TITLE

BI-DIRECTIONAL RECONSTITUTION INTRODUCER

BACKGROUND OF THE INVENTION The present invention generally relates to the delivery of a beneficial agent to a patient, such as in a delivery system for delivery of the beneficial agent into a fluid conduit. More specifically, the invention relates to cannula structures employed in such delivery systems.

Many drugs are mixed with a diluent before being delivered intravenously to a patient. The diluent may be, for example, a dextrose solution, a saline solution or even water. Many such drugs are supplied in powder form and packaged in glass vials or ampules. Other drugs, such as some used in chemotherapy, are packaged in glass vials or ampules in a liquid state.

Powdered drugs may be reconstituted in a well known manner, utilizing a syringe which is used to inject liquid into the vial for mixing, the syringe eventually withdrawing the mixed solution from the vial. When a drug must be diluted before delivery to a patient the drug is often injected into a container of diluent after it is reconstituted, where the container may be connected to an administration set for delivery to a patient.

More specifically, the diluent is often packaged in glass bottles, or flexible plastic containers such as are sold under the names MINI-BAG ^™ and VIAFLEX* by Baxter Healthcare Corporation of Deerfield, Illinois. These containers have administration ports for connection to an administration set which delivers the container contents from the container to the patient. The drug is

typically added to the container through an injection site on the container.

Drugs may be packaged separately from the diluent for various reasons. One of the most important reasons is that many drugs do not retain their chemical and physical stability when mixed with a diluent and thus cannot be stored for any substantial period of time. Also, drugs are often packaged separately from the diluent because many firms which manufacture drugs are not engaged in the business of providing medical fluids in containers for intravenous delivery, and vice versa.

Therefore, a doctor, nurse, pharmacist or other medical personnel must mix the drug and diluent. This presents a number of problems. The reconstitution procedure is time consuming and requires aseptic technique. The operator must provide the proper diluent and a syringe before beginning. Often the powdered drug is "caked" at the bottom of the vial. Thus, when liquid is injected into the vial from a syringe the surface area of contact between the liquid and the powdered drug may be quite small initially, thus making the mixing procedure even more time consuming. Because of the limited vial volume, the increasing drug concentration in the diluent makes it harder to finish the reconstitution process.

The operator may attempt to solve this by repeatedly injecting solution into the vial, mixing and withdrawing the solution but this makes necessary additional injections and movement of the syringe which increases the likelihood of contamination. Also, it is sometimes difficult to get all of the drug and/or liquid out of the vial, thus increasing the time required to perform the reconstitution procedure.

The reconstitution procedure should be performed under preferably sterile conditions. In addition to such a requirement making the operator justifiably more cautious and consuming more time, sterile conditions are often hard to maintain. In some instances, a laminar flow hood may be required under which the reconstitution procedure is performed.

Some drugs, such as some chemotherapy drugs, are toxic. Exposure of the operator to the drugs during reconstitution may be dangerous, especially if the operator works with such drugs on a daily basis and is repeatedly exposed to them.

A further problem is that the reconstitution procedure provides a source of confusion as to which container contains which drug. The diluent container should be marked with the drug with which it has been injected and the name of the patient to whom it should be delivered.

After a drug is reconstituted and withdrawn into a syringe barrel, the drug may in some instances be injected immediately into the intravenous system of a patient. More typically, however, the reconstituted drug is injected from the syringe into a larger container of solution as discussed above, for connection to an intravenous administration set. This is because often the drug reconstituted in the syringe is still at a concentration so high as to cause local toxicity in the veins of a patient near the injection site where the needle pierces the skin. This may create severe vein irritation which may be medically harmful.

Additionally, even though the proper dose of medication is in the syringe, immediate injection into the patient's blood stream may create a condition of

systemic toxicity wherein the level of drug concentration in the patient's entire blood stream is dangerously high. Yet another reason for not making the injection from the syringe directly into the patient is that it creates an additional injection site into the patient, which may be painful for the patient and provides another opportunity for infection.

For these reasons, the reconstituted drug is more typically injected into a diluent container. A patient may typically be administered a dextrose or saline solution from a large volume parenteral container, for example, such as a one liter container, delivered through an administration set such a CONTINU- FLO ^® administration set sold by Baxter Healthcare Corporation. If the reconstituted drug were injected into the large volume parenteral container, delivery of the drug would usually be made over too long a time period. Often, these large volume fluids are delivered at very slow flow rates. More typically, the reconstituted drug is injected into a small volume parenteral container, such as a fifty milliliter container sold by Baxter Healthcare Corporation. This MINIBAG ^™ container is hung at a higher elevation than the large volume parenteral container and is connected by a secondary administration set to an injection site on the primary administration set. Because it is maintained at a higher elevation, the reconstituted drug in the small volume container is delivered, after which fluid from the large volume container begins to flow once more. By utilizing a small volume container connected to an administration set for delivery of the drug or other beneficial agent instead of a direct syringe injection, the drug is delivered over

a preferred time period that tends to minimize negative side effects.

Closed reconstitution delivery systems are disclosed in U.S. Patents Nos. 4,410,321; 4,411,662; 4,432,755; and 4,458,733, all assigned to Baxter International. As shown therein, a container includes a drug and a diluent in separate compartments which are reconstituted in a closed system before the drug is delivered to the patient. Typically, the container is connected to an administration set which is connected at its other end to the primary administration set, such as with the small volume parenteral container described above. The container shown in these patents solves many of the problems associated with syringe reconstitution. The product does however necessitate a series of reconstitution steps which must be performed by the nurse or other operator prior to delivering the fluid from the container.

In U.S. Patent No. 4,850,978, there is disclosed a drug delivery system including a cartridge for introducing a beneficial agent into a fluid conduit for delivery of the agent to a patient. The cartridge includes a rigid, plastic hollow tube and an agent- containing chamber slidably mounted at least partially within the tube.

Typically, the housing includes a receptacle which is placed in-line in a medical liquid administration set and a separate cartridge including the beneficial agent. The cartridge is plugged into the receptacle when it is desired to deliver the beneficial agent to the patient. Active reconstitution by a nurse or other operator is not required. Instead, once the cartridge is plugged into the receptacle, liquid flowing from the source of medical

liquid through the administration set flows into the receptacle and the agent-containing cartridge, reconstituting the agent. The solution with agent therein flows out the receptacle, down the administration set to the patient's venous system.

In a first, pre-use position, the chamber extends farther from the hollow tube than it does in a second-use position. A cannula is mounted to the hollow tube extending opposite the chamber. When the chamber is in the second position, the cannula pierces a closure means creating a fluid flow path.

U.S. Patent No. 4,804,366 also discloses a drug delivery system including an adapter having a flow path means providing both an inlet and an outlet to the agent- containing chamber of a cartridge. The cartridge and adapter permit a single opening through the injection sites at opposite ends of the flow path means, while still permitting simultaneous flow both into and out of the chamber. Both an adapter and cartridge are provided including a rigid cannula with an inlet and an outlet and a shell substantially coaxial and spaced from the cannula intermediate of the cannula inlet and the cannula outlet, so that the cannula defines a channel therebetween. Both the cannula inlet and the cannula outlet are adaptable to form a single piercing opening in a resilient injection site associate with the receptacle of the delivery system. Both the channel outlet and channel inlet are adapted to form a single piercing opening in a resilient injection site associated with the cartridge. The two above described systems provide automatic systems for drug delivery and reconstituting a drug. Manual devices that can be used for reconstituting a drug in a vial do not typically have the same concerns that

are faced in automatic systems, such as those described above. Typically, in manual systems, the cannula is used to infuse liquid and a separate member is used to vent air as disclosed in U.S. Patent No. 4,537,593. High pressure and high velocity diluent is passed through the cannula for a short period of time. The vials, after the diluent is injected, are typically manually agitated prior to complete drug dissolution. Pressure differential between the vial contents and the syringe barrel drive the mixture into the syringe. To that end, the user can pull a vacuum in the syringe barrel.

A number of concerns and requirements are raised in automatic systems that are not typically present in such manual systems. In a reconstitution device, fluid passing through the drug bed by means of an inlet and an outlet at opposite ends of the vial erode the drug. Dissolution of the drug is correlated to fluid volume throughput. Due to the low operating system pressure and delivery rates of automatic systems, it is important that restrictions are not created through the outlet of the cannula that impede fluid flow.

A further requirement with respect to drug delivery or reconstitution devices is the need to maintain the integrity of the system. It is, therefore, important to maintain a closed system during vial inactivation, i.e., when the cannula pierces the septum.

Furthermore, unlike manual reconstitution devices, automatic reconstitution devices require a different set of flow conditions. Additional issues may also be raised in automatic systems, such as those set forth above, with respect to the manufacture of the needle/shell assembly.

SUMMARY OF THE INVENTION The present invention provides an improved cannula structure for a drug delivery device. The improved cannula structure is particularly useful in a reconstitution device.

In an embodiment, the invention provides a cannula structure having a cannula with a tubular member or shell secured thereabout in surrounding relationship. The shell is secured around the cannula solely by the exertion of sufficient force by the interior walls of the tubular member on the cannula. The shell, however, is secured so as to form at least one fluid path between an exterior wall of the cannula and the interior wall of the tubular member. The cannula structure then can be secured in a reconstitution device.

In an embodiment of the invention, a cannula is provided with a tubular member secured thereabout in surrounding relationship by crimping the tubular member on opposite sides of the cannula and forming at least two fluid paths on opposite sides of the cannula between an exterior wall cannula and an interior wall of the tubular member.

In an embodiment of the invention, the cannula is made of stainless steel. In an embodiment of the invention, the tubular member is made of stainless steel.

In an embodiment of the invention, the cannula has a non-coring end.

In an embodiment of the invention, the cannula has first and second ends and a channel therebetween, the first end being closed and including a member for piercing a septums.

In an embodiment, at least one end of the tubular member is sealed about the cannula and openings are provided in the tubular member near that end so as to provide fluid communication between an exterior of the tubular member and the channel formed between the cannula and the tubular member.

An advantage of the invention is that it provides a cannula structure that can be constructed without the production of flash which can interfere with fluid flow. A further advantage of the invention is to provide a cannula structure in which the cannula and tubular member can be constructed with reduced risk of misalignment therebetween.

Another advantage of the invention is the provision of a cannula structure for a reconstitution device cartridge with theoretical flow rates that are significantly better than prior art cartridge constructions.

Moreover, an advantage of the present invention is to provide an improved drug delivery device.

Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the presently preferred embodiments and from the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a fragmentary cross-section view of a drug reconstitution device including an embodiment of the cannula structure of the present invention.

Figure 2 illustrates in cross-section an adapter including an embodiment of the cannula structure of the present invention.

Figure 3 illustrates in longitudinal view the cannula structure of Figure 2.

Figure 4 illustrates a cross section of the cannula structure of Figure 3 taken generally along the line IV- IV of Figure 3.

Figure 5 illustrates an enlarged fragmentary view of a portion of the cannula structure of Figure 3.

Figure 6 illustrates an enlarged fragmentary view of a portion of another cannula structure. Figure 7 illustrates a longitudinal view of another cannula structure.

Figure 8 illustrates an enlarged fragmentary view of a portion of the cannula structure of Figure 7.

DETAILED DESCRIPTION OF THE

PRESENTLY PREFERRED EMBODIMENT

Pursuant to the present invention there is provided an improved cannula structure particularly useful for drug reconstitution devices. This improved cannula structure is believed to be more easily mass manufactured with fewer defects than prior structures.

Referring to the figures, and specifically Figure 1, illustrated generally is a receptacle 10 of a drug reconstitution device. Such a receptacle is described in greater detail in, for example, U.S. Patent No. 4,804,366, the disclosure of which is incorporated herein by reference. The receptacle 10 illustrated in Figure 1 is representative not only of the receptacle but also of the drug delivery system as also disclosed and described in U.S. Patent No. 4,804,366.

Briefly, however, the receptacle 10 is configured to be mounted on a fluid conduit adapted for receiving a separate cartridge 12 containing a beneficial agent,

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as is also illustrated in Figure 1. When the cartridge 12 is mounted on the receptacle 10, the liquid is removed from a liquid source container that flows through a conduit 14 into the receptacle 10, also flows through the cartridge 12 before passing downstream out of the receptacle 10 to the patient.

As will be appreciated from Figure 1 as well as with reference to U.S. Patent No. 4,804,366, the receptacle 10 includes a receptacle inlet 16 connected to the fluid conduit 14 and an outlet formed by an air flask inlet portion 18. The associated air flask is disposed downstream of the receptacle outlet 20.

The receptacle 10 includes upper and lower fitments 24 and 26, respectively. The upper fitment 24 includes the inlet 16. The lower fitment 26 includes the outlet 20. A pierceable, resilient injection site 28 is mounted within the upper fitment 24 of the receptacle 10, such as by ultrasonically swaging a mount 30 for the injection site 28. The upper and lower fitments 24 and 26 may be bonded together by adhesive, ultrasonic sealing, etc. It is important that the injection site be securely maintained within the receptacle because of a plurality of cartridges 12, each having a cannula structure 40 with a cannula 42, may be mounted on and removed from the injection site 28 during the useful life of the receptacle 10 and the administration set of which the receptacle is a part.

The receptacle 10 includes a resilient divider 44 trapped between the upper and lower fitments 24 and 26. The resilient divider 44 defines a narrow through bore 46 directly below the resilient pierceable injection site 28. Only that portion of the divider 44 that defines the

through bore 46 utilizes resiliency as a desirable quality; however, for ease of manufacture, it is simple to define the through bore 46 with the divider 44, the divider 44 defining the flow path through the receptacle 10.

As can be appreciated, fluid flowing from a container such as a parenteral container flows through the inlet 16, whereupon it flows into the receptacle 10 above the divider plate 44, through the through bore 46 and downstream to the receptacle outlet 20 and from thence downstream through the air flask inlet 18 to the patient.

The cartridge 12 is illustrated with an adapter 50 for introducing a drug or other beneficial agent into the fluid flowing through the receptacle 10. Alternatively, the adapter 50 may be a separate unit suitable for connecting a beneficial agent chamber, for example, a vial 52 with the receptacle 10.

As will be appreciated with reference both to Figures 1 and 2, the adapter 50 includes a rigid, hollow cylinder or tube 54 and a keyway wall 56 with keyway slot 57, with the keyway wall 56 forming part of the tube 54. A plate 58 is mounted across the tube 54 and defines the starting point for the keyway wall 56. A rigid cannula structure 40, extends through the plate 58. A generally cylindrical cannula structure holder 60 extends from both sides of the plate 58. The hollow tube 54, the plate 58 and the holder 60 may all be formed as a single piece of the same material, such as of plastic.

The cannula 42 includes an inlet 62 and an outlet 64. In the preferred embodiment, the outlet 64 is pointed to facilitate piercing. However, the cannula can

have a conical shape. The cannula 42 preferably is, but not necessarily so, made from a single piece. As described in more detail below, disposed about the cannula 42 is a tubular member or shell 70. The tubular member 70 is secured about the cannula 42 in surrounding relationship by the exertion of sufficient force by an interior wall of the tubular member on the cannula. The tubular member 70 and cannula 42 together form what is referred to herein as the cannula structure 40. As also illustrated, the surrounding tubular member

70 is shorter in axial length than the cannula 42. The manner by which the tubular member 70 is secured to the cannula 42 will be described in greater detail below. However, it is sufficient at this point to understand that the tubular member 70 is secured to the cannula 42 so as to remain sufficiently immobile relative thereto.

As also illustrated in Figure 2, the holder 60 is configured to accept therein the tubular member 70 in snug relationship such that the cannula structure 40 is rigidly maintained and secured in place within the adapter 50. If desired, the tubular member 70 can be secured to the holder by ultrasonic welding, swaging, adhesives, insert molding or other means.

The tubular member 70 and cannula 42 are sized such that an inner diameter of the tubular member 70 is greater than an outer diameter of the cannula 42. Thus, a space or gap 72 is formed between them through which fluid can flow. Accordingly, fluid can enter the space 72 at one axial end of the tubular member 70 and exit the space at the opposite axial end.

With respect to Figure 1, when the adapter 50 is secured to the injection site 28 as illustrated, fluid flowing from a container, such as a parenteral container,

flows through the unit 16, whereupon it flows into the receptacle 10 above the divider 44. From that point, the fluid flows up through the space 72 between the tubular member 70 and the cannula 42 and into the container 52. After entering the container 52, the fluid mixes with whatever is contained therein. When the level of fluid in the container 52 rises above the top of the cannula 42, it flows down through a flow path 74 in the cannula 42 and through the through bore 46 to the outlet 20 of the receptacle 10.

With reference now to Figures 3 to 8, preferred embodiments of various tubular structures or shells will be described.

In Figure 3, the cannula structure 40 of Figures 1 and 2 is reproduced standing alone. As more clearly illustrated in Figure 3, the tubular member or shell 70 is secured about the cannula 42 by crimping the tubular member 70 on opposite sides 71, 73 of the cannula 42 so that essentially the tubular member 70 is crushed to conform, in part, about the outer diameter of the cannula 42. The crimping is illustrated best in Figure 4 wherein a cross section of the cannula structure 40 of Figure 3 is illustrated.

As further illustrated in Figures 3 and 4, because the tubular member 70 is of a greater interior diameter than the outer diameter of the cannula 42, a space is provided between the tubular member 70 and the cannula 42 through which fluid can flow. As such, the cannula structure 40 provides two fluid flow paths, namely, the flow path 72 as well as the flow path 74 through the interior of the cannula 42 as well as the flow path 72 between an outer wall of the cannula 42 and an inner wall of the tubular member 70. It can be appreciated that the

flow path provided between the cannula 42 and the tubular member 70 is substantially annular in shape except at the point where the tubular member 70 is crimped so as to secure the tubular member 70 to the cannula 42. At that point, as illustrated in Figure 4, the singular fluid flow path is divided into two parallel fluid flow paths 76 and 78 on opposite sides of the cannula 42. After the point at which the tubular member 70 is crimped, these two fluid flow paths rejoin to form the annular fluid flow path 72.

As illustrated best in Figure 5, at an axial end 80 of the tubular member 70, there is provided an outlet 81 between the tubular 70 and the cannula 42 by forming an annular gap between the axial end 80 and the exterior wall of the cannula 42, so that fluid can flow out from the fluid flow path in the space 72 between the cannula 42 and the tubular member 70. As illustrated in Figure 5, the exterior of the axial end 80 of the tubular member 70 can be formed so as to be rounded thereby eliminating any sharp corners.

As illustrated in Figure 6, an axial end 90 of another tubular member 92 can be tapered so as to be merely angled toward a cannula 94. Similarly, however, an annular gap or opening 93 is provided between the exterior wall of the cannula 94 and the axial end 90 of the tubular member 92, so that fluid can flow from within a space 96 between the cannula 94 and the tubular member 92 to the exterior.

In Figures 7 and 8, there is illustrated another embodiment of the invention wherein there is provided a cannula structure 100 having a non-coring cannula 102, to this end, the cannula includes a closed conical piercing end 104, but that includes openings or slots 106

to allow fluid communication between an exterior of the cannula 102 and the interior flow path 107 thereof.

Additionally, in the structure 100 illustrated in Figures 7 and 8, an axial end 108 of a tubular member 110 secured about the cannula 102 is closed about the cannula 102 such that no gap or flow path is provided between the axial end 108 of the tubular member 110 and the cannula 102. Instead, to provide the requisite fluid flow path, a series of openings 112 are provided short of the axial end 108 of the tubular member 110 through which fluid can flow. Thus, fluid can flow into the opening 112 at one end of the tubular member 110 through an interior flow path 114 along the axial length of the tubular member 110, and thence out the opening 112 at the other axial end of the tubular member 110. Of course, this tubular member 110 can also be used with a pointed cannula.

The tubular member 110 is illustrated as being crimped or squeezed on opposite sides 116 and 118 in the manner described above to secure the tubular member 110 to the cannula 102.

While in the foregoing embodiments, the one end of the cannula was provided with a piercing end and the other end was provided with a blunt end, it can be appreciated that other types of cannulas can be used, for example, cannulas having two piercing ends. Further, cannulas having two non-coring ends as well as cannulas having two coring ends can be used.

In a preferred embodiment, both the cannula and the surrounding tubular member are made of stainless steel. The foregoing cannula structures provide benefits over prior insert molded cannula structures.

As would be appreciated, the results of loading of a cannula into a mold for overmolding with a plastic

shield and the like is operator dependent, and thus out- of-tolerance placement can occur. Further, serious mold damage could arise if the cannula is sufficiently out of placement during the molding process. In that regard, the tolerance window of a diagonal interference press fit for a cannula is very narrow, in the range of 0.003 inches. This dimension is one of the first defects seen as a result of mold wear. The second defect seen is the creation of flash which is a critical defect reducing flow.

In addition to the foregoing, short shots and knit lines may not be seen by in-process inspection and this can cause a poor interference press fit. Needle bending during molding can constitute another major defect. With respect to the cartridges, such as the cartridge 12 and adapter 50 assembly described above, the cartridge has at least one critical press fit. Sinks which intermittently appear in the press fit inner diameter can cause a poor interference press fit. These sinks could go undetected during inspection.

Further, flash or poor pin mismatch can cause blockage or reduce the flow in the resulting cartridge at the radial gap flow inlet.

Based on theoretical predictions, a receptacle and cartridge assembly, such as that illustrated in Figure 1 of the present invention and described in U.S. Patent No. 4,804,366, incorporating the cannula structure described herein will reduce a total cartridge pressure drop by approximately 42% over prior art structures. Moreover, in the press fit design illustrated and described in U.S. Patent No. 4,804,466, the inlet hub flow path which is provided in the press fit region accounts for approximately 50% of the total cartridge

drop. However, in utilizing the cannula structure of the present invention, the inlet flow path accounts for 14% of the total cartridge pressure drop and the cannula becomes a single dominating factor in the overall pressure drop.

The following are theoretical cartridge pressure drop comparisons:

(Pressure Drop in H ₂ 0) U Uttiilliizziinngg Utilizing Cannula Structure

Set Flow Rate Cannula Structure With Cannula Press Fit

(ml. Per Hour) of Invention Into Qvermolded Shell

60 0.60 1.01 1 12200 1 1..1166 2.02

150 1.45 2.52

240 2.32 4.02

500 4.83 8.39

1000 9.66 16.77 From the foregoing, it can be appreciated that the cannula structures disclosed herein and forming part of the present invention provide an improved structure for a reconstitution device.

It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.