CA2009984A1 - Intravenous system for delivering a beneficial agent - Google Patents
Intravenous system for delivering a beneficial agentInfo
- Publication number
- CA2009984A1 CA2009984A1 CA002009984A CA2009984A CA2009984A1 CA 2009984 A1 CA2009984 A1 CA 2009984A1 CA 002009984 A CA002009984 A CA 002009984A CA 2009984 A CA2009984 A CA 2009984A CA 2009984 A1 CA2009984 A1 CA 2009984A1
- Authority
- CA
- Canada
- Prior art keywords
- agent
- wall portion
- fluid
- chamber
- formulator
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/1407—Infusion of two or more substances
Abstract
ARC l609 CIP 1 ABSTRACT
An agent formulator (30, 60) for an intravenous administration set (14) is provided. The intravenous administration set (14) includes a container (12) of an IV fluid (13), a drip chamber (22), an agent formulator (30, 60) and an adapter-needle assembly (28).
The agent formulator (30, 60) has a fluid inlet (23) and a fluid outlet (25) for maintaining a flow of IV fluid (13) therethrough. A
portion (36) of the formulator wall (32) is comprised of a window material which allows the agent to diffuse therethrough but which prevents convective loss of the IV fluid (13). A flow distributor (38, 68) is provided within the chamber for distributing the flow of IV fluid (13) along the interior surface of the window (36). A
transdermal-type drug delivery device (40) is adhered to the exterior surface of the window (36). Drug is delivered by the delivery device (40) through the window (36) and into the flowing IV fluid (13). The device (40) delivers drug into the IV fluid (13) at a rate that is independent of the flow rate of IV fluid (13) through the formulator (30, 60). The rate of drug delivery from the device (40) into the IV
fluid (13) is controlled by either the window (36) itself or by a membrane layer (46) in the drug delivery device (40). A plurality of drug delivery devices (40) may be adhered to the window (36) to deliver a plurality of drugs or to deliver a single drug at a higher dosage rate. A similar window (11) may be placed in an IV bag to deliver a drug into the IV fluid therein.
Al/PATENTS.LGL/1609CIPl
An agent formulator (30, 60) for an intravenous administration set (14) is provided. The intravenous administration set (14) includes a container (12) of an IV fluid (13), a drip chamber (22), an agent formulator (30, 60) and an adapter-needle assembly (28).
The agent formulator (30, 60) has a fluid inlet (23) and a fluid outlet (25) for maintaining a flow of IV fluid (13) therethrough. A
portion (36) of the formulator wall (32) is comprised of a window material which allows the agent to diffuse therethrough but which prevents convective loss of the IV fluid (13). A flow distributor (38, 68) is provided within the chamber for distributing the flow of IV fluid (13) along the interior surface of the window (36). A
transdermal-type drug delivery device (40) is adhered to the exterior surface of the window (36). Drug is delivered by the delivery device (40) through the window (36) and into the flowing IV fluid (13). The device (40) delivers drug into the IV fluid (13) at a rate that is independent of the flow rate of IV fluid (13) through the formulator (30, 60). The rate of drug delivery from the device (40) into the IV
fluid (13) is controlled by either the window (36) itself or by a membrane layer (46) in the drug delivery device (40). A plurality of drug delivery devices (40) may be adhered to the window (36) to deliver a plurality of drugs or to deliver a single drug at a higher dosage rate. A similar window (11) may be placed in an IV bag to deliver a drug into the IV fluid therein.
Al/PATENTS.LGL/1609CIPl
Description
z~
l ARC 1609 CIP 1 INTRAVENOUS SY~TEM FOR DELIVERING A
BENEFI~IAL AGENT
This invention pertains to a parenteral drug delivery system, and to a drug formulat10n chamber 1n comb1nat10n w1th a drug delivery device. The invention relates also to a meth~d of parenterally (e.g., intravenously) administering a drug, and to a method of formulating the drug during parenteral adm1nistration.
8ACKGROUN~ ART
The parenteral adm1nistration of med1cal 11quids is an established clinical pract k e. The 11quids are administered particularly intravenously, and the practice is used extensively as an integral part of the daily treatment of medical and surgical patients. The liquids commonly administered include blood and blood substitutes, dextrose solutions, electrolyte solutions and saline.
Generally the liquids are administered from-an intravenous (IV) delivery system having a container suspended above the patient, with the liquid flow1ng through a catheter hypodermic needle set to the patient.
The admin~strat10n of liqulds intravenously is a valuable and important practlce that contr~butes ~o the opt~mal care of the patlent. How~ver, it does not eas11y prov1d@ a satisfactory means and methQd for admtn~sterlng concomttantly there~ith a benef101al agent, such as a drug. In the pas~, ben~f k~l agengs have been adm1nister~d lntravenously by one of the followln~ ~thods: [1) tempor2rl1y r~moY~ng or dlsconnectlng th~ IY syst~ ad~1n1ster1ng the agent to the pat1ent, th2n adm1n~ster~ng the dru~ ~y hypoderm~c injectlon (e1ther 1nto the d1sconn~cted IV lln~ or dlrectly 1nto the ve~n of the pat1ent), followed by re1nser~1ng th~ IV system ~nto the patient, (2) addlng the agent to the IV l~qu1d in the conta1ner which is then carried by the flow of the liqu1d to the pat~ent; (3) adding ~Q~
l ARC 1609 CIP 1 INTRAVENOUS SY~TEM FOR DELIVERING A
BENEFI~IAL AGENT
This invention pertains to a parenteral drug delivery system, and to a drug formulat10n chamber 1n comb1nat10n w1th a drug delivery device. The invention relates also to a meth~d of parenterally (e.g., intravenously) administering a drug, and to a method of formulating the drug during parenteral adm1nistration.
8ACKGROUN~ ART
The parenteral adm1nistration of med1cal 11quids is an established clinical pract k e. The 11quids are administered particularly intravenously, and the practice is used extensively as an integral part of the daily treatment of medical and surgical patients. The liquids commonly administered include blood and blood substitutes, dextrose solutions, electrolyte solutions and saline.
Generally the liquids are administered from-an intravenous (IV) delivery system having a container suspended above the patient, with the liquid flow1ng through a catheter hypodermic needle set to the patient.
The admin~strat10n of liqulds intravenously is a valuable and important practlce that contr~butes ~o the opt~mal care of the patlent. How~ver, it does not eas11y prov1d@ a satisfactory means and methQd for admtn~sterlng concomttantly there~ith a benef101al agent, such as a drug. In the pas~, ben~f k~l agengs have been adm1nister~d lntravenously by one of the followln~ ~thods: [1) tempor2rl1y r~moY~ng or dlsconnectlng th~ IY syst~ ad~1n1ster1ng the agent to the pat1ent, th2n adm1n~ster~ng the dru~ ~y hypoderm~c injectlon (e1ther 1nto the d1sconn~cted IV lln~ or dlrectly 1nto the ve~n of the pat1ent), followed by re1nser~1ng th~ IV system ~nto the patient, (2) addlng the agent to the IV l~qu1d in the conta1ner which is then carried by the flow of the liqu1d to the pat~ent; (3) adding ~Q~
2 A~C 1609 CIP 1 the agent to an IV l~quid in a secondary container (called a partial fill) that is then connected to the primary IV line; (4) adding the agent to an IV liquid contained in a piggyback vial which is subsequently connected to the primary IV line; or (5) administering intravenously an IV liquid conta~ning a beneficial agent using a pump. While these techniques are used, they have ma~or disadvantages. For ~xample, they often requ~re preformulation of the agent medicatlon by the hospital pharmacist or nurse. They often require separate connect~ons for joining the drug flow line to the primary intravenous line which further complicates intravenous administration. The use of certain types of pumps (e.g., reciprocating pumps) can produce pressures that can vary at the delivery site. Finally, the rate of agent delivery to the patient often is unknown as it ~s not rate-controlled agent delivery but rather is dependent on the rate of IV fluld flow.
In response to these difficulties, Theeuwes in U.S. Pat.
4,511,353 (and in related U.S. Patents 4,740,103; 4,740,200 and 4,740,201) developed a formulation chamber adapted to easily fit into a conventional IV administration set. The formulation chamber is adapted to contain a drug delivery device for delivering a drug or other bene~cial agent into the IV fluid flowing through the formulation chamber. The drug del~very device with~n the formulation chamber ls selected from osmot k pumps ~Figures 2a, 2b, 9, 10, and 25 11), release rate controlling membranes surround~ng a drug reservoir (Fiyures 3-5), rate-controlled delivery reservoirs within a pocket in the drug formulat~on chamber, the pocket formed by a permeable me~brane or screen/mesh whloh allows passage of both IV fluid and drug solut1On th~rethrough (F~gures 12 and 13) and pslym~r matrices containtng the drug, the drug be~ng able to d1ffuse through the matr~x 1nto th~ flowlng IV flu1d ~F1gures 6-8). All o~ thes@ devlces provide the advantage of controll1ng th~ rat~ at ~hlch the drug or other benef~cial agent ~5 released lnto the IV fluld, ~nd~pend~ntly of the rate at wh1ch the IV flu~d flows through the fonmulatlon chamber. Unfortunately, the drug delivery syste~s d~sclosed in these patents do not allow a med~cal techn~c~an to qu~ckly and easily z~
In response to these difficulties, Theeuwes in U.S. Pat.
4,511,353 (and in related U.S. Patents 4,740,103; 4,740,200 and 4,740,201) developed a formulation chamber adapted to easily fit into a conventional IV administration set. The formulation chamber is adapted to contain a drug delivery device for delivering a drug or other bene~cial agent into the IV fluid flowing through the formulation chamber. The drug del~very device with~n the formulation chamber ls selected from osmot k pumps ~Figures 2a, 2b, 9, 10, and 25 11), release rate controlling membranes surround~ng a drug reservoir (Fiyures 3-5), rate-controlled delivery reservoirs within a pocket in the drug formulat~on chamber, the pocket formed by a permeable me~brane or screen/mesh whloh allows passage of both IV fluid and drug solut1On th~rethrough (F~gures 12 and 13) and pslym~r matrices containtng the drug, the drug be~ng able to d1ffuse through the matr~x 1nto th~ flowlng IV flu1d ~F1gures 6-8). All o~ thes@ devlces provide the advantage of controll1ng th~ rat~ at ~hlch the drug or other benef~cial agent ~5 released lnto the IV fluld, ~nd~pend~ntly of the rate at wh1ch the IV flu~d flows through the fonmulatlon chamber. Unfortunately, the drug delivery syste~s d~sclosed in these patents do not allow a med~cal techn~c~an to qu~ckly and easily z~
change the type of benefioial agent being delivered into the flowing IV fluid or to quickly and easily change the delivery rate of the beneficial agent so delivered. In order to change the type of agent delivered or the agent delivery rate with the deli~ery systems S disclosed in these patents, it is necessary to compl2tely disassemble the drug formulation chamber and replace the rate-controlled drug delivery devlce w~thln the chamber. Unfortunately, when the drug formulation chamber ls d~sassembled, there ls a brea~ ~n the sterile field which can lead to pat~ent lnfect1On and therefore n~cessitat~s re-sterilizing the entire apparatus.
Thus, ~here remains a need for a drug formulat~on chamber which can deliver one or more benefi~ial agents, such as a drug, into an IV
fluid flowing in a standard IV adm~nistration set and which can quickly and easily change the type and/or change the deliYery rate of beneficial agent so delivered without contaminating the sterile field.
Accordingly, it is an object of this invention to provide a parenteral (e.g., intravenous) delivery system which deli~ers an agent at a controlled rate into a flowing parenteral fluid for optimizing the care of an an~mal (e.g., a human) whose prognosis benefits from parenteral dellYery.
It ~s another ob~ect of the 1nventlon to prov1de an ~ntravenous dellvery syste~ hav1ng an agent formulation cha~ber whkh ~s adapted to be used w~th a drug delivery device for adm~ttlng a drug or o~her ben~flcial agent at a rate controlled by etther the drug del~very devtce, the formul~t~on oh2mber, or both, ~nstead of by the flow rate of ~ntravenous ~lu1d through the syste~, for opt~ lng the care of a pattent on tntravenous del~very.
Another object o~ the ~nv~nt10n ~s to provtde an ~ntravenous del~very system havtng an agen~ formula~lon ehamber ~h~ch ts adapted 35 to be used with a transdermal-type drug del1very dev~ce wh1ch can deliver one or rore benef~c1al agents, suoh as a drug, ~nto an IV
Thus, ~here remains a need for a drug formulat~on chamber which can deliver one or more benefi~ial agents, such as a drug, into an IV
fluid flowing in a standard IV adm~nistration set and which can quickly and easily change the type and/or change the deliYery rate of beneficial agent so delivered without contaminating the sterile field.
Accordingly, it is an object of this invention to provide a parenteral (e.g., intravenous) delivery system which deli~ers an agent at a controlled rate into a flowing parenteral fluid for optimizing the care of an an~mal (e.g., a human) whose prognosis benefits from parenteral dellYery.
It ~s another ob~ect of the 1nventlon to prov1de an ~ntravenous dellvery syste~ hav1ng an agent formulation cha~ber whkh ~s adapted to be used w~th a drug delivery device for adm~ttlng a drug or o~her ben~flcial agent at a rate controlled by etther the drug del~very devtce, the formul~t~on oh2mber, or both, ~nstead of by the flow rate of ~ntravenous ~lu1d through the syste~, for opt~ lng the care of a pattent on tntravenous del~very.
Another object o~ the ~nv~nt10n ~s to provtde an ~ntravenous del~very system havtng an agen~ formula~lon ehamber ~h~ch ts adapted 35 to be used with a transdermal-type drug del1very dev~ce wh1ch can deliver one or rore benef~c1al agents, suoh as a drug, ~nto an IV
fluid flow~ng through the formulation chamber and whlch can quickly and easily change the type and/or change the delivery rate of beneficial agent so delivered without contaminating the sterile conditions within the drug formulation chamber.
A further objcct of the invention ls to provide an intravenous therapeutlc system including a contalner of an ~ntravenous medical fluld and a drug formulation chamber ~n comb~nation w1th a drug del1very devlce wh1ch can del~ver drug, to a flowlng IV flu~d, at a rate wh k h 1s variable and which ~s accurately controlled by the components of the system.
OL~CLO$URE OF THE INVEN~ION
These and other objects are met by an agent formulator, a parenteral admtnistration system and a method for the controlled parenteral a~mlnistration of a beneficial agent to an animal. The agent formulator comprises a chamber having fluid inlet and fluid outlet means to maintain a continuous flow of a parenterally acceptable fluid therethrough. The chamber has a wall portion that is permeable to a beneficial a~ent to be delivered into the fluid.
The beneftc1al agent should be soluble in the parenteral fluid to enable the agent to diffuse through the wall portlon. A flow dlstr1butor ts prov1ded wlth1n the chamber for d~str1but~ng the flow of parenteral fluld along an lnter10r surface of the wall port~on.
An agent d~l1v~r~ d~v~ce ~s releasably attached to an eas11y acce~s1ble exter~or surface of the wall port~on. The delivery device includes a r~servo1r contain~ng the benefic~al agent to be delivered into th~ par~nt~ral flu1d. Preferably, the delive~y dev~ce ls a transderm~l typ~ drug dellvery devic~ compr1s~ng a laMinate 1ncludlng a b4cklng me~b~r, a middlQ reservo1r contalntng the benef~c1al agent and an adhes1ve sur~ace adapted to r~l~asably adh~re to th~ ex~r10r surface o~ the wall port~on. Most preferably, the agent del1very dev~ce a7so 1nclud~ a rate controll~ng me~brane wh1ch controlj the rate at which the agent ~s del~vered through th~ w~ll port~on.
~ 9 ~3'~
In operation, the fluid flow1ng through the chamber is distributed by the flow distributor along th~ interior surface of the wall portion, thereby causing the agent to diffuse from the device through the wall portion and into the f10wing fluid. The agent is delivered at a rate that is controlled substantially by the formulator and which is substantially ind~pendent of the volumetric flow rate of the fluid flowing through the chamber.
The presPnt lnvent~on also provldes a parenteral delivery system for administer~ng an agent parenterally to an animal. The system comprises in combination, a conta~ner of a pharmaceutically acceptable parenteral flu~d that ls a carrler for the agent and a parenteral fluid administration set. The admin~stratlon set is connected to the container fsr permitt~ng the fluld to flow from the container through the administration set to the animal. The administration set comprises a drip chamber, tubing extending from the drip chamber to the animal, and an agen~ ~ormulator connected into the tubing such that the intravenous fluid flows through the formulator. The formulator lncludes a chamber having fluid inlet and outlet means to maintain a continuous flow of the parenteral fluid therethrough. The chamber has a wall portion that is permeable to a beneficial agent to be delivered into the flu~d. The beneficial agent should be soluble in the parenteral fluid to enable the agent to diffuse through the wall portion. A flow d~stributor ls provided with~n the chamber for d~str~butlng the flow of parenteral fluid along an inter~or surface of the wall port~on. The formulator also includes an agent deliv~ry device releasably attached ~o an easily access~ble external surface of the wall port10n. The delivery device includes ~ reservo~r containing ~h~ benef~clal agQnt to be delivered.
Pref~rably, th~ d~livery dev~ce ~s a transd~rmal drug d~l1very dev~ce compristng a l~nate ~nclud1ng a backing me~bar, a m~ddle res~rvoir contain~ng the benef~clal agent and an adheslv~ s~rf~ce ad~pted to releasably adhere to the external surface of th~ w~ll port~on. Most preferably, the agent dellvery device lncludas a rate controlling membrane which controls the rate at ~h k h ~he agent ls dcl1Yered through the wall portion.
A ~
6 Al In operation, the fluid flowing through the chamber distributed by the flow dlstributor ~long th~ internal sur~
wall portion, causing the agent to diffuse from the device ~
the wall portion and into the flowing fluid. The agent is de at a rate which is controlled substantially by the formulator which is substantlally tndependent of the volumetrlc flow rate fluid flow~ng through the chamber.
The present lnvent~on further provldes a method for the controlled parenteral admin1stratlon of a bene~clal agent, such as drug, to an animal, such as a human. The method compr1ses the steps of allow~ng a pharmaceutically acceptable parenteral flu~d, which is a carrier for the agent, to flow through an agent formulation chamber. The chamber has an inlet communicating with a conta~ner of the parenteral flutd and an outlet communicating with thc animal.
The chamber also has a wall port~on that is permeable to the agent and prevents convective flow of parenteral fluid therethrough. The method further comprises the steps of distributing the flow of parenteral fluid along an interior surface of the wall portion and releasably attaching an agent delivery device to an accessible exterior surface of the wall portion.
The delivery devlce includes a reservolr containing the benef1cial agent to b~ dellvered. Preferably, the d21~very device is a transdermal drug del~very device compr1sing a lam~nate including a backlng memb~r, a middle reservotr contain~ng the beneftc1al ag~nt and an adheslvQ surface adapted to releasably adhere to the external surface of the wall portion. Most preferably, the agent dellYery dev1ce ~ncludes a rate controlling membran~ wh~ch controls th~ rate at wh~ch th~ agent is del~vered through th~ ~ll portlon.
In operatlon, the fluld flow~ng through th~ charber ls d~str~butsd along th~ inter~or surface of th~ w~ll port10n, caus1ng the agent to diffuse from the deYice through the w~ll port~on and into the flowing flu~d. The agent ~s released at a r~te which ls controlled substanttally by the del~very d~v1ce and which is substantially independent of the volumetric flow rate of the fluid flowing through the chamber. The methnd is effective to administer the drug/agent to the animal in a beneficially effective amount over a prolonged period of time.
BRIEF ~ESCRIPTION OF THE DRA~L~
Figure 1 is a perspective view showing an agent formulator 30 and its use within an intravenous delivery system 10;
Figure 2 is a sectional view of one embsd~ment of an agent formulator according to the present invention;
Figure 3 is a sectional view of the agent formulator illustrat~d in Figure 2, taken along line 3-3;
Figure 4 is a detailed sectional view of a preferred drug delivery device 40 wh k h is adapted to be attached to formulator 30 as shown in Flgures 1-3;
Figure 5 is a perspective ~iew showing an agent formulator 60 which can be used in an intravenous delivery system 10; and Figure 6 ts a crass-sectlonal view of for~ulator 60 taken along line 6-6.
In the spec~flcat10n and the drawings, like parts in related F~gures are 1dentlfied by like numbers.
~
Figure 1 1llustrates an operatlve 1n~ravsnous dellv~ry system, genarally des19n~ted by the num~ral 10, showlng th~ poslt~on~ng of an agent farmulator 30 there1n. Syste~ 10 comprlses a cont~1ner 12 that contains a ~luid 13 suitable for intravenous admln~stratlon, and an admin~stration set, generally designated 14. The fluid 13 in container 12 will typically be a medical fluid, i.e., a sterile solution such as an aqueous solution of dextrose, saline, and/or electrolytes. Fluid 13 is a vehicle for intravenous administration of a pharmaceutical agent to a recipient. Container 12 is manufactured from glass or plastic, and is preferably of the no air-tube vacuum type and thus it is used with an admin~stration set that has an a1r inlet filter. Other types of containers such as the air-tube vacuum type, or the non-vented type, can b~ used for the intended purpose. These alternative containers do not requlre an air filter in the administration set. Container 12 can be rigid, semi-rigid or flcxible in structur~, and it is usually adapted to be hung neck-down from a hanger 15 by a handle 16 that connects or surrounds container 12. The neck of container 12 is covered by a closure 17, generally made of rubber and air-tight.
Alternatively, container 12 can take the form of an infusor or a syringe pump (not shown in the Figures), and in particular a portable infusor or syringe pump, of the kind known in this art.
Administration set 14 and container 12 ar~ interconnected by piercing closure 17 with one end of a hollow spike 18 attached to or formed as a part of administrat~on set 14. Spike 18 is equipped with a side air vent 19. The other end of spike 18 is enlarged and fits snugly ints a drip chamber 22. Drip chamber 22 traps air contained in the set 14 and fac11~tates ad~ust~ng the flow rate of intravenous flu1d 13 from conta~ner 12 as the flow proceeds drop w~se. The outlet at the bottom ~f drip chamber 22 ls connec~ed to a flrst segment of tubing 23 which fits into agent formulator 30, the details of wh1ch are presented in Figures 2 and 3. A second segment of tub1ng 25 leads from agent formulator 30 to bacterlal f~lter 27. A
third segment of tubing 29 extends from ~ilt~r 27 to an 1nfuslon agent receptor s1te, termlnat1ng ~n an adapter-n~edle assembly 28 that ls lns~rt~d into a ve1n of 2 ~arm-blooded an~mal 20, shown as a human arm. A piece of tape 21 hold~ adapter-needle assembly 28 f~rmly ln place on the rec1pient's arm. The adm~n1strat~on set can also include a pa~r of tubing clamps 24 and 26 located on e~ther side ~33 ~ 3r~
of formulator 30 which may be used to govern or stop the flow of intravenous fluid through the intravenous delivery system 10.
In one embodiment of the present invention, a portion of the wall of container 12 is comprtsed of a material 11 which is permeable to the beneflctal agent contatned wtthtn, and delivered by, the deltvery devtce 40. The wall portton 11 forms a ~drug delivery wtndow~ wtthtn the otherwtse tmpermeable wa11 of contatner 12.
Durtng delivery of beneftcial agent ~rom devtce 40, the IV fluid l3 must be tn contact wtth the intertor surface of wall portion 11.
Accord1ngly, the wall portton 11 ts preferably located tn a downstream portion of the wall of contatner 12 most preferably adjacent the neck of container 12.
As an alternative to, or in addition to the drug delivery window 11 in container 12, an agent formulator 30 may be provided downstream from the container 12. Agent formulator 30, as seen in Figures 2 and 3, comprises a wall 32 forming a chamber 34. At least a portion of the wall 32 is comprised of a material 36 which is permeable to the beneficial agent oontained within, and delivered by, the delivery device 40. The wall portton 36 forms a drug delivery window, stmilar to wall portion 11, within the otherwise impermeable wall 32 which may be formed of glass, plastic or the like.
As best shown in Figures 2 ~nd 39 a flow diverter 38 ts provtded w1thln chamber 34. The flow dtverter 38 is secured within chamb~r 3~ by supports 39. Preferably, formulator 30 h~s a cyl1ndrlcal shap~ and the wall portton 36 extends around th~ enttre ctrcumfer~nc~ o~ fo~mulator 30. The flo~ d1vert~r 3~ also preferably has a rsughly cyltndr k al shape. The entlre cha~b~r 34 preferably rsmatns f111ed w~th the flowtng IV ~lu1d 13 to ensure that the entire tnter10r surfar~ of wall portlon 36 1s ln contact wtth the flowlng IV
fluid 13. Th~ flo~ d1ver~er 38 provid~s two lmportant funct10ns in the formulator 30 of the present tnv~nt10n. Ftrst, th~ flo~ dtverter 38 dtverts the flow of IY flutd tn ths dtrection sho~n by the arrows in Figure 2, i.e., along the tntertor surface of w~ll portton 36.
Secondly, the flow diverter 38 minimizes the dead volume within formulator 30. Those skilled in the art will appreciate that the flow diverter 38 forces the IV fluid to flow in a relatively constricted space between the flow diverter 38 and the wall portion 36, thereby enabling a greater percentage of the IV fluid 13 to contact the interior surface of wall portlon 36.
The efflciency of drug transfer into the IV fluid 13 is greatly enhanced by the flow diverter ~8. Flow dlverter 38 creates a higher liquid flow veloclty (for any given liquid volumstric flow rate) along the interior surface of wall portion 36 which helps elim~nate any stagnant fluid layer. In accordance with well known flow principles, the thickness of the stagnant fluid layer along the walls of chamber 34 decreases as the fluid flow veloc1ty through chamber 34 increases. This creates several benef kial effects. First, there is a trend to reduce the number of air or gas bubbles which might otherwise form on the interior surface of the wall portion 36 and which reduce the effective area of the wall portion through which drug can be transfered into the IV fluid. The higher fluld flow velocity also promotPs higher drug transfer rates by maintaining a lower drug concentration in the IV fluid adjacent the wall portion 36.
An alternat1ve embodlment of an agent formulator is shown in Figures 5 and 6 and 1s designated by 60. Ilke formulat4r 30, formulator 60 1s also connectable to an ~ntravenous administration set by connectlng to ~nlet tub~ng 23 and outlet tub1ng 25. Agent fo~mulatsr 60 eomprlses a wall 32 and a wall port10n 36. The deltvery deYlce gO ~s adapted tu be secured to wall portlon 36. ~all port10n 36 ls csmprlse~ of a mater1al ~h1ch ~s peri~bl~ to the benef1e1al ag~nt conta1ned w1th1n, and d~l1Ysred by, th~ d~l1very device 40. The wall portion 36 forms a drug delivery window, similar to wall portlon ll (F~gure l) and wall port10n 36 (F~gur~ 2~, withln the otherwise ~mpermeable wall 32 which is preferably formed of a moldable plastic, e.g., polyethylene terephthalate.
Z ~ J ~
As shown in Figures 5 and 6, wall 32 is molded to form a tortuous flow path 67 defined by a plural1ty of flow diverters 68.
Wall portion 36 may be bonded to the wall 32 using heat and pressure according to well known methods. Thus, the IV fluid 13 flows along the interior surface of wall portlon 36 as shown by the arrows. The tortuous flow path 67 ach~eves the same bcnef1ts of higher liquid flow velocity, elimination of stagnant flu~d layers, reductlon in air or gas bubbles and higher drug transfer rates mentioned above with respect to flow diverter 38 (F~gur~s 2 and 3).
The wall portions 11 and 36 may be compr~sed of known drug permeable and/or microporous mater~als which allow the beneficial agent delivered by device 40 to diffuse therethrough but which prevent convective IV fluid flow therethrough. The composition of wall portions 11 and 36 should be selected in accordance with the type of beneficial agent being delivered by device 40. In general, the wall pcrtions 11 and 36 should be comprised of a polymeric composition that allows a drug or other beneficlal agent delivered by device 40 to diffuse through the wall portion and into the interior of container 12 and/or into chamber 34. Representative polymers for forming wall portions 11 and 36 include olefin polymers, ~inyl polymers, condensation polymers, addltion polymers, rubber polymers and silicone polymers, and in particular, poly~thylene, polypropylene, polyv1nyl acetate, polyvlnyl acetal, polyvinyl chloride, polya~1des, polyesters, butad~ene rubber, organo-silicone polymers and copolymcrs thereof.
Xhen th~ d@vlce 40 del1Yers a hydrophtl~c drug, the wall port10ns 11 and 36 ar~ preferably oomprlsed of a hydrophll1c or microporous ~ater1al. Examples of su~table hydrophil~c ~terl~ls lnGlud~ polyureth~nes, polyvinyl ~lcohols, polya~1d~s and cglloph~ne.
Of these, polyurethanes and celloph~n~ ar~ mos~ preferr~d. Su~table m1croporous mater1als are descr~bed belo~ ~n connect10n wlth the dellvery of polypeptld~s, proee1ns and oth~r macromolecules.
~ 3~3~3'~
When device 40 delivers a lipophilic drug, the wall portions 11 and 36 are preferably comprised of a lipophilic material. Examples of suitable lipophilic materials include natural rubbers, silicone rubbers, Hytrel~ (a thermoplastic polyester elastomer sold by E.I.
DuPont de Nemours of Wilmington, DE), ethylene vlnyl acetate (E~A), polyvinyl chlorlde, and Kraton~ (a styrene-butad~ene block copolymer sold by Shell Chemical Co. of Houston, TX). Of these, ethylene vinyl acetate copolymers, silicone rubbers and natural rubbers are preferred.
When device 40 delivers a polypeptide, prote~n or other macro-molecule, th~ wall portions 11 and 36 are preferably compr~sed of a microporous material. The pores in the microporous material will generally have a sl~e of less than about 0.2 m~crons, and preferably about 0.01 to 0.2 microns. Pores having the above recited size ranges are too small to allow bacterial cells to pass through the pores and can thereby maintain the sterility of the container 12 and/or the cha~ber 34. In general, microporous materials having pore sizes in the above mentioned range will allow water molecules from th~ parenteral fluid to diffuse into the membrane. In some cases, the exterior of the wall portions 11 and 36 will feel wet to the touch. However, mlcroporous membranes having the above mentioned pore si7e ranges w~ll be ef~ective to prevent convec~iYe flow losses of water-based parenteral fluids through the wall port~ons 11 and 36.
If necessary or des~rable, the microporous wall portions 11 and 36 can b~ treated w~th a water non-wetting ~aterial to further reduce cap1llary IV flu1d losses through the wall por~ons 11 and 36. In add1t1On, the dellvery devlce 40 may ut~llze a carr~er wh1ch ~s imm~sc~ble ln water. In such a casQ, th~ benef~clal agent 1s suspended ln a water-~mmlsclbl0 flu1d carrler (~.9., an o1ll. ~hen the o~l-based carrler ent~rs the pores of th2 ~1croporous ~æ~brane, the pores will repel any water-based parenteral flu~d wh1ch helps prevent convect~ve losses through the wall port~ons 11 and 36.
Examples of sultable microporous materlals ~nclude Celgard~ (a microporous polypropylene film sold by Celanese Chemlctl Co. o~
~ 3~-~ 9 ~3f~
Dallas, TX) cellophane, glass frits, vycor glass, porous glass and microporous membranes of the type utilized in known elementary osmotic pumps. Of these, porous glass is most preferred.
Selection of polymers for forming wall portions 11 and 36 for the passage of a drug therethrough can be determined by measur~ng the rate of diffusion through the polymeric wall materlal. Various techniques can be used So det2rmine the permeability of a homopolymer, copolymer, or terpolymer to the passage of a drug. One method that can be used is to position a fllm of the polymer, of known thickness, as a barrler between a rapidly stirred, saturated solution of the drug and a rapidly stirred solvent bath (typically water), at a constant temperature, typically 25-C, and periodlcally measuring the concentration in the drug solut10n and in the solvent bath. Then, by plotting the drug concentration in the solvent bath versus time, the permeability coefficient, P, of the polymeric film may be determined from Fick's Law of Oiffusion. Fick's Law of Diffusion is expressed by the following equation (I):
Slope o~ plot - (Q2 - Q~/e2 - tI) - P AC/h (I) wherein:
Ql ~ cumulatlve amount of drug ln the downstream solvent in micrograms at t1;
Q2 ~ cumulatlve amount of drug ln solvent in micrograms at t2;
tl ~ el~psed tlme to first sa~ple, l-e-7 Ql;
t2 ~ elapsed tlme to second sample, l.~ 2;
A - area o~ f~lm ln c~2;
C ~ concentration of drug ln sa~urated solut~on; and h ~ thickness of film in cm.
By determining the slope of the plot, i.e., [Q~ - ~2/t1 - t2J and solving the equation using the known or measured values of A, C and h, the permeability coefficient, P, in cm2/time of the film for a given drug is readily determined. The procedures used to determine the rate of release through the polymer can be ascertained easily by standard techniques known to the art as recorded in J. Pharm. Sci., Vol. 52, pp 1145-49, (1963); ibld, Vol. 53, pp 798-802, (1964);
ibid, Vol. 54, pp 1459-64, (1965); ibid, Vol., 55, pp 840-43 and 1224-39, (1966); EncYl. PolY~er ~1.. Technol., Vol. 5 & 9, pp 65-82 and 794-807, (1986); the references cited there~n, and the like.
Wall portions 11 and 36 may also optionally contain a plasticizer such as a member selected from the group conslsting of phthalate ester, adipate ester, sebacate ester, azelate ester, di(2-ethylhexyl~ phthalate, butyl phthalyl butyl glycslate7 diamyl phthalate, dibutyl succinate, diethylene glycol dipropionate, glycerol monooleate, ethyl phthalyl ethyl glycolate, triethyl citrate, tributyl citrate, trialkyl citrates sold under the tradename Citroflex by Morflex Inc. of Greensboro, NC, tributyl phosphate, triethylene glycol dibutyrate, glycol monoleate, polyethylene glycol 200; polyethylene glycol 400-mono laurate, diethyl lauramide, oleic and mineral oil, epoxidized soybean oil and the like. The amount of plasticizer in wall portions 11 and 36 is from about 5 weight percent (wt %) to 30 wt Z, or more.
In ~n alt~rnative embodiment of ~he invention, the agen~
permeable w~ll portion 36 ~ay be formed in s~tu. For example, wall 32 of forTulator 30 may be composed of a polymer, such as polyvinylchlor~de, a polyester or a polyur~thane, whkh is ini~ially 30 impermeable to the passage of drug or agen~. A portion 36 of wall 32 can be treated with a per~eability enhane~ng ~gent, such as a plastic1zer or a transderm~l per~at10n enh~nc~r, 1n srder to fora a druy permeable w~ll portion 36 ~n sltu. Th~ plast1c1z~r ~ay be del1~ered concurrently w~th the drug or agent frw~ d~liv~ry device 35 40. For example, when the wall 32 is fQrned of polyv1nylchlor~de, delivery device 40 contains both drug and a plastlcizer of ;2~ 3~8 ~
Thereafter the drug is delivered by device 40 through wall portion 36 into chamber 34.
When the wall portions 11 and 36 are comprised of a material ha~ing poor rigidity and/or strength, it may be supported by a rigid porous or grid-like polymer structure (not shown in the figures) provided within the contalner 12 or w~th~n chamber 34. The porous or grld-l~ke polymer structure should allow the IV fluid to contact the inter~or surface of wall port1Ons 11 and 36 to allow the beneficial agent to be delivered into the IV fluid. ~hen the wall portlons 11 and 36 are comprised of a fragile mater~al or a materlal having poor tear strength, it may be necessary to provide a protective covering (not shown in the figures) thereover. The protective covcring can take any number of forms but in any event should be effectlve to prevent or minimize unnecessary stresses placed on th~ wall portions 11 and 36 and yet provide easy access to attach a drug delivery device 40 thereon.
In its broadest sense, the drug delivery device 40 comprises a beneficial agent-containing reservoir which can be releasably attached to the exterior surface of the wall portion 11 and/or 36.
Typically, the reservo1r comprises a polym~ric matrix having a drug or other benef1c1al agent d1spersed therein. The reservo~r may be releasably attached to the wall portions 11 and/or 36 us~ng tape, clamps, adhes~vss or other convent~onal attachlng means. M2chanical attaching ~eans are preferred where the benefic~al agent delivered by the devlce ~s lncompat~ble w~th ~dh~s1ves. In eases where the beneflc1al agent 1s adheslve-compat~ble, the res@rvo~r preferably incorporat~s a r~1easabl2 cont~ct adhas1v~, or has a r~le~s~bl~
contact adheslve layer coated on on~ s~d~ th~reof9 so that th~
reservotr 1s ltself releasably adh~red to th@ ~ll port1On 11 and/or 36.
.
The ~gent delivery dev~ce 40 used in the present ~nvention ls not limited to any part~cular type or s~ruoture. Many ultable dev~ces are known 1n th~ art and have genQrally been used ~n ~ 3~3 applications wherein a drug sr other beneficial agent is administered transdermally. Examples of suitable agent del~very devices 40 may be found for example in U.S. Patents Nos. 3,536,809i 3,598,122;
3,598,123; 3,787,571; 3,699,963; 3,731,683; 3,734,097; 3,~42,951;
3,797,494; 3,964,482; 3,996,934; 4,031,894; 4,060,084; and others to name just a few. The teachings of the above listed patents concerning the relevant structures o~ the drug del~very devices and the particular drugs which may be su~tably administered using these devices are incorporated herein by reference.
A preferred drug delivery dev~ce 40 is illustrated in Flgure 4.
Device 40 is a multilaminate system comprised of an impermeable backing layer 42, a drug reservoir 48 and an adhesive layer 50.
Device 40 also includes a permeation enhancer-containing layer 44 (e.g., an ethanol gel layer) and a rate controlling membrane 46. A
strippable release liner 52, adapted to be removed prior to application, ~s normally included in the packaged product.
The drug reservoir 48 may be comprised of a polymeric matrix or carrier having the drug/beneficial agent to be delivered, d7spersed throughout. The polymer matrix stores and releases the beneficial agent/drug by diffusion or by osmotic action to wall port1On 11 and/or 36. Representative polymers for forming the matri~ may be selected from homopolymers, copolymers, cross-l1nked polymers, diffusion polymers and m k ropsrous pslym~rs. Examplss of sultable polymers include acrylic polymers and copolymers of m~thacrylate, ethylacrylate, ethylm~th2crylate, and m2~hylmethacrylate;
homopolym*rs and copolymers includ~ng vlnylchlorld~-vinylacetat~
copoly~er; chlorlnat~d vinyl chlortd~; poly~thylene; polypropylene;
ethylene-propylene copolymer; chlorinatgd poly~thylen~;
ethylene-vinyl acetate copolym~r (EVA) of th~ typ~ describ~d in U.S.
Patcnt No. 4,144,317; styrenebutad1~n2 copolyR~r;
acrylon~tr1le-styrene-butadiene terpoly~r; polyvinylid~n~ chloride;
vinylchloride-acrylonitrile cspoly~ær; v1nylchlor~ds-v~nyl~d~ne chloride copolymer; vinyl~denechlsr~de-acrylate ester copolymer;
polybutylene terephthalate; v~nylchloride-acrylat~ ester copolymer;
%~
cross-linked polyvinyl acetals such as cross-linked polyvinyl formal;
cross-linked polyvinyl acetal and cross-linked poly~inyl butyral;
polyethers; polyesters; sparingly cross-linked polyesters;
polyurethane; polyamide; chlorosulfonated polyolefins; polyolefins;
polybutadiene; polyisoprene; polysil k one; natural and synthetic rubbers; and the like. The polymers are known in The Handbook of Common PolYm~rs, by Scott et al., (1971), published by CRC Press, Cleveland OH; in Modern Plast1cs ~ncYclQ4e~ia, (1979), published by McGraw-H1ll Inc., New York, NY; and in H~ndbook of Plastics and Elastomers, by Harper, ~1976), published by McGraw-Hill Inc., San Francisco, CA.
The drug reservoir 48 may contain the drug alone or it may contain the drug along with one or more permeation enhancers. The drug/beneficial agent should either itself be soluble in the parenteral fluid or be capable of being solubilized using adjuvants such as surfactants and/or co-ions. The amount of drug in the reservoir 48 will depend upon the rate at which the drug is delivered from the system and the intended duration of therapy. The amount of drug/beneficial agent in reservoir 48 generally will be abou~ 0.1% to 80% by weight, with a more preferred amount of 5X to 50% by weight.
The device 40 can b~ manufactured for delivering benefic~al amounts of a drug over a prolonged period fro~ about 0.5 hours to several days or longer, wlth a more preferred perlod o~ about 4 to 50 hours.
The dev1ce 40 used in the pres~nt invent~on releases from 10 ng to 750 mg psr hour, or h1gher. Th~ reservo1r 48 may also include d1luents, stab~ ers, vehicles, gelling agents, and the like.
Th~ back1ng member 42 serves the purpose o~ insur~ng unid~r~ct10nal passag~ of drug throu~h ~ll port10n 11 and/or 36 1nto cont~1ner 12 and/or chamber 3~, and also of provld1ng support for the system, wher~ need~d. The back~ng la~r can be fl~x1bl~ or nonflex1bl~ and su1table materlals lnelud~, ~1thout l1mltat10n, cellophane, cellulose ace~ate, ethylcel1ulos~ plast1ct2ed vinylacetate-~1nylchlor1de copoly~ers, polyethylene t~rephthalate, nylon, high and low density polyethylene, polypropylene, metalized 9~3~
polyester films, polyvinylidene chloride, coated flexible fibrous backings such as paper and cloth and aluminum foil. Such backings can be in the form of precast films or fabrics which are bonded to the reservoir by heat or adhesives and can be coated onto the reservoir 48.
The device 40 is held in place on wall port10n 11 and/or 36 by means of an in-11ne pharmaceut1cally acceptable contact adhesive layer 50. Drug and/or a permeat10n enhancer may also be ~ncorporated into the adhesive layer 50. The compos1t10n and th k kness of the adhesive layer 50 are preferably such that 1t does not const1tute a significant p~rmeation barrier tn the drug or the permeation enhancer, if one 1s present. Any pharmaceut1cally acceptable contact adhesive may be used. Represen~ative adhes1ves include mixtures of 2-cyanoaerylate and dimethyl ~ethylenemalonate, monomeric ester of alpha-cyanoacrylic acid, cross-linked copolymer of dimethyl-aminoethylmethacrylate and an alkyl acrylate, adhesive compositions comprising a hydrocolloid gum, polyisobutylene and cross-linked dextran, silicone medical adhesives, mineral o11-polyisobutylene adhesives, contact adhesives such as those disclosed in U.S. Patent NGS. 3,797,494 and 4,031,894, and the like. The adhesiYe optionally can contain a rheological agent that imparts th~xotropic characteristics to the adhes1ve, a1ds 1n 1ncreasing its cohesiveness and bond strength, 1mparts slump control, ma1nta1ns the delivery device 40 1n eontact with wall port10n 11 ~nd/or 36, and lets it be eas11y removed th~refrom at the end oP the del1very per10d. ~he rheological agents useful for this purpose are sil k on compounds such as fumed s111ca.
The ~dh~s1ve ~ay also opt10nally car~a1n a surf~ctane wh1ch allows bett~r contact betw~en th~ surfac~ o~ thQ dellv~ry dQv~c~ 40 and the ex~er10r surf~ce of wall port~on 11 and/or 36~ . -If necessary or desirablel known per~eat10n ~nh~ncers, such as ethanol or glycerol ~onolaurat~, may b~ conta1ned e1ther wi~h1n the -separate layer 44 (if one is present), in the adhesive layer 50, in the drug reservoir 48, or in any combination of these.
Most preferably, device 40 includes a rate controlling membrane 46 which is effective to control the rate at which the beneficial agent is delivered from reservoir 48 into container 12 and/or chamber 34. When dev ke 40 contains a rate controll~ng membrane 46, the wall portions 11 and 36 should prov1de mlnimal res~stance to drug flux.
The rate controll~ng membrane 46 may be compr1sed of permeable, semipermeable or m k roporous mater~als which are known in the art to control the flux rate of the drug out of the device 40. Su~table materials include polyvinylacetate and ethylen~ vinylacetate polymers. When a rate controlling membrane 46 is present in device 40, the beneficlal agent delivery rate is determined by the delivery device 40, and not by the wall port~ons 11 and 36.
However, it is also within the scope of the present invention to utilize a delivery device 40 containing no rate controlling membrane 46. When no rate controlling membrane 46 is provided in delivery device 40, the wall portion 11 and/or 36 should be comprised of a material wh~ch is effective to control the rate at which the beneficial agent is delivered into container 12 and/or chamber 34.
When the wall port10n 36 itself controls the rate at which the b~neficial agent ~s dellvered into chamber 34, the formulator 30 will be relat1vely drug specific (i.e., the for~ulator w~ll only be su1table to control the rate of del~very of a sp~cified drug or class of drugs. L~ke~lse9 when the wall port~on 11 ltself controls the rate at whlch th~ beneficial agent ~s d~l~vered ~nto th~ oonta~ner 12, the oonta1n~r 12 w~ll be relat~vely dru~ spec~1c (~.e., the IV
flu~d conta~ner will only b~ su~tabl~ to control th~ rate of d~llvery of a sp~c1f~d drug or class of drugs.3.
On the other hand, when ~he wall port~on 36 prov~d~s ~n1mal res~stance/contPol oYer the drug flux th~r~through, th~ formulator 30 can be used w1th a wide rang~ o~ drugs. Si~larly, when the wall pcrt~on 11 provides minimal resis~anoe/control over th2~drug flu~
2V~
ARC
therethrough, the container 12 can be used with a w7de rang drugs. However, in this s~cond configuration, the control o delivery should be provided by the drug delivery device 40.
preferred since transdermal type drug del~very devices are gen~
manufactured to deliver a spec~ftc drug at a spectfic drug deli rate.
The size (e.g., the surface area of adheslve layer S0 which in contact with wall port~on II and/or 36) of the dev1ce 40 can typically vary from less than 1 cm2 to greater than 200 cm~. An average device 40 however, will typ1cally have a size within the range of about 5-50 cm2.
Embodiments of device 40 in wh k h the drug and per~eation I5 enhancer supplies are separate (such as that illustrated in F~gure 4) may be advantageous or necessary in instances where formulation or storage of the drug and the enhancer in contact with each other is impractical or undesirable or where separation of the drug and the enhancer facilitates selection of the rate controlling membrane.
The size (i.e., the surface area~ of wall portlons ll and 36 should be large enough to acco~modate at least one dellvery device 40, and preferably large enough to acco~modate two or more delivery devices 40. By maklng wall portions Il and 36 large enough to accommodate a plural~ty of the del~very devices 40, ~t is possible to simultaneously d~llver mor~ than one ben~ficial a~nt into the IV
flu1d I3. Llke~1se, it is also poss1ble to del~ver a single ben~fklal agent at a d~livery rate whlch ls a IllUltipl2 (~!.9., 2X, 3x, 4x, etc.l o~ the deliv~ry rate ach~eved by a slngle del1very 30 dev1ce 40 (e.g., ~ adherin~ 2, 3, ~, etc. ~d~nt1cal d~v~ces ~a to wall portions Il and/or 36).
Important advantages achlevQd by ths cont~in~r 12 and the formulator 30 of the present inventlon 1nclude ~I) easy ad~ust~ent of the benef7cial agent d~l~very rate, (2) eas~ly chan~ng ~he typ~ of b~neflcial agent del1vered, (3) it is unnecessary ~or a nurse or a æ~ 3~
the beneficial agent delivery rate, (2) easily changing the ty~e of beneficial agent delivered, (3) it is unnecessary for 3 nurse or a pharmacist to preformulate the drug or other beneficial agent and (4) the drug or other beneficial agent has a longer stablP shelf-life since the drug is mainta1ned in a solid, rather than in solution, form. For instance, lf it Is des1red to 1ncrease the rate of delivery of a beneficial ag~nt (e.g., an ant1blot1c) into the flowing IV fluid 13, one can simply select a suitable antiblot k delivery devlce 40 with a specified delivery rate. Furthermore, if it is desired to either double, triple or quadruple the delivery rate of this particular antibiotlc, ~t is only necessary to apply 2, 3, or 4 delivery devices 40, respectively, to the wall portions ll and/or 36.
Likewise, if instead of delivering an antibiotlc it is desired to deliver an anti-cancer agent into the flowing IV fluid, it is only necessary to remove the antibiotic-containing drug delivery device 40 and replace it with an anti-cancer drug-containing delivery device.
Beeause the agent delivery devices 40 are attached to the exterior surfaces of cuntainer 12 and formulator 30, there is no danger of contamination of the flowing IV fluld. Thus, changing the type of drug delivered or the drug delivery rate does not require time consuming sterilization procedures. This is especially important when ut11izing devices wh1ch dellver protein for~ulations since prote1ns are sensitlve to heat sterll~zatlon and have a tendency to denature when heated.
Th~ 1n~ent1On ~s further lllustrated by th@ follo~tng ~xamples.
~ L~_~
A nitroglycerln l~N6~)/triethyl c~tr~t~ rQs~rYo~r co~pos1t1On compr~s~ng a s111cone med~cal flu1d c~rr1~r ~elled with s11 k a, hav1ng N6 on lactose un1fo~mly dispers~d th~r~through and ~r~ethyl citrate (C~troflex A6, sold by Morflex Inc. of 6r~nsboro, NC) absorbed ~n a part~culate carr~er ~s ~abrlcated by plae1ng 5 kg of z~
silicone medical fluid having a vlscosity of abou~ 100 centistokes and 175 grams of colloidal s~licon dioxide in a high energy mixing vessel and blending to produce a gelled silicone fluid. 200 Grams of Accurel~ porous polypropylene aYailable from ARMAK Company is placed in a separate vessel and approximately 1200 grams of Citroflex A6 is added w1th st~rring to produce an essentlally dry flowable powder whlch on visual observat~on appears to have absorbed substantially all of the C1trofle~. S kg of nltroglycer1n-lactose (10 wt %
n~troglycerin) and the Citroflex loaded porous polypropylene is placed in the original high energy mix~ng vessel and mixed until a homogeneous blend is obtained. A fonm-fill-seal pouching machine is used to pouch the NG-Citroflex gel so form2d between an impermeable backing member comprising a medium density polyethylene/aluminized polyester/ethylene vinyl acetat~ multilam1nate (Medpa~ 1006 available from Minnesota M1ning & Manufactur1ng Company) peripherally thermosealed to the rate controlling membrane layer of a trilaminate film consisting of a release liner layer formed from polyester film coated with a film release agent, an adhesive layer formed of silicone medical adhesive and a release rate controlling membrane layer formed from a 1 mil thick ethylene vinyl acetate (12% VA) membrane. Oevices are fabrlcated having an NG/Citroflex releasing surface area of approximately 5 cm2.
One of the d~vic2s is adhered to an IV drug formulation chamber having the sam~ shape and configuration as the formulation chamber illustrated ~n F19ur~ 5. Wall portlon 36 ls formed of polyvlnylchlorlde whlch ~s initlally unplast1c~zed and imp~rmeable to th3 passaga of nltroglycer1n. ThQ thlckn~ss of wall portion 36 is 5 m1ls. Onc~ the drug del~very dev k e 1s attached to th~ ~all ~f the drug for~ulat10n cha~ber, the d~vic~ del~v~rs C~tro~l~x A6 lnto the polyv1ny k hlor1de wall. C1troflex A6 ls a plast1clzQr for polyv1nylchlor~de. After a perlod of t1~, th~ portlon of the chamber wall wh1ch 1s lm~d1ately adJ~cQnt to th@ drug dellvery d~vice becom~s plast~c k ~d and drug per~eabl~. Thereafter, n1troglycerlne is del1vered by the dev1ce through th~ drug permeable ~ 3~3'~
wall portion and into the IV fluid within the drug formulation chamber.
EXAMPlE I I
s A monolithlc transdermal devlce ls prepared by melt blendlng 33 parts ethylene v1nyl acetate (40% VA) wlth 32 parts Staybelite Ester No. 5, 5 parts estradlol val~rate and 2S parts triethyl cltrate (Cltroflex A4 sold by Morflex Inc. of Greensboro, NC). The m1xture IO is extruded and calendared to a th k kness of 12 m11s between an occlusive backing film of the type descrlbed in Example I and a strippable rel~ase liner film. Ind~vidual devices are rotary die cut with an area of 50 cm2.
One of the devices is adhered to an IV drug formulatlon chamber of the type described above in Example I. Once the drug delivery device is attached to the wall of the drug formulation chamber, the device delivers Citroflex A4 into the polyvinylchloride wall.
Citroflex A4 is a plasticizer for polyvinylchloride. After a period of time, the portion of the chamber wall which is immediately adjacent to the drug delivery device becom~s plasticized and drug permeable. Thereafter, estradlol valerat~ is delivered by the device through tbe drug permeable wall portiQn and into the IV fluid within the drug formulation chamber.
Other b~n~flts and advantag~s of th~ lnventlon will become apparent to those skllled ~n the art. ~hile the pr~ferred embod1m~nts of th2 lnvention hav~ been select~d for illustration in the dra~lngs and h2ve be~n descr~bed 1n d~tall h~reln, thsse skilled ln th~ art ~111 appreclat~ that v~P1ous ~od1flcatlon6, ehangas, addltlons and o~lsslons from th~ lllustrat~d ~b~dl~nt5 oan b~ ~ade wlthout departlng fro~ the splr1t and scop~ of th~ lnv~ntlon~ as daflned 1n the appended clal~s.
A further objcct of the invention ls to provide an intravenous therapeutlc system including a contalner of an ~ntravenous medical fluld and a drug formulation chamber ~n comb~nation w1th a drug del1very devlce wh1ch can del~ver drug, to a flowlng IV flu~d, at a rate wh k h 1s variable and which ~s accurately controlled by the components of the system.
OL~CLO$URE OF THE INVEN~ION
These and other objects are met by an agent formulator, a parenteral admtnistration system and a method for the controlled parenteral a~mlnistration of a beneficial agent to an animal. The agent formulator comprises a chamber having fluid inlet and fluid outlet means to maintain a continuous flow of a parenterally acceptable fluid therethrough. The chamber has a wall portion that is permeable to a beneficial a~ent to be delivered into the fluid.
The beneftc1al agent should be soluble in the parenteral fluid to enable the agent to diffuse through the wall portlon. A flow dlstr1butor ts prov1ded wlth1n the chamber for d~str1but~ng the flow of parenteral fluld along an lnter10r surface of the wall port~on.
An agent d~l1v~r~ d~v~ce ~s releasably attached to an eas11y acce~s1ble exter~or surface of the wall port~on. The delivery device includes a r~servo1r contain~ng the benefic~al agent to be delivered into th~ par~nt~ral flu1d. Preferably, the delive~y dev~ce ls a transderm~l typ~ drug dellvery devic~ compr1s~ng a laMinate 1ncludlng a b4cklng me~b~r, a middlQ reservo1r contalntng the benef~c1al agent and an adhes1ve sur~ace adapted to r~l~asably adh~re to th~ ex~r10r surface o~ the wall port~on. Most preferably, the agent del1very dev~ce a7so 1nclud~ a rate controll~ng me~brane wh1ch controlj the rate at which the agent ~s del~vered through th~ w~ll port~on.
~ 9 ~3'~
In operation, the fluid flow1ng through the chamber is distributed by the flow distributor along th~ interior surface of the wall portion, thereby causing the agent to diffuse from the device through the wall portion and into the f10wing fluid. The agent is delivered at a rate that is controlled substantially by the formulator and which is substantially ind~pendent of the volumetric flow rate of the fluid flowing through the chamber.
The presPnt lnvent~on also provldes a parenteral delivery system for administer~ng an agent parenterally to an animal. The system comprises in combination, a conta~ner of a pharmaceutically acceptable parenteral flu~d that ls a carrler for the agent and a parenteral fluid administration set. The admin~stratlon set is connected to the container fsr permitt~ng the fluld to flow from the container through the administration set to the animal. The administration set comprises a drip chamber, tubing extending from the drip chamber to the animal, and an agen~ ~ormulator connected into the tubing such that the intravenous fluid flows through the formulator. The formulator lncludes a chamber having fluid inlet and outlet means to maintain a continuous flow of the parenteral fluid therethrough. The chamber has a wall portion that is permeable to a beneficial agent to be delivered into the flu~d. The beneficial agent should be soluble in the parenteral fluid to enable the agent to diffuse through the wall portion. A flow d~stributor ls provided with~n the chamber for d~str~butlng the flow of parenteral fluid along an inter~or surface of the wall port~on. The formulator also includes an agent deliv~ry device releasably attached ~o an easily access~ble external surface of the wall port10n. The delivery device includes ~ reservo~r containing ~h~ benef~clal agQnt to be delivered.
Pref~rably, th~ d~livery dev~ce ~s a transd~rmal drug d~l1very dev~ce compristng a l~nate ~nclud1ng a backing me~bar, a m~ddle res~rvoir contain~ng the benef~clal agent and an adheslv~ s~rf~ce ad~pted to releasably adhere to the external surface of th~ w~ll port~on. Most preferably, the agent dellvery device lncludas a rate controlling membrane which controls the rate at ~h k h ~he agent ls dcl1Yered through the wall portion.
A ~
6 Al In operation, the fluid flowing through the chamber distributed by the flow dlstributor ~long th~ internal sur~
wall portion, causing the agent to diffuse from the device ~
the wall portion and into the flowing fluid. The agent is de at a rate which is controlled substantially by the formulator which is substantlally tndependent of the volumetrlc flow rate fluid flow~ng through the chamber.
The present lnvent~on further provldes a method for the controlled parenteral admin1stratlon of a bene~clal agent, such as drug, to an animal, such as a human. The method compr1ses the steps of allow~ng a pharmaceutically acceptable parenteral flu~d, which is a carrier for the agent, to flow through an agent formulation chamber. The chamber has an inlet communicating with a conta~ner of the parenteral flutd and an outlet communicating with thc animal.
The chamber also has a wall port~on that is permeable to the agent and prevents convective flow of parenteral fluid therethrough. The method further comprises the steps of distributing the flow of parenteral fluid along an interior surface of the wall portion and releasably attaching an agent delivery device to an accessible exterior surface of the wall portion.
The delivery devlce includes a reservolr containing the benef1cial agent to b~ dellvered. Preferably, the d21~very device is a transdermal drug del~very device compr1sing a lam~nate including a backlng memb~r, a middle reservotr contain~ng the beneftc1al ag~nt and an adheslvQ surface adapted to releasably adhere to the external surface of the wall portion. Most preferably, the agent dellYery dev1ce ~ncludes a rate controlling membran~ wh~ch controls th~ rate at wh~ch th~ agent is del~vered through th~ ~ll portlon.
In operatlon, the fluld flow~ng through th~ charber ls d~str~butsd along th~ inter~or surface of th~ w~ll port10n, caus1ng the agent to diffuse from the deYice through the w~ll port~on and into the flowing flu~d. The agent ~s released at a r~te which ls controlled substanttally by the del~very d~v1ce and which is substantially independent of the volumetric flow rate of the fluid flowing through the chamber. The methnd is effective to administer the drug/agent to the animal in a beneficially effective amount over a prolonged period of time.
BRIEF ~ESCRIPTION OF THE DRA~L~
Figure 1 is a perspective view showing an agent formulator 30 and its use within an intravenous delivery system 10;
Figure 2 is a sectional view of one embsd~ment of an agent formulator according to the present invention;
Figure 3 is a sectional view of the agent formulator illustrat~d in Figure 2, taken along line 3-3;
Figure 4 is a detailed sectional view of a preferred drug delivery device 40 wh k h is adapted to be attached to formulator 30 as shown in Flgures 1-3;
Figure 5 is a perspective ~iew showing an agent formulator 60 which can be used in an intravenous delivery system 10; and Figure 6 ts a crass-sectlonal view of for~ulator 60 taken along line 6-6.
In the spec~flcat10n and the drawings, like parts in related F~gures are 1dentlfied by like numbers.
~
Figure 1 1llustrates an operatlve 1n~ravsnous dellv~ry system, genarally des19n~ted by the num~ral 10, showlng th~ poslt~on~ng of an agent farmulator 30 there1n. Syste~ 10 comprlses a cont~1ner 12 that contains a ~luid 13 suitable for intravenous admln~stratlon, and an admin~stration set, generally designated 14. The fluid 13 in container 12 will typically be a medical fluid, i.e., a sterile solution such as an aqueous solution of dextrose, saline, and/or electrolytes. Fluid 13 is a vehicle for intravenous administration of a pharmaceutical agent to a recipient. Container 12 is manufactured from glass or plastic, and is preferably of the no air-tube vacuum type and thus it is used with an admin~stration set that has an a1r inlet filter. Other types of containers such as the air-tube vacuum type, or the non-vented type, can b~ used for the intended purpose. These alternative containers do not requlre an air filter in the administration set. Container 12 can be rigid, semi-rigid or flcxible in structur~, and it is usually adapted to be hung neck-down from a hanger 15 by a handle 16 that connects or surrounds container 12. The neck of container 12 is covered by a closure 17, generally made of rubber and air-tight.
Alternatively, container 12 can take the form of an infusor or a syringe pump (not shown in the Figures), and in particular a portable infusor or syringe pump, of the kind known in this art.
Administration set 14 and container 12 ar~ interconnected by piercing closure 17 with one end of a hollow spike 18 attached to or formed as a part of administrat~on set 14. Spike 18 is equipped with a side air vent 19. The other end of spike 18 is enlarged and fits snugly ints a drip chamber 22. Drip chamber 22 traps air contained in the set 14 and fac11~tates ad~ust~ng the flow rate of intravenous flu1d 13 from conta~ner 12 as the flow proceeds drop w~se. The outlet at the bottom ~f drip chamber 22 ls connec~ed to a flrst segment of tubing 23 which fits into agent formulator 30, the details of wh1ch are presented in Figures 2 and 3. A second segment of tub1ng 25 leads from agent formulator 30 to bacterlal f~lter 27. A
third segment of tubing 29 extends from ~ilt~r 27 to an 1nfuslon agent receptor s1te, termlnat1ng ~n an adapter-n~edle assembly 28 that ls lns~rt~d into a ve1n of 2 ~arm-blooded an~mal 20, shown as a human arm. A piece of tape 21 hold~ adapter-needle assembly 28 f~rmly ln place on the rec1pient's arm. The adm~n1strat~on set can also include a pa~r of tubing clamps 24 and 26 located on e~ther side ~33 ~ 3r~
of formulator 30 which may be used to govern or stop the flow of intravenous fluid through the intravenous delivery system 10.
In one embodiment of the present invention, a portion of the wall of container 12 is comprtsed of a material 11 which is permeable to the beneflctal agent contatned wtthtn, and delivered by, the deltvery devtce 40. The wall portton 11 forms a ~drug delivery wtndow~ wtthtn the otherwtse tmpermeable wa11 of contatner 12.
Durtng delivery of beneftcial agent ~rom devtce 40, the IV fluid l3 must be tn contact wtth the intertor surface of wall portion 11.
Accord1ngly, the wall portton 11 ts preferably located tn a downstream portion of the wall of contatner 12 most preferably adjacent the neck of container 12.
As an alternative to, or in addition to the drug delivery window 11 in container 12, an agent formulator 30 may be provided downstream from the container 12. Agent formulator 30, as seen in Figures 2 and 3, comprises a wall 32 forming a chamber 34. At least a portion of the wall 32 is comprised of a material 36 which is permeable to the beneficial agent oontained within, and delivered by, the delivery device 40. The wall portton 36 forms a drug delivery window, stmilar to wall portion 11, within the otherwise impermeable wall 32 which may be formed of glass, plastic or the like.
As best shown in Figures 2 ~nd 39 a flow diverter 38 ts provtded w1thln chamber 34. The flow dtverter 38 is secured within chamb~r 3~ by supports 39. Preferably, formulator 30 h~s a cyl1ndrlcal shap~ and the wall portton 36 extends around th~ enttre ctrcumfer~nc~ o~ fo~mulator 30. The flo~ d1vert~r 3~ also preferably has a rsughly cyltndr k al shape. The entlre cha~b~r 34 preferably rsmatns f111ed w~th the flowtng IV ~lu1d 13 to ensure that the entire tnter10r surfar~ of wall portlon 36 1s ln contact wtth the flowlng IV
fluid 13. Th~ flo~ d1ver~er 38 provid~s two lmportant funct10ns in the formulator 30 of the present tnv~nt10n. Ftrst, th~ flo~ dtverter 38 dtverts the flow of IY flutd tn ths dtrection sho~n by the arrows in Figure 2, i.e., along the tntertor surface of w~ll portton 36.
Secondly, the flow diverter 38 minimizes the dead volume within formulator 30. Those skilled in the art will appreciate that the flow diverter 38 forces the IV fluid to flow in a relatively constricted space between the flow diverter 38 and the wall portion 36, thereby enabling a greater percentage of the IV fluid 13 to contact the interior surface of wall portlon 36.
The efflciency of drug transfer into the IV fluid 13 is greatly enhanced by the flow diverter ~8. Flow dlverter 38 creates a higher liquid flow veloclty (for any given liquid volumstric flow rate) along the interior surface of wall portion 36 which helps elim~nate any stagnant fluid layer. In accordance with well known flow principles, the thickness of the stagnant fluid layer along the walls of chamber 34 decreases as the fluid flow veloc1ty through chamber 34 increases. This creates several benef kial effects. First, there is a trend to reduce the number of air or gas bubbles which might otherwise form on the interior surface of the wall portion 36 and which reduce the effective area of the wall portion through which drug can be transfered into the IV fluid. The higher fluld flow velocity also promotPs higher drug transfer rates by maintaining a lower drug concentration in the IV fluid adjacent the wall portion 36.
An alternat1ve embodlment of an agent formulator is shown in Figures 5 and 6 and 1s designated by 60. Ilke formulat4r 30, formulator 60 1s also connectable to an ~ntravenous administration set by connectlng to ~nlet tub~ng 23 and outlet tub1ng 25. Agent fo~mulatsr 60 eomprlses a wall 32 and a wall port10n 36. The deltvery deYlce gO ~s adapted tu be secured to wall portlon 36. ~all port10n 36 ls csmprlse~ of a mater1al ~h1ch ~s peri~bl~ to the benef1e1al ag~nt conta1ned w1th1n, and d~l1Ysred by, th~ d~l1very device 40. The wall portion 36 forms a drug delivery window, similar to wall portlon ll (F~gure l) and wall port10n 36 (F~gur~ 2~, withln the otherwise ~mpermeable wall 32 which is preferably formed of a moldable plastic, e.g., polyethylene terephthalate.
Z ~ J ~
As shown in Figures 5 and 6, wall 32 is molded to form a tortuous flow path 67 defined by a plural1ty of flow diverters 68.
Wall portion 36 may be bonded to the wall 32 using heat and pressure according to well known methods. Thus, the IV fluid 13 flows along the interior surface of wall portlon 36 as shown by the arrows. The tortuous flow path 67 ach~eves the same bcnef1ts of higher liquid flow velocity, elimination of stagnant flu~d layers, reductlon in air or gas bubbles and higher drug transfer rates mentioned above with respect to flow diverter 38 (F~gur~s 2 and 3).
The wall portions 11 and 36 may be compr~sed of known drug permeable and/or microporous mater~als which allow the beneficial agent delivered by device 40 to diffuse therethrough but which prevent convective IV fluid flow therethrough. The composition of wall portions 11 and 36 should be selected in accordance with the type of beneficial agent being delivered by device 40. In general, the wall pcrtions 11 and 36 should be comprised of a polymeric composition that allows a drug or other beneficlal agent delivered by device 40 to diffuse through the wall portion and into the interior of container 12 and/or into chamber 34. Representative polymers for forming wall portions 11 and 36 include olefin polymers, ~inyl polymers, condensation polymers, addltion polymers, rubber polymers and silicone polymers, and in particular, poly~thylene, polypropylene, polyv1nyl acetate, polyvlnyl acetal, polyvinyl chloride, polya~1des, polyesters, butad~ene rubber, organo-silicone polymers and copolymcrs thereof.
Xhen th~ d@vlce 40 del1Yers a hydrophtl~c drug, the wall port10ns 11 and 36 ar~ preferably oomprlsed of a hydrophll1c or microporous ~ater1al. Examples of su~table hydrophil~c ~terl~ls lnGlud~ polyureth~nes, polyvinyl ~lcohols, polya~1d~s and cglloph~ne.
Of these, polyurethanes and celloph~n~ ar~ mos~ preferr~d. Su~table m1croporous mater1als are descr~bed belo~ ~n connect10n wlth the dellvery of polypeptld~s, proee1ns and oth~r macromolecules.
~ 3~3~3'~
When device 40 delivers a lipophilic drug, the wall portions 11 and 36 are preferably comprised of a lipophilic material. Examples of suitable lipophilic materials include natural rubbers, silicone rubbers, Hytrel~ (a thermoplastic polyester elastomer sold by E.I.
DuPont de Nemours of Wilmington, DE), ethylene vlnyl acetate (E~A), polyvinyl chlorlde, and Kraton~ (a styrene-butad~ene block copolymer sold by Shell Chemical Co. of Houston, TX). Of these, ethylene vinyl acetate copolymers, silicone rubbers and natural rubbers are preferred.
When device 40 delivers a polypeptide, prote~n or other macro-molecule, th~ wall portions 11 and 36 are preferably compr~sed of a microporous material. The pores in the microporous material will generally have a sl~e of less than about 0.2 m~crons, and preferably about 0.01 to 0.2 microns. Pores having the above recited size ranges are too small to allow bacterial cells to pass through the pores and can thereby maintain the sterility of the container 12 and/or the cha~ber 34. In general, microporous materials having pore sizes in the above mentioned range will allow water molecules from th~ parenteral fluid to diffuse into the membrane. In some cases, the exterior of the wall portions 11 and 36 will feel wet to the touch. However, mlcroporous membranes having the above mentioned pore si7e ranges w~ll be ef~ective to prevent convec~iYe flow losses of water-based parenteral fluids through the wall port~ons 11 and 36.
If necessary or des~rable, the microporous wall portions 11 and 36 can b~ treated w~th a water non-wetting ~aterial to further reduce cap1llary IV flu1d losses through the wall por~ons 11 and 36. In add1t1On, the dellvery devlce 40 may ut~llze a carr~er wh1ch ~s imm~sc~ble ln water. In such a casQ, th~ benef~clal agent 1s suspended ln a water-~mmlsclbl0 flu1d carrler (~.9., an o1ll. ~hen the o~l-based carrler ent~rs the pores of th2 ~1croporous ~æ~brane, the pores will repel any water-based parenteral flu~d wh1ch helps prevent convect~ve losses through the wall port~ons 11 and 36.
Examples of sultable microporous materlals ~nclude Celgard~ (a microporous polypropylene film sold by Celanese Chemlctl Co. o~
~ 3~-~ 9 ~3f~
Dallas, TX) cellophane, glass frits, vycor glass, porous glass and microporous membranes of the type utilized in known elementary osmotic pumps. Of these, porous glass is most preferred.
Selection of polymers for forming wall portions 11 and 36 for the passage of a drug therethrough can be determined by measur~ng the rate of diffusion through the polymeric wall materlal. Various techniques can be used So det2rmine the permeability of a homopolymer, copolymer, or terpolymer to the passage of a drug. One method that can be used is to position a fllm of the polymer, of known thickness, as a barrler between a rapidly stirred, saturated solution of the drug and a rapidly stirred solvent bath (typically water), at a constant temperature, typically 25-C, and periodlcally measuring the concentration in the drug solut10n and in the solvent bath. Then, by plotting the drug concentration in the solvent bath versus time, the permeability coefficient, P, of the polymeric film may be determined from Fick's Law of Oiffusion. Fick's Law of Diffusion is expressed by the following equation (I):
Slope o~ plot - (Q2 - Q~/e2 - tI) - P AC/h (I) wherein:
Ql ~ cumulatlve amount of drug ln the downstream solvent in micrograms at t1;
Q2 ~ cumulatlve amount of drug ln solvent in micrograms at t2;
tl ~ el~psed tlme to first sa~ple, l-e-7 Ql;
t2 ~ elapsed tlme to second sample, l.~ 2;
A - area o~ f~lm ln c~2;
C ~ concentration of drug ln sa~urated solut~on; and h ~ thickness of film in cm.
By determining the slope of the plot, i.e., [Q~ - ~2/t1 - t2J and solving the equation using the known or measured values of A, C and h, the permeability coefficient, P, in cm2/time of the film for a given drug is readily determined. The procedures used to determine the rate of release through the polymer can be ascertained easily by standard techniques known to the art as recorded in J. Pharm. Sci., Vol. 52, pp 1145-49, (1963); ibld, Vol. 53, pp 798-802, (1964);
ibid, Vol. 54, pp 1459-64, (1965); ibid, Vol., 55, pp 840-43 and 1224-39, (1966); EncYl. PolY~er ~1.. Technol., Vol. 5 & 9, pp 65-82 and 794-807, (1986); the references cited there~n, and the like.
Wall portions 11 and 36 may also optionally contain a plasticizer such as a member selected from the group conslsting of phthalate ester, adipate ester, sebacate ester, azelate ester, di(2-ethylhexyl~ phthalate, butyl phthalyl butyl glycslate7 diamyl phthalate, dibutyl succinate, diethylene glycol dipropionate, glycerol monooleate, ethyl phthalyl ethyl glycolate, triethyl citrate, tributyl citrate, trialkyl citrates sold under the tradename Citroflex by Morflex Inc. of Greensboro, NC, tributyl phosphate, triethylene glycol dibutyrate, glycol monoleate, polyethylene glycol 200; polyethylene glycol 400-mono laurate, diethyl lauramide, oleic and mineral oil, epoxidized soybean oil and the like. The amount of plasticizer in wall portions 11 and 36 is from about 5 weight percent (wt %) to 30 wt Z, or more.
In ~n alt~rnative embodiment of ~he invention, the agen~
permeable w~ll portion 36 ~ay be formed in s~tu. For example, wall 32 of forTulator 30 may be composed of a polymer, such as polyvinylchlor~de, a polyester or a polyur~thane, whkh is ini~ially 30 impermeable to the passage of drug or agen~. A portion 36 of wall 32 can be treated with a per~eability enhane~ng ~gent, such as a plastic1zer or a transderm~l per~at10n enh~nc~r, 1n srder to fora a druy permeable w~ll portion 36 ~n sltu. Th~ plast1c1z~r ~ay be del1~ered concurrently w~th the drug or agent frw~ d~liv~ry device 35 40. For example, when the wall 32 is fQrned of polyv1nylchlor~de, delivery device 40 contains both drug and a plastlcizer of ;2~ 3~8 ~
Thereafter the drug is delivered by device 40 through wall portion 36 into chamber 34.
When the wall portions 11 and 36 are comprised of a material ha~ing poor rigidity and/or strength, it may be supported by a rigid porous or grid-like polymer structure (not shown in the figures) provided within the contalner 12 or w~th~n chamber 34. The porous or grld-l~ke polymer structure should allow the IV fluid to contact the inter~or surface of wall port1Ons 11 and 36 to allow the beneficial agent to be delivered into the IV fluid. ~hen the wall portlons 11 and 36 are comprised of a fragile mater~al or a materlal having poor tear strength, it may be necessary to provide a protective covering (not shown in the figures) thereover. The protective covcring can take any number of forms but in any event should be effectlve to prevent or minimize unnecessary stresses placed on th~ wall portions 11 and 36 and yet provide easy access to attach a drug delivery device 40 thereon.
In its broadest sense, the drug delivery device 40 comprises a beneficial agent-containing reservoir which can be releasably attached to the exterior surface of the wall portion 11 and/or 36.
Typically, the reservo1r comprises a polym~ric matrix having a drug or other benef1c1al agent d1spersed therein. The reservo~r may be releasably attached to the wall portions 11 and/or 36 us~ng tape, clamps, adhes~vss or other convent~onal attachlng means. M2chanical attaching ~eans are preferred where the benefic~al agent delivered by the devlce ~s lncompat~ble w~th ~dh~s1ves. In eases where the beneflc1al agent 1s adheslve-compat~ble, the res@rvo~r preferably incorporat~s a r~1easabl2 cont~ct adhas1v~, or has a r~le~s~bl~
contact adheslve layer coated on on~ s~d~ th~reof9 so that th~
reservotr 1s ltself releasably adh~red to th@ ~ll port1On 11 and/or 36.
.
The ~gent delivery dev~ce 40 used in the present ~nvention ls not limited to any part~cular type or s~ruoture. Many ultable dev~ces are known 1n th~ art and have genQrally been used ~n ~ 3~3 applications wherein a drug sr other beneficial agent is administered transdermally. Examples of suitable agent del~very devices 40 may be found for example in U.S. Patents Nos. 3,536,809i 3,598,122;
3,598,123; 3,787,571; 3,699,963; 3,731,683; 3,734,097; 3,~42,951;
3,797,494; 3,964,482; 3,996,934; 4,031,894; 4,060,084; and others to name just a few. The teachings of the above listed patents concerning the relevant structures o~ the drug del~very devices and the particular drugs which may be su~tably administered using these devices are incorporated herein by reference.
A preferred drug delivery dev~ce 40 is illustrated in Flgure 4.
Device 40 is a multilaminate system comprised of an impermeable backing layer 42, a drug reservoir 48 and an adhesive layer 50.
Device 40 also includes a permeation enhancer-containing layer 44 (e.g., an ethanol gel layer) and a rate controlling membrane 46. A
strippable release liner 52, adapted to be removed prior to application, ~s normally included in the packaged product.
The drug reservoir 48 may be comprised of a polymeric matrix or carrier having the drug/beneficial agent to be delivered, d7spersed throughout. The polymer matrix stores and releases the beneficial agent/drug by diffusion or by osmotic action to wall port1On 11 and/or 36. Representative polymers for forming the matri~ may be selected from homopolymers, copolymers, cross-l1nked polymers, diffusion polymers and m k ropsrous pslym~rs. Examplss of sultable polymers include acrylic polymers and copolymers of m~thacrylate, ethylacrylate, ethylm~th2crylate, and m2~hylmethacrylate;
homopolym*rs and copolymers includ~ng vlnylchlorld~-vinylacetat~
copoly~er; chlorlnat~d vinyl chlortd~; poly~thylene; polypropylene;
ethylene-propylene copolymer; chlorinatgd poly~thylen~;
ethylene-vinyl acetate copolym~r (EVA) of th~ typ~ describ~d in U.S.
Patcnt No. 4,144,317; styrenebutad1~n2 copolyR~r;
acrylon~tr1le-styrene-butadiene terpoly~r; polyvinylid~n~ chloride;
vinylchloride-acrylonitrile cspoly~ær; v1nylchlor~ds-v~nyl~d~ne chloride copolymer; vinyl~denechlsr~de-acrylate ester copolymer;
polybutylene terephthalate; v~nylchloride-acrylat~ ester copolymer;
%~
cross-linked polyvinyl acetals such as cross-linked polyvinyl formal;
cross-linked polyvinyl acetal and cross-linked poly~inyl butyral;
polyethers; polyesters; sparingly cross-linked polyesters;
polyurethane; polyamide; chlorosulfonated polyolefins; polyolefins;
polybutadiene; polyisoprene; polysil k one; natural and synthetic rubbers; and the like. The polymers are known in The Handbook of Common PolYm~rs, by Scott et al., (1971), published by CRC Press, Cleveland OH; in Modern Plast1cs ~ncYclQ4e~ia, (1979), published by McGraw-H1ll Inc., New York, NY; and in H~ndbook of Plastics and Elastomers, by Harper, ~1976), published by McGraw-Hill Inc., San Francisco, CA.
The drug reservoir 48 may contain the drug alone or it may contain the drug along with one or more permeation enhancers. The drug/beneficial agent should either itself be soluble in the parenteral fluid or be capable of being solubilized using adjuvants such as surfactants and/or co-ions. The amount of drug in the reservoir 48 will depend upon the rate at which the drug is delivered from the system and the intended duration of therapy. The amount of drug/beneficial agent in reservoir 48 generally will be abou~ 0.1% to 80% by weight, with a more preferred amount of 5X to 50% by weight.
The device 40 can b~ manufactured for delivering benefic~al amounts of a drug over a prolonged period fro~ about 0.5 hours to several days or longer, wlth a more preferred perlod o~ about 4 to 50 hours.
The dev1ce 40 used in the pres~nt invent~on releases from 10 ng to 750 mg psr hour, or h1gher. Th~ reservo1r 48 may also include d1luents, stab~ ers, vehicles, gelling agents, and the like.
Th~ back1ng member 42 serves the purpose o~ insur~ng unid~r~ct10nal passag~ of drug throu~h ~ll port10n 11 and/or 36 1nto cont~1ner 12 and/or chamber 3~, and also of provld1ng support for the system, wher~ need~d. The back~ng la~r can be fl~x1bl~ or nonflex1bl~ and su1table materlals lnelud~, ~1thout l1mltat10n, cellophane, cellulose ace~ate, ethylcel1ulos~ plast1ct2ed vinylacetate-~1nylchlor1de copoly~ers, polyethylene t~rephthalate, nylon, high and low density polyethylene, polypropylene, metalized 9~3~
polyester films, polyvinylidene chloride, coated flexible fibrous backings such as paper and cloth and aluminum foil. Such backings can be in the form of precast films or fabrics which are bonded to the reservoir by heat or adhesives and can be coated onto the reservoir 48.
The device 40 is held in place on wall port10n 11 and/or 36 by means of an in-11ne pharmaceut1cally acceptable contact adhesive layer 50. Drug and/or a permeat10n enhancer may also be ~ncorporated into the adhesive layer 50. The compos1t10n and th k kness of the adhesive layer 50 are preferably such that 1t does not const1tute a significant p~rmeation barrier tn the drug or the permeation enhancer, if one 1s present. Any pharmaceut1cally acceptable contact adhesive may be used. Represen~ative adhes1ves include mixtures of 2-cyanoaerylate and dimethyl ~ethylenemalonate, monomeric ester of alpha-cyanoacrylic acid, cross-linked copolymer of dimethyl-aminoethylmethacrylate and an alkyl acrylate, adhesive compositions comprising a hydrocolloid gum, polyisobutylene and cross-linked dextran, silicone medical adhesives, mineral o11-polyisobutylene adhesives, contact adhesives such as those disclosed in U.S. Patent NGS. 3,797,494 and 4,031,894, and the like. The adhesiYe optionally can contain a rheological agent that imparts th~xotropic characteristics to the adhes1ve, a1ds 1n 1ncreasing its cohesiveness and bond strength, 1mparts slump control, ma1nta1ns the delivery device 40 1n eontact with wall port10n 11 ~nd/or 36, and lets it be eas11y removed th~refrom at the end oP the del1very per10d. ~he rheological agents useful for this purpose are sil k on compounds such as fumed s111ca.
The ~dh~s1ve ~ay also opt10nally car~a1n a surf~ctane wh1ch allows bett~r contact betw~en th~ surfac~ o~ thQ dellv~ry dQv~c~ 40 and the ex~er10r surf~ce of wall port~on 11 and/or 36~ . -If necessary or desirablel known per~eat10n ~nh~ncers, such as ethanol or glycerol ~onolaurat~, may b~ conta1ned e1ther wi~h1n the -separate layer 44 (if one is present), in the adhesive layer 50, in the drug reservoir 48, or in any combination of these.
Most preferably, device 40 includes a rate controlling membrane 46 which is effective to control the rate at which the beneficial agent is delivered from reservoir 48 into container 12 and/or chamber 34. When dev ke 40 contains a rate controll~ng membrane 46, the wall portions 11 and 36 should prov1de mlnimal res~stance to drug flux.
The rate controll~ng membrane 46 may be compr1sed of permeable, semipermeable or m k roporous mater~als which are known in the art to control the flux rate of the drug out of the device 40. Su~table materials include polyvinylacetate and ethylen~ vinylacetate polymers. When a rate controlling membrane 46 is present in device 40, the beneficlal agent delivery rate is determined by the delivery device 40, and not by the wall port~ons 11 and 36.
However, it is also within the scope of the present invention to utilize a delivery device 40 containing no rate controlling membrane 46. When no rate controlling membrane 46 is provided in delivery device 40, the wall portion 11 and/or 36 should be comprised of a material wh~ch is effective to control the rate at which the beneficial agent is delivered into container 12 and/or chamber 34.
When the wall port10n 36 itself controls the rate at which the b~neficial agent ~s dellvered into chamber 34, the formulator 30 will be relat1vely drug specific (i.e., the for~ulator w~ll only be su1table to control the rate of del~very of a sp~cified drug or class of drugs. L~ke~lse9 when the wall port~on 11 ltself controls the rate at whlch th~ beneficial agent ~s d~l~vered ~nto th~ oonta~ner 12, the oonta1n~r 12 w~ll be relat~vely dru~ spec~1c (~.e., the IV
flu~d conta~ner will only b~ su~tabl~ to control th~ rate of d~llvery of a sp~c1f~d drug or class of drugs.3.
On the other hand, when ~he wall port~on 36 prov~d~s ~n1mal res~stance/contPol oYer the drug flux th~r~through, th~ formulator 30 can be used w1th a wide rang~ o~ drugs. Si~larly, when the wall pcrt~on 11 provides minimal resis~anoe/control over th2~drug flu~
2V~
ARC
therethrough, the container 12 can be used with a w7de rang drugs. However, in this s~cond configuration, the control o delivery should be provided by the drug delivery device 40.
preferred since transdermal type drug del~very devices are gen~
manufactured to deliver a spec~ftc drug at a spectfic drug deli rate.
The size (e.g., the surface area of adheslve layer S0 which in contact with wall port~on II and/or 36) of the dev1ce 40 can typically vary from less than 1 cm2 to greater than 200 cm~. An average device 40 however, will typ1cally have a size within the range of about 5-50 cm2.
Embodiments of device 40 in wh k h the drug and per~eation I5 enhancer supplies are separate (such as that illustrated in F~gure 4) may be advantageous or necessary in instances where formulation or storage of the drug and the enhancer in contact with each other is impractical or undesirable or where separation of the drug and the enhancer facilitates selection of the rate controlling membrane.
The size (i.e., the surface area~ of wall portlons ll and 36 should be large enough to acco~modate at least one dellvery device 40, and preferably large enough to acco~modate two or more delivery devices 40. By maklng wall portions Il and 36 large enough to accommodate a plural~ty of the del~very devices 40, ~t is possible to simultaneously d~llver mor~ than one ben~ficial a~nt into the IV
flu1d I3. Llke~1se, it is also poss1ble to del~ver a single ben~fklal agent at a d~livery rate whlch ls a IllUltipl2 (~!.9., 2X, 3x, 4x, etc.l o~ the deliv~ry rate ach~eved by a slngle del1very 30 dev1ce 40 (e.g., ~ adherin~ 2, 3, ~, etc. ~d~nt1cal d~v~ces ~a to wall portions Il and/or 36).
Important advantages achlevQd by ths cont~in~r 12 and the formulator 30 of the present inventlon 1nclude ~I) easy ad~ust~ent of the benef7cial agent d~l~very rate, (2) eas~ly chan~ng ~he typ~ of b~neflcial agent del1vered, (3) it is unnecessary ~or a nurse or a æ~ 3~
the beneficial agent delivery rate, (2) easily changing the ty~e of beneficial agent delivered, (3) it is unnecessary for 3 nurse or a pharmacist to preformulate the drug or other beneficial agent and (4) the drug or other beneficial agent has a longer stablP shelf-life since the drug is mainta1ned in a solid, rather than in solution, form. For instance, lf it Is des1red to 1ncrease the rate of delivery of a beneficial ag~nt (e.g., an ant1blot1c) into the flowing IV fluid 13, one can simply select a suitable antiblot k delivery devlce 40 with a specified delivery rate. Furthermore, if it is desired to either double, triple or quadruple the delivery rate of this particular antibiotlc, ~t is only necessary to apply 2, 3, or 4 delivery devices 40, respectively, to the wall portions ll and/or 36.
Likewise, if instead of delivering an antibiotlc it is desired to deliver an anti-cancer agent into the flowing IV fluid, it is only necessary to remove the antibiotic-containing drug delivery device 40 and replace it with an anti-cancer drug-containing delivery device.
Beeause the agent delivery devices 40 are attached to the exterior surfaces of cuntainer 12 and formulator 30, there is no danger of contamination of the flowing IV fluld. Thus, changing the type of drug delivered or the drug delivery rate does not require time consuming sterilization procedures. This is especially important when ut11izing devices wh1ch dellver protein for~ulations since prote1ns are sensitlve to heat sterll~zatlon and have a tendency to denature when heated.
Th~ 1n~ent1On ~s further lllustrated by th@ follo~tng ~xamples.
~ L~_~
A nitroglycerln l~N6~)/triethyl c~tr~t~ rQs~rYo~r co~pos1t1On compr~s~ng a s111cone med~cal flu1d c~rr1~r ~elled with s11 k a, hav1ng N6 on lactose un1fo~mly dispers~d th~r~through and ~r~ethyl citrate (C~troflex A6, sold by Morflex Inc. of 6r~nsboro, NC) absorbed ~n a part~culate carr~er ~s ~abrlcated by plae1ng 5 kg of z~
silicone medical fluid having a vlscosity of abou~ 100 centistokes and 175 grams of colloidal s~licon dioxide in a high energy mixing vessel and blending to produce a gelled silicone fluid. 200 Grams of Accurel~ porous polypropylene aYailable from ARMAK Company is placed in a separate vessel and approximately 1200 grams of Citroflex A6 is added w1th st~rring to produce an essentlally dry flowable powder whlch on visual observat~on appears to have absorbed substantially all of the C1trofle~. S kg of nltroglycer1n-lactose (10 wt %
n~troglycerin) and the Citroflex loaded porous polypropylene is placed in the original high energy mix~ng vessel and mixed until a homogeneous blend is obtained. A fonm-fill-seal pouching machine is used to pouch the NG-Citroflex gel so form2d between an impermeable backing member comprising a medium density polyethylene/aluminized polyester/ethylene vinyl acetat~ multilam1nate (Medpa~ 1006 available from Minnesota M1ning & Manufactur1ng Company) peripherally thermosealed to the rate controlling membrane layer of a trilaminate film consisting of a release liner layer formed from polyester film coated with a film release agent, an adhesive layer formed of silicone medical adhesive and a release rate controlling membrane layer formed from a 1 mil thick ethylene vinyl acetate (12% VA) membrane. Oevices are fabrlcated having an NG/Citroflex releasing surface area of approximately 5 cm2.
One of the d~vic2s is adhered to an IV drug formulation chamber having the sam~ shape and configuration as the formulation chamber illustrated ~n F19ur~ 5. Wall portlon 36 ls formed of polyvlnylchlorlde whlch ~s initlally unplast1c~zed and imp~rmeable to th3 passaga of nltroglycer1n. ThQ thlckn~ss of wall portion 36 is 5 m1ls. Onc~ the drug del~very dev k e 1s attached to th~ ~all ~f the drug for~ulat10n cha~ber, the d~vic~ del~v~rs C~tro~l~x A6 lnto the polyv1ny k hlor1de wall. C1troflex A6 ls a plast1clzQr for polyv1nylchlor~de. After a perlod of t1~, th~ portlon of the chamber wall wh1ch 1s lm~d1ately adJ~cQnt to th@ drug dellvery d~vice becom~s plast~c k ~d and drug per~eabl~. Thereafter, n1troglycerlne is del1vered by the dev1ce through th~ drug permeable ~ 3~3'~
wall portion and into the IV fluid within the drug formulation chamber.
EXAMPlE I I
s A monolithlc transdermal devlce ls prepared by melt blendlng 33 parts ethylene v1nyl acetate (40% VA) wlth 32 parts Staybelite Ester No. 5, 5 parts estradlol val~rate and 2S parts triethyl cltrate (Cltroflex A4 sold by Morflex Inc. of Greensboro, NC). The m1xture IO is extruded and calendared to a th k kness of 12 m11s between an occlusive backing film of the type descrlbed in Example I and a strippable rel~ase liner film. Ind~vidual devices are rotary die cut with an area of 50 cm2.
One of the devices is adhered to an IV drug formulatlon chamber of the type described above in Example I. Once the drug delivery device is attached to the wall of the drug formulation chamber, the device delivers Citroflex A4 into the polyvinylchloride wall.
Citroflex A4 is a plasticizer for polyvinylchloride. After a period of time, the portion of the chamber wall which is immediately adjacent to the drug delivery device becom~s plasticized and drug permeable. Thereafter, estradlol valerat~ is delivered by the device through tbe drug permeable wall portiQn and into the IV fluid within the drug formulation chamber.
Other b~n~flts and advantag~s of th~ lnventlon will become apparent to those skllled ~n the art. ~hile the pr~ferred embod1m~nts of th2 lnvention hav~ been select~d for illustration in the dra~lngs and h2ve be~n descr~bed 1n d~tall h~reln, thsse skilled ln th~ art ~111 appreclat~ that v~P1ous ~od1flcatlon6, ehangas, addltlons and o~lsslons from th~ lllustrat~d ~b~dl~nt5 oan b~ ~ade wlthout departlng fro~ the splr1t and scop~ of th~ lnv~ntlon~ as daflned 1n the appended clal~s.
Claims (54)
1. An agent formulator for use in a parenteral fluid delivery system, the formulator comprising:
(a) a chamber having fluid inlet and outlet means to maintain a continuous flow of the parenteral fluid therethrough, the chamber having a wall portion comprised of a material that (1) is permeable to a beneficial agent to be delivered into the fluid and (2) prevents convective flow of parenteral fluid therethrough;
(b) a flow distributor within the container for distributing the flow of parenteral fluid along an interior surface of the wall portion; and (c) an agent delivery device attached to an accessible exterior surface of the wall portion, the delivery device comprising a reservoir containing the beneficial agent, the reservoir being releasably attached to the exterior surface of the wall portion;
wherein in operation, the fluid flowing through the chamber is distributed by the flow distributor along the interior surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the flowing fluid, the agent being delivered at a rate which is controlled substantially by the formulator and which is substantially independent of volumetric flow rate of the fluid flowing through the chamber.
(a) a chamber having fluid inlet and outlet means to maintain a continuous flow of the parenteral fluid therethrough, the chamber having a wall portion comprised of a material that (1) is permeable to a beneficial agent to be delivered into the fluid and (2) prevents convective flow of parenteral fluid therethrough;
(b) a flow distributor within the container for distributing the flow of parenteral fluid along an interior surface of the wall portion; and (c) an agent delivery device attached to an accessible exterior surface of the wall portion, the delivery device comprising a reservoir containing the beneficial agent, the reservoir being releasably attached to the exterior surface of the wall portion;
wherein in operation, the fluid flowing through the chamber is distributed by the flow distributor along the interior surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the flowing fluid, the agent being delivered at a rate which is controlled substantially by the formulator and which is substantially independent of volumetric flow rate of the fluid flowing through the chamber.
2. the formulator of claim 1, wherein the delivery device comprises a laminate including: (1) a backing member, (2) a middle reservoir containing the beneficial agent, and (3) an adhesive surface adapted to releasably adhere to the exterior surface of the wall portion.
3. The formulator of claim 1, wherein the agent is a drug and the parenteral fluid is an intravenously acceptable fluid.
4. The formulator of claim 1, wherein the delivery device contains a membrane layer which controls the rate at which the delivery device delivers the beneficial agent into the chamber.
5. The formulator of claim 1, wherein the chamber is cylindrically shaped and said wall portion extends around the entire circumference of the chamber.
6. The formulator of claim 5, wherein the flow distributor comprises a cylindrically shaped member fixedly positioned within the chamber.
7. The formulator of claim 1, wherein the flow distributor forms a tortuous flow path along the wall portion within the chamber.
8. The formulator of claim 1, wherein the flow distributor channels the IV fluid flow into a constricted space between the flow distributor and the wall portion.
9. The formulator of claim 1, wherein said chamber contains an air release vent and is simultaneously employed as a drip chamber for providing a measurable number of drops per minute of the fluid, the fluid transporting the agent delivered by the delivery device to an agent receptor site.
10. The formulator of claim 1, wherein the rate at which the agent is delivered into the chamber is controlled by the wall portion.
11. The formulator of claim 1, wherein the wall portion is comprised of a solution-diffusion membrane.
12. The formulator of claim 1, wherein the wall portion is comprised of a microporous membrane.
13. The formulator of claim 1, wherein the wall portion is initially impermeable to the beneficial agent and the wall portion is made permeable to the agent by application of a permeability enhancing agent thereto.
14. The formulator of claim 13, wherein the permeability enhancing agent is delivered to the wall portion by the agent delivery device.
15. The formulator of claim 13, wherein the permeability enhancing agent comprises a plasticizer of the material forming the wall portion.
16. The formulator of claim 1, wherein the wall portion has a size and shape enabling a plurality of agent delivery devices to be attached to the exterior surface thereof.
17. The formulator of claim 1, wherein the delivery device is releasably adhered to the wall portion.
18. The formulator of claim 1, wherein the agent is osmotically active.
19. The formulator of claim 1, wherein the agent comprises a drug and an osmotically active solute.
20. A parenteral delivery system for administering an agent parenterally to an animal in which the agent is formulated in situ, comprising in combination:
(1) a container of a pharmaceutically acceptable parenteral fluid that is a carrier for the agent;
(2) a parenteral fluid administration set connected to the container for permitting the fluid to flow from the container through the administration set to the animal, the set comprising a drip chamber, tubing extending from the drip chamber to the animal, and an agent formulator connected into the tubing such that the intravenous fluid flows through the formulator;
the formulator comprising:
(a) a chamber having fluid inlet and outlet means to maintain a continuous flow of the parenteral fluid therethrough, the chamber having a wall portion that (1) is permeable to the beneficial agent to be delivered into the fluid and (2) prevents convective flow of parenteral fluid therethrough;
(b) a flow distributor within the chamber for distributing the flow of parenteral fluid along an interior surface of the wall portion; and (c) an agent delivery device attached to an accessible external surface of the wall portion, the delivery device comprising a reservoir containing the beneficial agent, the reservoir being releasably attached to the external surface of the wall portion;
wherein in operation, the fluid flowing through the chamber is directed by the flow distributor to flow along the internal surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the flowing fluid, the agent being delivered at a rate which is controlled substantially by the formulator and which is substantially independent of volumetric flow rate of the fluid flowing through the chamber.
(1) a container of a pharmaceutically acceptable parenteral fluid that is a carrier for the agent;
(2) a parenteral fluid administration set connected to the container for permitting the fluid to flow from the container through the administration set to the animal, the set comprising a drip chamber, tubing extending from the drip chamber to the animal, and an agent formulator connected into the tubing such that the intravenous fluid flows through the formulator;
the formulator comprising:
(a) a chamber having fluid inlet and outlet means to maintain a continuous flow of the parenteral fluid therethrough, the chamber having a wall portion that (1) is permeable to the beneficial agent to be delivered into the fluid and (2) prevents convective flow of parenteral fluid therethrough;
(b) a flow distributor within the chamber for distributing the flow of parenteral fluid along an interior surface of the wall portion; and (c) an agent delivery device attached to an accessible external surface of the wall portion, the delivery device comprising a reservoir containing the beneficial agent, the reservoir being releasably attached to the external surface of the wall portion;
wherein in operation, the fluid flowing through the chamber is directed by the flow distributor to flow along the internal surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the flowing fluid, the agent being delivered at a rate which is controlled substantially by the formulator and which is substantially independent of volumetric flow rate of the fluid flowing through the chamber.
21. The parenteral delivery system of claim 20, wherein the delivery device comprises a laminate including: (1) a backing member, (2) a middle reservoir containing the beneficial agent, and (3) an adhesive surface adapted to releasably adhere to the external surface of the wall portion.
22. The parenteral delivery system of claim 20, wherein a skin piercing means is connected to the tubing for administering the agent to the animal.
23. The parenteral delivery system of claim 20, wherein the animal is a human and the agent comprises a drug.
24. The parenteral delivery system of claim 20, wherein the parenteral fluid is an intravenously acceptable fluid.
25. The parenteral delivery system of claim 20, wherein the wall portion is initially impermeable to the beneficial agent and the wall portion is made permeable to the agent by application of a permeability enhancing agent thereto.
26. The parenteral delivery system of claim 25, wherein the permeability enhancing agent is delivered to the wall portion by the agent delivery device.
27. The parenteral delivery system of claim 25, wherein the permeability enhancing agent comprises a plasticizer of the material forming the wall portion.
28. The parenteral delivery system of claim 20, wherein the delivery device is releasably adhered to the external surface of the wall portion.
29. The parenteral delivery system of claim 20, wherein the chamber is cylindrically shaped and said wall portion extends around the entire circumference of the chamber.
30. The parenteral delivery system of claim 29, wherein the flow distributor comprises a cylindrically shaped member fixedly positioned within the chamber.
31. The parenteral delivery system of claim 20, flow distributor forms a tortuous flow path along the wal within the chamber.
32. The parenteral delivery system of claim 20, where flow distributor channels the parenteral fluid flow into a constricted space between the distributor and the wall portion.
33. A method for the controlled parenteral administration beneficial agent to an animal, which method comprises:
(a) allowing a pharmaceutically acceptable parenteral fluid, which is a carrier for the agent, to flow through an agent formulation chamber having an inlet communicating with a container of the parenteral fluid and an outlet communicating with the animal, the chamber also having a wall portion that (l) is permeable to the beneficial agent and (2) jpresents convective flow of parenteral fluid therethrough, (b) distributing the flow of parenteral fluid along an interior surface of the wall portion; and (c) releasably attaching an agent delivery device to an accessible exterior surface of the wall portion, the delivery device including a reservoir containing the beneficial agent;
wherein in operation, the fluid flowing through the chamber is distributed along the interior surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the flowing fluid, thereby administering the agent to the animal in a beneficially effective amount over a prolonged period of time.
(a) allowing a pharmaceutically acceptable parenteral fluid, which is a carrier for the agent, to flow through an agent formulation chamber having an inlet communicating with a container of the parenteral fluid and an outlet communicating with the animal, the chamber also having a wall portion that (l) is permeable to the beneficial agent and (2) jpresents convective flow of parenteral fluid therethrough, (b) distributing the flow of parenteral fluid along an interior surface of the wall portion; and (c) releasably attaching an agent delivery device to an accessible exterior surface of the wall portion, the delivery device including a reservoir containing the beneficial agent;
wherein in operation, the fluid flowing through the chamber is distributed along the interior surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the flowing fluid, thereby administering the agent to the animal in a beneficially effective amount over a prolonged period of time.
34. The method of claim 33, wherein the agent is released at a rate which is controlled by the delivery device.
35. The method of claim 33, wherein the agent is released at a rate which is controlled by the wall portion.
36. The method of claim 33, wherein the animal is a human and the agent is a drug.
37. The method of claim 33, wherein the wall portion is initially impermeable to the beneficial agent and the wall portion is made permeable to the agent by application of a permeability enhancing agent thereto.
38. The method of claim 37, wherein the permeability enhancing agent is delivered to the wall ]portion by the agent delivery device.
39. The method of claim 37, wherein the permeability enhancing agent comprises a plasticizer of the material forming the wall portion.
40. A parenteral fluid reservoir container for use in a parenteral fluid delivery system, the container comprising:
(a) a chamber for containing the parenteral fluid and having fluid outlet means to provide a continuous flow of the parenteral fluid out of the container, the chamber having a wall portion comprised of a material that (1) is permeable to a beneficial agent to be delivered into the fluid and (2) prevents convective flow of parenteral fluid therethrough; and (b) an agent delivery device attached to an accessible exterior surface of the wall portion, the delivery device comprising a reservoir containing the beneficial agent, the reservoir being releasably attached to the exterior surface of the wall portion;
wherein in operation, the fluid in the container contacts an interior surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the fluid, the agent being delivered at a rate which is controlled substantially by the wall portion or by the agent delivery device and which is substantially independent of volumetric flow rate of the fluid flowing out of the container.
(a) a chamber for containing the parenteral fluid and having fluid outlet means to provide a continuous flow of the parenteral fluid out of the container, the chamber having a wall portion comprised of a material that (1) is permeable to a beneficial agent to be delivered into the fluid and (2) prevents convective flow of parenteral fluid therethrough; and (b) an agent delivery device attached to an accessible exterior surface of the wall portion, the delivery device comprising a reservoir containing the beneficial agent, the reservoir being releasably attached to the exterior surface of the wall portion;
wherein in operation, the fluid in the container contacts an interior surface of the wall portion, causing the agent to be delivered from the device through the wall portion and into the fluid, the agent being delivered at a rate which is controlled substantially by the wall portion or by the agent delivery device and which is substantially independent of volumetric flow rate of the fluid flowing out of the container.
41. The container of claim 40, wherein the delivery device comprises a laminate including: (1) a backing member, (2) a middle reservoir containing the beneficial agent, and (3) an adhesive surface adapted to releasably adhere to the external surface of the wall portion.
42. The container of claim 40, wherein the parenteral fluid is an intravenously acceptable fluid.
43. The container of claim 40, wherein the animal is a human and the agent comprises a drug.
44. The container of claim 40, wherein the rate at which the agent is delivered into the chamber is controlled by the wall portion.
45. The container of claim 40, wherein the delivery device contains a membrane layer which controls the rate at which the delivery device delivers the beneficial agent into the chamber.
46. The container of claim 40, wherein the wall portion is comprised of a solution-diffusion membrane.
47. The container of claim 40, wherein the wall portion is comprised of a microporous membrane.
48. The container of claim 40, wherein the wall portion is initially impermeable to the beneficial agent and the wall portion is made permeable to the agent by application of a permeability enhancing agent thereto.
49. The container of claim 48, wherein the permeability enhancing agent is delivered to the wall portion by the agent delivery device.
50. The container of claim 37, wherein the permeability enhancing agent comprises a plasticizer of the material forming the wall portion.
51. The container of claim 40, wherein the wall portion has a size and shape enabling a plurality of agent delivery devices to be attached to the exterior surface thereof.
52. The container of claim 40, wherein the delivery device is releasably adhered to the wall portion.
53. The container of claim 40, wherein the agent is osmotically active.
54. The container of claim 40, wherein the agent comprises a drug and an osmotically active solute.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US311,906 | 1989-02-15 | ||
| US07/311,906 US4969871A (en) | 1989-02-15 | 1989-02-15 | Intravenous system for delivering a beneficial agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2009984A1 true CA2009984A1 (en) | 1990-08-15 |
Family
ID=23209012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002009984A Abandoned CA2009984A1 (en) | 1989-02-15 | 1990-02-14 | Intravenous system for delivering a beneficial agent |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US4969871A (en) |
| EP (1) | EP0458879B1 (en) |
| AT (1) | ATE90000T1 (en) |
| AU (1) | AU623983B2 (en) |
| CA (1) | CA2009984A1 (en) |
| DE (1) | DE69001812T2 (en) |
| DK (1) | DK0458879T3 (en) |
| ES (1) | ES2041174T3 (en) |
| GR (1) | GR1000496B (en) |
| NZ (1) | NZ232524A (en) |
| PT (1) | PT93152A (en) |
| WO (1) | WO1990009201A1 (en) |
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-
1989
- 1989-02-15 US US07/311,906 patent/US4969871A/en not_active Expired - Fee Related
-
1990
- 1990-02-14 EP EP90903659A patent/EP0458879B1/en not_active Expired - Lifetime
- 1990-02-14 AU AU51517/90A patent/AU623983B2/en not_active Ceased
- 1990-02-14 NZ NZ232524A patent/NZ232524A/en unknown
- 1990-02-14 CA CA002009984A patent/CA2009984A1/en not_active Abandoned
- 1990-02-14 PT PT93152A patent/PT93152A/en not_active Application Discontinuation
- 1990-02-14 DE DE9090903659T patent/DE69001812T2/en not_active Expired - Fee Related
- 1990-02-14 US US07/741,413 patent/US5160320A/en not_active Expired - Fee Related
- 1990-02-14 ES ES199090903659T patent/ES2041174T3/en not_active Expired - Lifetime
- 1990-02-14 AT AT90903659T patent/ATE90000T1/en not_active IP Right Cessation
- 1990-02-14 DK DK90903659.2T patent/DK0458879T3/en active
- 1990-02-14 WO PCT/US1990/000880 patent/WO1990009201A1/en active IP Right Grant
- 1990-02-14 GR GR900100104A patent/GR1000496B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR1000496B (en) | 1992-07-30 |
| EP0458879B1 (en) | 1993-06-02 |
| NZ232524A (en) | 1995-03-28 |
| US5160320A (en) | 1992-11-03 |
| DE69001812T2 (en) | 1993-09-23 |
| AU623983B2 (en) | 1992-05-28 |
| AU5151790A (en) | 1990-09-05 |
| ES2041174T3 (en) | 1993-11-01 |
| GR900100104A (en) | 1991-06-28 |
| US4969871A (en) | 1990-11-13 |
| ATE90000T1 (en) | 1993-06-15 |
| EP0458879A1 (en) | 1991-12-04 |
| DK0458879T3 (en) | 1993-08-23 |
| PT93152A (en) | 1990-08-31 |
| WO1990009201A1 (en) | 1990-08-23 |
| DE69001812D1 (en) | 1993-07-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |