Vortex feature for drug delivery system

An automatic injector separately stores liquid and dry components in respective compartments. When the injector is activated, a fluid-directing member between the liquid and dry compartments causes the liquid component to form a vortex as the liquid flows into the dry compartment. This allows the two components to combine more thoroughly and quickly to form a liquid solution that is delivered to an injection site.

FIELD OF THE INVENTION

The invention relates to drug delivery devices that deliver therapeutic agents. More particularly, the invention is directed to an automatic injector that quickly combines two components to form a liquid therapeutic agent delivered to an injection site.

BACKGROUND OF THE INVENTION

An automatic injector is a device that enables 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. As such, automatic injectors can 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, and without the user having 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 which is then injected. However, the long-term storage of a therapeutic agent as a liquid solution has drawbacks. For instance, some therapeutic agents are not stable in solution 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 mix the solid therapeutic agent with a liquid immediately prior to injection. 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., nerve gas and chemical agent poisoning).

Therefore, a need exists for a cost-effective automatic injector that stores a therapeutic agent in solid form, does not require manual premixing by the user, and quickly and effectively automatically mixes and delivers the therapeutic agent in a liquid solution.

SUMMARY OF THE INVENTION

The invention is directed to wet/dry automatic injectors having improved mixing capabilities. By introducing a “fluid-directing member” that causes the liquid component to form a vortex, mixing of the liquid component with the dry component is improved, including improved dissolution of the dry component into the liquid component. The vortical flow has axial, radial, and circumferential components that improve mixing. As a result, a greater amount of the dry component is dissolved in the liquid component in a shorter period of time, thus allowing the user to get a more immediate, effective dose of a therapeutic agent. Moreover, increased amounts of the dry component are ultimately delivered as compared to currently available systems.

Automatic injectors of the invention include a housing assembly having a central longitudinal axis and an interior chamber located within the housing assembly. The interior chamber has an inner side surface extending in the direction of the central longitudinal axis, a dry compartment suitable for containing a dry therapeutic agent, and a wet compartment suitable for containing a liquid component. The housing assembly also includes a seal structure positioned between the dry and wet compartments in the interior chamber. The seal structure has a sealed state that prevents liquid in the wet compartment from passing through the seal structure to the dry compartment. The seal structure also has a flow-through state that allows liquid from the wet compartment to pass there through to the dry compartment. A fluid-directing member is included at an end of the seal structure adjacent the dry compartment. The housing assembly further includes a needle assembly located therein that is in communication with the interior chamber for dispensing the liquid therapeutic agent.

The seal structure has an outer seal that sealingly engages the inner side surface of the interior chamber to prevent passage of liquid between the outer seal and the inner side surface. The outer seal has a first end adjacent the wet compartment and a second end adjacent the dry compartment. The outer seal may have an annular ridge around the second end of the outer seal. The fluid-directing member is preferably adjacent the outer seal on the second end, and is preferably integrated with the outer seal to form single unit.

In one embodiment of the invention, the seal structure has an outer seal, a rigid member in communication with the outer seal, at least one flow path, an inner seal plug, and a fluid-directing member. The outer seal attaches to the rigid member (i.e., they are configured to engage each other) and, alternatively, the outer seal and rigid member may form a single integrated unit. The fluid-directing member attaches to the rigid member and, alternatively, the fluid-directing member and the rigid member may form a single integrated unit. The rigid member may be formed from at least two rigid member parts that are welded or bonded together. The inner seal plug has a first position with respect to the rigid member that seals the liquid component in the wet compartment from the dry compartment. The inner seal plug also has a second position with respect to the rigid member that allows the liquid component to pass through the seal structure via the flow path. In one embodiment, the flow path comprises a by-pass channel that allows the liquid component to flow around the inner seal plug and through the seal structure when the inner seal plug is in the second position.

The fluid-directing member has at least one channel that has a fluid exit port with an opening into the dry compartment that fully faces the inner side surface of the chamber. In other words, the opening does not face forward (i.e., towards the needle assembly), but instead faces the side wall of the chamber. The channel is preferably helically shaped about the central longitudinal axis and is in fluid communication with the flow path of the seal structure. The channel is also preferably oriented at an angle ranging from about 80° to 90° with respect to the longitudinal axis of the housing assembly. The fluid-directing member may have a plurality of channels. For example, respective embodiments of the fluid-directing member may have one, two, three, or four helical channels. In preferred embodiments, the channels are separate; however, a fluid-directing member alternatively may have interconnected channels. Each channel preferably has at least one fluid exit port, and multiple fluid exit ports are arranged preferably equidistantly radially around the central longitudinal axis. The channels may be of shapes other than helical, provided that those shapes give the liquid component a substantial circumferential flow component and/or allow the liquid component to form a vortex within the dry compartment. For example, the channels may be circular, linear, inclined, helical, or a combination thereof. Additionally, multiple channels in the same fluid-directing member can each be of the same or similar shape or, alternatively, of different shapes. In preferred embodiments, the channels direct most if not all of the fluid into the dry compartment at angles ranging from about 80° to 90° with respect to the central longitudinal axis of the housing assembly. This facilitates formation of a vortex in the dry compartment. Optionally, the channels can be constructed to direct fluid into the dry compartment at angles ranging from about 10° to 90°.

The fluid-directing member has a preferably compact construction and is located radially inward from the outer seal on the end of the seal structure adjacent the dry compartment. The ratio of the fluid-directing member's diameter or height (measured perpendicularly to the longitudinal axis of the housing assembly) to its thickness (measured along the axis) preferably ranges from 2:1 to 1:2 and more preferably from 1.5:1 to 1:1. In some embodiments of the invention, the fluid-directing member or a portion thereof extends axially beyond the outer seal, while in others, the fluid-directing member does not extend axially beyond the outer seal. The fluid-directing member has an annular surface parallel to the central longitudinal axis, and the opening of each fluid exit port is located on the annular surface. In those embodiments where the seal structure has an annular ridge around the second end of the outer seal, certain embodiments of the fluid-directing member have the opening of at least one fluid exit port fully facing the annular ridge.

The invention is also directed to a method of assembling an automatic injector for administration of a therapeutic agent. In one embodiment, the method includes providing a chamber and inserting a seal structure in the chamber to create a wet compartment and a dry compartment. The seal structure has a sealed state and a flow-through state. The seal structure also has a helical channel adjacent the dry compartment. The helical channel is configured to allow a liquid to pass there through from the wet compartment to the dry compartment such that the liquid enters the dry compartment circumferentially at an angle of about 80° to 90° with respect to a longitudinal axis of the chamber. The method also includes loading a liquid component in the wet compartment, loading a therapeutic agent in the dry compartment, attaching a plunger to the end of the chamber adjacent the wet compartment, and attaching a needle assembly for dispensing the therapeutic agent to the other end of the chamber. The method further includes providing a housing having a hollow interior and placing the chamber, needle assembly, and plunger in the housing.

The invention is further directed to a method of preparing a liquid solution in an automatic injector, wherein the liquid solution comprises a liquid and a dry substance. In one embodiment, the method includes loading a liquid in a first compartment of a chamber and loading a dry substance in a second compartment of the chamber, the chamber having a longitudinal axis. The first and second compartments are separated from each other by a seal structure that has a sealed state and a flow-through state. The seal structure is initially in the sealed state, which seals the first compartment from the second compartment to prevent the liquid from flowing into the second compartment. The method also includes converting the seal structure from the sealed state to the flow-through state to allow the liquid to flow from the first compartment into the second compartment, and forcing the liquid to flow into the second compartment in the form of a vortex to mix with the dry substance. Note that in some embodiments, loading a dry substance occurs before loading a liquid. In other embodiments, forcing the liquid to flow into the second compartment comprises forcing the liquid to flow into the second compartment circumferentially at an angle of about 80° to 90° with respect to the longitudinal axis of the chamber. In still other embodiments, forcing the liquid to flow into the second compartment comprises forcing the liquid to flow through a helical channel into the second compartment to form a vortex in the second compartment.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to wet/dry automatic injectors that have improved mixing capabilities. The automatic injectors of the invention include a fluid-directing member that has at least one, preferably helical, channel. As liquid passes through and out of the helical channel of the fluid-directing member, a vortex is created. As used herein, a “vortex” may be any one or all of the following: a mass of fluid with a whirling or circular motion that tends to form a cavity or vacuum in the center, fluid flow that resembles a whirlpool or eddy, and/or fluid flow that has an angular velocity and a substantial circumferential flow component. As used herein, “substantial” means more than half. A vortex of liquid injection solution improves and accelerates the mixing and dissolution of the dry therapeutic agent.

Note that the invention is not limited to any one type of automatic injector device. 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 herein by reference. The invention may also include a push-button type auto-injector, wherein the user removes an end cap assembly and presses a button to trigger the injection process, as described for example in U.S. Pat. No. 6,641,561. Furthermore, the features described and illustrated herein can be used singularly or in combination with other features and embodiments.

FIG. 1shows a preferred embodiment of an automatic injector device that can be used in connection with the invention. Automatic injector device10has a needle end12and an activation end14. The device has an outer body or housing assembly100having an in-turned shoulder101. Located within the interior of housing assembly100are a cartridge holder body102and a cartridge assembly103. Cartridge holder body102has a shoulder104that fits against seat105provided by in-turned shoulder101. Cartridge holder body102also has a forward end portion106that is tapered to form a small circular aperture.

Cartridge assembly103within cartridge holder body102has an interior chamber120where the mixing of the therapeutic agent takes place. Chamber120is preferably a hollow cylinder with a smooth cylindrical inner surface. Chamber120has a first compartment121and a second compartment122. Preferably, the liquid injection solution or liquid component is located within the first compartment121(referred to hereinafter as the “wet” compartment), and the therapeutic agent or dry component is located within the second compartment122(referred to hereinafter as the “dry” compartment).

A seal structure123annularly engages the interior side walls (i.e., the smooth cylindrical inner surface) of chamber120to seal the wet compartment from the dry compartment and to prevent seepage of the liquid injection solution into the dry compartment prior to activation of the injector device. Seal structure123has a sealed state and a flow-through state.

A needle assembly130mounts to the forward end of chamber120to inject the therapeutic agent upon activation of the injector device. In this embodiment, the forward end portion of chamber120has an annular groove133formed therein for attachment of needle assembly130. Needle assembly130includes a funnel-shaped needle support131and has a crimp clamp132that is mechanically rolled into annular groove133to permanently secure and seal the needle assembly to chamber120. Needle support131can be made of a resilient plastic material or metal with a rubber seal. Needle support131forms a sealed fluid channel from chamber120to needle134. A rubber needle sheath135surrounds needle134and receives the narrow end of needle support131. The overall length of cartridge assembly103is such that it is all contained within cartridge holder body102, as shown inFIG. 1.

As also shown inFIG. 1, the outer body or housing assembly100has a length that accommodates cartridge holder body102and a stored energy assembly140. 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 herein by reference. In another example, rather than employing a spring, the stored energy assembly may employ a charge of compressed gas or other suitable stored energy source.

As further shown inFIG. 1, stored energy assembly140has an inner sleeve141and an outer sleeve160. Inner sleeve141has an out-turned flange142and an end wall143. Out-turned flange142fits up against the end of cartridge holder body102when the stored energy assembly is inserted in housing assembly100. Note that the length of outer sleeve160is slightly less than that of inner sleeve141to leave space between the wall of outer sleeve160and flange142of inner sleeve141. A collet145fits within the out-turned flange end of inner sleeve141. The collet has a body portion146and a head portion147. The diameter of head portion147is larger than body portion146and is generally slightly smaller than that of a plunger148. A coil spring152is positioned over collet body146and abuts head portion147at one end and the inner face of an end wall143of inner sleeve141at the other end.

FIG. 2shows activation end14of the automatic injector ofFIG. 1. Collet145has four equally-spaced, longitudinally extending spring fingers150terminating in frusto-conical locking detent heads151. These locking detent heads maintain collet145and inner sleeve141in an assembled position with a coil spring152compressed there between. Upon compression of coil spring152, detent heads151can be cammed inwardly by engaging the periphery of the opening of end wall143. Detent head151can then be passed there through, whereupon the bases of detent heads151come to rest on retaining surface144of end wall143of inner sleeve141to retain collet145and inner sleeve141in the assembled condition with coil spring152compressed there between. When desired, the rear planar surface of the inner sleeve can be overlaid with a metal washer, in which case providing a guide and holding-flange to surround the opening is advantageous.

Outer sleeve160has a closed end161with a central aperture from which extends a frusto-conical surface162. Surface162is sized and shaped to cooperate with frusto-conical detent heads151to cam the heads radially inward. Outer sleeve160is provided with a circumferential locking rib163that fits in an annular groove164in housing assembly100to retain the stored energy assembly in position in the housing assembly. As noted above, the length of outer sleeve160is slightly less than that of inner sleeve141to leave space between the inner wall of outer sleeve160and flange142of inner sleeve141. This allows the two sleeves to move relative to each other to cam frusto-conical detent heads151inwardly during operation of the device.

To make certain that frusto-conical detent heads151are not accidentally cammed inward, a safety pin assembly170is provided. Safety pin assembly170has a cylindrical sleeve171sized to fit over the end portion of outer sleeve160. A safety pin172extends inwardly from the center of safety pin assembly170into the opening formed by the inner portions of detent heads151to thereby prevent inward movement of the detent heads. Safety pin assembly170is provided internally with a plurality of spacer abutments174to assure proper positioning of the cap on outer sleeve160.

To activate the injector, safety pin assembly170is manually pulled off the rear end of the injector, thus removing pin172from between fingers150. Needle end12of injector10is positioned at the desired injection site. A telescoping action takes place between housing assembly100and cartridge holder body102. This telescoping action causes the sleeves of the stored energy assembly to telescope. This causes frusto-conical surface162of outer sleeve160to engage the sloping surface175of detent heads151of spring fingers150. This forces detent heads151inward toward one another and off of retaining surface144of end wall143. Coil spring152is then free to release the stored energy therein to move collet145forwardly (i.e., toward needle end12) under the force of coil spring152to effect an injection operation.

FIGS. 3 and 4show a known seal structure323that has no fluid-directing member. Seal structure323can be used to separate a wet compartment from a dry compartment and has a sealed state and a flow-through state. Seal structure323has an internal rigid member390, an outer seal391, and a movable inner seal plug392. Internal rigid member390has at least one by-pass channel393that creates at least one flow path, such that a liquid component in the wet compartment may be placed in fluid communication with the dry compartment. When plug392is moved forward (i.e., towards the needle) to by-pass area394, the seal structure is placed in the flow-through state, which opens a flow path through by-pass channel393. Internal rigid member390and outer seal391may optionally be secured together using any bonding techniques known in the art. Further, internal rigid member390and outer seal391may be formed such that they securingly engage each other using a combination of notched recesses395and extending shoulders396and397. Optionally, seal structure323can include a laminar flow membrane or filter200which can be held in place between internal rigid member390and shoulder397of outer seal391. Filter200can be made of any suitable medically-appropriate material that allows the therapeutic agent, when dissolved in the liquid component, to pass through while preventing any undissolved portions of the therapeutic agent or any impurities from passing through. The filter can be fabricated from metallic, ceramic, or polymeric materials, or a combination thereof. Suitable metallic materials include metals and alloys such as stainless steel.

FIGS. 5 and 6show seal structure123with a fluid-directing member220in accordance with the invention. Seal structure123has a sealed state and a flow-through state and preferably includes an internal rigid member190, an outer seal191, and a movable inner seal plug192. Rigid member190and outer seal191may be constructed as described above for rigid member390and outer seal391. Inner seal plug192is shown inFIGS. 5 and 6in a first position, which places seal structure123in the sealed state. That is, seal structure123prevents liquid in the wet compartment from flowing through the seal structure to the dry compartment. Internal rigid member190has at least one by-pass channel193. When plug192is moved from its first position to by-pass area194(i.e., a second position), a flow path is created via by-pass channel193, and seal structure123is in the flow-through state.

Outer seal191has a first end198(towards the back, or activating end of the injector device) and a second end199(towards the front, or needle end of the device). Preferably, the first end is adjacent the wet compartment and the second end is adjacent the dry compartment. The fluid-directing member220is located at the second end. Optionally, the seal structure can include a filter or membrane200(as in seal structure323) mounted between the flow path and fluid-directing member220.

Fluid-directing member220has at least one channel221having a fluid exit port222into the dry compartment. Fluid exit port222has an opening that preferably fully faces the inner side surface of chamber120(seeFIG. 8). More particularly, in one embodiment, the fluid port opening when viewed in a direction parallel to the central longitudinal axis600is parallel to the inner side surface of the chamber. Channel221is preferably shaped as a helix and is thus a helical channel. In other embodiments, the channels may be any shape that facilitates creation of a vortex by the liquid component as it enters the dry compartment. For example, the channels may be linear, circular, helical, inclined, or any combination thereof, provided a vortex is created. Multiple channels in the same fluid-directing member can each be a similar or identical shape or a different shape.

FIG. 7shows seal structure123with outer seal191and fluid-directing member220. Fluid-directing member220has an annular surface701preferably parallel to the central longitudinal axis600. The opening of each fluid exit port222is located on annular surface701. Outer seal191may include an annular ridge223extending from second end199. In preferred embodiments, the fluid exit port openings222fully face annular ridge223. That is, the curved planes of the openings are parallel to the curvature of the annular ridge. The fluid-directing member220may extend axially beyond second end199by the same distance as ridge223and, alternatively, may extend axially beyond ridge223. In those embodiments where the outer seal does not have a ridge, the fluid-directing member may be flush with second end199or, alternatively, may extend beyond the second end of the seal structure.

In the embodiment shown inFIG. 7, fluid-directing member220has three helical channels221and three fluid exit ports222(see alsoFIGS. 8 and 10). The fluid-directing member can have other numbers of channels. For example, the fluid-directing member can have one, two, three, four, or more channels. The channels can be separate or interconnected. Also, the channels can be oriented at various angles with respect to the longitudinal axis of the housing assembly. For example, the helical channels are preferably oriented at an angle Ø ranging from about 80° to 90° with respect to the longitudinal axis600of the housing assembly. Optionally, they can alternatively be oriented at an angle Ø ranging from about 10° to 90°. Also, multiple channels can each be oriented at a different angle or, alternatively, can each be oriented at the same angle.

FIG. 8shows a seal structure123with outer seal191and fluid-directing member220in an automatic injector chamber120. Outer seal191sealingly engages the inner side surface820of chamber120to prevent passage of liquid from wet compartment121to dry compartment122between the outer seal191and the inner side surface820. Preferably, first end198of outer seal191is adjacent wet compartment121, and second end199of outer seal191is adjacent dry compartment122. Second end199has fluid-directing member220thereon, which has three helical channels221and three corresponding fluid exit port openings222. Once by-pass channels193are open, liquid from the wet compartment can flow through the channels and into the fluid-directing member. The helical channels and fluid exit ports in the fluid-directing member cause the liquid entering the dry compartment to move in a circular motion, creating a vortex. The configuration of helical channels221, combined with the location of the fluid exit ports222radially around center longitudinal axis600and between the center longitudinal axis and the inner side surface of the chamber advantageously provides the liquid entering the dry compartment with flow components in axial, circumferential, and radial directions. Note that the openings of the fluid exit ports of the invention do not face directly forward toward needle assembly130. Preferably, most, if not all, of the liquid entering the dry compartment enter at an angle of about 80° to 90° with respect to longitudinal axis600of the outer body/housing assembly. This geometry causes the liquid to have a substantial circumferential flow component that facilitates formation of a vortex. The formation of a vortex effectively mixes the wet and dry components of the auto-injector when the device is activated, thus dispensing increased amounts of the (originally) dry therapeutic agent, as compared to a comparable device without the fluid-directing member. The vortex improves mixing of the liquid with the therapeutic agent, and thus improves dissolution of the therapeutic agent.

The outer seal and the fluid-directing member may be integrated into a single unit; that is, they may be manufactured as one piece, as shown inFIG. 9.

FIG. 10shows the inside of outer seal191with a fluid directing member220. In this embodiment, fluid-directing member220has three helical channels221each with a respective fluid exit port222. Each channel preferably has at least one exit port. Fluid exit ports222are offset from each other by preferably about 120° (i.e., the three exits ports are arranged radially equidistantly around the central longitudinal axis). Preferably, embodiments with multiple fluid exit ports222have the exit ports arranged radially equidistantly around the central longitudinal axis.

The invention is also directed to methods of assembling an automatic injector for administrating a liquid solution and to methods of preparing a liquid solution in an automatic injector. In one embodiment, a method includes providing a chamber and placing a seal structure in the chamber to create two compartments, a wet compartment suitable for containing a liquid component and a dry compartment suitable for containing a dry component. The seal structure has a first state that seals the liquid component in the wet compartment and at least one flow path that is closed when the seal structure is in the first state. The seal structure also has a second state, wherein the flow path is open to allow the liquid component to flow through the seal structure. The seal structure includes an outer seal that has an end adjacent the wet compartment and an end adjacent the dry compartment. The end adjacent the dry compartment has at least one helical channel capable of allowing the liquid component to flow into the dry compartment when the seal structure is in the second state. The method also includes loading a liquid in the wet compartment, loading a dry substance in the dry compartment, and attaching a needle assembly to the dry compartment of the chamber. The method further includes affixing a helical channel between the two compartments such that the liquid enters the second compartment circumferentially at an angle of preferably about 80° to 90° with respect to a longitudinal axis of the chamber. This facilitates formation of a liquid vortex in the dry compartment to improve and accelerate the mixing and dissolution of the dry substance with the liquid.

EXAMPLES

The results shown in Tables 1 and 2 below demonstrate the improved mixing and dissolution capabilities of the fluid-directing member of the invention.

Table 1 shows test results of administering a dry component mixed with a liquid component using an auto-injector with a fluid-directing member. Table 2 shows test results of administering a dry component mixed with a liquid component using an auto-injector without a fluid-directing member.

The tests were done by first loading a sample of a dry component into a wet/dry auto-injector. The auto-injector was then activated, allowing the liquid component to mix with the dry component before being dispensed. The dispensed sample was collected in a container and the dispensed sample and container were weighed. The liquid component was then removed and the dry component and container were weighed. The dispensed solid mass was determined. Also, the mixing/dispensing time was measured.

TABLE 1Devices with Fluid-Directing MemberLoadedDispensedOperationalDry PowderFluidDry PowderFluidTimemgmL%mgmLsec6872.19996.86651.8373.1026872.20696.76641.8442.3936882.20495.16541.8082.9006872.20396.26611.8302.798Average is last number in each column, indicated in bold

TABLE 2Device without Fluid-Directing MemberLoadedDispensedOperationalDry PowderFluidDry PowderFluidTimemgmL%MgmLsec6902.20785.95931.8063.0726962.21187.26071.5953.2446872.20397.26681.7883.4696912.20790.16231.7303.262Average is last number in each column, indicated in bold

The results show that the auto-injector with a fluid-directing member constructed in accordance with the invention dissolved and dispensed, on average, a greater amount of the dry component more quickly.

The greater amounts of dry component being dissolved, as well as, the faster dispensing time are attributed to the fluid-directing member. As the liquid component passes through the fluid-directing member, a vortex is created that helps the liquid quickly dissolve the dry component, and because the dry component obstructs the liquid component's path to the needle, the quicker the dry component is dissolved, the faster the liquid can pass through the needle.

The invention has thus been described in connection with the preferred embodiments. The invention is not, however, limited to these embodiments, which are only examples of the invention. Persons skilled in the art will appreciate that various changes and modifications can be made within the scope of the invention, which is limited only by the claims which follow.

All references cited above are incorporated herein, in their entirety, for all purposes related to this disclosure.