AU6949394A - Fluid delivery apparatus - Google Patents

Description

FLUID DELIVERY APPARATUS

S P E C I F I C A T I O N Background of The Invention This is a Continuation In Part Application of co-pending Serial No. 07/987,021 which is a continuation of co-pending 07/870,269 which, in turn, is a Continuation in Part of Serial No. 07/642,208 which has now issued to U.S. Patent No. 5,169,389 which is a Continuation In Part of Serial No. 07/367,304 Filed June 16, 1990 which has now issued to U.S. Patent No. 5,019,047 Field of The Invention -

The present invention relates generally to fluid delivery devices. More particularly, the invention concerns an improved apparatus for infusing medicinal agents into an ambu¬ latory patient at specific rates over extended periods of time.

Discussion of The Invention

Many medicinal agents require an intravenous route for administration thus bypassing the digestive system and precluding degradation by the catalytic enzymes in the diges¬ tive tract and the liver. The use of more potent medications at elevated concentrations has also increased the need for accuracy in controlling the delivery of such drugs. The deliv¬ ery device, while not an active pharmacologic agent, may en¬ hance the activity of the drug by mediating its therapeutic effectiveness. Certain classes of new pharmacologic agents possess a very narrow range of therapeutic effectiveness, for instance, too small a dose results in no effect, while too great a dose results in toxic reaction.

In the past, prolonged infusion of fluids has gener¬ ally been accomplished using gravity flow methods, which typi- cally involve the use of intravenous administration sets and the familiar bottle suspended above the patient. Such methods are cumbersome, imprecise and require bed confinement of the patient. Periodic monitoring of the apparatus by the nurse or doctor is required to detect malfunctions of the infusion apparatus.

Devices from which liquid is expelled from a rela¬ tively thick-walled bladder by internal stresses within the distended bladder are well-known in the prior art. Such blad¬ der, or "balloon" type, devices are described in U.S. Patent No. 3,469,578, issued to Bierman and in U.S. Patent No. 4,318,400, issued to Perry. The devices of the aforementioned patents also disclose the use of fluid flow restrictors exter¬ nal of the bladder for regulating the rate of fluid flow from the bladder.

The prior art bladder type infusion devices are not without drawbacks. Generally, because of the very nature of bladder or "balloon" configuration, the devices are unwieldly and are difficult and expensive to manufacture and use. Fur¬ ther, the devices are somewhat unreliable and their fluid discharge rates are frequently imprecise.

The apparatus of the present invention overcomes many of the drawbacks of the prior art by eliminating the bladder and making use of recently developed elastomeric films and similar materials, which, in cooperation with a, plate-like base defines a fluid chamber that contains the fluid which is to be dispensed. The elastomeric film membrane controllably forces fluid within the chamber into fluid flow channels pro¬ vided in the base. In one form of the apparatus of the inven¬ tion, a thin, planar, shaped flow rate control member is stra¬ tegically located within the chamber to precisely control the rate of flow of the liquid toward the fluid flow channels. The flow rate control member can be very thin and can be selected to have a very precise degree of permeability so that the rate of flow of fluid into the fluid flow channels can be controlled with great accuracy.

The use of state of the art thin membranes and films permits the construction of compact, low profile, laminated structures which are easy to use and inexpensive to manufac¬ ture. When the devices of the invention are to be used with ambulatory patients they are constructed of flexible materials and are provided with a thin adhesive backing which permits the device to be conveniently self-affixed to the patient's arm or other parts of the body.

The apparatus of the invention can be used with minimal professional assistance in an alternate health care environment, such as the home. By way of example, devices of the invention can be used for the continuous infusion of anti¬ biotics, hormones, steroids, blood clotting agents, analgesics, and like medicinal agents. Similarly, the devices can be used for I-V chemotherapy and can accurately deliver fluids to the patient in precisely the correct quantities and at extended microfusion rates over time.

Summary of The Invention

It is an object of the present invention to provide an apparatus for expelling fluids at a precisely controlled rate which is of a compact, low profile, laminate construction. More particularly, it is an object of the invention to provide such an apparatus which can be used for the precise infusion of pharmaceutical fluids to an ambulatory patient at controlled rates over extended periods of time.

It is another object of the invention to provide an apparatus of the aforementioned character which is highly reli¬ able and easy-to-use by lay persons in a non-hospital environ¬ ment.

Another object of the invention is to provide an apparatus which can be factory prefilled with a wide variety of medicinal fluids or one which can readily be filled in the field shortly prior to use.

Another object of the invention is to provide an infusion device in which fluids can be delivered either at a fixed rate or at variable rates and one which is operational in all altitudes and attitudes.

Still another object of the invention is to provide an apparatus of the class described which is soft, conformable and compliant so as to readily conform to the patient's anatomy proximate the point of infusion.

Yet another object of the invention is to provide an apparatus as described in the preceding paragraph which is pro¬ vided with a thin, flexible foam backing with adhesive for self-attachment. The apparatus can be unobtrusively worn under clothing.

A further object of the invention is to provide a low profile, fluid delivery device of laminate construction which can be manufactured inexpensively in large volume by automated machinery.

Another object of the invention is to provide a device of the character described in which fluid is dispelled from the apparatus through either an integral infusion needle, or through a luer type connector, by a thin, distendable mem¬ brane cooperatively associated with a thin, plate-like base.

Another object of the invention is to provide an apparatus of the aforementioned character in which the distend- able member is permeable to gases at least in one direction, whereby gases within the medicinal agent can be released from the fluid chamber and not injected into the patient.

Still another object of the invention is to provide an apparatus as described in the preceding paragraphs in which the rate of fluid flow from the apparatus is precisely con¬ trolled by a thin planar shaped, fluid permeable member which forms a part of the low profile, laminate construction of the apparatus.

Another object of the invention is to provide a fluid delivery device embodying an iostropic distendable membrane with a uniform modulus of elasticity which cooperates with a base to define a fluid chamber having a fluid outlet in commu¬ nication with dispensing port for dispensing fluid from the device and including a flow control element disposed interme¬ diate the fluid outlet and the dispensing port.

Still another object of the invention is to provide a device as described in the preceding paragraph in which the flow control element comprises a restriction which controllably restricts the flow of fluid between the fluid outlet and the dispensing port.

A further object of the invention is to provide a fluid delivery device embodying a distendable membrane assembly which cooperates with a base to define a fluid chamber having a fluid outlet in which the distendable membrane assembly is of multi-laminate construction being made up of a plurality of individual members or layers which cooperate to controllably urge fluid within the fluid chamber outwardly of the fluid outlet of the device.

Another object of the invention is to provide a fluid delivery device of the chamber described in the preceding para- graph which includes a rate control membrane and in which the base is provided with a multiplicity of micro-channels for conducting fluid to the rate control membrane at precise rate over a predetermined active area.

A principal object of one form of the invention is to provide a novel agent formulation dispenser adopted for use with a slightly modified version of the basic fluid delivery device of the present invention for administering an aqueous solution containing selected drugs or other chemical compounds at a controlled rate.

Brief Description of The Drawings

Figure 1 is a generally perspective view of one form of the fluid dispensing apparatus of the invention.

Figure 2 is an exploded, generally perspective view of the apparatus of Figure 1.

Figure 3 is a top view of the apparatus partly broken away to show internal construction.

Figure 4 is an enlarged cross sectional view taken along lines 4-4 of Figure 3.

Figure 5 is a cross sectional view taken along lines 5-5 of Figure 4.

Figure 6 is a fragmentary view taken along lines 6-6 of Figure 4.

Figure 7 is a cross sectional view taken along lines 7-7 of Figure 4.

Figure 8 is a view similar to Figure 4, but illus¬ trating the separation of the molded needle cover from the device.

Figure 9 is a cross sectional view taken along lines 9-9 of Figure 8.

Figure 10 is a generally perspective exploded view of another embodiment of the fluid dispensing apparatus of the present invention.

Figure 11 is a top view of the apparatus shown in Figure 10.

Figure 12 is a cross sectional view taken along lines 12-12 of Figure 11.

Figure 13 is a cross sectional view taken along lines 13-13 of Figure 12.

Figure 14 is a cross sectional view taken along lines 14-14 of Figure 12.

Figure 15 is a fragmentary view taken along lines 15- 15 of Figure 12.

Figure 16 is a view similar to Figure 12, but showing the molded needle cover separated from the device.

Figure 17 is a greatly enlarged fragmentary view illustrating the method of fluid fill of the apparatus of this form of the invention.

Figure 18 is a generally perspective exploded view of another embodiment of the apparatus of the present invention.

Figure 19 is a fragmentary top view of the apparatus of this form of the invention.

Figure 20 is a cross sectional view taken along lines 20-20 of Figure 19

Figure 21 is a cross sectional view taken along lines 20-20 of Figure 19.

Figure 22 is a generally perspective exploded view of still another form of the apparatus of the present invention.

Figure 23 is a plan view of the apparatus of Figure 22 partly broken away to show internal construction.

Figure 24 is a greatly enlarged fragmentary perspec¬ tive view of a portion of the apparatus illustrating the ar- rangement of the rate control membranes of the device.

Figure 25 is a cross sectional view taken along lines 25-25 of Figure 23.

Figure 26 is a fragmentary view taken along lines 26- 26 of Figure 25.

Figure 27 is a cross sectional view taken along lines 27-27 of Figure 25.

Figure 28 is a cross sectional view taken along lines 28-28 of Figure 25.

Figure 29 is a fragmentary, cross sectional view similar to Figure 25, but showing the needle cover separated from the apparatus of the invention.

Figure 30 is a generally perspective, exploded view of still another embodiment of the present invention.

Figure 30A is a fragmentary plan view taken along lines 30A-30A of Figure 32 showing the internal construction of the apparatus of Figure 30.

Figure 3OB is an enlarged cross-sectional view of the circled area shown in Figure 32.

Figure 31 is a fragmentary, generally perspective view of the circled portion of the flow rate control membrane as shown in Figure 30.

Figure 32 is a cross-sectional view of the apparatus shown in Figure 30.

Figure 33 is an exploded, generally perspective view of still another form the apparatus of the invention.

Figure 34 is a fragmentary plan view of the fluid outlet portion of the apparatus of Figure 33, partly broken away to show internal construction.

Figure 35 is a cross-sectional view taken along lines 35-35 of Figure 34. Figure 36 is a cross-sectional view taken along lines 36-36 of Figure 34.

Figure 37 is a cross-sectional view taken along lines 37-37 of Figure 36.

Figure 38 is a fragmentary, generally perspective view of a portion of the flow control means of this form of the apparatus of the invention.

Figure 39 is a fragmentary, generally perspective view of the distendable membrane of the latest form of the invention illustrating the laminate construction thereof.

Figure 40 is a plan view of yet another form of the invention, partly broken away to show internal construction.

Figure 41 is an exploded, generally perspective view of the form of the apparatus of the invention shown in Figure 40.

Figure 42 is a cross-sectional view taken along lines 42-42 of Figure 40.

Figure 43 is a cross-sectional view taken along lines 43-43 of Figure 42.

Figure 44 is a cross-sectional view taken along lines 44-44 of Figure 42.

Figure 45 is a generally perspective view of various forms of activating members for activating the parenteral fluid with a medicament which are usable with this embodiment of the apparatus of the invention.

Figure 46 is a fragmentary, cross-sectional view similar to Figure 44 illustrating the use of flow distribution materials within the liquid flow manifolds of the device.

Figure 47 is an exploded, generally perspective view of yet another embodiment of the invention. Figure 48 is an exploded, generally perspective view of still another form of the fluid delivery apparatus of the invention.

Figure 49 is a plan view of the apparatus partially broken away to show internal construction.

Figure 50 is a cross-sectional view taken along lines 50-50 of Figure 49.

Figure 51 is a cross-sectional view taken along lines 51-51 of Figure 50.

Figure 52 is an enlarged side elevational view partly in cross-section to show internal construction of a additive carrying subassembly of the invention.

Figure 53 is an enlarged end view of one end cap of the additive subassembly shown in Figure 52.

Figure 54 is a side elevational view partly broken away of the end cap shown in Figure 53.

Figure 55 is an exploded view of the additive subas¬ sembly shown in Figure 52 partly in cross-section to better illustrate the construction of the subassembly.

Figure 56 is a fragmentary, generally perspective view of one of the end caps of the additive subassembly of the apparatus.

Figure 57 is an enlarged, cross-sectional view taken along lines 57-57 of Figure 49.

Figure 58 is a side elevational view of the apparatus of this form of the invention being filled by a hypodermic syr¬ inge of standard construction.

Figure 59 is a fragmentary, side elevational view similar to Figure 57 showing the fluid flow path of the fluid flowing through the apparatus and outwardly toward the dispens¬ ing means. Figure 60 is a cross-sectional view taken along lines 60-60 of Figure 57.

Figure 61 is an exploded, generally perspective view of still another form of the apparatus of the invention.

Figure 61A, 61B, 61C and 61D are general diagramatic views illustrating various means for affinity attachment of ligands, protein molecules and enzymes to the substrates.

Figure 62 is a plan view of the form of the invention shown in Figure 61.

Figure 63 is an enlarged, cross-sectional view taken along lines 63-63 of Figure 62.

Figure 64 is a cross-sectional view taken along lines 64-64 of Figure 63.

Figure 65 is an exploded, generally perspective view of yet another form of the fluid delivery apparatus of the invention which includes an immobilized drug vial of unique construction that is disposed within the outlet fluid flow path.

Figure 66 is an exploded generally perspective, frag¬ mentary view of a device similar to that shown in Figure 65, but one in which the fluid enters the device from the side rather than the end.

Figure 67 is an enlarged, cross-sectional view of the immobilized drug vial assembly usable with the devices shown in Figures 65 and 66.

Figure 68 is an end view of the immobilized drug vial assembly.

Figure 69 is an enlarged side elevational view partly in cross-section of the upper portion of the device illustrated in Figure 65 showing the immobilized drug vial or additive carrying subassembly disposed within the device.

Figure 70 is a cross-sectional view taken along lines 70-70 of Figure 69.

Figure 71 is a fragmentary, cross-sectional view illustrating the fluid flow control check valve of the device in a closed position.

Figure 72 is a generally perspective view of another embodiment of the invention which includes a novel filling needle assembly having a unique check valve housing with luer end and safety shield.

Figure 73 is an enlarged, cross-sectional view of the filling needle assembly of Figure 72.

Figure 74 is an end view of the check valve housing of this form of the invention illustrating the location of the fluid flow channels.

Figure 75 is an enlarged side view partly in cross- section showing the filling needle assembly connected with a fluid inlet line and also interconnected with the housing assembly of the device, the needle of the assembly having penetrated the housing assembly septum.

Figure 76 is a cross-sectional view similar to Figure 75 but showing the device in a filling mode, the check valve having been moved to an open position.

Figure 77 is a cross-sectional view taken along lines 77-77 of Figure 76.

Figure 78 is a cross-sectional view taken along lines 78-78 of Figure 76.

Figure 79 is a generally perspective view of yet another form of the fluid dispensing apparatus of the inven¬ tion.

Figure 80 is an exploded, generally perspective view of the apparatus of Figure 79.

Figure 81 is a top view of the apparatus partly broken away to show internal construction.

Figure 82 is a cross-sectional view taken along lines 82-82 of Figure 81.

Figure 83 is a cross-sectional view taken along lines 83-83 of Figure 82.

Figure 84 is a cross-sectional view taken along lines 83-83 of Figure 82.

Figure 85 is a fragmentary cross-sectional view of the apparatus of Figure 84 showing deformation of the apparatus to rupture the membrane which encapsulates the sponge member.

Figure 86 is a fragmentary view similar to Figure 85, but illustrating the expansion of the sponge member into the fluid reservoir to expel the fluid therein.

Figure 86A is a fragmentary view similar to Figure 86 but showing further expansion of the sponge like member.

Figure 87 is a cross-sectional view similar to Figure 84 illustrating the expansion of the sponge to expell the fluid.

Figure 88 is a generally perspective, exploded view of another embodiment of the fluid dispensing apparatus of the present invention. This embodiment is similar to that shown in Figure 65 but also embodies a compressible sponge-like member which functions as the energy source in lieu of the distended membrane type energy source.

Figure 88A is a cross-sectional view of the device showing the sponge in a compressed state.

Figure 89 is a generally perspective view of still another form of the. apparatus of the invention.

Figure 90 is an enlarged, cross-sectional view of the immobilized drug vial assembly usable with the devices shown in Figures 88 and 89.

Figure 91 is an end view of the immobilized drug vial assembly.

Figure 92 is an enlarged side elevational view partly in cross-section of the upper portion of the device illustrated in Figure 88 showing the immobilized drug vial or additive carrying subassembly disposed within the device.

Figure 93 is a cross-sectional view taken along lines 93-93 of Figure 92.

Figure 94 is a fragmentary, cross-sectional view illustrating the fluid flow control check valve of the device in the closed position.

Description of The Invention

Referring to the drawings and particularly to Figures 1 through 9, one embodiment of the apparatus for use in infus¬ ing medicinal fluids into a patient is there illustrated and generally designated by the numeral 12. As indicated in Figure 1, the apparatus of this form of the invention comprises a laminate, or layered, structure made up of a plurality of thin plate-like components. As best seen by referring to Figure 2, the apparatus comprises a thin, generally planar plate-like base 14, having a pair of flow rate control channels provided here as longitudinally extending fluid conduits 16 and 18. Conduits 16 and 18 are interconnected by a fluid transfer manifold, or transverse conduit 20, which, in turn, is inter¬ connected with a fluid outlet passageway 22. A thin, generally planar distendable elastomeric membrane, or member, 24 cooper¬ ates with base 14 to form a chamber 25 (Figure 4) . Member 24 is distendable out of plane in the manner shown in Figure 4 by the introduction of fluid into the chamber under pressure. As the distendable member 24 is distended by the fluid pressure, internal stresses are formed in the member which continuously urge it to return to its original planar configuration. The method of introduction of fluids into chamber 25 will presently be described. As shown in Figure 5, to maintain the low pro¬ file character of the device, the height of the fluid chamber is substantially less than the width of base 14.

Forming an important aspect of the apparatus of the invention is the provision of flow control means which is dis¬ posed internally of chamber 25 for controlling the rate of fluid flow through the outlet 22 formed in base member 14. In the embodiment of the invention hereshown, the flow control means is provided in the form of a thin, permeable member 26 which is superimposed over base 14 in the manner shown in Figure 4. As will presently be described, member 26 precisely controls the rate of fluid flow from chamber 25 into fluid conduits 16, 18 and 20 formed in base 14. It is this precise control of the rate of fluid flow which enables infusion into the patient of medicinal fluids at an extremely precise rate over extended periods of time ranging from several hours to in excess of 24 hours depending on sized reservoir volume.

Superimposed over flow control member 26 is a dis¬ tendable membrane engagement means. This means is here provid¬ ed in the form of a generally planar member 28 having a periph¬ eral portion 28a to which the margins of distendable member 24 are bonded, as by adhesive or thermo-bonding. Member 28 also has a pair of longitudinally extending, spaced apart upstanding protruberances 30. Each of the protruberances 30 is provided with a longitudinally extending first fluid passageway or conduit 32. When the apparatus is assembled in the manner shown in Figure 9, passageways 32 are superimposed over fluid conduits 16 and 18 and protruberances 30 extend upwardly into fluid chamber 26 so as to define ullage "U" within chamber 25. In operation of the device, as distendable membrane 24 attempts to return to its original planar configuration (Figure 9) , it will move toward engagement with the upper surfaces of protru¬ berances 30 and in so doing will efficiently force the fluid contained within chamber 25 uniformly through the flow control member 26 and into passageways 16 and 18. The configuration of protuberances 30 ensure that all of the fluid within chamber 25 will be dispelled therefrom as the membrane returns toward its starting configuration. Passageways 16, 18, and 32 can be alternately configured to provide various degrees of fluid exposure to rate control membrane 26 whereby the active surface area of membrane 26 is increased or decreased.

Superimposed over the assembly comprising base 14, distendable membrane 24, flow control member 26, and distend¬ able membrane engaging member 28 is a porous plastic cover 34 which functions to provide a superstructure and a venting means for venting gases, if any, contained within the medicinal agent. Affixed to the top of cover 34 is a medicant and use instruction label 36 which can be used to identify the medicin¬ al fluid contained within chamber 25 of the device.

Affixed to the bottom of base 14 is a cushioning means shown here as a thin, planar shaped foam pad 38. Foam pad 38 is provided with adhesive on both its upper and lower surfaces. The adhesive on the upper surface of pad 38 enables the pad to be affixed to the lower surface of base 14. As indicated in Figures 2 and 4, a peel strip 40 is connected to the bottom surface of foam pad 38 by the adhesive provided thereon. When the device is to be used, peel strip 40 can be stripped away from pad 38 so that the adhesive on the lower surface of the foam pad 38 can be used to releasably affix the apparatus of the invention to the anatomy of the patient.

Turning now to Figures 4 and 8, a needle assembly 42 is integrally formed with base 14. Needle assembly 42 which includes a distal portion 42a and a proximal portion 42b, is provided with a longitudinally extending bore 44. As best seen in Figure 4, bore 44 is in communication with outlet passageway 22 formed in base 14. Fixedly received within that portion of passageway 44, which extends through distal portion 42a, is a hollow infusion needle 46 of the character typically used for injecting fluids into a patient. The fluid outlet end of needle 46 is received within that portion of passageway 44 which extends through proximal portion 42b. Intermediate portions 42a and 42b is a reduced diameter frangible portion 42c which can be broken so as to separate portions 42a and 42b to expose the outlet end of needle 46 in the manner shown in Figure 8. Also forming a part of proximal portion 42b is a protective sheath 48 for encapsulating and protecting needle 46. Needle assembly 42 also includes web means for further assisting in securing and maintaining the needle in an appro¬ priate invasive position to preclude inter-vascular trauma. The web means are here provided as a soft, flexible butterfly assemblage 49, which, as shown in Figures 1 and 7, is integral¬ ly formed with base 14 and joined therewith by webbing 49a. Butterfly assembly 49 also provides appropriate surface area for tape adhesion covering the injection site.

Turning now to Figures 2, 3, 4 and 6, the distendable membrane engagement element 28 which comprises the means for creating an ullage within chamber 25, also includes an upstand¬ ing transversely extending portion 50 having a fluid passageway 52 extending therethrough. In the present embodiment of the invention, the open end 52a of passageway 52 is closed by a closure member 54 which is adapted to sealably close passageway 52 after chamber 25 has been filled with the selected medicinal agent. Passageway 52 can also be closed by any suitable means such as thermal or mechanical sealing. As best seen by refer¬ ring to Figure 4, passageway 52 is in communication with a pair of longitudinally extending passageways 56 formed in element 28. Passageways 56 are, in turn, in communication with chamber 25 via passageways 58. As illustrated in Figure 2, passageways 58 extend through protuberances 30 and are disposed in the ends of protuberances 30 located proximate transversely extending passageway 52.

The apparatus of this first embodiment of the inven¬ tion is adapted to be filled with the selected medicinal fluid at time of manufacture. This is accomplished by removal of plug 54 so that fluid under pressure can be forced into passa¬ geway 52 and thence into chamber 25 via passageways 56 and 58. As the fluid under pressure flows through passageways 58, it will cause the membrane 24 to distend upwardly into initial engagement with cover 34 in the manner shown in Figure 4. After chamber 25 has been filled with the medicinal fluid, closure plug 54 is bonded or otherwise affixed in place within the open end 52a of conduit 52 so as to seal chamber 25 with respect to atmosphere.

So long as needle assembly 42 remains intact in the manner shown in Figure 4, the fluid will be retained within chamber 25. However, upon twisting and breaking the frangible section 42c so that portion 42b of the needle assembly can be removed as shown in Figure 8, distendable membrane 24 will begin to expel fluid through the needle 46. The rate of expul¬ sion of fluid is, of course, controlled by the permeable mem- brane 26 which is disposed intermediate the fluid flow passage¬ ways 32 of member 28 and fluid flow passageways 16 and 18 formed in base 14.

As previously mentioned, the state of the art materi¬ als used in the construction of the apparatus of the invention markedly contribute to the reliability, accuracy and manufac- turability of the apparatus. Before discussing the alternate forms of the invention shown in the drawings, a brief review of the materials used in constructing the apparatus is in order.

With respect to the base 14, a wide variety of mate¬ rials can be used, including; metals, rubber or plastics that are compatible with the liquids they contact and are preferably not non-allergenic. Examples of such materials are stainless steel, aluminum, latex rubber, butyl rubber, nitrile rubber, polyisiprene, styrene-butadiene copolymer, εilicones, polyole- fins such as polypropylene and polyethylene, polyesters, poly- urethane, polyamides and polycarbonates. Manufacturers of suitable materials include; Dow Corning of Midland, Michigan, General Electric of Schenectady, New York and Shell Chemical Company of Houston, Texas, DuPont Chemical of Wilmington, Delaware, and Eastman Chemical of Kingsport, Tennessee.

Considering next the important flow control means, or member 26, precision microflow through this important component is a pressure driven flow delivery process with controllable delivery rates between 0.1 to 4.5 illiliters per hour. De¬ pending on the medicinal agent to be delivered and the required flow rate regime, several microporous membranes can be em¬ ployed, including asymmetric substrate based films such as cellulose acetate, cellulose acetate buterate, and ethyl cellu¬ lose. These membrane films may vary from 20 microns to 100 microns thick and can be made of a porous substrate with a controlled skin where the active porosity can vary from ang¬ stroms to 50 microns in diameter. Additionally, other acrylic resins can also be used for thin film, delivery membranes such as poly-methyl-methacrylate (PMM) and polysulfone on PVC also with approximately 2 microns thickness of skin of active mem¬ brane surface on up to 100 microns of substrate backing. Other matrix polymer systems are also candidates for microfilm mem¬ branes and include PCCE copolyesters and nylon PEBAX-polyether- steramide (PEEA) , as well as PTFE, PVDF, P-P mixed ester cellu¬ lose and certain other polycarbonates. Manufacturers of these materials include; Bend Research (Cellulose Acetates, polysul- fones) , Eastman Chemical (PCCE Copolyester #9966) , Atochem (PEBAX Nylon) , Dupont (Hytrel) , Rohm Pharmaceuticals (Acrylic Resins) and Millipore (PTFE) , PVDF and mixed ester cellulose) .

Considering next the elastic distendable membrane 24, this important component can be manufactured from several alternate materials including rubbers, plastics and other thermoplastic elastomers. These include latex rubber, polyiso- prene (natural rubber) , butyl rubber, nitrile rubber, other homopolymer, copolymers (random, alternating, block, graft, crosslink and starblock) , mechanical poly-blends and interpene¬ trating polymer networks.

Examples of materials found particularly well suited for this application include; silicone polymers (polysiloxanes) (high performance silicone elastomers made from high molecular weight polymers with appropriate fillers added) . These materi¬ als are castable into thin film membrances and have high perme¬ ability (which allows maximum transport of vapor and gas) , high bond and tear strength and excellent low temperature flexibili¬ ty and radiation resistance. Additionally, silicone elastomers retain their properties over a wide range of temperature (-80° to 200° C) are stable at high temperatures, and exhibit tensile strengths up to 2,000 lb./in² elongation up to 600%.

Further, silicone (polyorganosiloxanes) are thermally stable, hydrophobic organometallic polymers with the lowest P-P interaction (of all commercially available polymers. This fact coupled with the flexibility of the backbone results in a low Tg (-80°C) and an amorphous rubbery structure for the high MW (polydimethylsiloxanes) . Silicone rubber membranes are con¬ siderably more permeable to gases than membranes of any other polymer. Depending on the medicinal fluid used and the filling of the storage mode, which will determine the desired mass transport characteristics of the membrane (permeability and selectivity) , other materials of choice include polyurethane- polysiloxane copolymers, blends and IPN's. By example, polydi- methylsiloxane (PDMS) and polyurethane (PU) multicomponent IPN containing 10%-20% weight of PU shows enhanced initial modulus relative to that of PDMS itself.

Interpenetrating polymer networks (IPNS) are unique blends of cross-linked polymers containing essentially no cova- lent bonds, or grafts between them. True IPNS are also homoge¬ neous mixtures of component polymers. Further examples of an additional candidate materials would be a polyurethane- polysiloxane (IPN) bilaminated with a polyparaxylene or alter¬ nately bilamination of polydimethylsiloxane (PDMS) and polypar¬ axylene. Coextruded laminates of this type can be selected according to the desired gas permeability for vapor and 0₂, N₂ and C0₂ diffusion and their specific selectivity requirements as well as for direction of gas migration when appropriately layered.

Manufacturers of materials suitable for use in the construction of the distendable membrane, include Dow Chemical, General Electric, B.P. Polymers, Mobay Chemical, Shell Oil Corp. , Petrarch Systems, DuPont, Concept Polymers and Union Carbide Corp.

With respect to the structural cover 34, in certain embodiments of the invention, this component can be produced from one of several polymer groups. The plastic structure of this component typically contains an intricate network of open celled o ni directional pores. The pores can be made in aver¬ age sizes for 0.8 micron to 2,000 micron and, gives the porous plastic a unique combination of venting filtering, wicking and diffusing capability and structural strength. Further, the material is strong, lightweight, has a high degree of chemical resistance and depending on the particular configuration of the apparatus, can be flexible. The degree of hardness can range from soft, resilient or rigid, and depending on the specific micro diameter range desired, the following polymers can be employed: Polypropylene(PP) , Ultra high molecular weight polyethylene (UHMW PE) , High density polyethylene (HDPE) , Polyvinylidene Fluoride (PVDF) , Ethylene-vinyl acetate (EVA) , Styrene Acrylonitrile (SAN) , Polytetrafluoroethylene (PTFF) . A suitable source of these materials is Porex Technologies of Fairburn, Georgia.

An alternate material for use in constructing the covers, as for example, covers 34 and 80, when the cover is to serve as a non-permeable gas barrier, is a material sold by B-P Chemicals International of Cleveland, Ohio, under the name and style "Barex". This material, which can also be used to alter¬ nately construct base 14 and element 28, is a clear rubber modified Acrylonitrile Copolymer which has wide application in the packaging industry because of its superior gas barrier, chemical resistance and extrusion (ther oforming) and injection molding capabilities. Structures using this material can be manufactured in either monolayer or coextrusion (with such other materials as polyethylene, polypropylene, polystyrene and other modified styrenes) . Combinations of different materials can be used to enhance the desired physical properties of the thermoformed part.

Finally, the foam pad adhesive 38 and peel strip 40 is preferably composed of a thin (1/32") 30 mil closed cell polyethylene (PE) foam double coated with a non-sensitizing acrylic pressure sensitive adhesive (PSA) , and 90 lb. white polyethylene coated release liner (peel strip) . This foam is also available in 1/16 inch and 1/8 inch thickness. The foam is stretchable, soft, elastic, conformable, cushioning, hypoal- lergenic, and is desirable for application where sustained use is required. The material is available from the 3M Company of Saint Paul, Minnesota and from Betham Corporation of Middlesex, New Jersey.

Turning now to Figures 10 through 17, another embodi¬ ment of the invention is thereshown. The apparatus of this form of the invention is similar in many respects to that previously described and like numbers are used to identify like components. Unlike the apparatus illustrated in Figures 1 through 9 which has a thermo sealed filling port, the apparatus of this second form of the invention is adapted to be filled using a hypodermic syringe. The device may have a cover made of the same material as cover 34, or may have a different type of impermeable cover, the function of which will presently be described.

Referring to Figure 10, the apparatus can be seen to comprise a base 14, .a distendable member 24 and a flow control member 26 all of which are of the same general character and function in the same manner as in the earlier described embodi¬ ment of the invention. The distendable member engaging element 60 is of slightly different construction and includes filling means which enables chamber 25 to be filled using a hypodermic syringe and needle of the character identified in Figure 17 by the numeral 62. Element 60 is superimposed over flow control member 26 and includes a pair of longitudinally extending, spaced apart upstanding protuberances 64. Each protuberance 64 is provided with fluid passageways 66 which communicate with fluid passageways 16 and 18 provided in base 14. Element 60 also includes an upstanding transversely extending portion 68 having a fluid passageway 70 extending therethrough (Figures 10, 11 and 17) . In this second embodiment of the invention, the open end 70a of passageway 70 is closed by a septum means for receiving a hypodermic needle. The septum means is here provided as a septum 72 which is adapted to sealably close the open end 70a of passageway 70. Septum 70 is constructed of a self-sealing, puncturable material such as silicone-SEBS (a composite incorporating a silicone interpenetrating network (IPN) into a styrene-ethylene butylene-styrene block copolymer) . If desired, the earlier form of the apparatus of the invention as shown in Figures 1 through 9 can alternatively have a fill means such as shown in Figure 17 to permit filling in the field. As best seen by referring to Figure 12, passa¬ geway 70 is in communication with a pair of logitudinally extending passageways 74 formed in element 60. Passageways 74 are, in turn, in communication with chamber 25 via passageways 76.

Cover 80 is formed of a clear plastic material which is impermeable to fluid including gases. This type of cover is used when the medicinal agent within chamber 25 is such that it must be sealed with respect to atmosphere. As best seen in Figure 18 cover 80 is provided with a pair of longitudinally extending protuberances 82 which are interconnected by a web 84. Web 84 carries on its upper surface an impermeable barrier peel strip 86 that covers vent means provided in web 84 to enable venting of chamber 25 at time of use.

The apparatus of this second form of the invention includes a needle assembly 42 of similar function and construc¬ tion as that previously described and includes a shielded injection needle 46. The needle assembly is provided with web means and a frangible section 42c to enable portion 42b of the needle assembly to be removed in the manner shown in Figure 16.

As before, so long as needle assembly 42 remains intact in the manner shown in Figure 12, the fluid will be retained within chamber 25. However, upon twisting off the frangible section 42c so that portion 42b on the needle assem¬ bly can be removed as shown in Figure 16, distendable membrane 24 will begin to expel fluid through the needle 46. The rate of expulsion of fluid is, of course, controlled by the perme¬ able membrane 26 which is disposed intermediate the fluid flow passageways 66 of member 60 and fluid flow passageways 16 and 18 formed in base 14.

Referring to Figures 18 through 21, another embodi¬ ment of the invention is thereshown. The apparatus of this form of the invention is similar in many respects to the em¬ bodiment shown in Figures 1 through 9 and like numbers are used to identify like components. Unlike the apparatus illustrated in Figures 1 through 9, the apparatus of this third form of the invention does not embody an injection needle assembly. Rath¬ er, the device of this embodiment includes a luer connector assembly 90, the function of which will presently be described. Turning particularly to Figure 18, the apparatus can be seen to comprise a base 14, and an operating assembly 92 associated therewith comprising a distendable member 24, a distendable member engaging element 28, a flow control member 26 and a cover 34, all of which are of the same general charac¬ ter and function in the same manner as the embodiment of the invention shown in Figures 1 through 9. The device also in¬ cludes an adhesive foam pad 38 and a peel strip 40 carried by base 14.

The luer connector assembly 90, which comprises the distinguishing feature of this form of the invention, is inte¬ grally formed with base 14 and includes a distal portion 90a and a proximal portion 90b. Distal portion 90a is provided with a longitudinally extending bore 94 which communicates with outlet 22 of base 14. Comprising the proximal portion 90b of assembly 90 is a luer connector of standard construction having a fluid passageway 96 which communicates with bore 94 of distal portion 90a. The outlet of passageway 96 is sealed by a fran¬ gible closure which is removable to activate fluid flow. The outboard end of distal portion 90a, designated in the drawings as 90c is of reduced diameter and is readily flexed to permit easy connection of the luer connector "L" with an external system "E" (Figure 20) .

As shown in Figures 18 and 21, base 14 includes fluid conduits 16, 18 and 20 which communicate with outlet passageway 22. Distendable membrane 24 functions to expel fluid from chamber 25, through flow rate control member 26 and outwardly through outlet passageway 22 in the manner previously de¬ scribed.

Referring to Figures 22 through 29 yet another form of the invention is shown and identified by the numeral 100. For certain medicinal agents, it is desirable to provide an initial high rate delivery followed by a slower rate sustained delivery. This form of the invention permits this to be accom¬ plished. The apparatus of this form of the invention is simi¬ lar in many respects to the embodiment shown in Figures 1 through 9 and like numbers are used to identify like compon¬ ents. Unlike the apparatus illustrated in Figures 1 through 9, the apparatus of this fourth form of the invention is not limited to a fixed rate infusion of the medicinal agent. Rather, because of the novel configuration of the distendable membrane engaging element and the dual flow rate control mem¬ bers of this form of the invention, a controlled variable rate of fluid flow is possible.

As best seen in Figures 22, 23 and 24, the apparatus of this last form of the invention also comprises a laminate, or layered, structure made up of a plurality of thin plate-like components. The apparatus includes a thin, generally planar plate-like base 102, having a transverse recess 104 in communi¬ cation with a fluid outlet passageway 106. A thin, generally planar elastic distendable membrane, or member 108 cooperates with base 102 to form a pair of discrete chambers 110 and 111 (Figure 27) . For certain applications, Chambers 110 and 111 may be of different individual size and configuration each having different volumes. As before, member 108 is distendable out of plane in the manner shown in Figure 25 by the introduc¬ tion of fluid into the chambers under pressure. The method of introduction of fluids into chambers 110 and 111 will presently be described.

Forming an important aspect of the apparatus of this fourth form of the invention is the provision of flow control means which are disposed internally of chambers 100 and 111 for controlling the rate of fluid flow of fluid from each chamber through outlet 106. In the embodiment of the invention here- shown, the flow control means is provided in the form of a flow rate control assembly 112 which is received within recess 104 formed in base 102 in the manner shown in Figures 22 and 24. Flow rate control assembly 112 includes a pair of permeable members 114 and 116 which, as will presently be described, pre¬ cisely control the rate of fluid flow from chambers 110 and 111 into fluid outlet 106. Passageway 106 is in communication with the fluid passageway of needle assembly 42 which is of the same construction as previously described herein.

As best seen in Figure 24, assembly 112 comprises a manifold member 118 which is closely receivable within recess 104 formed in base 102. Member 118 is provided with an inter¬ nal fluid conduit 120 having fluid inlets 122 and 124 at either end and a fluid outlet 126 proximate its center. Outlet 126 is adapted to communicate with outlet passageway 106 provided in base 102 when member 118 is in position within recess 104. Permeable members 114 and 116 overlay inlets 122 and 124 and, in a manner presently described, control the flow .of fluid into these outlets from chambers 110 and 111. Fluid inlets 122 and 124, can be constructed in various geometries and, in coopera¬ tion with the ullage means, presently to be described, to provide various degrees of active surface area of the rate control membrane.

The distendable member engaging element 130 of this latter form of the invention is of slightly different construc¬ tion and includes filling means which enable chambers 110 and 111 to be filled separately. As best seen in Figures 22 and 25, element 130 is superimposed over base 102 and flow control assembly 112 and includes a pair of longitudinally extending, spaced apart upstanding protuberances 132 and 134. Protuber¬ ances 132 and 134 are provided with fluid passageways 136 and 138 respectively. Passageway 136 communicates with fluid inlet 122 and passageway 138 communicates with inlet 124 of assembly 112. By varying the configuration of these passageways and fluid inlets alternate active surface areas of the flow control membrane can be exposed. Element 130 also includes an upstand¬ ing transversely extending portion 140 having a pair of fluid passageways 142 and 144 extending from the open ends 142a and 144a thereof. As shown in Figure 23, passageway 142 is in communication with passageway 136 of element 130 via a passage¬ way 152 and passageway 144 is in communication with passageway 138 of element 130 via a passageway 148. Passageways 146 and 148, in turn, communicate with chambers 110 and 111, respec¬ tively, via passageways 150 and 152 respectively (see Figures 25 and 26) . Open ends 142a and 144a of passageways 142 and 144 are closed by any suitable means such as heat sealing.

The apparatus of this fourth embodiment of the inven¬ tion is adapted to be filled with the selected medicinal fluid at time of manufacture. This is accomplished by .forcing fluid under pressure into passageways 142 and 144, and thence, into chambers 110 and 111 via passageways 150 and 152. As the fluid under pressure flows into the two chambers, it will cause the membrane 108 to distend upwardly into engagement with cover 34 in the manner shown in Figure 27. After chambers 110 and 111 have been filled with the selected medicinal fluid, passageways 142 and 144 are sealably closed. Cosmetic closure plugs 154 and 156 can be used if desired at the ends of conduits 142 and 144. It is to be observed that membrane 108 is bonded along its margins 108a to member 130 and is in sealable engagement along its longitudinal center line with member 130 intermediate protuberances 132 and 134. With this construction, chambers 110 and 111 are maintained independent from one another.

Upon twisting off the frangible section 42c so that portion 42b on the needle assembly can be removed as shown in Figure 29, elastic distendable membrane 108 will begin to expel fluid through flow control members 114 and 116. The rate of flow of fluid is, of course, controlled by the degree of perme¬ ability of each of the members 114 and 116. If one of these members has a greater permeability than the other, fluid will flow through that member at a greater rate. Accordingly, by varying the permeability of members 114 and 116, and with the output summed via flow channels 120 and 106, a larger initial volume of fluid can be injected into the patient. Continuous injection of fluid at a slower controlled rate will then fol¬ low. For example, if member 114 has a high degree of perme¬ ability, fluid will be forced out of chamber 110 at a rapid rate. On the other hand, if member 116 has a low permeability, fluid will be forced out of chamber 111 at a slower rate. With this arrangement, fluid can be simultaneously injected initial¬ ly at a high rate from chambers 110 and 111 then at a much slower rate from chamber 111.

As indicated in Figure 22, the apparatus is closed by a cover 34 having a medicant label 36. If a barrier cover and base configuration is used, cover vent means as previously described, must be provided. Affixed to the bottom of the base is an adhesive foam pad 38 and a peel strip 40 so that the apparatus can be self-attached to the patient.

Turning now to Figures 30, 31, and 32, another em¬ bodiment of the apparatus for use in infusing medicinal fluids into a patient is there illustrated and generally designated by the numeral 200. The device of this form of the invention is similar in many respects to that shown in Figures 18 through 21 and like numbers are used to identify like components. As best seen by referring to Figure 30, the apparatus comprises a thin, generally planar plate-like base 202 having at least one flow rate control channel. In the form of the invention shown in Figures 30 and 30A, the base is shown as having a pair of flow rate control channels provided here as longitudinally extending fluid conduits 204 and 206. Conduits 204 and 206 are intercon¬ nected by a fluid transfer manifold, or transverse conduit 208, which, in turn, is interconnected with a fluid outlet passage¬ way. Distendable membrane engagement means, shown here as protuberances 209, perform the same function as protuberances 30 previously described. It is to be understood that in some applications only a single protuberance is provided and in other applications no protuberance at all is required.

A thin, initially generally planar distendable elas¬ tomeric membrane, or member, 24 (Figure 32) cooperates with base 202 to form a chamber 25 (Figure 32). Member 24 is dis¬ tendable in the manner shown in Figure 32 by the introduction of fluid into the chamber under pressure. As previously de¬ scribed herein, as the distendable member 24 is distended by the fluid pressure, internal stresses are formed in the member which continuously urge it toward engagement with protuberances 209 as it trys to return to its original configuration. The method of introduction of fluids into chamber 25 is as pre¬ viously described in connection with the embodiment of Figures 12 through 21.

An important feature of this latter embodiment of the invention is the provision of a multiplicity of flow rate control micro-channels 210 in base 202. Micro-channels 210 are disposed on either side of conduits 204 and 206 and communicate therewith via flow control means of a character presently to be described.

In the embodiment of the invention shown in Figures 30 through 32, the flow control means is provided in the form of a thin, multilayered or gradiated assembly 212 which is superimposed over channels 210 in the manner shown in Figure 32. With this construction, when the device is in a fluid discharge mode, fluid within chamber 25 is forced by membrane 24 through channels 213 provided in protuberances 30, through assembly 212, through micro-channels 210, into conduits 204 and 206 and outwardly through outlet passageway 214. Passageway 214 is connected with dispensing means shown here as luer connection assembly 90 which includes a fluid flow conduit and fluid dispensing port or luer connector "L". By controlling the area of the micro-channels, the active surface area of membrane assembly 212 which is exposed to fluid can be varied in a manner to optimize fluid flow through assembly 212. Similarly by controlling the size and shape of the micro-chan¬ nels, the rate of flow of the fluid through membrane assembly 212 can also be uniformly maintained.

As indicated in Figure 31, the flow control means of this form of the invention, rather than consisting of a single layer of a permiable material having the desired fluid flow characteristics, here comprises an assemblage of a plurality of layers of permiable materials, P-l, P-2, and P-3, each having selected characteristics. These layers, which may be compo¬ sites, thin films, or porous substrates, may be constructed of any of the materials previously described herein so that the fluid pressure flow characteristics of the assemblage can be optimized for the particular medicinal or other fluid being dispensed. For example, layer P-l may comprise an asymmetric membrane, or film, having a first porosity, P-2 may comprise a resin membrane or film having a second porosity and layer P-3 may comprise a carrier substrate of predetermined porosity. In another application P-l and P-3 may take the form of carrier substrates and P-2 may comprise a very thin, rate control element. In this way a unique composite, sandwich-like assem¬ blage can be constructed. In certain applications assembly 212 can be constructed with gradient layers rather than with dis¬ crete elements in a manner to produce comparable results.

The multilayered, or gradient layer construction de¬ scribed in the preceding paragraph permits easier, thin-film manufacture, precise flow control over extended periods and easier handling of the membrane film during system manufacture.

Referring next to Figures 33 through 39, still anoth¬ er embodiment of the present invention is there shown. This embodiment of the invention is also similar to that shown in Figures 18 through 21 and like numerals are used to identify like components. As best seen in Figure 33, the device com¬ prises a base 300 having a pair of flow rate control channels 302 and 304 and a transversely extending fluid transfer mani¬ fold conduit 306. Conduit 306 is connected with an outlet 300 (Figure 34) which, in turn, is in communication with a fluid dispensing means, shown here as a fluid dispensing port 312.

Unlike the embodiments of the invention previously described, the device of this form of the invention does not include a flow rate control membrane of the character previous¬ ly described. Rather, the rate of fluid flowing from the dispensing means of the device is controlled by flow control means disposed intermediate outlet 310 and fluid dispensing port 312. The flow rate control means is here provided as a fluid flow micro-conduit 314 and a porous member 316 (Figure 36) which functions to restrict the flow of fluid between outlet 310 and dispensing port 312.

Another critical difference between the embodiment of the invention now being considered and the previously described embodiments resides in the unique character of the stored energy means used for discharging fluid from the device. Here the stored energy means, rather than being a single isotropic, elastomeric distendable membrane, comprises a laminate assem¬ blage made up of a plurality of initially generally planar distendable elements or films. Referring particularly to Figure 39, the stored energy means is there shown as a laminate assemblage 318 made up of individual elements or membranes 320, 322, 324, 326 and 328. Assemblage 318 functions in much the same way as the earlier described distendable membranes, and uniformly cooperates with base 300 to define fluid chambers or reservoirs 25. However, by constructing the stored energy means from a composite of several distinct elements or layers, the elastic characteristics of the stored energy means can be precisely tailored and the stored energy means can be uniquely constructed to function also as a gas permeability valve as well as the means for expelling fluids from the fluid reser¬ voir. This unique, multilayered or gradient construction permits venting to atmosphere through the membrane surface certain selected, entrained gases or vapors in the reservoir while simultaneously precluding any negative migration of selected atmospheric gases or vapors into the reservoir. Where the composite is made up of two or more layers of alternating thickness and permeability, and the permeability constants of the individual film layers are pressure dependent, the perme¬ ability of the stored energy means is effected and the direc- tion of flow of the permiant through the membrane wall is controlled by the order in which the individual layers or gradiations of the composite are assembled.

For example, referring to Figure 3^'9, layer 320 which may be distal to the reservoir comprises a thin film elastomer of a first thickness and a first permeability. On the other hand, layer 328, which may be proximal to the reservoir, com¬ prises a thin elastomer film of a second thickness and a second permeability. Layers 322, 324 and 326 may be of further alter¬ nating thickness and permeability and, if desired, may also have different perm-select characteristics. The selective arrangement of the different films each with its own individual permeability constants in ascending order, will dictate the direction of flow of selected gases and vapors through the stored energy means.

Turning now to Figures 40 through 45, another embodi¬ ment of the apparatus for use in infusing beneficial agents into a patient is there illustrated. The' device of this form of the invention is unique in that it provides the opportunity to add to the diluent or other parenteral fluid being intro¬ duced into the device selected elements, chemical compounds and biologically active materials such as drugs, medicaments, biological agents, or other therapeutic agents (additives). This addition is accomplished by removably affixing the select¬ ed additives to various forms of support structures which can be placed within the path of the fluid flowing through the device so that upon contact with the fluid, the additives are released at a controlled rate to the fluid. In this way, the delivery system of ;the invention can be safely rendered thera- peutically active upon hydration of the additive with a select¬ ed parenteral fluid such as a sterile diluent or other acquous solvent.

The basic structure of the device of this new form of the invention is similar in many respects to that shown in Figures 18 through 21 and in Figures 33 through 39 and like numbers are used to identify like components.

As best seen by referring to Figure 41, the apparatus comprises a base made up of a first, generally planar member 400 and a second companion member 401 which includes a pair of longitudinally extending flow rate control conduits or channels 402 and 404 which communicate with a transversely extending fluid transfer manifold conduit 406 (Figure 40) . Conduit 406 is, in turn, connected with a fluid outlet 408 which is in communication with a fluid dispensing means shown here as including a fluid dispensing port 410.

First base member 400 is also provided with a pair of longidutinally extending manifolds 411 which communicate with micro-channels 412 (Figure 44). As best seen in Figure 42, manifolds 411 and micro-channels 412 communicate with conduits 402 and 404 via flow control means of the general character described in connection with the embodiment of the invention shown in Figures 30 through 32. More particularly, the flow control means is here provided as a thin, multilayered or gra- diated assembly 212 (see Figure 31) which is superimposed over manifolds 411 and micro-channels 412 in the manner shown in Figure 41. Assembly 212 comprises an upper microporous layer, an intermediate rate control membrane and a lower support layer. With this construction, when the device is in a fluid discharge mode, fluid which is contained within chamber 25 (Figure 44), such as a diluent containing the additive (the beneficial agent) is initially forced by the stored energy means through channels 414 provided in a pair of upstanding protuberances 416 formed on base member 401. As the liquid passes through channels 414, it enters a pair of longitudinally extending manifolds 417 which are formed in base member 401 and which align with manifolds 411 formed in base member 400. Manifolds 417 function to uniquely distribute the fluid as it flows toward the flow control assembly 212 in a manner to disperse the fluid throughout a wide area of the flow control assembly. The uppermost layer of the assembly is designed to permit multi-axial flow distribution thereby effectively uti¬ lizing an extensive surface area of the rate control membrane. The beneficial agent flows through the rate control membrane layer, through the support layer, through micro-channels 412, and thence outwardly through outlet passageway 408. Passageway 408 in turn communicates with dispensing means, shown here as including a connector assembly 90.

As previously discussed, by controlling the area of the manifolds, the character of the uppermost layer of the flow control means, and the area of the micro-channels, the active surface area of the rate control membrane which is exposed to fluid can be precisely varied in a manner to predictably achieve the desired fluid flow control. Certain regimes of the various layers of assembly 212 can be rendered hydrophillic or hydrophobic by the appropriate use of materials and coatings in a manner and in amounts well known in the art. In this way, the wettability of the assembly can be precisely tailored as well as the initial gas venting capability of the system.

The distendable membrane engagement means, shown here as protuberances 416 (Figure 41) perform the same function as pre¬ viously described. It is to be understood that in some appli¬ cations only a single protuberance is provided and in other applications no protuberance at all is required. The stored energy means of this embodiment is of the same character as shown in Figure 39 and comprises a laminate assemblage 318 made up of individual elements or membranes 320, 322, 324, 326 and 328. Assemblage 318 functions in much the same way as the earlier described, single layer distendable membranes, and uniformly cooperates with base member 401 to define fluid chambers or reservoirs 25 (Figure 44) . However, as previously mentioned, by constructing the stored energy means from a composite of several distinct members or layers, the elastic characteristics and the resultant energy flux of the stored energy means can be precisely tailored. In this way, the stored energy means can also be uniquely constructed to function as a gas permeability valve (for example to prevent external negative migration of fluids into the reservoir) as well as the means for expelling fluids from the fluid reser¬ voir.

As indicated in Figure 41, superimposed over the base and the stored energy source is a structural cover 34 of the character previously described having appropriate medicant and use labels 36. Affixed to the bottom of base member 400 is a cushioning means or pad 38 having adhesive on both sides. A peel strip 40 is connected to the lower surface of pad 38. For certain applications, a thin protective film may be affixed over cover 34 to prevent ingress of liquids or other contami¬ nants into the device.

Like the apparatus shown in Figure 10, the present embodiment includes filling means which enables chambers 25 to be filled with a selected parenteral liquid using a hypodermic syringe and needle of the character identified in Figure 17 by the numeral 62 (see also Figure 43) . To accomplish filling of the chambers, base member 401 includes an upstanding trans¬ versely extending portion 418 having a fluid passageway 420 extending therethrough. In this embodiment of the invention, the open end 420a of passageway 420 is closed by a septum means for sealably receiving a piercing element such as a hypodermic needle. The septum means is here provided as a needle septum 422 which is adapted to sealably close the open end 420a of passageway 420. Septum 422 is preferably constructed of a self-sealing, noncoring, puncturable material such as silicone- SEBS. It should also be understood that the septum means can also take the form of a split septum for use with a state-of- the-art blunt cannula injector system. As best seen by refer¬ ring to Figure 40, passageway 420 is in communication with longitudinally extending channels 402 and 404. As before, channels 402 and 404 are, in turn, in communication with cham¬ bers 25. With this construction, an appropriate injectable such as a diluent or parenteral fluid contained within syringe 62 can be introduced into chambers 25 via passageway 420.

Before considering the highly important adding means of this latest embodiment of the invention a brief introductory background is perhaps helpful.

In the past it has been common practice to mix vari¬ ous types of separately packaged drugs with a suitable diluent immediately before they are delivered intravenously to a pa¬ tient. Typically the drugs are packaged separately from the diluent for various reasons. For example, 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 solutions in containers for intravenous delivery and vice versa.

Traditionally, the mixing of the drug and the diluent was accomplished by a doctor, nurse or medical professional injecting the injectable fluid into a glass vial containing the drug. After mixing of the drug and the diluent, the solution thus formed is withdrawn into a syringe barrel and in some in¬ stances 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 for connection to an intravenous administration set. This prior art procedure is time consuming, imprecise and generally undesirable.

The device of this latest form of the invention ele¬ gantly overcomes the drawbacks of the prior art reconstituting and delivery techniques by providing in conjunction with the basic fluid delivery device of the invention a simple and precise means for automatically mixing the desired drug with the appropriate diluent at the time the device is charged.

In the paragraphs which follow, wherein the details of this unique reconstitution process will be discussed, the following terms will have the following meanings:

Element - any of the fundamental substances that consist of atoms of only one kind and that singly or in combina¬ tion constitute all matter.

Additive - the element, compound, substance, agent, biologically active material, or other material which is to be added, all or in part, to the fluid introduced into the device of the invention.

Polymer - a chemical compound or mixture of compounds formed by polymerization and consisting essentially of repeating structural units. Parenteral Fluid - any solution which may be delivered to a patient other than by way of the intestines, including water, saline solutions, alkalizing solutions, dextrose solutions acidifying solutions, electrolyte solutions, reagents, solvents and like acquous solutions. Beneficial Agents - any drug, medicament, pharmaceutical, medical polymer, enzyme, hormone, antibody, element, chemical compound or other material useful in the diagno¬ sis, cure, mitigation, treatment or prevention of disease and for the maintenance of the good health of the patient. Biologically Active Material - a substance which is bio¬ chemically, Immunochemically, physiologically, or pharma¬ ceutically active or reactive. Biologically active mate¬ rial includes at least one or more of the following: biochemical compounds (such as amino acids, carbohydrates, lipids, nucleic acids, proteins, and other biochemicals and substances which may complex or interact with biochem¬ ical compounds) , such biochemical compounds biologically functioning as antibodies, antigenic substances, enzymes, co-factors, inhibitors, lectins, hormones, hormone produc¬ ing cells, receptors, coagulation factors, growth enhanc¬ ers, histones, peptides, vitamins, drugs, cell surface markers and toxins, among others known to those skilled in the art. Of the group of biologically active materials described, proteins are of utmost current interest because of the large molecule genetically engineered biopharmaceu- ticals as those species to be immobilized and congregated on the additive carriers hereinafter to be described. A discussion of the use of biomosaic polymers as carriers for biologically active materials is set forth in European Patent Application 0,430,517 A2.

Adding Means - an additive and any means for presenting the additive to the fluid flowing through the fluid passa¬ geways of the fluid delivery device of the invention in a manner such that all or any part of the additive will be added to the fluid. The adding means comprises the addi¬ tive and the additive presentation means which may take the form of a functional support, or carrier, an anchor¬ age, a deposition or reaction site or an element holder with or without some type of intermediate matrix or other release composition.

Additive Presentation Means - Any means such as a func¬ tional support or substrate for presenting the additive to the fluid flowing through the device. The functional substrate can comprise a polymer, copolymer, an inter- polymer, a ceramic, a crystal sponge, a carbon based matrix, a celullosic, glass, plastic, biomosaic polymers, azlactone-functional polymer beads, adduct beads, carbox- ylate-functional polymer beads, gums, gells, filaments and like carriers.

By way of illustration, the adding means of the invention can take several different forms such as those il¬ lustrated in Figures 43 and 45. However, in its preferred form, the adding means includes a cylindrically shaped, func¬ tional support structure which is inserted into passageway 420 and to which various additives, including beneficial agents such as drugs, biologically active materials, and chemical elements and compounds can be releasably connected. These additives are carried by the structure in a manner such that, as the liquid flows through passageway 420 and circulates through the support assembly in the manner shown by the arrows in Figure 43, the additives will be presented to the liquid flow and efficiently added to the liquid as it flows toward chambers 25.

The additives themselves can also take various physi¬ cal forms including liquid, solid, granular, powder, particle, gel, wax, hydrocolloid carrier, a gum, film, tablet, crystal¬ line, emulsions, microcrystalline, microspherical, spray dried compounds and lypohilized compounds and saturants. The addi¬ tives can be removably connected to, immobilized on, impregnat¬ ed within or supported by the support means in a number of ways. The additives can be chemically or mechanically at¬ tached, affixed, or bound directly or indirectly, linked or cross linked, anchored to the surfaces of the support, or surface active agent or they can be absorbed, reaction cata¬ lyzed, electrostatically encapsulated, attached by chemical modification or transformation to the carrier surface, polymer¬ ized on or through the carrier, with or without the use of an interpolymer, localized, entrapped, suspended, deposited, impregnated, coated, or occluded or otherwise removably affixed within voids, cells, tubules, and intersticies formed in the support. One important method for removably affixing the additive to the functional support means includes treating the functional support means with a compound having selected reac¬ tive functional groups such as azlactone functional compounds with their unique ability to react with aqueous media and their high binding capacity. In this way complexing agents, cata¬ lysts and biological materials such enzymes or other proteins, as well as biomacromolecules can be attached to the carrier for later removal and recovering. Additionally, the use of one or more monomeric or polymerized surface active agents allows for rapid dissolution and smooth liberation of the additives. A discussion of such surface active agents is contained in U.S. Patent 4,963,367 issued to Ecanow.

Similarly, the additives can be added to or inter¬ mixed with the liquid flowing through the device by one or more of various mechanisms, including mechanical release, chemical reaction, dissolution, disorbsion, debinding, delinking, bio- separation, diffusion, washing, disintegration, errosion, disassociation, solubilization, leeching, enzymatic cleavage, biological reaction, osmosis, separation from ring opening materials by a ring opening reaction, and other separation means.

Additionally, a polymer can be used as the carrier or support for some component of a reaction system. Three classes of polymeric supports can be used, namely polymeric reagents, polymeric catalysts and polymeric substrates. A discussion of polymers as carriers or supports is contained in Principles of Polymerization, Second Edition by George Odian. Microporouε polymers usable as carriers are also fully described in U.S. Patent 4,519,909 issued to Castro.

Turning now to Figures 41 and 43, one form of adding means, or combination additive carrier and additive is there illustrated and generally designated by the numeral 423. This form of the adding means comprises a generally cylindrically shaped assembly including a substantially cylindrical, porous substrate 423a into which an injector inlet tube 423b is close¬ ly received. Surrounding porous substrate 423a is a sleeve 423c having a multiplicity of flow channels 423d. As shown in Figure 43, the assembly thus formed is inserted into fluid passageway 420 formed in transversely extending portion 418. Receivable within the inlet opening of tube 423b is the pre¬ viously identified needle septum injection site 422. Connected to portion 418, as by bonding is an insert 424 (Figure 41) which functions to contain the septum within the device.

In using the apparatus of the embodiment of the invention shown in Figures 40-44, septum injection site 422 is penetrated by needle 62 and the sterile diluent is introduced into inlet passageway 420 using the needle syringe. As indi¬ cated by the arrows in Figure 43, as the diluent flows longitu¬ dinally of inlet passageway 420 it will pass through porous member 423a, into flow channels 423d and then into chambers 25 urging the distendable membrane 318 outwardly into the position shown in Figures 42 and 44. As the liquid flows through porous member 423a, the additives presented to the liquid will be added to the flow, or solubilized by the diluent, thereby activating the diluent to form the therapeutic solution to be dispensed to the patient.

The liquid, such as a parenteral fluid, which is introduced into passageway 418 can include, by way of example, a reagent, a sterile diluent, various electrolytes, aqueous solutions such as aqueous solutions of dextrose, saline solu¬ tions, alkalinizing solutions, acidifying solutions, polyonic solutions and any other liquids that can serve as a vehicle for the administration of therapeutic or beneficial agents which are desirable to administer to the patient by infusion.

Turning now to Figure 45, various other forms of adding means are there illustrated. For example, numeral 425 identifies an assembly comprising a porous substrate with interconnecting voids, such as a crystal sponge 425a, over which various outer coatings 425b exhibiting one or more addi¬ tives are laminated. The selected additives such as elements, chemical compounds, drugs and functional intermediates are provided on or within the coating layers by techniques well known to those skilled in the art. The additives exhibited by the layers are, of course, introduced into the sterile diluent as the diluent flows along of the inlet passageway 420. In this instance, since the substrate will not be damaged by the needle 62, as might a polymer or celullosic carrier, use of the injector inlet tube 423b is not required.

Another form of additive assembly designated in Figure 45 by the numeral 427, comprises a solid tubular member having an internal, axially extending fluid passageway 427a, the inner wall of which is lined with a separation coating affixing the additives such as chemical compounds and benefi¬ cial agents, or medicaments.

Still another form of additive assembly is identified in Figure 45 by the numeral 429. This assembly comprises a cylindrical, porous plug like member made up of a multiplicity of fused together microspheres or beads 429a, each of which is coated with a separation or reactive coating upon which is deposited an additive such as a biologically active material or other beneficial agent. The microspheres can be formed of glass, plastic or other suitable materials.

The numeral 431 of Figure 45 identifies yet another form of the adding means of the invention. In this form of the invention a generally cylindrically shaped functional support means for affinity attachment, and subsequent release of the additive, is formed from a multiplicity of microporous polymers 431a presenting a multiplicity of reactive sites over a wide area for species immobilization. In this form of the inven¬ tion, in order to avoid needle damage to the polymers, it is necessary to use an injector inlet tube of the character shown in Figure 41 and identified by the numeral 423b.

The additive assembly designated in Figure 45 by the numeral 433 may also require the use of an injector tube. This assembly is made up of high porosity, semi-sythetic celullosicε 433a formed into a generally cylindrical shape and having interconnecting, interstial surfaces or functional support means and is similar in size and configuration to activating assembly 423.

Another slightly more complex additive assembly is identified by the numeral 435. This assembly is made up of a plurality of spaced apart, porous disk shaped wafers 435a, 435b, 435c, and 435d each wafer being of the same or different construction and porosity and each having reactive sites pre¬ senting to the liquid flow specially selected additives such as beneficial agents, elements or compounds so that multiple reactivities and selectivities can be achieved. With this construction, a wide variety of liquid flow rates, and complex sequential separations and priority staged substance introduc¬ tion into the system reservoir can be achieved by specially designing each of the wafers that cooperate to make up the structural support.

Still another form of activating assembly is desig¬ nated in Figure 45 by the numeral 437. This assembly comprises a cylindrically shaped porous structure 437a which is provided with pores of varying sizes only some of which are coated, plugged or impregnated with selected additives 437b and, as necessary, functional intermediate materials.

Finally, the functional support member identified by the numeral 439 exemplifies yet another form of adding means of the invention. This member, which is also of a generally cylindrically shaped configuration, is constructed from a porous ceramic material into which selected additives and intermediate compounds have been removably affixed. Member 439, being made of a hard ceramic, would not be easily damaged by the needle 62 and therefore the injector inlet tube is generally not needed. Member 439 can also be constructed from fuzed activated carbon particles, coated porous zirconium oxide bonded spherules, or other porous forms of polymer reactive supports including joined azlatone-functional polymer beads suitable for the attachment of functional materials.

Assemblies 423 through 439 which may be soluble or insoluble are intended to merely exemplify, not to limit, the wide variety of materials and constructions that can be used to introduce the desired additives into the liquid flow introduced into the inlet flow passageway 420 of the device.

Turning now to Figure 43, another form of the inven¬ tion is shown. This figure shows in cross-section one set of the manifolds 411 and 417 which are formed in base members 400 and 401 of the device. In certain applications, it is sometimes advantageous to provide liquid distribution means within manifolds 411 and 417 to enhance the uniform flow of liquid through the manifolds. In the embodiment of the inven¬ tion shown in Figure 43, the liquid distribution means is provided as generally planar strips of felt-like hydrophillic polymer material 440 which is readily wetted by the solution being expelled from chambers 25 by the stored energy means, or distendable membrane 318. Material 440 can be of any type that will enhance the uniform flow of the solution contained within chambers 25 and can include ceramic, crystalline, polymer, sponge and other similar materials which have hydrophillic characteristics.

Turning to Figure 47, another embodiment of the apparatus for use in infusing beneficial agents into a patient is there illustrated. The basic structure of the device of this latest form of the invention is similar in many respects to that shown in Figure 41 and like numbers are used to identi¬ fy like components. The major difference between the device shown in Figure 47 and that shown in Figure 41 is that the transverse filling portion 418 is replaced by a longitudinally extending filling portion 518. As will be discussed in greater detail hereinafter, the adding means including the additive carriers of this form of the invention are also of a somewhat different configuration.

As in the apparatus of Figure 41, the apparatus here comprises a base made up of a first, generally planar member 500 and a second companion member 501 which includes a pair of longitudinally extending flow rate control conduits or channels 502 and 504 which communicate with a fluid outlet 508 which is in communication with a fluid dispensing means shown here as including a fluid dispensing port 510.

First base member 500 is also provided with a pair of longidutinally extending manifolds 511 which communicate with micro-channels of the character shown in Figure 44 and identi¬ fied by the numeral 412. Manifolds 512 as well as the micro- channels communicate with conduits 502 and 504 via flow control means. The flow control means is here provided as a thin, multilayered or gradiated assembly 512 which is superimposed over manifolds 511 in the manner indicated in Figure 47. Assembly 512 comprises an upper microporous substrate 512a, an intermediate rate control membrane 512c and a lower support substrate 512d. With this construction, when the device is in a fluid discharge mode, fluid which is contained within chamber 25 (Figure 44) , such as a diluent containing the additive (the beneficial agent) is initially forced by the stored energy means through channels 514 provided in a pair of upstanding protuberances 516 formed on base member 501.

As previously discussed, by controlling the area of the manifolds, the character of the uppermost layers of the flow control means, and the area of the micro-channels, the active surface area of the rate control membrane which is exposed to fluid can be precisely varied in a manner to pre¬ dictably achieve the desired fluid flow rate control. As before, certain regimes of the various layers of assembly 512 can be rendered hydrophillc or hydrophobic by the appropriate use of materials and coatings in a manner, amount, area and location well known in the art. In this way, the wettability of the assembly can be precisely tailored as well as the ini¬ tial gas venting capability of the system.

The distendable membrane engagement means, shown here as protuberances 516 perform the same function as previously described. It is to be understood that in some applications only a single protuberance is provided and in other applica¬ tions no protuberance at all is required.

The stored energy means of this embodiment is also of the same general character as previously described and compris¬ es a laminate assemblage 518 made up of individual elements or membranes 520, 522, and 524. Assemblage 518 functions in much the same way as the earlier described, single layer distendable membranes, and uniformly cooperates with base member 501 to define fluid chambers or reservoirs 25 (Figure 44) . However, as previously mentioned, by constructing the stored energy means from a composite of several distinct members or layers, the elastic characteristics and the resultant energy flux of the stored energy means can be precisely tailored. As before, the stored energy means can also be uniquely constructed to function as a gas permeability valve to control gas flow in one direction as well as the means for expelling fluids from the fluid reservoir.

As indicated in Figure 47, superimposed over the base and the stored energy source is a cover 34 which includes a porous structural member 34a and a film cover 34b. Appropriate medicant primary labels and instruction for use labels 36 are affixed to cover 34. Affixed to the bottom of base member 500 is a cushioning means or pad 38 having adhesive on both sides. A peel strip 40 is connected to the lower surface of pad 38.

Like the apparatus shown in Figure 10, the present embodiment includes filling means which enables chambers 25 to be filled with a selected injectable such as a parenteral liquid using a hypodermic syringe and needle of the character identified in Figure 17 by the numeral 62 (see also Figure 43) . To accomplish filling of the chambers, base member 501 includes the previously mentioned upstanding longitudinally extending portion 519 having a fluid passageway 520 extending there¬ through. In this latest embodiment of the invention, the open end of the passageway is closed by a septum means for sealably receiving a piercing element such as a hypodermic needle. The septum means is here provided as a needle septum 522 which is adapted to sealably close the open end of passageway 520. Passageway 520 is in communication with the fluid chambers 25 so that an appropriate parenteral fluid contained within syr¬ inge 62 can be introduced into chambers 25 via passageway 520.

One form of adding means and additive carrier of this latest embodiment is generally designated in Figure 47 by the numeral 523. This form of the adding means comprises an elon¬ gated, generally cylindrically shaped assembly including a substantially cylindrical, porous substrate 523a into which an injector inlet tube 523b is closely received. The assembly comprising substrate 523 and injector inlet tube 523b is close¬ ly receivable within longitudinally extending fluid passageway 520 formed in longitudinally extending portion 519. Receivable within the inlet opening of tube 523b is the previously identi¬ fied needle septum 522 which is held in position by insert 524 which is bonded to base member 50.

Disposed intermediate septum 522 and injector inlet tube 523b is a porous flow restrictor 525 which controllably resists the fluid which is flowing into the injector tube. This resistor can be constructed from any suitable porous inert material such as a ceramic or plastic which resists fluid flow in a manner to controllably regulate the residence time of the fluid being introduced into the carrier 523.

As was the case with the embodiment of the invention shown in Figures 40 through 45, various additives, including beneficial agents such as drugs, biologically active materials, and chemical elements and compounds can be releasably connected to additive carrier 523. These additives are carried by the structure in a manner such that, as the liquid flows through passageway 520, the additives will be presented to the liquid flow, separated and released and efficiently added to the liquid as it flows toward the reservoir chambers 25.

As before, the additives can take the various physi¬ cal forms previously described herein and can be removably or releasably connected to the carrier in the many ways previously described. Similarly, the additive can be added to the fluid introduced into the device by the various chemical and mechani¬ cal means previously described for easy removal and recovery.

Various other forms of adding means and additive assemblies of the character illustrated in Figure 45 can also be used with this latest embodiment. For example, a porous substrate with interconnecting voids, such as a crystal sponge 425a over which various outer coatings 425b of one or more additives are laminated can be used. Similarly, a solid tubu¬ lar member such as member 427 (Figure 45) having an internal, axially extending fluid passageway 427a, the inner wall of which is lined with a separation coating or surface active agent or intermediate matrix affixing the additives such as medicaments, drugs and other beneficial agents can be used.

Still another form of additive assembly which can be used is of the character identified in Figure 45 by the numeral 429. This assembly comprises a cylindrical member made up of a multiplicity of fused together microspheres 429a, each of which is coated with a surface active agent separation coating upon which is deposited and chemically anchored a biologically active material or other beneficial agent. Other forms of the additive means which can be used include those shown in Figure 45 and identified by the numerals 431, 433, 435, 437 and 439.

In certain applications the additive, as defined herein, can be deposited, coated or otherwise removably affixed interstitially of or onto a surface of the membrane 542 of the stored energy means which is exposed to the liquid. With this construction, the fluid entering chambers 25 will be exposed to the additive and the additive will be added to the fluid prior to its infusion into the patient.

Additionally in some applications, the additive can be removably affixed to, impregnated within or otherwise an¬ chored directly or indirectly on or within either or both of the base members 500 and 501. In this way, the additive can be separated from the base members and added to the liquid which contacts the base members at any time prior to its infusion into the patient. In other applications, the additive can be deposited, coated or otherwise removably affixed interstitially of or onto the rate control assembly 512 so that the additive is exposed to the fluids flowing through the rate control assembly in a direction toward the outlet of the device.

Referring to Figures 48 through 60, another embodi¬ ment of the apparatus for use in infusing beneficial agents into a patient is there illustrated. The device of this form of the invention is similar in many respects to the embodiment shown in Figures 40 through 45 in that it provides the oppor¬ tunity to add to the diluent or other parenteral fluid being introduced into the device selected elements, chemical com¬ pounds and biologically active materials such as drugs, medica¬ ments, biological agents, or other therapeutic agents (addi¬ tives) . However, in this latest form of the invention selected additives are removably affixed to various forms of support structures which are, in turn, contained within a novel addi¬ tive subassembly that can be inserted into the device in a manner to place the additives within the path of the fluid flowing through the device. In this way the additives, such as drugs, can remain sealed in the prepackaged additive subassem¬ bly, which preferably comprises a glass vial, until such time as the subassembly is interconnected with the base of the apparatus and diluent flow through the subassembly is com¬ menced.

Because the basic structure of the device in this latest form of the invention is similar in many respects to that shown in Figures 18 through 21, Figures 33 through 39 and Figures 48 through 54, like numbers are used to identify like components. As best seen by referring to Figure 48, the apparatus comprises a base made up of a first, generally planar member 600 and a second companion member 601. Member 600 includes a pair of a longitudinally extending fluid flow manifolds 602 and 604 which communicate with a transversely extending fluid transfer passageway 606 (Figure 48) . Passageway 606 is, in turn, connected with a fluid outlet 608 which is in communica¬ tion with a fluid dispensing means shown here as including a fluid dispensing port 610 (Figure 49) .

First base member 600 is also provided with a pair of longitudinally extending flow passageways 611 the purpose for which will presently be described. Passageways 611 communicate with a pair of transverse channels 612 (Figure 48) . Channels 612, in turn, communicate with reservoir inlet ports 613 of base member 601 which are of the character best seen in Figure 48.

Reservoir outlet passageways for fluid flowing out¬ wardly from the reservoir are provided in the form of longitu¬ dinally extending flow channels 614 provided in a pair of protuberances 616 which are integrally formed with base member 601. Channels 614, in turn, communicate with microchannels 617 of manifolds 602 and 604 via flow control means, shown here as membrane assemblies 618 (Figure 48) which are superimposed over manifolds 602 and 604 and micro-channels 617 in the manner shown in Figure 48 and 51. Assemblies 618 comprise an upper microporous layer 618a and a lower support layer 618b. With this construction, when the device is in a fluid discharge mode, fluid which is contained within reservoirs or chambers 620 (Figure 51) , such as a diluent containing the additive (the beneficial agent) , is initially forced by the stored energy means through channels 614 provided in upstanding protuberances 616 formed on base member 601. As the liquid passes through channels 614, it flows through flow control assemblies 618 and into manifolds 602 and 604. After passing through the flow rate control means, the beneficial agent flows through mi¬ crochannels 617, and thence outwardly through outlet passageway 606. Passageway 606, in turn, communicates with dispensing means, shown here as including a connector assembly 90.

The distendable membrane engagement means or protu¬ berances 616 perform the same function as previously described as does the unique stored energy means. The stored energy means of this embodiment is of the general character previously described and comprises a laminate assemblage 622 made up of at least two individual elements or membranes. As before, assem¬ blage 622 cooperates with base member 601 to define the fluid chambers or reservoirs 620 (Figure 51) .

As indicated in Figure 48, superimposed over the base and the stored energy source is a structural cover 34 of the character previously described having appropriate medicant and medicant use instruction labels 36. Affixed to the bottom of base member 600 is a cushioning means or pad 38 having adhesive on both sides. A peel strip 40 is connected .to the lower surface of pad 38. For certain applications, a thin protective film may be affixed over cover 34 to prevent ingress of liquids or other contaminants into the device.

Like the previously described embodiments, the pres¬ ent embodiment includes filling means which enables chambers 620 to be filled with a selected parenteral liquid. Here the filling means includes a hypodermic syringe and needle of the character identified in Figure 58 by the numeral 62 (see also Figure 43) .

As best seen in Figures 48, 53 and 57, base member 601 includes an upstanding, longitudinally extending portion 626 having a generally cylindrical chamber 628 extending there¬ through (Figure 57) . In this embodiment of the invention, chamber 628 is uniquely designed to closely receive the addi¬ tive subassembly that sealably contains the additive to be added to the parenteral fluid.

Referring to Figure 52, this unique immobilized adding means or additive subassembly comprises a glass tube or vial 630 which is sealed at either end by sealing means shown here as rubber stoppers 632 and 633. Stopper 632 is adapted to sealably receive a piercing element such as the hypodermic needle 62a of syringe assembly 62. (Figures 52 and 53) . The rubber stoppers 632 and 633 are preferably constructed of a self-sealing, noncoring, puncturable material such as silicone- SEBS. Tear open type aluminum sealing caps 637 are provided at each end of tube 630 and function to sealably encapsulate rubber stoppers 632 and 633.

Sealing caps 637 comprise an aluminum sleeve portion 637a which is crimped in place within a groove 630a provided at either end of tube or vial 630, and a removable end plate 637b. Disposed interiorly of tube 630 is a substrate .640 which re¬ leasably carries the additive such as a beneficial agent of the character earlier defined herein (Figures 52, 55 and 56) . Substrate 640 which, along with the additive, comprises the adding means of this form of the invention can be of the same character as the additive carriers of the assemblies shown in Figure 45 and identified by the numerals 425, 427, 429, 430, 433, 437 and 439. As indicated in Figure 59, vial 630 is provided with circumferentially spaced ribs 630b which maintain the substrate spaced apart from the interior wall of the vial . Such stand-off ribs may not be required when substrates of certain character are used.

Turning particularly to Figure 60, it can be seen that a uniquely configured needle 642 is integrally molded into base member 601. Needle 642 is provided with first and second fluid passageways 644 and 646 which are separated by a center section 645. Passageway 644 is in communication at one of its ends with passageway 650 of base member 601. At its opposite end, passageway 644 communicates with the interior of tube 630 after the needle point 642a has pierced rubber stopper 633 in a manner shown in Figure 59. Passageway 646 is in communication at one of its ends with passageway 648 of base member 601 and at its opposite end communicates with outlet passageway 608 of base member 601 (Figure 60) .

In using the apparatus of the embodiment of the invention shown in Figures 48 through 60, sealing caps 637 are opened in the manner shown in Figures 52 and 56 to expose the site injection portion of the rubber stoppers. The adding means, or glass vial 630 is then inserted into chamber 628 and urged forwardly with sufficient force to cause needle 642a to penetrate rubber stopper 633 in the manner shown in Figures 57 and 60. As best seen in Figure 57, vial locking means, here shown as detents 651, are provided at either end of chamber 628. These detents permit passage of vial 630 in an inward direction but function to lock the vial in place to prevent its withdrawal from the chamber.

With the vial locked in place within chamber 628, rubber stopper 632 is pierced by needle 62a of the needle syringe (Figure 58) and the sterile diluent is introduced into the in¬ terior passageway 640a of substrate 640. As indicated by the arrows in Figures 49 and 60, as the diluent flows longitudinal¬ ly of the additive presentation means, or substrate 640, it efficiently intermixes with the additive carried by the sub¬ strate. The mixture thus formed flows through passageway 644 of needle 642, into passageway 650 (Figure 60), through passa¬ geways 611 and 612 (Figure 49) and then into chambers 620 via ports 613. This fluid flow urges membranes 622 outwardly into the position shown in Figure 51 in close proximity with interi¬ or walls 653 of porous body 655.

As before, the liquid, such as a parenteral fluid, which is introduced into passageway 640a can include, by way of example, a reagent, a sterile diluent, various electrolytes and various other aqueous solutions.

After the additive carried by substrate 640 has been separate and released by the parenteral fluid and has been efficiently intermixed therewith, the solution or beneficial agent thus formed will remain within reservoirs 620 until the time it is to be infused into the patient. When the outlet port 610 is opened for fluid flow to the patient, the fluid contained within chambers 620 will flow downwardly through channels 614 in protuberances 616, (Figure 50) , through the flow rate control membranes 618 and into crossing microchannels 617. As best seen in Figure 48 manifolds 602 and 604 communi¬ cate with transverse manifold passageways 606 which, in turn, are in communication with the fluid outlet port 610 of the device. A hydrophilic porous flow filter 659 is disposed proximate the outlet end of substrate 640 (Figure 55) for filtering and controlling the residence time of the fluid within the substrate 640.

It is to be appreciated that a wide variety of addi¬ tives, such as drugs and the like, can be removably affixed to substrates of widely varying material composition and design. The substrates can then be safely sealably contained within the sealed glass vial of the additive subassembly for use at any later time with stored energy infusion devices of the character shown in Figure 48. This unique approach provides a completely new dimension to the preparation, packaging and controlled administration of virtually any kind of beneficial agent to an ambulatory patient.

Turning now to Figures 61 through 64, still another embodiment of the apparatus for use in infusing beneficial agents into a patient is there illustrated. The device of this form of the invention is similar in many respects to the device shown in Figures 40 through 45 and like numbers are used to identify like components. As before selected additives are removably affixed to various forms of additive presentation means such as substrates, matrices and scaffolds which can be placed within the path of the fluid flowing through the device so that upon contact with the fluid, the additives are released at a controlled rate to the fluid.

As best seen by referring to Figure 61, the apparatus comprises a base made up of a first, generally planar member 700 and a second companion member 701 which includes a pair of longitudinally extending flow conduits or channels 702 and 704 which communicate with a transversely extending fluid transfer manifold conduit 706 (Figure 62) . Conduit 706 is, in turn, connected with a fluid outlet 708 which is in communication with a fluid dispensing means shown here as including a fluid dispensing port 710.

First base member 700 is also provided with a pair of longitudinally extending manifolds 711 which communicate with micro-channels 712 (Figure 63). Manifolds 711 and micro-chan¬ nels 712 communicate with conduits 702 and 704 via flow control means of the general character described in connection with the embodiment of the invention shown in Figures 30 through 32. More particularly, the flow control means is here provided as a thin, multilayered or gradiated assembly 212 (see Figure 31) which is superimposed over manifolds 711 and micro-channels 712 in the manner shown in Figure 61. Assembly 212 is of the same construction and operates in the same manner as previously de¬ scribed. When the device is in a fluid discharge mode, fluid which is contained within chamber 25 (Figure 63), such as an elution buffer, diluent, or solvent containing the additive (the beneficial agent) is initially forced by the stored energy means through channels 714 provided in a pair of upstanding protuberances 716 formed on base member 701. As the liquid passes through channels 714, it enters a pair of longitudinally extending manifolds 717 which are formed in base member 701 and which align with manifolds 711 formed in base member 700.

The distendable membrane engagement means, shown here as protuberances 716 (Figure 61) perform the same function as previously described. It is to be understood that in some applications only a single protuberance is provided and in other applications no protuberance at all is required.

The stored energy means of this embodiment is of the same character as shown in Figure 1 and comprises an elastomer¬ ic distendable membrane 24. Membrane 24 functions in the same manner as previously described in connection with the embodi¬ ment of Figure 1.

As indicated in Figure 61, superimposed over the base and the stored energy source is a structural cover 34 of the character previously described having appropriate medicant and use labels 36. Affixed to the bottom of base member 700 is a cushioning means or pad 38 having adhesive on both sides. A peel strip 40 is connected to the lower surface of pad 38. For certain applications, a thin protective film may be affixed over cover 34 to prevent ingress of liquids or other contami¬ nants into the device.

Like the previously described embodiments of the invention, the present embodiment includes filling means which enables chambers 25 to be filled with a selected parenteral liquid such as a buffer, a detergent, a solvent, a diluent or other eluting agents. To accomplish filling of the chambers, base member 701 includes an upstanding transversely extending portion 718 having a fluid passageway 720 extending there through. In this embodiment of the invention, the open end 720a of the passageway 720 is closed by a novel filling-check valve means for controlling the flow of fluid into passageway 720, which here comprises a check valve housing 722, a check valve 724 and a safety luer cap 726 for interconnection with a standard luer fitting. As best seen in Figure 64, the filling- check valve means is receivable within an enlarged diameter portion 728a of a structural support 720 which is closely receivable within portion 718.

As best seen by referring to Figure 63, passageway 720 is in communication with longitudinally extending channels 702 and 704. As before, channels 702 and 704 are, in turn, in communication with chambers 25. With this construction, an appropriate injectable such as a diluent or parenteral fluid, or other elution agent as indicated by the flow arrows, can be introduced into chambers 25 via luer cap 726 and passageway 720. As the parenteral fluid enters the check valve housing 722, check valve 724 will be moved away from seat 722a (to the right as viewed in Figure 64) to permit fluid flow inwardly of passageway 720. When the chambers are filled, the buildup of back pressure will cause the valve to return to the closed position shown in Figure 64.

The adding means of the invention can take several different forms as, for example, the cylindrically shaped, functional support structure 730 which is inserted into passa¬ geway 720 and to which various additives, including beneficial agents such as drugs, biologically active materials, and chemi¬ cal elements and compounds can be releasably connected. The adding means can also be of the character shown in Figure 48 wherein the additive is encapsulated within a sealed container.

In the form of the invention shown in Figure 61, the liquid medium flows around, about and through the substrate support 730. In the form of the invention shown in Figure 48, the additive presentation means can be sealably contained within the container 630 and may include matrices suitable for affinity-based attachment such as a synthetic support, a mem¬ brane, a plate, a filament, a bead matrix column together with a suitable storage buffer, or a preactivated gel. The details of these matrices will be described more fully hereinafter.

The additives can take various forms and, as pre¬ viously mentions, can be removably affixed to the functional support means in various ways to enable the use of separation techniques broadly defined by the term chromotography. Chro- motography as used herein refers to a group of separation techniques which are characterized by a distribution of the molecules to be separated between two phases, one stationary and the other mobile. Affinity chromotography involves the use of biological interactions and contemplates the use of affinity chromotography supports through which the eluting fluid flow. In the present embodiment of the invention, the additive pre¬ sentation means assumes the character of an affinity chromotog¬ raphy support to which various ligands are attached. In the practice of affinity chromotography techniques, one of the members of the pair in the interaction, the ligand, is immo¬ bilized on a solid phase, while the other, the counterligand (most often a protein) , is absorbed from the extract that is passing the substrate during the manufacturing process. Impor¬ tantly, affinity chromotography techniques can include the use of highly versatile azlactone functional compounds, such as azlactone functional beads, as well as the use of a wide varie¬ ty of other media for activation and coupling chemistry. Examples of ligands that can be attached to the affinity sup¬ ports include antibodies, enzymes, lectins, nucleic acids hormones and vitamins. Examples of important counter ligands include antigens, virus, cells, cell surface receptors and the like. Chromotography and affinity chromotography techniques are described in detail in Protein Purification by Janson and Tyden, Copyright 1989 and reference should be made to this work to provide a working understanding of the techniques.

Polymeric azlactones are well known in the prior art. Their use in the production of homopolymers and copolymers has been described in a number of patents. See for example, U.S. Patent No. 3,488,327 (issues Jan. 6, 1970 to F. Kollinsky et al.) ; U.S. Patent No. 3,583,950 (issued June 8, 1971 to F. Kol¬ linsky, et al.) ; U.S. Patent No. 4,304,705 (issued December 8, 1981 to S. M. Heilmann, et al.) ; and U.S. Patent No. 4,737,560 (issued April 12, 1988 to S. M. Heilmann, et al.) ; and U.S. Patent No. 5,013,795 issued May 7, 1991 to Coleman, et al.

Azlactones, or oxazolones, are cyclic anhydrides of N-acylamino acids and have been used extensively in organic synthesis. The formation of a f ive-membered azlactone of particularly useful functionality for immobilization purposes can be accomplished through the reaction of a carboxylate group with a-methyl alanine using a two-step process. (See Immo¬ bilized Affinity Ligand Techniques-Hermanson, Mallia and Smith, Copyright 1992) . One method of forming azlatone beads, the use of which has been previously mentioned herein, makes use of this process in the polymerization of monomers to first yield a carboxyl group on the matrix. In the second step, the azlac¬ tone ring is formed in anhydrous conditions through the use of a cyclization catalyst. Suitable cyclization agents that will drive this reaction include acetic anhydride, alkyl chlorofor- mates, and carbondiimides. The process of forming these active groups and of making beaded polymeric supports containing them has been thoroughly described in patents assigned to 3M Corpo¬ ration (U.S. Patent No. 4,871,824 and 4,737,560). These sup¬ port materials are now available under the tradename "Emphase". U.S. Patent Nos. 5,045,615 and 5,013,795 which have been as¬ signed to 3M Corporation also describe recent advances in this technology.

As pointed out in the 3M Corporation Patent No. 4,737,560, azlactone-functional polymer beads are useful reac¬ tive supports for the attachment of functional materials to provide novel adduct beads. The adduct beads are useful as complexing agents, catalysts, reagents, and as enzyme or other protein-bearing supports. The term "support" or "affinity support" as used in this sense is usually understood to refer to a combination of (1) a ligand (usually of some known molecu¬ lar configuration) , that is firmly attached (e.g. , immobilized) , often by covalent means, and (2) a matrix (usual¬ ly a solid insoluble substance) . Azlactone support matrix materials and coupling chemistry is also of special interest because of its accessible matrix surface area and effective ligand diversity that can be attached to that surface. U.S. Patent No. 4,072,566 issued to Lynn in February 7, 1078, and entitled "Immobilized Biologically Active Pro¬ teins" discloses a method of bonding enzymes or other biologi¬ cally active proteins to an inorganic support material using p- phenylenediamine. The support materials disclosed as useful in the invention include siliceous materials, stannic oxide, tita- nia, manganese dioxide, and zirconia.

The functional support structure 730 of the present embodiment of the invention can take on the character of an affinity support and is uniquely construction to permit enzymes or other biologically active proteins to be bound thereto for later removal. This is accomplished by treating functional support 730 in the manner disclosed in the prior art patents identified in the preceding paragraphs with a compound having selected reactive functional groups such as azlactone function¬ al compounds. In this way complexing agents, catalysts and biological materials such as enzymes, proteins or other affini¬ ty absorbents, as well as biomacromolecules can be attached to the carrier for later removal and recovering.

When attaching certain biologically active proteins and other macro molecules, the use of spacer arms or leashes have been found to be very beneficial. Spacer arms or leashes are low-molecular-weight molecules that are used as intermedi¬ ary linkers between a support material and an affinity ligand. Usually spacers consist of linear hydrocarbon chains with func¬ tionalities on both ends of each coupling to the support and ligand. First, one end of the spacer is attached chemically to the matrix using traditional immobilization chemistries; the other end is connected subsequently to the ligand using a secondary coupling procedure. The result is an immobilized ligand that sticks out from the matrix backbone by a distance equal to the length of the spacer arm chosen.

Referring to Figure 61A, 61B, 61C, and 61D, the use of spacer arms to attach proteins and enzymes to the substrate is there schematically illustrated. The principal advantage of using a spacer arm is that it provides ligand accessibility to the binding site of a target molecule. When the target mol¬ ecule is a protein with a binding site somewhat beneath its outer surface, a spacer is essential to extend the ligand out far enough from the matrix to allow interaction. As indicated in Figure 61A, when the ligand binding site S is buried or in a pocket 733 located just below the surface of the protein P, a ligand L that is either below the surface of the support mate¬ rial 735 (upper portion) or a ligand L-l that is attached directly to the surface (middle portion) cannot reach the level of the binding site S on an approaching protein molecule. The result may be weakened interaction or no binding at all. Accordingly, in these instances, spacer arm 737 is required to provide the ligand L-2 accessibility to the binding site of the protein molecule (lower portion of Figure 61A) . The details covering the use of spacer arms are fully set forth in Section 3.1.1 of the previously referred to work entitled Immobilized Affinity Ligand Techniques. This Section 3.1.1 is incorporated herein by reference.

Turning now to Figures 61B, 61C and 61D, it is to be noted that immobilized protein A can be used to immobilize an antibody molecule by taking advantage of the natural affinity of protein A for immunogloblins. Incubation of a specific antibody with protein A matrix will bind the antibody in the Fe region, away from the antigen binding sites. Subsequent cross- linking of this complex with DMP (dimethyl pimelimidate) yields a covalently attached antibody with the antigen binding sites facing outward and free to interact with antigen.

With rigid support materials, a spacer molecule may also provide greater flexibility, allowing the immobilized ligand to move into position to establish the correct binding orientation with a protein. The degrees of freedom that a hydrocarbon extender can provide are much greater than the movement possible within the polymeric backbone of a matrix.

The choice of spacer molecule can affect the relative hydrophilicity of the immediate environment of an immobilized ligand. Molecules containing long hydrocarbon chains may in¬ crease the potential for nonspecific hydrophobic interactions, especially when the affinity ligand is small and of low molecu¬ lar weight. Selecting spacers that have more polar constitu¬ ents, such as secondary amines, amide linkages, ether groups or hydroxyls will help keep hydrophobic effects at a minimum.

It is also important to consider the ionic effects a spacer molecule may impart to a gel. Spacers with terminal primary amine groups should be completely coupled with ligand or blocked by a nonrelevant molecule (e.g., acetic anhydride; see Section 3.1.1.9 of Immobilized Affinity Ligand Techniques ) to eliminate the potential for creating a positive charge on the support. With small ligands, these residual charges can form a secondary environment that may cause considerable non¬ specific interactions with proteins. The same holds true for spacers with terminal carboxylic groups. In general, a nega¬ tively charged spacer will cause less nonspecific protein binding than a positively charged one, but blocking excess remaining groups is still a good idea. A good blocking agent for use with carboxylic residues is ethanolamine, which leaves a terminal hydroxyl group (See Immobilized Affinity Ligand Techniques for an expanded discussion of types of spacers and various immobilization a coupling protocols.)

As pointed out in Protein Purification_f Janson and Ryden, Copyright 1989 which describes some alternate form of protein immobilization at Page 310:

"Ligand-protein interaction is often based on a combination of electrostatic, hydrophobic and hydrogen bonds. Agents which weaken such interactions might be expected to function as effective non-specific eluants."

This work provides further teaching of the techniques described herein.

It is important to recognize that, as used in the present form of the invention, affinity supports are now cap¬ able of total binding capacity at a level that enables attach¬ ment to the support of additives in substantial amounts for subsequent release, recovery and infusion of beneficial agents in a manner which can be therapeutically efficatious to a patient.

Turning now to Figure 65, yet another form of the apparatus of the invention is there shown. The device of this form of the invention is similar in many respects to the em¬ bodiment shown in Figure 48 save that the distendable membrane is a single elastomeric sheet and fluid flow through the device is totally different. In this latest form of the invention selected additives are removably affixed to various form of support structures which are, in turn, contained within a novel additive subassembly that can be inserted into the outlet port of the device in a manner to place the additives within the path of the elution fluid flowing outwardly of the device from the fluid reservoirs. In this way the additives, such as beneficial agents or other pharmaceutically active materials, can remain coupled with an appropriate matrix support and sealed in the prepackage additive subassembly, which preferably comprises a glass vial, and can be mated with a device which has been precharged with an elution buffer, aqueous diluent, solvent or other parenteral liquid. In other words, unlike the previously described embodiments in which the additive is mixed with the fluid medium during the filling step, here the addi¬ tive is mixed with the elution fluid as the fluid flows from the pre-filled or precharged reservoirs of the device.

As best seen by referring to Figure 65, the apparatus comprises a base made up of a first, generally planar member 800 and a second companion member 801. Member 800 includes a pair of a longitudinally extending fluid flow channels 802 and 804 which communicate with a transversely extending fluid transfer passageway 806. Passageway 806, in turn, connected with a fluid inlet 808 (Figure 69) which is in communication with a fluid charging or filling means shown here as a syringe assembly 810 which includes a blunt cannula 812.

Reservoir outlet passageways for fluid flowing out¬ wardly from the reservoir are provided in the form of longitu¬ dinally extending flow channels 814 provided in a pair of protuberances 816 which are integrally formed with base member 801. Channels 814 communicate with transversely extending channels 816 which, in turn, communicate with a central passa¬ geway 818 (Figure 69) which leads to a check valve housing 820. Reciprocally mounted within housing 820 is a check valve 822 which includes a stem portion 824. In a manner presently to be described check valve 822 controls fluid flow between the fluid reservoirs of the device and the interior of the additive subassembly shown in Figure 67 and generally designated in the numeral 827. Additive subassembly 827 comprises a glass vial 830 which is closely received within a plastic shell 832 that is constructed in two parts 832a and 832b. Parts 832a and 832b are joined together by a gummed medicament label 834. The fluid inlet end of glass vial 830 is provided with external threads 836 while the outlet end of the vial is open to receive the skirt portion 838 of a luer fitting 840. Skirt portion 838 is maintained in position within the outlet end of vial 83 by an aluminum crimp seal 842, the circumferentially extending edge 842a thereof being adapted to be crimped over into a circumferential groove 831 provided in glass vial 830. An 0 ring seal 843 surrounds skirt 838 and abut the edge of the glass vial to prevent leakage between the vial and the luer fitting. Structure 850 also sealably closes the lumen 864.

The outlet portion 832b of shell 832 is provided with a reduced diameter portion 844 that defines an internal should¬ er 846 that abuts crimp seal 842. Reduced diameter portion 844 is provided with a circumferentially extending score line 846 that permits the outer, cap-like end 850 of portion 844 to be removed at the time of use of the additive subassembly 827 to expose luer fitting 840. A tear-off cap 852 is also provided at the inlet end of the additive subassembly. When this cape is removed, the thread 836 of vial 830 are exposed. Cap 852 also functions to sealably close inlet passageway 853.

Closely received within the inlet end of vial 830 is resistance and flow rate control means here provided as a porous plug 854 having a reduced diameter portion 854a which is closely receivable within neck 830a of vial 830. Plug 854 can be constructed from any suitable porous material such as a ceramic, glass, PTFE, carbon or other inert material and func- tions to controllably resist and precisely regulate fluid flow from the fluid reservoirs of the device toward the additive support or functional substrate. An elastomeric ring seal 857 is interposed between plug 854 and a shoulder 858 defined interiorly of vial 830 to prevent leakage therebetween.

The additive support or matrix, here identified by the numeral 860, is closely received within vial 830 and abuts plug 854 in the manner shown in Figure 68. As before support 860, can be of various constructions as previously described, including azlactone beads and distal porous glass frit contain¬ ment means. Support 860 removably carries selected additives, such as the beneficial agents previously described herein. A centrally disposed fluid flow channel 862 is provided in sup¬ port 860 and is adapted to communicate with the fluid outlet passageway 864 of the dispensing means, or luer fitting assem¬ bly 840.

The distendable membrane engagement means or protu¬ berances 816 perform the same function as previously described as does the unique stored energy means. The stored energy means is elastomeric member 24, of this embodiment is of the general character previously described in connection with the embodiment of Figure 1 and cooperated with base member 801 to define the fluid chambers or reservoirs of the device. The stored energy means can also be of a laminate construction of the character previously described herein.

As indicated in Figure 65, superimposed over the base and the stored energy source 24 is a structural cover 34 of the character previously described. Affixed to the bottom of base member 800 is a cushioning means or pad 38 having adhesive on both sides. A peel strip 40 is connected to the lower surface of pad 38. Turning now to Figures 65 and 69, base member 801 includes an upstanding, longitudinally, extending portion 865 having a generally cylindrical chamber 867 extending there¬ through. In this embodiment of the invention, chamber 867 is uniquely designed to closely receive the additive subassembly 827 that sealably contains the additive to be added to the elution fluid flowing from the fluid reservoirs outwardly of the device. As the inlet end of chamber 867 there is provided a septum housing 868 adapted to support an elastomeric septum 870 which is accessible by cannula 812 of the filling syringe via an opening 871. When cannula 812 pierces septum 870, fluid will be permitted to flow from the syringe into passageway 808 and thence to the fluid reservoirs in the manner indicated by the arrows 873 of Figure 65 via channels 873 and inlet ports 875. As the fluid flows through ports 875, distendable mem¬ brane 24 will be urged into its distended configuration in the manner previously discussed.

As the reservoirs are charged, fluid will flow down¬ wardly through channels 814 in protuberances 816 and into passageway 818 as indicated by the arrows 877 of Figure 65. This fluid under pressure will urge check valve 822 into its closed position with shoulders 822a in sealing engagement with seats 879 (Figure 71) . With the check valve 822 in the closed position, fluid cannot flow toward cylindrically shaped chamber 867 of base member 801.

In using the apparatus of the embodiment of the invention shown in Figures 65, 67, 68, 70 and 71, sealing caps 850 and 852 are removed to expose the luer filling 840 and the threaded end of glass vial 830b of the additive subassembly 827. The additive subassembly 827 is then inserted into cham- ber 867 so that threads 836 engage mating threads 881 of por¬ tion 865. Rotation of the vial will then cause stem 824 of check valve 822 to move the check valve from the closed posi¬ tion shown in Figure 71 to the open position shown in Figure 69. As the vial is rotated relative to portion 865 of base 801, locking tabs 883 provided on the vial subassembly (Figure 69) engage resiliently deformable tabs 885 provided internally of chamber 867 (see Figure 70) . Tabs 885 are designed to permit rotation of the vial subassembly in one direction but to block rotation in the opposite direction. With this construc¬ tion, once the vial assembly has been interconnected with the base assembly, it cannot be removed.

With the vial assembly 827 locked in place within chamber 867, and the check valve open, the sterile diluent is urged from the reservoirs by the distendable membrane and introduced into check valve housing 820 via channels 814, 816, and 818. The diluent then flows controllably through the porous plug 854 and longitudinally of the additive presentation means, or substrate 860 where it efficiently intermixes with the additive carried by the substrate. The mixture thus formed flows through passageway 862 into passageway 86.4 of the luer fitting and outwardly of the device.

Forming an important part of this embodiment of the invention is the unique feature for commonality of use with selected assemblies that contain both flow rate control means and an additive having an extended release rate. By appro¬ priate selection of assembly, this feature allows for individu¬ al control of the rate of dosing of the beneficial agent into the elution diluent independent of the rate of flow of the elution diluent.

The manual facility to individually control through proper assembly selection, the delivery of both drug dosing rate and diluent dispensing rate, over a given time period, is a desirable feature. In practice, alternate vial cartridges (827 - Figure 65) can be provided with control fluid flow rate at a given level and also additive release rates at a desired predetermined level. This capacity can insure delivery of a required dosage within a therapeutically acceptable time period over a broad range of fluid flow rates.

Additionally, the control of dosage rates and diluent flow rates can help prevent over-concentration of an adminis¬ tered drug which can result in patient local or systemic toxic¬ ity.

Selection of an appropriate vial containing the predetermined extended release over-time type additives com¬ bined with an appropriate preselected flow rate control format over a wide range of delivery protocols can facilitate the expanded ambulatory delivery opportunities of various therapeu¬ tic agents. New delivery protocols can also be established for pharmaceutical agent delivery modes and administrative regimes.

The extended release additives can comprise bounded proteins or other absorbents which can be attached to and eluded from the matrix over time in a variety of ways well known to those skilled in the art.

The rate control means is here shown at both the proximal end of the vial (854), and at the distal end of the vial (855-Figure 67) . However, for certain applications, the rate control means can be located proximate either end of the vial for selected flow rate control, filtering and elutant residence within the vial.

Referring to Figure 66 another form of the invention, similar to that just described is shown. This device operates in basically the same way as the device of Figure 65 save that filling is accomplished through a side inlet port 890 rather than an end inlet port of the character shown in Figure 65. The vial at sub assembly 827 is identical to that previously described and fluid is urged from the reservoir from distend¬ able membrane 24 and flows outwardly of the device through the vial sub assembly. The base member 892 of the device is of slightly different construction having angularly inclined flow channels 894 which received the diluent flowing from the reservoirs through channels 896 formed in protuberances 897. Filling of the reservoirs is accomplished by a filling means which urges fluid flow into port 890 and into the reservoirs via inlet ports 898. The arrows of Figures 66 clearly depicts the direction of fluid flow into and out of the device.

Referring to Figures 72 through 78, another form of the device of the invention is there shown. This device is very similar to that shown in Figures 61 through 64 save that filling is accomplished by using a filing means which comprises a novel needle assembly, rather than by using the luer connec¬ tor assembly shown in Figure 61.

As best seen in Figure 76, the luer cap and internal check valve assembly of the device of Figure 61 has been re¬ placed by a septum assembly which is mounted within the inlet passageway 720a of the device. Due to the close similarity between the devices, like numerals have been used in Figures 72 through 78 to identify like components shown in Figures 61 through 64.

The injection assembly, here designated by the numer¬ al 900, is best seen in Figure 73 and includes a check valve housing 9022, a check valve 904 reciprocally movable within housing 902 and a needle assembly 906 connected to housing 902. Housing 902 includes an internal seat 907 against which a shoulder 909 of the check valve seats when the valve is in the closed position shown in Figure 75. By referring to Figure 74, which is an end view of housing 902, it can be seen that a plurality of circumferentially-spaced flow channels 902a are provided in the wall of the housing. (See also Figure 78) .

Needle assembly 906 comprises a collar 910 which is receivable over one end of housing 902 and is connected thereto by any suitable means such as adhesive bonding. Integrally formed with collar 910 is a neck portion 912 having a bore 914 adapted to receive the inboard end 916 of a hollow needle 917. Integral with neck portion 912 is a safety needle shroud 920 which surrounds needle 917. Shroud 920 is specifically config¬ ured to eliminate accidental needle sticks. Also shroud 920 is adapted to fit over port structure 934 in the manner shown in Figure 76 where the needle 917 has penetrated septum 930. The internal passageway 917a of the needle communicates with the internal chamber 902b of the check valve housing to permit fluid flow through the needle to the fluid reservoirs of the device when the check valve is in an open position.

Turning to Figures 72 and 75, it is to be observed that check valve housing 902 includes circumferentially spaced luer lugs 902c which permit interconnection of a coupler member 924 which the needle assembly. Member 924 is, in turn, connected with a length of transfer cannula tubing 925 that connects to a source of diluent or other parenteral liquid.

In using the apparatus of this last form of the invention, the protected needle is caused to penetrate the septum 930 of the septum assembly in the manner shown in Figure 75. The septum 930 is of conventional construction and is maintained in position within the open end 720b of passageway 720 by a septum housing 932 having a skirt portion 934 which is receivable within enlarged diameter portion 728a of structural support 720 which is, in turn, closely receivable within por¬ tion 718 of the base assembly. Septum housing 932 has an inlet opening 932a which permits needle 917 to penetrate the septum.

As indicated in Figures 72 and 77, superimposed over the base and stored energy source 212 is a structural cover 34 of the character previously described. Affixed to the bottom of base member 700 is a cushioning means or pad 38 having adhesive on both sides. A peel strip 40 is connected to the lower surface of pad 38.

With the construction shown in the drawings, an appropriate injectable such as a diluent, parenteral fluid, or other elution fluid can be introduced into chambers 25 using the needle assembly 900. As the fluid flowing from the fluid source enters the check valve housing 902 of the needle assembly, check valve 904 will be moved away from seat 907 to the open position as shown in Figure 76 to permit fluid flow inwardly of the hollow needle. When the chambers are filled, the buildup of system back pressure will cause the check valve to return to the closed position shown in Figure 75 and the needle can be withdrawn from the septum.

Referring to Figures 76 and 77, the adding means of the invention can take several different forms as, for example, the cylindrically shaped, functional support structure 730 which is inserted into passageway 720 and to which various additives, including beneficial agents such as drugs, biologically active materials, and chemical elements and com¬ pounds can be releasably connected. The additives can be of the character described in connection with the previously described embodiments of the invention including those shown i Figures 61 through 64 and can be removably affixed to support structures of various configurations including synthetic porous matrices such as structure 730 which can be placed within the path of the fluid flowing through the device. As the fluid flows toward the reservoirs in the manner indicated by the arrows 937 of Figures 76 and 77, the additives can, if desired, be released at a controlled rate over time to the fluid. This can be accomplished by slow diffusion mass transport, slow equilibration kinetics or other types of absorbent dissociation techniques.

Referring to Figures 79 through 87, still another embodiment of the invention is there shown. The apparatus of this form of the invention is similar in many respects to the earlier described embodiments. However, unlike the earlier described embodiments, the apparatus of this later form of the invention does not use a distendable membrane as an energy source to expel fluid from the reservoir. Rather, the device of this embodiment includes a unique hyrophilic, expandable sponge-like member 950 which functions as the stored energy source. The character of this highly novel energy source will presently be described in greater detail.

Turning particularly to Figure 80 the apparatus can be seen to comprise a base assembly comprising a first base member 952 and an operating assembly 954 associated therewith. Operating assembly 954 comprises a frangible member 956, the stored energy source, shown here as a hydrophillic sponge 958, and a retaining means or sponge engaging member 959. A second base member 960 cooperates with first base member 952 to en¬ close the operating assembly in the manner shown in Figure 82. the device also includes a clam shell like, removable outer shell or enclosure which comprises first and second cooperating barrier material members 961 and 962.

A filling means 964 is operably associated with base members 952 and 960 and is used to fill the reservoir "R" (Figure 82) with either a medicament or parenteral fluid. After the reservoir is filled, the inlet port 965 of the fill means can be appropriately sealed in the manner illustrated in Figure 81, as for example by heat sealing or other appropriate means. The outlet means of the device for expelling fluid from the reservoir comprises an outlet port 966 which is initially sealed by a tear-away cap 966a of standard construction. As best seen by referring to Figure 87, outlet port 966 is normal¬ ly closed by a pierceable closure member 967 which can be ruptured by a delivery spike 968. Spike 968 activates fluid flow through the outlet port and into a delivery tube 969 within which the adding means, including an additive support 970 is carried. In a manner presently to be described, the energy source or sponge 958 functions to controllably and uniformly expel fluid from reservoir "R" through outlet port 966 into tube 969 and toward the patient via the adding means.

Turning particularly to figures 84 through 87, it is to be noted that sponge 958 is closely held in a dry configura¬ tion between frangible membrane 956 and distendable membrane 959. By removing the clam shell cover from the operating assembly 954 in the manner indicated in Figure 84, the operat¬ ing assembly 954 can be deformed, or flexed, in the manner illustrated in Figure 85. This causes frangible membrane 956 to be sharply stressed in tension and to rupture in the manner indicated in Figure 85 permitting the hydrating liquid "L" contained in a lower chamber C defined by base 952 and frangi¬ ble member 956, to reach the hydrophillic sponge 958 (see Figures 86 and 87) . As the liquid "L" is absorbed as a func- tion of time by the sponge 958, the sponge will controllably expand in the manner shown in the drawings causing membrane 959 to distend outwardly toward cover 960. As the membrane dis¬ tends, the fluid contained within the reservoir will be placed under pressure and urged to flow toward outlet port 966 which has been placed in communication with tube 969 by means of the delivery spike assembly.

As the hydrophillic cellular sponge 956 continues to expand, (Figure 86A) the fluid contained within the reservoir will be forced outwardly through outlet port 966 and will flow around, about and through the additive support 970. Additive support 970 is of the character previously described and the additive removably carried by the support, or scaffold, will be controllably intermixed with the fluid contained within the reservoir to form the infusible mixture which flows to the pa¬ tient via the outlet of the base which includes tube 969. The function of the adding means and the nature of the additives and the additive support are of the character previously de¬ scribed and need not be further discussed at this time.

The hydrophillic energy source can be any type of liquid expansible or swellable system and can be constructed into a shaped article or planar member form a number of suit¬ able particulate, fibrous, cellular and gelatinous materials of a character well known in the art including various polymers, and fluropolymers, resins, latexes and the like. The frangible member 956 can be constructed from a number of suitable plas¬ tics, including crystalline, semicrystalline and amorphous materials as can the base, cover and clam shell like enclosure.

It is to be appreciated that the additive can also be removable affixed to the barrier membrane 959 and to the in¬ terior surfaces of cover membrane 960 as well as within member 969. Additionally, the energy source 958 can be initially placed between members 956 and 959 in either a relaxed or compressed state.

Turning now to Figure 88, yet another form of the apparatus of the invention is there shown. The device of this form of the invention is similar in most respects to the em¬ bodiment shown in Figures 65 through 71, save that the distend¬ able membrane does not act as the energy source, but rather only as a barrier means for providing a barrier between a novel compressible dry sponge or elastic cellular mass foam like member which acts as the energy source. In this latest form of the invention selected additives are removably affixed to various forms of support structures which, as before, are contained within a novel additive subassembly that can be inserted into the outlet port of the device in a manner to place the additives within the path of the elution fluid flow¬ ing outwardly of the device from the fluid reservoirs.

As best seen by referring to Figure 88, the apparatus comprises a base made up of a first, generally planar member 800 and a second companion member 801. Member 800 includes a pair of longitudinally extending fluid flow channels 802 and 804 which communicate with a transversely extending fluid transfer passageway 806. Passageway 806 is, in turn, connected with a fluid inlet 808 (Figure 92) which is in communication with a fluid charging or filling means shown here as a syringe assembly 810 which includes a blunt end cannula 812 (Figure 88) .

Reservoir outlet passageways for fluid flowing out¬ wardly from the reservoir are provided in the form of longitu¬ dinally extending flow channels 814 provided in a pair of protuberances 816 which are integrally formed with base member 801. Channels 814 communicate with transversely extending channels 816 which, in turn, communicate with a central passa¬ geway 818 which leads to a check valve housing 820. Recipro¬ cally mounted within housing 820 is a check valve 822 which functions in the manner previously described (Figures 92 and 94) .

Additive subassembly 827 is the same construction as previously described and functions in an identical manner to present the additive to the fluid flow. The additive assembly 827 is also mated with the base in the same manner as described previously. As before, the additive can also be removably af¬ fixed to the barrier member 24 and to the base member 801 so long as it is disposed within the fluid flow path.

The distendable membrane engagement means or protu¬ berances 816 also perform the same function as previously de¬ scribed, but here cooperate with the alternate stored energy means or compressible elastomeric foam cell system or highly resilient member 975. The stored energy means, or cellular matrix 975 is disposed between cover 34 and member 24 and will be compressed by membrane 24 as the fluid chambers or reser¬ voirs "R" of the device are filled by the syringe assembly 810 in the manner previously described. (See Figure 88A wherein the reservoirs are filled and member 975 is shown in a com¬ pressed state.)

As before, the inlet end of chamber 867 is provided with a septum housing 868 which is adapted to support an elas¬ tomeric septum 870 which is accessible by cannula 812 of the filling syringe via an opening 871. When cannula 812 pierces septum 870, fluid will be permitted to flow from the syringe into passageway 808 and thence to the fluid reservoirs in the manner indicated by the arrows 873 of Figure 88 via channels 873 and inlet ports 875. As the fluid flows through ports 875, membrane 24 will be urged outwardly into a distended configura¬ tion causing member 975 to compress in the manner previously discussed (see Figure 88A) . As the reservoirs are charged, fluid will flow downwardly through channels 814 in protuberanc¬ es 816 and into passageway 818 as indicated by the arrows 877 of Figure 88. This fluid under pressure will urge check valve 822 into its closed position with shoulders 822a in sealing engagement with seats 879.

In using the apparatus of this last embodiment of the invention, sealing caps 850 and 852 are removed to expose the luer fitting 840 and the threaded end of glass vial 830b of the additive subassembly 827. The additive subassembly 827 is then inserted into chamber 867 so that threads 836 engage mating threads 881 of portion 865. Rotation of the vial will then cause stem 824 of check valve 822 to move the check valve from the closed position shown in Figure 94 to the open position shown in Figure 92. As the vial is rotated relative to portion 865 of base 801, locking tabs 883 provided on the vial subas¬ sembly engage resiliently deformable tabs 885 provided inter¬ nally of chamber 867 (Figure 93) .

With the vial assembly 827 locked in place within chamber 867, and the check valve open, the sterile diluent is urged from the reservoirs by the stored energy source, or member 975, acting on barrier member 24 and is introduced into check valve housing 820 via channels 814, 816, and 818. The diluent then flows controllably through the porous plug 854 and longitudinally of the additive presentation means, or substrate 860 where it efficiently intermixes with the additive carried by the substrate. The mixture thus formed flows through passa¬ geway 862 into passageway 864 of the luer fitting and outwardly of the device. When necessary, venting of the sponge-contain¬ ing chamber can be accomplished via vent means shown in Figure 88 and 88A as vent aperture "V" which is covered by hydrophobic membrane "M".

Member 975 comprises an elastic, compressible mass or cellular foam like sponge member which can be constructed from a wide variety of materials, including a number of flexible cellular polymers. Materials that are particularly attractive for this application include polyurethane, latex foam rubber, cellular rubber, various polyolefin foams, PVC foams, epoxy foams, urea formaldehyde, silicon foam, fluropolymer foams, and other elastic syntactic foams and similar materials of a char¬ acter well understood by those skilled in the art. Member 975 can be monolithic or it can be constructed from homogenous or nonhomogenous foam or laminates having the same or different characteristics.

Referring to Figure 89, another form of the invention similar to that just described is shown. This device operates in basically the same way as the device of Figure 88 save that filling is accomplished through a side inlet port 890 rather than an end inlet port of the character shown in Figure 88. The vial subassembly 827 is identical to that previously de¬ scribed and fluid is urged from the reservoirs by sponge member 975 acting on distendable membrane 24. The fluid flows out¬ wardly of the device through the vial subassembly in the manner previously described. The base member 892 of the device is of slightly different construction, having angularly inclined flow channels 894 which receive the diluent flowing from the reser¬ voirs through channels 896 formed in protuberances 897. Fill¬ ing of the reservoirs and compression of sponge 975 is accom¬ plished by a filling means which urges fluid flow into port 890 and into the reservoirs via inlet ports 898. The arrows of Figure 89 clearly depict the direction of fluid flow into and out of the device.

It is to understood that, while in the embodiment of the invention just discussed, the stored energy source or cellular elastic foam like member 975 is compressed by the fluid introduced into the device, for certain applications, member 975 can be precompressed to the extent desired at the time of assembly of the device and can be used to expel fluid from a prefilled reservoir. In this instance, member 975 can either be further compressed during filling or it can function in its precompressed state to expel the fluid from the reser¬ voir.

Having now described the invention in detail in accordance with the requirements of the patent statutes, those skilled in this art will have no difficulty in making changes and modifi¬ cations in the individual parts or their relative assembly in order to meet specific requirements or conditions. Such chang¬ es and modifications may be made without departing from the scope and spirit of the invention, as set forth in the follow¬ ing claims.

Claims (14)

I CLAIM

1. A fluid delivery device for delivering fluids to a patient extracorporeal at a controlled rate comprising:

(a) a base having a fluid inlet and a spaced apart fluid outlet interconnected by a fluid flow path;

(b) filling means for introducing fluid into said fluid inlet;

(c) a deformable membrane which is fitted over said base to define a chamber in communication with said fluid inlet and said spaced apart fluid outlet, said membrane being movable from a first position to a second position whereby fluid within said chamber will be expelled through said fluid outlet; and

(d) an expandable member disposed outside said chamber and in contact with said membrane for moving said membrane from said first position to said second position.

2. A device as defined in Claim 1 in which said expand¬ able member comprises an elastically deformable cellular struc¬ ture.

3. A device as defined in Claim 1 further including adding means disposed within said fluid flow path for adding an additive to fluid flowing therethrough.

4. A device as defined in Claim 3 in which said adding means comprises an additive and an additive presentation means for presenting said additive to the fluid, said additive pre¬ sentation means being disposed within said fluid flow path so that at least a part of said additive will be added to said fluid introduced into said fluid inlet.

5. A device as defined in Claim 3 in which said adding means comprises an additive and an additive presentation means for presenting said additive to the fluid, said additive pre- sentation means having exposed surfaces, said additive being removably connected to said exposed surfaces.

6. A device as defined in Claim 3 in which said expand¬ able member comprises a foamed polymer.

7. A device for use in infusing fluids into a patient at a controlled rate, comprising:

(a) walls defining a fluid chamber having a fluid inlet, a fluid outlet and a fluid passageway interconnect¬ ing said fluid inlet and said fluid outlet;

(b) filling means for introducing fluid into said fluid inlet;

(c) stored energy means for acting on one of said walls of said chamber for expelling fluid within said chamber through said fluid outlet, said stored energy means comprising an expandable member disposed in engage¬ ment with said one of said walls; and

(d) adding means disposed within said fluid passage¬ way for adding an additive to fluid flowing therethrough.

8. A device as defined in Claim 7 in which said adding means comprising a support and an additive removably connected to said support.

9. A device as defined in Claim 7 in which said expand¬ able member comprises an elastically deformable member having a cellular structure.

10. A device as defined in Claim 7 in which said expand¬ able member comprises a liquid expansible material.

11. A device as defined in Claim 10 further including a liquid chamber disposed adjacent said liquid expansible materi¬ al and a frangible membrane disposed intermediate said liquid chamber and said liquid expansible material, said frangible membrane being ruptured to expose said liquid expansible mate- rial to liquid in said liquid chamber, whereby said liquid expansible material will expand causing fluid within said fluid chamber to be expelled therefrom.

12. A device as defined in Claim 10 in which said fluid outlet includes infusing means communicating with said fluid passageway for infusing fluid to the patient.

13. A device as defined in Claim 12 in which said infu¬ sion means comprises a fluid conduit and adding means disposed within said fluid conduit for adding an additive to fluid flowing therethrough.

14. A device as defined in Claim 13 in which said adding means comprises a member having exposed surfaces and a biologi¬ cally active material present on said exposed surfaces.