Apparatus and methods for filling a drug eluting medical device via capillary action

Methods and apparatus are disclosed for filling a therapeutic substance or drug within a hollow wire that forms a stent. The stent is placed within a chamber housing a fluid drug formulation. During filling, the chamber is maintained at or near the vapor-liquid equilibrium of the solvent of the fluid drug formulation. To fill the stent, at least a portion of the stent is placed into contact with the fluid drug formulation until a lumenal space defined by the hollow wire is at least partially filled with the fluid drug formulation via capillary action. After filling is complete, the stent is retracted such that the stent is no longer in contact with the fluid drug formulation. The solvent vapor pressure within the chamber is reduced to evaporate a solvent of the fluid drug formulation. A wicking means may control transfer of the fluid drug formulation into the stent.

FIELD OF THE INVENTION

The invention relates generally to implantable medical devices that release a therapeutic substance or drug, and more particularly to apparatuses and methods of loading or filling such medical devices with the therapeutic substance or drug.

BACKGROUND OF THE INVENTION

Drug-eluting implantable medical devices are useful for their ability to provide structural support while medically treating the area in which they are implanted. For example, drug-eluting stents have been used to prevent restenosis in coronary arteries. Drug-eluting stents may administer therapeutic agents such as anti-inflammatory compounds that block local invasion/activation of monocytes, thus preventing the secretion of growth factors that may trigger VSMC proliferation and migration. Other potentially anti-restenotic compounds include antiproliferative agents, such as chemotherapeutics, which include sirolimus and paclitaxel. Other classes of drugs such as anti-thrombotics, anti-oxidants, platelet aggregation inhibitors and cytostatic agents have also been suggested for anti-restenotic use.

Drug-eluting medical devices may be coated with a polymeric material which, in turn, is impregnated with a drug or a combination of drugs. Once the medical device is implanted at a target location, the drug is released from the polymer for treatment of the local tissues. The drug is released by a process of diffusion through a polymer layer of a biostable polymer, and/or as the polymer material degrades when the polymer layer is of a biodegradable polymer.

Drug impregnated polymer coatings are limited in the quantity of the drug to be delivered by the amount of a drug that the polymer coating can carry and the size of the medical device. As well, controlling the rate of elution using polymer coatings is difficult.

Accordingly, drug-eluting medical devices that enable increased quantities of a drug to be delivered by the medical device, and allow for improved control of the elution rate of the drug, and improved methods of forming such medical devices are needed. Co-pending U.S. Patent Application Publication No. 2011/0008405, filed Jul. 9, 2009, U.S. Provisional Application No. 61/244,049, filed Sep. 20, 2009, U.S. Provisional Application No. 61/244,050, filed Sep. 20, 2009, and co-pending U.S. Patent Application Publication No. 2012/0067008, each incorporated by reference herein in their entirety, disclose methods for forming drug-eluting stents with hollow wires. Drug-eluting stents formed with hollow wires can achieve similar elution curves as drug-eluting stents with the therapeutic substance disposed in a polymer on the surface of the stent. Drug-eluting stents formed with hollow wires achieving similar elution curves as drug-polymer coated stent are expected to have similar clinical efficacy while simultaneously being safer without the polymer coating. In addition, a variety of elution curves can be achieved from drug-eluting stents formed with hollow wires. In some applications, such as coronary stents, the diameter of the hollow wire lumen to be filled with the drug or therapeutic substance is extremely small, e.g. about 0.0015 in., which may make filling the lumen difficult. As such, improved apparatus for and methods of filling or loading a therapeutic substance or drug within a lumen of a hollow wire of a stent are needed.

BRIEF SUMMARY OF THE INVENTION

Embodiments hereof are directed to methods and apparatus for filling a fluid drug formulation within a lumenal space of a hollow wire that forms a stent. A filling chamber of an apparatus is caused to reach a vapor-liquid equilibrium of a solvent of the fluid drug formulation. The filling chamber houses a reservoir containing a wicking means and the apparatus includes a valve positioned between the filling chamber and a loading chamber and the valve is closed such that the filling chamber and loading chamber are not in fluid communication. A liquid is added into a container housed within the filling chamber after the filling chamber has reached the vapor-liquid equilibrium of a solvent of the fluid drug formulation. The fluid drug formulation is added into the reservoir containing the wicking means after the filling chamber has reached the vapor-liquid equilibrium of a solvent of the fluid drug formulation. The fluid drug formation and the wicking means is mixed within the reservoir. A stent formed from a hollow wire is placed within the loading chamber of the apparatus. The loading chamber of the apparatus is caused to reach the vapor-liquid equilibrium of the solvent of the fluid drug formulation. After both the filling chamber and the loading chamber have reached the vapor-liquid equilibrium of a solvent of the fluid drug formulation, the valve is opened such that the filling chamber and loading chamber are in fluid communication. The stent is moved from the loading chamber of the apparatus into the filling chamber of the apparatus while the valve is opened, and the valve is closed such that the filling chamber and loading chamber are not in fluid communication after the stent is housed in the filling chamber. At least a portion of the stent is placed into contact with the wicking means within the filling chamber such that the lumenal space of the hollow wire that forms the stent is in fluid contact with the wicking means. Contact is maintained between the wicking means and the stent until a lumenal space defined by the hollow wire is at least partially filled with the fluid drug formulation via capillary action.

In another embodiment hereof, a filling chamber of an apparatus is caused to reach a vapor-liquid equilibrium of a solvent of a fluid drug formulation. The filling chamber houses a reservoir containing a wicking means and the apparatus includes a valve positioned between the filling chamber and a loading chamber and the valve is closed such that the filling chamber and loading chamber are not in fluid communication. The fluid drug formulation is added into the reservoir containing the wicking means after the filling chamber has reached the vapor-liquid equilibrium of a solvent of the fluid drug formulation. An implantable medical device formed from a hollow wire is placed within the loading chamber of the apparatus. The implantable medical device is transferred from the loading chamber into the filling chamber by opening the valve such that the filling chamber and loading chamber are in fluid communication, moving the implantable medical device into the filling chamber while the valve is open, and closing the valve such that the filling chamber and loading chamber are no longer in fluid communication after the implantable medical device is housed within the filling chamber. At least a portion of the implantable medical device is placed into contact with the wicking means within the filling chamber such that the lumenal space of the hollow wire that forms the implantable medical device is in fluid contact with the wicking means. Contact is maintained between the wicking means and the implantable medical device until at least the lumenal space defined by the hollow wire is at least partially filled with the fluid drug formulation via capillary action.

DETAILED DESCRIPTION OF THE INVENTION

Specific embodiments of the present invention are now described with reference to the figures, wherein like reference numbers indicate identical or functionally similar elements. The terms “distal” and “proximal” are used in the following description with respect to a position or direction relative to the treating clinician. “Distal” or “distally” are a position distant from or in a direction away from the clinician. “Proximal” and “proximally” are a position near or in a direction toward the clinician. In addition, the term “self-expanding” is used in the following description is intended to convey that the structures are shaped or formed from a material that can be provided with a mechanical memory to return the structure from a compressed or constricted delivery configuration to an expanded deployed configuration. Non-exhaustive exemplary self-expanding materials include stainless steel, a pseudo-elastic metal such as a nickel titanium alloy or nitinol, various polymers, or a so-called super alloy, which may have a base metal of nickel, cobalt, chromium, or other metal. Mechanical memory may be imparted to a wire or stent structure by thermal treatment to achieve a spring temper in stainless steel, for example, or to set a shape memory in a susceptible metal alloy, such as nitinol. Various polymers that can be made to have shape memory characteristics may also be suitable for use in embodiments hereof to include polymers such as polynorborene, trans-polyisoprene, styrene-butadiene, and polyurethane. As well, poly L-D lactic copolymer, oligo caprylactone copolymer and poly cyclo-octine can be used separately or in conjunction with other shape memory polymers.

The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Drug eluting stents described herein may be utilized in the context of treatment of blood vessels such as the coronary, carotid and renal arteries, or any other body passageways where it is deemed useful. More particularly, drug eluting stents loaded with a therapeutic substance by methods described herein are adapted for deployment at various treatment sites within the patient, and include vascular stents (e.g., coronary vascular stents and peripheral vascular stents such as cerebral stents), urinary stents (e.g., urethral stents and ureteral stents), biliary stents, tracheal stents, gastrointestinal stents and esophageal stents. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description.

An embodiment of a stent100to be loaded with a drug in accordance with embodiments hereof is shown inFIGS. 1-2C. Stent100is formed from a hollow strut or wire102and hereinafter may be referred to as a stent or a hollow core stent. Hollow wire102defines a lumen or lumenal space103, which may be formed before or after being shaped into a desired stent pattern. In other words, as used herein, “a stent formed from a hollow wire” includes a straight hollow wire shaped into a desired stent pattern or a stent constructed from any suitable manufacturing method that results in a tubular component formed into a desired stent pattern, the tubular component having a lumen or lumenal space extending continuously there through. As shown inFIG. 1, hollow wire102is formed into a series of generally sinusoidal waves including generally straight segments106joined by bent segments or crowns108to form a waveform that is wound around a mandrel or other forming device to form a generally cylindrical stent100that defines a central blood flow passageway or lumen113(shown inFIG. 2C) there through that extends from a first end or tip105to a second end or tip107of stent100. Selected crowns108of longitudinally adjacent turns of the waveform may be joined by, for example, fusion points or welds110as shown inFIG. 1. Methods of filling a drug within a stent in accordance with embodiments hereof are not limited to stents having the pattern shown inFIG. 1. Stents formed into any pattern suitable for use as a stent may be loaded with a drug by the methods disclosed herein. For example, and not by way of limitation, stents formed into patterns disclosed in U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 to Wiktor, U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 to Boyle, and U.S. Pat. No. 5,019,090 to Pinchuk, each of which is incorporated by reference herein in its entirety, may be loaded with a drug by the methods disclosed herein.

As shown inFIG. 2A, hollow wire102of stent100allows for a therapeutic substance or drug112to be deposited within lumen or lumenal space103of hollow wire102. Although lumen103is shown as uniformly filled with therapeutic substance or drug112inFIG. 2A, therapeutic substance or drug112is not required to fill or be uniformly dispersed within the lumenal space103of hollow wire102but is only required to occupy at least a portion of the lumenal space. Stated another way, in an embodiment hereof, luminal space103may be intentionally or purposely only partially filled. Lumen103may continuously extend from a first end114to a second end114′ of hollow wire102. Although hollow wire102is shown as generally having a circular cross-section, hollow wire102may be generally elliptical or rectangular in cross-section. Hollow wire102may have a wall thickness WTin the range of 0.0004 to 0.005 inch with an inner or lumen diameter IDranging from 0.0005 to 0.02 inch. Hollow wire102that forms stent100may be made from a metallic material for providing artificial radial support to the wall tissue, including but not limited to stainless steel, nickel-titanium (nitinol), nickel-cobalt alloy such as MP35N, cobalt-chromium, tantalum, titanium, platinum, gold, silver, palladium, iridium, and the like. Alternatively, hollow wire102may be made from a hypotube, which is a hollow metal tube of a very small diameter of the type typically used in manufacturing hypodermic needles. Alternatively, hollow wire102may be formed from a non-metallic material, such as a polymeric material. The polymeric material may be biodegradable or bioresorbable such that stent100is absorbed in the body after being utilized to restore patency to the lumen and/or provide drug delivery.

Hollow wire102further includes drug-delivery side openings or ports104dispersed along its length to permit therapeutic substance or drug112to be released from lumen103. Side openings104may be disposed only on generally straight segments106of stent100, only on crowns108of stent100, or on both generally straight segments106and crowns108. Side openings104may be sized and shaped as desired to control the elution rate of drug112from stent100. More particularly, side openings104may be slits or may be holes having any suitable cross-section including but not limited to circular, oval, rectangular, or any polygonal cross-section. Larger sized side openings104generally permit a faster elution rate and smaller sized side openings104generally provide a slower elution rate. Further, the size and/or quantity of side openings104may be varied along stent100in order to vary the quantity and/or rate of drug112being eluted from stent100at different portions of stent100. Side openings104may be, for example and not by way of limitation, 5-30 μm in width or diameter. Side openings104may be provided only on an outwardly facing or ablumenal surface116of stent100, as shown inFIG. 2, only on the inwardly facing or lumenal surface118of stent100, on both surfaces, or may be provided anywhere along the circumference of wire102.

In various embodiments hereof, a wide range of therapeutic agents or drugs may be utilized as the elutable therapeutic substance or drug112contained in lumen103of hollow wire102, with the pharmaceutically effective amount being readily determined by one of ordinary skill in the art and ultimately depending, for example, upon the condition to be treated, the nature of the therapeutic agent itself, the tissue into which the dosage form is introduced, and so forth. Further, it will be understood by one of ordinary skill in the art that one or more therapeutic substances or drugs may be loaded into hollow wire102. Therapeutic substance or drug112delivered to the area of a stenotic lesion can be of the type that dissolves plaque material forming the stenosis or can be an anti-platelet formation drug, an anti-thrombotic drug, or an anti-proliferative drug. Such drugs can include TPA, heparin, urokinase, sirolimus or analogues of sirolimus, for example. Of course stent100can be used for delivering any suitable medications to the walls and interior of a body vessel including one or more of the following: anti-thrombotic agents, anti-proliferative agents, anti-inflammatory agents, anti-migratory agents, agents affecting extracellular matrix production and organization, antineoplastic agents, anti-mitotic agents, anesthetic agents, anti-coagulants, vascular cell growth promoters, vascular cell growth inhibitors, cholesterol-lowering agents, vasodilating agents, and agents that interfere with endogenous vasoactive mechanisms.

In accordance with embodiments hereof, stent100is loaded or filled with therapeutic substance or drug112prior to implantation into the body. Therapeutic substance or drug112is generally mixed with a solvent or dispersion medium/dispersant in order to be loaded into lumen103of hollow wire102. In addition, the therapeutic substance or drug112can be mixed with an excipient to assist with elution in addition to the solvent or dispersion medium/dispersant in order to be loaded into lumen103of hollow wire102. Hereinafter, the term “fluid drug formulation” may be used to refer generally to therapeutic substance or drug112, a solvent or dispersion medium, and any excipients/additives/modifiers added thereto. In one embodiment, therapeutic substance or drug112is mixed with a solvent or solvent mixture as a solution before being loaded into hollow wire102. A solution is a homogeneous mixture in which therapeutic substance or drug112dissolves within a solvent or a solvent mixture. In one embodiment, a solution includes a high-capacity solvent which is an organic solvent that has a high capacity to dissolve therapeutic substance or drug112. High capacity as utilized herein is defined as an ability to dissolve therapeutic substance or drug112at concentrations greater than 500 mg of substance per milliliter of solvent. Examples of high capacity drug dissolving solvents for sirolimus and similar substances include but are not limited to tetrahydrofuran (THF), di-chloromethane (DCM), chloroform, and di-methyl-sulfoxide (DMSO). In addition to the high-capacity solvent, a solution may include an excipient to assist in drug elution. In one embodiment, an excipient may be a surfactant such as but not limited to sorbitan fatty acid esters such as sorbitan monooleate and sorbitan monolaurate, polysorbates such as polysorbate 20, polysorbate 60, and polysorbate 80, cyclodextrins such as 2-hydroxypropyl-beta-cyclodextrin and 2,6-di-O-methyl-beta-cyclodextrin, sodium dodecyl sulfate, octyl glucoside, and low molecular weight poly(ethylene glycol)s. In another embodiment, an excipient may be a hydrophilic agent such as but not limited to salts such as sodium chloride and other materials such as urea, citric acid, and ascorbic acid. In yet another embodiment, an excipient may be a stabilizer such as but not limited to butylated hydroxytoluene (BHT). Depending on the desired drug load, a low capacity solvent can also be chosen for its reduced solubility of therapeutic substance or drug112. Low capacity is defined as an ability to dissolve therapeutic substance or drug112at concentrations typically below 500 mg of drug per milliliter solvent. Examples of low capacity drug dissolving solvents for sirolimus and similar substances include but are not limited to methanol, ethanol, propanol, acetonitrile, ethyl lactate, acetone, and solvent mixtures like tetrahydrofuran/water (9:1 weight ratio). After a solution is loaded into stent100, therapeutic substance or drug112may be precipitated out of the solution, e.g., transformed into solid phase, and the majority of the residual solvent and any nonsolvent, if present, may be extracted from the lumenal space of hollow wire102such that primarily only therapeutic substance or drug112or therapeutic substance or drug112and one or more excipients remain to be eluted into the body.

In another embodiment, therapeutic substance or drug112is mixed with a dispersion medium as a slurry/suspension before being loaded into hollow wire102. In a slurry/suspension form, therapeutic substance or drug112is not dissolved but rather dispersed as solid particulate in a dispersion medium, which refers to a continuous medium in liquid form within which the solid particles are dispersed. Examples of dispersion mediums with an inability to dissolve therapeutic substance or drug112depend on the properties of therapeutic substance or drug112. For example, suitable dispersion mediums with an inability to dissolve sirolimus include but are not limited to water, hexane, and other simple alkanes, e.g., C5 thru C10. Certain excipients, suspending agents, surfactants, and/or other additives/modifiers can be added to the drug slurry/suspension to aid in suspension and stabilization, ensure an even dispersion of drug throughout the suspension and/or increase the surface lubricity of the drug particles. Surfactants thus generally prevent therapeutic substance or drug112from floating on the top of or sinking to the bottom of the dispersion medium and also prevent particles of therapeutic substance of drug112from clumping. Examples of surfactants include but are not limited to sorbitan fatty acid esters such as sorbitan monooleate and sorbitan monolaurate, polysorbates such as polysorbate 20, polysorbate 60, and polysorbate 80, and cyclodextrins such as 2-hydroxypropyl-beta-cyclodextrin and 2,6-di-O-methyl-beta-cyclodextrin. In one embodiment, the targeted amount of therapeutic substance or drug112is suspended in the dispersion medium and the appropriate additive/modifier is added on a 0.001 to 10 wt % basis of total formulation. In addition, an excipient such as urea or 2,6-di-O-methyl-beta-cylcodextrin may be added to the slurry/suspension to assist in drug elution.

Open ends114,114′ of wire102may be closed or sealed either before or after the drug is loaded within lumen103as shown in the sectional view ofFIG. 2B, which is taken along line2B-2B ofFIG. 1. Once positioned inside of the body at the desired location, stent100is deployed for permanent or temporary implantation in the body lumen such that therapeutic substance or drug112may elute from lumen103via side openings104.

Filling Process Via Capillary Action

Embodiments hereof relate to the use of capillary action to fill lumen103of hollow wire102. Capillary action as used herein relates to the ability of a liquid to flow in narrow spaces without the assistance of, and in opposition to, external forces like gravity. As will be explained in further detail herein, only a portion of stent100having an opening (i.e., at least one side hole104, first end114of hollow wire102, or second or opposing end114′ of hollow wire102) is required to be submerged or exposed to a fluid drug formulation, or submerged or exposed to a wicking means in contact with a fluid drug formulation such that the lumenal space of hollow wire102that forms stent100is in fluid contact with the wicking means. The fluid drug formulation will then wick or travel into lumen103of hollow wire102via submerged/exposed holes104(or first end114of hollow wire102, or second or opposing end114′ of hollow wire102) and fill or load the entire length of lumen103via capillary action. Capillary action occurs because of inter-molecular attractive forces between the fluid drug formulation and hollow wire102. When lumen103of hollow wire102is sufficiently small, then the combination of surface tension and adhesive forces formed between the fluid drug formulation and hollow wire102act to lift the fluid drug formulation and fill the hollow wire. Filling stents100via capillary action result in a filling method that streamlines the drug filling process because such a method may be utilized to batch fill a plurality of stents in a relatively short time period. In addition, filling stents100via capillary action reduces drug load variability and makes the drug fill process more controllable and predictable. Capillary action results in fluid drug formulation uniformly filling or deposited within lumen103of hollow wire102, and after solvent/dispersion medium extraction which is described in more detail below, lumen103of hollow wire102has a uniform drug content along its length.

More particularly,FIG. 3is a schematic illustration of an apparatus320which may be utilized to perform the method steps illustrated in the flow chart ofFIG. 4, which describes a method460for filling lumen103of a stent100with a fluid drug formulation334via capillary action.FIG. 4will be described in conjunction withFIGS. 5-24. As will be described in more detail herein,FIGS. 5-24represent an embodiment hereof in which apparatus320includes multiple valves and separate air-tight or air-locked chambers to efficiently mass produce a batch of drug-filled stents100via capillary action. “Chamber” has used herein does not have a size constraint but rather includes any enclosed space regardless of the size thereof which may vary according to application. The valves or airlocks are cycled between ambient conditions to a condition which suppresses formulation evaporation and allows for more drug-filled stent parts per formulation volume. Apparatus320and method460may be used to fill tens of thousands of stents100at a time via the multiple air-locked chambers and quicker saturation process thereof. For illustrative purposes only, stents100are represented as straight tubular structures inFIGS. 5-24although it will be understood by one of ordinary skill in the art that stents100are a hollow wire shaped into a desired stent pattern as previously described with reference toFIG. 1.

With reference toFIG. 3, apparatus320includes a first or filling chamber324, a second or loading chamber322, and a third or unloading chamber354. Filling chamber324is separated from loading chamber322via a first gate valve326positioned there-between, and similarly filling chamber324is separated from unloading chamber354via a second gate valve356positioned there-between. Each valve gate326,356is operable to alternate between an open configuration in which the adjacent chambers are in fluid communication, and a closed configuration in which the adjacent chambers are not in fluid communication. More particularly, when first gate valve326is closed, filling chamber324is not in fluid communication with loading chamber322and filling chamber324is air-tight, air-locked, or otherwise sealed with respect to loading chamber322. When first gate valve326is open, filling chamber324is in fluid communication with loading chamber322. Similarly, when second gate valve356is closed, filling chamber324is not in fluid communication with unloading chamber354and filling chamber324is air-tight, air-locked, or otherwise sealed with respect to unloading chamber354. When second gate valve356is open, filling chamber324is in fluid communication with unloading chamber354. Thus, if first gate valve326and second gate valve356are both simultaneously open, filling chamber324, loading chamber322, and unloading chamber354are in fluid communication with each other. Loading and unloading chambers322,354each include a vent359,358, respectively, and filling chamber324includes a vent357to be utilized in the method of filling stents100as described in more detail herein.

In addition to valve gates326,356, apparatus320includes a valve or sealable door321adjacent to loading chamber322and a valve or sealable door353adjacent to unloading chamber354. Sealable doors321,353permit stents100and other components utilized in the method of filling stents100to be loaded and unloaded from loading and unloading chambers322,354, respectively.

Filling chamber324includes a first reservoir332which houses or holds wicking means330and a fluid drug formulation334that includes therapeutic substance or drug112. InFIG. 3(as well asFIGS. 5-8), reservoir332is shown empty but is denoted as330/332to indicate the presence of wicking means330therein. Wicking means330according to an embodiment hereof is shown in more detail inFIGS. 20 and 21, and is described in more detail herein. Reservoir332is shown being filled with fluid drug formation334inFIG. 9during description of the method of use. In all figures, when present, fluid drug formation334is illustrated within reservoir332via the same cross-hatch pattern as shown inFIG. 9. Wicking means330is in contact with fluid drug formulation334to control transfer of the fluid drug formulation334into lumen103of hollow wire102during the capillary filling procedure as described inFIGS. 5-24. “Wicking means” as used herein refers to a medium or component that acts or functions to move or convey, or acts or functions to assist in the movement of, the fluid drug formulation334by capillary action from within reservoir332into lumen103of hollow wire102. In addition to controlling transfer of the fluid drug formulation, in some embodiments hereof, wicking means330also removes excess fluid drug formulation from the exterior surfaces of hollow wire102of stent100when stent100is retracted out of the wicking means. When wicking means330performs this excess removal function, an additional processing or cleaning step may not be required to make stents100free or substantially free of drug residue on the exterior surfaces of hollow wire102. Wicking means330preferably has several characteristics or properties, including that it does not degrade or add contaminants into fluid drug formulation334, that it does not change mechanical, dimensional, and or electrical properties, that it is inert in fluid drug formulation334, that it does not cause a phase separation within fluid drug formulation334, that is does not change the formulation in any measurable way, and that it is usable and/or stable for several days or weeks meaning that it does not change in any measurable way. As will be described in more detail with respect toFIGS. 21 and 22, wicking means330is a plurality of ceramic beads with fluid drug formulation334evenly dispersed within.

Filling chamber324also includes an open reservoir or container336which is filled with a liquid338. Container336is shown empty inFIG. 3, but is shown being filled with liquid338inFIG. 8during description of the method of use. In all figures, when present, liquid338is illustrated within container336via the same cross-hatch pattern asFIG. 8. Container336is any structure suitable for housing or containing a relatively large volume of liquid with high surface area which serves as a solvent vapor source as will be described in more detail herein. Liquid338is utilized in the method of filling stents100to prevent evaporation of solvent from fluid drug formation334contained within reservoir332as described in more detail herein. Further, filling chamber324, loading chamber322, and unloading chamber354are selectively in fluid communication with a supply of nitrogen gas346via tubing network348. Tubing network348includes valves351,349,347which may be opened to allow filling chamber324, loading chamber322, unloading chamber354, respectively, to be in fluid communication with the supply of nitrogen gas346and which may be closed to cause filling chamber324, loading chamber322, unloading chamber354, respectively, to no longer be in fluid communication with the supply of nitrogen gas346. Nitrogen gas346may be utilized in the method of filling stents100as described in more detail herein.

Apparatus320further includes a vacuum pump340and an evaporator344which are each selectively in fluid communication with loading chamber322, filling chamber324, and unloading chamber354via a tubing network342. Valve341adjacent to vacuum pump340may be opened to allow tubing network342to be in fluid communication with vacuum pump340and may be closed to cause tubing network342to no longer be in fluid communication with vacuum pump340. Valve343adjacent to evaporator344may be opened to allow tubing network342to be in fluid communication with evaporator344and may be closed to cause tubing network342to no longer be in fluid communication with evaporator344. Evaporator344is a separate chamber containing a supply of liquid and vapor solvent that is the same as or similar to the solvent utilized in fluid drug formation334. As described above, examples of low capacity drug dissolving solvents include but are not limited to methanol, ethanol, propanol, acetonitrile, ethyl lactate, acetone, and solvent mixtures like tetrahydrofuran/water (9:1 weight ratio).

Tubing network342includes a valve323for selectively controlling fluid communication with loading chamber322, a valve325for selectively controlling fluid communication with filling chamber324, and a valve355for selectively controlling fluid communication with unloading chamber354. More particularly, when valve323is closed, loading chamber322is not in fluid communication with tubing network342and loading chamber322is air-tight, air-locked, or otherwise sealed with respect to tubing network342. When valve323is open, loading chamber322is in fluid communication with tubing network342. Similarly, when valve325is closed, filling chamber324is not in fluid communication with tubing network342and filling chamber324is air-tight, air-locked, or otherwise sealed with respect to tubing network342. When valve325is open, filling chamber324is in fluid communication with tubing network342. Similarly, when valve355is closed, unloading chamber354is not in fluid communication with tubing network342and unloading chamber354is air-tight, air-locked, or otherwise sealed with respect to tubing network342. When valve355is open, unloading chamber354is in fluid communication with tubing network342. Valve343adjacent to evaporator344in conjunction with valves323,325,355control which chamber will be filled with vapor that supplied from evaporator344and valve341adjacent to vacuum pump340in conjunction with valves323,325,355control which chamber will have residual gas purged therefrom via vacuum pump340.

FIGS. 5-24illustrate the various steps of method460. InFIGS. 5-24, the cross-hatch pattern of various components is utilized to indicate the contents of thereof. More particularly, the cross-hatch pattern shown inFIG. 5of loading and unloading chambers322,354indicates residual vapor, gas, or other mixed components may be present therein. When any chambers and/or tubing network342are empty (such as filling chamber324inFIG. 5), the emptiness indicates that any residual vapor, gas, or other mixed components have been purged therefrom. When any chambers and/or tubing network342are filled with a vapor345, the cross-hatch pattern shown inFIG. 6of filling chamber324and tubing network342indicates that vapor345is present therein. Further, as previously described, when fluid drug formation334is present within reservoir332, its presence is indicated via the cross-hatch pattern utilized inFIG. 9. In addition, as previously described, when liquid338is present within container336, its presence is indicated via the cross-hatch pattern utilized inFIG. 8.

Turning now toFIGS. 5-7, a first step462of method460illustrated inFIG. 4will be described. First step462includes causing filling chamber324to reach a vapor-liquid equilibrium of a solvent of fluid drug formulation334. Prior to the initiation of first step462, both first and second valve gates326,356are closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. Valve325is open such that filling chamber324is in fluid communication with tubing network342, but valves323,355are closed such that loading and unloading chambers322,354, respectively, are not in fluid communication with tubing network342. Valve343adjacent to evaporator344is closed. Prior to performing first step462of method460, a preparation cycle may be performed multiple times within filling chamber324. The preparation cycle includes removing the gas within filling chamber324and tubing network342by opening valve341to vacuum pump340and then backfilling filling chamber324with nitrogen gas346by opening valve349until filling chamber324reaches atmospheric pressure or another predetermined or set pressure.

Once the preparation cycle is repeated as desired, first step462of method460is performed and the gas within filling chamber324and tubing network342is purged by opening valve341to vacuum pump340as shown inFIG. 5. Vacuum pump340lowers the pressure within filling chamber324to a pressure lower than atmospheric pressure. Via vacuum pump340, any residual vapor, gas, or other mixed components are purged from filling chamber324and the pressure in filling chamber324and tubing network342may be between 0 PSIA and 14.7 PSIA (0 Torr and 760 Torr).

With reference toFIG. 6, after gas is purged from filling chamber324and tubing network342via vacuum pump340, valve341is closed and then valve343is opened to backfill tubing network342and filling chamber324with a vapor345of the solvent of fluid drug formation334via evaporator344which houses a supply of the vapor. Filling chamber324is saturated with a vapor of the solvent of fluid drug formation334via evaporator344such that filling chamber324reaches solvent vapor saturation. Stated another way, filling chamber324is at the vapor-liquid equilibrium of the solvent of fluid drug formulation334. When vapor-liquid equilibrium is reached, valve343and valve325are closed. Vapor-liquid equilibrium is the condition or state where a liquid and its vapor are in equilibrium with each other, where the rate of evaporation equals the rate of condensation such that there is no net or mass transport across its respective phase. Such an equilibrium is practically reached in a closed location if a liquid and its vapor are allowed to stand in contact with each other for a sufficient time period. As used herein, the term “the vapor-liquid equilibrium” or “solvent vapor saturation” includes absolute pressures of ±5 torr within theoretical values that are stated by vapor pressure curves generated via Antoine Coefficients for a particular solvent at a particular temperature. As described above, examples of low capacity drug dissolving solvents include but are not limited to methanol, ethanol, propanol, acetonitrile, ethyl lactate, acetone, and solvent mixtures like tetrahydrofuran/water (9:1 weight ratio). Evaporation is considered very slow and practically negligible within this range of absolute pressure, and the filling process may be performed within this range of pressure without premature precipitation of therapeutic substance or drug112within lumen103of hollow wire102. Valves343,325are then closed.

In an embodiment, after backfilling tubing network342and filling chamber324with vapor345of the solvent of fluid drug formation334via evaporator344, filling chamber324may be backfilled with nitrogen gas346by opening valve349for stabilization of filling chamber324. Adding nitrogen gas346to filling chamber324enhances stability and prevents temperature fluctuations within the chamber and system when the filling chamber is saturated with a vapor of the solvent of fluid drug formulation334as described above with respect toFIG. 6. Absolute pressure in filling chamber324is still less than atmospheric pressure at this point in the method. After backfilling filling chamber324with nitrogen gas346, a dwell or wait time occurs to ensure temperature stabilization of filling chamber324. The dwell time may vary between 0.25-15 minutes.

Referring now toFIG. 7, after filling chamber324is sufficiently saturated, vapor345still fills filling chamber324as shown inFIG. 7, which is sealed off from tubing network342as well as loading and unloading chambers322,354. Gas or residual vapor is purged from tubing network342via vacuum pump340by opening valve341. Valve341is then closed.

Turning now toFIG. 8, a second step464of method460illustrated inFIG. 4will be described. Second step464includes adding liquid338into container336housed within filling chamber324. During step464, both first and second valve gates326,356remain closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. In addition, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills filling chamber324as shown inFIG. 8, which is now sealed off from tubing network342as well as loading and unloading chambers322,354. A syringe pump337is used to inject liquid338into container336via a self-sealing opening or port (not shown) formed in filling chamber324. Liquid338which is added into container336is selected from the group consisting of the solvent of fluid drug formulation334, fluid drug formulation334, or a solution having the same vapor-liquid equilibrium as fluid drug formulation334and the same solvent as fluid drug formulation334. As described above, examples of low capacity drug dissolving solvents include but are not limited to methanol, ethanol, propanol, acetonitrile, ethyl lactate, acetone, and solvent mixtures like tetrahydrofuran/water (9:1 weight ratio). With container336filled with liquid338, any evaporation that may occur within filling chamber324during the capillary fill process (i.e., during the remaining steps of method460) will happen from liquid338in container336. Stated another way, liquid338within container336provides a supply of solvent vapor for unintended evaporation that may occur during the capillary fill process to prevent evaporation of fluid drug formulation334which is added to reservoir332inFIG. 9as described below. Preventing evaporation of fluid drug formulation334ensures that there is an adequate supply thereof to fill stents100via capillary action and also ensures that there are no changes in concentration or other properties of fluid drug formulation334. For example, evaporation of fluid drug formulation334would include evaporation of the solvent thereof which would result in an undesired increase in the solute concentration thereof, thereby undesirably increasing the mass of solute that fills a fixed volume (i.e. stent100). After injecting liquid338into container336via syringe pump337, a dwell or wait time occurs to ensure saturation of filling chamber324. The dwell time may vary between 0.25-15 minutes.

Turning now toFIG. 9, a third step466of method460illustrated inFIG. 4will be described. Third step466includes adding fluid drug formulation334into reservoir332(which contains wicking means330) housed within filling chamber324. During step466, both first and second valve gates326,356remain closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. In addition, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills filling chamber324as shown inFIG. 9, which is now sealed off from tubing network342as well as loading and unloading chambers322,354. A syringe pump335is used to inject fluid drug formulation334into reservoir332via a self-sealing opening or port (not shown) formed in filling chamber324.

Turning now toFIGS. 10-15, a fourth step468of method460illustrated inFIG. 4will be described. Fourth step468includes agitating, stirring, or otherwise mixing/dispersing fluid drug formation334and wicking means330within reservoir332. As shown inFIG. 10, a stir cover350is inserted or positioned within loading chamber322via sealable door321. More particularly, sealable door321is opened and stir cover350is moved or transferred into loading chamber while sealable door321is opened. Sealable door321is then closed. Stir cover350is a lid or cover that is configured to be disposed on top of open reservoir332to seal or close reservoir332into a closed compartment so that the contents thereof may be mixed or agitated without spilling into filling chamber324as will be described in more detail herein. After positioning stir cover350within loading chamber322, a preparation cycle may be performed multiple times within loading and unloading chambers322,354. The preparation cycle includes removing the gas within loading and unloading chambers322,354and tubing network342by opening valve341to vacuum pump340and then backfilling loading and unloading chambers322,354with nitrogen gas346by opening valves351,347, respectively, until loading and unloading chambers322,354reach atmospheric pressure or another predetermined or set pressure.

Once the preparation cycle is repeated as desired, valves323,355,341are opened such that loading and unloading chambers322,354, and vacuum pump340respectively, are in fluid communication with tubing network342, but valve325remains closed such that filling chamber324is not in fluid communication with tubing network342. As shown inFIG. 11, gas is purged from loading and unloading chambers322,354and tubing network342via vacuum pump340to lower the pressure within loading and unloading chambers322,354to a pressure lower than atmospheric pressure. Any residual vapor has now been purged from loading and unloading chambers322,354and tubing network342and the pressure in loading and unloading chambers322,354and tubing network342may be between 0 PSIA and 14.7 PSIA (0 Torr and 760 Torr). Valve341adjacent to vacuum pump340is then closed, and valve343adjacent to evaporator344is subsequently opened so that evaporator344is in fluid communication with tubing network342. With reference toFIG. 12, tubing network342and loading and unloading chambers322,354are backfilled with vapor345of the solvent of fluid drug formation334via evaporator344which houses a supply of the vapor. Loading and unloading chambers322,354are saturated with vapor345of the solvent of fluid drug formation334via evaporator344such that loading and unloading chambers322,354reach at or near solvent vapor saturation. Stated another way, loading and unloading chambers322,354are at the vapor-liquid equilibrium of the solvent of fluid drug formulation334. AlthoughFIGS. 11-12describe saturation of both loading and unloading chambers322,354, only loading chamber322is required to reach saturation and undergo the steps shown and described inFIGS. 11-14. After loading and unloading chambers322,354are sufficiently saturated, valves323,355,343are closed such that loading and unloading chambers322,354, and evaporator344, respectively, are no longer in fluid communication with tubing network342.

In an embodiment, after backfilling tubing network342and loading and unloading chambers322,354with vapor345of the solvent of fluid drug formation334via evaporator344, loading and unloading chambers322,354may be backfilled with nitrogen gas346by opening valves351,347. Nitrogen gas346is added to loading and unloading chambers322,354for stabilization thereof. Adding nitrogen gas346to loading and unloading chambers322,354enhances stability and prevents temperature fluctuations within the chambers and system when the loading and unloading chambers are saturated with a vapor of the solvent of fluid drug formulation334as described above with respect toFIG. 12. Absolute pressure in loading and unloading chambers322,354is still less than atmospheric pressure at this point in the method. Valves351,347are then closed.

Referring now toFIG. 13, after loading and unloading chambers322,354are sufficiently saturated, vapor345still fills loading and unloading chambers322,354as shown inFIG. 13which are sealed off from tubing network342as well as filling chamber324and evaporator344. Gas or residual vapor is purged from tubing network342via vacuum pump340by opening valve341to purge any residual vapor from tubing network342.

Turning now toFIG. 14, with all chambers (loading chamber322, filling chamber324, and unloading chamber354) filled with vapor345, stir cover350is transferred into filling chamber324. More particularly, first valve gate326is opened such that filling chamber324and loading chamber322are in fluid communication. Stir cover350is moved or transferred from loading chamber322into filling chamber324while first valve gate326is opened. Stir cover350is positioned over reservoir332, which includes wicking means330and fluid drug formulation334. First valve gate326is then closed such that filling chamber324and loading chamber322are no longer in fluid communication. As previously described, stir cover350is a lid or cover that is configured to be disposed on top of open reservoir332to seal or close reservoir332into a closed compartment so that wicking means330and fluid drug formulation334disposed within reservoir332may be mixed or agitated without spilling into filling chamber324. An external vibrator or mixing means (not shown) is utilized to agitate or mix reservoir332disposed within filling chamber324after stir cover350is positioned over reservoir332. The external vibrator or mixing means agitates filling chamber324side to side, as well as up and down, to achieve a fluidized bed of wicking means330and fluid drug formulation334. In an embodiment, the external vibrator is a motor outside of filling chamber324and a shaft extends sealingly into filling chamber324between the external motor and reservoir332. In another embodiment hereof, the vibrator or mixing means may be internal to filling chamber324. After stir cover350is positioned or disposed over reservoir332, the stir cycle commences and mixes or agitates/disperses fluid drug formation334and wicking means330within reservoir332for a predetermined time.

After the stir cycle is complete, with all chambers (loading chamber322, filling chamber324, and unloading chamber354) filled with vapor345, stir cover350is transferred out of filling chamber324as shown inFIG. 15. More particularly, second valve gate356is opened such that filling chamber324and unloading chamber354are in fluid communication. Stir cover350is moved or transferred from filling chamber324into unloading chamber354while second valve gate356is opened. Second valve gate356is then closed such that filling chamber324and unloading chamber354are no longer in fluid communication. Vapor345is then purged from loading chamber322and unloading chamber354via respective vents359,358, and loading chamber322and unloading chamber354return to atmospheric pressure. In another embodiment hereof, venting may occur via opening valves351,347to backfill loading and unloading chambers, respectively, with nitrogen from the supply of nitrogen gas346to atmospheric pressure. Stir cover350may then be removed from unloading chamber354via sealable door353.

Turning now toFIG. 16, a fifth step470of method460illustrated inFIG. 4will be described. Fifth step470includes placing stents100into loading chamber322via sealable door321. During step470, both first and second valve gates326,356remain closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. In addition, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills filling chamber324as shown inFIG. 16, which is now sealed off from tubing network342as well as loading and unloading chambers322,354. Stents100are held on a manifold or stent suspension means (not shown) which holds or suspends them in place during the capillary filling procedure. Exemplary stent suspension means are described in U.S. patent application Ser. No. 13/457,398 to Peterson et al., filed Apr. 26, 2012, assigned to the same assignee as the present application and herein incorporated by reference in its entirety. The capillary filling procedures in accordance with embodiment hereof may be readily scalable as batch processes. When loaded onto stent suspension means, stents100are already formed, that is, hollow wire102has previously been shaped or formed into a desired waveform and formed into cylindrical stent100as described above with respect toFIG. 1. Alternatively, if desired, the capillary filling process may be performed on straight hollow wires prior to shaping or forming hollow wire102into the desired waveform and subsequent stent configuration.

Turning now toFIGS. 17-18, a sixth step472of method460illustrated inFIG. 4will be described. Sixth step472includes causing loading and unloading chambers322,354to reach the vapor-liquid equilibrium of the solvent of fluid drug formulation334. With reference toFIG. 17, valves323,355,341are opened such that loading and unloading chambers322,354, and vacuum pump340, respectively, are in fluid communication with tubing network342, but valve325remains closed such that filling chamber324is not in fluid communication with tubing network342. As shown inFIG. 17, the gas within loading and unloading chambers322,354and tubing network342is purged by opening valve341to vacuum pump340to lower the pressure within loading and unloading chambers322,354to a pressure lower than atmospheric pressure. Any residual vapor has now been purged from loading and unloading chambers322,354and tubing network342and the pressure in loading and unloading chambers322,354and tubing network342may be between 0 PSIA and 14.7 PSIA (0 Torr and 760 Torr). Valve341is then closed. With reference toFIG. 18, tubing network342and loading and unloading chambers322,354are backfilled with vapor345of the solvent of fluid drug formation334by opening valve343to evaporator344which houses a supply of the vapor. Loading and unloading chambers322,354are saturated with vapor345of the solvent of fluid drug formation334via evaporator344such that loading and unloading chambers322,354reach solvent vapor saturation. Stated another way, loading and unloading chambers322,354are at the vapor-liquid equilibrium of the solvent of fluid drug formulation334. After loading and unloading chambers322,354are sufficiently saturated, valves323,355,343are closed such that loading and unloading chambers322,354, and evaporator344, respectively, are no longer in fluid communication with tubing network342.

In an embodiment, after backfilling tubing network342and loading and unloading chambers322,354with vapor345of the solvent of fluid drug formation334via evaporator344, loading and unloading chambers322,354may be backfilled with nitrogen gas346by opening valves351,347for stabilization of loading and unloading chambers322,354. Adding nitrogen gas346to loading and unloading chambers322,354enhances stability and prevents temperature fluctuations within the chamber and system when the loading and unloading chambers are saturated with a vapor of the solvent of fluid drug formulation334as described above with respect toFIG. 18. Absolute pressure in loading and unloading chambers322,354is still less than atmospheric pressure at this point in the method. After backfilling loading and unloading chambers322,354with nitrogen gas346, a dwell or wait time occurs to ensure temperature stabilization of loading and unloading chambers322,354. The dwell time may vary between 0.25-15 minutes. Vapor345still fills loading and unloading chambers322,354, which are sealed off from tubing network342as well as filling chamber324. Gas or residual vapor is purged from tubing network342via vacuum pump340by opening valve341.

Turning now toFIG. 19, a seventh step474of method460illustrated inFIG. 4will be described. Seventh step474includes transferring stents100into filling chamber324. During step474, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills all chambers (loading chamber322, filling chamber324, and unloading chamber354) as shown inFIG. 19. First valve gate326is opened such that filling chamber324and loading chamber322are in fluid communication. Stents100are moved or transferred from loading chamber322into filling chamber324while first valve gate326is opened. First valve gate326is then closed such that filling chamber324and loading chamber322are no longer in fluid communication. First valve gate326sealingly closes around the stent suspension means which are holding stents100.

Turning now toFIGS. 20-22, an eighth step476of method460illustrated inFIG. 4will be described. Eighth step476includes filling stents100via capillary action. During step476, both first and second valve gates326,356remain closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. In addition, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. As shown inFIGS. 21 and 22, at least a portion of stent100is first positioned or placed into contact with wicking means330housed within reservoir332. At least one of the plurality of side openings104, or first or second ends114,114′ of hollow wire102, must be in contact with wicking means330. However, in an embodiment hereof, stent100may be entirely submersed or otherwise placed into contact with wicking means330. Stents100may be suspended by stent suspension means in a vertical orientation as shown inFIG. 20, or alternatively may suspend stents100in a horizontal orientation as shown inFIG. 21. Notably, only a portion of each stent having at least one side hole or port104is required to be submersed into wicking means330. As such, a minimal amount of the exterior surfaces of wires102of stents100are exposed to the fluid drug formulation and most of the exterior surface of the hollow wire of the stent is never exposed to the fluid drug formulation, therefore not requiring additional cleaning or removal of drug residue. When held vertically as shown inFIG. 20, only a tip107of each stent100is submersed into wicking means330such that at least one side hole104is in contact with wicking means330and exposed to fluid drug formulation334. For example, in an embodiment, approximately 0.3 mm of the length of each stent is exposed or driven into to the wicking means. When held horizontally as shown inFIG. 21, a longitudinal strip or segment2111along an outer surface of each stent100is submersed into wicking means330such that at least one side hole104is in contact with wicking means330and exposed to fluid drug formulation334.

As shown in bothFIGS. 20 and 21, wicking means330is a plurality of beads within the layer of fluid drug formulation334contained within reservoir332. In an embodiment, the beads of wicking means330may be a type of ceramic beads between 0.3 mm and 1.5 mm in diameter. Other suitable materials for the beads of wicking means330include glass, or metal such as steel, aluminum, titanium, or stainless steel. The individual size of the beads, as well as the height of the layer of beads, may vary according to application. The beads minimize the contact area between stents100and fluid drug formulation334to control surface energy properties during the filling procedure. In an embodiment, the layer of fluid drug formulation is approximately the same height as the layer of beads. However, in another embodiment, the layer of beads has a greater height than the layer of fluid drug formulation such that a layer of “dry” beads extend over the “wet” beads that are submersed in the layer of fluid drug formulation. The layer of “dry” beads provides additional cleaning of the exterior surfaces of stents100when stents100are retracted out of the beads. Although wicking means embodiments described herein may be shown with only one stent100, it will be understood by one of ordinary skill in the art that any wicking means described herein may accommodate a plurality of stents100. Other described as a plurality of ceramic beads, other wicking means described in U.S. patent application Ser. No. 13/457,398, previously incorporated by reference, may be used such as but not limited to an open-celled polyurethane sponge or foam.

After stents100are positioned or placed into contact with wicking means330, stents100are allowed or permitted to fill via capillary action. Wicking means330is in contact with fluid drug formulation334, to control transfer of the fluid drug formulation into lumen103of hollow wire102of stent100. Wicking means330transfer fluid drug formulation334from reservoir332into submersed holes104of stent100. Lumen103of hollow wire102of stent100is filled by surface tension driving fluid drug formulation334through the stent lumen, until the entire length of lumen103is filled via capillary action forces. During the filling step, filling chamber324is maintained at or near the vapor-liquid equilibrium of the solvent of fluid drug formulation334such that evaporation does not precipitate therapeutic substance or drug112as fluid drug formulation334fills lumen103of hollow wire102of stents100.

FIG. 22is a schematic illustration of a portion of a stent100submersed or in contact with wicking means330to demonstrate the capillary filling process. Fluid drug formulation334passes through hole(s)104on hollow wire102that are in contact with wicking means330as shown in FIG.22, which illustrates only a portion of hollow wire102having a side hole104submersed into wicking means330. Fluid drug formulation334forms a concave meniscus within lumen103of hollow wire102. Adhesion forces pull fluid drug formulation334up until there is a sufficient mass of fluid drug formulation334present for gravitational forces to overcome the intermolecular forces between fluid drug formulation334and hollow wire102, or the advancing fluid column completely fills the lumen. The height h of a column of fluid drug formulation334is determined by

where γ is the liquid-air surface tension (force/unit length), θ is the contact angle, ρ is the density of fluid drug formulation334(mass/volume), g is local gravitational field strength (force/unit mass), and r is the radius of hollow wire102(length). Due to the nature of capillary filling and the intermolecular forces between fluid drug formulation334and hollow wire102, fluid drug formulation334does not exit or leak out of non-submersed holes or ports104that occur along the length of the stent as fluid drug formulation334fills lumen103of hollow wire102.

The time required to fill the entire length of lumen103of hollow wire102of stent100depends upon the stent configuration and length. Fill time depends upon various factors, including but not limited to the length of hollow wire102, the size of holes104, the number of submersed holes104, the size of lumen103, and the properties of wicking means330and fluid drug formulation334. For example, in an embodiment in a horizontally-oriented 3 mm×18 mm stent is placed into contact with wicking means330, which is in contact with a fluid drug formulation including rapamycin dissolved in methanol, filling time is approximately 60 seconds. If it is desired to reduce the overall fill time, the number of submersed holes104may be increased. Often, horizontal orientation of stents may be utilized if it is desired to place a greater number of side holes into contact with the wicking means and thereby reduce the overall fill time. Contact is maintained between wicking means330and stent100until lumenal space103of hollow wire102is at least partially filled with fluid drug formulation334via capillary action.

After lumen103is completely filled, or partially filled if so desired, stents100are retracted or pulled up such that stents100are no longer in contact with wicking means330but is located within filling chamber324. As stents100are retracted out of wicking means330, wicking means330removes excess fluid drug formulation334from the exterior surfaces of wires102of stents100such that stents100are free or substantially free of drug residue on their exterior surfaces, leaving fluid drug formulation334only within lumen103of hollow wire102of stent100. During retraction of stents100, the beads of wicking means330pull or remove excess fluid drug formulation from the exterior surfaces of hollow wires102of stents100.

Turning now toFIG. 23, a ninth step478of method460illustrated inFIG. 4will be described. Ninth step478includes transferring stents100into unloading chamber354. During step478, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills all chambers (loading chamber322, filling chamber324, and unloading chamber354) as shown inFIG. 23. Second valve gate356is opened such that filling chamber324and unloading chamber354are in fluid communication. Stents100are moved or transferred from filling chamber324into unloading chamber354while second valve gate356is opened. Second valve gate356is then closed such that filling chamber324and unloading chamber354are no longer in fluid communication.

With continued reference toFIG. 23, a tenth step480of method460illustrated inFIG. 4will be described. Tenth step480includes reducing a solvent vapor pressure in unloading chamber354to evaporate the solvent of fluid drug formulation334after stents100have been transferred into unloading chamber354. During step480, both first and second valve gates326,356remain closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. In addition, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills filling chamber324as shown inFIG. 24, which is now sealed off from tubing network342as well as loading and unloading chambers322,354. More particularly, during step480, stents100are still positioned within unloading chamber354and vapor345is purged from loading chamber322and unloading chamber354via respective vents359,358, so that loading chamber322and unloading chamber354return to atmospheric pressure. Stated another way, loading chamber322and unloading chamber354are vented via respective vents359,358to reduce their solvent vapor pressure and to increase overall pressure back to ambient conditions. In another embodiment hereof, venting may occur via opening valves351,347to backfill loading and unloading chambers, respectively, with nitrogen from the supply of nitrogen gas346. As the solvent vapor pressure is reduced in loading chamber322and unloading chamber354, evaporation of fluid drug formulation334within lumen103of hollow wire102is initiated and the solvent of drug fluid formulation334is removed, thereby precipitating its constituents. After the solvent or dispersion medium is removed from lumen103, therapeutic substance or drug112fills at least a portion of lumen103. Thus, extracting the solvent or dispersion medium of fluid drug formulation334from within the lumen103of hollow wire102thus precipitates the solute, i.e., therapeutic substance or drug112, within lumen103and creates a drug-filled stent100with primarily only therapeutic substance or drug112and one or more excipients within stent100to be eluted into the body. After evaporation of fluid drug formulation334, filled stents100may be removed from unloading chamber354of apparatus320.

The next batch of unfilled stents100Nmay then be inserted or positioned into loading chamber322of apparatus320for filling thereof as shown inFIG. 24and according to eleventh step482of method460. Since vapor345still fills filling chamber324, additional batches of stents may be filled with the same fluid drug formulation without concentration changes. More particularly, the first four steps of method460(steps462,464,466,468) described above with respect toFIGS. 5-15do not need to be repeated for subsequent additional batches of stents that are to be filled. Rather, the method of filling subsequent additional batches of stents pick up atFIG. 16with the next batch of stents being positioned or placed into loading chamber322.

Although method460is described above with respect to apparatus320, method460may alternatively be carried out on an apparatus having only a filling chamber and a loading chamber. Stated another way, the method steps performed in the unloading chamber may alternatively take place within the loading chamber. As such, apparatus320is only required to have two distinct, air-locked chambers, namely a filling chamber and a loading/unloading chamber.

Alternative Method of Capillary Filling with Apparatus320

FIGS. 25-44illustrate an alternative method of using apparatus320for capillary filling of multiple, sequential batches of stents in a timely or effective manner. The alternative method illustrated inFIGS. 25-44essentially utilizes both loading and unloading chambers322,354as loading chambers that receive different components (i.e., the stir cover and the stents) at the same time in order to reduce the total time required for the capillary fill process and thus increase efficiency thereof. In addition, as will be described in more detail herein, by utilizing loading and unloading chambers322,354simultaneously, the number of total steps required in the alternative method of use is reduced as compared to the method of use described above.

FIGS. 25-27illustrate the first or initial step of the alternative method. The initial step of the alternative method of use is similar to method step462described above, and includes causing filling chamber324to reach a vapor-liquid equilibrium of a solvent of fluid drug formulation334. As such,FIGS. 25-27are the same asFIGS. 5-7and illustrate filling chamber324reaching a vapor-liquid equilibrium of a solvent of fluid drug formulation334. For sake of completeness a brief description of method step462is repeated herein. Prior to the initiation of the method, both first and second valve gates326,356are closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. Valve325is open such that filling chamber324is in fluid communication with tubing network342, but valves323,355are closed such that loading and unloading chambers322,354, respectively, are not in fluid communication with tubing network342. As described above, initially a preparation cycle may be performed multiple times within filling chamber324. The preparation cycle includes removing the gas within filling chamber324and tubing network342by opening valve341to vacuum pump340and then backfilling filling chamber324with nitrogen gas346by opening valve349until filling chamber324reaches atmospheric pressure or another predetermined or set pressure. Once the preparation cycle is repeated as desired, the gas within filling chamber324and tubing network342is purged by opening valve341to vacuum pump340to lower the pressure within filling chamber324to a pressure lower than atmospheric pressure as shown inFIG. 25. Any residual vapor has now been purged from filling chamber324and the pressure in filling chamber324and tubing network342may be between 0 PSIA and 14.7 PSIA (0 Torr and 760 Torr). Valve341is then closed. With reference toFIG. 26, tubing network342and filling chamber324are now backfilled with a vapor345of the solvent of fluid drug formation334by opening valve343to evaporator344which houses a supply of the solvent vapor. Filling chamber324is saturated with vapor345of the solvent of fluid drug formation334via evaporator344such that filling chamber324reaches solvent vapor saturation. Stated another way, filling chamber324is at the vapor-liquid equilibrium of the solvent of fluid drug formulation334. Valves343,325are then closed.

In an embodiment, after backfilling tubing network342and filling chamber324with vapor345of the solvent of fluid drug formation334via evaporator344, filling chamber324may be backfilled with nitrogen gas346by opening valve349for stabilization of filling chamber324. Adding nitrogen gas346to filling chamber324enhances stability and prevents temperature fluctuations within the chamber and system when the filling chamber is saturated with a vapor of the solvent of fluid drug formulation334as described above with respect toFIG. 26. Absolute pressure in filling chamber324is still less than atmospheric pressure at this point in the method. After backfilling filling chamber324with nitrogen gas346, a dwell or wait time occurs to ensure temperature stabilization of filling chamber324. The dwell time may vary between 0.25-15 minutes.

After filling chamber324is sufficiently saturated, vapor345still fills filling chamber324, which is sealed off from tubing network342as well as loading and unloading chambers322,354. Gas or residual vapor within tubing network342is purged via vacuum pump340by opening valve341as shown inFIG. 27.

FIG. 28illustrates the second step of the alternative method. The second step of the alternative method of use is similar to method step464described above, and includes adding liquid338into container336housed within filling chamber324. As such,FIG. 28is similar toFIG. 8and illustrates liquid338being added to container336. For sake of completeness a brief description of method step464is repeated herein. During this step, both first and second valve gates326,356remain closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. In addition, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills filling chamber324as shown inFIG. 28, which is now sealed off from tubing network342as well as loading and unloading chambers322,354. Syringe pump337is used to inject liquid338into container336via a self-sealing opening or port (not shown) formed in filling chamber324. After injecting liquid338into container336, a dwell or wait time occurs to ensure saturation of filling chamber324. The dwell time may vary between 0.25-15 minutes.

FIG. 29illustrates the third step of the alternative method. The third step of the alternative method of use is similar to method step466described above, and includes adding fluid drug formulation334into reservoir332(which contains wicking means330) housed within filling chamber324. As such,FIG. 29is similar toFIG. 9and illustrates fluid drug formulation334being added into reservoir332. For sake of completeness a brief description of method step466is repeated herein. During this step, both first and second valve gates326,356remain closed such that filling chamber324, loading chamber322, and unloading chamber354are distinct or separate closed chambers and are not in fluid communication with each other. In addition, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Valves351,349,347are also closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with the supply of nitrogen gas346. Further, valves341,343are also preferably closed since vacuum pump340and evaporator344are not in use. Vapor345still fills filling chamber324as shown inFIG. 29, which is now sealed off from tubing network342as well as loading and unloading chambers322,354. Syringe pump335is used to inject fluid drug formulation334into reservoir332via a self-sealing opening or port (not shown) formed in filling chamber324.

FIGS. 30-35illustrate the fourth step of the alternative method. The fourth step of the alternative method of use deviates from the previous method and illustrates how unloading both loading and unloading chambers322,354as loading chambers that receive different components (i.e., stir cover350and a first batch of stents100) at the same time in order to reduce the total time required for the capillary fill process and thus increase efficiency thereof. The fourth step of the alternative method still includes mixing fluid drug formulation334and wicking means330within reservoir332as described above with respect to fourth step468, but the fourth step of the alternative method combines step468and step470into one step and further eliminates the need for step472described above in which the loading chamber is caused to reach vapor-equilibrium again after loading stents100therein. More particularly, as shown inFIG. 30, a stir cover350is inserted or positioned within loading chamber322via sealable door321and a first batch of stents100is positioned in unloading chamber354via sealable door353. After positioning stir cover350within loading chamber322and the first batch of stents100within unloading chamber354, a preparation cycle may be performed multiple times within loading and unloading chambers322,354. The preparation cycle includes removing the gas within loading and unloading chambers322,354and tubing network342by opening valve341to vacuum pump340and then backfilling loading and unloading chambers322,354with nitrogen gas346by opening valves351,347, respectively, until loading and unloading chambers322,354reach atmospheric pressure or another predetermined or set pressure.

Next, with reference toFIG. 31, valves323,355are opened such that loading and unloading chambers322,354, respectively, are in fluid communication with tubing network342, but valve325remains closed such that filling chamber324is not in fluid communication with tubing network342. Gas is purged from loading and unloading chambers322,354and tubing network342by opening valve341to vacuum pump340to lower the pressure within loading and unloading chambers322,354to a pressure lower than atmospheric pressure. Any residual vapor has now been purged from loading and unloading chambers322,354and the pressure in loading and unloading chambers322,354and tubing network342may be between 0 PSIA and 14.7 PSIA (0 Torr and 760 Torr). Valve341is then closed.

With reference toFIG. 32, tubing network342and loading and unloading chambers322,354are then backfilled with vapor345of the solvent of fluid drug formation334by opening valve343to evaporator344which houses a supply of the vapor. Loading and unloading chambers322,354are saturated with vapor345of the solvent of fluid drug formation334via evaporator344such that loading and unloading chambers322,354reach solvent vapor saturation. Stated another way, loading and unloading chambers322,354are at the vapor-liquid equilibrium of the solvent of fluid drug formulation334. Valves323,355are then closed.

In an embodiment, after backfilling tubing network342and loading and unloading chambers322,354with vapor345of the solvent of fluid drug formation334via evaporator344, loading and unloading chambers322,354may be backfilled with nitrogen gas346by opening valves351,347for stabilization of loading and unloading chambers322,354. Adding nitrogen gas346to loading and unloading chambers322,354enhances stability and prevents temperature fluctuations within the chamber and system when the loading and unloading chambers are saturated with a vapor of the solvent of fluid drug formulation334as described above with respect toFIG. 32. Absolute pressure in loading and unloading chambers322,354is still less than atmospheric pressure at this point in the method. After backfilling loading and unloading chambers322,354with nitrogen gas346, a dwell or wait time occurs to ensure temperature stabilization of loading and unloading chambers322,354. The dwell time may vary between 0.25-15 minutes. Vapor345still fills loading and unloading chambers322,354, which are sealed off from tubing network342as well as filling chamber324. Gas or residual vapor is purged from tubing network342via vacuum pump340by opening valve341.

Turning now toFIG. 34, with loading and unloading chambers322,354and filling chamber324filled with vapor345, stir cover350is transferred into filling chamber324. More particularly, first valve gate326is opened such that filling chamber324and loading chamber322are in fluid communication. Stir cover350is moved or transferred from loading chamber322into filling chamber324while first valve gate326is opened. Stir cover350is positioned over reservoir332, which includes wicking means330and fluid drug formulation334. First valve gate326is then closed such that filling chamber324and loading chamber322are no longer in fluid communication. With stir cover350positioned or disposed over reservoir332, the stir cycle commences and mixes or agitates fluid drug formation334and wicking means330within reservoir332as described above. In another embodiment hereof, first valve gate326may remain open during the stir cycle.

With all chambers (loading chamber322, filling chamber324, and unloading chamber354) filled with vapor345, stir cover350is transferred out of filling chamber324after the stir cycle is complete as shown inFIG. 35. More particularly, stir cover350is moved or transferred from filling chamber324into loading chamber322while first valve gate326is opened. First valve gate326is then closed such that filling chamber324and loading chamber322are no longer in fluid communication. Vapor345is then purged from loading chamber322via vent359and loading chamber322returns to atmospheric pressure. In another embodiment hereof, venting may occur via opening valve351to backfill loading chamber322with nitrogen from the supply of nitrogen gas346. Stir cover350may then be removed from unloading chamber354via sealable door353.

FIG. 36illustrates the fifth step of the alternative method. The fifth step of the alternative method of use is similar to method step474described above, and includes transferring the first batch of stents100from unloading chamber354into filling chamber324. For sake of completeness a brief description of method step474is repeated herein. During this step, valves323,325,355are closed such that loading, filling, and unloading chambers322,324,354, respectively, are not in fluid communication with tubing network342. Vapor345still fills filling chamber324and unloading chamber354as shown inFIG. 36. Second valve gate356is opened such that filling chamber324and unloading chamber354are in fluid communication. The first batch of stents100are moved or transferred from unloading chamber354into filling chamber324while second valve gate356is opened.

FIGS. 37-39illustrates the sixth step of the alternative method. The sixth step of the alternative method of use is similar to method step476described above, and includes filling the first batch of stents100via capillary action. However, unlike the previous method, a second batch of stents100Nare positioned or placed into loading chamber322while the first batch of stents100are being filled in order to increase efficiency of filling multiple, sequential batches of stents in a timely or effective manner. More particularly, with second valve gate356still open or closed, the first batch of stents100are filled via capillary action while a second batch of stents100Nare positioned or placed into loading chamber322as shown inFIG. 37. As described in embodiments above, after the first batch of stents100are positioned or placed into contact with wicking means330, the first batch of stents100are allowed or permitted to fill via capillary action. During the filling step, filling chamber324and unloading chamber354remain in fluid communication and are maintained at or near the vapor-liquid equilibrium of the solvent of fluid drug formulation334such that evaporation does not precipitate therapeutic substance or drug112as fluid drug formulation334fills lumen103of hollow wire102of the first batch of stents100.

While filling the first batch of stents100, loading chamber322which holds the second batch of stents100Nis caused to reach the vapor-liquid equilibrium of the solvent of fluid drug formulation334inFIG. 38. Valves323,341are opened such that loading chamber322is in fluid communication with tubing network342, but valves325,355remain closed such that filling chamber324and unloading chamber354, respectively, are not in fluid communication with tubing network342. Gas residuals are purged via vacuum pump340to a prescribed set point. Valve341is then closed. Tubing network342and loading chamber322are backfilled with vapor345of the solvent of fluid drug formation334by opening valve343to evaporator344which houses a supply of the vapor. Loading chamber322is saturated with vapor345of the solvent of fluid drug formation334via evaporator344such that loading chamber322reaches solvent vapor saturation. Stated another way, loading chamber322is at the vapor-liquid equilibrium of the solvent of fluid drug formulation334. After loading chamber322is sufficiently saturated, valves323,343are closed such that loading chamber322and evaporator344, respectively, are no longer in fluid communication with tubing network342. In an embodiment, after backfilling loading chamber322with vapor345of the solvent of fluid drug formation334via evaporator344, loading chamber322may be backfilled with nitrogen gas346by opening valves351for stabilization of loading chamber322. After backfilling loading chamber322with nitrogen gas346, a dwell or wait time occurs to ensure temperature stabilization of loading chamber322. The dwell time may vary between 0.25-15 minutes. Vapor345still fills loading chamber322which is sealed off from tubing network342, while vapor345also still fills both filling chamber324and unloading chamber354. Gas or residual vapor is purged from tubing network342via opening valve341to vacuum pump340.

FIG. 39illustrates the seventh step of the alternative method. The seventh step of the alternative method of use is similar to method step478described above, and includes transferring the first batch of stents100from filling chamber345to unloading chamber354via open second gate valve356as shown inFIG. 39. After the first batch of stents100is positioned within unloading chamber354, second gate valve356is then closed such that filling chamber324and unloading chamber354are no longer in fluid communication.

FIG. 40illustrates the eighth step of the alternative method. The eighth step of the alternative method of use is similar to method step480described above, and includes reducing a solvent vapor pressure in unloading chamber354to evaporate the solvent of fluid drug formulation334after the first batch of stents100has been transferred into unloading chamber354. For sake of completeness a brief description of method step480is repeated herein. Vapor345still fills filling chamber324and loading chamber322which holds the second batch of stents100Nas shown inFIG. 40. Vapor345is purged from unloading chamber354via vents358and unloading chamber354returns to atmospheric pressure. Stated another way, unloading chamber354is vented via vent358to both reduce its solvent vapor pressure and return the overall pressure back to ambient conditions. In another embodiment hereof, venting may occur via opening valve347to backfill unloading chamber354with nitrogen from the supply of nitrogen gas346. As the solvent vapor pressure is reduced in unloading chamber354, evaporation is initiated and the solvent of drug fluid formulation334is removed, thereby precipitating its constituents. After the solvent or dispersion medium is removed from each lumen103, therapeutic substance or drug112fills at least a portion of each lumen103of each stent in the first batch of stents100. The filled first batch of stents100may then be removed from unloading chamber354of apparatus320(as shown inFIG. 40) and the second batch of stents100Nmay be immediately transferred into filling chamber324for filling thereof.

In any embodiment hereof, a cleaning step may be utilized after the stent is filled via capillary action to remove excess solid form of the fluid drug formulation or cast film from the exterior surfaces of stents100. In an embodiment hereof, the additional cleaning step is performed after the stent has been filled with the fluid drug formulation and after the therapeutic drug is precipitated within the lumen of the hollow wire (i.e., after the drying/evaporation step of the process). U.S. Patent Application Publication 2012/0284310 entitled “Apparatus and Methods for Filling a Drug Eluting Medical Device” to Peterson et al., herein incorporated by reference in its entirety, describes several stent cleaning methods that may be utilized herewith. In another embodiment, the additional cleaning step may occur between the filling and drying/evaporation steps of the process and stents100may remain in the filling chamber during the cleaning step as described in more detail in U.S. Patent Application Publication 2012/0284310 to Peterson et al., previously incorporated by reference herein. In addition or as an alternative to a cleaning step, at least a portion of the exterior surface of hollow wire102of stent100may be masked during the filling procedure to prevent the submersed exterior surface from being exposed to the fluid drug formulation. In one embodiment, a monolayer or coating may be applied over at least a portion of stent100to mask or cover the exterior surfaces of hollow wire102of stent100that are to be exposed to a fluid drug formulation, while leaving the drug delivery side ports or openings104of stent100open so that the fluid drug formulation can fill the lumen of the hollow wire. The monolayer or coating having any excess fluid drug formulation adhered thereto may be removed after the filling process is complete. In an embodiment in which the fluid drug formulation is hydrophilic, the coating is preferably hydrophobic. As the lumenal space of the wire fills, the hydrophilic fluid drug formulation does not stick to the coating or any exposed exterior surfaces of the hollow wire of the stent due to the hydrophobic property of the coating. In another embodiment, as opposed to a coating, a sleeve that slides over hollow wire102may be utilized to mask or cover the exterior surfaces of hollow wire102of stent100that are to be exposed to a fluid drug formulation. Any combination of the aforementioned cleaning and/or masking methods can be employed to clean the stent. The selection of cleaning and/or masking method(s) may be governed by factors such as the drug formulation components and the degree of drug residue after the filling process via capillary action is complete.

Other Applications of Capillary Filling Process

In addition to filling stents formed via a hollow wire for drug delivery, embodiments of the capillary action filling process described above may be applied to other structures. For example, structures having a lumen of a sufficiently small size, such as lumen103of hollow wire102of stent100, can be impregnated with any fluid formulation using a capillary action filling process described above. Since only one side opening104of the stent is required to be exposed to the fluid formulation, fill weight variation and waste is reduced. In addition to structures having a sufficiently small lumen, structures formed from a porous material, or having a porous material on at least an exterior surface thereof, may be impregnated with any fluid formulation using a capillary action filling process described above. For example, an implantable polyurethane sponge may be impregnated with a fluid drug formulation similar to those described herein for in situ delivery. Other examples include impregnating a wound dressing with antibiotic, impregnating a porous bioabsorbable disc that will be implanted subcutaneously with a fluid drug formulation that suppresses appetite, impregnating a porous bioabsorbable sphere that is to be implanted into a muscle with a fluid drug formulation that encourages muscle growth after atrophy, and impregnating a bioabsorbable stent formed from a porous material with a fluid drug formulation similar to those described herein. Various deformable porous materials that may be impregnated with any fluid formulation using a capillary action filling process described above include porous polymers and hydrogels such as polyurethanes, PEG, PLGA, PLA, PGA, and PE, cotton, silk, TELFA, and cellulose.

Rigid materials, such as metals, ceramics, and rigid polymers, are often utilized as implants and it may be desired to impregnate a rigid material with a fluid drug formulation. Exemplary rigid materials include aluminum, stainless steel, silver, gold, molybdenum, tungsten, tantalum, bronze, ceramics such as borosilicate, hydroxyapatitie, silicon nitride, zirconium dioxide, and polymers such as PET, Polypropylene, HDPE, PVC, polyamides, and fluoropolymers. In order to become porous, rigid materials may undergo processing steps, such as dry etch, a wet or acid etch, application of sintered metal or ceramic powder, application of a metal mesh, or injection of inert gas during liquid metal or polymer solidification. After becoming porous, the rigid materials may then be impregnated with any fluid formulation using a capillary action filling process described above. For example, a hip implant formed from a rigid porous material may be impregnated with a steroid to reduce inflammation after implantation or a spinal screw/plate/rod may be impregnated with an API that encourages bone growth and/or healing.

While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of illustration and example only, and not limitation. It will be apparent to persons skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments. For example,FIGS. 30-34illustrate positioning stents100in unloading chamber354and stir cover350in loading chamber322at the same time, and then bringing the loading and unloading chambers to vapor-liquid equilibrium simultaneously. However, in another embodiment hereof (not shown), stir cover350may be positioned in loading chamber322without positioning of stents100in unloading chamber354and only loading chamber322undergoes the vacuum and vapor backfill steps described above with respect toFIGS. 31 and 32. Stents100may then be positioned in unloading chamber354at a later time (such as but not limited to after the stir cover is transferred to filling chamber324or after the stir cycle) and unloading chamber354may undergo vacuum and backfill steps separately to reach the vapor-liquid equilibrium of the solvent of fluid drug formulation334. It will also be understood that each feature of each embodiment discussed herein, and of each reference cited herein, can be used in combination with the features of any other embodiment. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the detailed description. All patents and publications discussed herein are incorporated by reference herein in their entirety.