Patent Abstract:
A drug delivery system includes an automatic injector that can deliver a small, precise amount of a therapeutic agent. The automatic injector includes a chamber for containing a liquid component and a thin porous member that carries thereon and/or therein the small, precise amount of therapeutic agent. Upon activation of the automatic injector, a flow path opens from the chamber through the porous member, enabling the liquid component to rapidly mix with the therapeutic agent before being injected.

Full Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This claims the benefit of U.S. Provisional Application No. 60/928,594, filed May 9, 2007, the entire contents of which are incorporated herein by reference thereto. 
    
    
     FIELD OF THE INVENTION 
     The invention relates to drug delivery devices that deliver therapeutic agents. In particular, the invention is directed to automatic injection devices (also known as automatic injectors or auto-injectors) that can accommodate and deliver a small, precise amount of a therapeutic agent. 
     BACKGROUND OF THE INVENTION 
     An automatic injector is a device that performs intramuscular or subcutaneous administration of a therapeutic agent. An advantage of automatic injectors is that they contain a measured dose of a therapeutic agent in a sealed sterile cartridge. Automatic injectors can therefore be used in emergency situations to quickly and simply inject the therapeutic agent without having to measure dosages. Another advantage of automatic injectors is that the administration of the therapeutic agent is accomplished without the user initially seeing the hypodermic needle through which the therapeutic agent is delivered. Still another advantage is that the user does not have to manually force the needle into the patient. This is particularly advantageous when the therapeutic agent is being self-administered. 
     In some automatic injectors, the therapeutic agent is stored as a liquid solution. However, the long-term storage of a therapeutic agent in liquid term is problematic. For instance, some therapeutic agents in liquid form are not stable and thus have a shorter shelf-life than their solid counterparts. To address this concern, automatic injectors have been developed that store the therapeutic agent in solid form and, immediately prior to injection, mix the solid therapeutic agent with a liquid injection solution also stored in the injector. Such devices are generally referred to as wet/dry injectors. An example of such an injector is found in U.S. Reissue Pat. No. RE 35,986, entitled “Multiple Chamber Automatic Injector,” the disclosure of which is incorporated herein by reference. These injectors require the user to manually rupture a sealing member between the solid and liquid components and then manually shake the injector body to expedite dissolution of the solid component prior to injection. Unfortunately, steps such as manually shaking the injector increase the time needed to administer a dose of the therapeutic agent, which is undesirable in many emergency medical situations where rapid delivery of the therapeutic agent is needed (e.g., in nerve gas and chemical agent poisoning). 
     Additionally, many of the wet/dry devices available are not capable of storing or delivering a small, precise amount of a therapeutic agent even though many therapeutic agents are effective at very small doses. For example, a therapeutically effective dosage of epinephrine may be about 0.1 mg to about 0.5 mg. In known wet/dry devices, however, the dry chamber that accommodates the therapeutic agent is relatively large. In order to effectively fill the dry chamber to ensure effective mixing, a greater amount of the therapeutic agent should be loaded into the chamber, which is costly and potentially dangerous to the person receiving the injection. Alternatively, various excipients may be added to the therapeutic agent to effectively fill the dry chamber. However, adding excipients to a therapeutic agent requires additional expense and manufacturing in order to formulate and produce the therapeutic agent with the excipients prior to the agent being loaded into an injector. 
     Therefore, a need exists for a cost-effective automatic injector that can store a small, precise amount of a therapeutic agent and that does not require manual premixing by the user. 
     SUMMARY OF THE INVENTION 
     The invention provides a cost-effective automatic injector capable oil accommodating and delivering a small, precise amount of a therapeutic agent to a user without manual pre-mixing. In particular, the invention provides an automatic injector that has a thin or flat porous member carrying the small, precise amount of the therapeutic agent. This porous member advantageously does not require additional space within the injector, and thus the space typically required for a second, dry compartment common in wet/dry auto-injectors, and/or the space typically required for bulky scaffolds, substrates, sponges, cell structures, and tubular networks that hold therapeutic agents in some known injection devices, can be reduced in size, if not eliminated, from the injector. While existing automatic injectors may be able to use the porous member of the invention without significant re-design or modification, automatic injectors of the invention are advantageously shorter and/or more compact than existing automatic injectors. 
     One embodiment of the invention includes an automatic injector that has an interior chamber containing a liquid injection component, a seal structure inserted into an open end of the chamber, a needle assembly mounted to the open end of the chamber, a thin porous member located between the seal structure and the needle assembly, and a therapeutic agent disposed on and/or in the porous member. The seal structure has a first state that seals the liquid component in the chamber and a second state that allows the liquid component to flow from the chamber through the seal structure. The seal structure and the thin porous member may be integrated into a single assembly, or alternatively, the porous member and the needle assembly may be integrated into a single assembly. Either integration can be accomplished by any known means in the art, such as, for example, the porous member may be sonically welded to the seal structure or to the needle assembly. 
     Another embodiment of the invention is a method of assembling an automatic injector containing a therapeutic agent. The method includes filling a chamber with a liquid injection component and inserting a seal structure into the chamber. The seal structure is convertible from a sealing condition, which seals the liquid component in the chamber, to a flow-through condition, which allows the liquid component to flow out of the chamber through a flow path. The method also includes applying a therapeutic agent to a flat porous member, securing the flat porous member containing the therapeutic agent at or after the end of the flow path, and mounting a needle assembly onto the chamber to dispense the therapeutic agent mixed with the liquid component. 
     The term “thin” as used herein to describe the porous member is defined as having little extent from one surface to its opposite surface (i.e., its thickness). Similarly, the term “flat” as used herein to describe the porous member is defined as having little or no illusion of depth or thickness. For example, in one embodiment of the invention, the diameter or width of the porous member extending across the flow path (that is, measured in the lateral direction of the chamber) is about 0.30 inches (7.62 mm), while the thickness of the porous member (measured in the longitudinal direction of the chamber) preferably ranges from only about 0.005 inches (0.13 mm) to about 0.020 inches (0.51 mm). 
     The amount of therapeutic agent carried by the porous member is preferably less than or equal to about 25 mg. The therapeutic agent may be, for example, epinephrine. The porous member has a plurality of pores or holes, wherein the average pore width or diameter preferably ranges from about 0.02 microns to about 5 microns. The therapeutic agent carried by the porous member is either disposed on a surface of the porous member and/or contained within the porous member (i.e., disposed within the pores). The porous member has a surface facing the needle assembly and a surface facing the seal structure. The therapeutic agent is preferably disposed on at least one of those surfaces and may be disposed on both. Alternatively or additionally, the therapeutic agent may be disposed within at least some of the pores of the porous member. 
     The porous member may be made of a metallic material, a polymeric material, a ceramic material, or combinations thereof. The porous member may be, for example, a filter, a polymeric membrane, or a metal disc. 
     Another embodiment of the invention includes an automatic injector having an interior chamber with an open end, a seal structure positioned in the chamber, a needle assembly mounted to the chamber at the open end, a filter or membrane positioned either at the seal structure, at the needle assembly, or between the seal structure and needle assembly, and a therapeutic agent carried by the filter or membrane. The interior chamber contains a liquid injection component, and the seal structure converts from a sealing condition to a flow-through condition. The flow-through condition allows the liquid component to flow out of the chamber through a flow path to the needle assembly. The filter or membrane has an area that extends across the flow path and a negligible thickness and volume. The amount of therapeutic agent carried by the filter or membrane is preferably less than or equal to about 25 mg. 
     The term “negligible” as used herein to describe the thickness and volume of the filter or membrane is defined as being so small or unimportant as to warrant little or no attention—especially with respect to providing space for the filter or membrane within an automatic injector. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The features and advantages of the invention will be apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout, and in which: 
         FIG. 1  is a longitudinal cross-sectional view of an automatic injector according to the invention; 
         FIG. 2  is an enlarged, longitudinal cross-sectional view of the activation end of the automatic injector of  FIG. 1 ; 
         FIG. 3  is a longitudinal cross-sectional view of an assembled chamber, seal structure, and needle assembly of the injector of  FIG. 1 ; 
         FIG. 4  is a longitudinal cross-sectional view of the seal structure and needle assembly of  FIG. 3 ; 
         FIGS. 5-8  are lateral, longitudinal cross-sectional, perspective, and perspective cross-sectional views, respectively, of the seal structure of  FIGS. 1 ,  3 , and  4 ; 
         FIGS. 9 and 10  are longitudinal and enlarged, partial longitudinal cross-sectional views of the assembled chamber, seal structure, and needle assembly of the injector of  FIG. 1 ; 
         FIG. 11  is a longitudinal cross-sectional view of another embodiment of an automatic injector according to the invention; 
         FIG. 12  is a longitudinal cross-sectional view of another embodiment of an assembled chamber, seal structure, and needle assembly of the injector of  FIG. 11 ; 
         FIG. 13  is a longitudinal cross-sectional view of the assembled seal structure and needle assembly of  FIG. 12 ; 
         FIGS. 14 and 15  are longitudinal and enlarged, partial longitudinal cross-sectional views of the assembled chamber, seal structure, and needle assembly of the injector of  FIG. 11 ; 
         FIG. 16  is another longitudinal cross-sectional view of the seal structure and needle support of  FIGS. 11-15 ; and 
         FIGS. 17-20  are various perspective views of seal structures porous members, and needle assemblies according to the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention is directed to automatic injectors that can accommodate and deliver a small, precise amount of a therapeutic agent. The automatic injectors include a thin or flat porous member that carries thereon and/or therein the therapeutic agent. Advantageously, the thin or flat porous member with the therapeutic agent thereon and/or therein results in a shorter, more compact injection device because most, if not all, of the space needed for either (1) a second, dry compartment common in wet/dry automatic injectors or (2) the various types of known generally cylindrically-shaped scaffolds, substrates, sponges, cell structures, and tubular networks used to hold therapeutic agents in known injectors is unnecessary. 
     The invention is not limited to any one type of automatic injector. For example, the invention may include a nose activated auto-injector, as described, for example, in U.S. Pat. No. 5,354,286, the disclosure of which is incorporated by reference. The invention may alternatively include a push button type auto-injector, where the user removes an end cap and presses a button to trigger the injection process as described, for example, in U.S. Pat. No. 6,641,561, the disclosure of which is also incorporated by reference. 
       FIG. 1  shows an embodiment of an automatic injector that can be used in connection with the invention. Automatic injector  10  has a needle end  12  and an activation end  14 . The device has an outer body or housing  100  having an in-turned shoulder  101 . Located within the interior of outer body  100  is a cartridge holder  102 . Cartridge holder  102  has a shoulder  104  that fits against seat  105  of in-turned shoulder  101 . Cartridge holder  102  also has a forward end portion  106  that is tapered to form a small circular aperture. Received within cartridge holder  102  is a cartridge assembly  103 . The overall length of cartridge assembly  103  is completely contained within cartridge holder  102 . Cartridge assembly  103  has a chamber  120  that is preferably a hollow cylinder with either a smooth cylindrical interior surface or smooth interior side walls. Chamber  120  has a first compartment  121  and, optionally, a much smaller second compartment  122 . Preferably, the liquid injection solution or component is located within first compartment  121 . A seal structure  130  engages the interior surface or side walls of chamber  120  to seal the liquid injection solution in first compartment  121  and prevent seepage of the liquid injection solution into the optional second compartment  122  prior to activation of the injector device. 
     A needle assembly  140  is mounted to the forward end of chamber  120  to inject the therapeutic agent into a user upon activation of the injector. In this embodiment, the forward end portion of chamber  120  has an annular groove  123  formed therein for attachment of needle assembly  140 . Needle assembly  140  has a crimp clamp  142  that is mechanically rolled into annular groove  123  to permanently secure and seal the needle assembly to the chamber. Needle assembly  140  also includes a funnel-shaped needle support  141 , which can be made of a resilient plastic material or a metal with a rubber seal. Needle support  141  forms a sealed fluid channel from chamber  120  to needle  144 . A rubber needle sheath  145  surrounds needle  144  and receives the narrow end of needle support  141 . 
     In addition to cartridge holder  102  and needle assembly  140 , outer body  100  also includes a stored energy assembly  150 . The stored energy assembly can be any conventional type known in the art, such as the forward end activating device disclosed in U.S. Pat. No. 3,712,301, the disclosure of which is incorporated by reference. In another example, rather than employing a spring, the stored energy assembly may employ a charge of compressed gas. 
     As shown in  FIG. 1 , stored energy assembly  150  has an inner sleeve  151  and an outer sleeve  152 . Inner sleeve  151  has an out-turned flange  153  and an end wall  154 . Out-turned flange  153  fits up against the end of cartridge holder  102  when the stored energy assembly is inserted into outer body  100 . Note that the length of outer sleeve  152  is slightly less than that of inner sleeve  151  in order to leave space between the wall of outer sleeve  152  and flange  153  of inner sleeve  151 . Stored energy assembly  150  also has a collet  160  that fits within out-turned flange  153  of inner sleeve  151 . The collet has a body portion  161  and a head portion  162 . The diameter of head portion  162  is larger than body portion  161  and is generally slightly smaller than that of a plunger  163 . A coil spring  164  is positioned over collet body portion  161  and abuts head portion  162  at one end and abuts the inner face of end wall  154  of inner sleeve  151  at the other end. 
       FIG. 2  shows activation end  14  of the automatic injector of  FIG. 1 . Collet  160  has four equally-spaced, longitudinally extending spring fingers  165  terminating in frusto-conical, locking detent heads  166 . These locking detent heads maintain collet  160  and inner sleeve  151  in an assembled position with a coil spring  167  compressed there between. Upon compression of coil spring  167 , detent heads  166  are cammed inwardly by engaging the periphery of the end wall  154  opening so they can be passed through that opening, whereupon the bases of detent heads  166  come to rest on retaining surface  168  of end wall  154  to retain collet  160  and inner sleeve  151  in assembled condition with coil spring  167  compressed there between. When desired, the rear planar surface of the inner sleeve can be advantageously overlaid with a metal washer providing a guide and a holding flange to surround the opening. 
     Outer sleeve  152  has a closed end  170  with a central aperture from which a frusto-conical surface  171  extends. Surface  171  is sized and shaped to cooperate with frusto-conical detent heads  166  to cam the heads radially inward. The outer sleeve  152  is provided with a circumferential locking rib  173  that fits in an annular groove  174  in outer body  100  to retain the stored energy assembly in position in the outer body. As noted above, the length of outer sleeve  152  is slightly less than that of inner sleeve  151  in order to leave space between the inner wall of outer sleeve  152  and flange  153  of inner sleeve  151 . This allows the two sleeves to move relative to each other to cam frusto-conical detent heads  166  inwardly during operation of the device. 
     To make certain that the frusto-conical detent heads  166  are not accidentally cammed inwardly, a safety pin assembly  175  is provided. Safety pin assembly  175  has a cylindrical sleeve  176  sized to fit over the end portion of outer sleeve  152 . A safety pin  177  extends inwardly from the center of safety pin assembly  175  into the opening formed by the inner portions of detent heads  166  to prevent inward movement of the detent heads. Safety pin assembly  175  is provided internally with a plurality of spacer abutments  178  to assure proper positioning of the cap on outer sleeve  152 . 
     To activate the injector, safety pin assembly  175  is manually pulled off the rear end of the injector, thus removing pin  177  from between fingers  165 . Needle end  12  of injector  10  is then pressed against an injection site. A telescoping action takes place between outer body  100  and cartridge holder  102 . This telescoping action causes the sleeves of the stored energy assembly to telescope, which causes surfaces  171  of outer sleeve  152  to engage the sloping surface  179  of detent heads  166 . This forces detent heads  166  inward toward one another and off of retaining surface  168  of end wall  154 . Coil spring  167  is now free to release its stored energy. This moves collet  160  forward to effect an injection operation. 
       FIG. 3  shows an assembly of needle assembly  140  and chamber  120 . In this embodiment, chamber  120  has a first compartment  121  and a significantly smaller second compartment  122  separated by seal structure  130 . Liquid injection solution is stored in first compartment  121 . Seal structure  130  engages the interior surface or side walls of chamber  120  to seal first compartment  121  from second compartment  122 , thus preventing any liquid injection solution from entering second compartment  122 . Adjacent seal structure  130  is a thin or flat porous member  180 . Therapeutic agent  185  is disposed on a surface of porous member  180 , which is positioned adjacent seal structure  130 . The therapeutic agent may alternatively or additionally be disposed within the pores of the porous member. 
       FIG. 4  shows seal structure  130  and needle assembly  140 . Seal structure  130  has an outer seal  190 , an internal rigid member  191 , and a movable sealing plug  192 . Outer seal  190  and internal rigid member  191  securingly engage each other using a combination of notched recesses  195  and extending shoulders  196 . In other embodiments, outer seal  190  and internal rigid member  191  may be secured together using bonding techniques known in the art or may be formed as an integral component. Internal rigid member  191  may also be formed from two rigid bodies (e.g., two halves) that are annularly welded or bonded together. Internal rigid member  191  has a by-pass channel  193  which creates at least one flow path. When plug  192  is moved from its location as shown in  FIG. 4  to by-pass area  194 , by-pass channel  193  becomes a flow path such that a liquid component can flow through both seal structure  130  and porous member  180 , dissolving therapeutic agent  185 . 
       FIGS. 5-8  show seal structure  130  and porous member  180  with a therapeutic agent  185  disposed on a surface of the porous member  180 . Porous member  180  is held in place between internal rigid member  191  and shoulder  196  of outer seal  190  and may be welded or bonded to rigid member  191 . In embodiments where the internal rigid member is formed from two rigid bodies, the porous member can be secured between those two rigid bodies. Therapeutic agent  185  is carried on the surface of porous member  180  that faces away from internal rigid member  191  (that is, on the front side of the porous member). In alternative embodiments, the therapeutic agent can be disposed on the surface facing the rigid member or on both surfaces of the porous member. In still other embodiments, the therapeutic agent can be located within the plurality of pores or holes in the porous member or within the pores/holes and on one or both of the surfaces of the porous member. 
       FIGS. 9 and 10  show the assembly of chamber  120 , seal structure  130 , and needle assembly  140 . Chamber  120  contains seal structure  130 , which has an outer seal  190  and an internal rigid member  191 . Outer seal  190  forms an annular seal with the inner surface of chamber  120  to prevent liquid from seeping around the seal structure. Porous member  180 , which contains therapeutic agent  185 , is held in place between internal rigid member  191  and shoulder  196  of outer seal  190  and may be welded or bonded to rigid member  191 . The forward end portion of chamber  120  has an annular groove  123  formed therein about which needle assembly  140  is mounted. Needle assembly  140  preferably includes a needle support  141 , which includes at least one crimp clamp  142 . Crimp clamp  142  is mechanically rolled into groove  123  to secure and seal needle assembly  140  to chamber  120 . 
       FIG. 11  shows another embodiment of an automatic injector that can be used in connection with the invention. Automatic injector  200  has a needle end  210  and an activation end  211 . The device has an outer body or housing  212  that has an in-turned shoulder  213 . Located within the interior of outer body  212  is a cartridge holder  214 . Cartridge holder  214  has a shoulder  216  which fits against seat  217  of in-turned shoulder  213 . Cartridge holder  214  also has a forward end portion  218  that is tapered to form a small circular aperture. Received within cartridge holder  214  is a cartridge assembly  215 . The overall length of cartridge assembly  215  is completely contained within cartridge holder  214 . Cartridge assembly  215  has a chamber  220  that is preferably a hollow cylinder with either a smooth cylindrical inner surface or smooth interior side walls. In this embodiment, chamber  220  has a single compartment  221  that can contain a liquid injection solution or component. Advantageously, there is no second compartment. A seal structure  230  engages the inner surface or interior side walls of chamber  220  to seal compartment  221  and prevent seepage of the liquid injection solution prior to activation of the injector device. 
     Further, a needle assembly  240  mounts to chamber  220  to inject the therapeutic agent upon activation of the injector device. The forward end portion of chamber  220  has an annular groove  223  formed therein for attachment of needle assembly  240 . Needle assembly  240  includes a funnel-shaped needle support  241  that has a crimp clamp  242  mechanically rolled into annular groove  223  to permanently secure and seal the needle assembly to the chamber. Needle support  241  can be made of a resilient plastic material or a metal with a rubber seal. Needle support  241  forms a sealed fluid channel from chamber  220  to needle  244 . A rubber needle sheath  245  surrounds needle  244  and receives the narrow end of needle support  241 . 
     In addition to cartridge holder  214  and needle assembly  240 , outer body  212  includes a stored energy assembly  250 . The stored energy assembly can be any conventional type known in the art, such as the forward end activating device disclosed in U.S. Pat. No. 3,712,301. In another example, rather than employing a spring, the stored energy assembly may employ a charge of compressed gas. 
     As shown in  FIG. 11 , stored energy assembly  250  has an inner sleeve  251  and an outer sleeve  252 . Inner sleeve  251  has an out-turned flange  253  and an end wall  254 . Out-turned flange  253  fits up against the end of cartridge holder  214  when the stored energy assembly is inserted into outer body  212 . Note that the length of outer sleeve  252  is slightly less than that of inner sleeve  251  in order to leave space between the wall of outer sleeve  252  and flange  253  of inner sleeve  251 . Stored energy assembly  250  also has a collet  260  that fits within out-turned flange  253  of inner sleeve  251 . The collet has a body portion  261  and a head portion  262 . The diameter of head portion  262  is larger than body portion  261  and is generally slightly smaller than that of a plunger  263 . A coil spring  264  is positioned over collet body  261  and abuts head portion  262  at one end and abuts the inner face of end wall  254  of inner sleeve  251  at the other. 
     A significant difference between the automatic injector of  FIG. 1  and that of  FIG. 11  is the location of the seal structure. In  FIG. 1 , seal structure  130  is located in the main, large diameter portion of chamber  120 , while in  FIG. 11 , seal structure  230  is alternatively located in a neck portion  257  of chamber  220 . 
       FIG. 12  shows an assembly of chamber  220 , seal structure  230 , and needle assembly  240  of automatic injector  200 . The chamber has neck portion  257 , which has an annular groove  223 . Seal structure  230  engages the inner surface or interior side walls of neck portion  257  and is adjacent annular groove  223 . Therapeutic agent  285  is disposed on porous member  280 , which is located on seal structure  230 . The seal structure seals and prevents any liquid stored in compartment  221  from contacting the therapeutic agent prior to activation of the automatic injector. 
       FIG. 13  shows seal structure  230  and needle assembly  240 . Seal structure  230  has an outer seal  290 , an internal rigid member  291 , and a movable sealing plug  292 . Outer seal  290  includes at least one side flange  295 . Seal structure  230  is secured to needle assemble  240  by fitting side flange  295  into crimp clamp  242 . Seal structure  230  also includes thin or flat porous member  280 , which contains therapeutic agent  285 . Porous member  280  is held in place between outer seal  290  and needle support  241  and may be welded or bonded to rigid member  291 . Alternatively, the porous member may be secured in place between the outer seal and the internal rigid member and, in those embodiments where the internal rigid member is formed from two rigid bodies (e.g., two halves) that are annularly welded or bonded together, the porous member may be secured between those two rigid bodies. Internal rigid member  291  has a by-pass channel  293  which creates at least one flow path. When plug  292  is moved from its location as shown in  FIG. 13  to by-pass area  294 , by-pass channel  293  opens a flow path that allows the liquid component to flow through both seal structure  130  and porous member  280 . 
       FIGS. 14 and 15  show the assembly of chamber  220 , seal structure  230 , and needle assembly  240 . Chamber  220  has neck portion  257  and annular groove  223 . Seal structure  230  is located in neck portion  257  and has at least one side flange  295 . Note that, in contrast, seal structure  130  of injector  100  does not have a side flange. Needle assembly  240  mounts to chamber  220  by rolling crimp clamp  242  into groove  223 , further securing side flange  295  between chamber  220  and needle assembly  240 . Within chamber  220  is seal structure  230 , which has an outer seal  290  and an internal rigid member  291 . Outer seal  290  includes side flange  295 . Seal structure  230  is temporarily held in position between chamber  220  and needle assemble  240  when annular ridge member  296  is press fit to the flange of chamber  220 , thereby securing flange  295  between chamber  220  and needle assemble  240 . The lower portion of clamp  242  is rolled into groove  223  of chamber  220  securing flange  295  between chamber  220  and needle assembly  240 . In this embodiment, porous member  280 , which contains therapeutic agent  285 , is ultrasonically welded to ridge member  291 . 
       FIG. 16  shows seal structure  230  and needle assembly  240  (without chamber  220  and clamp  242 , for clarity). Seal structure  230  has outer seal  290 , internal rigid member  291 , and movable sealing plug  292 . Outer seal  290  includes at least one side flange  295 , and internal rigid member  291  has by-pass channel  293  such that movement of plug  292  to by-pass area  294  creates at least one flow path through by-pass channel  293 . Positioned between seal structure  230  and needle assembly  240  and possibly attached to rigid member  291  is porous member  280 , which contains therapeutic agent  285 . 
       FIGS. 17 and 18  each show a method of assembling a thin or flat porous member, a seal structure, and a needle assembly.  FIG. 17  shows porous member  380 , which carries a therapeutic agent (not shown), secured to needle support  341  of a needle assembly  340 . Seal structure  330  is then secured to needle assembly  340 .  FIG. 18  shows porous member  480 , which carries therapeutic agent  485 , secured to seal structure  430 . The combined porous member and seal structure are then secured to the needle assembly. The porous member can be secured to the seal structure or needle support by any means known in the art. In certain preferred embodiments, the porous member is secured by sonic welding. 
       FIGS. 19 and 20  each show a method in which a therapeutic agent is applied to a thin or flat porous member.  FIG. 19  shows a seal structure  530 , a porous member  580 , and a needle assembly  540 . In this embodiment, therapeutic agent  585  is applied to the surface of porous member  580  that faces needle assembly  540  (i.e., the front surface).  FIG. 20  shows a seal structure  630 , a porous member  680 , and a needle assembly  640 . In this embodiment, the therapeutic agent is applied such that it fills the pores of porous member  680 . Alternatively, the therapeutic agent can be applied to (1) the surface of porous member  580  that faces the seal structure (i.e., the rear surface), (2) both surfaces of the porous member, or (3) either or both surfaces and within the pores of the porous member. 
     The porous member is operative to carry a therapeutic agent and release the therapeutic agent into a liquid component flowing through the porous member. The porous member can be made out of any type of medically-appropriate material that can be made very thin or flat and have pores there through. The porous member can be fabricated from metallic, ceramic, or polymeric materials, or combinations thereof. Suitable metallic materials include alloys such as stainless steel. 
     Suitable ceramic materials include, but are not limited to, oxides, carbides, and nitrides of the transition elements such as titanium oxides, hafnium oxides, iridium oxides, chromium oxides, aluminum oxides, and zirconium oxides. Silicon based materials, such as silica, may also be used. 
     Suitable polymeric materials for forming the porous member include, but are not limited to, isobutylene-based polymers, polystyrene-based polymers, polyacrylates and polyacrylate derivatives, vinyl acetate-based polymers and its copolymers, polyurethane and its copolymers, silicone and its copolymers, ethylene vinyl-acetate, polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics, polyamides, polyesters, polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose, collagens, and chitins. 
     Other polymers that are useful as materials for forming the porous member include, without limitation, dacron polyester, poly(ethylene terephthalate), polycarbonate, polymethylmethacrylate, polypropylene, polyalkylene oxalates, polyvinylchloride, polyurethanes, polysiloxanes, nylons, poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes, poly(amino acids), ethylene glycol I dimethacrylate, poly(methyl methacrylate), poly(2-hydroxyethyl methacrylate), polytetrafluoroethylene poly(HEMA), polyhydroxyalkanoates, polytetrafluorethylene, polycarbonate, poly(glycolide-lactide) co-polymer, polylactic acid, poly(γ-caprolactone), poly(γ-hydroxybutyrate), polydioxanone, poly(γ-ethyl glutamate), polyiminocarbonates, poly(ortho ester), polyanhydrides, alginate, dextran, chitin, cotton, polyglycolic acid, polyurethane, or derivatized versions thereof, i.e., polymers which have been modified to include, for example, attachment sites or cross-linking groups, e.g., RGD, in which the polymers retain their structural integrity while allowing for attachment of cells and molecules, such as proteins, nucleic acids, and the like. 
     The particular size and shape of the thin or flat porous member depends on the automatic injector in which it will be used. Generally, the porous member is the shape of a thin or flat disc or membrane as shown in  FIGS. 17-20 , which shows the porous member having a thin profile or minimal thickness (measured in the longitudinal direction of the interior chamber). Representative thicknesses for porous members of the invention range from about 0.005 inches (0.13 mm) to about 0.012 inches (0.30 mm) for polymeric materials and from about 0.010 inches (0.25 mm) to about 0.020 inches (0.51 mm) for metallic membranes. The diameter/width of a representative porous member (measured in the lateral direction of the interior chamber) is about 0.30 inches (7.62 mm), so the ratio of porous membrane diameter/width to thickness ranges from about 15:1 to 60:1. Thus, for all practical purposes, the thickness of the porous member, and its volume for that matter, can be considered negligible with respect to providing space in the longitudinal direction of and within a chamber in an automatic injector, wherein the term “negligible” as used herein is defined as being so small or unimportant as to warrant little or no attention. 
     Advantages of the thin or flat therapeutic-agent-carrying porous members of the invention include (1) requiring little if any additional space within an automatic injector; (2) greater versatility in placing and securing the porous member within the automatic injector than in known injectors having a dry compartment and/or using scaffolds, substrates, sponges, cell structures, and tubular networks; and (3) more rapid mixing of the liquid component with the therapeutic agent than in known injectors. 
     The porous member comprises a plurality of pores. The pores can be of different sizes or shapes. The pores can be interconnected or separate. The pores can also be distributed randomly or in a pattern. The size of the pores depends on the type of therapeutic agent used. The pores should be large enough to allow the liquid injection solution and the therapeutic agent to pass through. The average width or diameter of the pores ranges from about 0.02 microns to about 5 microns. Pores can be formed in the porous member by any method known in the art, such as sand blasting, drilling, laser etching, or chemical etching. 
     Preferred porous members include without limitation thin or flat metal discs with a plurality of pores therein, thin or flat filters such as ceramic or metallic filters, and thin or flat discs or membranes made of polymeric material. 
     Therapeutic agents used with porous members of the invention preferably include, but are not limited to, anti-asthmatics including beta-agonists such as salbutamol, levalbuterol, formoterol, fenoterol, salmeterol, bambuterol, brocaterol, clenbuterol, terbutalin, tulobuterol, epinephrin, isoprenalin, and hexoprenalin. 
     Other suitable therapeutic agents include, but are not limited to, anti-angiogenesis factors: antibodies; antigens: polysaccharides: growth factors; hormones including insulin, glucogen, parathyroid and pituitary hormones, calcitonin, vasopressin, renin, prolactin, growth hormones, thyroid stimulating hormone, corticotrophin, follicle stimulating hormone, luteinizing hormone, and chorionic gonadotropins; enzymes including soybean trypsin inhibitor, lysozyme, catalase, tumor angiogenesis factor, cartilage factor, transferases, hydrolases, lysases, isomerases, proteases, ligases and oxidoreductases such as esterases, phosphatases, glycosidases, and peptidases; enzyme inhibitors such as leupeptin, antipain, chymostatin and pepstatin; and drugs such as steroids, anti-cancer drugs, or antibiotics. 
     The amount of therapeutic agent disposed in and/or on the porous member depends on the therapeutic agent used. In many cases, the appropriate amount of therapeutic agent is less than or equal to about 25 mg. 
     The invention is also directed to a method of assembling an automatic injector, which includes filling a chamber with a liquid component and inserting a seal structure in the chamber. In some embodiments, inserting the seal structure into the chamber forms first and second compartments in the chamber. In other embodiments, a second compartment is not formed. The seal structure has a first position that seals the liquid component in the chamber (or first compartment) and a second position that creates a flow path through the seal structure from the chamber to a needle assembly (or from the first compartment to the second compartment and then to the needle assembly). The method further includes (1) applying a therapeutic agent to a thin or flat porous member, (2) securing the porous member at or after the end of the flow path, (3) mounting a needle assembly onto the chamber to dispense the therapeutic agent mixed with the liquid component, and (4) providing a housing to carry the injection device components. 
     As described above, the therapeutic agent can be applied to a surface of the porous member that faces the needle assembly and/or a surface that faces the seal structure. The therapeutic agent alternatively or additionally can be applied such that at least some, most, or all of the pores of the porous member are at least partially filled with the therapeutic agent. Moreover, as also described above, the porous member can be secured to the seal structure or the needle assembly. Note that the order of the above method steps can be varied. For example, applying the therapeutic agent and securing the porous member may occur before insertion of the seal structure or the filling of the chamber with the liquid component. 
     While the automatic injectors of the invention have been described herein with respect to the medical treatment of humans, they are not limited to such use. For example, automatic injectors of the invention may be alternatively used in connection with the treatment of animals and related scientific research thereof (for example, the injectors can be used to inject zoo animals, farm animals, or laboratory animals). Automatic injectors of the invention may also be alternatively used in connection with agriculture, horticulture, or forestry and related scientific research thereof (for example, the injector can be used to inject fruit, vegetables, trees, and/or other types of plant life). 
     The invention has been described in connection with the preferred embodiments. These embodiments, however, are merely examples, and the invention is not limited to them. Those skilled in the art understand that other variations and modifications may be easily made within the scope of the invention and that the invention is limited by only the following claims.

Technology Classification (CPC): 0