U.S. patent number 3,817,248 [Application Number 05/303,773] was granted by the patent office on 1974-06-18 for self powered device for delivering beneficial agent.
This patent grant is currently assigned to ALZA Corporation. Invention is credited to Richard G. Buckles, Su Il Yum.
United States Patent |
3,817,248 |
Buckles , et al. |
June 18, 1974 |
SELF POWERED DEVICE FOR DELIVERING BENEFICIAL AGENT
Abstract
A self powered device for the continuous and controlled delivery
of an agent over a prolonged period of time to an agent receptor is
disclosed. The device is comprised of a pressure distendable
receptacle formed of an elastic material, with the receptacle
communicating with a discharge port having a flow resistive agent
metering means for releasing agent in fluid form. The receptacle
has an entry port providing access to its interior with the port
having a sealing means. The receptacle is dimensioned for insertion
in its collapsed state into a receptor site and it is expandably
responsive to an applied pressure induced by forced infusion of
agent through the port after the receptacle is in the receptor. The
infusion of agent establishes an internal stress in the elastic
material with the material maintaining as a result of the stress a
substantially constant internal pressure in the receptacle
throughout the discharge of the agent from the receptacle. The
receptacle is adapted for easy removal from the agent receptor
after the administration of agent.
Inventors: |
Buckles; Richard G. (Menlo
Park, CA), Yum; Su Il (Mountain View, CA) |
Assignee: |
ALZA Corporation (Palo Alto,
CA)
|
Family
ID: |
23173623 |
Appl.
No.: |
05/303,773 |
Filed: |
November 6, 1972 |
Current U.S.
Class: |
424/430;
128/DIG.12 |
Current CPC
Class: |
A61F
6/14 (20130101); A61M 31/00 (20130101); A61K
9/0039 (20130101); Y10S 128/12 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61F 6/00 (20060101); A61F
6/14 (20060101); A61M 31/00 (20060101); A61m
025/00 (); A61m 031/00 () |
Field of
Search: |
;128/214F,129,260,349B,DIG.12,184 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Medbery; Aldrich F.
Attorney, Agent or Firm: Sabatine; Paul L. Mandell; Edward
L. Benz; William H.
Claims
What is claimed is:
1. A device for the administration of a drug at a controlled and
continuous rate over a prolonged period of time comprising: (a) a
receptacle for containing a drug and adapted to be inserted into a
body orifice of a warm blooded animal, said receptacle having a
leading end for receiving a metering means and a trailing end for
receiving a filling means, (b) a wall defining the receptacle and
formed of a biologically inert, non-allergenic elastomeric material
suitable for exerting a pressure on a contained drug by the wall
moving from an expanded position when the receptacle is charged
with drug to a collapsed position throughout the release of drug
from the receptacle, (c) said metering means positioned in the
leading end for controlling the rate of drug administration from
the receptacle to its exterior, (d) a means for filling the
receptacle positioned in the trailing end, the means having a
tubular configuration and held in the end by the receptacle wall
pressed against the tubular member, (e) a means for maintaining
drug in the receptacle consisting of a uni-directional valve in the
tubular member and wherein, (f) said elastomeric material defining
a means for administering the drug from said charged receptacle by
the wall moving from an expanded to a collapsed position to exert
an internal pressure on drug and urge it through the metering means
to administer it from the device at a controlled and continuous
rate for a prolonged period of time.
2. A self powered device for the continuous and controlled
administration of a beneficial agent over a prolonged period of
time comprising: a pressure distendable receptacle for insertion
into a biological environment and adapted to contain an agent and
formed of an elastomeric material substantially impermeable to the
agent, a discharge port integral with the receptacle, a flow
resistive metering means for controlling the rate of agent
administration from the receptacle by passage through the means
with the means in communication with the discharge port and the
receptacle, an entry port distant from the discharge port and the
flow resistive means for providing access to the receptacle, means
housed in the entry port for internally closing the port and
maintaining agent in the receptacle, a catheter tube for filling
the receptacle with the agent in communication with the entry port
and the receptacle, and wherein the receptacle is dimensioned for
insertion and positioning in its collapsed state into an agent
receptor biological environment, said receptacle expandably
responsive to an applied pressure induced by infusion of said agent
through the entry port into the receptacle after the receptacle is
placed in the preselected environment of use to establish an
internal stress in the receptacle material, and wherein in
operation, when the receptacle is charged with said agent, the
elastomeric material constitutes a means for maintaining, as a
result of the induced stress, a preselected programmed pressure in
the receptacle wall to move agent through said flow resistive means
at a controlled and continuous rate throughout the discharge period
of the agent from the self powered device.
3. A self powered device for the continuous and controlled
administration of a beneficial agent over a prolonged period of
time comprising: a pressure distendable receptacle for containing
an agent, the wall of the receptacle formed of an elastomeric
material substantially impermeable to the agent, a discharge port
communicating with the receptacle, a flow resistive metering means
in contact with the discharge port and the receptacle for
controlling the rate of agent administration from the receptacle by
passage of agent through said metering means from the receptacle,
an entry port distant from the discharge port and flow resistive
means for providing access to the receptacle, a catheter for
internally receiving the receptacle at the entry port, selfclosing
valve means internally positioned in the catheter distant from the
entry port for providing entry to the receptacle and for
maintaining agent in the receptacle, and wherein the receptacle is
adapted for insertion and retention in its collapsed state into an
agent acceptor biological environment, the receptacle being
expandably responsive to an applied pressure induced by filling
receptacle with agent through the entry port after the receptacle
is placed in said preselected environment of use to establish an
internal stress in the receptacle wall, said elastomeric material
and the resultant internal stress when the receptacle is filled,
defining an agent administrating means operative to maintain, as
the result of said induced stress, a substantially constant
pressure in the receptacle wall to move said agent through the flow
resistive means at a controlled and continuous rate throughout the
discharge period of the beneficial agent from the self powered
device.
4. The device according to claim 3 wherein the entry port of the
receptacle is positioned within the catheter, the catheter formed
at the end that receives the entry port with an internal recess for
housing an O-ring which contacts the end of the receptacle at the
entry port and retains it within the catheter.
5. The device according to claim 3 wherein the entry port of the
receptacle terminates within the end of the catheter, the catheter
formed at this receiving end with an internal groove for containing
an O-ring that abuts against the receptacle at its entry port to
maintain it within the catheter, and the catheter formed at its
distant end with at least one protuberance for receiving force for
subsequently moving and positioning the device within a cavity.
6. The device according to claim 3 wherein the entry port is
integrally formed with the catheter, said catheter comprised of an
internal, one-way valve distant from the entry port with the valve
self closing after the receptacle is charged with agent for
maintaining it therein.
7. The device according to claim 3 wherein the device is adapted
for insertion and positioning in the uterus.
8. The device according to claim 3 wherein the agent is an
acceptable pharmaceutical agent that can produce a local or
systemic physiologic or pharmacologic response upon administration
from the device.
9. The device according to claim 3 wherein the environment of use
is a mammalian bladder.
10. The device according to claim 3 wherein the wall material
forming the receptacle is natural elastomeric non-toxic rubber.
11. The device according to claim 3 wherein the discharge port is
tubular with a flow resistive means for controlling the flow of
agent and it discharges agent into a receptor site distant from the
sites of the device.
12. The device according to claim 3 wherein the receptacle when
distended is of a size and configuration adapted to promote
retention thereof in the environment of use and is adapted for easy
removal from the environment of use and is adapted for easy removal
from the environment of use after the administration of drug from
the receptacle.
13. The device according to claim 3 where a one way valve is
positioned in the catheter to maintain agent in the receptacle with
the catheter made of a biologically inert material and having a
length adapted for maintaining it within a mammalian cavity.
Description
BACKGROUND OF THE INVENTION
This invention relates to an agent delivery device, and more
particularly to a self powered device for delivery of an agent
which device operates without any external energy source and is
capable of continuously dispensing an agent at a controlled rate
over a prolonged period of time. The device uses energy stored in
the materials employed to fabricate certain of its component parts
as the motive force to dispense the agent. In a preferred aspect,
the device is employed for internally administering a medicament to
a drug receptor such as an animal, human or avian.
There is an increasing interest and expansion of activity in the
art directed to the development of devices which can provide a
continuous and sustained administration of an active agent to a
system. One field of endeavor to which such devices have
applicability pertains to therapeutic programs relating to the
management of health and disease where it is desirable to use a
delivery device to provide a slow release of a beneficial agent,
such as a drug to a recipient at a controlled rate over a
relatively prolonged period of time to achieve a desired
physiologic or pharmacologic effect. Such prolonged and continuous
medication gives results which are far superior to periodic or
intermittent administration that may be dangerous because of the
high concentration of medicament at the time of administration, or
of no therapeutic value because of the low concentration of
medicament between the periods of administration. Frequently, it is
advantageous to implant or insert such devices within the recipient
at or near the area to be treated in order to avoid systemic
administration of the drug. Further, in many instances, such a rate
of release of drug from the delivery device should have a zero
order time dependence, that is, the rate of drug release is
independent of time.
Different approaches have been tried by the art to obtain such
devices. Among such devices are those which dispense compositions
of matter at a uniform delivery rate under a positively applied
pressure developed by the use of elastomeric materials, as
disclosed, for example, by Bierman in U.S. Pat. No. 3,469,578.
Devices of the type disclosed in the patent dispense their
composition by utilizing a pressure induced by internal stresses
stored in elastic materials used to fabricate its component
elements. An advantage of these devices is that, since the
dispensing is effected under a positively applied pressure, it is
not necessary to immobilize the drug receptor. The device is used
by securing it to the receptor by straps and the receptor is
allowed complete mobility and freedom of movement with full
assurance that the device will continuously release its contents
due to the positive pressure involved in actual operation.
Nothwithstanding these advantages, however, these prior art
elastomeric pressure operated devices have inherent disadvantages
in that the device must be secured to the external surface of the
receptor in some manner which is often cumbersome and awkward to
accomplish. In addition, such placement often restricts ambulatory
motions and, unless the device is hidden by clothing or the like,
it can present an unsightly condition causing embarrassment and
inconvenience to the user. Then too the devices are made without a
means for regulating the flow of drug from the receptacle to the
receptor. Moreover, such prior art devices are not adapted for
implantation or insertion within many areas of the anatomy, such as
the bladder, vagina, subcutaneously, rectum, ear, uterus or the
like, which can only be reached by prior passage through a
restrictive orifice or by surgical intervention. Such internal
placement of the device is advantageous in that these local areas
can be treated directly, thereby avoiding systemic administration
of the drug while concurrently obviating other problems created by
external placement.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to provide a self
powered delivery device using energy stored in the materials
employed to fabricate certain of its component parts, as the motive
force, which overcomes deficiencies of prior art devices of this
type as indicated above.
It is another object of the present invention to provide a device
or an elastomeric pump for the continuous and controlled
administration of a drug over a prolonged period of time to a drug
receptor, such as body openings, cavities, subdermal and the like
which device is adapted to be inserted or implanted in such
receptor sites, including those areas of the anatomy readily
accessible only via restrictive orifices, or via surgical
intervention.
A further object of the present invention is to provide a self
powered delivery device which does not require the use of auxiliary
means to secure the device to the user.
Still another object of this invention is to provide a self powered
delivery device which is suitable to dispense, for prolonged
periods of time, beneficial active agents having a wide variety of
chemical and physical properties and over a wide range of release
rates.
Yet still another object of the invention is to make available to
the medical and veterinary arts a device for releasing drug to a
biological site which device has a flow resistant means for
regulating the amount of drug released from the device per unit of
time.
Still yet another immediate object of the invention is to provide a
dispensing device for the administration of locally acting or
systemically acting drugs to produce a physiologic or pharmacologic
effect which device can dispense the drug at a rate produced by the
use of a flow resistive means and a continuous, dischargeable,
pressure set receptacle.
In attaining these objects, features and advantages, the invention
resides in a self powered device for the continuous and controlled
administration of a drug over a prolonged period of time to a drug
receptor including body cavities, passages, subdermal areas,
external areas such as nasal passages, the ear and the like
comprising: a pressure distendable receptacle formed of an
elastomeric material, the receptacle communicating with a discharge
port having a flow resistive drug metering means therein, and
having an entry port providing access to the interior thereof from
an extracorporeal position, the entry port also having a means for
sealing, the receptacle being dimensioned for insertion in its
collapsed state into or onto a drug receiving animal including
humans and avians and being characterized by being expandably
responsive to an applied pressure induced by forced infusion of
drug in the entry port after insertion of the receptacle in the
animal to establish an internal stress in the material, the
receptacle when distended being of a size and configuration so as
to promote retention thereof in the receptor, with the material
maintaining, as a result of the stress exerted, a substantially
constant internal pressure in the receptacle throughout a range of
discharge of the drug, the receptacle being adapted for easy
removal from the internal cavity after discharge of drug from the
receptacle.
Other objects, features and advantages of this invention will
become more apparent from the following description when taken in
conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
A preferred embodiment of this invention relates to the use of the
device of the invention for administration of a drug to mammals,
specifically to the uterus of an adult female. This embodiment has
been arbitrarily chosen for ease of presentation in order to best
explain the principle of the invention and its application so as to
enable others skilled in the art to best utilize the invention. It
will be appreciated that it is not intended to limit the invention
to the specific embodiment disclosed.
FIG. 1 is a diagrammatic frontal view of the female uterus
illustrating the first stage of installing the drug delivery device
of this invention.
FIG. 2 is a diagrammatic frontal view of the female uterus region,
illustrating the delivery device of this invention completely
inserted, filled with drug and in position within the uterus.
FIG. 3 is an expanded view of the device of FIG. 1 made with the
parts acting in combination.
FIG. 4 is a sectional view of another embodiment of the novel
product delivery device of this invention.
FIG. 5 is a view of part of the structure of a device of the
invention illustrating two components of a device united through an
O-ring.
FIG. 6 is a view of part of the structure of a device of the
invention illustrating a self closing valve integrally formed in
the receptacle.
Corresponding reference characters in the drawings are indicated by
responding numbers throughout several drawings.
DETAILED DESCRIPTION OF THE INVENTION
Referring to devices of the invention, particularly to FIGS. 1 and
2, the uterus 2 of an adult human female is schematically shown
comprised of the uterus having a cavity 6 termed the fundus, which
is a distendable muscular region having a volume of between 10 and
20 milliliters. At the entrance of the uterus there is located the
cervix 4 which can be described as a short canal 4a, 3 to 6
millimeters in diameter, and between 2 and 4 centimeters long. The
cervical os 5 is located at the entrance to the cervix and
communicates with the vagina (not shown). The distance from the
external cervical os 5 to the top of the fundus is from about 4 to
6 centimeters. Other details of the structure of the uterine area
are not concerned with the invention and a detailed description is
omitted in the interest of brevity.
The self powered delivery device 9, as illustrated in its preferred
form in FIGS. 1 and 2, can be viewed as a single unit comprising a
receptacle assembly 10 and catheter 15 joined together in
functional relationship by a male-female couple at 15a, shown in
one embodiment in FIG. 5 in detail, for the effective assembly of
device 9 for administration of drug. Receptacle assembly 10
comprises an elonged container 11, the walls of which are formed of
a highly elastic material which is inert when placed in the body
and not subject to deterioration by the action of body fluids. Flow
resistive means 12 is secured by a discharge port positioned in the
distal end of container 11. The other or proximal end of the
container 11 is joined with catheter 15 by placement thereover and
securing therewith by means of an adhesive. An optionally seated
O-ring 17 seen in FIG. 1 is tightly positioned about the end of
container 11 in recess groove 18 also seen in FIG. 1 molded into
the catheter body 15 as an aid in maintaining a seal and to assure
retention of container 11 about catheter 15. If desired, optionally
seated O-ring 17 can be omitted, with sealing and retention being
accomplished with adhesive, solvent sealed, heat sealed, or by any
fluid tight assembly. In order that container 11 comfortably be
able to pass through cervix 4, the overall dimensions thereof, it
its collapsed state, are quite small. Preferably, the overall
length of container 11 for uterine use is approximately 5 to 40
millimeters, or the like with the diameter in the collapsed state
being in the range of 1 to 10 millimeters. The diameter in the
collapsed state corresponds to the diameter of the cervical os for
easy insertion into the uterus. It will be appreciated that the
dimensions noted above may be varied in accordance with different
uteri and other body cavities.
Although container 11 is susceptible of embodiment in many
different forms other than that illustrated, and can assume any
shape when expanded such as elliptical, spherical, tapered, barrel,
tubular, arcuate and the like, with the proviso that such shape be
adapted, when filled with drug and inflated, to comfortably fit in
the body cavity; for placement in the uterus, cylindrical
configuration is presently preferred. The degree to which the
container expands will be determined partly by the amount of drug
injected therein after insertion in uterus 2 and its
pressure-volume characteristics. Preferably, the container when
expanded, as suggested by the broken lines in the drawings in FIG.
1 and seen in FIG. 2 in a charged state, should not occupy a volume
which is greater than 70 percent of the volume of uterine cavity 2
when filled with drug 3 as in FIG. 2, although this is not critical
to the practice of the invention.
The material employed to fabricate container 11 must be
elastomeric, at least in part, so as to be capable of storing the
required energy in order to develop a positive pressure sufficient
to discharge the contents from the interior of the container, and
be substantially impermeable to drug 3 in FIG. 2 as contained
therein. Further, the material must be such that it can be
distended to a size and configuration which is greater than the
size of ceruical os 5, for reasons of retention of the device, as
hereinafter described, and preferably, substantially conform to the
shape of the uterine cavity. Still further, the material must be
biologically inert, non-allergenic and chemically compatible with
the medicament contained therein. The thickness can vary widely and
is not a limitation on the invention. Typically, however, the
container will have a thickness in the range of 0.5 to 50 mils,
usually 1 to 20 mils thick, when deflated. The choice of materials
will be chosen with reference to the compositions contained therein
and the required positive pressure necessary to operate the device,
such as natural rubber as used for this invention. Containers
suitable for the performance requirements of the invention are
those materials that in normal air and atmospheric conditions at a
temperature of 37.degree. C have for a period of at least one
month, generally 1 month to 1 year with the maximum desirable
permanent radial set as 5 percent, and the maximum axial set of 5
percent, with the maximum change in steady state pumping rate under
the defined parameters not exceeding 10 percent when a zero release
is desired.
Catheter 15 comprises a hollow tube fabricated from non-elastomeric
material, which is preferably rigid in nature, such as
polyformaldehyde, nylon, polystyrene, poly(vinylchloride), high
density polypropylene, segmented polyurethane, polyethylene, Kraton
polymer, or the like, and it is formed at one end with retaining
groove 16 adapted to receive a plug 16a which is held in position
by a shoulder formed by groove 16. It will be noted, by referring
to the drawings, that when properly inserted in the uterus the
catheter portion 15 of the device is positioned in the cervical
canal 4a with catheter 15 and plug 16a in groove 16 extended out
from the cervical os 5 into the vagina. In order that this be the
case, the assembly unit is about 20 to 50 mm, the catheter 15 is
about 20 to 50 cm and the catheter has a diameter of 1 to 10 mm.
Plug 16a is comprised of a self-sealing rubber material and seals
receptacle assembly 10 from the external environment. Another
embodiment of a one-way value is seen in FIG. 6, where it is an
integral part of the elastomeric element 11, as described later in
the specification. However, plug 16a is capable of being penetrated
by a needle of a syringe of the type conventionally employed in the
medical field. Plug 16a acts to direct the flow of drug into
balloon 11 and maintaining it there even though the unit can be
drained with a syringe. Plug 16a is a uni-directional plug and it
can be substituted with other sealing or closing means such as a
one way valve or the like. A syringe, or the like, is utilized,
after placement of this device in uterus 2, to fill container 11
and catheter 15 with drug and maintain it under pressure of
container 11, with the container 11 expanding under such pressure
as the drug is forced therein, as illustrated by the broken lines
shown in FIGS. 1 and 2. Upon withdrawal of the needle the drug is
held under pressure in the assembly 10 of device 9 as seen in FIG.
2.
It is essential to the successful practice of this invention that
the flow resistive means 12 be self actuated, that is to say,
requires no auxiliary means for initiation of flow, when the device
is to be employed for continuous administration from within
internal body passages. Numerous types of self actuated flow
resistive elements for use as 12 are available, such as porous
plugs, microporous membranes, compressed fabrics, capillary tubes,
sintered plugs, pyrolyzed carbon, and the like. The flow resistive
element can be fabricated from a wide diversity of materials,
depending on the type, such as polyethylene, nylon, teflon,
poly(vinylchloride), poly(methacrylate), epoxy resin, carbon,
sintered metals or ceramics. Alternatively, the flow resistive
means can be a small hole or orifice bored into the distal end of
container 11 of predetermined calibrated size for releasing unit
amount. Flow resistive element 12 can be inserted into container 11
by any convenient means which provides a non-leaking seal in fluid
tight relation, for example, the means employed may be adhesive,
mechanical, such as threading, heat sealing or, alternatively, by
making flow resistive element 12 an integral member of the
container structure.
In FIG. 3 there is seen an enlarged view of the drug release
assembly 10 of device 9 of the invention. Assembly 10 is comprised
of a balloon 11 that can move from a collapsed to inflated position
suitably joined to a flow resistive means 12 and to a catheter 15.
Balloon 11 and catheter 15 can be integrally formed, as in FIG. 3,
or they can be formed in separate manufacturing operations and then
joined into one assembly as in FIG. 4. In FIG. 4 there is
illustrated assembly 10 with a balloon 11 illustrated in the
positions to which it can reversibly expand and collapse, a means
12 for controlling the flow of a drug from balloon 11 positioned at
one end of the balloon 11 and at distant end an O-ring 17 for
receiving catheter 15 in fluid tight relation for retaining
positioning receptacle 11 to catheter 15. Catheter 15 acts as a
male member for insertion between O-rings 17 that function as a
female couple within the terminal portion of receptacle 11. A one
way valve 16a, shown in hinged structure, is employed to fill
container 11 by injecting drug through valve 16a, with container 11
expanding as the drug is forced therein. Typically, from 1 cc to 25
cc of drug more or less is injected into container. It is important
to the successful practice of the invention that, prior to
injecting the drug into the device, substantially all air be
removed from the system. Air can be bled from the system by
injecting an empty syringe through self-sealing valve or plug 16a
to suck out the air. The syringe can then be removed, leaving the
system evacuated and free of air. Alternatively, the device could
be purged with liquid prior to insertion into the body cavity. The
increase in volume of container 11, suggested by the broken lines
illustrated in FIGS. 1 and 2 and by circular type lines in 3 and 4
will serve to anchor the device within the uterine cavity. The
critical aspect with regard to retaining the device in place during
the drug administration period is the size of the limiting orifice,
namely, the cervical os 5.
FIG. 5 depicts in detail receptacle 11 catheter 15 couple, joined
to operate as a unit device, as described for FIG. 1. In FIG. 5
there is seen the terminal end of receptacle 11 received by
catheter 15 and in intimate contact therewith. Catheter 15 is
formed with a means 17 for housing a seal and retaining ring 17,
typically an O-ring or the like, for positioning, receiving and
retaining member 11 within member 15. Means 17 can be a groove,
recess or the like, and it can be integrally formed or optionally
machined in 15 by cutting or the like after catheter 15 is
formed.
In FIG. 6 another embodiment of the invention is seen for
positioning receptacle 11 within catheter 15. In the figure,
receptacle 11 terminates with an integrally formed one way valve
16, that opens into receptacle 11 during filling of receptacle 11
and self closes by engaging its contactable, closable surfaces
after the filling of 11. Catheter 15 is also formed with a recessed
area for receiving member 11. The end of receptacle 11 comprised of
valve 16 is fabricated for intimately engaging catheter 15 in
nesting position for retaining 11 in leak tight manner within
catheter 15.
In practical use and delivery of a drug, the manner of operation of
the delivery device of the invention makes use of the energy stored
in the walls of container 11, resulting from the forced infusion of
drug therein, to create an internal stress in the elastomeric wall
material 11. This stress in turn creates a positive pressure within
container 11, that is, a pressure greater than that of the
environment external to the device, the uterus, to provide a
uniform and controlled rate of flow of drug through the flow
resistive element 12. Positive pressures, for example pressures in
excess of one atmosphere, such as from 100 to 400 mm of mercury,
are suitable, although higher or lower values can be employed,
depending on other flow parameters discussed hereinafter. As the
drug is uniformly dispersed, container 11 will slowly deflate. When
the agent or drug is fully discharged, container 11 will shrink
back approximately to its original shape and volume, such that it
can easily be removed from the uterine cavity, or any other cavity,
using the proximal end of catheter 15 as an aid for this
purpose.
In connection with the many uses of the present invention in the
medical field, it is quite important that the flow rate in the
discharge line be constant and at a low and steady pressure. An
important feature of the present invention, accordingly, lies in
the ability to realize a discharge having these characteristics,
and these ends are effected through the development of the device
which will discharge at a substantially constant rate over a
continuous and prolonged period of time. The constant discharge
flow rate of the agent is due to the internal stress in the elastic
material of container 11 which provides the motive operating force
and remains substantially constant throughout the discharge of drug
from the device. Other delivery rates, for example pulsatile
sinusoidal, can be achieved by suitable manipulations of the
geometry and mechanical properties of the elastic materials.
Placement of the delivery device 9 within the uterine cavity 6 can
be accomplished in various insertion methods. For example,
receptacle 11 and catheter 15 can be integrally formed as in FIG. 3
for easy insertion by manually pushing it into uterine cavity 6.
Placement of delivery device 9 within uterine cavity 6 can also be
assisted by the use of an inserting instrument represented
generally in FIG. 1 by numeral 30. Inserter 30 as shown is
comprised of a sleeve or tube 31 which pushes against a
protuberance which is integral to rigid catheter element 15. That
is, catheter 15 is formed with nobs or protuberances 32 and acts as
a plunger for receiving receptacle 11 and insert 30. Inserter 30 is
easily removed while catheter 15, now a plunger, is kept within the
cavity during drug release. Tube 31 can also be catheter 15, that
is, this part of the drug delivery device is endowed with dual
functionality for insertion of device 9 and delivery of drug 3.
Sleeve 31 can be straight or have a gradual turn or curved portion
indicated as 33 which is slidably received by catheter 15 up to
receiving means or plunger 32. An alternative embodiment for
insertion involves a separate tube of inside diameter larger than
outside dimensions of said delivery system. It is used to enlarge
the cervix prior to insertion of the delivery system and is
subsequently removed after the drug is introduced to the device.
Tube 31 may be made of a rigid material and it is perferably made
of flexible plastic material such as one of the long-chain
fluorinated polymers of ethylene such as tetrafluoroethylene, known
under one trademark as Teflon polymer. In cross-section, not shown,
the sleeve or tube 31 may be round or non-round such as being
oblong. Plunger 15 with its protuberance 32 is made of a rigid or
flexible material since it follows the contour of the tube 31. The
cross section of catheter 15 or plunger 32 generally corresponds to
that of tube 31 or it is slightly larger for easily receiving tube
31. It is preferred that the tube 31 have a diameter less than 2 to
10 millimeters for insertion to be accomplished painlessly through
the cervical canal without dilation. In use, the instrument 30,
comprised of sleeve or tube 31, which receives catheter 15 or
plunger 32 are first separated. The body portion of the delivery
device 9, comprised of receptacle assembly 10, are joined to
catheter 15 and these are joined to catheter 15 or plunger at nobs
32 to tube 31. The device is inserted therein from the end remote
from curved portion 33. With delivery device 9 so arranged in
instrument 30, the combined assembly is inserted through the vagina
and partially into the uterine cavity 6 through the cervix 4.
Thereafter, plunger 32 is gradually pushed unto sleeve 31 in a two
step insertion, or it can be previously assembled in a single step
insertion. A the body of the container 11 enters the uterine cavity
6, plunger 32, which is longer than the sleeve or tube 31, is
continuously pushed inwardly thereof until the entire receptacle
assembly 10 is accommodated within the uterine cavity 6 and the
catheter portion 15 in the preferred embodiment is positioned with
plug 17 extending outside ceruical os 5. Thereafter, instrument 30
is slidably withdrawn from catheter 15 and from the body.
It will be appreciated that other equivalents of the device
illustrated in FIGS. 1, 2, 3, 4, 5 and 6 will become apparent to
those versed in the art in light of the present disclosure. For
example, any appropriate body area, surface or cavity which is
accessable by surgery or is positioned or surrounded by an orifice,
that is, one having an opening which is dimensioned smaller than is
the cavity itself, can be employed to house the delivery device
while administering drug to the patient. Thus any area, such as
subdermal, or cavity having an opening for ingress or egress, which
is smaller than the size of the device when in its expanded
condition, will serve to trap the device within such area or cavity
for purposes of retention therein. Other areas and cavities in
addition to the uterus included the bladder, vagina, anal spincter,
trachea, nasal passages, ear, stomach, plumonary, subdermal, and
the like. Of course, the dimensions and design of the device will
have to be varied and adapted for use in the different situations.
Exemplary of other modifications intended to be included within the
spirit of the invention is to position the catheter so as to be
extended from the discharge port as illustrated in FIG. 4. Device
10 depicted in FIG. 4 is comprised of container 11 which can be
filled to the various amounts as depicted by the paired unconnected
elliptical lines as preferably formed of an elastomeric material
having drug entry port 15 molded in one end therein and comprised
of self sealing rubber, or formed separately for insertion into
container 11. Discharge port 12 formed of a flexible material such
as small diameter polyethylene tubing leading therefrom or a porous
body that rate controlls the passage of drug therethrough,
advantageously also serving as the flow resistive means for the
drug, is located on the other end of container 11. A device of the
design type illustrated in FIG. 4 is particularly suited for drug
administration applications wherein it is desired to locate the
device at a site remote from the desired point of application of
drug and where the device is accessible from an extra-corporeal
position such that it can be filled with drug with relative ease.
This embodiment permits placement of the device in one environment,
for example, an area of the anatomy having a cavity such as the
vagina for purposes of retention of device 10 to release drug 3 to
another area, the uterus, or it can be implanted under the skin for
release of drug 3 that is absorbed and carried by the circulation
to a distant body area for use. Thus, when the container is placed
in the vagina, the transfer of drug 3 is effected from uniformly
collapsable container 11, located in the vagina, to the uterus by
means of tube 12, not seen in full length in FIG. 4, that extends
through the canal into the uterus. In operation, the device is
placed in the vagina in a collapsed state, with delivery release
tube 12 positioned in the uterus. Drug is injected by means of a
medical syringe, not shown, through self sealing plug 16a to force
drug into container 11. When expanded, container 11 serves to
anchor device 10 in the vagina and supply the required positive
pressure by means of its elastomeric walls to discharge drug 3 at a
constant rate through a polyethylene tube 12, not shown in FIG. 4,
to the uterus. It will further be appreciated, in an alternative
modification of the device illustrated in FIG. 4, that for some
applications it will be advantageous to locate the entry port and
sealing means at 17 or a one way valve 16a in catheter 15.
The device of the invention is suitable for delivering agents, such
as drugs which are fluids or which can be fluidized by use of
mediums such as carriers, solvents, emulsifying agents or adjuvant
materials and the like, and include drug compositions which are
liquids, emulsions, gels, sols, suspensions, foams, pastes, and the
like. Any of the drugs used to treat the body, both topical and
systemic, can be incorporated as the drug in any of the devices of
this invention. "Drug" is used herein in its broadest sense as
including any composition or substance that will produce a local or
systemic pharmacological or biological response.
The active agents, such as drugs that can be administered with the
delivery device of the invention, in accordance with their known
use and dose, and combinations of these drugs, include, without
limitation: for example, drugs acting on the central nervous system
such as 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,
methylparaphenol 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, diphenyldantoin, ethotoin, pheneturide, ethoxuximide and
the like; muscle relaxants and antiparkinson agents such as
mephenesin, methocarbomal, trihexylphenidyl, biperiden, levo-dopa,
also known as L-dopa and L-.beta.-3-4-dihydroxyphenylalanine, and
the like; analgesics such as morphine, 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, dibucaine and the like; antispasmodics and
anti-ucler agents such as atropine, scopolamine, methscopolamine,
oxyphenonium, papaverine, prostaglandins such as PGE.sub.1,
PGE.sub.2, PGE.sub.1.sub..alpha., PGE.sub.2.sub..alpha., PGA and
the like; anti-microbials such as penicillin, tetracycline,
oxytetracycline, chlorotetracycline, chloramphenicol, sulfonamides
and the like; antimalarials such as 4-aminoquinolines,
8-aminoquinolines and pyrimethamine; hormonal agents such as
prednisolone, cortisone, cortisol and triamcinolone; androgenic
steroids, for example methyltestosterone, fluoximesterone and the
like; estrogenic steroids, for example, 17.beta.-estradiol and
ethinyl estradiol; progestational steroids, for example
17.alpha.-hydroxyprogesterone acetate, 19-norprogesterone,
norethindrone and the like; sympathomimetic drugs such as
epinephrine, amphetamine, ephedrine, norepinephrine and the like;
cardiovascular drugs, for example, procainamide, amyl nitrate,
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 insulins,
protamine zinc insulin suspension, globin zinc insulin, isophane
insulin suspension, and other art known extended insulin
suspensions, sulfonylureas such as tolbutamide, acetohexamide,
tolazamide, and chlorpropamide, the biguanides and the like;
nutritional agents such as vitamins, essential amino acids,
essential fats and the like; and other physiologically or
pharmacologically active agents. Also, the drugs can be present as
the pharmacologically acceptable derivatives, such as ethers,
esters, amides, acetals, etc., that lead themselves to passage into
the circulatory system. These derivatives can be prepared by art
known techniques and then used in the practice of the invention. Of
course, the drug derivative should be such as to convert to the
active drug within the body through the action of body enzymes
assisted transformations, pH, specific organ activities, and the
like.
Carriers acceptable for the purpose of this invention are the art
known carriers that do not adversely affect the active agent, the
host, or the material comprising the delivery device. Suitable
pharmaceutical carriers include sterile water, saline, dextrose,
dextrose in water or saline; 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; aqueous media in the
presence of a suspending agent, for example, sodium
carboxymethylcellulose, sodium alginate, poly(vinylpyrrolidone),
and the like, alone or with suitable dispensing agents such as
lecithin, polyoxyethylene stearate, and the like. The carrier may
also contain adjuvants such as preserving, stabilizing, wetting,
emulsifying, viscosity modifying agents, and the like.
The amount of active drug incorporated in the device varies widely
depending on the particular agent, the desired effect, and the time
span over which it is desired to have the agent released. Since a
variety of devices in a variety of sizes and shapes are intended to
provide complete dosage regimen for therapy for a variety of
maladies, there is no critical upper or lower limit on the amount
of drug incorporated in the device. In general, therefore, the
amount of the drug incorporated in the device is non-limited and it
is an amount equal to, or larger than, the amount of drug that on
release from the device is effective for bringing about the drug's
physiological or pharmacological local or systemic effects. For
example, the amount of drug present in the delivery device when the
device is used for a period of time to achieve local or systemic
effect is for various drugs, such as 11-desmethoxyreserpine, about
5 to 40 mg in the device; for acetophenazine, an amount in the
device of 100 to 200 mg; for methoxypromizine, about 600 to 750 mg
in the device. Additionally, the amount of drug in the device can
be 100 to 300 mg of thiopropazate for releasing 15 to 30 mg over a
24 hour period; 200 to 400 mg in the device of phenyltoloxamine for
a release of 150 to 200 mg per day; 100 to 200 mg of papaverine in
the device for a topical release of 30 to 75 mg over a 24 hour
period; 2.5 g to 4.0 g of mephenoxalone for a release of 1.0 to 1.5
g per day; 15 to 25 mg of tranylcypromane for a release of 10 to 15
mg as the standard dose; 1 to 2 gm of trimethadione present in the
device for a release of 10 to 15 mg as the standard dose; 1 to 2 gm
of trimethadione present in the device for a release administration
of 0.5 to 1.0 g per day; prostaglandins, or example PGE.sub.1,
PGE.sub.2, PGA.sub.1, PGF.sub.2.sub..alpha., in amounts of 0.5 mg
to 10 mg for release of 1 ng to 100 ng, and the like; for
progestogen, progesterone, an amount of 0.01 to 20 mg; and the
like.
The rate of release of drug from the device can be readily
determined by those skilled in the art by standard techniques, such
as measuring the release of drug per unit time, or as disclosed in
Mechanics of Materials, by Papov, E. P., published by Prentice
Hall, 1958. In this regard, by proper selection of the flow
resistive element, of various materials, diameter, length, pore
size are easily selected. The elastomeric container wall material
and the viscosity of the drug formulation, a wide range of
dispensing rates can be obtained, as well known to those skilled in
the art. Rates may vary, for example, from 0.01 ml per hour to 100
mls per hour, as desired, and for periods, for example, such as one
day up to and in excess of 1 year. For satisfactory discharge rates
viscosities of the medium employed with the drug can be in the
range, for example, of from 1 to 10,000 centipoise at the
temperature of use, with the exact selection depending on the other
fluid flow parameters and the desired delivery rate. In some
instances, it may be desirable to assist retention of the device in
the body cavity by attaching a weight or ballast to the device.
Suitable weights, depending on the animal involved, include iron,
brass, stainless plugs, or the like.
FIG. 3 represents a specific example of the manufacture of a
delivery device of the invention used for the controlled and
continuous administration of prostaglandin PGF.sub.2.sub..alpha. to
the uterus of an adult female over a period of 1 day to 3 days with
the preparation as follows and the device having the stated
dimensions and specifications; a drug container 11, is fabricated
from commercially available peroxide-curved natural latex rubber
linking with an internal diameter of 0.79 mm and outside diameter
of 1.59 mm. The receptacle has a deflated initial length of 5 mm
and it inflates to approximately 16 mm. The receptacle holds 3 cc
of drug formulation. A medical grade polyethylene catheter 15 of
0.79 mm outside diameter leads into receptacle 11. The inside
diameter of the catheter is 0.6 mm and its length is 15 cm.
The drug is receptacle 11 consists of 7 mg of PGF.sub.2.sub..alpha.
in 1 cc of sterilized isotonic saline mixed with the viscosity
agent sodium carboxymethyl cellulose. The formulation has a
viscosity of 10,000 cp at 37.degree. C. The device is equipped with
a flow control element 12, distant from catheter 15. The element is
comprised of a porous polyethylene rod potted to the front end of
receptacle 11. The size of the flow control element is 0.9 mm in
diameter and 1 mm in length. It has a porosity of 20 percent, a
tortuosity factor of approximately 2.0 and an average pore size of
1 cc for the controlled, continuous administration of the
prostaglandin to the uterus.
Although the foregoing invention has been described in some detail
by way of illustration of a preferred embodiment and examples, for
purposes of clarity and understanding, it will be understood that
certain changes and modifications may be practiced within the scope
and spirit of the invention, as defined in the appended claims.
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