U.S. patent number 3,797,485 [Application Number 05/128,303] was granted by the patent office on 1974-03-19 for novel drug delivery device for administering drug into blood circulation in blood vessel.
This patent grant is currently assigned to Alza Corporation. Invention is credited to John Urquhart.
United States Patent |
3,797,485 |
Urquhart |
March 19, 1974 |
NOVEL DRUG DELIVERY DEVICE FOR ADMINISTERING DRUG INTO BLOOD
CIRCULATION IN BLOOD VESSEL
Abstract
A novel drug delivery device for administering a drug into the
blood circulation comprising a means for positioning a drug supply
on the adventitial surface of an intact blood vessel for diffusing
the drug into the blood in the blood vessel.
Inventors: |
Urquhart; John (Malibu,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
22434669 |
Appl.
No.: |
05/128,303 |
Filed: |
March 26, 1971 |
Current U.S.
Class: |
604/288.04;
424/422 |
Current CPC
Class: |
A61K
9/0024 (20130101); A61M 31/002 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 31/00 (20060101); A61m
005/00 () |
Field of
Search: |
;128/1R,213,260,268,334
;424/14,16,19 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Truluck; Dalton L.
Claims
We claim:
1. A drug delivery device for directly diffusively administering a
drug into the blood through the walls of an intact blood vessel
confining the same, comprising a hollow, elongate, bulbous tubule
member tapered at its ends and having interior and exterior wall
surfaces adapted to sealingly circumferentially engage the
adventitial surface of a blood vessel longitudinally extending
therethrough at both the proximal and distal ends thereof to form a
pair of well-defined sealed interfaces therewith, and defining
reservoir means for confining a drug supply in an annular
interspace between the interior wall surface of said tubule member
and the exterior wall of such blood vessel, said tubule member
being provided with both inlet means and outlet means for filling
and emptying the interspace, and the said tubule member being
essentially impermeable to the drug and body fluid, whereby, in
vivo, and confining a drug supply, the drug diffuses therefrom and
through the walls of the intact blood vessel directly into the
blood circulation in the intact blood vessel.
2. A drug delivery device for directly diffusively administering a
drug into the blood through the walls of an intact blood vessel
confining the same, comprising an elongate first tubule member
having interior and exterior wall surfaces adapted to
circumferentially engage the adventitial surface of a blood vessel
longitudinally extending therethrough at both the proximal and
distal ends thereof; a second tubule member having interior and
exterior wall surfaces concentrically disposed within said first
tubule member, comprising drug release rate controlling membrane,
and sealingly circumferentially affixed to said first tubule member
at the proximal and distal ends thereof and adapted to
longitudinally extend therethrough closely adjacent the adventitial
surface of the blood vessel; the interior walls of said first
tubule member defining a sealed, annular interspace for confining a
drug supply, said first tubule member being provided with both
inlet means and outlet means for filling and emptying the
interspace; and the said first tubule member being essentially
impermeable to the drug and body fluid, whereby, in vivo, and
confining a drug supply, the drug diffuses therefrom through the
membrane and to and through the walls of the intact blood vessel
directly into the blood circulation in the intact blood vessel.
3. A drug delivery device for directly diffusively administering a
drug into the blood through the walls of an intact blood vessel
confining the same, comprising a hollow, elongate tubule member
having interior and exterior wall surfaces and circumferentially
inwardly descending skirt members integral therewith and annularly
depending therefrom at both the proximal and distal ends thereof,
said skirt members adapted to sealingly circumferentially engage
the adventitial surface of a blood vessel longitudinally extending
through the tubule member to form a pair of well-defined sealed
circumferential interfaces therewith, and said tubule member and
skirt members depending therefrom defining reservoir means for
confining a drug supply in an annular interspace between the
interior wall surface of said tubule member and the exterior wall
of such blood vessel, said tubule member being provided with both
inlet means and outlet means for filling and emptying the
interspace, and the said tubule member and skirt members being
essentially impermeable to the drug and body fluid, whereby, in
vivo, and confining a drug supply, the drug diffuses therefrom and
through the walls of the intact blood vessel directly into the
blood circulation in the intact blood vessel.
4. A drug delivery device for directly diffusively administering a
drug into the blood through the walls of an intact blood vessel
confining the same, comprising a hollow, elongate first tubule
member having interior and exterior wall surfaces and
circumferentially inwardly depending skirt members integral
therewith and annularly depending therefrom at both the proximal
and distal ends thereof, said skirt members adapted to sealingly
circumferentially engage the adventitial surface of a blood vessel
longitudinally extending through the tubule member to form a pair
of well-defined sealed circumferential interfaces therewith; a
second tubule member having interior and exterior wall surfaces
concentrically disposed within said first tubule member, comprising
drug release rate controlling membrane, and sealingly
circumferentially affixed to the skirt members annularly depending
from the said first tubule member and adapted to longitudinally
extend therethrough closely adjacent the adventitial surface of the
blood vessel; the interior walls of said first tubule member and of
the skirt members depending therefrom and the exterior walls of
said second tubule member defining a sealed interspace for
confining a drug supply, said first tubule member being provided
with both inlet means and outlet means for filling and emptying the
interspace; and the said first tubule member and the skirt members
depending therefrom being essentially impermeable to the drug and
body fluid, whereby, in vivo, and confining a drug supply, the drug
diffuses therefrom through the membrane and to and through the
walls of the intact blood vessel directly into the blood
circulation in the intact blood vessel.
5. A drug delivery device for directly diffusively administering a
drug into the blood through the walls of an intact blood vessel
confining the same, comprising a first saddle member having
interior and exterior wall surfaces adapted to sealingly engage the
adventitial surface of a blood vessel longitudinally extending
thereunder completely about the periphery thereof to form a
well-defined, sealed, continuous peripheral interface therewith; a
second saddle member having interior and exterior wall surfaces
disposed beneath said first saddle member, comprising drug release
rate controlling membrane, and sealingly continuously peripherally
affixed to said first saddle member and adapted to extend
thereunder closely adjacent the adventitial surface of the blood
vessel; the interior walls of said first saddle member and the
exterior walls of said second saddle member defining a sealed
interspace for confining a drug supply, said first saddle member
being provided with both inlet means and outlet means for filling
and emptying the interspace; and the said first saddle member being
essentially impermeable to the drug and body fluid, whereby, in
vivo, and confining a drug supply, the drug diffuses therefrom
through the membrane and to and through the walls of the intact
blood vessel directly into the blood circulation in the intact
blood vessel.
6. The drug delivery device as defined by claim 5, wherein the
first saddle member is essentially uniformly semi-circular in
cross-sectional configuration in the directon along the major axis
thereof.
7. The drug delivery device as defined by claim 5, wherein the
first saddle member is further of a configuration adapted to
helically engage the adventitial surface of the blood vessel.
8. The drug delivery device as defined by claim 1, wherein the
inlet means further comprises a bacterial filter.
9. In a process for administering a therapeutically effective
amount of an acceptable drug into the blood within an intact blood
vessel wherein the process comprises placing a drug delivery device
adapted for supplying a drug on the adventitial surface of a blood
vessel, the device comprised of a wall formed of a material
essentially impermeable to drug within the wall forming a reservoir
and adapted to embrace the adventitial surface of the blood vessel,
a reservoir for supplying drug and defined by the inner surface of
the wall, an inlet port and an outlet port connected to the
reservoir for supplying drug to the reservoir, and wherein drug is
released from the reservoir when charged with drug and in contact
with the adventitial surface for diffusively administering the drug
through the blood vessel and into the blood from the device.
10. In a process for administering a drug from a drug delivery
device according to claim 9 wherein the drug is diffusively
administered into the blood to produce a localized effect.
11. In a process for administering a drug from a drug delivery
device according to claim 9 wherein in the drug is diffusively
administered into the blood to produce a systemic effect.
12. In a process for administering a drug from a drug delivery
device according to claim 9 wherein the device further comprises a
drug release rate controlling membrane permeable to the passage of
drug for controlling the rate of drug diffusion from the device to
the adventitial surface of the blood vessel wall, said membrane
positioned and joined to the edges of inner surface of the wall
with the drug contained in the reservoir formed by the inner
surface of the wall and the membrane.
13. A process for administering a drug from a drug delivery device
according to claim 12 wherein the wall and membrane are adapted to
form a spiral or helix shaped device.
Description
BACKGROUND OF THE INVENTION
The present invention relates to a novel article of manufacture and
to a method for using the article. More particularly, the invention
pertains to a device for administering a drug into the blood
circulation by diffusing the drug from the device on the
adventitial surface of a blood vessel; and, to a method for
administering a drug into the blood circulation by positioning a
drug delivery device containing a drug on the adventitial surface
of a blood vessel to diffuse the drug through the blood vessel wall
into the circulating blood to produce either a localized or
systemic pharmacological or physiological effect.
It is known to the prior art since Megendie in the early 1800's
performed his experiment of exposing the jugular vein of a dog and
applying a watery solution of spirituous extract of nux vomica to
the exposed vein "that the walls of arteries and veins permit the
passage of certain solutions inwards into the blood." Megendie's
observations are recorded in A Monograph On Veins, by Franklin, K.
J., pages 115 to 119, 1937, published by Charles C. Thomas Inc.,
Springfield, Illinois. Yet, even though this knowledge was known to
the art since this early observation, a survey of the prior art
showed that not only was there no systematic study of the
permeability characteristics of the walls of arteries or veins to
drugs, the prior art never conceived of any practical devices or
methods for administering a drug through the walls of arteries or
veins to use this route for producing a local or systemic
pharmacological or physiological effect.
Prior to this invention, which makes available to the art a novel
and useful device for administering a drug through the wall of an
intact blood vessel, mainly arteries and veins, medical and
veterinary practice used other routes of drug administration. These
routes were used even though they possessed certain shortcomings
that are not found when the novel device and route of this
invention is used for administering a drug. For example, the oral
route is the oldest and most widely used by the prior art even
though many drugs administered by this route are rendered inactive
by gastric acid or digestive enzymes of the gastrointestinal tract.
Also, after the drug is absorbed into the blood from the
gastrointestinal tract it passes through the liver where the drug
is metabolized to an inactive product by that organ. These factors
coupled with the uncontrolled rate of drug transit through the
gastrointestinal tract makes it difficult to achieve a desired time
course of concentration of the drug in the blood.
Another route occasionally used for the administration of drugs is
absorption by the oral mucosa. Certain drugs are rapidly absorbed
by oral mucosa and an elevated concentration of the drug in
systemic blood may be achieved in this manner. However, during
times when the drug is not being applied to the oral mucosa, there
is an uncontrolled decline of the concentration of the drug in the
blood. A graphic illustration of the drug's concentration in the
blood during a dosage schedule for this route as the appearances of
a series of peaks and valleys; and, often these valleys may fall
below the drug concentration needed to achieve the desired
effect.
The administration of drugs by injection can entail certain
disadvantages. For example, very strict asepsis must be maintained
to avoid infection of the blood, the vascular system, or heart.
Drug administration by poor intravenous injection technique may
result in perivascular injection when it is not intended; and, the
typical result of injection into the blood is a sudden rise in the
blood concentration followed by an uncontrolled decline.
Another method for the administration of drugs directly into the
blood is the catheter technique. This technique involves the
incising of a blood vessel wall and the placing of one end of a
catheter through the blood vessel wall into the lumen. The other
end of the catheter is connected to a pump that delivers the drug
to the blood. The disadvantages associated with the catheter
technique are many; for example, possible damage to the blood
vessel wall, blood leaks around the catheter, the formation of
thrombosis intraluminally around the foreign catheter with a risk
of embolization, the blockage of the catheter lumen by thrombosis,
and the risk of infection. These factors dictate that an
intravascular catheter must be viewed as having a limited lifetime
and usefulness.
Other known routes of drug administration are the rectal mucosa and
the vaginal mucosa routes. These routes have certain known
shortcomings, for example, drug absorption by these routes is often
erratic or incomplete. The concentrations of drug in the blood by
these routes is often variable and uncontrolled.
The prior art of drug administration by the various routes
described above is largely limited to bringing about a pulsed
delivery of the drug. That is, by these routes a concentrated dose
of the drug is brought into contact with a drug absorbing surface
over limited periods of time, often creating undesirable
fluctuations in the concentration of drug in the blood and at the
site of drug action. The administration of drugs by the prior art
frequently failed to achieve a desired time course of drug action.
In addition, the prior art never produced any kind of drug delivery
device for directly introducing a drug into the blood without first
penetrating by mechanical, laser, ultrasound, microwave, or
surgically the wall of the blood vessels. Also, the art never
conceived either of the administration of a drug into the blood for
transport to an organ or receptor site or of introducing a drug
into the blood for a systemic effect by administering the drug into
the blood through the intact blood vessel wall.
In light of the limitations mentioned above, it should be apparent
to those versed in the art that if a novel drug delivery device is
made available that improves upon the prior art, such a drug
delivery device would represent a useful and valuable contribution
to the art. Likewise, it will be appreciated by those skilled in
the art that if a novel and unobvious drug delivery device is made
available to the art for the administration of drugs directly into
blood in a blood vessel to produce either localized or systemic
effects, without requiring any mechanical penetration of the blood
vessel walls, such a system would not only represent an advancement
in the art but would also have positive use in the management of
health and disease in the medical and veterinary fields.
BRIEF DESCRIPTION OF OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide a
novel device for drug administration that essentially overcomes the
problems encountered by the prior art.
Another object of the invention is to provide a novel means for
diffusively delivering drugs into the blood circulation in an
intact blood vessel.
Still another object of the invention is to provide a novel drug
delivery device.
Yet another object of the invention is to provide a device for
delivering drugs directly into the blood stream by diffusion
through blood vessel walls without any mechanical penetration of
the like of the blood vessel wall by the drug delivery device.
Still yet another object of the invention is to provide a drug
delivery device for administering drugs into the blood in a
specific artery for the direct circulation of the drug to the
tissues or organs supplied by that artery.
Another object of the invention is to provide a drug delivery
device for administering drugs into the blood in a vein as a means
of systemic administration of the drug.
A further object of the invention is to provide a drug delivery
device for administering drugs into the portal vein for transport
to the liver.
Still another object of the invention is to provide a drug delivery
device for the administration of a physiological or pharmacological
agent into the blood to produce a localized or systemic effect.
Yet still another object of the invention is to provide a drug
delivery device for providing over any predetermined periods of
time any predetermined concentration of drug in the blood.
Another object of the present invention is to provide a method for
administering therapeutically active materials for establishing
therapeutically effective concentrations of the material in the
blood by applying to the adventitial surface of a blood vessel a
drug delivery device for diffusively administering the material
into the blood.
Further objects, features and advantages of this invention will
become apparent to those skilled in the art from the following
specification, drawings and annexed claims.
SUMMARY OF THE INVENTION
The invention concerns a novel and useful drug delivery device for
administering a drug into the blood. The drug delivery device also
serves as a reservoir for at least one drug. The device comprises a
means contacting a part or the whole circumference of the
adventitial surface of a blood vessel for administering a drug into
the blood. The invention also concerns a method for administering a
drug into the blood to produce a systemic or localized effect by
positioning a drug delivery device on a part or the whole
adventitial surface of a blood vessel for diffusing the drug into
the blood.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing will become more apparent by reference to the
attached drawings of which:
FIG. 1 is a perspective view of one embodiment of a drug delivery
device of the invention;
FIG. 2 is a vertical, cross-sectional view of the drug delivery
device of FIG. 1 through 1--1;
FIG. 3 is a vertical, cross-sectional view through 2--2 of the drug
delivery device of FIG. 1;
FIG. 4 is a perspective view of the drug delivery device of FIG. 1
depicting a device surrounding an artery or vein prior to
closure;
FIG. 5 is a perspective view of another drug delivery device of the
invention illustrating a device with an interplaced rate
controlling membrane for metering the drug into the artery or
vein.
FIG. 6 is a schematic, cross-sectional view at 3--3 of FIG. 5
illustrating the membrane at the terminal positions of the
device;
FIG. 7 is a schematic, cross-sectional view at 4--4 of FIG. 5
illustrating the membrane at the mid-section of the device;
FIG. 8 is a perspective illustration of a drug delivery device
engaging and partially surrounding an artery or vein;
FIG. 9 is a vertical, cross-sectional view through 5--5 of FIG. 8
depicting the device prior to engaging the artery or vein.
FIG. 10 is a schematic illustration of the device of FIG. 8
engaging an artery or vein.
FIG. 11 is a schematic depiction of another drug device of the
invention engaging a part of an artery or vein.
FIG. 12 is a perspective view of another embodiment of the
invention showing a device engaging an artery or vein in
spiral-like manner.
FIG. 13 is a perspective view of an embodiment of the invention
showing a drug delivery device for continuously and intimately
engaging a large area of an artery or vein for administering a drug
into the blood stream. In the drawings in the specifications, like
parts in related figures are identified by like numbers. The terms
appearing earlier in the specification and in the description of
the drawings are defined later in the disclosure.
DETAILED DESCRIPTION OF THE DRAWINGS
Turning now to the drawings in detail, FIG. 1 represents one novel
and useful drug delivery device for administering a medical or a
veterinary drug into the blood in an artery or vein. For the
purposes of this invention, the terms artery or vein are construed
as the equivalent of blood vessel and this latter term is used to
assist in describing the devices. In FIG. 1, there is illustrated a
drug delivery device 10, comprising a design adapted for
surrounding a blood vessel 11. The device comprises an exterior
wall 12, of low drug or fluid permeability (examples of which are
presented later in the disclosure), which traverses the length of
the drug delivery device 10. The shape of the device conforms to
the external shape of blood vessel 11. The device 10, also
referrable to as a housing means, encapsulating means, means for
confining a drug for delivery, or the like, tapers at its ends 13
for placing and sealing the device to blood vessel wall 11. The
tapered ends 13 are adapted to confine a drug in the device 10 and
to prevent surrounding body fluids from entering the device 10.
Drug device 10 is provided with one or more pairs of inlet-outlet
ports 14, located at one or both ends of the device, or at any
position on the device, for extending outwardly through the host's
skin for admitting a drug into device 10. Inlet port 14 is
optionally equipped with a bacterial filter, not shown, for
preventing bacterial contamination of the device and the host
during its use.
In FIG. 1, the drug device 10 is illustrated with tapered end 13;
however, the device can be constructed with non-tapered ends, not
shown. In this latter device, the device comprises at its outer
ends a pair of terminal skirts, integrally and continuously formed
for sealingly engaging the curvature of the exterior surface of an
artery or vein for housing drugs in the device and for essentially
preventing body fluids from entering the device. The drug device of
FIG. 1 is shown as an integral unit; however, the device can be
manufactured as a two part device such as two hemi-envelopes or two
hemi-circles, not shown, for enclosing any given length of artery
or vein. The ends of a two part device can be made with integral
tapered ends or the ends can be closed with plugs, not shown,
suitably provided with a means for letting a blood vessel enter and
exit the device. A two part device can include inlet and outlet
ports for occasionally or continuously admitting a drug into the
device.
FIG. 2 is a cross-sectional view through 2--2 of FIG. 1 wherein
device 10 at its tapered ends 13 engages blood vessel 11. In FIG.
2, body wall 12 of device 10 surrounds the adventitial surface 19
of blood vessel 11 to form at interface 17, by sealingly closing
wall 12, an integral device 10. The cross-sectional view also shows
intimal surface 15 defining lumen 16 of blood vessel 11.
FIG. 3 is a cross-sectional view through 3--3 of FIG. 1
illustrating device 10 with its wall 12 surrounding blood vessel 11
to form a sealed, closed device at interface 17. Drugs, not shown,
in space 18 defined by the outer surface of blood vessel 11 and the
inner surface of wall 12 diffuse through the adventitial surface 19
and intimal surface 15 into blood in lumen 16 of blood vessel 11.
In accompanying FIG. 4 there is illustrated another cross-sectional
view of device 10 of FIG. 1 surrounding blood vessel 11 before wall
12 closes to form device 10. The wall surrounds blood vessel 11 to
meet at its interface 17 as seen in FIGS. 2 and 3 to form device
10.
In FIG. 5 there is illustrated another novel drug delivery device
of the invention. This device comprises a main body 10 having an
exterior wall 12, an interior membrane 20 and a space 21 formed by
wall 12 and membrane 20 for containing a drug or a pharmaceutical
composition comprising a carrier and a drug for diffusing through
membrane 20 into blood vessel 11. The device of FIG. 5 is
constructed with inlet-outlet ports for admitting drug into the
device or for draining drugs from the device. Inlet port 14, is
optionally equipped with a bacterial filter, not shown, for
preventing bacterial contamination of the device during its use.
The filter is generally not needed in this device if membrane 20 is
impermeable to bacteria. FIG. 6 is a cross-sectional illustration
of device 10 at 6--6 of FIG. 5 at its tapered ends where the device
engages blood vessel 11. Device 10 forms a closed unit where wall
12 meets at interface 17. In FIG. 6, wall 12 contacts membrane 20
as it surrounds blood vessel 11 for positioning and holding device
10 to blood vessel 11. FIG. 7 is a cross-sectional illustration at
the middle section at 4--4 of FIG. 5. FIG. 7 shows wall 12 and
membrane 20 joined at their interfaces 17 to form space 21. Blood
vessel 11 is surrounded by membrane 20 for controlling the rate of
drug delivery into blood vessel 11. The physical dimensions for the
drug devices of the invention are to be construed as non-limiting,
and they are generally the dimensions that correspond to the
dimensions of the blood vessel and the amount of drug present in
the device. A typical device constructed according to the spirit of
the invention, for example, FIG. 5 comprises blood vessel 11
surrounded by space 21 of about 2 mm to 15 mm deep for carrying a
drug, a pharmaceutical vehicle, penetrating agent and the like. The
inner membrane, when present, is usually about 10 to 500.mu. thick,
or thicker if desired to regulate the rate of drug diffusion, and
the outer wall 12 about 0.2 mm to 5 mm thick or of like dimensions.
The drug delivery device 10 generally has a longitudinal length of
about 10 mm to 75 mm, and shorter or longer devices with varying
circumferences can be constructed and its length and circumference
will depend on the length, and circumference of the blood vessel
placed within the device, the age and the size of the host, and the
amount of drug to be diffused into the blood.
Turning to FIG. 8, there is illustrated a drug delivery device
fabricated according to the invention for engaging at least a part
of blood vessel. The drug delivery device 10 of FIG. 8 comprises a
body wall 12 which surrounds a part of the circumferential traverse
surface of blood vessel 11. In FIG. 8, a part of the blood vessel
is illustrated as surrounded and part not surrounded by device 10.
The device is also constructed with inlet-outlet ports 14 that it
may optionally house an in-line bacterial filter, not shown, and be
filled and drained via transcutaneous tubes. The device may have a
rate controlling membrane, not shown in FIG. 8. FIG. 9 illustrates
a cross-sectional view through 10--10 of FIG. 8 depicting a part of
a blood vessel 11 partially surrounded or saddled by device 10
comprised of wall 12 and an inner rate controlling membrane 20
prior to the closing of the device. The device of FIG. 9 can be
closed by a membrane that joins the device to the artery or vein,
or the device can be made with an inwardly curving wall and
membrane to intimately contact the adventitial wall for sealing
thereto. FIG. 10 illustrates the device of FIG. 8 positioned on
blood vessel 11 in a closed or saddled engagement of 11. FIG. 11 is
a top elevational view of another embodiment of the invention
illustrating a small device 10 with a body wall 12 with
inlet-outlet ports 14 staddled on a part of blood vessel 11, for
diffusing a drug into a small area of 11. FIG. 12 is still another
embodiment of the invention depicting a device 10 with a body wall
12 wrapped around a blood vessel 11 in spiral or helix arrangement
for diffusing drugs into blood in 11. This device can be used for
diffusing a drug over a small or a large area of blood vessel. FIG.
13 illustrates a device 10 having a body wall 12 surrounding blood
vessel 11. This device is similar to the device of FIG. 12 and it
can be used for contacting a large area of a blood vessel in a
small space for diffusing a drug into the bloodstream.
DESCRIPTION OF INVENTION EMBODIMENTS
Turning now to the construction and use of the devices of the
invention, wherein the devices are intended for administering a
drug into blood in an artery or vein, the devices are described in
the light of the drawings, example, and accompanying claims. The
anatomical terms artery or vein are to be broadly construed for the
purpose of this invention to include the blood vascular system. The
blood vascular system herein comprises blood and the naturally
occurring conduits that circulate blood within the mammalian body
that includes by way of non-limiting example the various types of
blood vessels that are of general consideration of the circulation
of the blood such as arteries and veins. The non-limiting examples
of the system also includes blood circulation to the brain and
spinal cord, coronary circulation, pulmonary circulation,
gastrointestinal circulation, the hepatoportal-lienal circulation,
the renal circulation, the blood vessels of the pituitary and the
thyroid, placental circulation, cutaneous circulation and the like.
Also, in the specification and the accompanying claims, the terms
administering or administration of a drug refers generally to
passage or entrance of a drug into the blood through the blood
vessel wall, without any mechanical or physical instrumental
penetration of the blood vessel wall. Thus, administration
generally includes for the purpose of the invention the equivalent
terms such as diffusion, permeation, osmosis, and the like.
In fabricating a device for surrounding at least a part or the
whole surface of a blood vessel, the body wall 12 of the drug
delivery device of the invention is made of natural or synthetic
polymers, singly, or laminates of more than one like or unlike
polymer. The polymers suitable for the purpose of the invention are
those polymers that posses a low to essentially no permeability to
the drugs, its carrier, or to components present in surrounding
tissues or biological fluids. The phases "low permeability" and
"essentially no permeability" for a drug generally are to be
construed for the purpose of this invention to mean that very
little or essentially none of a particular drug will pass through a
given polymer as ascertained by known techniques for determining
the rate of passage of drugs and the like through polymeric
materials. Examples of known techniques are disclosed in The J.
Pharm. Sci., Vol 59, No. 9, pages 1341 to 1346, and 1412 to 1419,
1970. This just described physical property of the polymer aids in
substantially preventing drug diffusion from the delivery system
into undesired body areas, and it also serves to prevent
surrounding body fluids from entering the system.
For use with drugs of high water solubility, polymers which display
low moisture permeabilities are presently preferred. Generic
examples of such polymers known to the art are polyolefins such as
polyethylene and polypropylene; polymers such as
polytetrafluoroethylene; poly(vinylchloride); poly(vinylidene
chloride); polychlorotrifluoroethylene; polyisobutylene;
poly(acrylonitrile); poly(ethylene terphthalate); natural and
synthetic rubber; and the like. The general characteristics of
polymers possessing low moisture permeability suitable for the
purpose of the invention are the polymers that have a saturated or
nearly saturated carbon chain; a minimum of chain branching; a high
degree of lateral symmetry, a fair degree of longitudinal symmetry
and a very high proportion of relatively small, non-hydrophilic
substituents. A high degree of compliance with most of these
characteristics may serve to mask the lack of conformity in some
one respect, such as unsaturation. Various methods and means for
ascertaining and measuring moisture permeability are well known to
the prior art, and they are recorded in Industrial and Engineering
Chemistry, Vol 45, pages 2296 to 2306, 1953; and the references
cited therein. Exemplary of specific polymeric films having low
moisture permeabilities are polymeric species such as vinylidene
chloride vinyl chloride copolymer with a compositional range of 92
to 8 to 50 to 50; commercially available vinylidene chloride
acrylonitrile composition of 92 to 8 and 80 to 20; vinylidene
chloride-acrylonitrile-vinyl chloride of 75 to 80/10/10 to 15;
vinylidene chloride isobutylene of 70 to 30; butyl rubber-G-1;
rubber hydrochloride and the like.
For drugs physically characterized by low water solubility, but
moderate to high organic solvent solubility, the wall 12 is usually
made from one or more natural or synthetic polymers that display
low drug permeability and such polymers are generally those in
which the specific drug has low solubility. The general
characteristics known to the art for such polymers that are least
permeable for organic like materials are those whose molecular
structure permits close packing and usually strong intermolecular
bonding. The selection of a low permeability polymer for a specific
drug can usually be made by following the art known guide of like
dissolves like. That is, if a particular drug is highly soluble in
a particular solvent and if that solvent also swells or dissolves a
particular polymer, then the solubility permeability of the drug in
the polymer will be high. For example, drugs which are highly
soluble in alkanols will permeate slowly through polymers which are
unaffected by or insoluble in the alkanol; also, drugs which are
soluble in aromatic solvents will not permeate through polymers
that are unaffected by the aromatic. Examples of polymeric
materials are as follows: poly(ethylene terephthalate) a
condensation polymer resulting from the esterification reaction
between ethylene glycol and terephthalic acid, or formed by the
alcoholysis of a terephthalic acid ester with ethylene glycol;
cellophane and its flexible cellulosic derivatives made from
viscose; fluorocarbon polymers such as tetrafluoroethylene
homopolymer; polyolefin such as polyethylene; acetal homopolymers
and copolymers; modified acrylics; and the like. The polymer can be
used alone or in combination with one or more polymeric materials,
or it can be lined, coated, or laminated with a film or a layer of
a metal or an alloy. Exemplary of metals and alloys suitable for
the present purpose are tantalum, titanium, stainless steel,
platinum, alloys comprising nickel, cobalt, platinum, iridium,
copper, iron, manganese, tungsten and the like. Exemplary of
commercially available alloys are vitallium consisting of cobalt,
chromium and molybdenum; Kovar alloy consisting of about 29 percent
nickel, 17 percent cobalt, 0.3 percent manganese and the balance
iron; Sylvania No. 4 alloy consisting of 42 percent nickel, 5.5
percent chromium and the balance iron; and the like.
Body wall 12 can also be made from metals and alloys per se, for
example, stainless steel, tantalum, titanium, vitallium, and the
like. The use of a metal or alloy is similar to the use of any of
the above mentioned polymeric materials. For example, a thin sheet
of a metal or an alloy is shaped into a single part or into two
parts, for example, hemi-circles for surrounding any desired length
of an artery or vein. The ends of the shaped body wall is suitably
sealed about an artery or vein by forming the body wall with
annular skirts, closing with plugs or by using an elastomeric
material that is sealed to the body wall and the artery or vein.
The body wall can also have tapered ends for joining the metal or
alloy to the artery or vein, usually through a thin, accordian like
piece of an elastomeric polymer sealed to the body wall and the
artery or vein.
The closable surfaces of wall 12 at the interfaces 17 of the device
10, and the fixing of the device to the blood vessel as shown in
the accompanying Figure can be effected by conventional methods.
For example, the sealable surface may be contacted and adhesively
closed to produce a liquid tight seal between the surfaces. The
adhesives suitable for performing according to the mode and manner
of the invention are the medically acceptable adhesives, sealants
and the like. Exemplary of adhesives are acrylic adhesives,
polymers of esters of acrylic acid with alkanols, alone or
copolymerized with ethylenically unsaturated monomers such as
methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl
acrylamides, N-alkoxymethyl methacrylamides,
N-tert-butylacrylamide, itaconic acid, N-branched alkyl meleamic
acid wherein the alkyl group has 10 to 24 carbon atoms, glycol
diacrylates, alpha-cyanoacrylate monomers, or mixtures of these;
elastomeric silicone sealants; polyurethane sealants; rubbery
polymers such as polyisobutylene, polyisoprene and polybutadiene;
epoxy adhesives, and modified epoxy adhesives and the like. The
adhesives may be of the various kinds well known to the art such as
hot melt adhesives, fast setting adhesives, cold set adhesives,
single or multi-component adhesives and the like. The adhesives may
be compounded with tackifiers, stabilizers, hardners and other
modifiers as is well known in the art.
The closable surface 17 of the blood drug delivery device 10 can be
closed by other conventional methods. For example, the system can
be manufactured with an integral closable zipper, not shown; the
walls may be closed by medical suturing; by plastic film tapes; by
heat sealing such as impulse, radiant, infrared heat and the like;
by ultrasonic sound waves in the order of 18,000 cycles and over;
and by other known techniques.
The inner drug rate controlling membrane 20 that is adhesively or
heat sealed to the inner surface of wall 12 is generally a
naturally occurring or a synthetic material, usually a polymer, and
it serves to control or regulate the rate of drug entry into an
artery or vein. Membrane 20 is usually formed of a material
permeable to the drug to permit the passage of the drug from the
inner space or reservoir area 21 to make it available for
subsequent diffusion through the wall of the artery or vein 11 and
into the blood. The rate of passage of the drum from and through
the membrane 20 is usually dependent on the drug, the membrane
thickness and the presence and nature of the pharmaceutical vehicle
and penetrating agents present for contacting the membrane. Thus,
the selection of appropriate materials for fabricating the membrane
will be dependent of the particular drug, and by varying the
composition and thickness of the membrane, the drug release rate
per area of membrane can be controlled.
The membrane can be formed by molding onto the device containing
the drug, or the membrane can also be in the form of sheets of
polymeric material permeable to the passage of the drug. The
membrane can be placed at different positions from the inner
surface of wall 12, or it can be laminated, adhesively affixed and
the like, thereto. In spiral type devices the device is composed of
an outer low permeability polymer with a rate controlled membrane
joined thereto. The rate controlling membrane surrounding and
contacting the adventitial surface of the blood vessel.
The materials acceptable for forming the rate controlling membrane
generally are materials known to the art like organopolysiloxane
rubbers, commonly known as silicone rubbers, including the
heat-curable silicone rubbers and the room temperature vulcanizable
silicone rubbers. The silicone rubbers which are converted to the
rubbery state by heat and they are predominately linear
organopolysiloxanes having an average degree of substitution of
about two organic groups attached to the silicon per silicon atom.
The organic groups are alkyl, aryl, alkenyl, alkaryl, aralkyl and
the like. One representative class of silicone polymers are the
dimethylpolysiloxanes. The room temperature vulcanizable silicone
rubbers are also commercially available, and, they usually employ
the same silicone polymers mentioned above, although the polymer
often contains a greater amount of silicon bonded hydroxy group.
This type of silicone rubber will cure at room temperature in the
presence of an appropriate catalyst, such as stannous
2-ethylhexoate. Exemplary patents disclosing the preparation of
silicone rubbers are U.S. Pats. Nos. 2,541,137; 2,723,966;
2,863,846; 2,890,188; 2,927,907; 3,002,951; and 3,035,016.
Other polymeric materials suitable for use in forming the rate
controlling membrane are the commercially available
poly(hydroxyethylacrylate) and poly(hydroxyethylmethacrylate) as
described in U.S. Pats. Nos. 2,976,579 and 3,220,960, and in
Belgian Patent No. 701,813. Exemplary of further materials include
the commercially available materials such as, vinylidene chloride
vinyl chloride copolymer 40/60 and 10/90; vinylidene chloride
acrylonitrile copolymer 60/40 and 12/88; vinyl chloride
acrylonitrile copolymer 80/20, 75/25, 50/50 and the like; vinyl
chloride diethyl fumarate; vinyl chloride
butyl-.alpha.-chloracrylate; polyethylene vinyl acetate; polyvinyl
acetate; polyvinyl alcohol; polyesters; plasticized polyvinyl
chloride; polycarbonates; plasticized nylon; collagen; modified
collagen; gelatin; and the like. Another class of materials
suitable for forming the membrane are the materials known to the
art as microporous, reverse osmosis and the like. Exemplary of
these materials include the anisotropic permeable microporous
membranes of ionically associated polyelectrolytes, the polymers
formed in the coprecipitation of a polycation and a polyanion as
disclosed in U.S. Pat. Nos. 3,276,589; 3,541,005; 3,541,006;
3,546,142; and the like; treated aliphatic polyamide membranes as
in 2,071,253; 2,966,700; 2,999,296; 2,385,890; 3,551,331; and the
like; galactose methacrylate-methyl methacrylate copolymers as in
3,542,908; and the like; cellulose ethers; and the like.
The rate of drug diffusion of any preselected drug through the
membrane can be ascertained by techniques well known to the art.
For example, one standard technique comprises the casting or hot
pressing of a film of the material, that will eventually carry the
drug, to a thicknes of about 0.5 to 100 mils, and then using the
film as a barrier between a rapidly stirred saturated solution of
the drug and a rapidly stirred solvent bath, both maintained at a
constant temperature. Samples are periodically withdrawn from the
solvent bath and analyzed for drug concentration. By plotting drug
concentration in the solvent bath versus time, the permeability
constant P of the membrane is determined by the Fick's First Law of
Diffusion as follows:
Slope of plot = (Q.sub.1 -- Q.sub.2 /t.sub.1 -- t.sub.2) = P
(AC/h)
wherein Q.sub.1 is the cumulative amount of drug in solvent in
micrograms at t.sub.1 ; Q.sub.2 cumulative amount of drug in
solvent in micrograms at t.sub.2 ; t.sub.1 is elapsed time to first
sample i.e. Q.sub.1 ; t.sub.2 is elapsed time to second sample i.e.
Q.sub.2 ; A is the area of membranes in cm.sup.2 ; C= initial
concentration of drug; and h is the thickness of membrane in cm.
Thus, by determining the slope of the plot, i.e. (Q.sub.1 --
Q.sub.2 /t.sub. 1 -- t.sub.2), and solving the equation using the
known or measured values of A, C, and h, the permeability constant,
P, in cm.sup.2 /time of the material or membrane for a given drug
is readily determined. From this data, an appropriate polymeric
membrane for any selected drug can be chosen. This polymer can be
one of those mentioned above or any other polymer having the
appropriate drug permeability and low toxicity when in contact with
blood vessels.
The drug device may be, as mentioned above, optionally equipped
with an inlet-outlet port means 14 for feeding and draining active
agents and the like into or from the device. The ports can be
formed integral with wall 12 or they can be preformed and secured
to the wall. The materials used to form the ports are those
materials that are compatible with the agents and the host, and
they include the materials set forth above, such as polyethylene,
silicone rubber, Teflon, vitreous carbon, graphite and the like.
The inlet port 14, is optionally equipped with a bacterial filter
such as the commercially available Milipore filters with pore sizes
of 0.025 microns to 14 microns, Seitz filter, Amicon
ultrafiltration molecular membranes, and the like.
In the specification and the accompanying claims, the term "drug"
broadly includes physiologically or pharmacologically active
substance for producing a localized or systemic effect or effects
in mammals including humans and primates; avians; valuable domestic
household, sport or farm animals, such as sheep, goats, cattle,
horses etc.; or for administering to laboratory animals such as
mice, rats, guinea pigs; and the like. That is, the novel drug
delivery device can be used for administering drugs that are
physiologically or pharmacologically active at a point in near
relation to the drug delivery device, or, for administering a
systemically active substance which will produce a physiological or
pharmacological response at a site remote from the point of
application of the drug delivery device. The active agents that may
be administered include without limitation, those materials that
transport across a vessel, for example, drugs acting on the central
nervous system such as nitrous oxide, ethylene, cyclopropane,
diethyl ether, divinyl ether, methoxyflurane and the like;
hypnotics and sedatives such as pentobarbital sodium,
phenobarbital, secobarbital, thiopental, etc.; heterocyclic
hypnotics such as dioxopiperidines, and glutarimides; hypnotics and
sedatives such as amides and ureas exemplified by
diethylisovaleramide and .alpha.-bromoisovaleryl urea and the like;
hypnotics and sedative alcohols such as carbomal, naphthoxyethanol,
methylparafynol and the like; and hypnotic and sedative urethans,
disulfanes and the like; psychic energizers such as isocarboxazid,
nialamide, phenelzine, imipramine, tranylcypromine, pargylene and
the like; tranquilizers such as chloropromazine, promazine,
fluphenazine reserpine, deserpidine, meprobamate, benzodiazepines
such as chlordiazepoxide and the like; anticonvulsants such as
primidone, dipenylhydantoin, ethotoin, pheneturide, ethosuximide
and the like; muscle relaxants and anti-parkinson agents such as
mephenesin, methocarbomal, trihexylphenidyl, biperiden, levodopa,
also known as L-dopa and L-.beta.-3-4-dihydroxypenylalanine, and
the like; analgesics such as morphone, codeine, meperidine,
nalorphine and the like; antipyretics and anti-inflammatory agents
such as aspirin, salicylamide, sodium salicylamide and the like;
local anesthetics such as procaine, lidocaine, naepaine,
piperocaine, tetracaine, dibucane and the like; antispasmodics and
antiulcer agents such as atropine, scopolamine, methscopolamine,
oxyphenonium, papaverine, prostaglandins such as PGE, PGE.sub.2,
PGF.sub.1.sub..alpha., PGF.sub.2.sub..alpha., PGA and the like;
anti-microbials such as penicillin, tetracycline, oxytetracycline,
chlorotetracycline, chloramphenicol, sulfonamides and the like;
anti-malarials such as 4-aminoquinolines, 8-aminoquinolines and
pyrimethamine; hormonal agents such as prednisolone, cortisone,
cortisol and triamcinolone; androgenic steroids, for example,
methyltestosterone, fluoxmesterone and the like; estrogenic
steroids, for example, 17.beta.-estradiol and ethinyl estradiol;
progestational steroids, for example, 17.alpha.-hydroxyprogesterone
acetate, 19-nor-progesterone, norethindrone and the like;
sympathomimetic drugs such as epinephrine, amphetamine, ephedrine,
norepinephrine and the like; cardiovascular drugs, for example,
procainamide, amyl nitrite, nitroglycerin, dipyridamole, sodium
nitrate, mannitol nitrate and the like; diuretics, for example,
chlorothiazide, flumethiazide and the like; antiparasitic agents
such as bephenium hydroxynaphthoate and dichlorophen, dapsone and
the like; neoplastic agents such as mechlorethamine, uracil
mustard, 5-fluorouracil, 6-thioguanine, procarbazine and the like;
hypoglycemic drugs such as insulin, protamine zinc insulin
suspension, globin zinc insulin, isophane insulin suspension,
extended insulin zinc suspension, and other like insulins derived
from animal and synthetic origin, tolbutamide, acetohexamide,
tolazamide, chlorpropamide and the like; nutritional agents such as
vitamins, essential amino acids, essential fats and the like; and
other physiologically active agents.
The above listed and other drugs are usually admixed with a
pharmaceutical carrier for feeding into the drug delivery system
through the inlet conduit 14. The pharmaceutical carriers
acceptable for the purpose of this invention are the art known
carriers that do not adversely affect the drug, the host or the
polymers comprising the drug delivery device. Suitable
pharmaceutical carriers include sterile water; saline; dextrose;
dextrose in saline or in water; condensation products of castor oil
and ethylene oxide combining about 30 to about 35 moles of ethylene
oxide per mole of castor oil; liquid glyceryl triester of a lower
molecular weight fatty acid; lower alkanols; oils such as corn oil,
peanut oil, sesame oil and the like with emulsifiers such as mono-
or di-glyceride of a fatty acid, or a phosphatide, e.g. lecithin,
and the like; glycols; polyalkylene glycols; acetamide; N,N-dilower
alkyl acetamides such as N,N-diethyl acetamide, N,N-dimethyl
acetamide, N-(2-hydroxyethyl) acetamide and the like; aqueous media
in the presence of a suspending agent, for example, sodium
carbozy-methylcellulose, sodium alginate, polyvinylpyrrolidone and
the like, alone, or with suitable dispensing agents such as
lecithin, polyoxyethylene stearate and the like. The carriers may
also contain adjuvants such as preserving, stabilizing, wetting,
emulsifying agents and the like.
The drug can also be mixed with penetrating compounds that aid or
assist the drug's passage through the blood vessel wall into the
blood. The penetrating aid suitable for the purpose of the
invention are the therapeutically acceptable penetrating aids that
do not adversely affect the host, the drug or alter or adversely
affect the polymers forming the drug delivery device. The
penetrating aids can be used alone or they can be admixed with
acceptable carriers. Exemplary of penetrating aids include,
monovalent, saturated and unsaturated aliphatic, cycloaliphatic and
aromatic alcohols having four to 12 carbon atoms such as hexanol,
cyclohexane and the like; aliphatic, cycloaliphatic and aromatic
hydocarbons having from five to 12 carbon atoms such as hexanol,
cyclohexane and the like; aliphatic, cycloaliphatic and aromatic
hydrocarbons having from five to 12 carbon atoms such as hexane,
isopropylbenzene and the like; aliphatic, cycloaliphatic and
aromatic aldehydes and ketones having from four to 10 carbon atoms
such as cyclohexanone; and other penetrating agents such as
aliphatic, cycloaliphatic and aromatic esters; essential oils;
halogenated or nitrated aliphatic, cycloaliphatic and aromatic
hydrocarbons; polyalkylene glycol salicylates; and mixtures
thereof.
DESCRIPTION OF EXAMPLES OF THE INVENTION
The following examples are merely illustrative of the present
invention and they should not be considered as limiting its scope
in any way, as these examples and others will become apparent to
those versed in the art in the light of the present disclosure and
the accompanying claims.
EXAMPLE 1
An in vitro radioactively labeled drug experiment is performed for
demonstrating the diffusion into a blood vessel as follows: first,
one end of an isolated section of canine carotid artery about 4.1
cm long with an outer diameter of 1.2 cm and a thickness of 0.11
cm, is attached to a piece of poly(vinyl) chloride tubing which
leads from a peristaltic pump which draws from a reservoir. The
other end of the artery is cannulated with another piece of
poly(vinyl) chloride tubing which leads back to the reservoir. The
reservoir contains Ringer's solution. The peristaltic pump is
adjusted to a rate of 80 pulses per minute to give a flow rate of
the Ringer's solution of about 20 to 30 milliliters per minute, and
a mean hydrostatic pressure within the artery of about 30 mm of Hg.
The carotid artery is next placed into a drug delivery device made,
according to the invention, of polyethylene constructed in a long,
closable U-shape. The delivery system contained a mixture of 523.1
micrograms per milliliter of 1,2-H.sup.3 hydrocortisone,
commercially available from New England Nuclear Corporation, and
unlabeled hydrocortisone commercially available from the Mann
Laboratories Inc. The mixture is made by mixing 120 micrograms of
unlabeled hydrocortisone and 60 microcuries of the isotope in 200
ml of Ringer's solution. The mixture is made to the concentration
and to the specific activity for a convenient volume to perform the
experiment. The temperature of the drug delivery system and the
reservoir is maintained at ambient temperature, about 25.degree.C.
Next, aliquots are taken of the Ringer's solution circulating in
the artery and the reservoir at various times beginning at zero
time; 0.5; 1; 1.5; 2; 3; and 4 hours, and the labeled
hydrocortisone in the aliquots counted with a Nuclear Chicago, Mark
II liquid scintillation spectrometer. The concentrations of the
hydrocortisone in the various aliquots permits computation of the
quantities of hydrocortisone that diffused across the carotid
arterial wall. From 0.5 to 4 hours, the quantity increased linearly
with time. The data indicated that the using a novel device of the
invention, the transfer rate of hydrocortisone diffusion across a 1
cm.sup.2 section of canine carotid arterial wall is 0.4 mg/cm.sup.2
/24 hrs.
EXAMPLE 2
Following the in vitro procedure described in Example 1, an
isolated section of a canine carotid artery 3.5 cm long by 1.1 cm
in outside diameter and having a wall thickness of 0.093 cm is
submerged in the drug delivery system containing 10 g of unlabeled
.alpha.-amino acid, glycine, and 10 microcuries of 1--C.sup.14
glycine. All the other conditions are as described above. Next, six
aliquots are taken and counted for measuring the rate into the
artery from the drug delivery system. The results showed at 30
minutes, 10,940 .mu.g of glycine had diffused across the arterial
wall; at 1 hour a total of 24,610.0 .mu.g if glycine had diffused
across the arterial wall; at 1 1/2 hours a total of 35,390 .mu.g;
at 2 hours a total of 47,770; at 3 hours a total of 74,000; and at
4 hours a total of 100,600 .mu.g had diffused across the arterial
wall from the drug delivery system. The average diffusion or
transfer rate for glycine is 6,780 .mu.g/cm.sup.2 /hr; or,
expressed as the transfer rate of diffusion across a 1 cm.sup.2 of
canine carotid arterial wall from this drug delivery system is 170
mg/cm.sup.2 /24 hours.
EXAMPLE 3
The procedure of Example 1 is repeated in this example and all the
experiment conditions are as set forth, except that the drug
delivery system now contains a mixture of 1 g of unlabeled
D-L-Dopa, 3-(3,4-dihydroxyphenylalamine) and 10 .mu.c (microcuries)
of 1--C.sup.14 -L-Dopa dissolved in 200 ml of Ringer's solution to
give an initial concentration in the drug delivery system for both
labeled and unlabeled Dopa of 6,840 .mu.g/cm.sup.3. The measured
results for this experiment indicated that 550 .mu.g/cm.sup.2 /hr
of Dopa diffused into the artery. The experiment was repeated
twice, with initial concentrations in the delivery system of 10,700
.mu.g/cm.sup.3 and 10,600 .mu.g/cm.sup.3. The measured diffusion
rates for these experiments were 1,050 .mu.g/cm.sup.2 /hr and
1,180.1 .mu.g/cm.sup.2 /hr respectively. The diffusion rate across
a 1 cm.sup.2 section of canine carotid arterial wall for Dopa is 12
to 24 .mu.g/cm.sup.2 /24 hrs.
EXAMPLE 4
The procedure of Example 1 is repeated in this example and all the
conditions were as previously described, except that the drug
delivery system contained 22.6 .mu.g/cm.sup.2 of testosterone
labeled with C.sup.14 at position C--4. The diffusion transfer rate
for testosterone is 7.07 .mu.g/cm.sup.2 /hr.
EXAMPLE 5
An in vivo procedure that effectively demonstrates the operability
of the novel drug delivery device is performed as follows: first,
the left common carotid artery of an anesthestized dog is exposed
by standard surgical technique and freed from it fascia. Next, a 40
millimeter section of the exposed artery is partially surrounded
within a drug delivery device that is positioned in communicating
axial alignment to the artery. The drug delivery device is of an
open top saddle-like configuration about 60 millimeters long, 15
millimeters wide and 15 millimeters deep, and it is made of butyl
rubber. The device is fabricated with integrally formed ascending
terminal skirts for retaining drugs within the device and with an
inlet and outlet tubing means adhesively mounted on the side of the
device thereby forming passageways. for fluid interchange with the
outside environment and the interior of the drug delivery device.
The inner area of the drug delivery device housing the carotid
artery is filled with a saturated solution comprising 400 mg of
unlabeled L-Dopa[levo-3-(3,4-dihydroxyphenyl)-alanine], and 20
.mu.c of L-Dopa-3-C.sup.14 in 80 percent Ringer's solution. Blood
samples at the femoral artery, and left lingual artery, a branch of
the left carotid artery at about 3 cm downstream from the drug
delivery device, and cerebrospinal fluid samples for radioactive
counting are taken at 20 minute intervals and the measured activity
expressed as .mu.g/ml is set forth in Table 1, as follows:
TABLE 1
SOURCE
Time of Sample Femoral Left Lingual Cerebrospinal Minutes Arterial
Arterial Fluid Blood Blood 20 1.7 5.0 1.5 40 2.3 7.6 1.6 60 2.9 6.8
2.0 80 2.8 7.2 2.1 100 3.6 10.2 2.6 120 4.1 8.9 2.9 140 4.0 9.6
2.9
The appearance of measurable labeled samples in the femoral artery
as set forth above indicates a diffusion of the drug into blood,
and mixing through the general systemic circulation. The appearance
of labeled material in the left lingual artery at higher
concentrations than in the femoral arterial blood indicates an
advantageous localization of L-Dopa in arterial blood that supplies
the brain. The presence of labeled activity in the cerebrospinal
fluid indicates that L-Dopa or a derivative crossed the blood brain
barrier.
EXAMPLE 6
An in vivo drug delivery device for administering testosterone is
performed according to the procedure as set forth in Example 5. All
the conditions were as described except that the drug delivery
device in this example circumferentially surrounds the artery, as
in FIG. 1 and its accompanying description, and its contiguous
surfaces are sealed with a commercially available cyanoacrylate
adhesive to provide a closed drug delivery device. The inlet and
outlet ports in this device are joined to a drug reservoir
comprised of a small plastic bag, suitably mounted in the host for
continually supplying drug to the device for diffusion across the
arterial wall. A novel drug delivery device coupled to a drug
reservoir, as described herein, can be used for supplying a drug to
a needed host for extended periods for example up to 2 years.
EXAMPLE 7
The procedure described in Examples 5 and 6 is repeated in this
example, and all conditions were as described with the addition of
a rate controlling poly(ethylene)-vinyl acetate membrane positioned
in the device. The membrane is adhesively joined to the tapered
ends of the device and it contacts the advantitial surface of the
blood vessel for regulating the diffusion of drugs into the
bloodstream.
EXAMPLE 8
An in vivo drug delivery system for administering testosterone is
performed according to the procedure as set forth in Example 5 and
Example 7. All the conditions are as described except that the drug
delivery device in this instance example circumferentially
surrounds the artery according to FIG. 5, and its contiguous
surfaces are sealed with a commercially available cyanoacrylate
adhesive to provide a closed drug delivery system. The inner
surface ends of the drug delivery device has attached thereto a
silicone drug release membrane that is formed by mixing 70 parts by
weight of polydimethylsiloxanes and 5 parts of silicone oil. The
well stirred mixture of the three ingredients is first formed and
then cured by adding 0.25 parts by weight of stannous octoate, then
it is fixed to the device. The delivery device provides a depot of
the hormone for diffusion into the blood.
EXAMPLE 9
The procedure of Example 8 is repeated in this example except that
the silicone is replaced with a commercially available
polyethylene-vinyl acetate copolymer, 84/16, membrane containing
the hormone therethrough, and the membrane is free-floating within
the system for making available the drug for diffusion across the
arterial wall and into the blood.
EXAMPLE 10
A drug delivery device for diffusively administering a drug into
the portal vein is manufactured as follows: first, a pair of holes
in spaced apart relation are cut into a sheet of commercially
available nylon for receiving a pair of nylon tubes. Then, the
tubes are sealingly joined with surgically acceptable adhesive such
as methyl-2-cyanoacrylate to the sheet of nylon to form an inlet
and outlet port system. Next, the nylon sheet is cut and formed to
a shape that corresponds to the shape of the portal vein and the
ends of the sheet are inwardly tapered to define a pair of openings
for the vein and for positoning and fastening the nylon to the
vein. The nylon sheet, that becomes the wall of the drug delivery
device, is manufactured with a drug defining space formed by the
inner wall of the nylon and the advantitial wall of the vein. Next,
the shaped nylon device is positioned around the vein and its
contiguous surfaces formed by the longitudinal edges of the device
and in axial alignment with the vein are sealingly joined with the
above mentioned adhesive. The tapered ends are then sealed to the
vein. The inlet-outlet ports that extend outwardly through the
host's skin can be used to occasionally supply drugs to the device,
or they can be joined to an internally or externally carried drug
reservoir, usually a small plastic bag for continuously supplying
drugs to the device.
DESCRIPTION OF INVENTIVE APPLICATION
This invention makes available to the art of novel, unobvious and
useful drug delivery device for administering drugs directly into
blood within a blood vessel. The drug delivery device can serve as
an in vivo reservoir of drugs and act thereby as a source of drugs
for the passage or diffusion of the drug in vapor, liquid or solid
form through a blood vessel wall. The drug delivery device also
makes available means for regulating the rate of drug passage, that
is, the device can function as a drug pace maker for metering into
the blood various quantities of drugs as they are needed at various
drug receptor sites, for immediate, occasional, or for continual
supply.
The drug delivery device can be used by the medical and the
veterinary arts in a variety of ways. For example, the delivery
device can be applied to the portal vein for the direct delivery of
a drug to a target organ, the liver. The delivery device can be
placed on the carotid artery for administering drugs to the brain
for the management of Parkinson disease. The delivery device can
also be used for the delivery of any material for systemic or
regional administration, for any material indicated for local
administration to an organ, for the delivery of medications for
local perfusion in malignancy of an extremity and the like. The
drug delivery device can be used as an internal drug reservoir, and
its ports can be employed for refilling the device from an external
reservoir supplying predetermined quantities of a medication to an
artery or vein.
The above examples and disclosure are set forth merely for
illustrating the mode and the manner of the invention and various
modification and embodiments can be made by those skilled in the
art in the light of the invention without departing from the spirit
of the invention.
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