CA2118022A1 - Improved fluid delivery apparatus - Google Patents

Abstract

An apparatus for precisely mixing parenteral fluids with infusing agents into an ambulatory patient at specific rates over extended periods of time. The apparatus is of a compact, low profile, laminate construction and includes an elastic distendable membrane (209), or a membrane assemblage, which, in cooperation with a thin planar base (202), defines a fluid chamber (211) having a fluid outlet (214). In certain embodiments of the invention, a thin fluid permeable membrane (215) or membrane assemblage is disposed within the fluid chamber (211) to precisely control the rate of fluid flow through the fluid outlet (214).

Description

W093/2~863 ~ 0~ 2 PCT/US92/10~2 INPROV~D FLUID DELIVERY APPABA~US

S P E 5 I ~ I C ~ T I O N
Background of Th~ In~ention Field of The Invention -The present invention relates generally to fluid '`~
deli~ery devices. More particularly, the invention concerns a~
improved apparatus for infusing medicinal age~ts into an ambulatory patient at specific rates over extended periods~of time. ~ ~
:
Discu~ion of Th~ Inv~tio~ ~
Many medicinal agents require an intravenous route for administration` thus bypassing the digestive system !and precluding degradation by the catalytic enzymes in the ~ !i digestive tract and the liver. The use~ of~more potent mediaatlons~ àt~elevated concentrations has also~increased~the~ ~ ¦
ne`ed for accuracy in controlling the `delivery of~ such drugs.
The~delivery devi~e~,~while not an active ph~armacoloqic~agent, may ~enhance the activity of the~ drug~by mediat~ing its therapeutic effèctiveness.~ ~ Certain ;;~classes of new ~,. ~ . ,;
pharmacologic agen~s pos;~ess a very narrow~ànge of therapeutic e~fectivehess, far instance, too sma;ll a dose re~ults in~no~ ~;
e~oct, while too great~a~dose~result~s in~toxic reaction.
In the pas~ prolonged infusion of ~luids has generally been accomplished~us~lng~gravi~y~flow~methods~, which typic~ally invol~e the use~o~f~ intravenous administration sets~and~ the ;~
amiliar bottle s~ispendot above~the patient. Such methods are cumbe~some, Lm~rèçise~anù require~ bed~con~;inementl of lthe patient. Periodic monitoring of the`apparatus by the~nurse or docto`r~is~required~to~detect~ malfùn¢tlons of the~in~us~ion~
apparatus.
Devi~es from~which liquid is~expelled~from a relatively ~ t thick-walled~lâdder~by~internal stress~s~within the distended~
bIadder are~well-known; ln the prior art~ Such bladder~,~or "balloon"~type, devices~ar~e desarib~d ~in; U.S. Patent~No.

SUBSTITUT~ SHEET

~093/20863 PCT/US92/10~2 ~
0 2 2 ~ ~
~ , ` ; , .

3,469,578, issued to ~ierman 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 external 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 unwleldy and are difficult and expensive to manufacture and use.
Further, the devices are somewhat unreliable and~their fluid discharge rates are frequently imprecise. ~
A much more sophisticated fluid delivery~apparatus is described in U.S. Patent No. 5,019,047 issued~to the present inventor. This device eliminates the ~Ladder altogether and makes use of recently developed elastomeric film laminates which, in cooperation with a plate-like base define a flùid chamber that contains the fluid which is to be dispensed. The , elast~omeric film membrane~laminate controllably forces fluid within the chamber into fluid flow channels provided in the base. In one form of the apparatus of the invention, a thin, planar shaped flow rate control ~èmber`~is strategically located within~the chamber to precisely control the rate of flow of the liquid toward the fluid flow~channels. The flow rate control memb;er can be very thin and can be selected to have a very precise~ tegree of permeability so that~ the ~rate of flow of fluid into the fluid ~low channels can be controll~d with great a~cu~racy.~
The; apparatus~of the~present invention comprises~an ;improvement upon the~device described in~the 5,019,047 patent ~y providing a novel means ~or mixing selected parenteral fluidsi~wlth va;rious!aidditives such as;~rugs and biologically~
ac~tive~materials which;are carried by substrates of a num~er of different~types upon which~the additive~or berleficial agent~is~
i ~ obilized or~removably~affixed.~The~additives~can~be placad wi~thin the`;fluid flow~path of~parenteral~ fluld ~as it is int~oduced into~the~device,~ or ~alternatively,~i~as it fl~ws outwardly~ of th2 devlce from the~internally~disposed~ fluid r~s~-o~rs~

U~STITUTE~SHEET

W0~3/20863 P~T/US9ZtlO482 1~
~ ~ il8~22 The devices of the present invention can be used for precisely mixing ~irtually any type of beneficial agent such as a drug or other pharmaceutical, with a parenteral fluid such as a diluent. Following mixing, the internal stored energy means of the device controllably dispenses the mixture which may comprise antibiotics, hormones, steroids, blood anti-clotting agents, analgesics, and like medicinal agents. Similarly, the device can be used for IV chemotherapy and can accurately de`liver fluids to the patient in precisely the correct quantities and at extended microfusion rates over time.
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 manufacture. When the devices of the invention are to be used with ambulatory patients they are constructed of flexiible materials and are provided with a thin adhesive~backing which pexmits the device to ~e conveniently self-affixed to the patient's arm or other parts of the ~ody.

Summ~ry of the I~v~tion It is an object of the present invention to provide an apparatus for expelling fluids at a preclsely controlled rate whlch is of a compact, low profile, laminate ~construction.
More particularly, it is an object of th~;invention to provide~
such an apparatus which can be used for the precise infuslon of pharmaceutical fluids to an ambulatory~patient at controlled rates over extended perio~s of time. ~ ;
It is another object of the invention to~provide an apparatus of the aforementioned character which is~highly re11ia~1je and easy-t~-use by lay persons i~ a ;non/-hospital ~
environment. ~ ;
Another object of the invention is to provide an apparatùs which can be factory prefilled~with a wide variety of .`
m~dicinal~fluids or one which can readily be filled in the field shortly prior to use.~
Another obiect~ of the ~invention is to provide an fusion device in which fluids~can be~dèlivered either at a W093~0863 PCT/US92/10~2 ~.
02~

4 ' '`':
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 can be used to precisely ' mi~ selected parenteral fluids with a wi.de variety of additives such as drugs, biologically active materials and other ~
beneicial a~ents and then to controllably dispense the mixture `;:
from the device.
: Yet another object of:the invention is to provide an :'``
: : apparatus as described i~n the~preceding paragraph in which the ~ '~
additive can be mixed with the parenteral fluid either as it:is: ::
introduced into the device or alternatively as it is expelled from the device by the~internally disposèd stored energy means ' or elastomeric laminates. ; ' .'`'~
A further object of the invention is to provide ailow ~ :i profile, 1uid delivery device o laminate construction which : can be manufactured inexpensively in large volume by automated machinery. `
Another object of the invention is to provide a device l; ` :~
of:~:the:character desoribed in which fluid is dispelled from the apparatus throuqh either an :integral~:infusion needle,~ or~
through a luer type connector, by a thin, distendabl~ membrane cooperatively associated;wit:h a thin, plate-like base. :~
Another object~of t~he invention is~ to provide an apparatus~: of the ~:aforementioned character in~ which the :distenda~le member~ is permeable~ to~gases at~ least in~:one d~irection, ~ whèreby~:.gases~within the~ medicina}~agent can~be;
`rèleased from the~ fluid~;~chamber and~:not~ ln:jected ~lnto the :
patient. ': :~
1 Still another object~of the inventionilis to provide an~
I appàratus as described in the preceding paragraphs in which the ::
rate'~of~;fluid flow~`f:rom;~the~apparatus`~i precisely controlled by~a:~thin~planar shaped,;fluid~permèable~member which~forms a~
part~of the:`'low~ profile, laminate~ construction of the::::~
apparatus.:
Another obj~ect~of the invention~:isl~tQ::provide~a;~fluid~
dclivery~device~ embo~dyinq n isotroplc'dislendable ~membrane~

; ; SU~BSTITUTE S~ EET~

W093t20863 .~ 2 PCT/US92/10~2 ~ ' ', ' ;
1`` `~`"
with a uniform modulus of elasticity which cooperates with a I -base to define a fluid chamber having a fluid outlet in communication with dispensing port for dispensing fluid from the device and lncluding a flow control element disposed ~ `
intermediate 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 cham~er having a fluid outlet in which the distendable membrane assembly is of `"
multilaminate 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 If the chamber described in the preceding paragraph which includes a rate control membrane and in which ,!
the base is provided with a multiplicity of micro-channels for `-`
conduc~ing fluid to the rate control mem~rane at precise rate over a predetermined active area.
A principal object of one fonm of the invention is to ~-~
provide a novel agent formulation dispenser adopted for use with a slightly modi~ied`version of the basic fluid delivery device of the present invention for administering an aqueous h;
solution containing selected dxugs or other chemical compounds at a ! cqntrolled rate.

Brief Deæcriptio~ of Tho Drawing~
Figure I is a ge~erally perspectlve, exploded view of s one am~odiment of the present invention. ~ ~' Figure lA is~a fragmentary plan view taken along lines lA-lA of Figure 3 showing the internal constru tion of the apparatus of Figure 30. ~ -: - ~ .'., "

SlJBSTlTUTE SHEET : ~

W093/20863 PCT/US92/10482 ~ ~
3 0 ~ 2 Figure lB is an enlarged cross-sectional view o~ the circled area shown in Figure 3. ~
Figure 2 i5 a fragmentary, generally perspective view ~-of the circled portion of the flow rate control membrane as shawn in Figure l. ~`
Figure 3 i5 a cross-sectional view of the apparatus shown in Figure 1.
Figure 4 is an exploded, generally perspective view of ~`~
still another form of the apparatus of the invention.
Figure 5 is a fragmentary plan view of the ~luid outlet ;~
portion of the apparatus of Figùre 4, partly hroken away to show internal construction.
Flgure 6 is a cross-sectional view taken along lines-6-6 of Figure 5. ;~
Figure 7 is a cross-sectional view ~aken along lines 7-7 of Figure 5.
Figure 8 is a cross-sectional view taken along lines ~' B-8 of Figure 7.
Figure 9 is a fra~mentary, generally perspective view of a portion of the flow control means of this form of the `
~apparatus o~ the invention.
;Figure lO is a fràgmentary, gene`rally perspective view o the distendable membrane of the present form of the , ~ invention illustrating the laminate construction thereof.
: `
Figure ll is a plan view of~another form of the ~ ~
~venkion, partly broken away to show internal constructlon. ~ ~`
Figure 12 is an;exploded, generally perspective view "i of the foFm o~ the apparatu- of the lnvention shown in F~gure Figure 13 isla cross-sectional view takenlalong~lines 1!' 13-13 of Figure 11.
~;Fiyure 14 is a cro S~-sectional vi~ew taken along lines ;14-14 of Figure 13.
Figure 15 is a cross-sectional view~taken along~lines lS-l5~of Figure~ 13.
Figure 16 is a gen~rally perspective vlew~of various `
forms~of activating members ~or a tivating the parenteral fluid S U B ST~TUTE S H E ET ; ~

W093/20X63 PCT/VS9~ilO482 ~ `

!
7 1 `
with a medicament which are usable with this embodiment of the ! ::
apparatus of the invention. ¦
Figure 17 is a fragmentary,~ cros~-sectianal view similar to Figure 15 illustrating the use of flow distribution materials within the liquid flow manifolds o~ the device. ' ;
Figure i8 is an exploded, genexally perspective view of another embodiment of the invention.
Figure l9 is an exploded, generally perspective view of still another form of the fluid delivery apparatus o~ the invention.
Figure 20 is a plan view of~the apparatus partially ~`
broken away to show internal~construction.
Figure 21 is a cross-sectional view taken along lines 21-21 of Figure 20. `~
Figure 22 i5 a cross-sectional view taken along lines 22-22 o~ Figure 21. ` `
Figure 23 is an enlarged side elevational view partly ` -in cross-section to show internal construction of an additive~
carrying subassembly shown in Figure 23.
Figure 24 is an enlarged end view o~ one end cap of the additive subassembly shown in Figure 23.
Figure 25 i~ a side elevational view partly broken away of the end cap shown in Figure 24~
Figure 26 is an exploded view of the additive subassembly shown in Figure 23 partly in cross-section to better~illustrate the construction of the subassembly.
Fiqure ~7 is a fragmentary, generally perspective view , ~ , of one of the end caps of the additive subas~embly of the L ~,',,,,~`
apparatus.
Figure ~8 is lan enlarged, cross-æectional view taken along lines 28-28 of Figure 20. ~ ; J` ' . `, Figure 29 is a side elevational view of the apparatus of this ~orm of the inven~ion being filled ~by~ a hypodermic ~ `
syringe of standard construction.
Figure 30 is a~ fragmentary,~sida elevational view~
similar to Figure 28~showing tbe ~luid~f1ow path of the fluid~
flowing hrough; th- apparaeus: ;~d outwardly towara the , .
SU~iSTlTUTE SHEET

W093/20863 i~ 1 1 8 ~ ~ ~ PCT/US~2/10~

B
dispensing means. ~
Figure 31 is a cross-sectional view taken along lines ``;`
31-31 o~ Figure 28.
Figure 32 is an exploded, generally perspective view of still another form of the apparatus of the invention. i ` `
Figures 32A, 32B, 32C, and 32D are general diagramma~ic views illustrating various means for affinity attachment of !,.;~
ligands, protein moleculès and enzymes to substrates.
Figure 33 is a plan view of the form~of the invention ;
shown in Figure 32.
Figure 34 is an enlarged, cross-sectional view taken -along lines 34-34 of Figure 33.
Figure 3~ is a cross-sectional view taken along lines 35-35 of Figure 34~ Ai,~`,,' Figure 36 is an exploded, generally perspective view of yet another form of the fluid delivery apparatus of the inventlon which includes an immobilized drug vial of unique construction that i~ disposed within the outlet fluid flow path~
Figure 37 is an exploded generall~ perspective, fragmentary view of a device similar to that shown in Figure 36, but one in which the fluid enters the device from the side ` `
rather than the end. ; ;`~
Figure 38 is an enlarged, cross-sectional view of the `~
immobilized drug vial as~embly usable with the de~ices shown in `
Figures 36 and 37.
~;~ Figure 39 is an end view of the immobilized drug viaL r'"'"l, assem~ly.
Figure 40 is an enlarged side elevational view partly , in cross-section of ~he upper portion of the device illustrated i ! :
in Figure 36 showing the immobilized drug vial or additive ~i "
carryi~g subassembly disposed within~the device.
Pigure 41 is a cross-sectional view taken along lines 41-41 of F1gure 40.~
Figure 42 is ~a fragmentary,~cross-sectional view illustrating the fluid~flow control check valve of the device in a closed position.

~ . ; .,:

SUB:STlTUTE S hEET

wo 93/2n~6,3 ~t. ~ PCT/US92/10~2 ..
9 `' ' ';
Figure 43 is a generally perspective view of another .: ' e~odiment of the invention which includes a novel filling ..
needle assemhly having a unique check valve housing with luer end and s.afety shield.
. .
Figure 44 is an snlarged, cross-sectional view of the .. `:
filling needle assembly of Figure 43.
. Figure 45 i5 an end view of the check valve housing of this form of the invention illustrating the location of the .
fluid flow channels.
Figure 46 is an enlarged~side~view~partly in cross~
section showing the filling needle assembly connected with a fluid inlet 1ine and also intérconnected with the housing ... :
assembly of the device, the needle of the assembly having~
penet~ated the housing assembly septum. :
Figure 47 is a cross-sectional view similar to Figure .~'~
. .
46 but showing the device in a filling mode, the check valve ,'~
having~been moved to:an open p~osition.
: Figure 48 is a cross-sectional view taken along lines 48-48~of:Figure 47.
: Figure 49 is a oross-;sectional view ~aken along lines : l",,;'~
49-49 of Figure 47. :~
: De~cription of The Invention ~eferring to the drawings and parti~cularly to Figures ,~::i~'~',through:~ 3, one embodiment: of ~the ~apparatus for use `in : :' inusing~medicinal fluids~:into a~patient~is~;there illustrated and generally designated::by~the numeral.200.~ The apparatus of' ::: .;.,~,this:f~orm of the invention~includes: a~base~which comprises a 2~ ','.,",, pair of thin,:generally~pla~ar plate-like~base members 201 and : `~,~'~.''',',', 202. Base member 202 has a palr of flow rate control channels :
p~o~ide~d'~.here~as longltudina~lly extendi`ng fluid 'conduits l20 4 ~
:~and 20;6.~ Conduits~204~and 206 are interconnected~by a~fluid: ~ 3 :transer`manifald,~:or tran~sverse;~conduit 208, whlch, in~turn, is~interconnected:with~a~fluid~outlet:~passageway~214. Affixed to~:;the~bot:tom~:of'base~:: ~ er~:20,2 ~is~a:~planar~shaped foam:~pad 3~ ;A peel~strip~:40~,is~connecte~ to~t~he ~ottom of pad ;38 by~ ";:i.
any:suita~le means~s~o~that~it~can~be:~removed:~to expose al~layer~
of;~adhe~si~e`provided on~the bottom~surface~of~pad 38.

S~ ~8 ITUTE SHEET~

W0~3/~0863 ~ `2 2 ~ PCT/US9~/104X2 A thin, initially :generally planar distendable ,`,.
elastomeric laminate, or assemblage 209 cooperates with base 202 to form chambers 211 ~Figure 3). Assemblage 209 is ', distendable in the manner shown in Fi~ure 3 by the introduction of fluid into the chambers under pressure in various manners which will presently be described. As the distendable laminate ~ , 209 i5 distended by the fluid pressure, internal stresses are '' formed therein which continuously urge it to return toward its :original non-distended configuration and toward engagement with '`.
distendable membrane engagement means here provided as !~.
: protuberances 212 formed on base member 201. ; ~
~n important feature o:f this embodiment of the invention, in addition to the laminate membrane constructions, ; ,;
is the provision o~ a multiplicity of ~low 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 ;c,ontrol means~ of a character presently to be ~ ',"
described.
, : ~In the embodiment of the invention shown in Figures 1 : ' khrough 3, the flow control means is also provided in the form of ;a~ thin, laminat~e or gradiated assembly `21$ which~ is uperimposed over channels:210;in:the manner~shown in Figure 3. ~.i.'`~
With~;this~:c:onstruction,:when~th~e device is in a fluid dischar~e mode,,~;~1uid within~ chamber:s ~211~is ~forced ~by me~brane:`209 : .
;::through~channels` 213 provided in~ pràtuberances 212, through assemblg 215, thr~ough~micro-channels 210, into conduits 204 and~
206'~and~'outwardly through~outlet passaqeway Z}4. Passagew~ay 2:14~is connected ~with`~dispens~ing ~means shown ~here~as luer connection a~sembly L which includes a fluid ~low conduit and ~ ':~ ",i`~
luidiidispensing port~o~ luer connector ~"L". ~y! controlli`ng ' : the~area of the micro-channels, the active: surface area of ~, . ..
membrané assemb:ly 21~5 whlch~is:~exposed~;to fluid can be~:varied in~ :a~ manner to ~optimize~ fluid flow'~thr~ugh asse~ ly~ 215.
5 ~ilarly:;by:~controlling~ the~s~ize:and~shape;of the micro~ "'~
hannels:~ the~rate~of~ f1Ow~ of' the~ f~1uld;~ through me~ rane~
s`se~ ly~;2~15~:can al50~be,:ùni~0 ~l~:m~intained.~
As ~ndi~ated~ n~Figure ~, th- flow controL means of SU~B:S ITUTE~:~SH~E E ~

W093/20863 ~;fi~ 22 PCT/US92/104X2 ~ ;"`~`
t'`"

11 ,. `~' this form of the invention, here comprises an assemblage of a plurality of layers of permeable materials, P-l, P-2, and P-3, each having selected characteristics. These layers, which may` :
be composites, thin films, or porous substances, may be constructed of any of the materials previou~ly descrlbed herein 50 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 assemblage can be constructed. In certain applications assembly 215 can he constructed with gradient layers rather than with discrete elements in a manner to produce comparable results. The flow control means can also consist of a single layer.
The multilayered, or gradient layer constructions of the stored energy source and the flow control means described in the preceding paragraphs permits easier, thin-film manu~acture, precise flow control over extended periods and easier handling of the membrane film durin~ system manufacture.
Superimposed over the assembly comprising base members 201 and 202, distended mem~rane 209 is a porous plastic cover as~embly 34 which functions to provide an inner engagement surface for mem~rane 209 and a venting means for venting gases, if any, contained within the medicinal agent.
, Referring now t~ Figures 4 through 10, still another ~, embodiment of the present invention is there shown. This ~L '' embodiment of the in~ention is also similar to that shown in ~;
Figures 1 throu~h 3 and like numerals are used to identify like components. As best se~n in Figure 4, the device comprises base members 300 and 301. Base member 300 has a pair of ~low rate control channels 302 and 304 and a transversely extending fluid transfer manifold conduit 306. Conduit 306 is connected , SlJBSTlTUTE SHET ~`

W093/20863 ~ 02'I PCT/U592/1~2 : ^ i !

with an outlet 310 ~Figure 5) which, in turn, is in communication with a ~luid dispensing means, shown here as a ~luid dispensing port 312~
Unlike the embodiment of the invention previously described, the device of this form o~ the inventlon does not include a flow rate control membrane of the character pr~yiously described. Rather~, the rate of fluid flowing from the dispensing means of the de~ice is contralled ~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 7) which functions to restrict~the flow of fluid between outlet 310:and dispensing port 312~
In the present em~odiment of the invention stored energy means once again comprises a lt~minate assemblage made up o a pIurality of initially~ generally ;plaDar~ distendable elements or films. Referring particularly to Figure 10, the st:ored energy means is there~shown as~a làminate~assemblage 318 made up of~individual elements or membranes 320~, 322, 324, 326 and:328~.~ Assem~lage 318 functions in much thè~same way as the~
earliex` described distendable~ mem~ranes,~ and ~uniformly~; ; : :~::; ~ .
coopera~es with base 300 t`o:define fluid chambers or reser~oirs 25~ However, iby~constructing~the stored:~energy means from~a composite~j:of several :~distinct:~elements; ~or~:layers, ~the eiastomeric characteristic:s~of::the~stored~ene~gy means can be~
precisely tailored~and:~the~st~ored enexgy~means can be uniquely con~tructed~ to: function~als;o as~a gas permeability valve as~
well ~as the: means :~`or~ expelling fluids ::~;rom the fluid re8ervoir. This unique, multilayered or~gradient construction per~its~lventing~tolatmosphere through ~the mè~`rane surf~cè~ ',t,~
certaint 5elected, entrained~ases~or vapors~:in the~reservoir :while s~ultaneoustly ::~precluding any~negative :migration of:~ tL . e~
selected atmospheric gases~or vapors~into~the~reservoir.~Where~
the composite is;:made~:up~:~of~two:~or:more~lay~ers of alternatLng thickness;and permeability~ and~:the permeability~constants~of~
the;~individual ~film;~layers~ are;:~pressure; dependent, ~the:~
,perm~ability~ of the stored energy~means~ls~effected and~:the U;B~STITUTE~5HEET

W093/20863 ~ 022 PCT~Us92il0~

13 '`~ '' '"'' direction of flow of the permiant through the membrane wall is '';'' controlled by the order in which the individual layers or t ~-gradiations of the composite are assembled. ` ~, For e7xample, referring to Figure 10, layer 320 which ~ ,, may be dista`l to the r ser~oir comprises a thin film elastomers '; , ``~
of ~ first thickness and a first permeability. On the other ~' hand, layer 328, which may be proximal to the reservoir, ,~/``
comprises a thin elastomer film of a second thickness and a '~'`
second permeability. Layers 322, 324 and 326 may be of ~urther alternating thickness and permeability and, if desired, may also have different perm-select characteristics. The selective ',`'i arrangement of the different films each with its own individual ` "
pèrmeability constants in ascending order, will dictate the ,~
di,rection of flow of selected gases and vapors through the `,~
stored energy means. `'~
Turning now to Figures ll through 16, 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 unique in that it provides the ~"'i, opportunity to adll to the diluent or other parenteral fluid ,',';' being introduced into the device selected elements, chemical , .
compounds and bioloqically active materials such as drugs, ,.. i meticaments, biological agents, or other therapeutic agents (a~ditives). This addition is accomplished by removably '`~'' a~ixing the selected 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 reieaseù at a controlled rate to the ~luid.
In this way, the delivery system of the invention can be safely rendeied therapeutically active upon hyd~ration of'the'additive "
with a selected parenteral fluid such as a sterile diluent or ~ ' other a~ueous solvent~
The basic structure of the de~ice of this new form of ~he invention is sLmilar in many respects to the previously , `'~-described embodiments of the invention and like~ numbers are used to identi~y like components.
As best seen by referrlng to Figure 12, the apparatus : SUBSTITUTE SHEF~ ` `

W~3/20863 PCT~US92/10~2..

comprises a base made up of a first, generally planar member `
400 and a second companion member 401 which includes a pair of ;~;:
lon~itudinally extending flow rate control conduits or channels ..
402 and 404 which commiunicate with a transversely extending fluid transfer manifold conduit 406 (Figure 11). Conduit 406 .. :;
is, ~in turn, connected with~a rluid outlet 408 which is in communication with a fluid~dispens:ing;~means shown here as `
including a fluid dispensing port 4:10. : ;.
First bas:e member~400~:~is~al:so~pro~ided with a:pair of ngitudinally~ext~ending:manifolds 411~which communicate with mic~ro~-channels 412 :~(Figure 1~5)~ As~best~seen in~ Figure 13, ~manifolds:411 and micro-chà;nnels~412~communicate with conduits 402 and~ 404 ~via flow:~contro}: means~of~the~ general character described in connection with the previously described embodiment of the invention. More particularly, the flow control: means~is here~ pro~ided~as a thin, multiIayered:or~
gradiated assèmbly~ 215 (~see~;Fi~gure ~2) which~is superimpos`èd ~ : ~ ``.over:manifolds`~4~ and~mlcro-channels~412 in the manner shown~
in~:Figure~12-~ ~A~sembly:;~2~15 :comprises:~an upper~microporo:us layer,~ àn~intermèdiate:;~rate:~control~: membrane and a lower:
support~1ayer. With this~`con;struotion,:~when~the~device is in~
a ~:fluid~ discharge modè,~fluid:whic~h~:~i:s~ contained within~
chambers~ (Fiqure~ 15)~ such as a diluent~contalning the~
additiue :(the ~beneficial~agènt) is initially ~orced by the :~
stored~energ~ means through~cha~nnels 414:provided~in a pair of upstanding protuberances~41~6~formed~on base~member 401. As the :~
liquid~ pàsse~s;;~through~;ohannelæ 414, it;~`e~nters ~a pair~of :~
:`long`itudina~lly extendi`nq:~manifolds 417 whieh ~re formed:in base;~
::member~401 and which align;with~manifolds 411 formed in base memb~ 400. Manifolts~17~ function to uniquely`~dibtr~utelthe~
$1uld~:as~it~flows~ toward ~th`e~:f:low~control~asse~ ly 2~15 in~ a :
manner to~disperoe~the fluid~throughout a`wide aré~a of the flow~
control~ass~emb~1y.:~ T e~ uppe ~ost layer~of~the~as6e~ ly~ls~
desl~nèd~ to:~pe mit~ mult~i-axlal ~f1OW ~distrLbution thereby~
:e~ectively~ utilizin~ an~extensive~sur~ace~area:~of~ the~:~rate~
control~membrane~ The~béneficial:agent;:flows through the~rate ;~
;co~ntrol~membrane~`l:ayer,~ through~:the: support~layer~, through~

S U B STITUTE~ S H E ET :

W093~20863 ~ t~ PCT/US92/1~2 !

micro~channels 412, and thence outwardly through outlet passageway 408. Passageway 408 in turn communicates with dispensing means, shown here as including luer conne~ctor assembly L.
As previously discussed, by controlling the area of the manifolds, the character of the uppermost layer of the ~low control means, and the area of the micro-channels, the active surface area o~ the rate control membrane which is exposed to fluid can ~e prècisely varied in a manner to predictably achi~ve the desired fluid flow control. Certain regLmes of the various lay~ers of asse`mbly~215 can be rendered hydrophilic 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 o~the system.
The distendable membrane engagement means, shown here as protuberances 416 (Figure 12)~ perform the siame function as previously d`escribed. I~t 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 o~f this embodiment comprises a ~laminat~e assem~lage 318~made up~ o~ individual elements or mem~ranes 320, 322, 324, 326 and 328.~Assemblage 318~functions in~ much~ the same way as the;~earlier described, sin~le and double~layer distendable;membranes, and uniformly cooperates with base member 401 to de~ine fluid chambers or reservoirs 211 (Eigure 15)~ However,~a9~previously mentioned, by constructing the stored energy~means~fram~a composite of several distinct members or layers, the elastic charactPristics and the resul~ant energy flux of the~ stored !energy~;meansl cani bë
preciael~y tailored. In this way, the stored~energy means~can ~also be~uniquely constructed;to function as a~as permeability vaive~(for example to~prevent external negative mlgration of flulds into the reser~oir) as well ~as the~means for expelling fluids from the~fluid reservoir.~
As indicated in~Figure 12, superLmposed over the hase :.. ... ..
~ and th~ stored energy~source i5:~ a structural cover 34 of the :

S U B STITUTE S H E ET

W093/208S3 PCT/US92/10~2 ~ ~ ` `

~ 1 ~ 3 0 2~ s character previously described having appropriate medicant and use labels 36. Affixed to the bottom of the 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 contaminants into the device.
Like the previously described forms of the invention, the present embodlment includes filling means which enables cham~ers 211 to be filled with a selected parenteral liquid using any suita~le means such as a hypodermic s~yringe. To accompLish filling of the chambers, base member 401 includes an upstanding transversely extending portion 41B having a fluid passa~eway 420 extending therethrough. In this em~odLment of the invention, the open end 4i20a of passageway 420 is closed by a septum means for sealably receiving a piercing e}ement such as the hypodermic needle of a hypodermic syringe. 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 sel~-sealing, noncoring, punctura~le materia} such as silicone-SEBS. It should also be understood that the septum~means can also take the form of a split septum ~or use with a state-o~-the-art blunt cannula injeqtor system. As best seen by referring ~to Figure ll, passageway 420 is in communication with Iongitudinally extending channels 402 and 404. As before, channels 402 and 404 are~,; in turn, in communication with chambers 2ll~ With this const~uction, àn`appropriate injectable such as a diluent or parenteral ~luid contained within the syringe can ~e intr~d~uced into~chambers 211 ~ia pa5sageway 4Z0.~ 3,1j~j'' ~ efore considering the highly important adding means of this latest embodiment of the invention a brief introductory background is perhaps help~ul.
In the past it has been common practice to mlx varLous ~ypes of separately packaged drugs with a suitab}e; diluent ~immediately before they are deli~ered intravenously ~o~ a patient.~Typically~the~drugs are~packaged separately~from~the~

SUBSTITUTE`:SHE~ET

W093/20863 ~ 2 PCT/US9i/10~2 ~ ~

l` ';"`'::

diluent for various reasons. For example, many drau~s do not retain their chemical and physical stability when mixed with a diluent, and thus cannot be stored for any substantial pe~riod 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 proressional injecting the injectable fluid into a glass vial containing the drug. After mixing o the drug and the diluent, the solution thus formed is withdrawn into a syringe barrel and in some instances injected immediately~into the intravenous system of a patient. More typically, however, the reconstituted drug is injected from the syringe into a lar~er 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 elegantly overcomes the drawbacks of the prior art reconstituting and delivery `techniques ;by providin~ in~ ~ `
conjunction with the basic fluid delivery de~ice of the invention a simple and precise means for automatically mlxing the~de;sired drug with the appropriate diluent at the time the de~ice is changed.
In the paragraphs which follow, wherein the details of this~ uni~ue reconstitution process will be discussed, the following term~ will have the following meanings~
any of the fundamental substances that onsist o~ a~oms of only one kint and thàt sing1y oi in combination 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 fluld introduced into the~device of the invention.
Poly~er - a chemical compound or mixture of compounds . .
; ~ formed by polymerization and ~consisting essentially of SUBSTITUTE ~SHEET ~ -;

. W0~3~20863 PCT/US92/104X2 ~
2 1 ~
~ 18 repeating structural units.
Parenteral Fluid - any solution which may be delivered to a patient other than by way o~ the intestines, including water,:saline solutions, alkalizing solutions, dextrose solutions, acidi~ying solutions, electrolyte solutions, reagents, solvent~s and like aqueous solutions.
Bene~icial Aqents - any drug, medicament, pharmaceutical, medical polymer, enzyme, hormone, antibody, element, chemical compound or other material useful in the diagnosis, cure, mitigation, treatment or prevention of disease and::for:the maintenance o~ the good health o~ the patlent.~
~ ioloqicall~ Active~~Material: - :a su~stance:~which ls ~iochemically, immunochemically, physioIogically, or pharmaceutically active or reactive. Biologically active material includes at least one or more of the ~ollowing~
biochemical compounds~(such as amino acids, carbohydrates, ~lipids, nucleic acids, proteins, and other~biochemicals and substances which may: complex~ or: interact with .biochemical compounts), "such biochemic~l compounds biologically functionlng as antibodies, ~ antigenic substances, enzymes, co-factors,~ inhibitors, ~lectins, hormones, hormon`e producing.cells, receptors, coagulation :actors~, growth enhancers,~histones, peptides, vitamins, ;druqs, ccll surface~markc:rs and~toxins,;among others known to~those skilled;in:the art. Of the group of biolc,gically activc matcrials dcscribed,:protcins~are~o~utmost current intorest ~:becaùse:~ of~ the ~large `moleculc genetically:
engineered biopharmaceuticals as those: species to be ~mmobiliz~ed and congregated on thc~:additive~l`:carri~ers hereinafter to be~`described. A discussion of the use of biomosaic polymer~s~as:.carricrs for biologically activc~
matcrials is~ set~:~forth in Europe~an~Patcnt Application;
0,~430~,517 A2.
Addinq e ~- ~an~:additive and any mcans f~or presenting the, additive~ to::the~fluid flowing through `~he ~luid passageways~of the:fluid dellvery~devlce o~the~invention~

sU 8 5TlTUTE S H E ET:

W093/20863 ~ 2 2 PCT/US92/10482 19 ' 1 ` - - :
in a manner such that all or any part of the additive will be added to the fluid. The addin~ means compxises the additive and the additive presentation means whic~, may take the form of a functional support, or carrier, an I ~
anchorage, 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 functional support or ~substrate for presenting the additive to the ~luid flowing through the device. The .
, . .
unctional substrate can comprise a pol~ner, copolymer, an inter-polymer, a ceramic, a~cry tal sponge, a car~on based matrix, a celluloslc, glass, plastic, biomosaic poly~.ers, azlactone-functional polymer ;beads, adduct beads, carboxylate-functional poly~.er beads, gums, gels, filaments and like carrier~
By way of illustration, the adding means o~ the invention can take several different forms such as those illustrated in Figures 43 and~45. However, in its preferred for~., the adding means includes :a cylindrically shaped, functional support structure which is inserted into passageway 420 and to which various additives, including beneficial agents such as~ drugs, biologLcally 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 42Q and circulates through t~he support assembly:in the manner shown by the arrows in Figure 43, the additi~es will be pre~ented to the liquid flow and efficiently added to the liquid as it flaws toward ch~m~ers 211 via inlets:413.
The additives~themselves can also take va~ious physical orms~in._luding liquid, solid, granular, powder, particle, gel, wax, hydrocolloid:carrier,~ a gum, film, tablet, crystalline, ;~ ~emulsion, ~ microcrystaLline,: mlcrosphericaL,~ spray dried .ompounds~ and,~`~:lyophiLized :compounds~ and ~:saturants. The additives can be removably~ conne._ted to,:~immobilized on, impregnated within or supported ~by the support means i~ a : SUgSTITUTE SHEET
.

W093/20863 2 1 1 ~ ~ 2 ~ PCT/US92/~2 ~ ~ ~

20 . ~
. j .
number of ways. The additives can be chemically or mechanically attached, affixed, or ~ound directly or indirectly, linked or cross linked, anchored to the surfaces of the support, or surface active ayent or they can be absorbed, reaction catalyzed, electrostatically encapsulated, attached by ; ~chemical modification or transformation to the carrier surface, polymerized on or through the carrier, with or without th~ use of an interpoly~er, localized, entrapped, suspended, deposited, impregnated, coated~, or occluded or otherwise removably affixed within voids, cells, tubules,~and interstices;f`ormed in the support. One i~mportant~ method~ for removably affixing the additive to the f~unctional:s~upport means~includes treating the functional support means with~a compound having selected reactive functional groups such as ~azlactone functional compounds with their unique ability to react with aqueous media and~ their hiqh binding capàclty. ~In this way~complexing ;agents~,~catalysts and biol~oqical materials such as enæymes or other~proteins, as well as~biomacromolecules can be~attached to the~carrier~for later~removal and recovering. Additionally, the us~e~of cne or~more monomer~ic or polymerized surface active agen~ts allows~for rapid~dissolution and smooth liberation of the additives. A discussion~`of such surface active agents is~
containet in~U.S. Patent~4,963,367 issued to Ecanow~
SLmilarly, the~additives~can be~added~to or~intermixed~
with~th~ lLquid flowin~g~``through~the device by one or more~of V4rious~ mechanisms~ ~including mechanical release, chemical;
reaction,~ dis olution~ disorbsion, de~inding,~ ~de~linking, bio~eparation,~ dif~us~ion,; wa~shing, disintegration, erosion, di~association, solubilization, leeching, enxymatic cleavage, bio~ogical~rea~t~ion,l~ogmosis, separatloh from ringl openlng materials by ~a ring~opening~reaction, and other~separation Additio~nal1y,~a polymer can~ge~used as;the~carrier or `suppo~t~for~some~oomponent~of a r~eaction~;system.~Three~classes of polymeric`supports~can`~be~used,~namely polymeric reagents~
poly~eric~catalysts~and~polymerio su~strates. ~A discusslon ~of~
poLymers~as carriers~or~supports is contALn-d in r1nciples of SUB5TITUT5~5HE~

~21 Polymerization, Second Edition by George Odian. Microporous polymers usable as carrie~s are also fully described in U.S.
Patent 4,5l9,909 issued to Castro.
Turning now to Figures 12 and 14, 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 assem~ly includin~ a substantially cylindrical, porous substrate 423a into which an injector inlet tube 4~3b is closely received. Surrounding porous substrate 423a is a sleeve ~23c having a mul~tiplicity of flow channels 423d. As shown in Figure 14, the~as`s~emb1y~thus ~ormed~is inserted into fluid passageway 420 farmed in~transversely extending portion 418. Receivable within the inlet opening of tube 423b is the previously identified` needle septum injection site 422.
Connected to portion 418, as~by bonding is an insert 424 (Figure~lZ) which funations to contain the septum within the ~device.` ~ ` `
~;
~; ~ In using the apparatus o~ the~em~odiment of the invention~shown i~ Figures lI-l5, septum injection site ~22 is penetrated by a syringe needle and the sterile diluent is ~-introduced into inlet~passageway 420 using the ~syringe ~ ~
~; as~embly.~ As indicated by the arrows in Figure 14, as the ``
`dlluent flows longitudinally~of inlet passageway 420 it will pass~hrough porous member 4~23a, into ~low channels 423d and~
~then into ch ~ ers 211 ;urging~ the distendable membrane 318 outwardl~ into the p~sition shown in Figures 13 and 15.~ As the `
liguid flows through~porous member 423a,~ the additi~es presented to the liquid will be added to the flow, or - ' ;
solu~ilized~by~t~he~diluent,~thereby activatingithe diluent to form the therapeutic so~lution to be dispensed to the patient. ~ L
~ The liquid,;such as` a parenteral ~fluid, which is~
;~ introduced into passageway 418 c n include, by way of example, a reagent, a sterile~diluent, Yarious electrolytes, a~ueous solutions such~ as~`aqueous solutions;~ of dextrose, saline ~ j!",,~,":
solutions~, alkalinizing~solutions, acidifying~ solutions, polyonic solutions and~any other liquids;that can serve as a `
SU BSTITUTE SH E ET~
,, ~.

W0~3/20863 ~ 2 2 PCTJUS92/10~2 ` ' ,~,~ I ' '. `

~2 `
vehicle for the administration of therapeutic or beneficial .'"'!"-agents which are desirable to administer to the patient by infusion. :
Turning now to Figure 16, various other forms of adding ' ,`~
means are there illustrated. For e~ample, 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 additlves are laminated.~ ~The~selected additives such as elements, chemical ~compounds, drugs ~and functional , -;~
intermediates are provlded~on or~within~the coating layers by techniques~ well known~ to ~those skilled ~in the art. The ~:?~
additiv~s`exhibited by layèrs ar`e, of course, introduced into the sterile diluent as the diluent flows along of the inlet - ``
passageway 420. In this instance, since the su~strate will not ;-~i be damaged by ~the syringe~ às~ might a polymer or cellulosic ~` carrier~ use of;the injeotor~inlet tube 423b is not required.
; ~Another form of addi~tive assembly designated in Figure I6 by the numeral 427~, comp~i~ses a solid tubular member having an internal~,~axially extending f~luid passageway 427a, the inner wall`~ whic~h is lined~wLth~a~separation~coating affixing the additi~è`s~ suoh as~ chemical compounds and~beneficial;agents, or -`medicaments.~
St~ill another~form~of~;additive asse~ ly~is identified in~Figure ~16 by the numeral~42.9.~ This~ assembly comprises`a cyl;indr;ical, porous piug~iike~member made up of a multiplicity oflfused together microsphères~or beads 429a, each of which is coatéd~with~;a separation~or reactive ~coating~upon which lS
deposited an additive such às a biologically active materiaI or otherlbene~icial~`ag!eLt~.~ The microsphe~és can` be flormed o`f ~glass,~ plastic~or~other~suitable materials. ~
The numeral~4~31~of Figure 16 identifias yet another ~; ~form~of~the;atding means of~lthe invention.~In~this~;form^of~the~
in~ntion~a generally;cyIindricalLy s~haped~functional support means~ for~affinity àttach~ment, and sub~sequent release of the~
àdditive,;is~formed~from~a~multipli~ity of~microporous polymers ~; 431a presenting-a multlplicity of re ctive sites over a wide ~ ~ ~ " . ~

5 U R STITUT` S H ~ ET ~

W093~20863 PCT/US~2/10~2 ~ ~ ;
21~ g~22 i'~
~., ~ ., 23 ~ ~:
area for species immobilization. In this form of ~he ¦
invention t in order to avoid needle damage to the polymers, it I
is necessary to use an injector inlet tube of the char~acter shown in Figure 41 and identified by the numeral 423b. , ~ :~
The additive assembly designated in Figure 16 by the ' ; .
numeral 433 may also requirP the use of an injector tube. This assem~ly is made up of high porosity, semi-synthetic cellulosics 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 43S. 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 presenting 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 ~: ;
introduction into the system reservoir can be achieved by ~specially designing each of~:the wafer5 tha~ cooperate to make up th~structural support.
Still another~form o:~ activating assembly is designated in Figure 16 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 neae~sa~y, functional intermediate materials~0 !
Finally, the functional support member identified b~
the numeral 439 exemplifies yet another form of adding means of~
:the in~ention. `This member:, which~ is also of:a generaIly ~
cylindrically shaped configuration, is :constructed from a : : i :
:porous ceramic material :into which selected~additives and lntermediate compounds have been removably aff~ixed.: :Member :;: :
439, being made of a hard ceramic, would not be easily damaged :: ~ SUBSTITUTE SHEET ~ `
~ ., .

W093/Z0863 Z~ 2 PCT/Us92ilO~32 ~

~ "~ .
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 ~irconium o~ide bonded spherules, or other porous forms of polymer reactive supports including joined azlactone-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 pa~sag way 420 of the device.
Turning now to Figure 17j another form of the invention is shown. This igure shows in~cross-section one set of the manifolds 411 and 417 whi~h are formed in base members 400 and 401 of the device. In certain applications, it is sometimes advantageous to provide li~uid distribution means within manifolds 411 and 417 to enha`nce the uniform flow of liquid through~the manifolds~ In the embodiment of the invention shown in Figure 43, the li~uid distribution means is provided as generally planar strips o~ felt-like`hydrophilic polymer materia} 440 which is~readily wetted by the solution being expelled from chambers 25 by the stored energy means, or :distendabla membran~ 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,:: ~ ,"l'""!~
~sponge:and other similar :materiaIs which have hydrophilic charackeristics. ~
Turning to Figure 18, another embodiment of the apparatus for use in infus'ing beneficial agents into a patient is the~e !~ illust,ratedO~ The basic structure of'~the devi~e~ o~
this latest for,m of the invention is similar in many respects to that sh~wn: in Flgure 12: and like :numbers~are used to identify like components. The major difference ~etween the deYice shown in Figure 18 and that shown in~Figure 12 is that the t~ansverse filling portion 413 is replaced by a longitudinally exte~ding~filling portion 518:. As will be :discussed in greater detail hereinafter, the adding means : ~:: ~A!,, j, SUB5TITUTE 5HEET,i . .

W093~20863 Xl~ 3 ~ ~ ~ PCT/US92/10~2 : ~25 including the additive carriers of this form of the invention are also of a somewhat different configuration.
As in the apparatus of Figure 12, the apparatus ~ere comprises a base made.up of a first, generally planar member 500 and a second companion member 501 which incIudes à pair of longitudinally extending f 1QW rate control conduits:or~channels 502 and 504 which communicate with a fluid outlet 508:which is in:commiunication~with a fluid dispensing means shown here as including a ~luid dispensing port 510.
~ First~base member 500 is:also provided with a pair of longitudinal~ly extending~manifolds 511 which~communicate with micro-ahannels of~ the ~character shown:~ in: Figure 15 and identified by:the numeral:412~` Manifol:ds 512 as:well as the .. ... .
micro-channels communicate with conduits 502 and 504 via flow control means. The flow control means is here pro~ided as a : thin,~ multilayered or~ gradiated assembly~ 512 which is :~ `superlmposed~over manifold~ 51;1:~ in the: manner:indicated in:
Figure~ 8.:~ Assembly~512 ~;comprises an~ upper microporous substrat:e 512a, an intermediate rate controI membrane 512c and ~ a 1ower support sllbstrate~512d.~ With this construction, when : ~the ~de~ice is in: a~ fluid discharge~ mode, fluid which is contained within chambers~21~ (Figure 15)~, ~such as a diluent ~containing~::the additive~(the;::~beneficial:agent) is initially orced:b~:~he:stored energy:~means through channels 514 pro~ided in a pair~of~upstanding`protuberances 516 formed:on base mem~er:

pre~iously discu~ssed, by controlling:the area of the :manifolds,~the character`~of~the uppe~most~layers of the~flow c~ontrol means, and the area of the micro-channels, the active surfà¢e~area of the ~ate control membrane which is~exposedlto : :f:luid can: be precisely~varied in a manner to ~predictab~ly~
achie~e~the desired ~fluid flow~ rate :control.~ s be~ore, certain~regimes o~ the~ various layers of~assembly. 5:12 can: be rendered`~:hydrophilic~or hydrophobic by the:appropriate use of materials:and coat1ngs~in~a~manner, amount, area;and locatlon :weL~l~known~in the art. ~ In this way, the~wettabilLty:o:f the `assembl:y Fan be precisely~tai1Ored~as wel~l~as the initlal gas~

SUBSTITUTE`SHEET :~

W093/20863 ~ PCT/~S92/10482 ~Q U ~

venting capability o~ the system~ `
The dis~endable 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 applications no protuberance at all is required.
The stored energy means of this embodiment is also of ; the same general c~aracter as previously described and comprises a laminate assemblage 518 made up of individual ~ .
elements or membranes 520, 522, and 524. Assemblage 518 functions in much~the~sàme~way~as the earlier described, single layer distendable membranes, and uni~ormly cooperates;with base~
mèmber 501 to de~ine fluid~cham~ers or reservoirs 211 (Figure lS). However, as previously mentioned, by constructing the stored energy means from a ~composite of several disti~nct members ~or layers, the el~astic 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 1uids from~the fluid reservoir.
s indicated in Figure 18, superimposed over the base and~the~storet energy source~ is a cover 34 whlch includes a ; porous structural member 34a ~and film cover 34b. Appropriate medicant primary labels and~instruct`ion for use labels 36 are ~1~ affixed~to coYer 34. A ~ixéd~to the bottom of~base mem~er 500 i8 a~cushioning~means~or~pad~38 having adhesive on both sides.
A peel~strip~40 is connectet~to the lower~surface of pad 38~
The present embodiment also includes filling means w~hiah~ enables ~chambers~ 211 `to be ~illed with~a selec,ted injectable such as a~ parenteral liquid~ uslng a hypodermic ;syringe~and needle ~of~a~character ~wel~l known in art. ~ To~
cc~mplish~illing of~the~ch ~ ers,~base~member 501 includes the~previously mentionet ~upstanting longitudinally~extenting portion ~519 having~ a~ fluid ~passageway~ ~520~;~ extenting therethr~ugh.~ In this~latest embodiment of the invention, the open ~ent of the pa-sayeway~;is clo-ed~b. a~septum means for SlLlBSTITUTE SHEET

~ W0~3~0863 ~ 2 P~T/Us9i~10~2 ~ ~

seala~ly re~eiving 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 the passageway 520~ Passageway 520 is in communication with the fluid chambers 211 so that an appropriate parenteral fluid contained within a syringe assembly can be introduced into chambers 211 via passageway 520.
One form o~ addin~ means and additive carrier of this latest embodiment is generally designated in Figure 18 by the numeral 523. This form of the adding means comprlses an elongated, generally cylindrically~shaped assembly including a substantial cylindrical, porous substrate 523a into which an injector inlet tube 523~ is closely received. The assembly comprising substrate 523 and injector inlet tube 523b is closely receivable within longitudinally extending fluid passageway 520 formed in longitudinally extending portlon 519.
Receivable within the inlet opening of tube 523b is the previously identified needle~ septum 522 which is held in position b~ inse~t 524 which is bonded to base mem~er 50.
Disposed interme~iate septum 522 and injector inlet tube 523b is a porous flow:restrictor 525 which controllably resists the fluid which is flowing into ~he 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 controlIably regulate the residence time of the ~luid bein~ introduced into the carrier 523.
As was the case with the em~odiment of the invention shown in Figures 1 through 16, various additives, including bene~icial 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 b~ presented to the li~uid flow, separated and released and~efficiently added tG the liquid as it f ows t~oward the reservoir chambers 211.
As before, the additi~es can take the various physical forms~ previously described herein and can be removably or ,", .

SUBSTITUTE SH:~T - ~ ::

W093/20863 PCT/US92/10~2 `` T~ 2 !

releasably connected to the carrier in the many way previously `
described. Similarly, the additive can be added to the fluid introduced into the device by the various chemlcal and mechanical means prevlously described for easy removal and ~`~
recovery.
Various other forms of adding means and ~additive assemblies of the character illustrated in Figure 16 can also ~
be used with this latest embodiment. For example, a porous `
~substrate~with interoonnecting~voids, such as a crystal sponge ~425~a~`over` which various~outer coatings 425b~of one or more additives ~are laminated ~can~e used. Similarly, a solid tubul;ar~mem~er~such ~as~;memb~er ;427 (Figure 16) having an :~
internal, axially~extending~fluid passageway 427a, the inner wall of which is lined with a separation coa~1ng or surface ~ ~
active agent or intermetiate matrlx affixlng the additives such ``
; as medicaments,~drugs and~other ~eneficial agents can be used.
`Still~another ormiof~ àdditive ~assem~ly which can be used~is~ one of the character ldentified~in~Figure 16 by the numeral~;~429. Thls;assembly~comprises a cyllntrlcal~member made up of~a~multiplicity o`f~f:used~together microspheres 429a, each of~which~is~ coatet ~with ~a~ surf~ace active agent separatlon~
coating ;~upon which ~is~tèpositet ant~chemlc~`lly ~anchoret a iologicaily~active materlal~or other~ benefic;ial agent. Other forms~o~the~atditlve~means~`whlch can;~be used lnclude those shown~in F~igure 1~ and~ ltènti~fied by the~numeraLs 431, 433, ~ k;

4~35,~;4~37~ and~439.
In certaln ~applic~ ions the ~attltlve, as definet herein,~can be~tepositet~ coatet~o~r otherwls~e~removably af~fLxet in~erstitially of or ~nto a surface of the mem~rane 542 of the sto~ed~energy mqans whioh is exposet to ~he liquit.~With thi construction, t~he~flult entering chambers 2Il~will;be exposet ~ T
to~thè~ àdditive~ant~the~àdditive~will be~adtet to~he fluit~
prior to~it9~ nfu~9i0n~int0~the~P
`Adtitional~ly~in~-some~applications, the~addit~ve can~be~
removably a~fixet~to, ~pregnated wlthln or~othe ~ise~anchoret d~i~ectly~or~`intLrectly~on;~or~withln~elther~;or`both~of the-base mem~ers~ 500 and~ 50I.~ In this~ way~, the~additive can~ be ` ~ S U B ~ UT ~ S H E ~ ~
, ,"", ", W093~20863 PC~IUS9~/10~2 l~
~i ! ~ .l 1 ;~ 0 2 2 t 2S t j ;
`:'` ' ~`.
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 interstitialIy of or onto 1 :
the rata control asse~bly 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 19 through 31, another embodiment o`f the~apparatus for use-in infusing beneficial agents into a ` i patient is there illust;rated.~The device of this form of the ``~;
invention is similar in many respects to the em~odiment shown in Figures 11 throuqh 16 in that it provld~es the opportunity to add to the diluent or other parenteral f~luid~beLng introduced `~
into the device selected elements, chemical compounds and -biologically active mat~eria;ls~ such~ as`~drugs, medicaments, biological agents, or otherwise therapeutic agents ~additives). `--However, in this latest fonn of the invention iselected additives are removably affixed to various;for~s of support structures~ which are, in~ turn, contained within a no~el `~;i`
~additive subassem~ly that can;be inserted into~the~device in a manner~to place the additives~ within the path of the fIuid flowing through the device.~ In this way, the~additives, such as ~drugs,~ can remain~sealed~ in the~ prepackaged~additive su~assembly, which preferably~comprises~ a glass~vial, until sùch t`ime;~as;the subassembly~is interconnected with the base of t~he~apparàtus and diluent~flow through~thc~subassembly is commenced~
Because the basic structure of the device in this lateistlform o~l thè~invention is similar in many reSpects!to ~ ;
that previously described herein, like numbe~s are used to identify~like components.
As best seen by;referring to Figure l9,~th ~apparatus~
c~omprises~a~base made;~up~of;a;;first, generally planar member 600 and a second companion~member 6Q1. Member 600 includes a palr ~f`a longitudinally~extending fluid f~low~manlfolds 6~02 and ~6Q4`~which~ communicate~ with a trans~e~sely extending fluid SU B STITUTE ~S H E ET

: W093t208~3 1~ ~ ~ 2 2 PCT/US92t10~2 ~
i 30 ~ ~ : !'' .`"```''.
transfer passageway 606;.~ Passageway 606 is, in turn, connected -.. ~' with a fluid outlet 608 which is in communication with a fluid 1 `".' .
dispensLng means shown here as including a f.luid dispensing ;'` ' port 610:~Figure 20).
: First base member.60~0 is aLso provided with a pair of .
l;ongitùdinally extending~flow~passa~eways~61} the purpose for whic~h will presently~be~-tescribed. Passageways~611 communicate :; .`-.
;with~a~;:pair~.o~transverse:;c~hannèls~:612:(Flgure~l9:). Channels ''.;.~
~612~ in~'`turn',~ com unicate~wit~h~reservolr~ n~let~port~s 613 of : ~ ''.-';'`' base.~member~`601 whl`ch.are~o~f`~.t~e~character~be:st:~seen in:Figure:~

Rese~voir~ ou~ èt`` pasaageways ~ or;" ~luid ~flowing outwàrdly~ from ~thè~;r~èserv r ~ e~pr ed~:in;~`the~'fo ;of longitudinàlly:extending~flow~channel 614'~:provided:in a pair of :~
:protuberances~616~which.`are~;integrally~formed~with'base member~
:60~'1..~''':;Channels 614,~in~'~.'tù'rn,~cà~unicate~:with'~microchannels 617 o`f~:~mànLf:olds~602~and~60:4`via' ~contro;l~:~means~,~:show ~`herè:as~
me ~ranè`a~`e~ lie 6-1 (F é~`48) which~.are~superimposed o r~
man f lds~6~a~ a ~604~.an ~mi ro-chan els ~6~1~7~ n~the manner~
s ~ n~.:in~figure~19~and 2~2.:~A~semb1ies~618:~co~ r se a mic'ro ~ ' 8 ~.1 er~6~18a~`n ~ 'wer~'supp`rt~:layer;6~18b~ With~
;this~con~s'tructl'on,~ whe~n~:t~é'~device:~i~s~:`;''n~

s~ch, ~ ~ ~ad~ivo ~the annèls;'~6~ ~ed:in ups:t n ng:~ tuber 1- 6~ ~ flow~contrl àssembli~os~618 and~
:into manifolds `602~:and~ 6~04~ `After .pas~sin~g.~:~through the:~flow~ Z~
rato~ ~ rol`'means~ f ial~ ` ``t~ S ~ hrough !t~h ;`'~

W~ 93/2fl8s~3 Prr/US9~/10~2 ~, ` ` `

previously described and comprises a laminate assemblage 622 made up of at least two individual elements or membranes. As be~ore, assemblage 622 cooperates with base membSer 601 to define the fluid chambexs or reservoirs 620 tFigure 22).
~ s indicated in Figure 19, superimposed over the base and the stored energy source is a structural cover 34 OI the character previously described having appropriate medicant and medicant use instruction lahSels 36. A~fixed to the bottom of base me7nber 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 present embodiment includes fillins~ means which enables chambers 6~0 to be filled with a selected parénteral liquid. Here the filling means includes a hypodermic syringe and needle of the char~cter identified in Figure 29 by the numeral 62.
As best saen in Figures 19 and 20, base member 601 includes an upstanding, longitudinally extending portion 626 having generally cylindrical chamher 62B~extending therethrough (Figure 28). In this embodiment of the invention, chambs-r 628 is uniq5uely desisSyned to closely receive~ the additive subassembly that sealably contains the additive to be added to the parenteral fluid.
~ ~ ; ; Refexring to Figure 23, this unique immobilized adding : means or additive subassembly comprises a glass tube or vial ; 630 which is sealed at e~ither end by sealing means shown here as rubber stoppers 632 and 633. Stopper 632 is adapted to sealabIy receiye a Ipiercing element such as~the hypodermic~
naedle 62a of syrinqe assembly 62. (Figures 23 and 24). The ~rubber~stoppers 632 and 633~are preferably constructed of a aclf-sea~ing, noncoring, puncturable material such as silicone~
SE~S. Tear~o:pen type aluminum sealing caps 637 are provided at ~each end o~ tube 630 and ~unction~to sealably encapsulate rubber stoppers 632 and 633. ~
Sealing caps 637 compr`ise an aluminum~sleeve portion SUBS~ITUTE:~SI IEET

W093t20~63 pcT/uss2/ln4s2~
0 2 2 ! i ;
, . . . .

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. ~isposed interiorly of tube 630 is a substrate 640 which releasably carries the additive sueh as a beneficial agent of the character earlier defined herein (Figures 23, 26, and 27).
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 16 and identified by the numerals 425, 427, 429, 430, 433, 437, and 439. As indicated in Figure 31, 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 ri~s may~ not be required when~substrates of certain character are used.
Turning particularly to Figure 30, it can be seen that a uniquèly configured needle 642 is integrally molded into base ;member 601. Needle ~4~ 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 65:0 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 st~pper 633 in a manner shown in Figure 59. Passageway 646 is in commiunication at one of its ends with a pas:sageway 648 of the~base member 601 and at:its opposite end communicates with outlet passageway 608 ~o~ base member 601.
In using the apparatus of the embodiment of the invention shown in Figures l9~through 30, sealing caps 637:are opened in the manner shown in Figures 23 and 27 to ex~ose ~he sitei~in~ection portion of the ru~ber: stoppers. The adding means, or glass ~ial 630 is then inserted into chamber 628 and urged~orwardly with sufficient forc~ t:o cause~ neetle 642a to penetrate rubber stopper 633 in the manner shown in Figures 28 and 3~. As~best seen in Figuxe 28, vial locking m~ans, here shown as detents 651,~are provided at elther end: of ch ~ er 628. These detents permit passage~of vi 1 ~630 in an inward direction but function to lock the vial in;plac~e to prevent its SUBSTITUTE SHEET

~093/20863 PCT/US92/10~

33 i ~`
withdrawal from the cham~er. ~ ';``
With the vial` lo~k~d in place within chamber 628, ! "
rubber stopper 632 is pier~-ed by needle 62 of the needle ! ```-syringe and the sterlle diluent is introduced into the interior passageway 640a of substrate 640. As indicated by the arrows in Figures 20 and 30, as the diluent flows longitudinally of the additive presentation means, or substrate 640, it efficiently intermixes with ~the additive carried by the ~^
substrate. The mixture thus formed flows through passageway 644 of needle 642, Lnto pàssageway 650 (Figure 30), through `
passageways`611 and S12 (Figure 20) and then into cham~ers 620 ;
via ports 613. This fluid f;low urges membranes 622 outwardly `;~
into the position shown in Figure 22 in close proximity with interior walls 653 of porous ~ody 655. `~
As before, the liquidt such as a parenteral flùid, which is introduced into passageway 640a can include, by way of ;
example, a reaqent, a sterile diluent, various electrolytes and ;
various other aqueous solutions.
~fter the additive carried by substrate 640 has been i ;
separate and rel~,ased by the parenteral fluid and has been i ~;
efficlently intermixed therewith, the solution or bene~icia1 agent thus formed will remain within reservoirs~620 until the time it is to be infused into the patient. When the outlet ~port 610 i9 opened for fluid ~flow to the patient, the fluid contained within chambers~ 620 will flow downwardly through channels 614 in protuberances 616, (Figure 21), through the flow rate con~rol membranes 618 and into crossing microchannels 617. ~ As;best seen in Figure 19 manifo1ds 602 and~ 604 communicate with transverse manifold passageways 606 which, in turn, lare in ~ommunlc~ation with the fluld outlet port 610l of the device. A hydrophilic porous flow filter 659 is disposed ~`
proxLmate ~the outlet end of su~strate~ 640 (~Figure 26) ~for ~:
filtering and controlling the residence time of the fluid within the substrate 640.
It is to be ~appreciated that~ a wide variety of atditives,~such as drugs and the like, can be removably a~fixed to substrates of widely varying ~material comFosition and ~ `

.;'-~

~: : SUB~TITUTE SHEET ` ~ ~;

W0~3/~0863 PCT/US9i/10~2 ~
~.~,. . .

:34 design. The substrates can then be safely sealably contained , :, within the sealed glass vial of the additive subassem~ly for i: ' use at any later time with stored energy infusion devices of . `~ :the character shown in Figure~ l~. 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 patlent. :
Turning now ~t~o~:Flqures 32~through 35, stlll another ".,,' ~::embodiment: of the appar.atus`~ or use in infusing beneficial '.,'.':
~agents~into.a:patient~is the~re~illustràted.:~The~devlce of this '`"~
form~of~the invention~ls~similar~in:many~re5pects~to the:device : ,v-~
shown~;in~ Fi,gures ll'thr`ough~`1`6 ;and;~like ~num~e~rs~`are~ u~sed to Ldentify~::like:~components.~ As~before ~seIected~adtitives are removably affixed to various~ forms of iadditive~pr~e~sentation ''~`~
means such as substrates, matrices and scaffolds~which can be placed within::the path;~of~the~fluid flowing~through~ithe~device so~that~upon:contact witb~ the ~f~luidr ~the additive~s~are released ;~
at~a~co~ntrolled~;r`ate to the'`fluid.~
:As: best seen by re:ferring to Figure 32, the apparatus comprises,a base~made~of'~a~fi:rst, generally~:~planar member~700 and~:a~: se¢,ond~companion~:~ mem~er~companion :member 701 which~
includès a pair ~of~longitudlnally~ext'ending flow'canduits:or.:~
channels~702;~ and~70.4,~wh~ich~communicate:~wit~h~:a~:transversely~
extending:~fluid ~transfer`:manifold conduit`~:7~06~(Flgure :33).:
Co`nduit'~;706~ s,~:in .turn`,.~co''nected~wLth~a~ f~uid.di`penslng m~:ans ~ s;h~n~ here~ as ~ including~ ~ a~ fluid~dispensing port~710 irst:~base~m'm~ ~70~0 ~;is: also pro idqd~ th:~a pair of :~
lon tudinàlly~:extend' n'folds~711~which~co nicat'~with~
micro-channels~:7l2 ~(Figure~ 34). Manifolds 711 and micro~
chan~,ls~ 71~2~communic'ate with`~conduits~7`02~a'nd~7104~:via~fl1~ow' ~r~

rol ~e~ns ~ here provided~
as~a~t:hin,.multil ~ -`or,gradia ed~a:s~ 'y;212:~(seé~
2)~.which~is~superimposed~ ver~,'nifolds~.71~ and~mic~o-ch~a nel :712~in~the~manner~'~:s ~ n ~n;~:F ~ re 32~ A e~ 1~:2l2:is~of~th'`~
s~a e:const~ruction~and operà~:e~si~in~th~:;s ~e~manner~as pre~i~ousl'~

SUeSTlTUll~SHEET~

W093/~0863 r~ jlr~D22 pcT/ussi/ln~2 described. When the device is in a fluid discharge mode, fluid which is contained within chamber 211 (Figure 34) such as an elution bu~fer, diluent, or solvent containing the additive ~the beneficial agent~ is initially forced by the stored energy means through channels 714 in a pair of upstanding protuberances 716 formed on base member 701.` As the liquid passes thxough 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 angagement means, shown here as protuberances 716 (Figure 32) per~orm the same function as previously described~ It is ~o be understood that in some applications only a single protuberance is provided and in other applications no protuberance at all is require~d.
The stored energy means of this embodiment is of the same general character previously described and comprises an elastomeric distendable membrane 717. The membrane or membrane a~sembly is provided in the same manner as previously described herein.
As indicated in Figure 32, superimposed over the base and the stored energy souxce is a structural cover 34 of the character previously described having appropriate medicant and use labels 36. Affixed to the bottom of the base memher 700 is a cushioning means or pad 38 having adhesive on both sides. A
;p~el strip 40 is connected to the lower surface of pad 38. For certain applications, a thin protecti~e film may be affixed o~ex ~cover 34 to prevent ingress of }iqu;ids or other contaminants into the device.
Like the previously described embodLments of the invention, the present embodLment includes filling means whlich`
enables chambers 211 to be filled with a selected parenter~al liquid such ~s a buffer, a detergent, a solvent, a diluent or other elu~ing agents-. To accomplish filling of the chamber, base member 701 includes an upstanding t~ransversely extending portion 718 having a fluid passageway 720 ex~ending therethrou~hO In this~embodiment o~ the invention, the open ~end 720a~of passageway~720 is closed by a novel filling-check-SUBSTITUTE SHEET
~;

W~93~0863 PCT/US92'/10~2~
21~ d~ , ` ``` i` ~`~ ``~`~ `
`` I `~"
36 .: ~;`-.. :;
valve means for controlling the flow of fluid into passageway .` "
720, which here comprises a check valve housing 722, a check "~
valva 724 and a safety luer cap 726 for interconnection wi~h a .
standard luer fitting. As best seen in Figure 35, the filling- .
check valve means is receivable:within an enlarged diameter portion ~728a of a structural support 720 which is closely `'"::~
receiva~le within portion 718. ; ~
~As best see:n by referring~to Figure 34, passageway 720 ~
is in communication~with~longitudinally~;extending channels 702 '':'.`'`
a~nd 704.~ :As be:fore, channel~ 702 ~and ~7~04~are, :in turn, in : ~'.. :`
:communieation with chambers~211~.~ With~this~c~onst~uction, an ~ ~'x'~;~
~appropriate i:n~jectable suc~h~as~a diluent or~;parenteral fluid or other elution agent, as-indicated~by the~:flow.~arrows, càn be introduced into chambers 211 via luer cap 726 a~nd passageway :~ i~.`''"
720. IAS the parenteral fluid enters the:check:valve housing .:;~;.~'i'~'.
722, check valve:724 WL~ be~mo`ved away from sëat~7~22a (to~the : right~as~'viewed in~Figure 3~5)~to permit fluid flow~inwardly of ;~
passageway~720. When~the chambers are::filled, the ~uildup of back~pres~sure~ will cause~the; check valve~ to;return to: the~
:¢losed~positlon shown in~Figure~:35.
'The~:adding` me~ans.~;o~ the~inventio~n can take~ several~
dlf~ferent~:forms as, ~for~éxample, the~cylindrically shaped,~
'fu~ncti'onal~: support structurè~ 730 which~ is~ inserted~:into pas~sageway~ 7~20 and to~ which~ various additives,~ including ;~
bene~icial agents such as drugs,~biologically:active materials,~
and~chemic'al:` element;s`~and~ ~compounds~ can be`-:;releasably~
conne~ted~.~ The~adding~means;'~;ean`also be of the character shown ini Figure':l9 wherein~ th~e~additive i5 encaps:ulated ~within:~a~
sealed~contaLner.
In~the~pflormiof~:the~invention shown in Figuré ~32, the`':~
;liquid~medium flows~around,;~about and~through:the~substrate~
9upport~ :In~lthe~form of`~thel~invention~shown~in Figure 19~,~t~he liqùid~ m~dium:~can-~bè-sea~lably~contained~wlt~hin~the container~
1 630`~and~ may ~:inclùde'~'-matrices~:;sultable~:.f:or affinity-based~
separation;sùch~as'~a syn he ;~s p t,~ a~ ead~matrix:materlal~
`together~'wlth~`a~suitable'~storage~buff`er~or a~gel.::~The detalls~
~o,:ehese~matrLce- will ~e~describ-d more ~fDl~y b-r-inaft~

SU~STIllJTE~SH~EET

W093/2~863 ~c~ 2 PCT/US92/1048 The additives can take various forms and, as previously mentioned, can be removably af~lxed to the functional support means in various ways to enable the use of separation techniques broadly defined by the term chromotography.
Chromotography as used herein reers to a 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 o~ the invention, the additive presenta~ion means assumes the character of an affinity chromotography 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 immobilized on a so}id phasP ~ while the other, the counterligand (most often a protein), is absorbed from the extract that is passing the substrate during the manufacturing pr~ce~g:s. Importantly, affinity chromotography tech~iques can include the u~e of highly ~versatile azlactone functional compounds, such as azlactone functional beads, a well as the u3e of a wide variety o~ other media for a~tivation and coupl~ing chemistry~ Examples of ligands that can be attached to the~afinity supports include antibodies, enzymes, lectins,~
nucleic~acids, hor~ones and vi~amins. Exæmples of important~ `
counterligands include~an~igens, ~irus,~cells, cell surface ~receptors and the ~like. ~ Chromotography and affinity~
chromotography technique~s;are descxibed in detail in ~Protein~
Purification by Janson~and Ryden, Copyright 1989 and reference ;l should be made to this work ko provide a working understanding of the techniques.
Polymeric az~actoneæ are well known in~the~prior;art.
Their use in the~production of homopolymers and copol~mers~has been~desc~ibed in a~number of patents. See for example, U.S.
Patent No. 3,488,327 ~(is~ued Jan. 6,~ 1970 to F. Kollinsky et al.); U.S. Patent No. 3,583,950 (issued Janu~ary 8, 1971~to F.
Kollinsky et al.?; U.S.~Patent No. 4,304,705 (issued December ! .`~.
:
SUBSTITUTE 5~ET : ~ "

WO9:3/20863 2~ 022 PCI`/US9~/1048~

3 8 ~ ` ` . :; " `
8, 1981 to S.M. Heilmann et alO); 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, Coleman, et al.
Azlactones, or oxazolones, are cyclic anhydrides of N- i -acylamino acids and have been used extensively in organic ~ `
synthesis. The formation of a five-membered azlactone o' particuIarly useful functionality for immobilization purposes `- ;`
can be accomplished through the reaction of a carboxylate group with a-methyI alanine usinq a two-step process ~See Immobillzed ;~
Affinitv Liqand Techniques - Hermanson, Mallia_and Smith, CopYriqht 1992.~ One method of formin~ azlactone 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 azlactone ring is formed in anhydrous conditions through the use of a cyclization cata}yst. Suitablé cycli~ation agents that~will drive this reaction include acetic;anhydride, alkyl ~chloroformates, and carbondiimides. The process~of forming these~active groups and~of making beaded polymeric sùpports containing~them has been thoroughly described in patents assigned to 3M Corporation (U.S. Patent No. 4,871,824 and 4,737,560). Th~se support materials are now~a~ailable under the tradename "Emphase". U~.S. Patent Nos. 5,045,615 and ` 5,013,795 which have been ~assignèd to 3M C~orporation al50 describe recent advances in this technology.
As pointad out in the 3M Corp~oration Patent ~o.
4,737,560, azlactone-functional polymer beads are useful reactive~supports for the attachment of functional materials to pro~ide novel adduct beads. The adduct beads are useful as complexing agents, ¢atalysts, reagents,land as enzyme or other l-protein-bearing supports. The term "support"~or "affini~y support" as used in this sense is usually understood to~refer~
to ~a combination of;~ a ligand ~usually of some known molecular configuration), that is firmly attached (e.g., mmo~ilized)~, often by covalent means, ~and~(2)~ a matrix ~ Y
~usually a solid insoluble s~ubstance).~ ~ Azlactone support matrix ~materials and coupling chemistry is also of special SUBSTITUT~ SHEET .; .

W093/~0863 PCT/US92ilO~2 ~j ;
i~ 2 2 ~: ;

.
interest because of its accessible matrix surface area and effetive Iigand diversity that can be attached to that surface.
U.S. Patent No. 4,072,566 issued to Lynn on February 7, 1978, and entitled "Immobilized Bioloqically Active Proteins" discloses a method o~ bonding enzymes or other biologically active proteins~to an inorganic support material using p-phenylenediamine. The support materials disclosed as usefùl in the invention include siliceous materials, stannic oxide, titania, manganese dioxide~, and zirconia.
The functional support structure 730 of the present embodiment of the invention is uniquely constructed to permit the bonding thereto of en~ymes or other biolo~ically active proteins. 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 a~lactone functlonal compounds. In this way complexing agents, catalysts and biological materials such as~`enzymes, 'proteins, or other affinity absorbants, as well as biomacromolecules can be attached to the carr:Qr for later removaI and recovery~
When~bonding certain biologically active~proteins and other~macro molecules, the use~of spacer arms or leashes have be~n ound to be very beneficial~ Spacer arms or leashes are low-molecular~weight molecules~that are~used a~s intermediary linkers b`etween a~ support ~material and an affinity ligand.
Usual`ly spacers consist ~of linear hydrocarbon chains with unctionalities on both~endo~for~each coupling~to the support and ligand. First, one end of the spacer is attached chemically `; ~ to the~altrix ushng`t~aditional immobiliz~tion chëmlstries; the' other ~end is connected subs~equently to thF~ and; usi.ng a seconda~ry~ ooupling procedure.~ `~The result is~an immobilized ligand that sticks out;~from the matrix backbone by a distance ~equal to the length o~ the spacer arm chosen.
Referring to Figures~32A, 32B, 32C,~and~32D the use of space~arms to bond proteins and en ymes to the substrate is there schematically illustratedO~ The princi;pal ad~antage in 5lJBST!TUTE 5HEET

W093/20863 2 1 1 3 ~ 2 2 PCT/US92/1~2 ~

1 . i .~..
using a spacer arm is that it provides li~and accessibility to the binding site of a target molecule. When the target molecule is a protein with a biding site somewhat beneat~ its outer surface, a spacer is essential to extend the ligand out far enough from the matrix to allow interaction. As indicated in Figure 32A, 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 material 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 o~ the protein molecule (lower portion of Figure 32A). The details concerning use of spacer arms are fully set .forth in Section 3.1.1 of the previously referred to work entitled I~mobili~ed A~initY Liqand Techniques. This Section 3~1.1 is incorporated herein ~y reference.
Turning now to Figures 32A, 32B, 32C,:and 32D, it is to be noted that immobilized Protein A can be used to immobilize an antibody molecule by taken advantage of the natural affinity of protein A for immunoglobulins.; Incubation of a specific antibody with a protein A matrix will bind the antibody in the Fc region, away from the antigen biding sites.
Subsequent cross-linking of this complex with DMP (dimethyl pimelimidate) yields a covalently attached antibody wi~th the antigen binding sites facing outward and free to interact with antigen.
With rigid support materials, a spacler moleculelmay 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 ovement po~sible within the polymeric back~one of a matrix.
The choice of spacer molecule can affect the relative hydrophilicity of thé immediate environment of an Lmmobilized ~ . ';'.!.
~ ~ '" "' ~ '~
SUBSTITUTE SHEET ~- :

W093/20863 PCr/US92ilO482 41 1 "
ligand. Molecules containing long hydrocarbon chains may increase the potential or nonspecific hydrophobic` I "
interactions, especially when the affinity ligand is small~and i ~ ~`
o~ low molecular weight. Selecting spacers that have more 1 `~
polar constituents, such as secondary amines, amide linkages, ~ `;
ether groups or hydroxyls will help keep hydrophobic effects to ` ~
a minimum. ~.. `
It is also important to consider the ionic efects a spacer molecule may impart to a gel. Spacers with terminal primary~amine groups should~e completely coupled with ligand or blocked by~a nonrele~vant molecule (e.g.,~acetic anhydride;
see Section 3.1.1.9 of Immobilized A~finitv Liqand Techniques) ` m`
to eliminate the potential~or`creating `a positive charge on `
the support. With small ligands, these residual charges can form a secondary environment that may cause considerable nonspeci~ic interactions with proteins. The same holds true for~spacers with terminal~carboxylic groups.~ In; general, a negatively charge~ spacer will cause less nonspecific protein i;`
binding than a positively~charged one, but blocking excess ~ ;~
r~màining groups is still à~good~idea. A~good blocking agent for use with~carboxylic~residues is ethanolamine, which laves~
a terminal hydroxyl group (Sec~ Immo~Lized Affinitv Liqand Techniques for a ~omplete discusslon of typcs of spaccrs;and various lmmobilization and coupling protocols.) Another wcrk with fu1ly~;describcs altcrnate~forms of protein~ immobiIi2ation~ls~Protein Purific_tion, Janeon and Ryden, Copyright 1989.~ As pointcd out in;this~work at ~Page Ligand~protein interaction is~ often`~based! on! a combination o~ electrostatic, hydrophobic and ~hydrogen bonds.~ Agents which wcakcn~such~intcractions~mlght~ bc expected to function as~ effective non-specific eluants."

: This~ work provides~ a~`further teaching of~the techniques : d e ~ c r i b e d h e x e i n .
It is lmport~ant to~ rccognize that, as uscd in; the SUSSTITUTE:SHE~ET ~

W093/20863 ?, PCI'/IS92ilO482 present ~orm of the invention, affinity supports are capable of¦ '`
total ~inding capacity of a magnitude that enables attachment1 1 , to the support of additives in substantial amounts ~for subsequent release, recovery and infusion of such beneficial , ~'~
agents at a level which can be therapeutically e~ficatious~
Turning now to Figure 36, yet another form of the ~`
apparatus of the invention is there shown. The device of this ''' ~orm of the invention is similar in many respects to the ' ~`
embodiment shown in Figure 19 save that the distendable ~';
membrane is a single elastomeric sheet 717. However, as will become apparent, fluid flowing through the device is totally ','~
different. 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 `'~'`
additive subassembly that can be inserted into the outlet port o~ th~ device in a manner to place the additives within the '',`, path of the elution fluid flowing outwardly of the device from` '`~, the ~luid 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 has been `''' precharged with an elution buffer, aqueous diluent, solvent or. ",~
other paren~eràl liquid. In~other words, unlike the previously` ,`"-' described em~odiments in which the additive is mixed with the fluid medium during the filling step, here the additive is ~`', mixed with the elution fluid as the fluid flows from the prefilled or precharged reservoirs of the device. , , As best seen by referring to Figure 36, the apparatus compxises a base made up of a ~irst, generally planar member I ,~
~i 800 iand a second companion member 801. Member 800 includes a pair of a longitudin~lly extending ~low channels 802 and 804 which communicate with a transv~rsely extending ~luid transfer~-'-;,~,' ; pa~sageway 806. Pa~sageway 806 is, in turn, connected with a ¦
fluid inlet 808 (Figure 40)~ which is in communication with a fluid charging or filling m~ans~shown here as a syringe I ~';;"
assembly 810 which includes a blunt cannula 812. ', ,',' Reservoir outlet passageways for fluid flowing ~, '~
,, . ~, - ;.
SUBSTITUTE SHEET

093/2n863 ~ 0 2 2 PCT/US9~il0~2 outwardly from the reservoir are provided in the form of ~ `
longitudinally 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 t `~
central passageway 818 (Figure 40) 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 re3ervoirs of the device and the interior of the additive subassembly shown in Figure 38 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 832~
are joined together by a gummed medicament label 834. The fluid inJet end of glass vial 830 is provided with external threads fl36 while the outlet ènd of the vial is open to receive ~ , .
the skirt portion 83~ o~ a luer fitting 840. Skirt portion 838 i9 maintaLned in position~within the outlet end of vial 83 by an aluminum crimp seal 842,~ the circumfèrentlally extending edge 842a thereof being adapted to be crimped over into a circumferentia} groove 831 provided in~glass vial 830. An O
ring seal 843 surrounds~skirt~838~ and abuts the~edge of the glass vial to pre~ent~leakage~between~the~ vial and the luer f~itt~ing~ Structure 850~also~sealably cloBe6 the lumen 864.
The outlet portion 832b of shell~;832 is provided with a xeduced diameter~portion~84~ that ~defines an~ internal shoulder B46 that abuts crimp~ seal 842. ~Reduced diameter portionl844 1s~ provIded with a circumferentially ëxtending ~score~ line 846 that permits the outer, cap-like ~end 850 of porti~n 844; to be~removed at~the time~of use of the additive su~asse~ ly 827 to expose~luer~fittin~ 840. ~A tear-o~f cap 852 ;;is~al~so~proYided at the inlet end of the~additive~subassembly.
When ~this cap is~removed, the~thread;s~836;~of vial 830 are ;exposed.~ Cap 852 also~functions ~to sealably~close inlet~
p~s-~geway 853.

; SUBSTITUTE SH EET~

~093/~0863 PCT/US9i/10~2 ~r~ l 2i2 j 1~

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 rom any suitable porous material such as ceramic, glass, PTFE, carbon or other inert material and ~`
functions to controllable resist and precisely regulate fluid flow from the fluid reservoirs of thè device toward the additive support or functional substrate. An elastomeric ring ;;
seal 857 is interposed between plug 854 and a shoulder 85B
defined interiorly of vial 830 to prevent leakage between the plug and the shoulder.
The additive support or matrix, here identlfled by the `;
numeral 860, is closely received within vial 830 and abuts plug ```~
854 in the manner shown in Fi~ure 68. As before, support 860 `
can be of various constructions as previously~ described, including azlactone beads and distal porous glass frit~ ``
containment means. Support 860 removably carries selected additives, such as the beneficial agents previously described~ ~-7-herein. A centrally disposed fluid flow channel 862 is ~ ;
provided in support 860 and is adapted to communicate with the ~ ' ~luid ~outlet passageway 864 of the dispensing~ means, or luer itting assemb1y 840.
The distendable membrane engagement means or protuberances 816 perform the ~same function as previously dqscribed as does the unique~stored energy means. The stored energy~means, or elastomeric member 717, of this embodiment is of the~ general character-previou91y describcd in connection with the embodLment of Figure 1 and cooperates with base member 3O1I to def ine~the fluid chambers or reservoirs'of the device;~
The stored energy means~can also be of a laminate construction of the character prevLou~ly described herein~
As indicated in Figure 36, superlmposed over the base and stored energy source 24 is a structural cover 34 o~ the~ ~
character p~è~iously described. Affixed to~the bottom of base~ ' -mcmber 800~is a cushionlng means or pad;38~having adhesive on~
both~sidcs. A peel strip 40 is connected to the~lower surface~

SUBSTITUT SH~E~

S W093/20863 ~ 022 PCTJUS92/iO~2 ~`
. . . ~ . .
.

of pad 38. : .
Turning now to Figures 36 and 40, base meim~er 801 includes an upstanding, longitudinally extending portion 865 having a generally cylindrical chamber 867 extendin~
therethrough. In this embodiment of the invention, chamber 867 ~.
is uniquely designed to closely receive the additive subassem~ly 827 that sealably contains the additive to bie added ;:
.
to the elution fluid ~flowing from the~ fluid reservoirs .
outwardly of the device. At the inlet end of cham~er 867 there is provided a septum housing 868 adapted to support an elastomeric septum 870 which is accessible by cannula 812 of the fil1ing syringe via an opening 871. When cannula 812 :
pierces septum 870, fluid will:be permitted to ~low from the ~`
syringe into passageway 808 and thence to the fluid reservoirs ` -in the manner indicated by the arrows 873 of Figure 36 via channels 873 and inlet ports 87S. ;As the:~luid flows through ports 87~, di~t~endable membrane 24 will be~ urged into its~
distended:configuxation in the manner previously discussed.
As the reservoirs are charged, fluidi will flow downwardly though channeIs 814 in protuberances 816 an~ into j;` ~.
passagewa~ 818 as indicated:by the arrows 877 of Figure 36.
This fluid~und~r pressure will urge check~valve 822 into its:
clos;ed~:poæition with shoul~exs 822a in sealing engagement with eats~87~ ~Figure 4~ With the check v~l~e 822:in the closed position~, fluit cannot flow toward cylindrically~shaped chamber 867~of:~base membe~r 801.
;In using the~apparatus~ of the embodlment ~of the~
nvention: shown in Figures 36,~ 38, 39, 41 and:42, sealing caps~
~50 and 852 are r~moved to expose the luer:fitting 840 and the thre~aded end o~ g}aiss vial 830b of the~add~itive:subasse~bly~
827. ` The ad~itive ~sukassembly 827 is then inserted:inito:
. 1 ....
cham~er:867 so that~:th:reads 836: engage:mating;~hreads 881 of~
portion~865. Rotation~of the vial will~then cause stem 824:of~
ch~ck~:valve~ 822` to:;:move;~the check valve::from the ~elosed~
poslt~io~n shown in Figure 4~ to the:open~ position shown~ln Figure~40.:~As:the;~ial is rotated relative to portion:~865~o:f base~:801~ locking tabs~883:~provlded on~the vial ~su~assembly~

: SU B S:l ITUTE: S:H ~ ET:

W093/20863 PCT/US92/10~2 h.`.`':;' `
2 2 ~ ~ ` :::
i'-.``, ~, ..`
46 !
(Figure 38) engage resiliently de~ormable tabs 8~5 provided internally of chamber 867 tsee Figure 41). Tabs 885 are designed to permit rotation of the vial subassembly in one ~ ` -direction but to bloc~ rotation in the opposite direction.
With this construction, once the vial assembly has been interconnected with the base assembly, it cannot be removed.
With the vial assembly 8~7 locked in place within ~ `
chamber 867, and the check valve open, the sterile diluent is `~
urged from the reservoirs by the distendabIe membrane 717 and ```~`-`
introduced into check valve housing 820 via channels 814, 816 and 818. The diluent~ then flows controllably through the porous plug ~54 and longitudinally of the additivè presentation ~
means, or substrat~ 860 where it efficiently intermixes with ~`
the additive carried by the substrate. The mixture thus formed flows through passageway 862 into passageway ~64 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 appropriate selection of this assembly, this feature allows for individual control of the rate of dosing of the beneficial agent into the elution diluent independent of the rate of fIow o the elution diluent.`
The manual facility to individually control, through ;p~oper assembly selection, the delivery of ~oth drug dosing ;~
rate and diluent dispensing rate, over a given time period, is ~ `
a desireable feature. In practice, alternative vial cartridges (827 - Figure 36) can be provided which control fluid flow rate i `
at al~iven level and also additive release rates at a desired~l ;
predetermined leveI. This capacity can insuxe delivery of a ~`;`
required dosage within a therapeutically acceptable time pe~iod~
~ver a broad range of fluid flow rates. t ,', ;Additionally, the control of dosage~rates can~also help prevent over-concentr~tion of an administered drug~which can j result in patient local or systemic toxicity.
Selection of an ~appropriate vial containing the SUBSTITUTE SHEET :

~VOg3/20863 ~ PCTIUS92ilO~2 ~ `
(3 2 2 "; `:
~, ` ` ' ` ! ~ . .
47 ` 1 ~ `
"
predetermined extended release over-time type additives combined wlth an appropriate preselectèd flow rate control ¦ r :~
format over a wide range o~ delivery protocols can facili~tate ! ````:~
the expanded ambulatory:~delivery opportunities- o~ various , .;~therapeutic agents. New delivery protocols can also be '~
~e~stablished for pharmaceutical agent ~delivery modes and i , adminis:tration regimes.~
The extended~`release~additives can comprLse bounded ''~,'' proteins or other absor~ant:s~which: can be~ attached to and ,`~eluded~:from~:~he~matri~oYer,:time~;ln~a~varléty~of~ ways we~l ~ , .~!., known to~those skillèd~in:the~:art.
The~rate:~control~`means~ is ~here: shown~ at both the , :~
proximal~end~of`the`vlal`(~854~ and`at~the~d~lst:al~end~of the~
vial (855). ; However,~the rate~contro~l~means can~be locateq~
proximate either end~of`the:Yial::for selected:rate control, : : ~.'.~.'.
filterLng~and'elut-nt reaiden~e"tLme~ln~the vial.
m~Referring t:o`Figure~::'3:7~'ànother~orm:of,the invention,:~
s ~ llar~to~thàt just dèscrlbèd is~sh n.~This;~devlae operates~
in~basically~;the~:same,way~as:'t,he,device~of:Flgure~36 save~:that ill;Lng`~;i:s~ accomplished~through~ à::side inlet` port:8`90 rather~ 'thàn:an~,'`end~inlet~port:::~of`the:~character, shown~in Fl re~36.
The :~vial~subassemb}y,~82~7~.is~ identical~to~t~hat~ previously desc~ribed,~and~fluid i~ ur,ged~`~9r`~om:~the~reservoir9~by:~dlstendable:~
membra:nq:7~17,~:and:~`flows~outwar`dly-of thé~device:through the vial `~
subas's ~ 'ly.~; The;~baae'~me `~89Z of the~de 'ce~ls~of sl' htly ;~
d~ fer~ construction,;~h ~ g,langularLy;~inclin d~flow:channels~
,89:,'4`,'.:whic ~`~re eive~`the~`;dil nt~ f`low ng:~fro ~:the: `eservoirs;~through~chànnéls~896 fo ~ d in protuberances~`~:89;7.~ ~Fllllng~of;`
:the reservoIrs is acc~omp:lished~by a filling means which urges fl~uid~lf'l!ow'~into, porb~.'890~``and into the reservoirs'vila inile~
:ports~ 89;8~.~ The~:~arrow ~ o~ Figure 37;~clea~1y~;dep1ct:~:th '~
dirèc ~ on o'f~fluid~fl'ow`'~lnto~and~out of~the~dey ~e.~
'`` Ref,erring to:~ ~ re9`~43~through~;49:,~'ano r~f~o ~of~th de~i'ce~`o;f~ t,he:~inventlon~'s:~ here~shown.~ Th's~de i~e~ is~ver .,~
sl~la`r~ to~ that~ : g r ~.3 ~ t r~ gh.~35~ s :~, h ~f~ ng `~i's~acco~ L' h ;` `by~ ~us~g ~ a~ f~i ling `:;
co~yr s :a,:nov-} ~eedle ass ~ rab~cr~ an ~ b ~ua Lnq ~ the~

W~g3/20~63 PCT/US92ilO~2 ,~
- 2~ ~ 3022 luer connector assembly shown in Figure ~2.
As best seen in Figure 47, the luer cap an internal check valve assem~ly o~ the device of Figure 32 has been replaced by a septum assem~ly 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 43 through 49 to identify like components shown in Figures 32 through 35.
The injection assembly, here designated by the numeral 900, is best seen in Figure 44 and includes a check valve housing 902, a check valve 904 reciprocally movable within housiny 902 and a needle assem~ly ~06 connected to housing 9Q2.
Housing 902 includes an internal` seat 907 agalnst which a shoulder 909 nf the check valve seats when the valve is in the closed position shown in Figure 46. By referring to Figure 45, which is an end view~ of ho~sing 902, it can be seen that a plurality of circumferentially-spaced ~low channels 902a are provided in the wall of the housLng. (See also Figure 49).
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 aæ adhesive bonding. Integrally ~ormed with collar 910 is a neck portion 912 having ~ore 914 ~adapted to receive the inboard end 916 of a hollow needle 917.
Integral with neck partion 912 is a safety needle shroud 920 which~s~urrounds needle 917. Shroud 920 is ~specifical~ly configured to eliminate accidental needle sticks. Also shroud 920 is adapted to fit over port structure 934 in the manner hown in~Figure 47 where the needle 917 has~punctured septum 930. The internal passageway 917a of the needle communicates with the~ internal chamber 920b of the check val~e housinglto permit fluid fIow through the needle to the fluid reservoirs of the device when the check valve is in an open position.
Turning to Figures 43 and 46, it is to be observed that chec~ valve housing 902 includes circumferentially spaced luer lugs 902c which permit interconnection of a coupler member 924 which the ne~dle assemkly. Member 924 is, ~:in~turn,~ connectPd with~a length of transf~er cannula~tubing 925 that`~connects to St~lBSTlTUTE SHEET

WO 93/20863 h 1 .~ g O ~ 2 PC~/US92/10482 .

a source of diluent or other parentera~ liquid.: ~ ` .`` .``:;
In using the apparatus of this last form of the invention, the protracted needle is caused to penetrate the septum 930 of the septum assembly in the manner shown in Figure 46. The septum 930 is of~ conventional construc~ion 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 receivahle within portion 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 43 and 48, superimposed over i i.
the base and stored energy source 21S is a structural cover 34 :`. ;
of the character previously described. Affixed to thè 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 }ower surface of pad 38.
With the construction shown in~ the drawings, an ~.
:appropriate injec~:able such~ as diluent, parenteral fluid, or : ;.. :.
other elution flu~d can be introduced into chambers 211 using 1~`5 the needle assembly 900. ;As the fluid flowlng from the fluid source enters the check~valve housing 902~o the needle .;:
ass~embly,:check valve~:904 will~be moved`away~from seat 907 to~
`the open~po~ition: as shown~in Figure 47~to:~permit fluid flow;:
inwardly o~~the hollow needle~ When the:chambers are filled,~
the~b~uildup of system~back:~pres;sure will causq the check valve ; `~
to return:~o the closed~:position shown in Figure: 46 and the needle can be withdrawn~from the septum.
Referring to Figures 47 and 48~:the~adding means of the' inventi~on can take several different forms as, for example, the~
cylindric~a~lly shaped, functional suppo~t:structure 730 which is in9erted into:passageway 720 and to which var1où:s ~additives,~
including~beneficial agents~such as dr~gs~, hiologically~active~ ?;:
mat~r~ials,~ and ~chemical:~elements~ and ;:compounds can ~ be~ t~' releasably:~connected. ~The addi~ives can~be of the: character~
de;scribed in~ connection with the previously described :` SUBSTITUTE SHEET ~ :

W093/20863 ~ 1¦DO~ PCT/US92/10~2 ~ i~ ~

1 .`
embodiments of the invention:including those shown in Figures 32 and 35 and can be removably affixed to support structures of ,, .
various configurations includlng synthetic porous matrices~such as structure 7~0 which can be placed within the path of the 1.
~luid flowing through the device~ As the fluid flows toward the reservoirs in the manner indicated by the arrows 937 of .:::
Figures 47 and 48, the additives are~released at a controlled ~:
rate over time to the fluid. This can be accomplished by slow ..
dif~usion mass transport, slow equilibration kinetics or other types of absorbent disas.sociation techniques.
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 modifications in the individual parts of their relative -~ :
assembly in order to meet specific requirements or conditions.
Such changes and modifications may be made without departing .:
from the scope and spirit of the invention, as set forth in the following claimsO :.
.:, '.'~ "`.

;. ~, ; ~;
- :~
. ...

;,; ; .,:
' ~f,'~
: . :~ .' '.'; ~' ''."`'':

~: SUBSTITUTE SHEET . -

Claims (42)

I CLAIM:

1. A device for expelling fluids at a controlled rate, comprising:
(a) a base;
(b) a stored energy means comprising at least one distendable membrane constructed of an elastic material cooperating with said base to form a chamber having a fluid outlet;
(c) dispensing means operably associated with said fluid outlet for dispensing fluids from said device;
(d) first flow control means disposed internally of said chamber for controlling the rate of flow of fluid through said outlet, said first flow control means comprising at least one thin permeable member superimposed over said base; and (e) second flow control means disposed intermediate said fluid outlet and said dispensing means for controlling the rate of flow of fluid from the device.

2. A device as defined in Claim 1 in which said stored energy means comprises an assemblage comprising a plurality of generally planar-shaped, distendable members.

3. A device as defined in Claim 2 in which at least one of said planar-shaped, distendable members is permeable to gas.

4. A device as defined in Claim 3 in which at least one of said distendable members comprises a membrane having a first permeability constant.

5. A device as defined in Claim 4 in which at least one of said distendable members comprises a membrane having a second permeability constant.

6. A device for use in infusing fluids into an ambulatory patient at a controlled rate comprising:
(a) a base having a fluid inlet and fluid outlet interconnected by a fluid flow path;
(b) filling means for introducing fluid into said fluid inlet;

(c) a distendable membrane constructed of an elastic material which is fitted over said base to define a chamber in communication with said fluid inlet and said fluid outlet, said membrane being distendable by fluid introduced into said chamber under pressure through said fluid inlet, said membrane having a tendency to return to a less distended configuration whereby fluid within said chamber will be expelled through said fluid outlet; and (d) adding means disposed within said fluid flow path for adding an additive to fluid flowing therethrough.

7. A device as defined in Claim 6 in which said adding means comprises an additive and an additive presentation means for presenting said additive to the fluid, said additive presentation 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.

8. A device as defined in Claim 6 in which said adding means comprises an additive and an additive presentation means for presenting said additive to the fluid, said additive presentation means having exposed surfaces, said additive being removably connected to said exposed surfaces.

9. A device as defined in Claim 6 in which said adding means comprises a structural support having exposed surfaces and a beneficial agent present on said exposed surfaces, said structural support being disposed within said fluid flow path so that at least a portion of said beneficial will be added to said fluid introduced into said fluid inlet.

10. A device as defined in Claim 6 in which said adding means comprises a polymer support and an additive carried by said polymer support, said polymer support being disposed within said fluid flow path so that at least a portion of said additive will be added to the fluid flowing through said fluid flow path.

11. A device as defined in Claim 6 in which said adding means comprises a member having exposed surfaces and a biologically active material present on said exposed surfaces, said member being disposed within said fluid flow path so that said biologically active material will be added to said fluid introduced into said fluid inlet.

12. A device for use in infusing beneficial agents into a patient at a controlled rate comprising:
(a) a base having a fluid inlet, a fluid outlet and a fluid passageway interconnecting said fluid inlet and said fluid outlet;
(b) filling means for introducing fluid into said fluid inlet;
(c) a distendable membrane constructed of an elastic material which is fitted over said base to define a chamber in communication with said fluid passageway, said membrane being distendable by fluid introduced into said chamber under pressure through said fluid passageway and having a tendency to return to a less distended configuration whereby fluid within said chamber will be expelled through said fluid outlet;
(d) adding means mounted within said base for adding an additive to fluid introduced by said filling means, said adding means comprising;
(i) additive presentation means disposed within said fluid passageway for presenting an additive to the fluid flowing therethrough; and (ii) an additive removably interconnected to said additive presentation means, said additive comprising a beneficial agent.

13. A device as defined in Claim 12 in which said distendable membrane includes a surface in contact with the fluid introduced by said filing means and in which said additive is removably interconnected with slid surface.

14. A device as defined in Claim 12 in which said additive presentation means comprises a flow rate control membrane disposed between said fluid outlet of said base and said chamber, said flow rate control membrane having exposed surfaces, said additive being removably connected to said exposed surfaces.

15. A device as defined in Claim 12 in which said additive presentation means comprises a surface in said base, said additive being removably connected to said surface.

16. A device as defined in Claim 12 in which said adding means comprises a vial assembly having said additive presentation means sealably contained therein.

17. A device as defined in Claim 16 in which said vial assembly comprises a glass vial having first and second ends sealed by first and second sealing members.

18. A device as defined in Claim 17 in which said base includes a chamber for receiving said glass vial.

19. A device as defined in Claim 18 in which a hollow needle is mounted within said chamber for piercing said second sealing member, said hollow needle having a fluid passageway in communication with said fluid passageway of said base.

20. A device for use in infusing fluids into an ambulatory patient at a controlled rate comprising:
(a) a base having an upstanding portion including a fluid inlet passageway and a fluid outlet, said fluid outlet and said fluid inlet passageway being interconnected by a fluid flow path; fluid inlet and said fluid outlet;
(b) filling means for introducing fluid into said fluid inlet passageway, said filling means including filling check valve means for controlling the flow of fluid into said fluid inlet passageway;
(c) a distendable membrane constructed of an elastic material which is fitted over said base to define a chamber in communication with said fluid inlet and said fluid outlet said membrane being distendable by fluid introduced into said chamber under pressure through said fluid inlet, said membrane having a tendency to return to a less distended configuration whereby fluid within said chamber will be expelled through said fluid outlet;
(d) adding means disposed within said fluid flow path for adding an additive to fluid flowing therethrough.

21. A device as defined in Claim 20 in which said adding means comprises an additive and an additive presentation means for presenting said additive to the fluid, said additive presentation means being disposed within said fluid inlet passageway intermediate said fluid outlet and said filling check valve means.

22. A device as defined in Claim 20 in which said adding means comprises an additive and an additive presentation means for presenting said additive to the fluid, said additive being removable from said additive presentation means using affinity chromographic techniques.

23. A device as defined in Claim 22 in which said additive is removably connected to said additive presentation means using azlactone functional compounds.

24. A device as defined in Claim 22 in which a ligand is connected to said additive presentation means and a target molecule is connected to said ligand.

25. A device as defined in Claim 24 in which a spacer arm is connected to said support and in which enzymes are connected to said spacer arm.

26. A device as defined in Claim 24 in which a spacer arm is connected to said support and in which a protein is connected to said spacer arm.

27. A device as defined in Claim 26 in which an antibody is bound to said protein.

28. A device for use in infusing fluids into an ambulatory patient at a controlled rate comprising:
(a) a base having a fluid inlet, a fluid inlet passageway and a fluid passageway interconnecting said fluid inlet and said fluid outlet passageway;
(b) filling means for introducing fluid into said fluid inlet;
(c) a distendable membrane constructed of an elastic material which is fitted over said base to define a chamber in communication with said fluid passageway, and with said membrane being distendable by fluid introduced into said chamber under pressure through said fluid inlet passageway and having a tendency to return to a less distended configuration whereby fluid within said chamber will be expelled through said fluid outlet; and (d) adding means disposed within said fluid outlet passageway for adding an additive to fluid flowing therethrough, said adding means comprising a support and an additive removably connected to said support.

29. A device as defined in Claim 28 in which said filling means comprises a syringe assembly.

30. A device as defined in Claim 28 in which said upstanding portion extends transversely of said base.

31. A device as defined in Claim 28 in which said upstanding portion extends longitudinally said base.

32. A device as defined in Claim 28 in which said additive is removable from said support using affinity chromographic techniques.

33. A device as defined in Claim 32 in which said additive is removably connected to said support using azlactone functional compounds.

34. A device for use in infusing beneficial agents into a patient at a controlled rate comprising:
(a) a base having a fluid inlet, a fluid outlet and a fluid passageway interconnecting said fluid inlet and said fluid outlet passageway;
(b) filling means for introducing fluid into said fluid inlet;
(c) a distendable membrane constructed of an elastic material which is fitted over said base to define a chamber in communication with said fluid passageway, and with said membrane being distendable by fluid introduced into said chamber under pressure through said fluid passageway and having a tendency to return to a less distended configuration whereby fluid within said chamber will be expelled through said fluid outlet;
(d) adding means mounted within said fluid outlet passageway for adding an additive to fluid introduced by said filling means, said adding means comprising:
(i) additive presentation means disposed within said fluid passageway for presenting an additive to the fluid flowing therethrough; and (ii) an additive removably interconnected to said additive presentation means for removal using affinity chromotograph techniques.

35. A device as defined in Claim 34 in which said additive presentation means comprises an immobilized ligand.

36. A device as defined in Claim 35 in which said additive presentation means comprises a spacer arm.

37. A device as defined in Claim 35 in which a target molecule is a fixed to said ligand.

38. A device as defined in Claim 36 in which a protein is connected to said spacer arm.

39. A device as defined in Claim 38 in which an antibody is connected to said protein.

40. A device as defined in Claim 38 in which an immunoglobulin is connected to said protein.

41. A device as defined in Claim 38 in which an antibody is covalently attached to said protein, said antibody having binding sites facing outwardly from said protein.

42. A device as defined in Claim 41 in which an antibody enzyme conjugate is applied that has specificity for the bound target molecule.