Intravenous system for delivering a beneficial agent with delivery rate control via permeable surface area variance

A drug formulation chamber for an intravenous administration set is provided. The intravenous administration set includes a container of an IV fluid, a drip chamber, a drug formulation chamber, and an adapter-needle assembly. The drug formulation chamber houses a diffusional or an osmotically driven drug delivery device. The osmotically driven delivery device has a semipermeable, microporous or diffusional wall which surrounds a compartment containing the drug. Drug is delivered through an orifice in the semipermeable/microporous wall or through the diffusional wall itself, into the IV fluid. The device delivers drug into the IV fluid at a rate that is independent of the flow rate of IV fluid through the formulation chamber. The rate of drug delivery is controlled by variably adjusting the surface area of the semipermeable/microporous/diffusional wall that is exposed to the IV fluid flowing through the drug formulation chamber.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention pertains to an intravenous delivery system, and to a 
formulation chamber containing a drug delivery device. The invention 
relates also to a method of parenterally (e.g., intravenously) 
administering a drug, and to a method of forming the drug during 
parenteral administration. 
2. Description of the Prior Art 
The parenteral administration of medical liquids is an established clinical 
practice. The liquids 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 flowing through a catheter hypodermic needle set to the patient. 
The administration of liquids intravenously is a valuable and important 
component that contributes to the optimal care of the patient. However, it 
does not easily provide a satisfactory means and method for administering 
concomitantly therewith a beneficial agent, such as a drug. Beneficial 
agents have been administered intravenously by one of the following 
methods: (1) temporarily removing or disconnecting the IV system 
administering the agent to the patient, then administering the drug by 
hypodermic injection (either into the disconnected IV line or directly 
into the vein of the patient), followed by reinserting the IV system into 
the patient; (2) adding the agent to the IV liquid in the container which 
is then carried by the flow of the liquid to the patient; (3) adding the 
agent to an IV liquid 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 
containing a beneficial agent using a pump. While these techniques are 
used, they have major disadvantages. For example, they often require 
preformulation of the agent medication by the hospital pharmacist or 
nurse. They often require separate connections for joining the drug flow 
line to the primary intravenous line which further complicates intravenous 
administration. The use of pumps can produce pressures that can vary at 
the delivery site and the pressure can give rise to thrombosis. Finally, 
the rate of agent delivery to the patient often is unknown as it is not 
rate-controlled agent delivery but rather is dependent on the rate of IV 
fluid flow. 
Eckenhoff et al in U.S. Pat. No. 4,474,575 discloses an IV administration 
set (FIG. 6) providing excellent control over the rate at which beneficial 
agent is administered to a patient. Unfortunately, the device disclosed by 
Eckenhoff et al is not easily adapted to a conventional IV administration 
set which typically includes an IV fluid container, a drip chamber for 
visually determining the rate of IV fluid flow from the container, a 
bacterial filter, and terminating in an adaptor-needle assembly that is 
inserted into the vein of a warm-blooded animal (e.g., a human patient). 
In order to adapt the Eckenhoff device to a conventional IV administration 
set, a secondary IV fluid line must be connected into the primary IV line 
which complicates the intravenous administration. 
In response to these difficulties, Theeuwes in U.S. Pat. No. 4,511,353 (and 
in related U.S. Pat. Nos. 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 beneficial agent into the 
IV fluid flowing through the formulation chamber. The drug delivery device 
within the formulation chamber is selected from elementary osmotic pumps 
(FIGS. 2a, 2b, 9, 10, and 11) release rate controlling membranes 
surrounding a drug reservoir (FIGS. 3-5, 12 and 13) and a polymer matrix 
containing the drug, the drug being able to diffuse through the matrix 
into the flowing IV fluid (FIGS. 6-8). All of these devices provide the 
advantage of controlling the rate at which the drug or other beneficial 
agent is released into the IV fluid, independently of the rate at which 
the IV fluid flows through the formulation chamber. 
While these devices represent a significant advance in the art, there 
remains a need for a drug formulation chamber which can provide an even 
higher degree of control over the rate at which a beneficial agent, such 
as a drug, is introduced into an IV fluid flowing in a standard IV 
administration set. 
Accordingly, it is an object of this invention to provide a parenteral 
(e.g., intravenous) delivery system which delivers an agent at a 
controlled rate into a flowing parenteral fluid for optimizing the care of 
an animal (e.g., a human) whose prognosis benefits from parenteral 
delivery. 
It is another object of the invention to provide an intravenous delivery 
system having an agent formulation chamber which contains an agent 
delivery device for admitting agent at a rate controlled by the delivery 
device, instead of the flow rate of intravenous fluid through the system, 
for optimizing the care of a patient on intravenous delivery. 
Another object of the invention is to provide an intravenous therapeutic 
system including a container of an intravenous medical fluid and a drug 
formulation chamber which contains an agent delivery device which can 
deliver drug, to a flowing IV fluid, at a rate which is variable and which 
is accurately controlled by the device. 
SUMMARY OF THE INVENTION 
These and other objects are met by an agent formulator, a parenteral 
administration system and a method for the controlled parenteral 
administration 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. An 
agent delivery device is positioned in the chamber. The delivery device 
contains a beneficial agent to be delivered into the parenteral fluid. 
In one embodiment, the delivery device has a semipermeable or microporous 
wall portion that is permeable to the parenteral fluid and substantially 
impermeable to the agent. The delivery device of the first embodiment also 
has a passageway through which the agent is delivered into the fluid at a 
controlled rate. In a second embodiment, the delivery device has a 
diffusional wall portion which is hydrated by the parenteral fluid and 
permits the beneficial agent, which is soluble in the parenteral fluid, to 
diffuse through the wall portion at a controlled rate for delivery into 
the fluid. In a third embodiment, the delivery device comprises a polymer 
matrix containing a beneficial agent. The polymer matrix has the property 
of releasing the beneficial agent at a controlled rate over a period of 
time when exposed to the parenteral fluid. 
The agent formulator also includes means for adjustably varying the surface 
area of the wall portion or matrix which is exposed to the fluid flowing 
through the chamber. 
In operation of the first embodiment, the parenteral fluid flowing through 
the chamber contacts a predetermined area of the semipermeable or 
microporous wall portion and is imbibed therethrough. The imbibed fluid 
causes the agent to be delivered from the device through the passageway 
and into the flowing fluid. In the second embodiment, the parenteral fluid 
flowing through the chamber contacts a predetermined area of the 
diffusional wall portion causing the beneficial agent to diffuse 
therethrough. In the third embodiment, the parenteral fluid flowing 
through the chamber contacts a predetermined area of the polymer matrix 
causing the beneficial agent to be released into the fluid. In all 
embodiments, the beneficial agent is released by the delivery device at a 
rate which is variable, which is controlled substantially by the area of 
the wall portion exposed to the fluid or by the area of the matrix exposed 
to the fluid and which is substantially independent of the volumetric flow 
rate of the fluid flowing through the chamber. 
Preferably, the beneficial agent comprises a drug and the agent formulator 
is positioned within an intravenous administration system including a 
container of a pharmaceutically acceptable intravenous fluid and an 
intravenous administration set used to deliver an intravenously acceptable 
fluid to a human patient. 
The present invention also provides a method for the controlled parenteral 
administration of a beneficial agent to an animal. The method comprises 
the steps of: 
(a) placing an agent delivery device in an agent formulation chamber having 
an inlet communicating with a container of a pharmaceutically acceptable 
parenteral fluid and an outlet communicating with the animal; 
(b) allowing the parenteral fluid, which is a carrier for the agent, to 
flow from the container, through the chamber and into the animal. 
In one embodiment, the delivery device has a semipermeable or microporous 
wall portion that is permeable to the parenteral fluid and substantially 
impermeable to the agent. The delivery device of the first embodiment also 
includes a passageway through which the agent is delivered into the fluid. 
In a second embodiment, the delivery device has a diffusional wall portion 
which is hydrated by the parenteral fluid and permits the agent to diffuse 
through the wall portion at a controlled rate for delivery into the fluid. 
In a third embodiment, the delivery device comprises a polymer matrix 
containing the beneficial agent. The polymer matrix has the property of 
releasing the agent at a controlled rate over a period of time when 
exposed to the parenteral fluid. 
The method also includes the step of adjustably varying the surface area of 
the wall portion or matrix which is exposed to the fluid flowing through 
the chamber. 
In operation of the first embodiment, the fluid flowing through the chamber 
contacts a predetermined area of the semipermeable or microporous wall 
portion and is imbibed therethrough. This causes the beneficial agent to 
be delivered from the device through the passageway into the flowing 
fluid. In the second embodiment, the parenteral fluid flowing through the 
chamber contacts a predetermined area of the diffusional wall portion 
causing the beneficial agent to diffuse therethrough. In the third 
embodiment, the parenteral fluid flowing through the chamber contacts a 
predetermined area of the polymer matrix causing the beneficial agent to 
be released into the fluid. In all three embodiments, the agent is 
released at a rate which is variable, which is controlled substantially by 
the area of the wall portion or by the area of the matrix exposed to the 
fluid and which is substantially independent of the volumetric flow rate 
of the fluid flowing through the chamber. The method is effective to 
administer the beneficial agent to the animal in a beneficially effective 
amount over a prolonged period of time. Preferably, the method is used to 
deliver a drug intravenously to a human patient.

DETAILED DESCRIPTION OF THE INVENTION 
FIG. 1 illustrates an operative intravenous delivery system, generally 
designated by the numeral 10, showing the positioning of an agent 
formulator 30 therein. System 10 comprises a container 12 that contains a 
fluid 13 suitable for intravenous administration, and an administration 
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 administration set 
that has an air inlet filter. Other types of containers such as the 
air-tube vacuum type, or the non-vented type, can be used for the intended 
purpose. These alternative containers do not require an air filter in the 
administration set 14. Container 12 can be rigid, semi-rigid or flexible 
in structure, 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. 
Administration set 14 and container 12 are interconnected by piercing 
closure 17 with one end of a hollow spike 18 attached to or formed as a 
part of administration set 14. Spike 18 is equipped with a side air vent 
19. The other end of spike 18 is enlarged and fits snugly into a drip 
chamber 22. Drip chamber 22 traps air contained in the set 14 and 
facilitates adjusting the flow rate of intravenous fluid 13 from container 
12 as the flow proceeds drop wise. The outlet at the bottom of drip 
chamber 22 is connected to a first segment of tubing 23 which fits into 
agent formulator 30, the details of which are presented in FIG. 2. A 
second segment of tubing 25 leads from agent formulator 30 to bacterial 
filter 27. A third segment of tubing 29 extends from filter 27 to an 
infusion agent receptor site, terminating in an adapter-needle assembly 28 
that is inserted into a vein of a warm-blooded animal 20, shown as a human 
arm. Tape 32 holds adapter-needle assembly 28 firmly in place on the 
recipient's arm. The administration set can also include a pair of tubing 
clamps 24 and 26 located on either side of formulator 30 that may be used 
to govern or stop the flow of intravenous fluid through the intravenous 
delivery system 10. 
Agent formulator 30, as seen in FIG. 2, is the unique component of the 
intravenous delivery system 10. Agent formulator 30 comprises a wall 32 
forming a chamber 34. An air release valve 31 of a conventional design may 
optionally be provided in wall 32 for admitting or releasing air from 
chamber 34 in order to adjust the fluid level 35. An agent delivery device 
40 is housed within the chamber 34. Device 40 contains a beneficial agent 
44 to be delivered into the IV fluid 13. The beneficial agent 44 exhibits 
an osmotic pressure gradient across wall 41 of device 40 against the IV 
fluid 13 in chamber 34. The beneficial agent 44 can comprise an agent that 
exhibits an osmotic pressure gradient, or the agent 44 can comprise a drug 
mixed with an osmotically effective solute, such as sodium chloride, 
potassium chloride and the like, that exhibits an osmotic pressure 
substantially greater than the fluid in the formulator 30. A retaining 
means 36 keeps device 40 fixedly positioned within formulator 30, 
permitting the free passage of IV fluid through formulator 30. Wall 32 may 
be comprised of glass, plastic or the like, and is preferably a 
transparent material thereby enabling a nurse or other medical technician 
to see the level 35 of IV fluid 13 contained in formulator 30. Formulator 
30 can also be manufactured as a two-piece unit with the delivery device 
40 therein, or formulator 30 can be manufactured with a closable lid for 
admitting the delivery device 40. 
As shown in FIG. 2, the exterior surface of wall 41 is provided with a 
plurality of marking lines 45 along its length. Because the wall 32 of 
formulator 30 is made of a transparent material, a medical technician can 
easily determine the air/liquid interface level 35 in relation to the 
markings 45 on delivery device 40. The interface level 35 may be adjusted 
in a number of different ways. For example, the wall 32 of formulator 30 
may be comprised of a flexible and transparent material such as 
polyethylene or plasticized polyvinyl chloride. The tube 25 is first 
clamped closed and the formulator 30 is simply squeezed by the technician, 
thereby causing air within chamber 34 to be vented either into the fluid 
container 12 or through the air release valve 31. Alternatively, a squeeze 
bulb and catheter (not shown in the Figures) can be connected to valve 31. 
After allowing the chamber 34 to become completely filled with fluid 13, 
air can be forced into chamber 34 by pumping the squeeze bulb of the 
bulb/catheter set in order to lower the level 35 to the desired point. A 
check valve may also be provided in the balloon/catheter set which may be 
opened to release air from the chamber 34 in order to raise the level 35. 
Other known methods for adjusting the air/liquid interface level 35 within 
chamber 34 may also be utilized. 
Agent delivery device 40, in the illustrated embodiment, may be an osmotic 
rate-controlled pump of the type described by Eckenhoff et al in U.S. Pat. 
No. 3,987,790. Device 40 has a semipermeable or microporous outer wall 41 
which is permeable to fluid 13 and has a sufficent degree of 
impermeability to solute 44 to generate an osmotic pressure differential 
across wall 41. Wall 41 may be comprised of a material such as cellulose 
acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, 
cellulose diacetate or cellulose triacetate. The outer wall 41 surrounds 
and forms an inner compartment containing the beneficial agent 44. 
Generally, when the outer wall 41 is comprised of a semipermeable or 
microporous membrane, the device 40 will have a passageway 47 extending 
through the outer wall 41 so that a solution of the drug or other 
beneficial agent can be pumped into chamber 34. In the illustrated 
embodiment, a hollow open-ended catheter 42 is connected with the 
passageway 47 through the semipermeable/microporous wall 41. The free end 
43 of catheter 42 is positioned beneath device 40. In this way, beneficial 
agent 44 is delivered from device 40 through the hollow catheter 42 
directly into the IV fluid 13. 
When wall 41 is made of a semipermeable or microporous material that is 
permeable to the IV fluid 13, IV fluid enters chamber 34 and is imbibed 
through the portion of semipermeable/microporous wall 41 which is 
submerged in the IV fluid 13. The IV fluid is imbibed through wall 41 into 
device 40 which contains the beneficial agent 44 in a tendency toward 
osmotic equilibrium. The rate at which IV fluid enters device 40 is 
determined by the surface area of semipermeable/microporous wall 41 which 
is submerged in the IV fluid 13, as well as by the permeability of the 
wall 41 and the osmotic gradient across the wall 41. The IV fluid entering 
device 40 forms a suspension or a solution of agent 44 that is dispensed 
through the catheter 42 over a prolonged period of time. The delivery rate 
of agent 44 into the IV fluid is controlled by device 40 and is 
independent of the rate of IV fluid flow and the pH of the IV fluid in the 
chamber 34. In the embodiment illustrated in FIG. 2 which utilizes a 
semipermeable wall 12, beneficial agent 44 is delivered through catheter 
42 into the liquid 13. However, it is also within the scope of the present 
invention to utilize a delivery device 40 having a passageway 47 at its 
bottom end, in which case no catheter 42 is required. 
Other known osmotically powered agent dispensing devices may also be 
substituted for the illustrated osmotic agent delivery device 40. Examples 
of suitable osmotic delivery devices are disclosed in U.S. Pat. Nos. 
3,760,984; 3,845,770; 3,995,631 and 4,111,202, which disclosures are 
incorporated herein by reference. 
In a second embodiment, the outer wall 41 is comprised of a diffusional 
membrane which is hydrated by the IV fluid 13. Only that portion of wall 
41 which is submerged in the IV fluid 13 becomes hydrated. The beneficial 
agent 44 is able to diffuse through the hydrated portion of wall 41 into 
the IV fluid 13. When wall 41 is made of a diffusional membrane material, 
the beneficial agent 44 should be soluble in the IV fluid 13 and no drug 
delivery passageway 47 is provided in device 40. The composition of 
diffusional wall portion 41 may be selected from known diffusional 
membrane materials in accordance with the type of beneficial agent being 
delivered by device 40. In general, the diffusional wall 41 is comprised 
of a polymer that allows the drug or other beneficial agent 44 contained 
in device 40 to diffuse therethrough and into the IV fluid 13. When the IV 
fluid 13 contacts the exterior of the diffusional wall 41, the beneficial 
agent 44 diffuses through the portion of the membrane wall 41 that is 
wetted by the IV fluid 13. Representative diffusional polymers include 
olefin polymers, vinyl polymers, condensation polymers, addition polymers, 
rubber polymers and silicone polymers, and in particular, polyethylene, 
polypropylene, polyvinyl acetate, polyvinyl acetal, polyvinyl chloride, 
polyamides, polyesters, butadiene rubber, organo-silicone polymers and 
copolymers thereof. 
When the device 40 delivers a hydrophilic drug, the diffusional wall 41 is 
preferably comprised of a hydrophilic or microporous material. Examples of 
suitable hydrophilic materials include polyurethanes, polyvinyl alcohols, 
polyamides and cellophane. 
When device 40 delivers a lipophilic drug, the diffusional wall 41 is 
preferably comprised of a lipophilic material. Examples of suitable 
lipophilic materials include natural rubbers, silicone rubbers, 
Hytrel.RTM. (a thermoplastic polyester elastomer sold by E. I. DuPont de 
Nemours of Wilmington, DE), ethylene vinyl acetate (EVA), polyvinyl 
chloride, and Kraton.RTM. (a styrene-butadiene block copolymer sold by 
Shell Chemical Co. of Houston, TX). 
When device 40 delivers a polypeptide, protein or other macro-molecule, the 
wall 41 is preferably comprised of a microporous material. The pores in 
the microporous material will generally have a size of less than about 0.2 
microns, and preferably about 0.1 to 0.2 microns. Examples of suitable 
microporous materials include Celgard.RTM. (a microporous polypropylene 
film sold by Celanese Chemical Co. of Dallas, TX) cellophane, glass frits, 
vycor glass, porous glass and microporous membranes of the type utilized 
in known elementary osmotic pumps. 
As in the osmotically driven agent dispensing devices utilizing 
semipermeable/microporous walls 41, the diffusional device also delivers 
beneficial agent 44 into fluid 13 at a rate that is variable and that is 
dependent upon the surface area of wall 41 that is exposed to (i.e., 
hydrated by) fluid 13 within chamber 34. 
Thus when using either a semipermeable or a diffusional agent delivery 
device 40, a technician may accurately vary the delivery rate of agent 44 
from device 40 by varying the air/liquid interface level 35 within chamber 
34. When substantially the entire device 40 is submerged in IV fluid 13, 
the delivery device 40 will deliver beneficial agent 44 at a maximum rate. 
Conversely, when only a small portion of delivery device 40 is submerged 
in the IV fluid 13 (i.e., when the air/liquid interface level 35 is at a 
level lower than that shown in FIG. 2) the delivery device 40 will deliver 
beneficial agent 44 at a relatively low rate. As will be appreciated by 
those skilled in the art, the delivery rate of agent 44 can be easily 
adjusted simply by adjusting the air/liquid interface level 35 in relation 
to the markings 45 provided on device 40. 
A third embodiment of an agent dispensing device (not shown in the figures) 
which may be used in the formulator 30 of the present invention comprises 
an agent-containing polymeric matrix. When the matrix is exposed to IV 
fluid 13, it releases the beneficial agent dispersed therein at a 
controlled rate. The rate of agent release is dependent upon the surface 
area of the matrix which is exposed to the IV fluid. Suitable polymeric 
matrices are known in the art and disclosed for example in U.S. Pat. Nos. 
3,921,636; 4,066,747; 4,070,347; 4,190,642; 4,246,397; 4,281,654; 
4,303,637; 4,304,765; 4,432,964; and 4,478,818. The disclosures of the 
relevant portions of these patents are incorporated herein by reference. 
In the embodiment illustrated in FIG. 2, formulator 30 simultaneously acts 
as a drip chamber while housing the agent delivery device 40. The agent 
formulator 30 is used to achieve a desired drip flow rate of IV fluid 13. 
For example, the agent formulator 30 can have a fast drip rate for adults, 
or it can have a slower drip rate for pediatric use. The agent formulator 
30 can be made with various sized inlets for controlling the rate of drip, 
or the drip rate can be controlled by a regulating clamp on the tubing 
conveying fluid thereto. The agent formulator 30 can deliver, for example 
from 2 to 75 drops per minute over a period of from 1 minute to 1 hour. 
More preferably, the therapist can adjust the rate of flow to between 
about 2 and 20 drops per minute, or for the needs of the patient. 
Agent administration that is independent of intravenous fluid flow rate is 
extremely advantageous since careful control of the volumetric flow rate 
of intravenous fluid through the formulation chamber is not required. 
Hence, repeated adjustment of the flow by medical personnel, or the use of 
expensive, automated flow monitors is not needed. The operation also 
provides the advantage that the formulation of agent and intravenous fluid 
is carried out automatically in situ within formulator 30. The present 
invention eliminates the need to have the agent formulated into a 
parenteral solution by a pharmacist, and it also eliminates the need for 
the agent to be packaged separately from the intravenous fluid container 
12. Another advantage provided by this invention is the ease with which 
the intravenous delivery system 10 can be sterilized. Since agent 
formulator 30 and the agent delivery device 40 are compatible with 
conventional sterilization techniques used to sterilize intravenous 
therapy systems, the agent formulator 30 and the agent delivery device 40 
may be incorporated into the intravenous system 10 at the time of 
manufacture and sterilized therewith. 
FIG. 3 illustrates another agent formulator designated 130. Formulator 130 
comprises a wall 132 and a housing 150 holding a plurality of agent 
delivery devices 140a, 140b and 140c. The wall 132 and the housing 150 
form an internal chamber 134. In this embodiment, the chamber 134 is 
continuously and completely filled with flowing IV fluid which enters 
through tubing 23 and exits out of tubing 25. 
Each of the agent delivery devices 140 is movable within a cylindrical 
opening 151 in housing 150 in the direction of arrow A. Thus, each 
delivery device 140 may be extended into, or retracted from, chamber 134. 
One or more O-rings 152 provide a fluid-tight seal between the housing 150 
and the delivery device 140. When wall 141 is composed of a semipermeable 
or microporous material, an agent delivery orifice 147 is provided in the 
end of device 140 which extends into the chamber 134. The position of the 
delivery devices 140 with respect to the O-rings 152 can be adjusted 
according to conventional means. The devices 140 and/or the housing 150 
may be provided with markings 145 enabling a medical technician to 
accurately adjust the length of the device 140 that extends beyond the 
left-most O-ring 152 into chamber 134 and thus, the area of wall 141 that 
is exposed to IV fluid in chamber 134. 
In operation, IV fluid enters chamber 134 and is imbibed through the 
portion of semipermeable/microporous wall 141 which extends beyond the 
O-rings 152. The IV fluid is imbibed through the exposed portion of wall 
141 into device 140 in a tendency towards osmotic equilibrium. IV fluid is 
imbibed by device 140 at a rate determined by the surface area of wall 141 
which extends into chamber 134 beyond the O-rings 152, as well as by the 
permeability of the wall 141 and the osmotic gradient across the wall 141. 
The imbibed IV fluid forms a suspension or a solution of the beneficial 
agent that is dispensed through the delivery orifice 147 and into the IV 
fluid within chamber 134 over a prolonged period of time. The rate of 
agent delivery into the IV fluid is controlled mainly by the surface area 
of wall 141 which extends beyond the O-rings 152 into the chamber 134 and 
thus exposed to the IV fluid. 
The lowermost delivery device 140c illustrates an alternate embodiment of 
the delivery device 140a. Delivery device 140c has an internal chamber 
which filled with a beneficial agent 144. The internal chamber is divided 
into three subchambers by dividers 148. The dividers 148 are impermeable 
to both the IV fluid and to the beneficial agent 144. Each of the three 
subchambers carries a predetermined dose of beneficial agent 144. When the 
wall 141 of delivery device 140c is composed of a semipermeable or 
microporous material which is substantially impermeable to the passage of 
agent 144, each subchamber of device 140c is provided with its own 
delivery orifice 147. Suitable markings may be provided on the exterior of 
delivery device 140c to enable a medical technician to expose only the 
leftmost subchamber (i.e., for delivery of a single predetermined dose of 
agent 144) to the IV fluid flowing through chamber 144. Once the first 
dose is completely delivered, the delivery device 140 can be extended 
further into chamber 134 to deliver second and third doses if desired. 
A device 160, for adjustably positioning any of the three delivery devices 
140, is also shown in conjunction with the delivery device 140c in FIG. 3. 
Device 160 comprises a micrometer-like device and includes a plunger 161 
which is attached to one end of the delivery device 140c, a housing 162, a 
barrel 164 and a rotatable knob 166. By turning knob 166, the plunger 161 
is extended into the opening 151, thereby pushing delivery device 140c 
into chamber 134. Markings 163 are provided on barrel 164 to enable a 
technician to determine the extent to which the delivery device 140c 
extends into chamber 134. 
In a second embodiment, wall 141 is comprised of a diffusional membrane 
material. The delivery of beneficial agent into the IV fluid is achieved 
by the beneficial agent diffusing through the membrane wall 141 rather 
than IV fluid being imbibed therethrough. When delivery device 140 
utilizes a diffusional wall 141, the beneficial agent must be soluble in 
the IV fluid and no delivery orifice 147 is provided. As with the 
semipermeable delivery device 140, the rate of delivery of beneficial 
agent from the diffusional delivery device 140 into the IV fluid is 
controlled by the surface area of wall 141 which extends beyond the 
O-rings 152 into the chamber 134 and thus exposed to the IV fluid. 
In the configuration illustrated in FIG. 3 (and assuming that all three 
devices 140 are of identical construction and composition), the topmost 
delivery device 140 delivers beneficial agent at a relatively high rate 
(since a large percentage of its wall 141 is exposed to IV fluid), the 
middle delivery device 140 delivers beneficial agent at a medium rate, 
while the lowermost device 140 delivers beneficial agent at a negligible 
rate (since a negligible portion of its wall 141 is exposed to IV fluid). 
Of course, it is within the scope of the present invention to utilize one, 
two, three or more delivery devices 140 within a single formulator 130. 
As an alternative to the semipermeable, microporous and diffusional 
delivery devices described heretofore, the delivery device 40 illustrated 
in FIG. 2 and the delivery devices 140 illustrated in FIG. 3 may be 
comprised of a polymer matrix containing a beneficial agent dispersed 
therein. The polymer matrix may be comprised of the same matrix materials 
described above in connection with device 40. The matrix can possess any 
shape such as rod, disk and the like that fits into chamber 134. 
FIG. 4 illustrates another agent formulator designated 230. Formulator 230 
comprises a wall 232 and a semipermeable or microporous membrane 241. A 
delivery orifice 247 is provided in the lowermost portion of membrane 241. 
Formulator 230 contains a beneficial agent 244 to be delivered into the IV 
fluid 13 which enters through tube 23 and exits through tube 25. 
Membrane 241 may be comprised of the same or similar materials used to make 
the semipermeable/microporous outer wall 41 of device 40 illustrated in 
FIG. 2 and described above. 
The beneficial agent 244 exhibits an osmotic pressure gradient across 
membrane 241 against the IV fluid 13 flowing through chamber 234. The 
beneficial agent 244 can comprise an agent that exhibits an osmotic 
pressure gradient or the agent 244 can comprise a drug mixed with an 
osmotically effective solute, such as sodium chloride, potassium chloride 
and the like, that exhibits an osmotic pressure substantially greater than 
the fluid in chamber 234. 
Preferably, the wall 232 of formulator 230 is comprised of a transparent 
material, such as plastic or glass, enabling a medical technician to see 
the air/liquid interface level 235 within chamber 234. Suitable marking 
lines (not shown) may be provided along the length of wall 232 for setting 
the level 235 at the desired point. 
Because membrane 241 is made of a semipermeable or microporous material 
that is permeable to the IV fluid 13, the rate at which IV fluid permeates 
through membrane 241 will be controlled by the surface area of membrane 
241 that is exposed to the fluid 13 within chamber 234. Likewise, the rate 
at which the agent 244 is delivered from device 230 is controlled by the 
surface area of membrane 241 that is exposed to the fluid 13 within 
chamber 234. The air liquid interface level 235 can be adjusted using the 
same methods described above in connection with the adjustment of the 
air/liquid interface level 35 in formulator 30. An air release valve (not 
shown in FIG. 4) similar to valve 31 shown in FIG. 2 may optionally be 
provided in wall 232 to adjust the air/liquid interface level 235. Thus, 
by varying the air/liquid interface level 235 within chamber 234, a 
technician may accurately vary the delivery rate of agent 244 from device 
230. As with device 40 shown in FIG. 2, the IV fluid 13 entering 
formulator 230 forms a suspension or a solution of agent 244 that is 
dispensed through orifice 247 over a prolonged period of time. The 
delivery rate of agent 244 into the IV fluid 13 is controlled by 
formulator 230 and is independent of the rate of IV fluid flow and the pH 
of the IV fluid in the chamber 234. 
Alternatively, membrane 241 can be comprised of a diffusional membrane 
material similar to those described above in connection with the 
diffusional embodiments of delivery devices 40 and 140. When membrane 241 
is comprised of a diffusional membrane material, no orifice 247 is 
provided. In addition, the beneficial agent 244 should be soluble in the 
IV fluid 13. As with the semipermeable/microporous delivery device, the 
rate of delivery of beneficial agent from the diffusional delivery device 
230 into the IV fluid is controlled by the surface area of wall 241 which 
is exposed to the IV fluid. 
As with the semipermeable, microporous and diffusional membrane-containing 
drug delivery devices 40 and 140 described earlier, device 230 can also 
take the form of a polymer matrix having a beneficial agent dispersed 
therein. The agent-containing polymer matrix is simply used in place of 
the membrane 241 and the agent 244 shown in FIG. 4. As in the 
semipermeable and diffusional devices 230, the rate at which the 
beneficial agent is delivered from the agent-containing polymer matrix 
device 230 is also dependent upon the surface area of the matrix which is 
exposed to the IV fluid. Thus, the rate at which a beneficial agent, such 
as a drug, is delivered into the flowing IV fluid can be controlled simply 
by adjusting the surface area of the matrix exposed to the fluid. This may 
be done by suitably adjusting the liquid level 235 of the IV fluid in 
chamber 234. 
While there has been described features of the invention as applied to 
presently preferred embodiments, those skilled in the art will appreciate 
that various modifications, changes, additions, and omissions in the 
systems illustrated and described can be made without departing from the 
spirit of the invention, as defined in the appended claims.