U.S. patent number 3,788,322 [Application Number 05/318,799] was granted by the patent office on 1974-01-29 for drug delivery device with means for maintaining device in environment of use.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Alan S. Michaels.
United States Patent |
3,788,322 |
Michaels |
January 29, 1974 |
DRUG DELIVERY DEVICE WITH MEANS FOR MAINTAINING DEVICE IN
ENVIRONMENT OF USE
Abstract
A drug delivery device for the continuous administration of a
drug at a controlled rate for a prolonged time is comprised of a
drug delivery device attached to a support means for maintaining
the device in the environment of use. The device is comprised of a
housing with an internal space that acts as a reservoir for
containing a drug and a discharge means communicating between the
reservoir and the exterior of the device for releasing drug
therefrom. The drug delivery device and the support are optionally
contained in a container, and in the environment of use, the device
is released from the container and the support inflated. Drug is
discharged from the reservoir by the reservoir walls collapsing to
exert an internal pressure against the drug to urge it through the
discharge means. On completion of the drug discharge from the
reservoir, the support collapses enabling the device to pass from
the environment of use.
Inventors: |
Michaels; Alan S. (Atherton,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
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Family
ID: |
23239613 |
Appl.
No.: |
05/318,799 |
Filed: |
December 27, 1972 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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300674 |
Oct 25, 1972 |
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Current U.S.
Class: |
604/890.1;
206/522; 123/222; 424/453 |
Current CPC
Class: |
A61M
31/002 (20130101); A61K 9/0004 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 31/00 (20060101); A61m
031/00 () |
Field of
Search: |
;128/1,1.2,260,271,272 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Medbery; Aldrich F.
Attorney, Agent or Firm: Paul L. Sabatine et al.
Parent Case Text
This invention is a continuation of application Ser. No. 300,674
filed on 10-25-72 now abandoned.
Claims
I claim:
1. A drug delivery device for the controlled and continuous
administration of a drug to an environment of use to produce a
therapeutic effect comprising: a hollow expandable closed member
having therein self-contained means for expanding the member and
self-contained means for contracting the member after a given
period of time of expansion, the member being affixed to drug
delivering means for delivering a drug at a controlled rate over
the given period of time, the delivering means comprising a drug,
elastomeric container means defining a single compartment for
enclosing the drug and applying an elastomeric pressure to the drug
and discharge means communicating with the drug for discharging the
drug at a controlled rate from the container by the elastomeric
pressure, the delivering means thereby causing a therapeutically
effective amount of drug to be released through the discharge means
for the given period of time while the member is in an expanded
state, thereafter the means for contracting causing the member to
contract.
2. A drug delivery device for the controlled and continuous
administration of drug according to claim 1 wherein the
self-contained means for expanding the member comprises a liquid
that vaporizes at physiological temperature to produce a gas which
expands the hollow expandable closed member from a collapsed
position to an expanded position.
3. A drug delivery device for the controlled and continuous
administration of a drug according to claim 2 wherein the
self-contained means for contracting the member comprises means for
venting the interior of the member to the environment of use.
4. A drug delivery device for the controlled and continuous
administration of drug according to claim 3 wherein the means for
venting the interior of the member to the environment of use
comprises a bioerodible plug.
5. A drug delivery device for the controlled and continuous
administration of drug according to claim 3 wherein the means for
venting comprises the hollow expandable closed member, the member
being formed of a material that lets the gas slowly diffuse through
the material to the environment of use.
6. A drug delivery device for the controlled and continuous
administration of drug according to claim 1 additionally comprising
an outer bioerodible container.
Description
BACKGROUND OF THE INVENTION
It relates to a novel and useful drug delivery device for releasing
drug internally to a drug receptor such as a cavity in an animal,
human or avian at a controlled rate for a prolonged period of time
to produce a local or systemic physiological or pharmacological
beneficial effect. The drug delivery device of the invention is
comprised of a drug delivery device fixed to a hollow member,
optionally housed in a container that is bioerodible in
physiological environments. The hollow member is expandable from a
collapsed state to an expanded state in the environment of use or
on its release from the container and it is returnable to a
collapsed state after an extended period of time. The device is
comprised of a wall surrounding and forming an internal space to
serve as a reservoir, that is a means for containing a drug. The
wall of the reservoir is made of a flexible, or elastomeric
material and it is substantially impermeable to drug and biological
fluids. The device is provided with a drug discharge means for
metering the release of drug from the reservoir to the environment
of use or to any preselected drug receptor. Drug is released from
the reservoir by its walls automatically collapsing thereby
exerting a force into the reservoir to apply an internal pressure
on the drug causing it to move through the discharge metering
outlet while concurrently reducing its own volume for administering
the drug at a controlled rate over a prolonged period of time.
Beneficial agents, such as medicaments, essential nutrients,
vitamins, prophylatics and the like, normally are introduced into
the body at repeated, spaced intervals, or in a sustained release
form that attempts to release the agent over a prolonged period of
time, especially if a particular dose level is to be maintained in
vivo. In many instances, in the management of health and disease,
for example, drug administration into body drug receptor sites such
as the bladder, vagina, uterus or the gastrointestinal tract, it is
especially desirable that the drug delivery have a preferred zero
order time dependence, that is, the rate of drug release be
independent of time.
Prior to the present invention various approaches have been tried
to obtain a particular dose level over a prolonged period to these
drug receptor sites, but these approaches have not led to generally
acceptable results. One approach, which has received attention as
used for administering a drug to the gastrointestinal tract, or for
administering a drug to the vagina, uterus or the like, is to mix a
drug with a carrier material that is gradually broken down by the
body fluids with the drug released as the carrier disintegrates.
Numerous drug carriers have been used for this purpose, including
waxes, oils, fats, soluble polymers, and the like, and while some
of these have provided for a moderate delayed release of drug,
generally, the desired constant release rate for a prolonged period
has not been achieved. One reason for this is that as the carrier
disintegrates, the surface area of the dosage unit decreases,
concomitantly exposing increasingly smaller quantities of the
carrier and the drug to the surrounding body fluids. This
inherently results in a decline in the release rate over time.
Another approach for administering a drug to drug receptor sites,
such as the gastrointestinal tract, has been to enclose the drug
within a single drug delivery capsule having a wall permeable to
the drug through which it can pass, for example, by diffusion. An
approach of this kind is set forth in U.S. Pat. No. 3,279,996;
however, these too have inherent difficulties. For example, one
difficulty associated with this prior art is that different
delivery capsules having different drug release rates cannot
readily be made because the only variable parameter is the
thickness of the material used to make the capsule. Additionally,
these drug delivery capsules have generally been based merely on
the high permeability of a single material as the diffusion control
wall for some important drug molecule without a consideration of
release rate controlling properties over a large number of hours
which can inherently defeat the primary object of the acceptable
drug dose regimen.
Another method widely used to obtain a necessary and beneficial
drug level in a drug recipient over a large number of hours
comprises administering a pill or a number of pills at regular time
intervals to achieve a dose frequency response relationship.
However, this method, in addition to being troublesome and
subjected to forgetfulness, has certain inherent limitations that
tend to defeat its purpose. For example, the pills often are
rapidly cleared from the drug receptor site such as the
gastrointestinal tract or the bladder before they are fully
utilized, or an excessive quantity of fluid can be present in the
environment of use that unfavorably effects the reaching of the
desired drug level. Thus, a graphic illustration of the drug's
concentration in the blood during a dosage schedule for this method
has the appearance of a series of peaks and valleys; and, often
these valleys may fall below the drug concentration needed to
achieve the desired beneficial effects.
One other approach used by the art to obtain controlled release
over a prolonged period is the sustained or coated slow release
technique. In this technique, the dose of drug is divided into a
group of pellets about one to two millimeters in diameter, and each
group coated with a material resistant to mammalian fluids such as
gastric, intestinal, vaginal fluids and the like. To time control
the release, each group is coated with an increased number of
coats, that is, the first group one coat, the second group two
coats and so forth. However, this technique, as with the dose
frequency response relationship technique described immediately
above, has those certain inherent limitations, such as the high
possibility of uneven coatings, an unequal bioerosion in the
environment of use and like limitations that diminish the
attainment of constant blood levels during a particular therapeutic
program. Therefore, these types of coated slow release beads often
are not suitable for releasing drug at a controlled rate for a
prolonged period of time.
SUMMARY OF THE INVENTION
Accordingly, it is an immediate object of this invention to provide
a drug delivery means for the administration of locally active or
systemically active drugs to produce a physiologic or pharmacologic
effect which means essentially overcomes the disadvantages
associated with the prior art means of administration.
Still another important object of the invention is to provide a
drug delivery device for releasing drug at a controlled and
continuous rate for a prolonged period of time.
A further object of this invention is to provide a complete dosage
regimen for administering a drug for a particular time period, the
use of which requires intervention only for initiation of the
regimen.
Still a further object of the invention is to provide a drug
delivery device suitable for continuously administering drug to a
preselected drug receptor site such as the stomach, the
gastrointestinal tract, the uterus, vagina or bladder and remain
there until the desired dosage regimen is essentially complete
before the device is eliminated or removed from the drug receptor
site.
Yet still a further object of the invention is to provide an
administrable drug delivery device that is self-contained and
self-powered and will remain at the drug receptor site such as in
the stomach for an extended time while administering drug from the
device through a drug flow control element in response to forces
produced in the drug delivery device.
In attaining the objects, features and advantages of the invention,
a novel device is provided for the continuous dispensing of a drug
which device is self-contained, operates independently of its
surroundings and has its own energy source for producing the
desired pressure used as the driving force necessary for dispensing
a drug from the drug delivery device. The device is optionally
housed in an erodible container with the device consisting
essentially of a shell suitably fixed to a hollow support with the
shell having an internal space for a drug reservoir. The drug
reservoir is comprised of a wall consisting of a flexible,
elastomeric material which is substantially impermeable to vapor,
drug and fluid, and it surrounds a space for containing a drug. The
device has a discharge metering outlet for releasing the drug from
the reservoir to the drug receptive environment. In operation, the
wall of the reservoir automatically and continuously applies
pressure on the drug in the reservoir and upon the opening of the
reservoir's discharge outlet with the accompanying release of drug
the wall automatically collapses and reduces the volume of the
reservoir. These actions progressively exert an internal pressure
on the drug to urge it through the discharge outlet. The hollow
support is reversible from a collapsed to an inflated position in
the environment of use or upon the device's freedom from the
container. The support is also returnable to a collapsed position
after the device has returned drug for an extended period of time
to let the device pass from the environment of use.
Other objects, features and advantages of the invention will be
apparent to those skilled in the art from the following detailed
description of the invention, taken in conjunction with the
drawings and the accompanying claims.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, which are not drawn to scale, but rather are set
forth to illustrate various embodiments of the invention, the
drawings are as follows:
FIG. 1 is a plane, side view of a drug delivery device of the
invention housed in a container.
FIG. 2 is an enlarged perspective side view illustrating a drug
delivery device in a closed container with a section of the
container removed for showing one of the devices of the invention
therein.
FIG. 3 is a magnified, central elevational section illustrating the
drug delivery device of the invention confined in a container with
a section removed for showing details of the device.
FIG. 4 is an exploded side view of a drug delivery device with a
memory for generating pressure affixed to a deformable member in
the collapsed position.
FIG. 5a is a view diagrammatically illustrating a drug delivery
device that has partially discharged some of its drug still fixed
to an expanded hollow support.
FIG. 5b is a view of another embodiment of the invention
illustrating a drug delivery device similar to the device of FIG.
5a, except that in FIG. 5b one wall acts as the housing and as the
wall of the reservoir of the device.
FIG. 6 is a side view diagrammatically illustrating one embodiment
of the invention comprising a container housing a drug delivery
device descending in the esophagus.
FIG. 7 is a side view diagrammatically depicting a drug delivery
device in one environment of use, that is, in the stomach.
In the drawings and specification, like parts in related figures
are identified by like numbers. The terms appearing earlier in the
specification and in the description of the drawings, as well as
embodiments thereof, are further described elsewhere in the
disclosure.
DETAILED DESCRIPTION OF THE DRAWINGS
Turning now to the drawings in detail, which drawings are examples
of various drug delivery devices of the invention, and which
examples are not to be construed as limiting, one generic example
of a novel drug delivery device is generally indicated in FIG. 1 by
numeral 10. Drug delivery device 10 is illustrated in side
perspective view and it is comprised of a container 12 made of a
material having bioerodible properties housing a drug delivery
device 14 affixed to a hollow member 16 formed of a material that
has expansible and deformable characteristics. In FIG. 1 a drug
delivery device 14 is depicted in miniature in container 12 to
exemplify one optional operative embodiment of the invention. An
enlarged detailed illustration of FIG. 1 is set forth in FIG.
2.
Referring to FIG. 2, drug delivery device 10 is seen in a
bioerodible container 12, with a section of container 12 removed to
illustrate a device 14. Device 14 has a metering means 20 for
administering a drug from device 14, not shown in FIG. 2, and it is
housed in container 12 and mounted onto a deformable collapsed
hollow member 16. Container 12 is advantageously formed of two
parts with one part designed to telescope into the other for easily
housing device 14 in container 12 to form a container that readily
fits into body cavities or is of a swallowable size. The material
forming container 12 is bioerodible at the temperature of use,
preferably physiological temperatures, and in one embodiment it is
made from gelatin or like materials. This feature generally lends
itself to quick and easy movement through body passages such as the
alimentary canal and also to quick disintegration when it reaches
the stomach. On reaching the stomach, the container quickly
bioerodes, and device 14 is freed for drug administration.
Containers made of other bioerodible materials can also be used for
releasing the device in the stomach. Device 14 is intimately joined
to an expandable deformable hollow member 16 which member 16 is
made of naturally occurring or synthetic flexible, polymeric
materials essentially impermeable to gases and fluids that lend
themselves to reversible changes in shape and size. Device 14 in
one embodiment is suitably heat sealed or joined with adhesives
such as with .alpha.-cyanoacrylate adhesives, acrylic and
methacrylic adhesives, epoxy adhesives, plasticized polyvinyl
adhesive, and the like, to member 16. Member 16 in FIG. 2 is
optionally a completely sealed envelope, a tube, a flat bag, a
balloon or the like, which member is represented as an elongated
tube as shown in a collapsed state. Member 16 contains a fluid, a
compound, or a mixture of chemicals that readily change at the
temperature of use to a gas which inflates member 16 so it can act
as a floating support or structure for device 14 in the environment
of use, such as the stomach. Member 16 is optionally equipped with
an erodible plug 18 that erodes after a predetermined time to
release the gas from member 16, thereby deflating it to a collapsed
state for eventual passage from the environment of use, such as
through the lower gastrointestinal tract. Member 16 can also be
made of a material that is bioerodible and does so after a period
of time to deflate the member, or it can be made of a material that
is permeable to gas to let it diffuse therethrough to slowly
deflate the support over a period of time.
In FIG. 3 a drug delivery device of the invention is set forth in
detail to illustrate the mode and manner of the invention. In FIG.
3, a novel drug delivery device is generally indicated by numeral
10 which is comprised of a container 12 preferably of swallowable
size and it is made of non-toxic bioerodible material formed into
two telescopically associated envelopes having an interior cavity
12a for housing the drug delivery device 14. Container 12 in one
embodiment has a size and shape for swallowing and it is adapted
for humans, farm animals such as cows, household pets such as dogs,
and valuable sport animals for passage to their stomach by normal
peristalsis. Device 14 is suitably joined to an expandable
deformable hollow bladder 16 by adhesive sealing, integral
fabrication, heat union and the like, and it is made of naturally
occurring or synthetic flexible polymeric materials that can freely
change their size and shape. Member 16 in FIG. 3 is illustrated as
a completely sealed envelope which is shown in a collapsed state.
The envelope is sealed at its margins and folded in a number of
staggered folds 16a. Envelope 16 contains an agent, usually a fluid
that readily changes at physiological temperatures to a gas to
inflate member 16 to serve as a floating platform for device 14 in
the animal environment of use, such as the stomach. Folded member
16 in the device illustrated is equipped with an erodible plug 18
that erodes after a predetermined time to release gas from member
16 causing it to deflate to essentially its original collapsed
size.
Device 14 of FIG. 3 is comprised of a shell or wall 15 with an
internal space for containing a drug reservoir 17. Shell 15, in
this embodiment, is made from a semi-rigid, or a thick flexible,
material such as plastic, metal, alloy, plastic metal laminates and
the like and it can optionally be made of materials impermeable to
fluids and gases. Drug reservoir 17 is formed of a polymeric
elastomeric material as discussed later in this application and it
is equipped with a flow control means 19 that acts both as a
passageway between reservoir 17 and the exterior of device 14 and
as a means for metering drug from reservoir 17 to the exterior of
the device 14. Flow control means 19 is suitably made of a porous
inert material, a calibrated aperture, a needle valve, or the like
to act as a meter for releasing a drug, for example according to
the Hagen-Poiseuille equation, at a constant rate over a prolonged
period of time. This controlled and constant rate of drug release
substantially occurs throughout a decrease in volume of the
reservoir as the flow control means meters drug therefrom. Flow
control means 19 is originally sealed with an erodible plug that is
made of commercially available materials such as cocoa butter,
gelatin, mixtures thereof, or like bioerodible materials that
readily erode at body temperatures to place flow control means 19
in operative condition.
Drug reservoir 17 serves as a reservoir for containing a drug 21
and it is optionally a thin walled bag, a thin walled tubing
suitably sealed at one end, a foldable bag, a balloon, or the like.
Reservoir 17 is made from naturally occurring or synthetic
elastomeric materials generally possessing stress and strain
properties similar to natural rubber, such as silicones, butyl
rubber, chlorobutyl rubber, ethylene propylene terpolymers, and the
like. Reservoir 17 is usually made from commercially available
elastomers and it is filled with drug 21 that is released under a
constant tension or pressure exerted on drug 21 by the walls of
reservoir 17. This tension moves it through flow meter 20 at a
constant rate until reservoir 17 is essentially evacuated. In one
embodiment, constant tension is introduced into the reservoir for
application on the drug contents for a long period of time by
prestressing and annealing the reservoir. These processes are
accomplished by preinflating the reservoir with a gas, for example
nitrogen, or a fluid, for example water, to a size larger than
required when filled with drug, and then soaking the reservoir in
boiling water for a period of time, from 1 to 30 hours, usually 1
to 3 hours, while inflated to produce desired degree of constant
tension. Next, the reservoir is emptied and filled with the desired
drug. Other processes that introduce reproducibility into the
reservoir to give the same pressure over time while eliminating
short and long term creep to give a normal and constant elastomeric
tension can optionally be used for the purpose of this
invention.
Device 14 of FIG. 3 is designed to release drug in the stomach, and
in operation it is administered through the mouth for passage to
the stomach. After it reaches the stomach, it is freed from
container 12, deformable member 16 inflates to place the device in
drug release position in the stomach. Drug 21 is discharged from
device 14 by the constant pressure of reservoir 17 against drug 21
to move it through the discharge outlet 20 at a constant and
controlled rate into the external environment of use. The flow
control element 20 also could be preprogrammed to yield a wide
variety of drug delivery rate patterns. In addition, to be self
regulatory, it could also be controlled by external means using
telemetry and an electronically activated element.
FIG. 4 graphically represents another embodiment of the invention
for self administering a drug to the environment of use, such as
the stomach with subsequent passage into the intestinal tract. In
FIG. 4 a drug delivery device 10 is comprised of a container 12
having an internal space 12a for a drug delivery device 14. Device
14 consists essentially of a housing 15 having an internal space
15b and optionally vented at 15a. Housing 15 is suitably integrally
formed or sealed to balloon 16 that contains a chemical for
producing a gas or a gas in liquified form. Housing 15 has an
erosion gas release plug 18 at one of its ends. A reservoir 17 is
confined in housing 15 for containing a drug 21. Reservoir 17 has a
drug metering outlet 20 extending through housing 15 for conveying
drug from reservoir 17 to the exterior of the device, such as the
stomach. Reservoir 17 has a memory 22 capable of automatically
collapsing reservoir 17 to exert an internal pressure on the
contents of reservoir 17 to easily advance the contents through the
reservoir and out of the discharge meeting outlet 20.
Memory 22 of reservoir 17 is capable of rolling or coiling upon
itself as the contents of reservoir 17 are metered therefrom.
Memory 22 is conveniently imparted to reservoir 17 by winding
reservoir 17 while emptying into a jelly roll or around a mandrel
and treating it by standard thermal or irradiative methods to
permanently impart the memory to the walls of reservoir 17.
Generally, thermoplastic materials having a high tensile moduli,
that is, a high ratio of stress to strain in the elastic range of
the thermoplastic such as poly(ethylene), poly(propylene),
poly(styrene), poly(butylene), poly(vinylchlorides), poly(amides),
poly(urethanes), poly(styrene-acrylonitriles), copolymers thereof
and the like can be used for the purpose of the invention.
The standard thermal process can be performed by heating the rolled
reservoir in a bath of water, oil, or the like to a temperature
below the melting point of the material, for example 175.degree. to
200.degree. C, for about 5 minutes to 5 hours or longer. It will be
obvious to those in the art that the specific temperature used is
dependent on the particular material and these temperatures are
known to the art in standard handbooks. the irradiative method
consists of cross linking the material by irradiation with a Van De
Graf generator, cobalt 60 radiation and the like. Next, the
reservoir is unwound by filling it with drug and stoppering it with
an erodible plug. In the stomach the plug erodes and drug is
administered from the reservoir as its walls automatically collapse
by progressively returning the reservoir to the pre-imparted jelly
roll configuration.
In FIG. 5a is seen a drug delivery device 14 consisting of a
housing 15 having an internal space for a drug reservoir 17.
Reservoir 17 has a drug metering outlet 20 at one of its ends.
Housing 15 in this embodiment is attached to an inflated balloon 16
equipped with an eordible plug 18. Reservoir 17 is seen in drug
discharge position with part of the drug discharged, that is, the
reservoir has continuously metered some of its contents into the
stomach. Member 16 initially contained a gas stored in solid or
liquified form for producing a gas with a vapor pressure usually in
excess of one atmosphere at the temperature of use, that is, the
temperature of the stomach to cause it to inflate, as shown, to a
predetermined size and shape. The dimensions of member 16 in the
inflated state will, of course, be different for different
environments of use or drug receptor sites, but it will be large
enough to retain the device in the environment. For example, in the
stomach it will be slightly larger than the diameter of the pyloric
canal which is about 1 cm to 4 cm, usually 2 cm in humans, until
completion of the prescribed therapeutic regimen. At the end of the
therapeutic regimen, plug 18 erodes to vent balloon 16 causing it
to collapse to a size smaller than the pyloric canal. Member 16 can
alternatively be made of a material permeable to the gas to let the
gas slowly diffuse therethrough causing it to collapse. Device 14
then passes through the lower gastrointestinal tract and out of the
body.
FIG. 5b illustrates a drug delivery device 14 similar to the drug
delivery device 14 illustrated in FIG. 5a. In FIG. 5b, device 14 is
designed and manufactured without housing 15 and it is comprised of
a wall 17 surrounding a reservoir for carrying drug. The reservoir
is defined by the internal surface of wall 17. In this device of
the invention, a single wall 17 simultaneously functions as the
housing and the reservoir while achieving the desired programmed
rate of drug release. Reservoir 17 is equipped with a drug metering
outlet 20 that communicates with the interior of reservoir 17 and
the exterior of device 14 for discharging drug therefrom. Reservoir
17 is either integrally formed or suitably heat sealed or
adhesively bound to support 16. In FIG. 5b, support 16 is
optionally equipped with a bioerodible plug, of the general type
described above. The material forming 17 or the reservoir wall, in
the present device, is a naturally occurring or synthetic material
possessing elastomeric properties and it has a thickness that gives
both dimension and support to the reservoir. For example, the wall
can be about 5 to 25 mils thick, usually 15 to 20 mils, and the
reservoir can have a capacity of about 5 to 25 milliliters. This
device, while having a unitary wall is simultaneously capable of
automatically collapsing to exert an internal pressure on the
contents of the reservoir to easily urge the contents from the
reservoir through the discharge metering outlet.
FIG. 6 and FIG. 7 diagrammatically illustrate the device of the
invention in actual use. In FIG. 6 there is seen the outline of a
human 24 with a device 14 moving through the esophagus 27 and on
into the stomach 25. In FIG. 7 the device 14 is seen in stomach 25
of human 24 administering a drug at controlled rate over a
prolonged period of time.
DETAILS OF THE INVENTION
Drug delivery device 14 of this invention can be made into assorted
sizes and shapes with these dimensions adapted for administering a
drug to a particular biological environment or animal and to the
ease of manufacture. The shape of the device is usually tubular but
other shapes such as cylindrical, oblong, oblate, prolate,
spherical and the like can be made. The device is usually
fabricated for administration into a body cavity or body opening,
such as for oral administration into the stomach. In use, the size
of the deformable hollow member 16 of the device in the inflated
state will be slightly larger than the diameter of the cavity or
opening, for example, the pyloric canal to let the device stay in
the stomach during thee period of drug release. The dimensions of
various cavities and openings are known to the art and recorded in
medical literature, and for the purpose of the invention the
following example will serve to illustrate the spirit of the
invention. For example, the size needed to keep an inflated member
in the stomach of a human, that is, to prevent premature passage
through the pyloric canal will be for an inflated member about 2 to
6 cm in diameter to about 7 to 12 cm in length. Usually, for adults
about 3 cm in diameter to about 10 cm in length. Of course, other
sizes about 2 cm by 5 cm, 3.14 cm by 5 cm, 4 cm by 4 cm and the
like are also within the mode and the manner of the invention.
Member 16 is generally made of naturally occurring or synthetic
material that lends itself to reversible volume change in shape and
size. In one embodiment, when an erodible plug is used to deflate
an inflated member, the material is an elastomeric polymer that is
essentially impermeable to gases and fluids. In another embodiment,
the material can be permeable to gases to let a gas slowly diffuse
through the material to deflate the member. The material is usually
0.2 to 100 mils thick and it can be natural rubber, silicone,
poly(urethane), poly(acrylonitrile), poly(ethylene), copolymers of
vinylidene chloride and vinyl chloride, or acrylonitrile,
poly(ethylene terephthalite), acrylic elastomers, laminates such as
poly(ethylene)-poly(vinylidene chloride), nylon-poly(vinylidene
chloride) acrylic elastomers laminated with metal foils, and the
like.
Shell or housing 15 of the device, when optionally used herein, can
be flexible or rigid or modifications thereof, and it can be made
from a wide variety of materials such as aluminum, teflon,
poly(ethylene), laminates of poly(propylene),
poly(methylmethacrylate), poly(formaldehyde), nylon, laminates of
poly(styrene), metal foils such as aluminum foil, tin foils,
poly(vinylidene chloride), coated tin foil and the like. In an
economical aspect, the devices of this invention are made of
materials that lend themselves to single use devices and as such
they are made from relatively inexpensive materials. The thickness
of the shell can vary over a wide range, usually from 0.5 to 20
mils or the like, generally in the range of 1.0 mils to 10.0
mils.
Materials suitable for forming reservoir 17 positioned in shell 15,
or for forming reservoir 17 when it is both the housing and the
reservoir, that can be used to contain drug 21 and also used to
urge drug 21 from device 14 are elastomeric, flexible materials
that are essentially impermeable to vapors, fluids and the like.
The reservoir has a size and shape corresponding to the volume of
the drug originally stored therein, and that can freely fit in a
drug receptor site. Optionally it has a size that can be easily
contained in housing 15. Reservoir 19 is manufactured to hold a
maximum amount of drug for a prolonged drug delivery time and to
permit the use of high drug delivery rates. This is preferably
achieved by maximizing the drug volume and minimizing all other
design features. Reservoir 17 is typically made from a naturally
occurring or a synthetic material, and it is about 0.2 mils to 100
mils thick, or more, usually 0.4 to 20 mils and the like. The
reservoir can be made of a single material, a combination of
materials in laminated forms, such as elastomeric materials bonded
on foils and the like. Illustrative materials include silicones,
poly(urethanes), poly(vinylidene chloride), poly(vinylidene
fluoride), acrylic elastomers, ethylene propylene terpolymers,
laminates such s poly(vinylidene)-poly(ethylene), poly(vinyl
chloride)-butyl rubber, poly(vinylidene chloride-cis-polyisoprene),
and the like.
Exemplary materials suitable for support or for inflating balloon
16 or the like are inorganic and organic compounds whose vapor is
an equilibrium with its liquid phase to exert a constant pressure
at physiologic temperature regardless of liquid volume.
Representative of compounds are those that are liquids at ambient
temperatures, usually 20.degree. to 25.degree. C or less, and have
a boiling point, BP, above this temperature to exert a vapor
pressure greater than one atmosphere at physiological temperatures
for inflating the balloon. Exemplary materials useful for inflating
deformable hollow member 16 are halogenated hydrocarbons,
fluorochlorinated lower saturated aliphatic hydrocarbons,
halogenated unsaturated hydrocarbons, halogenated lower alkanes of
1 to 4 carbon atoms and the like, such as diethyl ether BP
34.6.degree. C, methyl formate BP 31.5.degree. C, tetramethyl
silane BP 26.5.degree. C, perfluoropentane isomers BP 31.0.degree.
C, n-pentane 36.0.degree. C, iso-pentane 27.9.degree. C, diethenyl
ether 28.degree. C, and the like. Usually, the amount of gas stored
in the liquified phase in the deformable hollow member 16 will be
about 0.2 cc to 5.0 cc or higher, and the volume of the vapor phase
will be from 80 to 100 percent of the inflated member.
Support member 16 can also be inflated by having an effervescent
couple contained therein that generates gas by the reaction of
contained reagents in the presence of aqueous type fluids that
diffuse through member 16 wall from the environment of use. The
materials of the effervescent couple can be any of the known
pharmaceutically acceptable materials used to generate carbon
dioxide. For example, the effervescent couple can comprise either
citric acid or a mixture of citric acid and tartaric acid and
sodium bicarbonate or potassium bicarbonate to yield
effervescence.
Materials suitable for use as bioerodible plug 18 are those
materials that bioerode in the environment of use, such as the
stomach, at a predetermined given time. The materials are those
that erode by known processes, such as chemical degradation, acidic
hydrolysis, enzymatic action, acidation, reduction, dissolution,
slow solubilization, and the like. The bioerosion rate for suitable
materials can be determined by standard assay procedures consisting
of placing a section of material in natural or artificial gastric
juices at normal body temperatures and observing the rate of
erosion over a period of time. By prolonged period of time is
meant, for the present purposes, 8 hours to 30 days, usually 1 day
to 8 days.
Representative materials for use of plug 18 comprise hydrophilic
polymers of uncross-linked hydroxylalkyl acrylates and
methacrylates, hydrolytically biodegradable poly(anhydride)polymers
as described in U.S. Pats. Nos. 2,073,700; 2,668,162; and
2,676,945; and in Introduction to Polymer Chemistry, Stille, J. K.,
Chapter 6, 1962, published by Wiley Publishing Co., bioerodible
polyesters as described in Industrial and Engineering Chemistry,
Vol. 36, No. 3, pages 223 to 228, 1964; Macrmol. Chem., Vol. 75,
pages 211 to 214, 1964; U.S. Pats. Nos. 2,703,316; 2,668,162;
3,297,033; and 2,676,945; cross-linked gelatin prepared with a
cross-linking agent reactive with the hydroxyl carboxyl or amino
functional groups of the gelatin molecule as described in J.
Polymer Science, Part A-1, Vol. 5, No. 1, 1967; J. Polymer Science,
Vol. 54, pages 321-335, 1961; Advances in Protein Chemistry, Vol.
VI, Cross Linkage in Protein Chemistry, 1961, published by Academic
Press, Inc.
Other materials include proteins and hydrocollides of animal and
plant origins such as modified collagen, elastin, keratin, fibrin,
karaya, algin, pectin, carrageenin, chitin, locust bean gum and the
like. Also, synthetic polymers such as poly(ethylene oxide),
poly(acrylic acid) copolymers of acrylamide and methacrylamide up
to 40 percent by weight of N-methylene bisacrylamide or
N,N-dimethylol urea, and the like.
The active 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, as described in The Pharmacological
Basis of Therapeutics, 14th Edition, Goodman, L. S., and Gilman,
A., 1970, The Macmillan Co.; Physicians' Desk Reference, 25th
Edition, 1971, Medical Economics, Inc; and Remington's
Pharmaceutical Sciences, 14th Edition, 1970, Mack Publishing Co.,
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, diphenyhydantoin,
ethotoin, pehneturide, ethosuximide and the like; muscle relaxants
and anti-parkinson agents such as mephenesin, methocarbomal,
trihexylphenidyl, hiperiden, 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 antiulcer 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; anti-malarials such as
4-aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal
agents such as prednisolone, cortisone, cortisol and triaminolone;
androgenic steroids, for example, methyltestosterone,
fluoximesterone and the like; estrogenic steroids, for example,
17.beta.-estradoil and ethinyl estradoil; 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
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 dichloropehn, dapsone and the like;
neoplastic agents such as mechlorethamine, uracil mustard,
5-fluorouracil, 6-thioquanine procarbazine and the like;
hypoglycenic drugs such as 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 lend 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.
The above and other beneficial agents can be used per se or they
are conveniently formulated into a pharmaceutical form by mixing
with a non-toxic carrier. 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. For example, 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
caster 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 agent incorporated in the device varies
depending on the particular agent, the desired effect, and the time
span over which it is desired to have the agent released. Since
devices of different sizes and shapes are intended to provide
complete dosage regimen, there is no critical upper limit on the
amount of drug incorporated in the device. The lower limit will
depend on the activity of the drug and the time span of its release
from 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
for larger farm animals will vary with the size of the device,
while the amount of drug present in the delivery device when the
device is used for adult humans for a period of time of 4 to 6 days
to achieve local or systemic effect is for various drugs, such as
propantheline 120 to 300 mg in the device; for glutamic acid
hydrochloride an amount in the device of 100 to 500 mg; for
pargyline hydrochloride 50 to 100 mg; for erythrityl tetranitrate
50 to 100 mg; mannitol hexanitrate 75 to 100 mg; ephedrine sulfate
400 to 600 mg; nylidrin hydrochloride 12 to 48 mg; bethanechol
chloride 120 to 480 mg; phentolamine 100 to 400 mg; guanethidene
100 to 1,000 mg; methyl dopa 3 to 12 gms; atropine 100 mcg to 1,250
mcg; and the like.
The discharge outlet 20 suitable for the purpose of the invention
includes flow resistive means for continuous administration of the
drug in the body. The flow resistive elements are essentially self
actuated, that is, no external intervention is needed to initiate
the flow of drug. Numerous flow resistive means are commercially
available, such as porous plugs, microporous membranes,
capillaries, etched polymers, perforated polymers and the like. The
flow resistive means can be made from a variety of materials such
as poly(ethylene), nylon, teflon, epoxies, poly(methyl
methacrylate), metals, alloys, ceramics, sintered ceramics,
stainless steel capillaries of 0.1 to 1 cm in length with a
diameter of 0.1 to 20 microns, a stainless steel porous desk having
a thickness of 0.1 cm, a diameter of 0.1 cm, a pore size of 0.1
micron, a porosity of 20 percent and a tortuosity of 0.5, and the
like. The rate of flow through the resistive means is governed by
the Hagen-Poisseuille equation wherein Q = D.sup.4
.DELTA.P/128.mu.L, where Q equals flow in ml/sec, D equals diameter
in cm, .mu. equals viscosity in poise, .DELTA.P equals pressure in
dynes/cm.sup.2, and L equals length of the means. The use of this
equation allows the flow rate to be easily predicted and readily
adjusted by changing the length and diameter parameters of the flow
resistive means. Also, by altering the viscosity of the carrier the
flow rate can easily be varried without altering the specifications
of the flow resistive means. The viscosity of any carrier can
easily be ascertained by employing standard viscometers, such as
the Wells-Brookfield viscometer. The device of this invention can
effectively meter from 0.001 ml/hour to 0.5 ml/hour, smaller or
larger for various times such as 4 hours, 6 hours, a day, or
longer. The viscosity of the carrier medium used to convey the drug
can vary over a range of 1 to 10,000 centipoise at physiological
temperature for administering a drug to a host.
A typical example of a drug delivery device prepared according to
the spirit of the invention is comprised of a spherical collapsable
balloon approximately 4 cm in diameter and it is fabricated from
commercially available polyethylene terephthalate by a vacuum
forming and heat sealing process. Before the final heat seal is
made, 0.25 cm.sup.3 of isopentane is metered into the balloon.
Passing through the final heat seal is a water soluble polyurethane
erodible seal. A self powered delivery device consisting of a
peroxide cured natural latex elastic member with an uninflated
inner diameter of 0.8 mm and outer diameter of 1.6 mm and
uninflated length of 3 mm is secured to the collapsed polyethylene
terephthalate balloon by means of a cyanoacrylate adhesive. The
elastic member is closed at one end and is equipped wth a flow
control means consisting of a porous polyethylene plug 0.9 mm in
diameter and 1.0 mm long which has a porosity of 20 percent, an
average pore size of 1 micron, and a tortuosity factor of about 2;
for example, the effective length is about twice the actual length.
The elastomeric self powered delivery device is filled with 1
cm.sup.3 of drug formulation containing 16 mg of the diuretic,
bendroflumethiazide in 95 percent ethanol to which carboxymethyl
cellulose has been added to give a viscosity of 10,000 centipoise
at 37.degree. C. The inflated length of the elastomeric device is
12 mm. The porous flow control element is sealed with the water
soluble polymer, sodium polystyrene sulfonate. The collapsed
balloon is folded around the elastomeric delivery device and the
whole assembly is placed in a gelatin capsule. On ingestion the
capsule dissolves and the balloon inflates by virtue of
vaporization of the isopentane. The sodium polystyrene sulfonate
seal dissolves and the elastomeric device delivers 2 mg of
bendroflumethiazide per day for seven days at which time
dissolution of the water solube polyurethane seal is complete which
allows for collapse of the polyethylene terephthalate balloon. The
whole assembly is then eliminated from the gastrointestinal tract,
that is, the environment of use.
Among the advantages of the device of the invention are the ease of
construction by standard manufacturing techniques devices into
units of different sizes, especially of a miniaturized size, also
of shapes and forms that are suitable for delivering a drug
internally to an animal or human. Another important advantage of
the claimed delivery device is its ability to dispense at a
controlled rate a beneficial agent having a wide variety of
chemical and physical properties and over a wide range of release
rates. Still another important advantage of the invention resides
in the device's ability to effectively control the rate of release
of the drug from the device throughout the major portion of drug
administration in a substantial zero order release rate. A further
advantage of the device resides in the use of low cost
substantially vapor and fluid impermeable materials for the power
communicating element resulting in a unit suitable for disposal,
after comparatively short periods of use, for example, a day or
week, without undue economic hardship on the user, yet providing a
continuous and controlled administration of drug without any
external energy source. And, although the invention has been
described in detail, it will be understood that certain changes and
modifications can be made without departing from the spirit and
scope of the invention.
* * * * *