Note: Descriptions are shown in the official language in which they were submitted.
CA 02265806 2001-01-26-1-SYRINGE SYSTEM ACCOMMODATING SEPARATEPREFILLED BARRELS FOR TWO CONSTITUENTSTECHNICAL FIELDThis invention relates to a syringe system forpackaging, mixing and delivering two constituents orcomponents that are stored separately in isolation fromeach other but which must be combined or mixed togetherprior to delivery. The invention is particularlysuitable for use with a medicament, such as ea drug inpowder form, which must be dissolved and diluted in aliquid prior to delivery.BACKGROUND OF THE INVENTION ANDTECHNICAL PROBLEMS POSED BY THE PRIOR ARTIn some medical applications, as well as in someindustrial or other applications, it is necessary, or atleast preferable, to maintain two components orconstituents in isolation prior to combining the twocomponents for subsequent delivery as a solution,mixture, or other combination.For example, some pharmaceutical preparations, suchas injectable solutions or suspensions of a drug, are notsufficiently stable to accommodate prolonged storageprior to use. However, the components of the solution orsuspension may have adequate stability if the componentsare stored separately prior to being combined.It would be desirable to provide an improved syringesystem that will accommodate the packaging of two suchcomponents in isolation from each other, but which can besubsequentlyâ operated to combine or mix the componentsfor delivery. In particular, it would be advantageous toprovide such an improved syringe system101520253035CA 02265806 l999-03- 16W0 98/ 13088with the capability, where necessary, for employingcomponent prefilled barrels that can be manufacturedand/or stored separately as well as together.It would be especially advantageous if such anemployed with two liquidcomponents as well as with at least one solid component.It would be desirable with such a system toseal both components from the ambientatmosphere as well as from each other.improved system could bepositivelyIt would also be beneficial if such an improvedsystem could be provided in a self-contained form that iscompact, portable, simple to manipulate, land readilyadaptable to different proportions and dosages of thecomponents.Additionally, it would be desirable if such animproved system could readily accommodate the storage,mixing and administration of a variety of drugs whichrequire reconstitution and/or dilution including, amongother types, a medicament in powder form requiring mixingwith a «diluent, a medicament in liquid form requiringmixing with a diluent, and arequiring mixing with a diluent.The presentlyophilized compoundinvention. provides an improvedpackaging, mixing and deliveryembodimentsbenefits and features.system whichthecanaccommodate having aboveâdiscussedSUMMARY OF THE INVENTIQNThe present invention provides a syringe systemfor storing two components or constituents in isolationfrom each other. The system can be subsequently operatedfor combining or mixing the two constituents and for thendelivering the combination.The syringe system includes first and secondprefilled containers which each includes first and secondPCT/US97/171941015'202530W0 98/13088CA 02265806 l999-03- l6PCT/US97/17194prefilled syringe barrels, respectively. The first barrelincludes an open end and an opposite substantially closeddelivery end. The delivery end defines a delivery passageor dispensing passage to accommodate the delivery ordispensing of fluid from the first barrel.first removablePreferably, aclosure âis provided to occlude thedelivery passage. A reciprocable stopper or moveable sealis slidably disposed in the first barrel to define a firstchamber. The first chamber is preferably prefilled witha first constituent between the reciprocable stopper andthe delivery end.The second barrel is sized to be disposed in thefirst barrel and has an open end and an oppositesubstantially closed discharge end having a dischargepassage to accommodate the discharge of fluid from thesecond barrel. Preferably, a second removable closure isprovided to occlude the discharge passage. A slidableplunger is sealingly disposed within the second barrel todefine a second chamber. The second barrel is preferablyVprefilled with a liquid second constituent in the second_chamber between _thedischarge end and the slidableplunger.In order to combine the two constituents, theâsecond closure, if any, is first removed from the secondbarrel discharge end. The first barrel reciprocablestopper and the second barrel discharge end are engageableto cooperatively define a coupling or fluid transferconnector means for accommodating the flow of the liquidsecond constituent from the second chamber into the firstchamber. connecting means forconnecting the second barrel with the reciprocable stopperin the first barrel, and (b) fluid communicating means forThis can include (a)establishing fluid communication between the first andsecond chambers. As the second barrel discharge end and1015202530W0 98/13088CA 02265806 l999-03- l6PCT/US97/17194plunger are moved closer together, the liquid constituentis moved (i.e., pushed) from the second chamber into thefirst chamber where the liquid second constituent mixeswith the first constituent. The assembly may be shaken topromote mixing.Subsequently, the first closure can be removedfrom the first barrel. Then the second barrel, which isengaged with the reciprocable stopper, can be pushedinwardly. This movement carries both the second barreland coupled reciprocable stopper inwardly into the firstchamber. This coupled movement dispenses the mixedcontents of the first chamber through the deliverypassage.Numerous other advantages and features of thepresent invention will become readily apparent from thefollowing detailed description of the invention, from theclaims, and from the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGSIn the accompanying drawings that form part of_the specification, and in which like numerals are employedto designate like parts throughout the same,FIG. 1 is a partial cross-sectional view of afirst embodiment of the syringe system of the presentinvention showing the first and second containers beforethe container barrels are coupled together;FIG. 2 is a greatly enlarged, fragmentary,crossâsectional view of the discharge end of the secondbarrel;FIG. 3 is a view of the components of FIG. 1 ina coupled condition with the reciprocable stopper in thefirst barrel penetrated by the piercing needle of thesecond barrel just prior to the plunger of the secondbarrel being moved toward the discharge end;1015202530W0 98/13088CA 02265806 l999-03- l6PCT/US97/17194FIG. 4 is a view similar to FIG. 3, but FIG. 4shows the liquid contents of the second barrel completelydischarged into the first barrel;FIG. 5 is a greatly enlarged, fragmentary,cross-sectional view of the delivery end of the firstbarrel shown with the first closure removed and replacedwith a needle; 'FIG. 6 is a cross-sectional view of a secondembodiment of the present invention showing the separatefirst and second barrels of the containers prior to beingcoupled together;FIG. 7 is a greatly enlarged, fragmentary,cross-sectional view of the conduit assembly andreciprocable stopper in the first barrel of the secondembodiment; 6FIG. 8 is a perspective view of the valve memberemployed in the reciprocable stopper of the secondembodiment;FIG. 9 isâa top plan view of the valve membershown in FIG. 8;FIG. 10 is a view similar to FIG. 7, but FIG. 10shows a third embodiment of the present invention havinga modified reciprocable stopper;FIG. 10A is a fragmentary, bottom plan viewtaken along the plane 10A-10A in FIG. 10;FIG. 11 is a cross-sectional view of a fourthembodiment of the present invention showing the separatefirst and second barrels of the containers prior to beingcoupled together;FIG. 12 is a greatly enlarged, fragmentary,cross-sectional view of a portion of the assembledcomponents of the fourth embodiment showing the secondbarrel being operated to open the mixing valve of thefirst barrel;10153202530WO 98/13088CA 02265806 l999-03- l6PCT/U S97/ 17194FIG. 13 is a cross-sectional view of a fifthembodiment of the present invention showing the separatefirst and second barrels of the containers prior to beingcoupled;FIG. 14 is a greatly enlarged,cross-sectional view offragmentary,a portion of the assembledcomponents of the fifth embodiment showing the secondbarrel being operated to open the mixing valve of thefirst barrel;FIG. 15 is a cross-sectional view takengenerally along the plane 15-15 in FIG. 14;FIG. 16 is a cross-sectional view takengenerally along the plane 16-16 in FIG. 15; andFIG. 17 is a fragmentary, cross-sectional viewof a portion. of the assembled components of a sixthembodiment of the present invention showing the secondbarrel being operated to open the mixing valve in thefirst barrel.DESCRIPTION OF THE PREFERRED EM'BODIME§§â_While this invention is susceptible ofembodiment in.many different forms, this specification andthe accompanying drawings disclose only some specificforms as examples of the invention. The invention is notintended to be limited to the embodiments so described,however. The scope of the invention is pointed out in theappended claims.Figures illustrating the apparatus show somemechanical elements that are known and that will berecognized tar one skilled in the art. The detaileddescriptions of such elements are not necessary to anunderstanding of the invention, and accordingly, areherein presented only to the degree necessary to1015202530W0 98/ 13088CA 02265806 l999-03- l6PCT/US97/17194facilitate an understanding of the novel features of thepresent invention.A first embodiment of the prefilled syringesystem of the present invention is illustrated in FIGS.1-5 and is designated generally therein by the referencenumber 20. The system may be generally characterized asincluding two "containers" for separately storing twoconstituents or components in isolation from each other,but which can be subsequently operated to combine or mixthe components for deliveryu The first container includesa first barrel 22 having an open end 24 and an opposite,substantially closed, dispensing end or delivery end 26defining a delivery passage or dispensing passage 28. Thefirst barrel 22 is preferably fabricated from a syntheticpolymer, such as a thermoplastic material, but the barrelmay be made of other suitable material such as glass.A first constituent or component 40 is providedin the first barrel 22. The constituent 40, in thepreferred embodiment contemplated for use in medicalapplications, can be a drug or other medicament ingranular form, powder form, or other particulate form.The first constituent may" also be a liquid. It iscontemplated that the constituent 40 in the first barrel22 would typically be a drug which, if in solid form,requires reconstitution, or if in liquid form, requiresdilution. Thus, the system of the present invention willbe useful in the containment of hazardous drugs such asare used in oncological applications or in biotechnologydelivery applications.Preferably, the delivery end 26 defines anexterior thread form 30 for receiving a threaded cap orfirst removable closure 32 and for subsequently receiving,upon removal of the closure 32, a suitable dispensingcomponent, such as a hollow needle 34 described1015202530W0 98/13088CA 02265806 l999-03- 16PCT /US97/17194hereinafter in detail with reference to FIG. 5. Any othersuitable conventional or special capping system may beemployed. ,A reciprocable stopper 42 is slidably disposedin the first chamber 24 above the first constituent 40.Preferably, the reciprocable stopper 42 is fabricated froma resilient, elastomeric material. In the preferred form,_the reciprocable stopper 42 has an uncompressed diametersomewhat larger than the diameter of the chamber 24. Afriction-fit engagement is established between the stopper42 and the chamber 24 that is sufficient to hold thestopper 42 in place on top of the constituent 40 duringnormal packaging, shipping and handling. However, theforce of engagement is sufficiently lowito permit slidingof the stopper 42 along the chamber 24 when the stopper 42âis subjected to a sufficiently high. axial force asdescribed in detail hereinafter.The reciprocable stopper 42 may'be alternativelydescribed as a moveable seal, slidable seal, piston, orgrommet. All of these terms may be regarded asinterchangeable herein. The term."moveable seal" has beenused imx the above-identified parent patent applicationSerial No. 08/408,463. However, the term âreciprocablestopper" is generally used herein to define the same oranalogous components.As illustrated in Fig. 1, it is also preferredto provide an outer cover 44 over the upper, open end ofthe first container barrel 22. This prevents ingress ofcontaminants. The cover 44 may be an adhesive backed,flexible web that can be readily pulled off just prior touse of the system.The first barrel 22 may be regarded as a firstcontainer together with the closure 32, stopper 42, andcover 44 for storing the first component 40 and1015202530W0 98/ 13088CA 02265806 l999-03- l6PCT/US97/ 17194subsequently mixing the first component 40 with anothercomponent as explained in detail hereinafter.A second constituent or component 46, in theform of a liquid, is sealed within a second barrel 48.The liquid constituent 46 would typically be a diluent fordiluting and/or reconstituting the first constituent 40.The second barrel 48 may be formed from the same syntheticpolymer materials as used for the first container 22.The second barrel 48 preferably includes agenerally cylindrical wall portion 50 that is sized to bedisposed in the first container 22 (ï¬xes. 3 and 4).Initially, in the pre-assembled condition, the secondbarrel 48 is preferably encased in a protective sleeve 52which must be removed prior to use.The second barrel 48 also includes a plungerassembly' or plunger assemblyâ or plunger 64 which isslidably disposed within the cylindrical barrel 50. Theplunger 64 includes a plunger shank or stem 70 with athumb push flange at one end and a piston 68 at the otherend slidably received within the barrel cylindrical wallportion 50.The piston 68 is preferably elastomeric and isinitially located at the upper end of the second barrel 48in contact with. the liquid second constituent 46 asillustrated in FIG. 1. For packaging convenience, theplunger shank 78 may be provided with a threaded end orsnap-fit end 72 for engaging a mating thread form or snap-fit form in the top of the piston 68. Such a structurepermits packaging of the system components with theplunger shank 70 not initially connected or assembled withthe piston 68. when it is subsequently desired to use thesystem, the user can thread or snap-fit the shank 70 intothe piston 68.1015202530W0 98/ 13088CA 02265806 l999-03- l6PCT/US97/17194.10.The second barrel 48 has a discharge end 56defining a discharge passage communicating through thedischarge end to accommodate the discharge of fluid fromthe barrel 48. In the first embodiment illustrated inFIGS. 1-5, the second barrel discharge passage is definedby the hollow interior of a piercing needle 60 which ismounted in the discharge end of the second barrel 48.Preferably, the second barrel 48 is initiallyprovided to the user with a second cap or removableclosure 62 mounted to the second barrel discharge end 56over the piercing needle 60 as shown in FIG. 2. Thesecond closure 62 may be held on the discharge end of thesecond container by means of a snapâfit (or by othermeans, e.g.; a threaded engagement (not illustrated).The second barrel 48 may be regarded as a secondcontainer together with the closure 62 and plunger 64 forstoring" and subsequentlyâ functioningâ as a. syringe todischarge the liquid second constituent 46 into the firstcontainer barrel 22 as will be explained in detailhereinafter.The operation.of the packaging syringe system 20will next be described with reference to the sequentialoperational steps illustrated in FIGS. 3-5. The firststage of the operation is illustrated in FIG. 2.Just prior to use, the second closure 62 isremoved to expose the piercing needle 60. Preferably,before the second closure 62 is removed, the second barrel48 is inverted (so that the piercing needle 60 is pointinggenerally upwardly). This will ensure that the liquidconstituent 46 cannot drip out. However, even if thesecond barrel 48 is not inverted, the liquid constituent46 will not drip out. This is because the second barrel48 has no vent system. A vent system would admit ambientair into the second barrel 48 so as to permit the liquid1015202530W0 98/ 13088CA 02265806 l999-03- l6PCT/US97/ 17194.11-constituent to flow out through the needle 60 solely underthe influence of gravity. Without such venting, theliquid constituent 46 remains in the second barrel 48 andis not able to flow out through the piercing needle 60._ with the second barrel 48 preferably inverted topoint the piercing needle 60 upwardly, the first barrel 22is inverted and aligned with the second barrel 48. Thenrelative movement is effected so as to locate the distalend of the second barrel 48 in the first barrel 22. Asillustrated in FIG. 3, the second barrel 48 is insertedinto the first barrel 22 until the piercing needle 60engages, and penetrates completely through, thereciprocable stopper 42 of the first barrel 22.Before and during the step of inserting thesecond barrel 48 inside the first barrel 22, the moveableplunger 64 is not moved relative to the second container48. The plunger 64 remains in the initial, outermostorientation. After the two barrels are telescopicallydisposed with the piercing needle 60 fully penetrating thestopper 42 in the first barrel 22, the plunger 64 ispushed inwardly within the second barrel 48 (i.e., towardthe discharge passage in the needle 60 of the secondbarrel 48). The plunger movement causes the liquid secondconstituent 46 to flow out through the hollow piercingneedle 60 to mix with the first constituent 40 within thefirst chamber 24, The hydraulic pressure within the firstchamber 24 acts on the stopper 42 and the abutting distalend of the second barrel 48. The increasing pressuremoves (i.e., pushes) the reciprocable stopper 42 and thesecond barrel 48 outwardly relative to the first barrel22. It will be appreciated that the ambient atmosphericpressure bears on the outside surface of the plungerpiston 68, and this additional pressure is effective in1015202530WO 98/13088CA 02265806 l999-03- l6PCT/US97/17194-12.aiding the discharge of the liquid second constituent 46into the first chamber 24.When the piston 68 is seated at the bottom,discharge end of the second barrel 48, the top, open endof the second barrel 48 is adjacent to the thumb pushflange at the top of the plunger 64 (as shown in FIG. 4).Substantially all of the liquid second constituent hasbeen discharged through the hollow piercing needle 60 intothe first chamber 24 of the first barrel 22 where it formsa solution.with, mixes with, or is otherwise combined withthe first constituent 40. The assembly can be shaken toensure good mixing.After the constituents are sufficiently mixed,the first closure 32 is removed from the first barrel 22,and the delivery end 26 can be connected to a receivingcomponent or discharge component, such as a flexiblecontainer or tubing set (not illustrated). Optionally, ahollow needle 34 is mounted at the distal end of the firstbarrel delivery end 26. The needle 34 may be of aconventional, singleâended type with a straight, hollow,stainless steel shaft, typically 20 gauge in size. Theneedle 34 may be provided with a swaged or molded hub 74(FIG. 5) for engagement with the bottom, distal end of thedelivery end 26 of the first barrel 22.When properly mounted on the first barrel 22,the needle 34 is in alignment with the delivery passage28, and fluid communication is established between thedelivery passage 28 and the needle 34. After the needle34 is properly mounted on the first barrel 22, (or afterthe first barrel 22 is otherwise properly connected tosome suitable receiving component), the plunger 64 andsecond barrel 48 can be moved forward by applying an axialforce. This causes the combined constituents in the first1015202530WO 98/13088CA 02265806 l999-03- l6PCT/US97/ 17194.3.chamber 24 to be dispensed or expelled from the chamber 24through the needle 34.It will be appreciated that the first barrelstopper 42 has a portion which is fullypenetratable by the needle 60. That stopper centralportion and the piercing needle 60cooperatively define a fluid transfer connector means orcoupling means incorporating (a) fluid communicatingtneansand (b) connecting means.l The fluid communicating meansincludes the flow passage through the needle 60 which isoperative to accommodate the flow of the liquid secondcentralsecond barrelconstituent from the second barrel 48 into the firstchamber 24 of the first barrel 22. The connecting meansincludes the sealing engagement between the exterior ofthe needle 60 and the stopper 42 which accommodates themovement of the stopper 42 together with the second barrel48--first outwardly as the liquid second constituent 46 ismoved (i.e., forced or pushed) into the first chamber 24,and subsequently inwardly outwardly into the first chamber24 to dispense the combined constituents.An alternate second embodiment of the syringesystem of the present invention is illustrated in FIGS. 6-9. Elements in the alternate embodiment which are thesame as, or which function in an analogous manner to,elements of the first embodiment illustrated in FIGS. 1-5are designated with three digit reference numbers whereinthe last two digits are the same as the two digits of thereference number of the corresponding element in the firstembodiment.with reference to FIG. 6, the second embodimentof the syringe system includes a first barrel 122 and asecond barrel 148. The first barrel 122 has an open upperend which is initially sealed with a removable cover 144.The first barrel 122 containsa first component or101520-2530W0 98/13088CA 02265806 l999-03- l6PCT/US97I 17194.u.constituent 140. The first constituent 140 is depositedin the bottom of the first barrel 122 which defines adispensing end or delivery end 126 having a dispensingpassage or delivery passage 128 communicating through thedispensing end or delivery end 126 to accommodate thedispensing of fluid from the first chamber 124.The closed delivery end 126 preferably includesa concentrically extending collar with an interiorthreaded form for receiving a first removable closure 132as shown in FIG. 6. Upon removal of the closure 132, thedelivery end 126 can be threadably mated with a suitablereceiving component, such as a stopcock or an .IVadministration set (not illustrated).A reciprocable stopper 142 is slidably disposedin the first barrel 122 and, together with the firstbarrel 122, defines a first chamber 124 which is initiallyfilled with the first constituent 140. The stopper 142 is'retained with sufficient frictional engagement to preventits movement within the first barrel 122 during normalstorage, transport, and handling.stopper 142 may bealternatively described as a moveable seal, slidable seal,The reciprocablepiston, or grommet. All of these terms may be regarded asinterchangeable herein. The term "moveable seal" has beenused in the above-identified parent patent applicationSerial No. 08/408,463. However, the term "reciprocablestopper" is generally used herein to define the same oranalogous components.Preferablyy the reciprocable stopper 142 isfabricated from a resilient elastomeric material. In thepreferred form, the reciprocable stopper 142 has anuncompressed diameter somewhat larger than the diameter ofthe first barrel 122 for a frictionâfit slidableengagement with the first barrel 122. The reciprocable1015202530W0 98/13088CA 02265806 l999-03- l6PCT/US97/17194.15.stopper 142 is retained with sufficient frictionalengagement to prevent its movement with the first barrel122 during normal storage, transport, and handling.As can be seen in FIG. 7, a novel conduit andvalve assembly 176 is mounted in the reciprocable stopper142. The conduit and âvalve assembly 176 includes agenerally elongate conduit 177 (which may be in the formof a luer socket) extending through the stopper 142 anddefining an internal flow'passage 178 having an inlet 177Aand an outlet 1778.The conduit and valve assembly 176 includes alaterally projecting boss 180 defining a receiving cavity181 for receiving a ribbed anchor portion 184 of a valvemember insert 185. The valve member insert 185 includesa transversely oriented, resilient, spring member 186extending from the lower end of the anchor portion 184.A frusto-conical, flapper valve member 187 projectsupwardly from the spring member 186. The exterior surfaceof the valve member 187 is adapted to seal against theconduit outlet 177B. The spring member 186 normallybiases the valve member 187 in tight sealing engagementagainst the conduit outlet end 1778 as illustrated in FIG.7. This defines a one-way flow valve.The inlet end of the conduit and valve assembly176 includes a standard female luer socket which definesthe inlet 177A and from which extends a connector flange179, such as is employed in conventional connectionsystems narketed under the trademark LUER-LOK. Thisaccommodates connection of the conduit and valve assembly176 to the second. barrel 148 as described in detailhereinafter. Other suitable conventional or specialconnecting systems may be employed.The first barrel 122 mayâ be regarded as acontainer together with the closure 132, reciprocable1015202530W0 98/ 13088CA 02265806 l999-03- l6PCT/US97l17l94.15.stopper 142, conduit and valve assembly 176, and cover 144for storing, and subsequently mixing, the first component140.The second barrel 148 is preferably initiallyprovided with a surrounding, protective sleeve 152 whichis removed and discarded subsequent to use. The secondbarrel 148 preferably has a cylindrical barrel portion 150containing a liquid second constituent 146 that isretained within the barrel portion 150 by a plungerassembly or plunger 164 which includes a stem or shankhaving a piston 168 at one end slidably disposed withinthe barrel portion 150 and having a thumb push flange atthe other end.The bottom end of the second barrel 148 definesa discharge end 156. The end 156 includes an outwardlyprojecting discharge conduit 158 (which is preferably inthe form of a standard luer nozzle) defining an internaldischarge passage 159 communicating through the dischargeend 156 to accommodate the discharge of fluid from thebarrel portion 150 of the second barrel 148. The conduit158 accommodates fluidâtight connection with the femaleluer socket which defines the inlet 177A of the conduitassembly 176 in the first barrel 122.An axially extending collar 161 is spaced from,and surrounds, the discharge conduit 158. The collar 161defines an internal thread form «of the type that isemployed in connection systems marketed under thetrademark LUER-LOK. Thus, the collar 161 can bethreadingly engaged with the thread flange 179 at theinlet end of the conduit and valve assembly 176 whichprojects from the reciprocable stopper 142 in the firstbarrel 122. The second barrel projecting conduit 158 isadapted to enter into the inlet 177A of the conduit andvalve assembly 176 to form a leak-tight seal with the1015202530W0 98/13088CA 02265806 l999-03- l6PCT/US97/ 17194.17.conduit 177. The second barrel collar 161 and conduit158, and the first barrel conduit and valve assembly 176thus function as a cooperating fluid transfer connectormeans or coupling means for connecting the second barrel148 with the first barrel 122 first chamber 124 throughthe reciprocable stopper 142. other suitable connectionstructures could be used in place of the specific form ofthe collar 161, conduit 158, and conduit and valveassembly 176 illustrated.Preferably, a secondary, removable closuremember 162, in the form of a threaded plug, is threadinglyengaged with the collar 161, and it must be removed priorto use. This prevents ingress of contaminants and insuresthat the liquid second constituent will not leak out ofthe second barrel 148. Of course, even if the removableclosure 162 is not employed, the liquid second constituent146 cannot leak out of a small diameter passage 159because there is no vent system that would admit ambientair into the second barrel 148 so as to permit the liquidconstituent 146 to flow out solely under the influence ofgravity.The second barrel 148 may be regarded togetherwith the closure member 162 and plunger 164 as a secondcontainer or syringe for holding, and subsequentlydischarging, the liquid second constituent 146.To mix the two components, both barrels arepreferably held in an inverted position. The closure 162is removed from the second barrel 148. The second barrel148 is inserted into the first barrel 122 to connect thesecond barrel discharge conduit 158 with the first barrelconduit assembly 176.The second barrel luer nozzle conduit 158 isinserted into the female luer socket inlet 177A of thefirst barrel conduit and valve assembly 176. The thread1015202530W0 98Il3088CA 02265806 l999-03- l6PCT/US97/17194.18.in the second barrel collar 161 is then engaged with.theflange 179 on the first barrel conduit and valve assembly176. Then relative rotation between the two barrels iseffected to complete the threaded engagement.. Subsequently, the second barrel plunger 164 canbe pushed toward the discharge passage 159. The liquidsecond constituent 146 flows from the second barrel 148.through the conduit and valve assembly 176 (where thevalve member 187 opens) into the first barrel 122, and thereciprocable stopper 142 moves outwardly in the firstbarrel 122 along with the second barrel 148 connected tothe assembly 176.The first barrel 122 and second barrel 148 couldalso merely be pulled outwardly relative to each otherwhile ambient air pressure acts on the exterior surface ofthe plunger piston 168 and is transferred to the liquidsecond constituent 146. As the stopper 142 is pulledoutwardly, the volume beneath the stopper 142 within thefirst barrel chamber 124 increases while the pressureThis results in apressure differential which opens the valve member 187 asthe liquid second constituent 146 flows into the firstbarrel 122 to combine with the first constituent 140.within the chamber 124 decreases.As the liquid second constituent 146 istransferred to the first barrel 122, the outward movementof the two barrels 122 and 148 relative to each other iscontinued until the bottom interior surface of the plungerpiston 168 engages the bottom, interior surface of thesecond barrel 148. At this point, all of the liquidsecond constituent 146 has been expelled from the barrelportion 150 of the second barrel 148 into the first barrel122. The assembly can be shaken to ensure good mixing.The first closure 132 can then be removed fromthe first barrel 122, and the delivery end 126 can be1015202530W0 98/13088CA 02265806 l999-03- l6PCT/US97/17194. 19 .connected to a suitable receiving component or dischargetubing (not illustrated). Alternatively, a needle, suchas the needle 34 illustrated for the first embodiment inFIG. 5, may be attached to the first barrel 122.Subsequently, the thumb push flange of theplunger 164 can be pushed inwardly to move the secondbarrel 148 and connected reciprocable stopper 142 inwardlyfurther into the first barrel 122. This expels thecombined constituents 140 and 146 from the first barrel122. 'It will be appreciated that the first barrelconduit and valve assembly 176, second barrel collar 161,and the second barrel conduit 158 cooperatively define afluid transfer connector means or coupling means in theform of a flow-accommodating connection which permits theliquid second constituent 146 to flow from the secondbarrel 148 into the first barrel 122. This fluid transferconnector means or coupling means also accommodates theoutward movement of the second barrel 148 relative to thefirst barrel 122 during the transfer of the liquid secondconstituent 146 from the second barrel 148 to the firstbarrel 122. Additionally, this fluid transfer connectormeans or coupling means accommodates the subsequent âinwardmovement of the second barrel 148 during the dispensing ofthe combined constituents from the first chamber 124 ofthe first barrel 122.The unique fluid transfer connector means orcoupling means employed in the embodiment illustrated inFIGS. 6-9 may be characterized as including (1) a fluidcommunicating means, and (2) an cooperating connectingmeans.The "fluid communicating means" includes (a) a"first fluid connector," preferably in the form of theluerâtype socket or conduit 177 defining a flow passage1015202530W0 98/13088CA 02265806 l999-03- 16PCT/US97/17194.20.into the first barrel 122, and (b) a cooperating "secondfluid connector" in the form of the luer-type nozzle orconduit 158 defining a flow passage out of the secondbarrel 148.The "cooperating connecting means" may includea friction-fit connection of luer-type nozzle or conduit158 with the luer-type socket or conduit 177. Preferably,however, the connecting means also includes the threadform on the second barrel collar 161 and the radial flange179 on the conduit and valve assembly 176 in the firstbarrel 122 to cooperatively establish a threadedconnection.A third embodiment of the present invention,which includes a modified form of the conduit and valveassembly, is illustrated in FIGS. 10 and 10A. Thisembodiment includes a first barrel 222 defining a firstchamber 224 in which a reciprocable stopper 242 isslidably disposed above a first constituent (not visiblein FIGS. 10 and 10A). A conduit 277 is mounted in thereciprocable stopper 242 and extends through thereciprocable stopper 242. The conduit 277 defines aninternal passage 278 and has an inlet 277A and an outlet2778. At the inlet 277A, the conduit 277 defines astandard.female luer socket from*which extends a connectorflange 279 which may be identical to the flange 179described above with reference to the embodimentillustrated in FIGS. 6-9.The bottom of the reciprocable stopper 242 hasa frusto-conical shape 243 with a partial slit 289oriented transversely to the axis of the frusto-conicalshape at a outlet 277B of the conduit 277. This slitdefines a flap or valve member 287 which is attached withan unslit portion 290 (FIG. 10A) to the main body of thestopper 242. The portion 290 is resilient and normally1015202530W0 98/13088CA 02265806 l999-03- l6PCT/US97/17194.21.biases the valve member 287 upwardly against the outlet2778 of the conduit 277 to occlude the passage 278.The stopper 242 and conduit 277 illustrated inFIGS. 10 and 10A are adapted to cooperate with a secondcontainer or barrel (not illustrated) that can beidentical to the second barrel 148 described above withreference to the second embodiment illustrated in FIG. 6.The second barrel can be inserted into the first barrel222 and connected to the conduit 277 in the same manner asdescribed above for the connection of the embodiment ofthe second barrel 148 with the first barrel 122illustrated in FIG. 6. The operation of the embodiment ofthe system illustrated in FIGS. 10 and 10A with respect tocombining the two constituents and subsequently dispensingthem is identical with the operation of the secondembodiment described above with reference to FIGS. 6-9.A fourth embodiment of the syringe system isillustrated in FIGS. 11 and 12. A number of the elementsof the fourth embodiment of the syringe system areidentical or functionally analogous to correspondingelements in the first embodiment illustrated in FIGS. 1-5.The elements of the fourth embodiment illustrated in FIGS.11 and 12 are designated by three digit reference numbersbetween 300 and 399. The last two digits of the fourthembodiment reference numbers for elements corresponding toelements in the first embodiment are identical to the lasttwo digits of the reference numbers used to designatethose corresponding elements in the first embodiment.with reference to FIG. 11, the fourth embodimentof the syringe system includes a first barrel 322 whichhas a first chamber 324 containing a first constituent340. The lower portion of the first barrel 322 includesa delivery end or dispensing end 326 defining a deliverypassage or dispensing passage 328. Preferably, the1015202530W0 98/13088CA 02265806 l999-03- 16PCT/US97/17194.22.delivery passage 328 is occluded with a first, removableclosure 332 which may be held in a friction fit on thedelivery end 326. Other connection systems may beemployed, such as snap-fit beads and grooves, threads,etc.A reciprocable stopper 342 (which may bealternatively characterized as a moveable seal, grommet,_or plunger piston) is provided above the first constituent340 in the first chamber 324.â The reciprocable stopper342 has a lower end surface defining a conical shape 343.As shown in FIG. 11, the apex of the cone has at least oneslit 3&9 (or two intersecting slits, not illustrated).The single slit 389 defines two lips or flaps 387. Twointersecting slits would define four lips. The lips 387are normally biased to a closed.position.as illustrated inFIG. 11 .has an enlarged receiving cavity 393 and a smallerentrance passage 394 which together define a retentionshoulder 395.The reciprocable stopper 342 is initiallyinstalled in the first barrel 322 in a frictionalengagement sufficient to prevent movement of the stopperduring transport, storage, and handling.The first barrel 322 may be regarded as a firstcontainer together with the reciprocable stopper 342 andclosure 332 for storing the first constituent 340.The reciprocable stopper 342 is adapted to beengaged, and moved, with a second barrel 348 whichincludes a cylindrical barrel portion 350 sized to bedisposed in the first barrel 322.The barrel portion 350 has a discharge end 356defining a discharge passage 359 communicating through thedischarge end 356 to accommodate the discharge of fluidfrom the barrel portion 350. The discharge end 356 has an The upper end of the reciprocable stopper 342â1015202530W0 98/13088CA 02265806 l999-03- 16PCT/US97/17194-23.enlarged head 396 and a smaller neck 398 (FIG. 11). _Theneck 398 and head 396 together define a transverseshoulder 399.A liquid second constituent 346 is containedwithin the barrel portion 350 below a plunger 364 whichhas a piston 368. Preferably, in order to minimize thelikelihood of contaminant ingress and to ndnimize thelikelihood of leakage of the constituent 346, a suitableclosure 362 is removably mounted to the discharge end 356.The closure 362 may be held on the discharge end 356 bymeans of a friction fit or by other suitable conventionalor special means, such as threads, snap-fit beads andgrooves, etc.The second barrel 348 mayâ be characterizedtogether with the closure 362 and plunger 364 as a secondcontainer or syringe for holding and storing the liquidsecond constituent 346 and subsequently discharging it.Preferably, a protective sleeve (notillustrated) may be provided for surrounding the secondbarrel 348 in substantially the same manner that thesleeve 52 surrounds the second barrel 48 of the firstembodiment illustrated in FIG. 1.Also, if desired, the first barrel 322 mayinclude a removable cover (not illustrated), such as thecover 44 shown pn the top of the first barrel 22 of thefirst embodiment illustrated in FIG. 1.In order to use the system illustrated in FIGS.11 and 12, the closure 362 is removed from the secondbarrel 348. The second barrel 348 is then disposed withinthe first barrel 322. Preferably, this step isaccomplished by first inverting the second barrel 348before the closure 362 is removed. The first barrel 322is also inverted, and the two barrels are telescopicallyengaged in the inverted position. The second barrel 3481015'202530W0 98/13088CA 02265806 l999-03- 16PCT/US97/17194.24.is pushed into the first barrel 322 until the secondbarrel head 396 sufficiently expands the seal entrancepassage 394 and enters into the seal receiving cavity 393.In this position, the second barrel dispensing end neck398 is received in the smaller entrance passage 394 which,owing to the resiliency of the reciprocable stopper 342,has assumed its smaller diameter configuration whereby theseal retaining flange 395 engages the second containerflange 399. This prevents separation of the second barrel348 from the first barrel reciprocable stopper 342.In the initially engaged position, wherein thesecond barrel discharge end 356 is connected to the firstbarrel reciprocable stopper 342, the stopper lips, flaps,or valve members 387 remain closed so as to ensure thatthere will be no leakage of the liquid second constituentinto the first constituent 340.Subsequently, the first and second barrels aremoved outwardly relative to each other, as by pushing thesecond barrel plunger 364 to force the liquid secondconstituent 346 through the valve members 387 into thefirst barrel first chamber 324. This forces the secondbarrel 348 outwardly relative to the first barrel 322.Alternatively, the two barrels 322 and 348 maybe pulled apart. Ambient air pressure acting on theplunger 368 results in the liquid second constituent 346in the second barrel 348 being maintained under theambient atmospheric pressure. The increasing volume ofthe first chamber 324 under the reciprocable stopper 342creates a negative pressure differential, and the liquidsecond constituent 346 forces the valve members 387outwardly to the open position illustrated in FIG. 12.The liquid second constituent 346 can thus flow into thefirst constituent 340.1015202530W0 98/ 13088CA 02265806 l999-03- l6PCT/US97/17194. 25 .The two barrels move outwardly relative to eachother until the bottom surface of the plunger piston 368engages the bottom of the cylindrical barrel portion 350of the second barrel 348. At this point, all of theliquid second constituent 346 has been expelled into thefirst constituent 340 in the first chamber 324. The valvelips 387 then close. The assembly can then be shaken toensure good mixing.Subsequently, the closure 332 is removed fromthe first barrel delivery end 326. The first barreldelivery end 326 can then be connected to a receivingcomponent or discharge tubing (not illustrated) or to ahypodermic needle (such as the needle 34 described abovewith reference to the first embodiment illustrated inFIGS. 1-5). Then the plunger 364 and second barrel 348are pushed inwardly. This urges the plunger piston 368against the bottom of the cylindrical barrel portion 350of the second barrel 348 to move the second barrel 348 andconnected reciprocable stopper 342 toward the bottom ofthe first container 322. This results in the combinedconstituents being dispensed from the first container 322.A fifth embodiment of a syringe system,incorporating a design that may be pmeferred in someapplications, is illustrated in FIGS. 13-l6. A number ofthe elements of the fifth embodiment of the syringe systemare identical or functionally analogous to correspondingelements in the first four embodiments illustrated inFIGS. 1-12. The elements of the fifth embodimentillustrated in FIGS. 13-16 are designated by three digitreference numbers between 400 and 499. The last twodigits of the fifth embodiment reference numbers forelements corresponding to elements in the first and fourthembodiments are identical with the last two digit1015202530CA 02265806 l999-03- 16PCT/US97/17194W0 98/13088-25.reference numbers used to designate those correspondingelements in the first and fourth embodiments.With reference to FIG. 13, the preferred form ofthe syringe system includes a first barrel 422 which hasa first chamber 424 containing a first constituent 440.The lower portion of the first barrel 422 includes adelivery end or dispensing end 426 defining a deliverypassage or dispensing passage 428. Preferably, thedelivery passage 428 is occluded with a first, removableclosure 432 which may be held in a threaded engagement onthe delivery end 426. To this end, the first barreldelivery end 426 includes a tapered luer fitment 433surrounded by an annular collar 435 defining an interior,female thread form 436. The closure 432 includes a stem437 for being received in the delivery passage 428 and hasan exterior flange or lug 438 for engaging the femalethread form 436.A reciprccable stopper 442 is provided above thefirst constituent 440 in the first chamber 424. Thereciprccable stopper 442 maycharacterized as a moveable seal, grommet, or plungerThe reciprccable stopper 442 has a lower enddefining an inner side or end surface 443 which has aconical shape. The apex of the cone has one slit 489.The slit 489 defines two lips or flaps 487 that arenormally biased to a closed position as illustrated insolid line in FIG. 15.The reciprccable stopper 442 has an outer sidealternatively bepiston.or upper end surface 439. Between the stopper outer sidesurface 439 and the stopper inner side surface 443 thereis an enlarged receiving cavity 493 and a smaller entrancepassage 494 which together define a retention shoulder495.1015202530W0 98/ 13088CA 02265806 l999-03- 16PCT/US97/17194The reciprocable stopper 442 is initiallyinstalled in the first barrel 422 in a frictionalengagement sufficient to prevent movement of the stopperduring transport, storage, and handling. The reciprocablestopper 442 is adapted to receive a support member 441.The support member 441 defines a flow passage445 and a communicating luer socket 444 which can receivea luer nozzle (as described hereinafter). The support~member 441 has an enlarged head 496 and a smaller'neck 498(FIG. 14). The neck 498 and head 496 together define atransverse shoulder 499.The support member 441 can be pushed into theresilient, reciprocable stopper 442 until the supportmember head 496 sufficiently expands the seal entrancepassage 494 and enters into the seal receiving cavity 493.In this position, the support member neck 498 is receivedin the smaller entrance passage 494 which, owing to theresiliency of the reciprocable stopper 442, has assumedits smaller configuration whereby thereciprocable stopper retaining flange 495 engages thesupport member shoulder 499. This prevents separation ofthe support member 441 from the first barrel reciprocablestopper 442. The member 441 also preferably has a supportflange 457 (FIG. 14). This prevents the reciprocablestopper 442 from being deformed to the extent that itmight leak.diameterThe first barrel 422 may be characterizedtogether with the reciprocable stopper 442, support member441, and closure 432 as a first container for storing thefirst constituent 440 and for subsequently mixing it witha liquid second constituent 446 contained in a secondbarrel 448 (FIG. 13).with reference to FIG. 13, the liquid secondconstituent 446 is contained within the cylindrical barrel10202530W0 98/ 13088CA 02265806 l999-03- 16PCTIUS97/ 17194.23.portion 450 of the second barrel 448 below a plunger 454which has a piston 468. The barrel 448 has a lowerdischarge end 456 defining a discharge passage 459. Thedischarge end 456 preferably has the configuration of aluer-type nozzle for" beingâ received in the luerâtypesocket 444 of the support member 441.Preferably, in order to minimize the likelihoodof contaminant ingress and to minimize the likelihood ofleakage of the constituent 446, a suitable closure 462 isremovably mounted to the discharge end 456. The closure462 may be held on the discharge end 456 by means of afriction fit or by other suitable conventional or specialmeans, such as threads, snapâfit beads and grooves, etc.The second barrel 448 together with the closure462 and plunger 464 may be characterized as a secondcontainer or syringe for storing and subsequentlydischarging the liquid second constituent 446.Preferably, a protective sleeve (notillustrated) may be provided for surrounding the secondbarrel 448 in substantially the same manner that thesleeve 52 surrounds the second barrel 48 of the firstembodiment illustrated in FIG. 1.Also, if desired, the first barrel 422 mayinclude a removable cover (not illustrated), such as thecover 44 shown on the top of the first barrel 22 of thefirst embodiment illustrated in FIG. 1.In order to use the system illustrated in FIGS.13-16, the cap 462 is removed from the second barrel 448.The second barrel 448 is then disposed within the firstbarrel 422. Preferably, this step is accomplished byfirst inverting the second barrel 448 before the closure462 is removed. The first barrel 422 is also inverted,and the two barrels are telescopically engaged in theinverted position.1015â202530W0 98/ 13088CA 02265806 l999-03- 16PCT/US97/17194.29.The luerâtype nozzle at the discharge end 456 ofthe second barrel 448 is disposed within the luer-typesocket 444 of the support member 441. This may be afriction fit connection. Alternatively, a more positivemechanical connection could be employed as discussedhereinafter with respect to the sixth embodiment shown inFIG. 17.In the installed position, wherein the secondbarrel discharge end 456 is mounted via the member 441 tothe first barrel reciprocable stopper 442, the stopperflaps, lips, or valve members 487 remain closed so as toensure that there will be no leakage of the liquid secondconstituent into the first constituent 440.The plunger 464 can be pushed to discharge theliquid second constituent 446 through the,reciprocab1estopper slit 489 into the first chamber 424 of the firstbarrel 422. As the second constituent 446 flows into thefirst barrel chamber 424, the reciprocable stopper 442 andsecond barrel 448 move outwardly. .Alternatively, thefirst and second barrels 422 and 448 can be pulledoutwardly relative to each other. Ambient air pressureacting on the plunger piston 468 results in the liquidsecond constituent 446 being maintained under the ambientatmospheric pressure. The increasing volume of the firstchamber 424 under the reciprocable stopper 442 creates anegative pressure differential, and the liquid secondconstituent 446 forces the stopper lips or valve members487 outwardly to the open position illustrated in FIG. 14.The liquid second constituent 446 can thus flow into thefirst constituent 440.The two .barrels 422 and 448 move outwardlyrelative to each other until the bottom surface of theplunger piston 468 engages the bottom of the cylindricalbarrel portion 450 of the second barrel 448. At this1015202530WO 98113088CA 02265806 l999-03- 16PCT/U S97/ 17194.30.point, all of the liquid second constituent 446 has beenexpelled into the first constituent 440 in the firstchamber 424. The valve flaps 487 then close. Theassembly can then be shaken to ensure good mixing.Subsequently, the closure 432 is removed fromthe first barrel delivery end 426. The first barreldelivery end 426 can then be connected to a receivingcomponent or discharge tubing (not illustrated) or to ahypodermic needle (such as the needle 34 described abovewith reference to the first embodiment illustrated inFIGS. 1-5). Then the plunger 464 is pushed inwardly.This urges the piston 468 against the bottom of thecylindrical barrel portion 450 of the second barrel 448 tomove the second. barrel 422, support member 441, andconnected reciprocable stopper 442 toward the bottom ofthe first container 422. This results in the combinedconstituents being dispensed from the first barrel 422.FIG. 17 illustrates a sixth embodiment of thepresent invention. The sixth embodiment is a modificationof the fifth embodiment described above with reference toFIGS. 13-16.In particular, the sixth embodiment includes asupport member 441A generally similar to the fifthembodiment support, memberâ 441. However, the supportmember 441A includes an upwardly extending skirt 451Awhich has an internal, female thread form 453A.A âsecond barrel 448A is provided with aconfiguration generally similar to that of the fifthembodiment second barrel 448 except that the sixthembodiment second barrel 448A includes 21 radial lug,flange, or thread form 455A to threadingly engage thesupport member thread form 453A. This provides a positivemechanical connection between the second barrel 448A andthe support member 441A.1015202530W0 98/13088CA 02265806 l999-03- 16PCT/US97/17194.31.In each of the fourth, fifth, and sixthembodiments illustrated in FIGS. 11-17, it is preferableto provide a clearance between the end of the head 496 ofthe support member 441 and the closed stopper valve lipsor flaps (e.g., 487 in FIG. 16) when the stopper lips orflaps are closed. This insures that the stopper canproperly collapse as far as necessary to close the slit.The embodiments illustrated in FIGS. 11-17 maybe characterized as employing a tuuque fluid transferconnector means or coupling means. The fluid transferconnector means or coupling means may be characterized asincluding (1) fluid communicating means, and (2)'cooperating connecting means.In the embodiment illustrated in FIGS. 11 and12, the fluid communicating means include a first fluidconnector in the form of a passage 359 in the secondbarrel discharge end 356 and a second fluid connector inthe form of the flow path through the reciprocable stopper.342 and stopper flaps or lips 387. The cooperatingconnecting means include the enlarged head 396 on thesecond barrel 348 and the cooperating stopper receivingcavity 393 and retention shoulder 395.In the embodiments illustrated in FIGS. 13-17,the fluid communicating means includes the flow passagethrough the reciprocable stopper 442 as well as a firstfluid connector in the form of the luer-type socket orconduit 444 (FIG. 14) defining a flow passage in thesupport member 441 and a cooperating second fluidconnector in the form of the luer-type nozzle 456 defininga flow passage in the second barrel 448. The cooperatingconnecting means may include just a friction-fitconnection of luer-type nozzle 456 in the luer-type socket444 as well as the engagement between the support member441 and stopper 442. Preferably, however, as shown in1015202530W0 98/ 13088CA 02265806 l999-03- 16PCT/US97/17194.32.FIG. 17, the connecting means also includes the threadform 453A on the support member 441A and the radial flange455A on the second barrel 448A which cooperativelyestablish a threaded connection.It will be appreciated that, in all of theembodiments illustrated, the dispensing ends or deliveryends of the first barrels are sealed. with removableclosures (such as the first containerâ dispensing endclosure 32). The second barrel discharge end may includea closure (i.e., closure 62 illustrated in FIG. 1).Further, such closures, if employed, may be provided inalternate -forms such as threadable elastomeric sealmembers, flexible adhesive seal members, shrink wrapfilms, or other closure systems.The above-described syringe system of thepresent invention provides an advantageous means fordispensing a combination of two constituents that must bekept separate from each other until they are to be used incombination. The system is self-contained and sealed.Reconstitution or dilution of a drug using this system canbe effected at bedside when the drug is needed. Thechoice of the diluent liquid is not restricted or limitedbecause the system accommodates any diluent compatiblewith the structural materials employed.The systenlpermits the constituents to be storedin forms in which the stability of the components ismaximized. Because the reconstituted product is usedimmediately, provisions do not have to be made forrefrigeration or other storage procedures which ndghtotherwise be required for certain types of reconstitutedproducts.It will be readily apparent from the foregoingdetailed description of the invention and from theillustrations thereof that numerous variations andCA 02265806 1999-03-16wo 98/13088 ' PCT/US97/17194.33.modifications may be effected without departing from thetrue spirit and scope of the novel concepts or principlesof this invention.
