System for providing intravenously administrable drug formulation

An intravenous delivery system is disclosed for formulating an intravenously administrable solution in the delivery system. The delivery system comprises means for transferring a fluid and for mixing the fluid with a drug in the delivery system.

FIELD OF THE INVENTION 
This invention pertains to a system for (a) formulating a fluid drug 
formulation, and for (b) delivering the fluid drug formulation 
intravenously to a host. The system comprises (1) a fluid container of an 
intravenously administrable fluid, (2) a drug container containing 
initially a drug or a means for providing a drug, (3) means for conveying 
fluid from the fluid container to the drug container for forming a fluid 
drug formulation in the container, and (4) means for intravenously 
administering the fluid drug formulation to a recipient. 
BACKGROUND OF THE INVENTION 
The intravenous administration of fluids is an established clinical 
practice. The clinical practice of administering fluids is used 
extensively as an integral part of the daily treatment of medical and 
surgical patients. The fluids administered intravenously usually include 
aqueous solutions of dextrose, sodium chloride and solutions of various 
other electrolytes. Generally, the fluids are administered from a 
container that is suspended above a patient, with the fluid flowing from 
the container through an administration set and thence to a catheter or a 
hypodermic needle placed in a blood vessel, usually a vein of a patient. 
The administration of fluids intravenously is a valuable and important 
component of patient care; moreover, the use of intravenous fluids in 
recent years has expanded beyond its original role of fluid and 
electrolyte replacement to include serving as the vehicle for the 
intravenous administration of beneficial drugs, notably those which are 
desirable to administer by infusion via the intravenous route. For 
example, presently a beneficial drug is administered intravenously by one 
of the following procedures: (1) temporarily halting the flow of medical 
fluid and intravenously administering the drug, followed by resumption of 
medical fluid into the patient; (2) the drug is added to the fluid in a 
container and then carried by the flow of fluid to the patient; (3) a drug 
is introduced into a so-called "piggyback" container, which is 
subsequently connected to a primary line through which the drug is 
administered to a patient, or (4) the drug is administered by a pump that 
exerts a force on a fluid containing a drug for intravenously 
administering the fluid containing the drug. 
While these delivery techniques are used, they have certain disadvantages 
associated with their use. For example, they often require performulation 
of the drug with the medical fluid by the hospital pharmicist or the 
nurse, and this frequently requires storing the premixed formulation at a 
lower temperature to prevent degradation of the formulation. Also, 
beneficial drugs that are fluid sensitive and require formulation with a 
fluid at the time of administration presently cannot be administered by 
these prior art systems. Additionally, the prior art systems often require 
separate connections for joining into the intravenous line that further 
complicates intravenous administration, and the use of pumps can produce 
pressures that can vary at the delivery site and the pump pressure can 
give rise to thrombosis. 
DISCLOSURE OF THE INVENTION 
A principle object of this invention is to provide both a novel and useful 
intravenous delivery system that overcomes the disadvantages associated 
with the prior art, and which present delivery system is an improved 
delivery system for intravenous drug administration. 
Another object of the present invention is to provide an intravenous 
delivery system comprising means for the in situ, self-formulation of a 
fluid drug formulation for administering to a patient whose prognosis 
benefits from intravenous drug administration. 
Another object of the invention is to provide an intravenous delivery 
system comprising initially a drug and a means for adding a medical fluid 
to the drug for forming a fluid drug formulation for administering to a 
patient at the time it is prepared for optimizing the care of the patient. 
Another object of this invention is to provide an intravenous delivery 
system originally containing a drug and a means for automatically 
constituting a drug formulation in situ by dissolving a given amount of 
drug in a given volume of a fluid that can be administered at any 
preselected time to a patient on intravenous therapy. 
Another object of the present invention is to provide an intravenous 
delivery system that is self-contained and makes attainable a program of 
drug administration adapted to a specific need by furnishing a fluid drug 
formulation formed in situ by mixing a known volume of fluid with from a 
trace to a saturating amount of a beneficial drug. 
Another object of the present invention is to provide an intravenous 
delivery system comprising initially a drug free of fluid to which drug 
fluid can be added as needed for forming a fluid drug formulation 
acceptable for intravenous therapy. 
Another object of the invention is to provide an intravenous delivery 
system that is easy to manufacture, is inexpensive, is easy to operate, 
and provides instant drug formulation and delivery to a needy patient. 
Another object of the invention is to provide an intravenous delivery 
system that can administer a drug in solution at a controlled and 
continuous rate to a human for a particular time period, the use of which 
requires intervention only for initiation and termination of the delivery. 
Other objects, feature, aspects and advantages of the invention will be 
more apparent to those versed in the art from the following detailed 
specification taken in conjunction with the drawing figures and the 
accompanying claims.

In the specification and the drawing, like parts in related figures are 
identified by like numbers. The terms appearing earlier in the 
specification and in the description of the drawing figures are disclosed 
hereinafter in this disclosure. 
DETAILED DESCRIPTION OF THE DRAWINGS 
FIG. 1 represents an intravenous delivery system provided by the invention 
and designated by the numeral 10. System 10 comprises a first or fluid 
container 11 that contains a medical fluid 12 acceptable for intravenous 
administration. Container 11, in the embodiment illustrated in FIG. 1, is 
made of plastic, preferably a flexible, transparent nontoxic plastic. In 
the embodiment illustrated, container 11 is shaped like a bag, and it is 
formed from a nontoxic poly(olefin), poly(vinyl chloride), or the like. In 
another embodiment, container 11 can be made from glass and it has the 
shape of a conventional intravenous glass container. Container 11 
manufactured from plastic or glass is in a presently preferred embodiment 
a large volume container. Container 11, in the embodiment illustrated, 
represents a nonvented container containing medical fluid 12, which 
container is at atmospheric pressure, and collapses as it empties of 
medical fluid 12. 
Container 11 is connected to the rest of intravenous delivery set 10 
through an adaptor 13 that is suitably connected to the bottom of 
container 11. Adaptor 13 is hollow and it is optionally integrally formed, 
or it is suitably connected to container 11. Adaptor 13 is a means for 
conveying medical fluid 12 from container 11 to the rest of delivery 
system 10. The other end of adaptor means 13 is connected to a first 
section of medical grade tubing 14. Tube 14 passes through a fluid 
regulating clamp 15 used for adjusting the rate of fluid 12 flow from 
container 11 and through delivery system 10. Tube 14 optionally is 
provided with a one-way valve 9, typically of the duck-bill type, used to 
prevent solution from backing up into container 11. The other end of tube 
14 is connected to means 16 for Permitting the passage and the conveyance 
of medical fluid 12 to other sections of delivery system 10, or for 
letting medical fluid 12 flow directly to a patient. In FIG. 1, means 16 
is manufactured as a three-way valve. 
Intravenous delivery system 10 comprises also a second or drug container 
17. Container 17, in the embodiment illustrated, initially is essentially 
fluid-free and it initially contains drug 18. Container 17, in the 
embodiment illustrated is made of plastic, preferably a flexible 
transparent nontoxic plastic. In the embodiment illustrated, container 11 
is shaped like an intravenous bag, and it is formed from a nontoxic 
poly(olefin), poly(vinyl chloride), and the like. In another embodiment, 
container 17 can be made from glass and it has the shape of a conventional 
intravenous glass container. Container 17 manufactured from plastic or 
glass is in a presently preferred embodiment a small volume container. 
Container 17, in the embodiment illustrated is nonvented, and container 
17, after receiving an incoming fluid, collapses as it empties over time. 
Container 17 is connected to the rest of intravenous delivery set 10 
through adaptor means 19. Adaptor means 19 is connected to the bottom of 
container 17. Adaptor 19 is hollow and it is optionally integrally formed, 
or it is suitably connected to container 17. Adaptor 19 is a means for 
introducing fluid into container 17 and it is a means for permitting fluid 
to flow from container 17. The other end of adaptor means 19 is connected 
to a second section of medical tubing 20. Tubing 20 passes through a fluid 
regulating clamp 21 used for governing the rate of fluid flowing from 
container 17. The other end of tube 20 is connected to means 16, presently 
manufactured as a three-way valve. 
A third section of medical grade tubing 22 releasably connected to means 16 
is a fluid path for the passage of fluid from valve means 16 to a drip 
chamber 23. Drip chamber 23 is used to trap air and it also permits, in 
cooperation with regulator clamp 15, regulator clamp 16 and regulator 
clamp 26 adjustment of the rate of fluid flow through delivery system 10, 
as the flow proceeds dropwise 24. An outlet of drip chamber 23 is 
connected to one end of a third section of medical tube 25 that passes 
through a regulator clamp 26. Regulator clamp 26 is used for adjusting the 
internal diameter of tube 25 to regulate fluid flow in cooperation with 
sight drip chamber 23. The other end of medical tube 25 is connected to an 
adapter needle assembly 27 that is inserted, for example, into the vein of 
a warm-blooded animal. 
Three-way valve means 16, as seen in FIG. 1, in one position permits the 
passage of medical fluid 12 to flow from container 11 directly into drip 
chamber 23, and hence into tube 25 through needle assembly 27 and into a 
patient, while concomitantly stopping fluid flow in tube 20 by clamp 21. 
In a second position, valve 16 allows fluid 12 to flow from container 17 
into tube 20 and into container 17 when container 17 is lowered to a 
position lower than container 11. In a third position, valve 16 allows 
fluid 12 containing drug 18 to flow through tube 20 into drip chamber 23 
and hence into tube 25 and through needle assembly 27 for administering 
drug 18 to a patient. Additional operating details of system 10 are 
presented later in this disclosure. 
Referring now to FIG. 2, there is illustrated an intravenous delivery 
system 10 similar to the intravenous delivery system 10 as seen in FIG. 1. 
In FIG. 2, delivery system 10 is provided with a two-way fluid-flow valve 
28 that permits fluid 12 to flow from container 11 to needle assembly 27, 
or valve 28 can be set for permitting a drug solution formed in situ in 
container 17 to flow into needle assembly 27. FIG. 2 optionally is 
provided with a one-way valve 9 that can be used in cooperation with valve 
28. Valve 28 also has an optional non-flow position for preventing fluid 
flow in tube 14 and tube 20. In FIG. 2, delivery system 10 additionally is 
provided with a bypass means for conveying fluid 12 from container 11 to 
drug container 17. The bypass means consist of a first T-couple 29 on tube 
14, a second couple 30, which couples are suitably united by a connecting 
tube 31. Tube 31 is equipped with a bypass valve 32 that permits fluid to 
flow from container 11 into container 17. Thus, as seen in FIG. 2, an 
empty container 17 containing drug 18, in operation, would be lowered to a 
position below the position of container 11, bypass valve 32 would be 
opened, permitting fluid to flow from large volume container 11 into small 
volume container 17. When the small volume container 17 is filled with the 
desired amount of incoming fluid 12, thereby forming a drug 18 solution in 
situ in container 17, valve 32 is closed. Then, container 17 is raised 
from the lower position to a higher position, preferably higher than 
container 11. The contents of container 17 will thereafter be 
preferentially delivered through opened valve 28 into needle assembly 27 
for administering drug 18 solution to a needy patient. 
Referring now to FIG. 3, there is illustrated an intravenous delivery 
system 10 similar to delivery system 10 as seen in FIG. 1 and FIG. 2. In 
FIG. 3, delivery system 10 is provided with means 33, a branch coupler 
that can be made as a Y-type couple for receiving incoming tube 14, tube 
20 and tube 22. Means 33 permits fluid flow in tube 14, tube 20 and in 
tube 22 to be correspondingly adjusted via flow regulator 15, flow 
regulator 21 and flow regulator 26. Further in FIG. 3, small volume 
container 17 is seen housing means 34 containing drug 35 for automatically 
constituting a beneficial drug solution in container 17 with medical fluid 
admitted into container 17. Originally, container 17 does not contain any 
medical fluid. Means 34, manufactured as a beneficial drug delivery device 
containing drug 35, releases drug 35 to fluid 12 that subsequently enters 
container 17. Means 34 releases a therapeutically effective amount of drug 
to form in container 17 a beneficial drug solution for administering to a 
patient. 
Referring now to FIG. 4, FIG. 5 and FIG. 6, intravenous delivery system 10 
is seen in operation preparing a drug solution acceptable for intravenous 
administration. In FIG. 4 and in FIG. 5, a drug is added to an 
intravenously administrable fluid 12. In FIG. 4 and in FIG. 5, fluid is 
added to container 17 by gravity flow. This procedure is performed by 
lowering container 17 that initially contains a drug, or a dosage unit 
amount of drug for executing a therapeutic program, to a lower position 
than the higher position occupied by fluid container 11. In an embodiment 
not shown both container 11 and container 17 can have a volumetric scale 
thereon for indicating the volume of fluid in container 11 and for 
indicating the volume of fluid transferred into container 17. When 
container 17 has been filled with the desired volume of fluid, container 
17 is raised from the lower position, as seen in FIG. 4 and in FIG. 5, to 
the higher position as seen in FIG. 6. The drug solution 36 formed in 
container 17 by drug 18 dissolving in fluid 12, is then administered to 
the patient. In additional operations, the contents of container 17 will 
be administered through needle assembly 27 until the level of fluid in the 
tube leading from container 17 falls to the same level as the fluid in 
container 11. When it is desired to provide another dose of fluid drug 
formulation from container 17, container 17 is moved to its lower position 
and a volume of fluid required to provide the drug solution is allowed to 
flow into container 17 from container 11. Then, the above described 
administration procedure is repeated for the desired therapy. Container 17 
also can be allowed to administer all of its drug solution and remain 
empty of fluid until the next time drug is indicated for administration. 
The above procedure then is repeated for forming and administering the 
drug solution. The same procedures are used when container 17 contains a 
drug delivery device. 
Medical fluid 12, as used herein, is typically a sterile solution, such as 
a solution of dextrose, a solution of an electrolyte, or saline. Medical 
fluid 12 also is a pharmaceutical vehicle, or a pharmaceutically 
acceptable carrier for beneficial drug 18 for forming a fluid drug 
formulation 35 that is to be administered to a recipient. The initial 
volume of medical fluid 12 in large volume container 11 is a volume 
sufficient for performing a therapeutic program, usually 500 ml to 1000 
ml. Container 17, a small volume container, will generally have a capacity 
of 250 ml to 500 ml. It is understood, containers of other capacities 
likewise can be used for the present purpose. 
The beneficial drug 18 initially present in container 17 is in any 
pharmaceutical state that forms a drug formulation solution with medical 
fluid 12 that enters container 17. The use of drug 18 in container 17 does 
not require any reconstituting, or admixture prior to use. The 
pharmaceutically acceptable form of drug, in a presently preferred 
embodiment, is solid. For the purpose of this invention, the term solid 
includes crystalline, microcrystalline, particle, pellet, granule, powder, 
tablet, dry, spray-dried, lyophilized, compressed powder, compressed 
granule, friable layers, forms that disintegrate and/or dissolve in the 
presence of incoming medical fluid, and the like. Container 17 generally 
contains an amount of beneficial drug for executing a prescribed 
therapeutic program, that is, an amount of drug for the preprogrammed 
delivery of a therapeutically effective amount of drug to a recipient to 
produce the desired beneficial therapeutic effect. Generally, the 
contianer will house from 1 mg to 25 g of drug, or more. 
The delivery device containing drug as initially housed in container 17 are 
those that release drug by dissolution, diffusion, osmotic mechanism, or 
by other physical-chemical mechanism that produce a drug formulation. 
Representative drug delivery systems are the osmotic powered dispensing 
device disclosed by Theeuwes in U.S. Pat. No. 3,760,984; the osmotic 
dispensing device as disclosed by Theeuwes et al. in U.S. Pat. No. 
3,916,899; the diffusion powered device a disclosed by Zaffaroni in U.S. 
Pat. No. 3,993,072., the osmotic miniature pump as disclosed by Higuchi in 
U.S. Pat. No. 3,995,631; the dispensing devices made from 
poly(orthoesters) and poly(orthocarbonates) as disclosed by Choi et al. in 
U.S. Pat. No. 4,138,344, dispensing devices made from a poly(ester), a 
poly(lactic), or a poly(glycolic) acid as disclosed by Ramwell in U.S. 
Pat. No. 3,888,975, and the like. The terms host and recipient as used 
herein denote animals, including warmblooded animals, which expression 
includes humans. 
FIG. 7, FIG. 8, FIG. 9 and FIG. 10 illustrate additional embodiment of the 
invention for providing a drug for mixing with a medical fluid. The 
embodiment illustrated in FIG. 7 comprises a small volume container 37 
provided with a pulse dosage dispenser 38 seen in dash-lines. Pulse 
dispenser 38, in one manufacture is made as a raised pouch, as illustrated 
in FIG. 8 in dash-lines. The pulse dispenser 38, made as a raised pouch is 
similar to a marsupial pouch. In this manufacture, the pouch is on the 
inside wall of container 37. The pouch contains drug and it serves to 
discharge a part of its drug through opening 39 into container 37 each 
time container 37 is lowered and inverted for receiving an incoming 
medical fluid. It is presently desired to keep the size of opening 39 
small in order to minimize the amount of active drug released into 
container 37, and for keeping drug in reserve in pouch 38 for later use. 
In this manufacture pouch 38 functions as a pulse dosage dispenser, and 
acts as a reservoir of drug. Container 37 is used like container 17 with 
intravenous delivery system 10. FIG. 9 is a side view in opened section of 
the pouch as depicted in FIG. 7 and 8. The pouch is formed by a wall 40 
made of a flexible polymeric material defining a pocket-like structure 
bonded around its edges to the inside surface 41 of container 37. The 
edges and the inside surface are bonded to each other by adhesive or 
solvent bonding or by any other suitable means to provide a fluid tight 
seal. This permits drug to be maintained in pouch 38 and it permits 
discharge only through opening 39 specifically provided for that function. 
FIG. 10 is similar to FIG. 9 with the added embodiment of a dispensing 
passageway 42 integrally formed in the bottom of the pouch and positioned 
distant from opening 39. FIG. 10 operates as previously described and it 
contains a medicament that can be added to an incoming fluid for 
intravenous use. 
The novel and unobvious invention uses means for obtaining the precise 
control of drug delivery in an intravenous delivery system. While there 
has been described and pointed out 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 
delivery system illustrated and described can be made without departing 
from the spirit of the invention.