Note: Descriptions are shown in the official language in which they were submitted.
~ 3~ ARC 319/801
SYSTEM FOR PARENTERAL DELIVERY
OF A BENEFICIAL AGENT
FIELD OF THE INVENTION
. _
This in~ention pertains to both a parenteral delivery
system and to a formulation chamber containing a beneficial
10 agent. The invention also relates ~o a method of administering
parenterally a beneficial agent using the parenteral delivery
system comprising the agent formulation chamber, and to a
method for adding an agent to a fluid.
15BACKGROUND OF THE INVENTION
The parenteral administration of medical liquids is ~ ;
an established clinical practice. The liquids are adminis-
tered 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
solution, electrolyte solution, and saline. Generally,
the liquids are administered from an intravenous delivery
~ system having a container suspended above the patient, with
;~ 25 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 provide
a satisfactory means and method for administering con-
comitantly therewith a beneficial agent. Presently, a
beneficial agent is administered intravenously by (1)
.
temporarily removing the intravenous system and halting the
flow of liquid, and then intravenously administering the
3; agent to the patient followed by reinserting the intravenous
system into the patient; (2) the agent is added to the liquid
in the container and then carried by the flow of the liquid
to the patient; (3) agent is added to a liquid in a separate
`'' ~
.~.. ,~. .. - '
-2- ARC 319/301
container called a partial fill that is connected to the
primary intravenous line through which line the agent is
carried by the flow o~ liquid to the patient; t4) an agent
is contained in a piggyback vial into which is introduced
an intravenous fluid, with the vial subsequently connected
to the primary line through which the drug is administered
to the patient; or (5) the agent is administered by a pump
that exerts a force on a liquid containing agent for intra-
venously administering the liquid containing the agent.
While these techniques are used, they have major dis-
advantages. For example, the administration of an agent
through repeated insertion of a needle leads to unnecessary
pain and trauma, they require separate connections for
joining 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, the rate of agent delivery to the
patient often is unknown as it is not rate-controlled agent
delivery but dependent on the flow of fluid, and they often
require preformulation of the agent medication by the hospital
pharmacist or nurse. In view of this presentation, it is
immediately apparent a critical need exists in the field of
parenteral therapy, particularly in the field of intravenous
delivery for a hsspital acceptable and dependable manufacture
and method for administering a beneficial agent at a controlled
rate by parenteral particularly by intravenous delivery systems.
DISCLOSU~E OF THE INVENTION
Accordingly, a principal object of this invention
is to provide a parenteral delivery system for administering
a beneficial agent at a controlled rate and in an improved
manner for optimizing the care of a human whose prognosis
benefits from intravenous delivery of a beneficial agent.
3;
The invention provides a parenteral delivery system
comprising: (a) a first container of a pharmaceutically acceptable
fluid; (b) a first drip chamber in fluid communication with the
container for de-termining the rate o-f -fluid flow through the
parenteral delivery system; and, (c~ a first formulation chamber
in communication with the drip chamber, the formulation chamber
comprising: (1) a wall surrounding a lumen; (2) an inlet for
admitting fluid from the drip chamber into the formulation chamber;
(3) an outlet for letting fluid leave the formulation chamber;
(4) a beneficial solid agent in the formulation chamber for form-
ing a fluid agent formulation with fluid admitted into the formu-
lation chamber; and wherein said formulation chamber further com-
prises: (i) a membrane that releases fluid agent formulation
from the formulation chamber; or, (ii) an agent delivery device
containing said agent that is released -to fluid admitted into the
formulation chamber.
In the formulation chamber containing the beneficial
agent is admitted into the parenteral fluid for optimizing the
care of a patient on parenteral therapy.
The formulation chamber may contain a dosage form of a
beneficial agent and is adapted for use in a parenteral delivery
system for admitting the beneficial agent at a controlled rate by
the dosage form into a parenteral fluid admitted into the chamber.
- 3 -
`
:, . .'. .: ., . . ' . .
~ ' . .
3 ~ ~ ~
The parenteral delivery system may comprise (1) a primary
fluid path, and (2) a secondary fluid path comprising a formulation
chamber containing (a) an agent delivery device for delivering an
agent into a medical fluid that flows into the chamber, or ~b) a
beneficial agent, which agent in either instance forms in situ an agent
solution for administration to an aminal, including a human patient.
The parenteral delivery system may comprise (1) a primary
fluid path comprising a formulation chamber containing (a) an agent
delivery device for delivering an agent into a medical fluid that flows
into the chamber~ or (b) a beneficial agent; and (2) a secondary fluid
path comprising a formulation chamber containing (a) an agent delivery
device for delivering an agent into a medical fluid that flows into
the chamber, or ~b) a beneficial agent, which agent in either (a) or
(b) forms in situ an agent solution for administering to an animal or
human.
Ihe invention concerns a parenteral delivery system and
an agent formulation chamber, which formulation chamber is adapted
for use with the parenteral system. The formulation chamber contains
(a) a beneficial agent that is self-formulating or self-mixing with
- a parenteral fluid entering the formulation chamber in situ and then
infused lnto a biological recipient, or the formulation chamber
contains (b) a-beneficial agent wherein the agent is originally pre-
sent in an agent delivery means such as an agent delivery device, or
a rate controlled dosage form housed in the chamber, which stores
.
,
`
-5- ARC 319/801
an amount of a beneficial agent for executing a prescribed
program and provide for a preprogrammed, unattended delivery
of agent into fluid that enters into the formulation chamber.
The beneficial agent on its release by the delivery means is
formulated in situ with parenteral fluid tha~ enters into
the f~ormulation chamber. The delivery means in one presently
preferred embodiment releases beneficial agent at a controlled
rate that is essentially independent of the volume rate of
parenteral fluid entering the formulation chamber, and then
infused into a recipient. The invention also is a parenteral
delivery system for administering a fluid agent formulation,
wherein the agent is formulated in situ with fluid and
wherein the parenteral delivery system comprises in combination:
(a) a container for storing a pharmaceutically acceptable
lS fluid which is also a pharmaceutically acceptable carrier
for the agent; (b) a formulation chamber comprising a wall
surrounding a lumen and having a surface inlet that permits
communication with the container to let fluid flow from the
container into the formulation chamber, and an outlet surface
through which agent formulation exits the chamber; ~c) a
beneficial agent, a dosage form, or a delivery device in the
formulation chamber; and (d) a conduit that communicates
with the chamber outlet and exte~ds to a patient recipient
site.
The invention concerns also a parenteral delivery
system that comprises: (1) a primary fluid path consisting
of a container of a medical fluid and a primary tube that
communicates from the container to a common tube that leads
to an infusion site in the animal; and (2) a secondary fluid
path consisting of a minicontainer of a medical fluid in
fluid communication with an agent formulation chamber that
communicates with a secondary tube and then with the common
fluid path for infusion into the animal.
3S
:`
L.Y~ ~,t;;~
The invention concerns also the parenteral delivery system
comprising: (1) a primary fluid path consisting of a container of a
medical fluid, a drip chamber, an agent formulation chamber, and a
primary tube that communicates with the formulation chamber and a
common tube that leads to an infusion site in an animal; and ~2) a
secondary fluid path consisting of a container of a medical fluid, a
drip chamber, an agent formulation chamber, and a secondary tube
that communicates with the formulation chamber and the common tube
that leads to an infusion site.
MODES FOR CARRYING OUT THE INVENTION
Figure 1 is a perspective view of an operative intravenous
delivery system in accordance with the invention;
Figures 2 to 7 illustrate other operative parenteral
therapeutic systems in accordance with the invention;
Figures 8 to 1~ depict different structurai embodiments of
formulation chambers;
Figures 17 to 24 illustrate various formulation chambers
housing a delivery device; and
Figure 25 illustrates a formulation chamber having an
internal pocket.
Figure 1 illustrates an operative intravenous delivery system
provided by the invention and it is generally designated by the numeral
10. System 10 comprises a container 11 formed of a flexible, or a semi-
rigid, preferably transparent plastic, such as polyvinylchloride, or a
polyolefin, and it contains a medical fluid 12 adapted for intravenous
administration. Medical fluid 12 in container 11 will typically be a
:
``
3 ~L 7~
sterile solution, such as an aqueous solution of dextrose, a
solution of dextrose in saline, an electrolyte solution and
saline. Medical fluid 12 also is a pharmaceutical vehicle or
carrier for intravenous administration, and it is a pharmaceutical
carrier for a beneficial agent that is to be administered to a
recipient. Container 11, in the embodiment illustrated, is non-
vented, the medical fluid in it is at atmospheric pressure, and
the container collapses as it empties of fluid 12. Container 11
usually is adapted to be hung neck-down from a hanger 13 by a bib
or hole 14 that connects or is integrally formed as part of con-
tainer 11. Container 11, at its end distant from its hanging end,
that is, at its neck end has an administration port 15 adapted for
receiving an administrative set.
- 6a -
-7- ARG 319/801
3t7~
The administration set provided by this invention
is used to deliver fluid 12 and a beneficial agent admitted
into intravenous delivery system 10 to a patient. The
administration set is sterile, pyrogen-free and disposable.
The administration set comprises the components described
hereafter, and it connects with port 15 of container 11.
Port 15 can be a diaphram in container 11, not shown, or
port 15 can be a hollow connector 16. Connector 16 is
adapted to receive end 17 of drip chamber 18, which end 17
fits snugly over connector 16. Drip chamber 18 is used
to trap air and permit adjustment of the rate of flow of
fluid 12 from container 11 as the flow proceeds drop wise.
An outlet 19 of drip chamber 18 is connected to a first
segment of tubing 20 that fits into outlet 19. An
adjustable clamp 21 of the roller or screw type on tubing
20 pinches the internal diameter of tubing 20 to regulate
flQw in cooperation with drip sight chamber 18. A second
segment of tubing 20 connects to inlet 23 of agent formulation
chamber 22. A third segment of tubing 20 connects to outlet
26 of formulation chamber 22 and to an adapter-needle assembly
27 that is inserted into a vein and sometimes an artery of
a warm-blooded animal.
Agent formulation chamber 22 is a unique component
of the intravenous delivery system both as the chamber alone
and in combination with the system. Formulation chamber 22
is sized and adapted for use in intravenous systems, it i5
self-contained, self-priming, self-powered, self-formulating,
and amenable to low cost manufacturing. Formulation chamber 22
contains an intravenously administrable beneficial agent,
and the use of formulation chamber 22 with agent therein does
not require any reconstitution or admixture prior to use.
Agent formulation chamber 22 is a lightweight disposable
chamber comprlsing a wall 24 that surrounds and defines an
internal space or lumen 25. Chamber 22 has an inlet 23
adapted and sized for placing chamber 22 into an intravenous
delivery system, and it has an outlet 26 also adapted for placing
-8- ARC 319/801
737~
the chamber in the system. Inlet 23 and outlet 26 are made
for receiving tube 20. Chamber 22 is made of glass, plastic
or the like, and as illustrated it is made of a transparent
material for illustrating its structure and an agent housed
therein. The agent in chamber 22 can be in any pharmaceutical
state that forms an agent formulation with the fluid that
enters the chamber. Exemplary pharmaceutically acceptable
forms include solid, crystalline, microcrystalline, particle,
pellet, granule, powder, tablet, spray-dried, lypohilized,
compressed forms that undergo disintegration and dissolution
in the presence of parenteral fluid including intravenous
fluid such as compressed particles, compressed powders,
compressed granules, friable layers of agent, in a delivery
device that releases the agent at a rate controlled by the
device into fluid that enters formulation chamber 22, in a
dosage, and the like. Agent,formulation chamber 22 generally
will store an amount of beneficial agent in a delivery device,
a dosage form, in a pharmaceutical form, and the like, for
executing a prescribed therapeutic or beneficial program.
That is, an amount of agent for the preprogrammed, unattended
delivery of a therapeutically or a beneficially effective
amount of the agent to produce a therapeutic or a beneficial
result. Agent formulation chamber 22 generally will have a
.. . .
/capacity of from about 10 milliliters to 250 milliliters of
~ fiuid or moré, and it can house from about 5 malligr~ to
20 grams of agent~or more in the various pharmaceutical forms
and delivery devices.
The expression beneficial agent, as used
herein, generically denotes any substance that produces a
therapeutic or a beneficial result, such as a drug, a car-
bohydrate, an electrolyte and/or the like. The term fluid
or liquid denotes a fluid or liquid that can be administered
parenterally including intravenously, comprising pharma-
ceutically acceptable fluids that are also a pharmaceutically
acceptable carrier for an agent, such as water, isotonic
saline, Ringer's lactate, and the like. The term formulation,
-9- ARC 319/801
~7~
an~ agent formulation as presently used herein, ~enerically
indicates the beneficial agent is ~ormulated, mixed, added,
dissolved, suspended, caxried, and/or the like in or by the
fluid ln a physical-chemical form acceptable for parenteral
including intravenous administration. In an additional
emb~diment of the invention, ~ormula~ion chamber 22 can
simultaneously act as a drip chamher while housing a device
or an agent. In this embodiment, the formulation chamber-
drip chamber is used to achie~e a desired fluid drop rate.
For example, the formulation chamber-drip chamber can have a
fast drop rate for adults, or it can have a slower drop rate for
pediatric use. The formulation chamber-drip chamber can
be made with various sized inlets for controlling the rate
of drip, or the drip can be controlled by a regulating clamp
on the tubing conveying fluid thereto. The formulation
chamber-drip chamber can deliver, for example from 2 to 75
drops per milliliter over from 1 minute to 1 hour. ~ore
preferably, the'therapist can adjust the rate of flow of
1 to 20 drops per minute, or for the need of the patient.
An additional disclosure pertaining to formulation chamber
22 is presented later in this specification.
Figure 2 illustrates another operative parenteral
therapeutic system generally designated 10 as provided
by the invention. System 10 is supported in delivery
position by support 30. System 10 is a vented-type
system that requires air to operate. System 10 comprises
a container 31 made of glass or rigid clear plastic
suitably sealed with a rubber stopper, not shown, that is
held in container 31 by annular closure rim 32. Container 31
contains a fluid 33 designated preferably for intravenous
administration. Air enters sys~em 10 through air inlet 34
formed as part of the inlet closure 35 of drip chamber 36.
A spike 37 that is hollow pierces the rubber closure of
container 31 and it serves as a conduit for letting air
-10- ~RC 319/801
7~
travel from air inlet 34 into container 31 and as a conduit
for letting fluid 33 travel from container 31 into drip
chamber 36. One point 38 of spike 37 is seen in con~ainer
31, the other point of spike 32, not seen, enters drip
chamber 36 for conveying fluid 33 from container 31 to
drip chamber 36. ~rip chamber 361 is of conventional,
hollow, tubular-like design consisting of a wall surrounding
an internal fluid receiving lumen and it is connected to an
agent formulation chamber 39 through a first section of tube
40 inserted into its outlet end 41 of drip chamber 36, and it
also is inserted into formulation chamber end 42 adapted
for receiving tube 40. The other end 43 of formulation
chamber 39 is adapted for receiving a second section of
lS tube 44. Formulation chamber 39 is made of glass or
plastic, and it is preferably transparent. Formulation
chamber 39 can have any shape adapted for use in a par-
enteral delivery system including intravenous delivery
systems, and it is preferably round and its length exceeds
its width. Ends 42 and 43 fit snugly over the wall of chamber
39 to form an air-tight, leak-proof closure for housing a
delivery system that releases an agent for forming an
agent solution in situ, in chamber 39 with fluid 33
entering chamber 39 from container 31 by mi~ing or dis-
solving therein. Tubing 44 conveys solution containing bene-
ficial agent from chamber 39 to needle 45 for administration
to a host. A regulating clamp 46 is provided on tube 40
for pinching the internal diameter of tube 40 for regu-
lating the flow of fluid 33 through the system 10.
Figure 3 illustrates another parenteral mainly intra-
venous system 10 provided by the invention. System 10 com-
prises in combination a container 48 that is a reservoir of
a pharmaceutically acceptable fluid and it has an internal
venting tube 49 which allows air to enter the container as
medical fluid is infused into a patient. Container 48 is
-11- ARC 319/801
~l73~5
closed with a stopper, now shown, and it has a hole for
venting tube 49. Container 48 is connected through a non-
vented hollow spike adaptor 50 to the parenteral system for
sending medical fluid from container 48 through system 10
to a patient. Spike 50 connects to a first section of tubing
51 th~t enters into a drip chamber 52. Drip chamber 52 is,
as previously described, made preferably of a see through
material such as glass or a plastic for visibly counting a
l measurable number of drops that pass through said chamber
over unit time. A second section of tubing unites drip
chamber 52 with a formulation chamber 53. The second section
of tubing 51 passes through a clamp 54 used for regulating
flow. Formulation chamber 53 comprises a wall 55 that
surrounds an internal space 56. Chamber 55 houses in space
56 a dosage unit amount of agent 57, as represented by dots,
for performing a beneficial program, or it can house a
delivery device, or other pharmaceutical form. Agent 57
is present in a pharmaceutically acceptable form that can
undergo dissolution, or it can disintegrate into smaller
parts and dissolve in the presence of liquid in chamber 55
to form an agent solution. The chamber 55 can optionally
contain a filtering element for providing a sterile fluid
by removing particulate matter and/or bacteria from the fluid,
which element does not interfer with the rate of fluid pass-
ing through the chamber. Delivery from such system can be
controlled, for example, by the rate of dissolution as
governed by particle size of agent and the solubility of
the agent in the fluid,by the rate of release by a delivery
device, and the like. Chamber 55 has an end 58 for receiving
incoming tube 51 and medical fluid from container 48, and
it has an end 59 for receiving outgoing tube 51. Tube 51
carries the agent solution from chamber 53 comprising a
beneficially effective amount of agent 57 through needle 60
to a patient for producing the intended beneficial effect.
3S
., .
-12- 319/801
737~35
Figure 4 represents a parenteral delivery system provided
by the invention and designatPd by the numeral 10. System 10 comprises
a primary container 62 formed of a flexible, or a semi-rig~d preferably
transparent plastic, such as a non toxic polyolefin, polyvinyl chloride
or the like. Primary container62 is a large volume parenteral, LVP,
container and it contains a medical fluid 63 adapted for parenteral,
intravenous or other therapy. Medical liquid 63 in container62 will
be typically a sterile solution, such as an aqueous solution of dextrose,
10 electrolytes, or saline. Container 62, in the embodiment illustrated,
is non-vented, the medical fluid is at atmospheric pressure, and the
container collapses as it empties of medical fluid 63. Container 62
usually is adapted to be hung neck-down from a hanger 64by a bib or
hole 65 that connects, or is integrally formed as part of container62.
lS Container 62, at its end distant from its hanging end, that is, at its
neck end, has an administration port adapted for receiving a primary
fluid path.
The primary path is used to deliver medical fluid 62by
parenteral therapeutic system 10 to a patient. The primary path is
20 sterile, pyrogen-free, and disposable. The primary path comprises the
components described hereinafter, and it connects with port 66 of
container 62. Port 66can be a diaphram in container 62, not shown,
or port 66 can be an adapter for receiving a hollow connector 67.
Connector 67 is made to receive end 680f drip chamber 69 . Drip
chamber 69 is used to trap air and it also permits, in cooperation with
regulator clamp 70, adjustment of the rate of flow of medical fluid 63
from container 62 as the flow proceeds dropwise. An outlet 71 of drip
chamber 6g is connected to one end of a primary tube 72 that passes
through regulator clamp 70 for pinching its internal diameter to regulate
30 flow in cooperation with drip sight chamber 69. The other end of
primary tube 72 connects to a valve 73, beyond which common tube 74
connects from valve 73 to an adapter needle assembly 75 that is inserted,
for example, into the v~in of a warm-blooded animal.
-13- ARC 319/801
3..~ 73 7~
System 10 further comprises a secondary fluid path, which
secondary path consists of a secondary container 76 or minibag formed
of a flexible, or a semi-rigid preferably transparent plastic, such as
a non-toxic polyolefin, polyvinyl chloride or the like. Secondary
container 76 is a small volume parenteral, SVP, container and it
contains a medical fluid 78 adapted for parenteral, intravenous or
other therapy. Medical fluid 78 is a pharmaceutical vehicle for
parenteral administration, that is, it is a pharmaceutical carrier for
a drug that is to be administered to a recipient. Container 76, in the
embodiment illustrated, is non-vented, medical fluid 78 is at atmos-
pheric pressure~ and the container collapses as it empties of medical
fluid 78. Container 76 is adapted to be hung neck-down from a hanger
64 by a bib or hole 79 that connects, or is integrally formed as a
part of container 76. ~ontainer 76, at its end distant from its hanging
end, that is, at its neck end, has an administration port adapted for
receiving a secondary fluid path.
The secondary fluid path provided by the invention is used to
deliver medical fluid 78 to which a drug is added to a patient. The
secondary path is sterile, pyrogen-free and disposable. The
secondary path comprises the components describer hereinafter,
and it connects with port 80 of container 76-
Port 80 can be a diaphram in container 76, not shown, or port 80can be an adapter for receiving a hollow connector 81. Connector 81 is
made to receive end 82 of drip chamber 83. Drip chamber 83 is used to
trap air and it also permits, in cooperation with regulator clamp 84,
3 adjustment of the rate of flow of medical fluid 78 from container 76
as the flow proceeds dropwise. An outlet 85 of drip chamber 83 is
connected to one end of a segment of secondary tube 86 passing through
regulator clamp 84 for pinching its internal diameter to regulate flow in coop-
eration with sight drip chamber 83. The other end of secondary tube 86
connects to an agent formulation chamber 87. Regulator clamp 84 jS
3; used for governing the flow of fluid into an agent formulation chamber
87. Formulation chamber 87 is made of glass or plastic, and it is
-14- ARC 319/801
~'73~
preferably transparent. Formulation chamber 87 can have any shape
adapted for use in a parenteral therapeutic system, and it is
preferably round and its length exceeds its width. The end of secondary
tube 86 mates snugly with end cap 89 of chamber 87. The end of the
secondary tube can fit into cap 89 or it can slide over a tube receiving
member of cap 89 to form an air-tight, leak-proof chamber for containing
at least one beneficial agent, or a delivery device. Chamber 87
optionally is equipped with a release rate controlling membrane, not
shown , ~or example a microporous membrane or the like, that
governs the rate of release of agent solution from chamber 87. A
release rate controlling membrane can rest on a sintered glass support
integrally made into the chamber, optionally a membrane can be sealed
adhesively to the inside wall of chamber 87, ~used thereto, be supported
by the wall of the chamber pinched inwardly, rest on a rim in the chamber,
or it can be supported or suitably fixed to end cap 90 positioned in
chamber 87. A segment of secondary tube 91 conveys agent solution from
chamber 87 to valve 73. A regulator clamp 92 is provided optionally on tube 91
as an aid in governing the flow of agent solution from the formulation chamber.
Regulator clamps 91 can be used alone, in cooperation with clamp 8~ in
cooperation with valve 73, and both in cooperation with valve 73 for
2 governing fluid flow and agent solution flow through the secondary path.
Valve 73, in a presently preferred embodiment, is a three position valve.
Agent solution is conveyed from valve 73 through common tube 74 to needle
assembly 75 for administration to a recipien~. That is, fluid can be
2 conveyed from the primary path, from the secondary path, or from both
paths by setting the valve for flow to a recipient. For example, fluid can
be conveyed through tube 72 valve 73, tube 74 and needle 75, or from
tube 91, valve 73, tube 74 and needle 75, or the valve can be set for
conveying fluid from both paths.
Figure S represents a parenteral delivery system provided by
the invention and designated by the numeral 10. System 10 of Figure 5
illustrates a vented-type system that requires air to operate. System 10
comprises a glass container 94, suitably sealed with a rubber stopper
and it contains a medical fluid acceptable for parenteral including
intravenous administration. Container 94 is supported in delivery
,
-15~ ARC 319/801
~ 7 3 ~3~
position by support 95, and air enters container 94 via air filter 96
connected to container 94 through spike 97 that is hollow and pierces
the rubber closure of container 94. The other point of spike 97, not
seen, enters a drip chamber 98 and it conveys medical fluid from container
94 into drip chamber 9B. Drip chamber 98 is connected to a primary fluid
path 99 formed of a medical grade tubing that conveys medical fluid to
needle 100. A roller valve clamp lOlis provided on fluid path 99 for
restricting the internal diameter of primary path 99 for regulating the
flow of fluid through primary path 99. System 10 of Figure 5 also
comprises a secondary fluid path 102that joins a common pathlO3 at
branch couplerlO4. Branch coupler 104can be made as a Y-type connecting
tube for receiving primary path 99, secondary path 102and common path 103.
The secondary path comprises a containerlO5 that is a mini-
container or a minibottle formed of glass, and suitably sealed with a
rubber stopper, not visible, and it contains a medical fluid acceptable
for parenteral including intravenous administration. Container 105is
supported in delivery position by support 95, and air enters container 105
through a filter 106connected to container105through spike 107, which
spike is hollow and pierces the rubber closure of container 105.
The other point of spike 97, not seen, enters a drip chamber 108
and it conveys medical fluid from containerlO5into drip chamberlO8.
Drip chamber 108is connected to a secondary fluid path 102 formed of a
medical grade tubing that conveys medical fluid transporting
a beneficial agent to needle lOQ. A roller valve clamp 109is provided
on secondary fluid path 102for restricting the internal diameter of
secondary path102 for regulating the flow of fluid through the secondary
path into agent formulation chamberllo- Agent formulation chamber 110
is sized and adapted for use in parenteral delivery system 10. Agent
formula.tion chamberllo is self-contained, self-priming, self-powered
and amenable to low cost manufacture. Formulation chamber 110 is light~
weight and disposable and it comprises a wall 111 that surrounds and
defines an internal lumen or space 112. Formulation chamber 110 has an
inlet 113 for receiving secondary path 102and it has an outlet 114 also
-16- ARC 319/801
;~L73~
adapted for placing chamber 110 in secondary path 102. Chamber 110 is made
s o~ glass, plastic or the like, and as illustrated it is made of a trans-
parent material for viewing its structure. Chamber 710 can hous~ a
beneficial agent or an agent delivery device. An agent formulation
formed in chamber 110 leaves cha~ber 110 through secondary path 102,
joins fluid from path 9~ at couple 10~ and the~ into common path 103
for infusion into a recipient.
Figure 6 illustrates another parenteral system 10
provided by the invention. System 10 comprises a primary
path 118 and a secondary path ll9supported agent fluid
delivery position above a patient by looped support 120.
Primary path 118comprises in combination a container121
that is a reservoir o a pharmaceutically acceptable liquid
122 and it has an internal venting tube123 which allows air
to enter container121 as medical fluid leaves container 121
and is infused into a patient. Container 121is a large
volume parenteral of a sterile fluid intended for the
modification and maintainment of physiological functions
in a recipient. Container 121is closed with a stopper124
held in place by a crimped rim 125. Venting tube 123 extends
thrpugh stopper 124 for admitting air into container 121.
Container 121is in fluid communication with drip chamber 126
through its hollow spiked end 127 that pierces stopper 124.
Drip chamber 126, is as previously described, used for
visibly counting the number of drops 128of medical fluid 122
that passes through said drip chamber 126 over unit time.
Drip chamber 126 comprises an enclosed space for holding
medical fluid and it is closed at its end by a pair of caps
129 and 130 that snugly slide over tubular wall 131 to form
said sterile fluid chamber. The fluid chamber is made of
see-through material such as glass or clear plastic for seeing
the drops. Medical fluid 122 leaves drip chamber126 through
-17- ARC 719/801
-~l737~5
a first section of tube 132 that carries medical fluid to
formulation chamber 133. Formulation chamber133 comprises
a wall 134 that surrounds an internal space135 and it is
closed at its ends 136 and 137 by closures that fit over said
chamber wall. Tube ~2 enters closure136 for establishing
fluid communication between the formulation chamber and the
drip chamber, and a second tube 138 that passes through a flow
regulator clamp 139 transport fluid to a two-way valve 140.
Fluid passes through valve 140 into common tube 141 and
needle assembly 142 to a recipient.
Secondary path ~9 consists of container 143 that is
a means for storing a pharmaceutically acceptable liquid l44.
Container 143 has an internal venting tube 145 for letting
air enter container 143. Container 143 is closed by stopper
146 held in place by rim 147. Container 143 is a minicontainer,
or a minibottle and it holds about 100 to 500 milliliters
of liquid that is used for continuous drug transport, or
for intermittent drug transport to a patient. Container 143
is connected to drip chamber 148 through hollow spike adaptor
149 for sending medical liquid from container 143 through
the secondary path to a patient. Drip chamber 148 is
designed for counting the number of drop 150 that pass
through said drip chamber 148 over time. Medical fluid
lea~es the drip chamber through a first section of tubing
151that leads to a formulation chamber 152. Agent formu-
lation chamber 152is as described earlier comprised of a
wall formed of a fluid impermeable material that surrounds
an internal space for housing a dosage unit amount of a
beneficial agent, or a delivery device. Chamber 152 has a
known volume and preferably a volumetric scale thereon
for indicating the volume of fluid in said chamber.
Chamber 152 has an end 153 adapted for receiving incoming
tube 151 and an end 154 adapted for receiving outgoing tube 155.
-18- ARC 319/801
~ ~ 7 ~ ~ ~ ~
Tube 155 passes through clamp 156 and it can be used as an
on-off, or a volume flow regula~or for controlling fluid
flow rate through the secondary path. Tube 155 conveys
fluid carrying beneficial agent from chamber153 to valve 140,
and thence through fluid communicating common tube 141 to
needle assembly 142 and into a living recipient.
In operation, parenteral delivery system 10 of
Figure 6 is used like parenteral delivery system 10 of
Figure 5. That is, system 10 of Figure 6 can be used
(1) for administering a preselected medical fluid containing
a preselected beneficial agent by opening regulator
clamp 139 closing regulator clamp ~6 and positioning
valve 140 to let fluid flow from tube 138 into tube 149;
~2) for administering a different preselected medical fluid
containing a different preselected beneficial agent by
opening regulator clamp 156 closing regulator clamp 139
and positioning valve 140 to let fluid flow from tube 155
into tube 141 and ~3) for administering at a selected
dosing time a given volume of fluid containing a known
am~unt of agent by (a) permitting fluid to flow through
the primary or the secondary path while setting valve 141
in closed position for the primary or the secondary path,
~b) permitting a known volume of fluid to enter either
formulation chamber, which volume is ascertained by reading
the meniscus against the volumetric scale on the chamber~
(c). formulating the agent formulation in the chamber by
dissolving a given amount of agent present in the chamber,
or delivered by a device therein, in the known volume of
fluid, which amount of agent solubility in the fluid dis-
solves over time, and (d) dosing a recipient with the agent
solution whenever desired by position valve 141to let it
flow from the desired formulation chamber. Thus, the
-19- ARC 319/801
invention provides for delivering the same fluid and different
drugs, or different fluids and different drugs to a patient
by preselecting the fluid and the drug for the primary or
secondary path. The invention also provides for continuous,
alternating or interrupted modes of drug therapy.
Figure 7 represents a parenteral system 10 provided
by the invention. Parenteral system 10 is a gravitational
flow system for the administration of two medical fluids
and two beneficial agents at independent, or cooperating
flow rates through two distinct delivery paths, a primary
path and a secondary path. The primary path 158 comprises
a container l59that contains a primary medical liquid 160
to be administered to a patient over a prolonged time and
it is supported in delivery position by a hanger 161.
Primary fluid supply container 159 is made from glass or
transparent non-toxic plastic and it is sealed under sterile
conditions. Container 159 is sealed with a rubber stopper 162
held in container 159 by annular retaining rim closure 163.
Primary container 159 is in fluid communication
with a drip chamber 164. Drip chamber164 is in fluid
communication with container 159 through a hollow puncture
spike 165 that passes through stopper 162 into container159.
Drip chamber 164 is a conventional, vented-type 165 drip chamber
well-known to medical practice. Basically, drip chamber 164
is formed of two parts, a conical housing 166 for receiving
fluid, and it is capped 167 at its inlet and terminates in
an outlet orifice 168. Drip chamber 164 lets air enter the
parenteral system through air inlet 16~ integrally formed
as part of capped inlet 16~. The drip 169 rate of fluid
flow from container 159 is regulated by a clamp 170 pro-
vided down stream on the primary path. A first section of
medical grade tubing 171 inserted into outlet 168 establishes
fluid communication between drip chamber 164 and inlet 171
of formulation chamber 172.
-20- ARC 319/801
~ ~ 7 ~
Agent formulation chamber 172 is sized and adapted
for use in parenteral delivery system 10. Agent formu-
lation chamber 172 is self-contained, self-primary, self-
powered and amenable to low cost manufacture. The formu-
lation chamber is light-weight, disposable, and it is made
in a presently preferred embodiment of a clear, trans-
parent material such as glass or plastic. Formulation
chamber 172 comprises a wall 173 that surrounds and forms
an internal space 17~, and it has an inlet closure 175
that receives tube 171 , and an outlet closure 176 adapted
to receive tube 177. Tube 177 passes through clamp170
designed for restricting the internal diameter of tube 177
for regulating, or stopping the flow of fluid through the
primary path. Tube 177 enters a coupler 178 made as a
Y-type connecting tube for receiving primary path tube 177
and a common tube 179 that leads to an injection member 180
for administering agent formulation to a patient.
Secondary path 181 comprises a container 182 that
is a minicontainer or a minibottle formed of glass or
plastic, suitably sealed with a rubber stopper 183 held in
container 182 by closure rim 184. Container 182 is
supported in delivery position by support 161 and it contains
a medical fluid 185 acceptable for both parenteral
including intravenous administration and as a transporting
carrier for a beneficial agent. Air enters container 182
through an air inlet 186 formed integral as part of
spike 187, which spike is hollow and pierces the rubber
closure -183 of container 182. The other point 188 of spike
187 passes through the closure inlet 189 of drip chamber
190 for conveying medical fluid drop-like 191 from the
con,tainer into the drip chamber. Drip chamber 190 is in
fluid communication via a tube 192 with formulation chamber
193. Agent formulation chamber 193 is constructed like
3; formulation chamber 172 described in the primary path,
-21- ARC 319/801
3~
and that description is included and is applicable ~or
chamber 193 Formulation chamber 193 is connected to a
secondary tube 194, formed of a medically acceptable
material, that passes through a V-clamp 195 for regulating
or stopping agent formulation flow through the secondary
path. Tube 194 enters couple 178 for flow into common path
179 for infusion through needle assembly 180 into a
patient.
The agent in formulation chambers 172 and 193 can be in
any pharmaceutical state, present as agent per se, or in a
device, which device forms a ~luid formulation comprising an
agent and a medical fluid that enters chambers 172 and 193, and
and a medical fluid that enters chambers 172 and 193, and
lS does not require any reconstitution or admixture prior to use.
The flow of medical fluid into formulation chamber 172 or
193 can be started, stopped, regulated, or interrupted by
clamp 170, or 195, alone or together, that permits tube 177
or 194 to remain open, shut, or to partially obstruct the
2 passage of fluid through tube 177 or 194, and correspondingly
the flow of agent solution likewise can be governed from
chamber 172 or 193.
In operation, parenteral delivery system 10 as
25 illustrated in Figure 7 can be used by a physician, a
nurse, or a practitioner in a hospital setting as follows:
(l) for administering medical fluid containing a bene-
ficial agent through the primary path by adjusting regu-
lator clamp 170 to open and by closing regulator clamp 194
to prevent the flow of fluid in the secondary~ thus
assuring the flow through the primary path and in-to skin
piercing needle 180, (2) for administering a medical fluid
containing a beneficial agent through the secondary path
by adjusting regulator clamp 195 to open and by closing
regulator clamp 170 to prevent the flow of fluid in the
.
-22- ARC 319/801
~:~'73~7~i
primary path, thus assuring the flow through the secondary
path and in~o skin piercing needle 180; and (3) for adminis-
tering an amount of agent in a known volume of fluid fromboth paths by regulating fluid flow through regulator
clamps 170 and 195, which fluid in both instances mixes
into a common fluid at coupling 178 for its subsequent
administration to a patient. The operations provided by
these embodimen~s of the inventlon make available continuous
and interrupted administration of ~wo different agents in
two different fluids through two different paths, and
administration of two different agen~s in different fluids
during the same time interval of agents administration.
~ Figures 8 through 25 depict strùctural embodiments of
formulation chambers that can be used in the intravenous
delivery system of Figures l to 7. Figure ~ illustrates
a formulation chamber 197that is light.weight, di~posable
and indicated for use in patients requiring parenteral
administration of a fluid containing a beneficial agent.
In Figure 8, chamber 197 comprises a body 198 of tube shape
and it has a pair of caps ~9 and 200 for forming a closed
25 chamber for containing fluid and agent. Caps ~9 and 200
fit body lg8and they are preferably made of self-sealing
rubber through which a needle or hollow spike can be in-
serted, or of rubber with a pre-drilled hole covered by a
latex disc through which communication can be made with
the inside chamber 197. Formulation chamber 197 can pre-
ferrably be hermetically sealed, is moisture proof, micro-
organism impermeable, ionizing ray permeable for sterilizingit.
-23- ARC 319/801
~3~
Figure 9 illustrates a formulation chamber 201
with a æection removed for depicting the inside of the
hollow body of the chamber. In Figure 9, chamber 201 com-
prises a wall 202 with a section removed and ends 203 and
2040 Closure ends 203 and 204 fit over the body of formu-
latiQn chamber 201 which ends 203 and 204 are made with a
receiving hollow member 20S and 206 for accepting a tube
that can slide into or slide over the receiving member.
Formulation chamber 201 contains a beneficial agent 207
that is soluble in parenteral fluid, such as in an intra-
venously acceptable fluid and a film 208 ~ormed of a
material for controlling the flow of fluid and agent from
chamber 201. Film 208 in a preferred embodiment is formed
of an agent release rate controlling polymer, such as a
microporous polymer like a polycarbonate, a semipermeable
polymer like cellulose acetate, or a diffusional polymer
like ethylene-vinyl acetate copolymer. The polymeric film
according to the mode of the invention is used in a presently
preferred embodiment for governing the rate of release of
solution containing agent from chamber 201, that is, agent
release and fluid flow through chamber 201. Chamber 201
i~ illustrated with a film at its exit, and optionally it
can have a film at its inlet.
Figure loillustrates a formulation chamber 209, in
opened view, comprising agent 210 in particle form, a release
rate controlling polymer film 211 such as cellulose acetate
or the like, and a filter 212. Filter 212 is a conventional
filter with a pore size of 0.1 micron to 5 micron, and more
preferably 0.22 micron or 0.45 micron, for removing bacteria
and unwanted matter from the flowing solution thereby, aiding
in maintaining a sterile solution.
-24- ARC 319/801
7~3~
Figure 11 illustrates formulation chamber 213
comprises a walled body 214 of tube shape and it has a pair
of caps 215 and 216 for forming a closed chamber containing
fluid and a delivery system. Caps 215 and 216 fit chamber
213 and they can have an integrally formed tubular ext`ension
217 a~d 218 for receiving an incoming tube. Hollow tubular
member 217 and 218 are preferably round for receiving a
tube that slides into, or slides over the member. The
delivery system depicted in formulation chamber 213
comprises a multiplicity of tiny timed pills 219
for the controlled delivery of an agent, including drug,
into a fluid entering chamber 213. The tiny pills are seen
in detail, in opened section pills 220, and they comprise a
core of drug 221 surrounded by a wall 222 formed of a
release rate controlling material. The tiny timed pills 219
provide a high membrane surface area for achieving high
release rates of agent for forming an agent solution. The
total number of tiny pills 219 in formulation chamber 213 can
be varied as an added means for regulating the amount of
agent made available for forming an agent solution. The
materials forming wall 222 can be selected from materials that
release drug 221 by different physical-chemical mechanisms.
These mechanisms include erosion, diffusion and osmosis mecha-
nisms. Wall 222 when releasing drug by osmosis, released drug
by bursting. Drug 221 in this embodiment is present in the
form of an osmotic solute, such as a therapeutically
acceptable salt, and it exhibits an osmotic pressure
gradient across wall 22Z against an external fluid. The
membrane materials used to form wall 222 are those per-
meable to the passage of an external fluid and substan-
tially impermeable to the passage of drug. Typical
materials include a member selected from the group con-
sisting of cellulose acylate, cellulose diacylate, cellulose
triacylate, cellulose acetate, cellulose triacetate, and
the like. The osmotic wall can be coated around the drug
in varying thickness by pan coating, spray-pan coating,
-25- ARC 319/801
73~5
Wurster fluid air-suspension coating and the like. The
wall is formed using organic solvents, including methylene
chloride~methanol, methylene chloride-acetone, methanol-
acetone, ethylene dichloride-acetone, and ~he like.
Osmotic wall forming materials, procedures for forming
the wall, and osmotic bursting procedures are disclosed
in United States Pt. Nos. 2,799,241; 3,952,741; 4,014,334;
and 4,016,880.
Wall 222 of tiny pills213 in another embodiment can
be made of a drug release rate controlling material. That
is, drug 221 dissolves in the wall or through pores within
the wall and passes through the wall or through said pores
at a controlled rate by diffusion over time. Exemplary
materials useful for forming a diffusional wall or a wall
with pores include ethylene-vinyl acetate copolymer, ethyl
celluIose, polyethylene, cross-linked polyvinyl pyrrolidone,
vinylidene chloride-acrylonitrile copolymer, polypropylene,
silicone, and the like. The wall can be applied by techniques
described above, and materials suitable for forming wall
81 are described in United States Patent Nos. 3,938,515;
e,948,262; and 4,014,335.
Wall 222 of tiny pills 213 can be made of bioerodible
material that bioerodes at a controlled rate and releases drug
221to the fluid in chamber 213. Bioerodible materials useful
for forming wall 222 include polycarboxylic acid, polyesters,
polyamides, polyimides, polylactic acid, polyglycolic acid,
polyorthoesters, and polycarbonates. These polymers and
procedures for forming wall 22Zare disclosed in United
States Pat. Nos. 3,811,444; 3,867,519; 3,888,975; 39971,367;
3,993,057; and 4,138,344. The amount of drug present in a
tiny timed pill generally is about 10 ng. to 20 mg, and
the number of tiny pills in a chamber is about 10 to 1000,
preferably 50 ~o 150. The tiny pills comprising the wall
and the inner core of drug have a diameter of at least 100
'' .
-26- ARC 319/801
73~5
microns, and in a presently preferred embodiment a diameter
5 of at least 2000 microns. The tiny pills can have one or
more coatings of wall-forming materials thereon. Chamber 213
optionally is equipped with a support 223 for ~he tiny pills.
Support 223 can be a film having release rate controlling
properties and made of a polymer that releases drug from
lO chamber 213, sUpport223 can be a microporous polymeric
membrane, a sintered glass support, a perforated grid, and/or
the like.
Figure 12 illustrates a formulation chamber 224
illustrating a similar chamber comprising a wall 226
surrounding a lumen 2Z7 having an inlet 228 and an
outlet 22~. Chamber 224lhouse's a plurality of tiny
capsules 230 further seen in opened section capsule 231.
Capsules 230 comprise a wall 232 surrounding a mass of
liquid drug 233, The tiny capsules can be made by co-
20 acervation technique consisting essentially of formingthree immiscible phases, a liquid manufacturing phase, a
core material phase and a coating phase. The coating phase
is deposited as a liquid on the core material and rigidized
usually by thermal, cross-linking or desolvation techniques,
25 to form tiny microcapsules. The capsules made by this
technique have an average particle size of from several
tenths of a micron to 5,000 microns, and in some embodiments
a lzrger tiny capsule can be used herein. Particle
size however, is not critical in the practice of this
30 ~ invention. Suitable techniques for preparing tiny micro-
capsules are reported by Bungenberg de Jong and Kass,
Biochem.Z., Vol. 232, pages 338 to 345, 1931; Colloid
Science, Vol. 11, "Reversible System," edited by H.R. Kruyt,
1949, Elsevier Publishing Co., Inc., New York; J. Pharm.
Sci., Vol 59, No. 10, pages 1,367 to 1,376, 1970; and
35 Pharmaceutical Science, Remington, Vol. XIV, pages 1,676
to 1,677, 1970, Mack Publishing Co., Easton, PA. Formu-
lation chamber 224also contains a film 234that supports the
tiny capsules and which Eilm can also serve as a means for
regulating the release of drug solution from formulation
chamber 224.
.,:
.
.
~; ' ' , ..
-27- ARC 319/801
~ 7~i7~35
Figure13 illustrates a formulation chamber 236
comprising a wall 237that surrounds an internal lumen 238
with an inlet end 239 and an outlet end 240. Chamber236
houses a multiplicity of hollow fibers 241 , with one fiber
seen in opened section comprising a wall 242, that can be
formed of a semipermeable polymer, a diffusional polymer,
a microporous polymer, a lamina, or a laminate of two or
more lamina, surrounding a lumen 243 containing drug 244.
The hollow fibers provide a large e~posed surface area
for concomitantly releasing a large amount of agent into
the .formulation chamber. The hollow fibers can have a
length of a few millimeters to many centimeters or longer,
a diameter of a millimeter or larger, and the chamber
houses at least one hollow fiber to several hundred or
more. The hollow fibers have openings at each end 241a,
241b, and they can be produced from non-cellulosic polymers
using melt spinning techniques using shaped spinnerettes.
Hollow fibers can also be produced by spinning an organic
solvent cellulosic solution into certain regenerants,
n-octanol where the solvent is dialkylacylamide, and
n-hexanol ~here the solvent is dimethylsulfoxide. The
hollow fibers can be filled with drug by using a solution
of drug injected into one opened end of the fiber, by
soaking in a drug solution, and the like. The hollow
fibers can release an agent by diffusion, dialysis, osmotic,
leaching and like techniques. The amount of agent released
from the fibers further can be regulated by selecting the
dimensions and number of hollow fibers housed in the
formulation chamber. A procedure for manufacturing hollow
ibers is disclosed in U.S. Pat. -No. 4,086,418. Formulation
chamber 236optionally contains a support 245 for holding the
fiber which support permits the passage of drug formulation
from chamber 236.
3;
, "~,,. "
-28- ARC 319/801
37~
Figure 14illustrates a formulation chamber 246,
seen in opened section, and it comprise~ a wall 247 that
surrounds a lumen 248 with an inle~ 249 and an outlet 250
for admitting and exiting fluid from chamber 246. Chamber
246 houses a multiplicity of fibers 251 containing drug
252 , represented by dots. The fibers 251 forming the drug
delivery system can be of natural or synthetic origin,
and they can have a wide variety of structures, such as
solid, semi-solid, porous, and the like, a variety of
geometric shapes such as round, oval, square, trilobal, various
lengths and cross-sections, and the like. The fibers
can function effectively as a reser~oir by having drug
disp~ersed therethrough. Suitable fibers can be made by
conventional fabrication techniques. For example, fiber
material and drug may be dissolved in a solvent, extruded
through small holes of a die and then solidified by standard
melt spinning, wet spinning, or dry spinning techniques.
In another embodiment, the fibers can be produced by pumping
a melt of fiber and drug through a spinneret. With such a
method, fiber diameter may be varied from a few tenths to a
micron to a millimeter or so by down-drawing, or by up-drawing
techniques. The lumen of the chamber can house fibers of
mixed denier. The fibers forming the reservoir can be filled,
saturated, or semi-filled with drug by immersing, soaking or
the like and permitting the desired amount of drug to ~rans-
fer into the fibers. Other techniques and drugs for forming --
fibers are disclosed in U.S. Pat. Nos. 3,228,887 and
30 3, 921, 636. The materials forming the fibers can be poly-
olefins, polyamides, polyurethanes, cellulosic materials and
the like. Fiber procedures are set forth in Encyclopedia
of Science and Technology, Vol. 5, pages 263 to 276, 1971,
published by McGraw Hill Co., New York. Chamber 246 also
contains a membrane 253 for supporting the fibers and it can
be formed of a diffusional or porous polymer for cooperating
with the fibers for regulating the amount of drug solution
infused into a patient.
. . .
-29- ARC 319/801
3~7~5
Figure 15 illustrates a formulation chamber 255
5 having a section of its wall 256 removed for depicting the
internal space 257 as a means for housing for a beneficial
agent delivery system 258. System 258 comprises a reservoir
formed of an erodible polymer, and a section is removed
259 for illustrating agent 260 dispersed therein. The
10 erodible polymer can be a member selected from the group
including polyorthoesters, polyorthocarbonates, polyglycolic
acid, polylactic acid, polyacetals, polyketals, polyamino
acid,s, and the like. Procedures and erodible polymers are
disclosed in United States Pat. No. 4,180,646; in
Int. J of Pharmaceutics, Vol. 7, pages 1 to 18, 1980;
in Biodegradables and Delivery Systems for Contraception,
Chapter 2, edited by E.S.E. Hafex and W.A.A. Van Os,
published by G.K. Hall, Boston, 1980. Chamber 255 can
also have a release rate controlling polymeric film 261
such as cellulose acetate or the like, and a filter 262-
20 Filter 262 is a conventional filter with a pore 263 having
pore size of 0.1 micron to 5 micron, and more preferably
0.22 micron or 0.45 micron, for removing bacterial and
unwanted matter from flowing solution, thereby aiding in
maintaining a sterile solution.
Figure 16 illustrates a formulation chamber 265
housing an agen~ delivery system comprising a plurality
of ion-exchange resin particles 266 having an agent 267
ionically attracted thereto. The resins can be particles, bead,
30 and droplet shaped. The particles and the like can vary in size,
usually from 10 to 350 mesh. The resins can be homopolymers, co-
polymers, derivatives thereof, or cross-linked resins. Typical
resins include ion-exchange resins such as cross-linked
styrene-divinyl benzene and the like, having agent 267
ionically bonded thereto. Active agent 267 is released
35 from resin 266 into fluid that enters the formulation
-30- ARC 319/801
~ .~7~5
chamber to form in the chamber an agent solution for adminis-
tering to a patient. Chamber 265 also can house a release
rate controlling film 268 and a filter 269 having pores 270
for preventing bacteria and unwanted matter from leaving
the formulation chamber. The ion-exchange resins are dis-
closed~ in United States Patent No. 4,203,440.
Pigure 17 depicts a formulation chamber housing a
1 delivery device. The formulation chamber can be used in a
primary path, a secondary path, or in both paths, that is,
the formulation chambers illustrated herein can be used in
either or both paths. Agent formulation chamber 272, as
seen in Figure 17 is another unique component of the
parenteral delivery system. Formulation chamber 272 is the
unique component of the parenteral delivery system, and in
the embodiment illustrated, the, formulation chamber comprises
a wall 273 that surrounds and defines an internal space 274.
Chamber 272 has an inlet 275 adapted and sized for placing
chamber 272 into an intravenous delivery system, and it has
an outlet 276 also adapted and sized for placing the chamber
in the system. Inlet 275 and outlet 276 are made for
receiving an incoming or outgoing tube. Chamber 272
is manufactured of glass, plastic or the like, and as
illustrated it is made of a transparent material for illus-
trating its structure and a device housed therein. In theembodiment shown, chamber 272 comprises a pair of inter-
fitting housing halves 277 and 278 for containing agent
delivery device 279 within space or lumen 274. A retaining
means 280 in housing 278 permits the passage of fluid, keeps
device 279 in lumen 274, and it also prevents device 279
from blocking outlet 276.
-31- ARC 319/801
~3~
The delivery device 279 illustrated in Figure 17
an osmotic rate-controlled solid dosage delivery form as
described by patentee Felix Theeuwes and Takeru Higuchi
in United States Patent No. 3,845,770. The osmotic device
279 seen in transparency comprises a semipermeable wall 281,
such as cellulose acylate, cellulose diacylate, cellulose
triacylate, cellulose acetate, cellulose diacetate, cellulose
triacetate, and the like, that surrounds and forms a
compartment 282 containing an agent 283, or drug represented
by dots. The agent formulation 283 exhibits an osmotic
pressure gradient across wall 281 of device 279 against
fluid in chamber 272. The agent formulation can comprise
an agent that exhibits an osmotic pressure gradient, or
the agent formulation can comprise an agent mixed with an
osmotically effective solute, such as sodium chloride,
potassium chloride, and the like that exhibit an osmotic
pressure gradient substantially greater than the fluid in
chamber 272. A passageway 284 extends through semipermeable
wall 281 and communicates with compartment 282 and the
exterior of device 279. In operation fluid enters chamber
272 and is imbibed through the semipermeable wall 281 of
device 279 into compartment 282 in a tendency towards
osmotic equilibrium at a rate determined by the permeability
of the wall and the osmotic pressure gradient across the
wall, thereby producing a solution containing agent 283
in compartment 282 that is dispensed through passageway
284 at a rate controlled by device 279 over a prolonged
period of time. The delivery of agent solution from
device 279 for homogenously blending with fluid in chamber
272 is controlled in this embodiment by device 279 ~nd it
is essentially independent of the rate of fluid flow
tl.rough chamber Z72. Device 279 maintains its physical
and chemical integrity throughout its releasing history.
;~Li73t7~3~
Figure 18 depicts agent formulation chamber 272 in opened
section, containing another device 285 for delivering an agent into
an intravenously acceptable fluid that enters chamber 272. Device
285 is illustrated in opened-section and it comprises an inner mass
transfer conductor 286, illustrated as a solid core and formed of
a polymeric material such as cured polydimethylsiloxane, with agent
287 dispersed therethrough. Surrounding mass transfer conductor
286 is an agent release rate controlling membrane 288, preferably
formed of a polymeric material, such as polyethylene. Both con-
ductor 286 and membrane 288 are permeable to the passage of agent
287 by diffusion, that is, agent can dissolve in and diffuse
through conductor 286 and membrane 288. However, the permeability
of conductor 286 is greater than that of membrane 288, and membrane
288 thus acts as the rate controlling member for agent release from
device 285. Device 285 maintains its physical and chemical
integrity throughout the period of agent delivery. Agent delivery
device 285 is disclosed in United States Patent No. 3,845,480.
Figure 19 illustrates the agent formulation chamber,
with a section of its wall removed/ housing delivery device 289
for delivering an agent at a rate controlled by device 289 into a
fluid that enters chamber 272. Device 289 is seen in opened-
section and it comprises a reservoir 290 formed of a liquid mass
transfer conductor 291 such as a medical oil liquid carrier,
per~eable to the passage of agent, containing agent 292 such as
the drug phenobarbital. Reservoir 290 is surrounded by a wall 293
formed of an agent or drug release rate controlling material
permeable to the passage of agent 292, such as a polyolefin. The
rate of passage of agent 292 is lowex through wall 293 than the
32-
, j !
~t7~t~
rate of passage through conductor 291, so that agent release by
wall 293 is the agent release rate controlling step ~or releasing
agent 292 from device 289. Device 289 maintains its physical and
chemical integrity throughout its agent release history. Agent
delivery device 289 is disclosed in United States Patent No.
3~993~073O
Figure 20 illustrates agent formulation chamber 272,
with a part of its wall removed, housing another device 294 for
delivering an agent into a liquid that enters chamber 272 for form-
ing an intravenously acceptable agent formulation. Device 294 is
seen in opened-section and it comprises a wall 295 surrounding a
reservoir 296 containing agent 297. The reservoir is formed of a
solid carrier permeable to the passage of agent such as cured
polydimethylsiloxane containing the drug diazepam. Wall 295 is
formed of a microporous material, the pores of which contain an
agent release rate controlling medium permeable to the passage of
agent 297 for example, formed of a microporous polymer made by
coprecipitation of a polycation and a polyanion. The release of
agent 296 is controlled by device 294, which device maintains its
physical and chemical integrity during the period of time it is in
chamber 272. De~ice 294 is disclosed in United States Patent No.
3,993,072.
Figure 21 is a view of formulation chamber 272 having
part of its housing removed and housing device 298 for delivering
an agent into a medical fluid that enters chamber 272 for forming
in situ an intravenously acceptable agent formulation solution.
Device 298 comprises a matrix 299 containing agent 300 distributed
therethrough. Matrix 299 is formed from a polymeric material that
-33-
, . . .
~7~
is non-erodible, that is, it keeps its physical and chemical
integri-ty over time, and it is permeable to the passage of agent
300 by the process of diffusion. The rate of agent release from
the matrix is determined by the rate the agent dissolves in and
passes through the matrix by diffusion, so that from the matrix it
is the agent release rate controlling step. The matrix can possess
any shape such as rod, disc and the like that fits into chamber 272.
The polymers include polyolefins such as polyethylene containing
muscle relaxants and the like. Materials useful for manufacturing
the devices are disclosed in United States Patent No. 3,921,636.
-33a-
-34- ARC 319/801
~ ~7~ 3S
Figure 22is a view of agent formulation chaMber 272, in
opened view, housing device 301for delivering an agent into a
fluid that enters chamber272 . Device 301 is seen in opened
section, and it is formed of a microporou9 polymeric material
302 containing agent 303 distributed therethrough. Matrix 302
is formed of a non-toxic, inert polymer, that is non-erodible
and has a plurality of micropores for releasing agent at a
controlled rate to fluid entering chamber 272. Microporous
1~ materials useful for the present purpose are disclosed in
United States Pat. Nos. 3,797,494 and 3,948,254.
Figure 23 illustrates agent formulation chamber 2729 in
opened view, housing device304 for delivering an agent into
a medical fluid that enters chamber272. Device304 is seen
in opened section and it comprises depots of agent solute 305
dispersed in and surrounded substantially individually by a
polymer 306 that is impermeable to the passage of agent solute
and permeable to the passage of fluid that enters chamber272.
Agent or a medication solute 305 exhibits an osmotic pressure
gradient across the polymer against fluid that enters chamber
272. Agent 305 is released at a controlled rate by fluid
from the chamber being imbibed through the polymer into the
depots to dissolve the solute and generate a hydrostatic
pressure in the depots, which pressure is applied against the
wall of the depots thereby forming apertures that release the
agent at a controlled rate over time. Polymer 306 is
non-erodible, and device 304 can be shaped as a matrix, a rod, a
disc, or like shapes. Procedures and materials useful for
manufacturing osmotic bursting delivery systems are described
in United States Pat. No. 4,L77,256.
Figure 24illustrates agent formulation chamber272 , in
opened view, containing device307 useful for delivering an
agent into a medically acceptable fluid passing through chamber
272 Device 307 is seen in opened view and it comprises an
exterior wall 308 Eormed of a semipermeable polymer permeable to
fluid and substantially impermeable to the passage of agents
and solutes. A layer309 of an osmotically effective solute,
-35- ARC 319/801
~.~73~
for example sodium chloride, is deposited on the inner surface
of wall 308. Solute layer309 s~rrounds an inner container 310
formed of a flexible material that is impermeable to solute and
agent. Container 310 has a passageway 311for delivering an
agent 312 into a fluid in chamber 272. Device 307 dispenses agent
by fluid permeating from chamber 272 through the outer wall 308
to continuously dissolve solute 309 in a tendency ~owards
osmotic equilibrium, thereby continuously increasing the volume
between wall 308 and container 310. This increase causes container
310 to continuously collapse and dispense agent 312 from device
3n7 at a controlled.rate through passageway 311tO fluid passing
through chamber 272. Osmotically powered agent dispensing
devices are disclosed in United States P~t. Nos. 3,760,984 and
3,995,63l.
Figure 25 illustrates a formulation chamber 314 made
with an internal pocket 315 for containing agent 316, for example
a drug such as ephedrine sulfate. Pocket 315 is formed of a
wall 317 made of a material such as a diffusional, semipermeable,
or a microporous polymer that permits the passage of medical
fluid into pocket 35 and agent solution formed therein from
pocket 315. In an embodiment, when wall 317 is a semipermeable
polymer, it can be provided with a delivery orifice to dis-
pense the agent solution into chamber 314. Wall 317 is joined
by adhesive, heat sealing or the like to wall 318 of chamber
314. Wall 318 is made of a material substantially impermeable
to the passage of agent, medical fluid and agent solution
formed therein. In operation, fluid enters chamber 314 and
then into pocket 315, wherein it forms a solution containing
the agent that passes into chamber 314 and then is administered
therefrom to a recipient. The system in Figure 25 allows
regulation of fluid flow independently from agent delivery.
Delivery is governed by the mass transport characteristics
of membrane 317, and fluid flow is governed by a resistance
element, for example, a flow regulator, in the fluid path.
~.~7~S
-36- ARC 319/801
The parenteral delivery system can be used for
administering many beneficial agents, especially where it is
desirable to administer by infusion, and more particularly
via the intravenous, intra-arterial, intraperitioneal, or
subcutaneous routes. For example, in one embodiment, for
intraperitioneal administration of fluid and beneficial
drug, the parenteral administration set is connected to a
cannula transversing the abdominal wall of the patient.
The parenteral delivery system in a presently preferred
embodiment is used for intravenous ~herapy. In intravenous
therapy, the parenteral delivery set can be used in intra-
venous fluid replacement, such as administering plasma,
saline, or the like and simultaneously, or intermittently
administering a therapeutically effective amount of drug
therewith; in another embodiment in a method of intravenous
electrolyte-balance replacement, such as supplying sodium,
potassium, chloride ions, or the like with a drug administered
therewith to a patient in need of electrolyte restoration and
intravenous drug; and in a method of intravenous nutrition,
2 such as supplying dextrose and concomitantly administering
or periodically administering a parenterally administrable
drug to a patient in need of such therapies. Also, the
parenteral delivery system comprising the primary path,
the secondary path with agent formulation chambers in one,
or in both paths, can be used as an intravenous therapy
system in the practice of veterinary medicine.
