resistive heating, which vaporizes the release system. The increase in temperature causes the release system to vaporize and thus producing a fragrance. It is also understood that the fragrance molecules may be released into the surrounding environment using any method that degrades or exposes the release system to the surrounding envirotnent, such as the release mechanisms described herein.

In another application, the microchip device is integrated into a game or novelty item for entertainent purposes. For example, a fragrancecontaining microchip device can be contained within a cartridge that is inserted into an entertainment console, such as an audio or video system television). Upon reaching certain scenes in a movie), electrical signals are sent to activate specific reservoirs that containing scents related to the scene or situation, Alternatively, the fragrance-containing microchip device can be integrated into a separace unit that communicates with the console. The separate unit optionally includes the carrier gas source, such as a replaceable canister of compressed gas.

E. Beverage Additive System In a further embodiment, a system is provided to deliver one or more additives into a carrier to formi one or more consumer beverages. The microchip device containing the additive molecules selectively releases the additive molecules into a liquid carrier fluid, which typically is a beverage missing only one or more additives or which is water or another base from which the beverage is ultimately formed. Representative additives include natural and artificial flavoring agents, sweeteners, taste masking agents, and coloring agents.

Release of the molecules can, be active or passive.

In a preferred embodiment the molecules are released shortly before the beverage is to be consumed. This provides the advantage of minimizing the exposure of the molecules to the liquids contained within the beverage thus extending the stability and effectiveness of a wide range of chemical used for flavor enhancement.

In one embodiment, a microchip device containing one or more additives artificial sweetener and flavoring agent) is located in a chamber that is an integral component in a beverage dispensing system, eg., a soda fountain. In this embodiment, the microchip device includes a passive release system that is soluble in aqueous solutions. The Carier fluid, which typically is carbonated water (for sodas), flows into a mixing chamber where the artificial sweetener and flavors are released by the dissolution of the release system. The microchip devices can be, for example, integrated into a disposable or refillable cartridges magazines) that can be replaced, for example, when the micochip device is emptied. Cartridge replacement allows for new flavoring molecules to be added to a new batch of beverage mixtures, and can reduce the inventory Of various premi xed beverages, where the flavoring occurs at the end of the beverage production, Another variation of this embodiment is illustrated in Figure 11. In this case, a Plurality (here, three) of magazines comprising microchip devices, which contain flavoring agents, are Provided in a chamber that is a discrete component in-line with the flow Of a beverage base input liquid) such as carbonated water. The microchip device can be passive or active release. Figure 11I also shows arn optional secondary container that can serve as a mixing chamber in which the solution can be uniformly mixed prior to consumption. It is understood that the microchip device can be provided at essentially any location along the flow path. The microchip magazine design conveniently otters the vender the capability to replenish the flavor System when depleted or to easily change from one flavorcd beverage to another.

This can serve to reduce the inventory of various premixed beverages.

F. Diaenostic Sstemi Microchips containing molecules for release into liquid and gaseous carrier fluids have a wide range of potential applications in diagnostics and analytical chemistry. In one embodiment of a diagnostic system, the microchip technology described herein can be integrated with a microfluidic array used in DNA testing, blood analysis, or testing of an environmental sample. In a preferred embodiment, a carrer fluid such as a saline solution is electrophoretically pumped through a tiny channel in a microfluidic array.

Reservoirs containing reagent molecules and having active reservoir caps are located along the bottom of the microfluidic channels. As the saline solution is pumped into a channel containing the reagent tilled reservoirs, a signal an electric current) is sent to the reservoir caps to cause them to disintegrate, allowing the reagents inside the reservoirs to diffuse out into the saline solution in the channel. The release of reagents can occur while the fluid is stopped above the reservoirs or while the carrier fluid is flowing by the reservoirs. The saline solution containing the reagents is now pumped to a mixing chamber where the reagents are mixed with the sample of interest a blood sample) and the desired interaction occurs.

Another example of a diagnostic system comes from combinatorial chemistry, Colloidal Practices the Paint and coating industry) often necessitate the stabilization of Suspensions which require a large array of experiments in search of an optimum chemistry. Chemicals such as surface active catalysts, macromolecules and ionic salts, arc just a few of the reagents used to determine the proper colloidal composition- Microchip devices filled with one or mnore of these colloidal additives can be placed in an agitated liquid mediumn containing the particulates. By disintegrating specific reservoir caps, for example by using a thermal activation technique, specific chemical species can be released in a controlled maimer over time.

This offers a method for accurately and automatically carrying out extensive combinatorial experiments.

Microchip devices also can be provided with integrated electrodes: and circuitry that provide the means to characterize the stability of the colloid. Characterizations techniques such as ultrasound vibration potential (IJVP) and electrokinetic sonic amplitude (ESA) are well known and have been described in detail by M. Rahamian in "Ceramics Processing and Sintering" (New York 1995). Therefore, the microchip device can provide information on both the chemistry required for stabilization and the stabilization kinetics. It is understood that the microchip device can serve in many other diagnostic and combintorial applicatons such as DNA or genetic analyses, drug discovery, and environmnental testing.

G. irci eiewt m latbj Pump In another embodiment, a microchip device is incorporated into an implantable micropuniping system, for example for the delivery of drugs over extended periods of time, such as is needed the delivery of insulin to diabetics and treating certain kind of severe chronic pain. Micropump apparati suitable for use in these devices are known in the art (see,

U.S.

Patent No. 4,596,575 to Rosenberg). The microptunp Pumps the carrier fluid across one or more surfaces of the microchip device. A variety of' carrier fluids can serve as the pumped fluid, including, but not limited to, filtered extra-cellular fluid, saline solution, or water.

WO 0L05fl paT/usoI 59 .UI a preferre_ cmbodiMt, release of dose is ac~vely controllcd.

such as by ds=rc oz of- rescvoir caps via eleccca dizsoluzion. as deftribed in U.S. Patents No. 5.7r97298.and No. 6,123,861 to Sentin. Tie rte S~st= Prtfenabiy i in the form of a solid that. is soluble in the can'er )WC OU&s the Ould pases over or around the ac~ivated and openied rservo ir, Ehe solid dr4- dissolves in the catier Dud. fornning solution thaz. is Puwnped irntC di et-celujar ovironment Ren-al Anulcflom in xenal diaysis procedures, the patienot's blood flows through aD ra 110 iwo dialysis ma~hize wheim toxic molernies arc selectively removed f4rom the blood, and The "cimincr" blood is rerttned to the paies body. These ICIO lcs, which sr. normally removed from the blood by the kidneys, accumulate ov e rs due to the dc~efd or imvrouc functonin of the EidDwys. While toxic molculs ame removed from the otbenfs blood as it Pa== thoug~s the dialysis machine. terapeite moiecl and 0US$ca asily be add--ed to the blood. Th i eds tD a poamial method for systewac dclivery of M ltipizz drug or other molccles to a paxien wing a microchip devic locazed ar vitro in a pree embodimem micrwcinp devces filed with drug MoLecules are placed in tobig tbrough Muhic blood flows during a diaysis proethu. The nicochips act'ely or pastvely delivery one or MOM types of molecules to the paciem blood as it passes flough the wb4ng This metho11d Allows multiple drug to he dtlivered acctnizeIy and directly int a patient's blood without havin to implan the delivery device into the panienfes body.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comp rises" and 'cdmprising".

will he understood to imply the inclusion of a stated integer or step or group of integers or steps hut not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not. and should not be taken as. an acknowldedgement or any form of suggestiofl chat the prior art forms part of the common general knowledge in Australia

Claims (37)

1. 2. The device of claim 1, wherein the discrete reservoir caps are disintegabe in vivo to conrol the time ofrelease of the one or more drugs from the at least two reservoirs.
2. 3. The device of claim 1, wherein micron. wherei the reservoir cap has a thickness between 0.1 and 100
3. 4. The device of claim 1, wherei l the at least one r more drugs compris e a Fhemotherapeutic agent The device ofclaim I, wherein the release system comprises one or more drugs in a biodegradable or water-soluble matrix.
4. 6. t h e device of claim 5 wherein at least one of the drugs is heterogeneously distributed in the matrix
5. 7. The device of claim 5, wherein at least one of the drugs is homogeneously distribute in the matrix.
6. 8. The device of any one of claims 5-7, wherein the matrix comprises one or more synthetic polymers. 9, The device of claim 1, wherein the releae system of at least one of the reservoirs comprises two or more biodegradable or water-soluble layers. The device of claim wherein the amount of one drug provided for release from at least a first of the reservoirs is diffent from the t ofthedrug provided for release from at least a second of the rese 0 rvos. S. The device ofclaim wherein the time of release of one of the drugs from at least a first of the reservo rs is different fr he time frele of the drug from at least a second of the resrvoirs. ondofthe
7. 12. The device ofclaim I, wherein a first drug is i at least on ofth reservoirs and a scod drug is in at least one other of the reservoirs, the first edr and the second drug being different in kind or dose. and the second drug beg differnt in
8. 13. The device of claim wherein eachof the at least two reservoirs comprises at least two laers of a release system and at least one lyer of a degradable or dissolvable material which does not compris the one or more drugs. 4. The devie dev of claim 9, wherein at least a first drug is contained in a fst layer ofthe two or more layers, and wherein a second drug is contained in a Second layer of th e two or mor layers.ntained in a second lay te two ormo The device of claim I, wherein the release systm provides release of the one or more 1 6d The device of claim 1, wherin thereleas 16. The device of clim here the rele yste provides release of the one or more l ui m thh te implanted ste drugs into a bioloioafluid pasing thou e implat e 'tent
9. 17. The device of claim 1, which provides pusatile release of the onc or more drugs. Is. The device of claim I, wherein the implantable stent is formed of a metal.
10. 19. The device of claim 1, wherein at least one of the discete reervoir caps comprises a polymeric material,. th discreteservoircapScopris a The device of claim I, wherein at least one discrete reservoir cap is formed of a first Material and a' least One other discrete material and a different one other discre servoir cap is formed ofa second material, wherein the first material has a different degation rate, a different dissolution rate, or a different permeability to the drug molecules compared to the second material.
11. 21. The device of claim 1, wherein at least one discrete rservoir cap has a first thicknes and at least one other discrete reservoir cap has a second thickne wherein the first thickness is diffe t rO the second thicknsap has a e ond thickness, wherein the firt thickness Is differunt from the second ticness, thereby providing different times of release of the one or more drugs from the reteroirs overed respectively by the discrete reservoir cap having the first tdhcke and the discrete reservoir cap having the second thickness,
12. 22. The device of claim 1, comprisig at least two rows of said at least two reservoirs in an ay in the impantable stent 23 The device of claim 22, wherein a first releaseystem is in each of the at least two reservoirs of a first row and a second release system is in each of the at least two reervoirs of the other of the at least two rows other of the reservoirs, the firt releas ystem rleasing the one or more drugs at rate or in a dosage amount different from releasing the one or more drugs from the Second release system. o ne or more drugs from d24.c d byof cirespe er each disrte reservoir cap covers the entire opening defined by a rpliw fl rtA v&, A device for thecontrolld release ofo or m d co si: an implantable non-degradable stent; at least two rsevoir in the sten wh in each of the at least two reservoirs are coverd by a discrete reservoir cap; and a release system ontained n each ofte at least two res wherein the release syster compis one ormore drugs for r.leu. a nt r, whereinratethe wherein each discrete reseiYr cap are dstelra in vivo to control the time of release of the one or more drugs. I I m26. The device of claim 25, wherein each reservoir cap has a thickness between 0.1 and 100 microns.
13. 27. The device of claim 25, wherein the at least one or More drugs comprises a chemotherapeutic agent. one or more drugs compris
14. 28. The device of claim 25, wherein the release system Compres ne or more drugs in a biodegradable or water-soluble matric.u in
15. 29- The device of claim 28~ hri t29. Tr device Of cla 28, wherein at least one of the drugs is heterogeneously distributed in the matrix. The device of claim 28, wherein at least one of the dms is homogeneoy dsribut in the matrix. 11~oeeul'& btdi 3. The ti device of any One of claims 28-30, wherein the matrix omprises one or more syntheticmp s one o mor
16. 32. The device of claim 25, wherein the release system of at least one of the reservoirs comprises two or more bodcgrdable or water-soluble layers.
17. 33. The device ofclaim 25, wherein the amon ofone dug povided frree a r least a tirst of the reservoirs is different &n the amount of to drug provided for rlase from a least a second of the ervoirs auof the drug pmvided for release fom at
18. 34. The device of claim 25 wherein th timeof rlease of one othe drugs from t least a first of the resvors is different from the time of reacas of the drug om at least a reeroirs. reservoirs. time ofreleas of the drug from at least a second of the The device ofclaim whin 2fi5tdrug Secon d i ce ca 2 wher f rst drug is in at least on e of th e reservoirs and a seond drug is in at least one other of. th servoirs, th first drug and the second drug being different in kind or dosec. r
19. 36. The device of claim 25, wherain each of the at least two reservois comprises at le layers of a release system and at least one layer ofa de radable or disolvable m atera which does not comprise the one r mor drugs.dab or dissolvable material whi
20. 37. The device of claim 32, wherein at leas a firsdrug is ontained in a firstayer ofe two or more layers, and wherein a second drug is contained in a second layer the two or or layers.d il oftht mo 38 The devicveofclaim 25, wherini
21. 38. tohe device of cli 25, herein the release system provides release of the one or more drug towa tissue surround the implanted stent.
22. 39. The device ofclaim 25, wherein the release system provides release of the one or more drugs towards a biological fluid passing through the implanted stent The device of claim 25, which provides pulsatile release of the one or more drugs.
23. 41. The device of claim 25, wherein the nondegradable sten is formed of a metal.
24. 42. The devic of claim 25, wherein at least one of the discrete reservoir caps comprises a polymeric material.
25. 43. The device of claim 25, wherein at least one discret reerv cap is fored of a first material and at least one other discrete reservoir cap is fomed of. second materia whrein the first material has a different degradation rate, a diffent dissolution rate, or a different ermeabilty to hdrug molecules compared to the second material
26. 44. The device of claim 25 wherein at least oe disreter and at least one other discrete re d reerir cap has a first thickness different from the sec. res erv cap has a second thickness, wherein the fRst thickness is modiereugnts from the ervoirs covd thices, therey providiiffe times of release of the one or mo dugthickness and the rervoirs covered repectively by the disrete reservoir cap having the first k and discrete reservor cap having the second thickness. The device of claim 25, wherein each reservoir defines a opening in the implantable stent and each discrete reservoir cap covers the entire opening defined by a respective reservoir.
27. 46. The device of claim 25, comprising at least two rows of said at least two reservoirs in an arry in the implantable steal.
28. 47. The device of claim 46, wherein a firt release system is in each of the at least two reservoirs of a first row and a second release system is in each of the at least two reservoirs of the other of the at least two rows other of the reservoirs, the firt release system releasing the one or more drugs at a rate or in a dosage amount different from release of the one or more drugs from the second release system.
29. 48- A device for the controlled release of one or more drugs, comprising: an implantable metallic stent; at least two reservoirs in the steat; and a release system, contained in each of the at least two reservoirs, the release system comprising two or more layers of a biodegradable or water-soluble matrix material and a therapeutic agent distributed therein; wherein the matrix material degrades or dissolves in vivo to controllably release the therapeutic agent
30. 49. The devic of claim 48, wherein the amount of the therapeutic agent provided for release flow at least a first offt. reservoirs is diferet from the amount of the therapeutic agent Provided for release from at least a second of the reservoirs. The device of claim 48, wherein the time of release of the therapeutic agent from at least a first of the reservoirs is different from the tim of release of the therapeutic agent from at least a second of the reservoirs.
31. 51. The device of claim 48, wherein the therapeutic agent is in at least one of the reservoirs and a second therapeutic agent is in at least one other of the reservoirs, the firt therapeutic agent and the secod therapeutic agent being different in kind or dose.
32. 52. The device of claim 48, wherein the release system of at least one reservoir tfther comprises at least one layer of a degradable or dissolvable material which does not comprise the therapeutic agent.
33. 53. The device of claim 48, wherein each of the at least two reservoirs comprise a discrete reservoir cap which covers the release system contained therein. 54, The device of claim 53, wherein each discrete reservoir caps comprises a polymeric material, the in vivo disintegration of which controls the time at which release of the therapeutic ageti is initiated. The device of claim 53, wherein at least one discrete reservoir cap Is formed of a firs material and at least one other discrete reservoir cap is formed of a second material wherein the first material has a different degradation rate, a different dissolution rate, or a different permeability to the drug molecules compared to the second material,
34. 56. The device of claim 53, wherein at least one discrete reservoir cap has a first thickness and at least one other discrete reservoir cap bas a second thickness, wherein the first thickness i s different fromn the second thickness, thereby providing different times of release of the one or more dngs from the reservoirs covered respectively by the discrete reservoir cap having the first thickness and the discrete reservoir cap having the second thickness.
35. 57. The device of claim 5 whervin each reservoir defines an opening in the implantable stent and emh discrete reservoir cap covers the entire opening defined by a respective reservoir.
36. 58. The device of claim 48, comprising at least two rows of said at least two reservoirs in an array in the implantable stant
37. 59. The device of claim 58, wherein a first release system is in each of the at least two reservoirs of a first row and a second release systm is in echb ofthe at least two reservoirs of the other of the at least two rows other of the reservoirs, the first release system reeasing the one or more drugs at a rate or in a dosage amount differet from releae of the one or more drugs from the second release system.