Patent Publication Number: US-2006020240-A1

Title: Method of loading drug delivery pack

Description:
REFERENCE TO RELATED APPLICATION  
      This application is a continuation of co-pending U.S. application Ser. No. 10/339,715, filed Jan. 8, 2003, which is a divisional of U.S. application Ser. No. 09/559,692, filed Apr. 27, 2000 (now U.S. Pat. No. 6,527,738), and claims the priority benefit under 35 U.S.C. § 119(e) from provisional Application No. 60/132,088 of Jones et al., filed Apr. 30, 1999. 
    
    
     BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      The present invention relates generally to drug delivery devices, and more particularly to devices for storing, transporting and dissolving dry reagents.  
      2. Description of the Related Art  
      Medical treatments often involve solutions or suspensions of drugs or other reagents. Transporting and storing such solutions can be extremely expensive. Accordingly, it is advantageous to transport and store drugs or other reagents in a dry powdered or lyophilized form, reducing the bulk and weight, and to mix the reagents with a fluid just prior to administration.  
      U.S. Pat. No. 5,259,954 to Taylor, issued Nov. 9, 1993 (hereinafter “the &#39;954 patent”) and U.S. Pat. No. 5,725,777, issued Mar. 10, 1998 (hereinafter “the &#39;777 patent”) disclose a drug pack or “reagent module” suitable for storing dry reagents and for preparing solutions for administration by passing a fluid through the pack. Specifically, FIGS. 9-10 and 12-15 of the &#39;777 patent illustrate two embodiments in which a porous compression element constantly exerts an inward force on the dry reagent bed, keeping the reagents compacted even as the bed is eroded by passing fluid through the porous compression element and through the bed. This arrangement advantageously enables efficient, uniform dissolution of the reagent bed.  
      While the reagent modules of the &#39;954 and &#39;777 patents operate well in storing and dissolving reagent beds efficiently, there remains room for improvement. Specifically, automated assembly of the disclosed compression elements is difficult, tending to result in mis-orientation and tangling. Furthermore, the foam compression elements disclosed in the &#39;954 patent are difficult to disinfect and tend to retain any contaminants they are exposed to prior to assembly and during operation.  
      Accordingly, a need exists for improved drug delivery packs of the type disclosed in the &#39;954 and &#39;777 patents.  
     SUMMARY OF THE INVENTION  
      In satisfaction of this need, the present application provides a number of improvements over prior drug delivery packs. As the skilled artisan will readily appreciate from the disclosure herein, the improvements described herein can be employed in conjunction or independently of one another.  
      In accordance with one aspect of the present invention, an apparatus for delivering reagent in fluid form is provided. The apparatus includes a housing defining a fluid inlet and a fluid outlet, the housing including a slide mechanism movable between a first position and a second position. At least one dry reagent bed is housed within the housing. A compression component is positioned within the housing to compact the reagent bed in at least the second position. The slide mechanism engages and compresses the compression component in the second position, as compared to the first position.  
      In accordance with another aspect of the present invention, a method is provided for preparing a reagent delivery device for delivery of fluid form of reagent from dry form of the reagent. The method includes providing a reagent bed and a compression component enclosed within a housing. Subsequently the compression component is compacted to exert pressure on the reagent bed.  
      In accordance with another aspect of the present invention, a device is provided for delivering fluid form of a dry reagent housed therein. The device includes a housing that defines a fluid inlet and a fluid outlet. A dry reagent bed is housed within the housing and a compression component is positioned within the housing to exert pressure upon the dry reagent bed. The compression component includes a top end, a bottom end, and at least two spring elements that extend parallel along a spring axis between the top end and the bottom end.  
      In accordance with another aspect of the present invention, a spring is provided for reciprocation within a bore. The spring includes a top platform and a bottom platform, each with perforations for fluid flow therethrough. The spring additionally includes at least one spring column that extends between the top platform and the bottom platform. The spring column comprising a series of alternating loops along a spring axis.  
      In accordance with another aspect of the present invention, a reagent delivery device is provided. The device includes a dry reagent bed and a housing enclosing the dry reagent bed. The housing has a fluid inlet and a fluid outlet. A ratcheting mechanism allows at least two housing components to slide with respect to one another between a first locking position and a second locking position. In the first locking position, the housing defines a first fluid flow path between the inlet and the outlet, which path excludes the reagent bed. In the second locking position, the housing defines a second fluid flow path between the inlet and the outlet, which path includes the reagent bed.  
      In accordance with another aspect of the present invention, a method is provided for delivering a fluid form of a reagent from a dry form of the reagent within a housing. The method includes initially flowing a fluid through the housing but outside the reagent bed. A flow path is then altered to direct the fluid through the reagent bed.  
      In accordance with another aspect of the present invention, a method is provided for forming a device for delivering a fluid form of a reagent from a dried form of the reagent. The method includes lyophilizing an initial fluid form of the reagent within the device. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      These and other aspects of the invention will be apparent to the skilled artisan from the detailed description of the preferred embodiments below and the appended drawings, which are meant to illustrate and not to limit the invention, and wherein:  
       FIG. 1A  is a side elevational view of a spring, constructed in accordance with a first embodiment of the invention;  
       FIG. 1B  is a front elevational view of the spring in  FIG. 1A ;  
       FIG. 1C  is a front elevational view of the spring of  FIG. 1B  in a fully compressed position;  
       FIG. 1D  is a top plan view of the spring of  FIG. 1A ;  
       FIG. 2A  is a partial elevational cross-section of the spring of  FIG. 1  shown in relation to walls of a drug delivery pack housing;  
       FIG. 2B  is a cross sectional view taken along lines  2 B- 2 B of  FIG. 2A ;  
       FIG. 3A  is a top down view of a spring shown in relation to a drug delivery pack housing, constructed in accordance with another embodiment of the invention;  
       FIG. 3B  is a partial, elevational cross-section taken along lines  3 B- 3 B of  FIG. 3A ;  
       FIG. 4  illustrates a drug delivery pack incorporating the spring of  FIG. 1  and a plunger mechanism, constructed in accordance with another embodiment of the invention;  
       FIGS. 5A  to  5 C illustrate the drug delivery pack of  FIG. 4  in unassembled ( FIG. 5A ), assembled ( FIG. 5B ), and cocked ( FIG. 5C ) conditions;  
       FIG. 6  illustrates the cocked drug delivery pack of  FIG. 5C  in connection with a water purification pack;  
       FIG. 7  is a detailed view of the assembled drug delivery pack of  FIG. 5B ;  
       FIG. 8A  is a partial, elevational cross-section of a water purification pack configured for irreversible locking with a preferred drug delivery pack;  
       FIG. 8B  is a bottom plan view showing an outlet portion of the water purification pack of  FIG. 8A ;  
       FIG. 8C  is a partial, elevational cross-section of a drug delivery pack configured for mating with the water purification pack of  FIG. 8A ;  
       FIG. 8D  is a top plan view showing an inlet portion of the drug delivery pack of  FIG. 8C ;  
       FIG. 9  illustrates the drug delivery pack and water purification pack of  FIGS. 8A  to  8 D in an irreversibly engaged condition;  
       FIG. 10  is a cross-sectional view of a drug delivery pack constructed in accordance with another embodiment of the invention;  
       FIG. 11  is a cross-section of a drug capsule portion of the drug delivery pack of  FIG. 10 ;  
       FIG. 12  is an end view of a ribbed outer wall of the capsule in  FIG. 11 ;  
       FIG. 13A  is schematic cross-section, similar to that of  FIG. 10 , illustrating water flow within the drug delivery pack but outside the drug capsule during a priming stage;  
       FIG. 13B  illustrate the drug deliver pack of  FIG. 13A  after priming and during compression to cock the pack and initiate drug delivery;  
       FIG. 13C  illustrates the drug delivery pack of  FIG. 13B  after the reagent bed has been fully discharged; and  
       FIG. 14  is a flow chart illustrating a process of lyophilizing reagents within the drug delivery packs of the preferred embodiments. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
      As noted in the Background section above, U.S. Pat. No. 5,259,954, issued Nov. 9, 1993 (hereinafter “the &#39;954 patent”) and U.S. Pat. No. 5,725,777, issued Mar. 10, 1998 (hereinafter “the &#39;777 patent”), each issued to Taylor, disclose drug packs for reagent modules suitable for storing dry reagents. Flowing a diluent fluid through the packs forms medical solutions. The disclosures of the &#39;954 and the &#39;777 patent are incorporated herein by reference. While the features and aspects of the invention described herein are particularly suitable for utilization in drug packs of the type disclosed in the &#39;954 and &#39;777 patents, the skilled artisan will readily find applications for many of the principles disclosed herein in other contexts.  
      Elastomeric Spring  
       FIGS. 1A  to  1 D illustrate an elastomeric spring  5 , constructed in accordance with a preferred embodiment of the invention. While described in the context of a particular drug delivery pack, the skilled artisan will find application for the disclosed spring design in a number of other contexts. The spring is particularly advantageous for applications where it is desirable to have bio-compatibility, a constant spring rate through a range of compression states and even pressure across the width of the spring.  
      As shown in  FIGS. 1A  to  1 D, the spring  5  includes a top end  10 , a bottom end  20 , and at least one, preferably a plurality of adjacent and generally parallel spring columns  30 ,  40  (two in the illustrated embodiment) extending between the ends  10 ,  20 . Each of the spring columns  30 ,  40  comprises a series of undulating folds or loops  35 ,  45  along the spring axis. Each column  30 ,  40  has the shape that would be obtained if a planar strip of material were folded in alternating directions, in zigzag or accordion fashion, down the length of the strip. The loops  30 ,  40  can thus be considered the peaks and troughs of a waveform. In one embodiment, the spring columns  30 ,  40  can be joined at a bridge  50  between adjacent inner loops  35 ,  45 , to maintain even pressure on both sides of the spring  5 .  
      The spring  5  has a fairly uniform spring rate at various degrees of compression, due to the illustrated cylindrical configuration of the loops  35 ,  45  and even distribution of these loops along the length of the columns  30 ,  40 . By modifying the loop configurations, various other spring rates can be achieved. For example, the loops (or peaks/troughs of a waveform) can have a variety of geometries. The waveforms preferably have curved peaks and troughs. Most preferably, the loops  35 ,  45  have the illustrated cylindrical configuration for consistent spring rate at various compression levels, though other configurations (e.g., elliptical, parabolic, hyperbolic or any other smooth curvatures) will demonstrate good results as well. In still other arrangements, the spring columns  30 ,  40  can have a sawtooth waveform (alternating folds having sharp peaks and troughs), which can advantageously compress further, enabling a smaller overall size of the drug delivery pack. Such an arrangement, on the other hand, would not distribute stress as evenly as the illustrated loops, and would rather tend to focus stress at sharp corners of the folds. The spring rates can also be increased significantly by connecting the inner loops of the right and left columns (as shown at bridge  50 ), by utilizing denser material or by utilizing thicker columns.  
      With reference to  FIGS. 1B and 1C , during compression, the spring  5  expands radially until the inner loops  45  of the right spring  40  and the loops  35  of the left spring  30  contact one another. The outer loops  35 ,  45  expand to have about the same width of, or slightly larger than, the ends  10 ,  20 . Vertically adjacent loops contact one another in the fully compressed (solid height) condition, leaving the volume of the loops themselves to absorb any excess external pressure. A depth  60  ( FIG. 1A ) of the columns  30 ,  40 , in a dimension orthogonal to each of the width and height, is significantly less than the maximum width of the ends  10 ,  20 .  
      Referring to  FIGS. 1B and 1D , each end  10 ,  20  includes a platform  62  preferably having a plurality of perforations  64  therein for the illustrated embodiment. Additionally, the platform includes a plurality of protrusions in the form of ribs  70  that are advantageous for the illustrated drug delivery pack discussed below. Each of the top end  10  and bottom end  20  can have identical construction.  
      For the illustrated application within a drug delivery pack, the spring  5  is preferably molded from polyethylene, polypropylene, Delrin™ and other plastic resins that are bio-compatible with sensitive drugs, reagents and other powders used in drug delivery applications. Preferably, the material is resilient and elastic to serve as the compression element of a drug delivery pack. The spring  5  is designed so that it can be readily injection molded, desirably with separate mold sections in the radial and axial planes of the spring, allowing extraction of the spring without damage to either the looped columns or the ribbed ends. Thus, the two sides and the two ends are desirably integrally molded together. Unlike a molded helical spring coil, no unwinding or special core pulls are required. The skilled artisan will readily appreciate numerous other materials and methods of construction (including compression molding, heat shaping, etc.), depending upon the desired characteristics of the spring.  
      Advantageously, the use of the alternating loop construction of the spring column(s)  40 ,  50  facilitates molding, as compared to coiled springs. Furthermore, the use of two (or more) columns, facilitates even pressure across the ends  10 ,  20 , avoiding tipping of the ends  10 ,  20  relative the spring axis. In the illustrated context, this feature facilitates even pressure across a reagent bed, and thus even dissolution thereof.  
      With reference to  FIG. 2A , the illustrated spring  5  is particularly constructed for fitting within a housing. A sidewall  80  of such a housing, preferably cylindrical, is shown in the drawings. The maximum width of the spring  5  is designed so that it matches the inner width of a housing within which the spring  5  is designed to be fitted. In particular, as best seen from  FIG. 2A , the periphery of each end  10 ,  20  is designed to be equal to or slightly smaller than the housing sidewall  80 , while the width of the fully compressed spring  5  ( FIG. 1C ) is equal to or slightly larger that of the ends  10 ,  20 . Thus, the spring  5  self-centers within the housing defined by the sidewall  80 .  
      The spring  5  is also designed to allow fluid flow through the housing in which it fits, despite the close fit of the spring  5  with the housing sidewall  80 . In particular, the ribs  70  ensure that fluid flow is not blocked off when the spring ends  10 ,  20  mate with the corresponding ends (not shown) of the housing, and allow fluid flow distribution across the full inner width of the housing. The perforations  64  allow fluid flow into the housing through the top end  10  and out of the housing through the bottom end  20 . As best seen from  FIG. 2B , because the depth  60  of the columns  30 ,  40  is significantly less than the width of the housing, fluid readily flows in the housing around the spring  5 , both when the spring  5  is at its free length as well as in the fully compressed (solid height) condition. Preferably, the depth  60  of the spring represents between about 10% and 90% of the housing diameter, and is about half the housing diameter in the illustrated embodiment.  
      With reference to  FIGS. 3A and 3B , a spring  5   a  is shown in accordance with another embodiment of the invention, wherein like parts are referenced by like numerals, with the addition of the prefix “a”. In accordance with the illustrated embodiment, the ends  10   a ,  20   a  (top end  10   a  shown) of the spring  5   a  includes a peripheral collar  90   a  that extends axially from the edge of the platform  62   a . For the illustrated circular end  10   a , the collar  90   a  represents a short cylinder having an outer diameter approximately equal the inner diameter of the housing sidewall  80 . The collar  90   a  further minimizes the potential for the spring ends  10   a ,  20   a  to tip during usage, since it tends to keep the top end  10   a  and the bottom end  20   a  level. As will be better understood in light of the discussion below regarding operation of the preferred drug reagent packs, the collar aids in keeping constant pressure across a reagent bed.  
      The skilled artisan will recognize other features and advantages of the illustrated spring for delivery pack or other applications, in view of the drawings and the description herein.  
      Plunger Design  
      The drug delivery packs or “reagent modules” of the &#39;954 and &#39;777 patents have numerous advantages, including the ability to store and easily transport drugs in a stable, dry form. Unfortunately, storage over extended periods of time can result in a loss of elasticity, reducing the effectiveness of the compression function. Many plastics, in particular, tend to set in the stored position over time due to a natural phenomenon with plastic resins known as “creep.” 
      Referring to  FIG. 4 , in order to better maintain elasticity and thus compression force of the spring over the storage life of a product, the present invention provides a drug delivery pack  100  having a sliding mechanism. The sliding mechanism is such that, at different positions, the compression component or spring  5  is compressed by different amounts from its free length. The slide mechanism is operated after assembly, such that the reagent and compression component is already enclosed by the housing. Accordingly, the drug delivery pack  100  can be packaged and shipped prior to compression of the spring  5  for operation. Desirably, the sliding mechanism ratchets or locks at at least a first position and at a second position.  
      In the illustrated drug delivery pack  100 , the sliding mechanism is formed by a lower or inner housing portion  102  that fits coaxially with an upper or outer housing portion  104 , the two portions being slidable relative to one another. The lower housing portion  102  is also referred to herein as a “spring housing” or “reagent housing” while the upper housing portion  104  is also referred to as a “top plunger.” 
      The lower portion  102  includes the housing sidewall  80  (preferably cylindrical) and houses at least one reagent bed  106 , preferably comprising a dry form of drug, buffering salt or other desirable constituent of a fluid to be formed. The reagent bed  106  is disposed above a housing floor  108  in which a bottom or outlet port  110  is formed, and the bed  106  is sandwiched between porous frits  120 . Advantageously, the frits have a porosity that allows fluid carrying reagent (e.g., in solution form) to pass therethrough, but does not allow the dry particulates of the reagent bed  106  to pass therethrough. The lower portion  102  also houses a compression component arranged to exert pressure upon the reagent bed  106 , desirably in the form of the novel spring  5  described hereinabove. While the illustrated embodiment includes one reagent bed, it will be understood that a plurality of such reagent beds can be provided within the same housing such that diluent flows sequentially therethrough. Such an arrangement is particularly advantageous for separately storing and reconstituting dry forms of incompatible reagents. More than one compression component can also be provided for multiple reagent beds.  
      The upper portion  104  includes an inner plunger  130 , shown as a cylindrical wall or collar, and an outer sidewall  140  (preferably cylindrical) sized fit over the sidewall  80  of the lower portion. The plunger  130  depends from a housing ceiling  145  in which a top or inlet port  150  is formed.  
      The reagent pack  100  also includes features that facilitate temporarily locking the lower portion  102  to the upper portion  104  in at least two different positions representing different relative compressions of the spring  5 . In the illustrated embodiment, the upper portion  104  includes, at the lower end of the cylindrical sidewall  140 , an annular groove  152  defined by inwardly protruding ridges  154 , best seen from the enlarged view of  FIG. 7 . The lower portion  102  includes, on the outer surface of the cylindrical sidewall  80 , two vertically spaced rings  170  and  180  configured to mate with the groove  152  of the upper portion. The lower portion  102  also includes a small, flexible sealing lip  160  extending outwardly from the top of the cylindrical sidewall  80 .  
       FIGS. 5A  to  5 C show the various stages of assembling and cocking the drug delivery pack  100 .  
      Referring initially to  FIG. 5A , prior to assembly, the plunger top  104  and reagent housing  102  of the unassembled drug delivery pack  100   a  are separate as shown. The reagent housing  102  is assembled by first placing the bottom frit  120  into the bottom. Then a suitable amount of reagent is added to form the reagent bed  106  and the top frit  120  is placed over the bed  106  to prevent escape of particulates from the bed  106 . In accordance with one aspect of the invention, reagent can be loaded into the housing in liquid form, followed by in situ lyophilization. The spring  5  is inserted into the reagent housing  102  to rest on top of the top frit  120 .  
       FIG. 5B  shows the assembled drug delivery pack  100   b  after the plunger top  104  has been fitted over the reagent housing  102 . As the reagent housing  102  is inserted into the plunger top  104 , the sealing lip  160  of the reagent housing  102  contacts the bore of the plunger top  104 , which has a smaller diameter than the sealing lip  160  diameter, causing the sealing lip  160  to deflect and seal against the sidewall  140  of the plunger top  104 . The pack  100   b  is compressed such as by hand until the upper ring  170  of the reagent housing  102  snaps into the groove  152  of the plunger top  104 . At the same time, the plunger  130  of the plunger top contacts the spring  5  and slightly compresses the spring  5 .  
       FIG. 7  best shows the temporary interlocking of the reagent housing  102  with the plunger top  104  in the assembled condition. As shown, the groove  152  engages with the upper annular ring  170 , at least with enough friction to oppose any expansive tendencies of the slightly compressed spring  5 . The spring  5  is compressed by a distance  185 , desirably just sufficient to prevent movement of parts within the assembled drug delivery pack  100   b  during shipping.  
      Referring again to  FIG. 5B , the drug delivery pack is shipped and stored in this assembled configuration  100   b  until used by the consumer. In the assembled condition, the housing encloses the spring  5  and the reagent bed  106 , though the enclosure is not necessarily sealed airtight. Preferably, however, the outlet port  110  and inlet port  150  are sealed, such as with caps (not shown) over conventional Luer connectors and/or foil seals. Preferably, the seals are applied prior to assembly. After assembly, the assembled pack  100   b  is packaged and shipped to the point of use.  
       FIG. 5C  shows the cocked or loaded drug delivery pack  100   c . Upon removal from the packaging and just prior to usage, the plunger top  104  is further compressed over the reagent housing  102 . Sufficient force is applied to allow the upper ring  170  to unsnap from the groove  152 . The plunger top  104  is pushed downward until the lower annular ring  180  of the reagent housing  102  snaps into the groove  152 . The plunger  130  of the plunger top  104  further compresses the spring  5 , such that the reagent bed  106  is under spring load. Advantageously, the distance between the upper ring  170  and the lower ring  180  is equal to or greater than the height of the reagent bed  106 . Thus, the spring  5  can expand as reagent dissolves until the two fits  120  meet (see  FIG. 13C ).  
      In the illustrated embodiment, cocking the pack  100   c  involves sliding portions  102 ,  104  relative to one another in a manner that reduces the volume enclosed by the housing. The skilled artisan will appreciate that, in other arrangements, a separate sliding mechanism or plunger can be provided to load the compression component without changing the volume enclosed by the housing.  
      The illustrated drug delivery device allows controlled compression of a powder or drug during dissolution, as disclosed in the &#39;954 and &#39;777 patents, while avoiding the creep problem mentioned above. The illustrated device is particularly advantageous with a plastic spring  5 . The spring  5  is kept in a relatively relaxed assembled condition  100   b  (not under load) during normal shelf life of the product, as shown in  FIG. 5B  storage and handling conditions that can last over a year, depending upon the shelf life of the particular drug or other powdered reagent. Once ready for usage, the spring  5  is compressed in a cocked or loaded condition  100   c , as shown in  FIG. 5C , and used within a short period of time, thus avoiding creep or spring set usually associated with a compressed spring over time.  
      With reference to  FIG. 6 , a diluent source  200  is shown attached to the upstream or inlet port  150  of the assembled and cocked drug delivery pack  100 . The diluent source  200  can comprise any suitable reservoir of sterile diluent, such as a bag of sterile saline. Preferably, the diluent source  200  comprises a water purification pack that purifies non-sterile water as it flows therethrough, such as that disclosed in the &#39;954 and &#39;777 patents. More preferably, the diluent source comprises a water purification pack as disclosed in U.S. patent application Ser. No. 09/364,631, filed Jul. 30, 1999 and entitled IMPROVED WATER PURIFICATION PACK, the disclosure of which is expressly incorporated herein by reference. The downstream end of the diluent source  200  can be connected in any suitable fashion, such as by standard Luer lock connections, as shown in  FIG. 6 . In particular, the drug delivery device inlet port  150  includes a standard male Luer lock connector, and a diluent source outlet port  210  includes a standard female Luer lock connector.  
      Referring to  FIGS. 8A  to  8 D, in one embodiment, the connection between the diluent source  200  and drug delivery pack  100  is irreversible. As used herein, “irreversible” connection means that if the diluent source  200  and drug delivery pack  100  were separated, the features allowing connection would be so damaged as to render re-use impractical. Accordingly, the irreversible connection is designed to permit only one-time use of the drug delivery pack, such that partial doses or refilled reagents could not be delivered after the sterility of the device has been compromised. As will be appreciated by the skilled artisan, irreversible connection of any device, tube, etc., to either the inlet or outlet sides of the drug delivery device, will accomplish the same goal.  
      In the illustrated embodiment, the connection includes the standard Luer lock connection between the inlet port  150  of the drug delivery pack  100  and the outlet port  210  of the diluent source  200 , as discussed with respect to  FIG. 6 . Additionally, however, the drug delivery pack  100  has a collar  220  coaxially surrounding the inlet port  150 , having vertical ratchet teeth  225  on an inside surface thereof. The diluent source  200  includes a mating collar  230  configured to fit within the collar of the drug deliver pack  100 . The mating collar  230  includes mating ratchet teeth  235 .  
      Referring to  FIG. 9 , when the devices  100 ,  200  are fitted together and twisted to engage the Luer lock components  150 ,  210 , the ratchet teeth  225 ,  235  interact to permit rotation that engages the Luer lock components but do not allow rotation to disengage the Luer lock connectors. Once engaged, the drug delivery pack cannot be readily removed from the diluent source  200  without visible or functional damage to the connectors. Accordingly, the drug delivery device  100  is unlikely to be reused accidentally or even intentionally.  
      By-Pass Mechanism  
      FIGS.  10  to  14 C illustrate another improvement over the drug delivery devices of the &#39;954 and &#39;777 patents. In particular, mechanisms and methods are provided herein for establishing an initial flow of diluent that by-passes the reagent bed. The initial flow of diluent is particularly advantageous for priming the drug delivery device for establishing a consistent drip rate prior to activation of the drug delivery device, as will be understood from the disclosure herein.  
      Referring initially to  FIGS. 10-12 , a drug delivery device  250  of the illustrated embodiment comprises a housing  300  and a sealed a reagent capsule  400  surrounded or enclosed by the housing  300 . Desirably, the reagent capsule  400  includes a plurality of spacers, illustrated in the form of axially elongated ribs  310 , along the outer surface thereof. The housing  300  comprises a two-piece sliding mechanism, similar to the plunger mechanism previously described. In a first or assembled configuration, the reagent capsule is surrounded by the housing  300  but is arranged to allow diluent flow within the housing but outside the reagent capsule  400 , desirably along a flow path defined by the spacers (ribs  310 ) between the housing inner surface and reagent capsule  400 . In a second or primed configuration, the housing  300  is compacted and shifts the diluent flow path such that diluent flows exclusively through the reagent capsule  400 , eroding the reagent bed and carrying reagent with it as it flows.  
      Referring to  FIG. 10 , in the first preferred embodiment, the housing  300  comprises an upper housing portion  320  and a lower housing portion  350 . Unlike the previously described embodiment, the upper housing portion  320  fits within the lower housing portion  350 , though it will be understood that this arrangement can be readily reversed.  
      The upper housing portion  320  includes an inlet port  322  at an axial upper end. While shown in the form of a bag spike for accessing diluent from a sterile bag, it will be understood that, in other arrangements, the inlet can take the form of a standard Luer lock connector, as described for the previous embodiment. The inlet port  322  extends downstream into an inlet or plunger collar  324 , the downstream or distal end of which is sharpened into a piercing member  326 . The upper housing portion  320  also includes an axially extending outer cylindrical sidewall  335  sized to receive the maximum outer width of the reagent capsule  400 , with is defined by the ribs  310 . Though not shown, it will be understood that the sidewall  335  also includes at least two annular rings protruding from the outer surface thereof, facilitating snap-fit into a correspond groove on the inner surface of the lower housing portion  350  for an assembled configuration and a cocked configuration.  
      The lower housing portion  350  includes an outlet port  360  at an axial lower end. Downstream of the outlet is a drip chamber  370  for collecting diluent and reagent. The skilled artisan will appreciate that the drip chamber  370  allows for a metered delivery of dissolved or suspended reagent, as desired for many intravenous (IV) applications. Advantageously, the drip chamber  370  is formed of a flexible material, such as vinyl, such that the chamber can be squeezed to vent lines prior to activation of the drug delivery pack  250 . The drip chamber  370  can be separately or integrally provided. It will be understood that, in assembly prior to use, an integral drip chamber  370  would be capped to maintain sterility. The outlet port  360  extends upstream into an outlet collar  374 , the upper end of which is sharpened into a lower piercing member  376 . The outlet collar  374  is sized to be received within an outlet of the reagent capsule  400 , as described below. The outlet collar  374  is surrounded by a plurality of support columns  380 . In the illustrated embodiment, the support columns  380  comprise four arcuate posts, forming a discontinuous cylinder with openings at 90° to one another. The discontinuities serve to provide fluid flow paths during priming and to permit outward deflection during cocking, as described below. The lower housing portion  350  further includes an axially extending cylindrical sidewall  385 , sized to receive the sidewall  335  of the upper housing portion  320 . The sidewall  385  includes on an inner surface thereof a groove  387  arranged to receive the annular rings of the upper housing portion  320  in a snap-fit relation.  
      Referring to  FIG. 12 , the reagent capsule  400  comprises a cylindrical sidewall  405  with the described spacers in the form of elongated ribs  310  extending integrally outward therefrom. An upstream reagent seal  410  extends across an upstream end of the sidewall  405 . The downstream end of the reagent capsule  400  terminates in a reagent outlet collar  420 , across which a downstream seal  425  preferably extends. The reagent capsule  400  houses a reagent bed  106  sandwiched between two frits  120 , and having an adjacent compression component, preferably in the form of the polymeric spring  5 . In the illustrated embodiment, these elements can be similar to the corresponding elements of the previously described embodiment, such that like numbers refer to like parts. Desirably, the reagent bed  106  and spring  5  are loaded into the reagent capsule, the spring is slightly pre-loaded (see  FIGS. 5B and 7  and accompanying description) to prevent shifting of parts during transport, and the seals  410 ,  425  are applied prior to assembly.  
      The seals  410 ,  425  are desirably resistant to the passage of diluent. They can comprise foils or suitable hydrophobic barriers such as polymeric sheets or laminates. Exemplary hydrophobic polymers includes polypropylene, PVDF (polyvinylidene difluoride), and acrylic copolymer. These and other polymers can be treated in order to obtain specific surface characteristics that can be both hydrophobic and oleophobic (repelling liquids with low surface tensions, such as multivitamin infusions, lipids, surfactants, oils, and organic solvents). Another property of the hydrophobic barrier  410  is that it allows air to flow through it.  
      The housing  300  and reagent capsule  12  are assembled to form the assembled drug delivery pack  250  shown in  FIG. 10 . Prior to the process of  FIGS. 13A  to  13 C, the drug delivery pack  250  is assembled by inserting the reagent capsule  400  within the upper housing portion  320 , and inserting both of these units within the lower housing portion  350 . The housing portions  320 ,  350  are compacted together, with the upper portion  320  sliding within the lower portion  350  until the groove and first ring snap together. The inlet port  322  of the assembled housing  300  and the outlet port  360  (and/or the outlet of the drip chamber  370 ) are preferably provided with caps or port covers (not shown) to maintain sterility. The device can be packaged, shipped and stored in this form until ready for use.  
      With reference to  FIGS. 13A  to  13 C, the operation of the drug delivery device  250  and its by-pass mechanism is shown.  
      Initially referring to  FIG. 13A , the assembled drug delivery pack  250   a  is primed for operation by initiating diluent flow through the pack  250   a . Arrows show the direction of fluid flow in the drawings. Diluent first enters the inlet port  322  and through the cavity defined by the inlet or plunger collar  324 . In the illustrated embodiment, this involve piercing a diluent reservoir with the spike of the inlet port  322 , though the skilled artisan will readily appreciate numerous alternative diluent sources and connectors. The reagent capsule upstream seal  410  prevents diluent from entering the reagent capsule  400 . Accordingly, diluent flows along a by-pass path provided by the annular space between the housing  300  and the reagent capsule  400 . In particular, the elongated ribs  310  provide channels in the space between the reagent capsule sidewall  405  and the upper housing portion sidewall  335 . The diluent continues downstream though gaps or discontinuities among the support columns  380  that surround the outlet collar  374 , through the collar  374 , though the outlet port  360  and into the drip chamber  370 . Squeezing the drip chamber expels air from the pack  250   a  and establishes a drip rate for the device.  
      Referring to  FIG. 13B , the cocked or activated drug deliver pack  250   b  is formed by compacting the housing  300  around the reagent capsule  400 . Applying hand pressure, for example, to the top of the upper housing portion  320  and the bottom of the lower housing portion  350  closes off the by-pass flow path. In particular, the reagent capsule  400  is forced downward relative to the lower housing portion  350 , such that the reagent outlet collar  420  fits over and surrounds the outlet collar  374  of the lower housing portion  350 . The sharpened ends  376  of the outlet collar  374  pierce or rupture any downstream seal  425  ( FIG. 13A ) over the reagent outlet collar  420 , opening fluid communication between the reagent capsule  400  and the outlet port  360 . Similarly, the upper housing portion  320  is forced downward relative to the reagent capsule  400 , such that the inlet or plunger collar  324  slides within and is surrounded by the sidewall  405  of the reagent capsule  400 , cutting off fluid communication between the inlet port  322  and the by-pass flow path. The sharpened ends  326  of the plunger collar  324  pierce the upstream seal  410 , opening fluid communication between the inlet port  322  and the reagent capsule  400 . The plunger collar  324  also preferably charges the spring  5  by pushing down on the top end  10  thereof.  
      Diluent continues to flow, entering the reagent capsule  400  through the perforated top end  10  of the spring  5 , around the spring  5 , through the perforated bottom end  20  of the spring  5 , through the upstream frit  120 , the reagent bed  106  and the downstream frit  120 . As the diluent flows through the reagent bed  106 , the bed is eroded, such as by dissolution into the flowing diluent, and the reagent-carrying fluid continues past the downstream frit  120 , through the reagent outlet collar  420 , through the housing outlet  360  and into the illustrated drip chamber  370 . The skilled artisan will appreciate that, in other arrangements, the reagent-carrying fluid (e.g., solution) can be delivered directly to a collection reservoir for use as a standard medical fluid soon thereafter. As the reagent bed  106  is eroded, the compression component (spring  5 ) continues to compact the bed  106  to prevent erosion channels from forming therein. An even rate of dissolution is thus obtained until the reagent bed  106  is completely or substantially consumed.  
      Referring to  FIG. 13C , the expended or spent drug delivery pack  250   c  is shown after all of the reagent bed  106  ( FIG. 13B ) has been consumed. As shown, the spring  5  has fully expanded during the process until the upstream and downstream frits  120  that had sandwiched the reagent bed  106  meet. Desirably, the housing sidewalls  335 ,  385 ,  405  of each component are made substantially transparent, such that an operator can visualize delivery of the reagent from the bed into the flowing diluent and the completion of the process. Failure to deliver a full does would thus be easily detected.  
      Lyophilization within the Drug Delivery Pack  
       FIG. 14  illustrates a method of forming a dry reagent bed within a drug delivery device, in accordance with another embodiment of the present invention. Though the method is not exclusive to them, the above-described drug delivery packs  100 ,  250  are particularly advantageous for implementing the method. Accordingly, the method will be described with reference to drug delivery pack  100  of FIGS.  4  to  7 .  
      The preferred embodiment begins with the unassembled drug delivery pack  100   a  ( FIG. 5A ) prior to loading frits  120 , reagent and compression component (spring  5 ). As shown in  FIG. 14 , the lower or downstream frit  120  is first loaded  500  into the lower housing portion  102 . The frit  120  preferably comprises a hydrophobic material that will support a fluid thereupon, yet is permeable to air and vapors. An exemplary frit is a multilayered polypropylene laminate, having a porosity between about 1 μm and 100 μm, more preferably between about 10 μm to 50 μm. Further details on the preferred material are given below, with respect to the reagent restraints.  
      An initial liquid form of the reagent to be lyophilized is then loaded  510  into lower housing portion  102  over the lower frit  120 . Note that the initial liquid form need not have the same concentration or diluent as ultimately formed upon delivery. Rather, the initial liquid form is preferably more concentrated than that desired for delivery, and is most preferably as concentrated as possible without having the reagent fall out of solution and lower yield.  
      The remaining components of the drug delivery device are then at least partially assembled  520 . For the illustrated pack  100 , this involves inserting the upper or upstream frit  120  over the initial liquid form of the reagent, followed by the spring  5  and the upper housing portion  104 . It will be understood that some of these components can alternatively be loaded prior to loading  510  the initial liquid form of the reagent; for example, in another arrangement the compression component can be positioned downstream of the reagent bed.  
      The pack  100  is left unsealed at this point. Preferably at least one of and more preferably both of the inlet port  150  and the outlet port  110  are left uncovered at this stage of the process. Moreover, the “partially assembled” drug delivery pack  100  is preferably not closed off, unlike the pack  100   b  of  FIG. 5B . Rather, “partial assembly” in the sense of  FIG. 14  means only that the components are sufficiently assembled to bring slight pressure to bear on the initial liquid form of reagent sandwiched between the frits  120 . In the illustrated embodiment, the inner plunger  130  of the upper housing portion  104  is allowed to rest under gravitational force on the spring  5 , but the upper housing portion  104  is preferably not compacted under force enough to catch the groove  152  upon the first annular ring  170 . Accordingly, the sealing lip  160  does not quite reach the thick upper section of the upper portion sidewall  140  and therefore does not form a seal between the upper housing portion  104  and the lower housing portion  102 . While the most preferred arrangement thus leaves three potential exhaust points (the outlet  110 , the inlet  150  and the joint between the housing portions  102 ,  104 ), the skilled artisan will appreciate that, in accordance with some aspects of the invention, one exhaust point can suffice for achieving the function of the subsequent steps.  
      The initial liquid form of reagent is frozen  530  within the pack  100 . For example, the partially assembled pack  100  can be dipped into a bath of acetone chilled with dry ice. This method was applied using an acetone bath temperature of about 78° C. The skilled artisan will readily appreciate a number of other suitable methods of freezing the initial liquid form of reagent. For example, the pack can be temporarily sealed for the freezing step, enabling a wider variety of freezing methods. The ratcheting plunger design of the embodiments above is particularly well adapted for such temporary sealing.  
      Following freezing  530 , the frozen solution or suspension is subjected to vacuum  540  for sufficient time to vaporize the liquid component of the initial liquid reagent. Under laboratory conditions in a simple vacuum flask, this process consumed 12 hours. It will be understood that the process would ordinarily be conducted in batch under commercial conditions with high vacuum chambers. After the vacuum process, the dry reagent bed  106  is left within the pack  100 , preferably sandwiched between frits and having the compression component already loaded adjacent thereto.  
      Thereafter, the assembly of drug delivery device can be completed  550 . In the illustrated embodiment, this involves compacting the upper and lower housing portions  104 ,  102  and attaching port covers over the inlet port  150  and outlet port  110 , as discussed with respect to  FIG. 5B .  
      Advantageously, the in situ lyophilization process described with respect to  FIG. 14  greatly simplifies mass production of delivery devices. Rather separately lyophilizing and then loading dry reagent into individual delivery devices, loading in liquid form facilitates batch loading of the reagent. Moreover, in situ lyophilization also reduces risk of contamination of both the device and the reagent itself, as time and transportation between forming a dry reagent and loading it within a delivery device are eliminated.  
      Although the foregoing invention has been described in terms of certain preferred embodiments, other embodiments will be apparent to those of ordinary skill in the art. Additionally, other combinations, omissions, substitutions and modification will be apparent to the skilled artisan, in view of the disclosure herein. Accordingly, the present invention is not intended to be limited by the recitation of the preferred embodiments, but is instead to be defined by reference to the appended claims.