U.S. patent number 3,797,492 [Application Number 05/318,900] was granted by the patent office on 1974-03-19 for device for dispensing product with directional guidance member.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Virgil A. Place.
United States Patent |
3,797,492 |
Place |
March 19, 1974 |
DEVICE FOR DISPENSING PRODUCT WITH DIRECTIONAL GUIDANCE MEMBER
Abstract
A drug product dispensing device is comprised of a product
compartment having a metering means for dispensing its product in a
body cavity, and a propellant compartment communicating with the
product compartment for producing a propellant. In one embodiment,
a self actuated valve is positioned between the product and the
propellant compartment for directing the flow of propellant into
the product compartment. In another embodiment, a slidable piston
is positioned in the product compartment for receiving the flow of
propellant moving into the product compartment. A collapsed bag is
joined to the propellant compartment with the bag capable of being
inflated by a propellant from the propellant compartment to
maintain the device in a product receptive area. The device is
optionally housed in a bioerodible container and released therefrom
prior to its dispensing a product. In both embodiments of the
device, product is moved through the metering means by propellant
either moving through the valves or against the piston to urge
product through the means.
Inventors: |
Place; Virgil A. (Palo Alto,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
23240038 |
Appl.
No.: |
05/318,900 |
Filed: |
December 27, 1972 |
Current U.S.
Class: |
604/890.1;
206/522; 424/453 |
Current CPC
Class: |
A61K
9/0004 (20130101); A61M 37/00 (20130101); A61M
31/002 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 31/00 (20060101); A61M
37/00 (20060101); A61m 005/00 () |
Field of
Search: |
;128/2R,260,214F,1R,213
;222/386.5 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Medbery; Aldrich F.
Claims
I claim:
1. A drug type product delivery device for the continuous
administration of a product, said device comprising,
a. a wall surrounding an internal space, the space housing,
b. a product compartment which serves as a reservoir for containing
a beneficial product with the product compartment adjacent to,
c. a propellant compartment which serves as a means for containing
an agent for producing a gas having a vapor pressure above one
atmosphere at the temperature of product administration,
d. a valve between the compartments for directing the flow of a gas
from the propellant compartment to the product compartment,
e. a discharge metering means communicating with the product
chamber and the exterior of the device for metering a product at a
controlled and continuous rate from the product chamber,
f. a hollow deformable member comprised of a flexible distendable
material joined to the propellant compartment,
g. the hollow deformable member freely movable from a collapsed
position to an expanded position and movable from an expanded
position to a collapsed position after a period of time,
h. and wherein the device when positioned in the environment of
use, the deformable member is moved from a collapsed to an expanded
position by gas produced in the propellant compartment that moves
into the deformable member and on release of the gas therefrom it
subsequently returns to a collapsed position and while in the
environment of use and when charged with product, said product is
metered through the discharge means on movement of gas through the
valve into the product compartment to continuously move a
therapeutically effective amount of product from the product
delivery device.
2. A product delivery device for the continuous administration of a
product according to claim 1 wherein the hollow deformable member
is provided with a bioerodible plug that on bioerosion vents the
interior of the member to its exterior.
3. A product delivery device for the continuous administration of a
product according to claim 1 wherein the hollow deformable member
is formed of an elastic material permeable to an inflating gas that
slowly let the gas diffuse through the material to move the member
from an expanded to collapsed position.
4. A product delivery device for the continuous administration of a
product according to claim 1 wherein drug is metered through the
discharge means in response to gas filling the product compartment
to increase its volume while reducing the volume of drug in the
product compartment.
5. A product delivery device for the continuous and controlled
administration of a product according to Claim 1 wherein the device
is contained in a bioerodible container.
6. A product delivery device for the continuous and controlled
administration of a product according to claim 1 wherein a valve is
positioned between the propellant compartment and the hollow
deformable member.
7. A drug type delivery device for the continuous and controlled
administration of a product for producing a beneficial effect,
wherein the device comprises:
a. a wall surrounding an internal space and formed of a material
substantially impermeable to product, the space containing
b. a reservoir compartment for containing a beneficial product,
and
c. a propellant compartment as a means for containing a chemical
agent for producing a gas having a vapor pressure in excess of one
atmosphere, at the temperature of product administration from the
device,
d. a piston slidably positioned between the reservoir compartment
and the propellant compartment, the piston movable in response to
gas produced in the propellant compartment,
e. a metering means communicating with the reservoir and the
exterior of the device for metering an effective amount of product
at a controlled rate from the reservoir,
f. a hollow deformable member comprised of a distendable material
joined to the propellant compartment,
g. the hollow deformable member movable from a collapsed to an
expanded position and returnable to a collapsed position after a
period of time,
h. a passageway communicating with the propellant compartment and
the deformable member,
i. and wherein the device when positioned in the environment of use
and when charged with product, the deformable member is inflated by
gas flowing from the propellant compartment into the member, and
product is urged through the metering means by the movement of the
piston into the product compartment in response to gas produced in
the propellant compartment to progressively decrease the volume of
the reservoir as product is administered from the device.
8. A product delivery device for the continuous administration of a
product according to claim 7 wherein the hollow deformable member
is provided with a bioerodible plug that is capable of bioerosion
in the environment of use to vent the interior of the member to its
exterior.
9. A product delivery device for the continuous administration of a
product according to claim 7 wherein the hollow deformable member
is formed of an elastic material permeable to an inflating gas and
slowly lets the gas diffuse through the material to move an
expanded member to a collapsed member.
10. A product delivery device for the continuous administration of
a product according to claim 7 wherein the product is a beneficial
drug that can produce a local or systemic effect.
11. A product delivery device for the continuous administration of
a product according to claim 7 wherein the device is contained in a
bioerodible container formed of a material that can bioerode at a
physiological temperature in a physiological environment.
12. A product delivery device for the continuous and controlled
administration of a product according to claim 7 wherein a
unidirectional valve is positioned between the propellant
compartment and the deformable member.
13. A product delivery device for the continuous and controlled
administration of a product according to claim 1 wherein the
product delivery device is made of a material that can bioerode at
biological temperatures over a period of time.
Description
BACKGROUND OF THE INVENTION
This invention relates to a novel and useful drug type product
delivery device for delivering a product at a controlled rate for a
prolonged period of time to produce a local or systemic
physiological or pharmacological effect. The device is comprised of
a wall surrounding an internal space with the space consisting of a
product compartment for containing a product and a propellant
compartment for storing a propellant or propellant producing agent.
The product compartment has a discharge flow control means that
communicates with the compartment for releasing the product to the
environment. In one embodiment of the invention, a self actuated
valve is positioned between the product and propellant compartments
for guiding propellant into the product compartment to move the
product through the flow control means. In another embodiment of
the invention the product and propellant compartment are separated
by a slidable piston that moves in response to propellant
generating in the propellant compartment to move the product
through the flow control means. A collapsed bag is fixed to the
propellant compartment with the bag expandable to an inflated state
by propellant flowing therein prior to the delivery of product from
the device, for keeping the device in a product receptive area
during delivery of the product. The device leaves the product
receptive area after delivery of the product by the bag returning
to a collapsed position by release of its propellant or by
biodegradation of a part of the whole device. The device is
optionally initially internally housed in a container and released
therefrom in the environment of use prior to its delivery of the
product.
A long felt need exists, especially in the medical and the
veterinary arts for a product dispensing device that can
effectively administer a product, for example, a drug, vitamin,
nutrient, antibiotic or the like to a drug receptor environment,
such as the stomach, reliably at a controlled and continuous rate
over a prolonged period of time. In many instances, such a rate of
product release from a product dispensing device should have a
preferred zero order time dependence, that is, the rate of drug
release is independent of time. In some instances it is also
desirable to have a delivery system with a programmed delivery
rate.
Different approaches have been tried by the pharmaceutical and
manufacturing arts to obtain such a product dispensing device that
can achieve these goals, but the results obtained have not led to
their acceptance by the medical and veterinary arts for the
management of health and disease. One approach, which has received
attention comprises administering a product to the environment of
use, such as a drug to the gastrointestinal tract, by first mixing
the drug with a pharmaceutical carrier material to give a product
that is gradually broken down by the body fluids such as
gastrointestinal fluids with the drug released as the carrier
disintegrates. Numerous drug carriers have been used for this
purpose including waves, oils, fats, soluble polymers and the like.
While some of these products have provided a slow release of drug,
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 product decreases,
concomitantly exposing increasingly smaller quantities of the
carrier and the drug to the surrounding fluids that inherently
results in a decline in the release rate over time. Another
approach for dispensing a drug to the environment of use,
particularly to the gastrointestinal tract, has been to enclose the
drug within a single, dispensing capsule having a permeable wall
through which the drug can pass by diffusion. An approach of this
kind is set forth in United States Pat. No. 3,279,996. These
dispensing devices too have inherent difficulties. For example, one
difficulty associated with the prior art is that different devices
having different drug release rates cannot readily be made bcause
the only variable parameter for the device is the thickness of the
material used to make the device. Additionally, the structure of
these prior art devices generally is based merely on the high
permeability of a single material as the diffusion control for some
important drug molecules without a consideration of release rate
controlling properties over a large number of hours which can
defeat the primary object of an acceptable drug dispensing
device.
Another method widely used to obtain a necessary and beneficial
product or drug level in a drug receptor over a number of hours
comprises administering a number of pills or tablets at regular
time intervals to achieve a dose frequency response relationship.
However, this method has certain inherent limitations that tend to
defeat its purpose. For example, the pills often are rapidly
cleared, for example, from the gastrointestinal tract before they
are fully utilized, or an excessive amount of fluid present in the
tract can unfavorably affect the drug reaching the desired drug
level. Also, the administration of a number of pills at set times
requires attention and frequently a particular administration is
inadvertently overlooked which diminishes the results of this
method. 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 a controlled rate of
product release over a prolonged period is through the use of
coated slow release bead technique. In this technique, the dose of
drug is divided into a group of pellets about 1 to 2 milli-meters
in diameter, and each group coated with a material resistant to
gastric and/or intestinal fluids. 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 above, has those certain, common
inherent limitations that tend to diminish its purpose. Therefore,
these types of coated slow release beads 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 type product dispensing device for the delivery of locally
active or systemically active products that produce a physiologic
or pharmacologic effect, which device essentially overcomes the
aforesaid disadvantages associated with the prior art dispensing
devices.
Still another important object of the invention is to provide a
bioerodible product dispensing device for releasing a product at a
controlled and continuous rate for a prolonged period of time.
Still yet another object of this invention is to provide a reliable
and easily used product delivery device for administering a product
such as a drug to a drug receptor area and remain in the area
during the administration of drug from the device.
Yet still another object of the present invention is to make
available to the art a product dispensing device for continuously
administering controlled quantities of drug to the environment of
use, such as the stomach and the gastrointestinal tract to produce
a beneficial effect and then pass from the environment after a
predetermined amount of drug is released in the environment.
A further object of this invention is to provide a device that
provides a complete dosage regimen for administering a drug to a
drug receptor site 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 oral administration for continuously
administering drug in the gastro-intestinal tract and remaining
therein until the desired dosage regimen is essentially complete
before the device is eliminated from the gastrointestinal tract
either by passing through the tract or by bioeroding, then passing
through the tract.
Yet still a further object of the invention is to provide an
administerable drug delivery device that is self-contained and
self-powered and will remain in the environment of use, such as the
uterus, vagina or the stomach for an extended time while
administering drug from the device through a drug self actuated
flow control outlet in response to energy produced in the drug
delivery device.
In attaining the objects, features and advantages of this
invention, a novel and useful product dispensing device is provided
for the controlled and the continuous dispensing of a product in
the environment of use by using a propellant as the driving force
for dispensing the product from the device. The device is comprised
of a product chamber and a propellant chamber separated by either a
self actuated single directional valve or a piston. The product
chamber is a reservoir for containing a drug, a vitamin, a nutrient
or other beneficial product or useful agent, and it is suitably
equipped with a discharge passage for conveying product at a
metered rate from the chamber to the environment of use. The
propellant chamber is positioned next to the product chamber and it
contains a fluid with a vapor pressure in excess of one atmosphere
at the temperature of use. Product is discharged from the device by
the action of vapor pressures arising in the propellant chamber
that pass through the valve into the product chamber, or against
the piston, to exert a constant and positive pressure against the
product to urge the product through the metering passage. A
collapsed hollow balloon is suitably joined to the propellant
chamber, and a passageway communicates between the chambers. The
balloon is inflated by vapors from the propellant chamber that move
into and fill the balloon for keeping the device in the environment
of use during the period of product administration. At the end of
this period, the balloon collapses as vapors leave the balloon to
permit the device's passage from the environment. In another
embodiment the device's length of stay in the environment can be
controlled by fabricating the entire device of material that
biodegrades after an extended period of time to let the device pass
from the environment of use. The product dispensing device
optionally is internally housed in a container and it is released
therefrom prior to its product dispension operation in 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.
BREIF 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 plan side view of drug delivery device of the invention
initially optionally housed in a container.
FIG. 2 is an enlarged, detailed perspective side view illustrating
a drug delivery device of the invention housed in a container with
a section of the container removed.
FIG. 3 is an enlarged, detailed isometric view illustrating another
drug delivery device confined in a container with a section removed
illustrating a directional member.
FIG. 4 is an enlarged, detailed view of another device of the
invention showing a device having a piston member.
FIG. 5 is a view diagrammatically illustrating a drug delivery
device descending through a body passage into an environment of
use.
FIG. 6 is a side view diagrammatically illustrating a drug delivery
device in use in the environment of use, such as 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 INVENTION
Turning now to the drawings in detail, which are examples of
various drug delivery devices of the invention, and which examples
are not to be construed as limiting, one general example of a novel
drug delivery device is indicated in FIG. 1 by numeral 10. Drug
delivery device 10 is illustrated in side perspective view and it
is comprised of a bioerodible container 12 housing a drug delivery
device 14 affixed to a collapsed hollow balloon 16. In FIG. 1 drug
delivery device 10 is depicted in miniature to exemplify one
general operative embodiment of the invention suitable for passing
through a body opening or positioning in a body drug receptor area.
An enlarged detailed description of FIG. 1 is set forth in FIG.
2.
Referring to FIG. 2, a drug delivery device 10 is generally seen in
a bioerodible container 12 with a section removed to illustrate the
operative drug delivery device 14 housed in the container 12.
Container 12 is advantageously formed of two parts each made of
bioerodible materials and designed to telescope into each other for
easily housing device 14 in container 12. Device 14 in another
embodiment can optionally be housed in a container of single unit
construction also made of a bioerodible material. Container 12 in
one embodiment is made from gelatin or the like because it can move
quickly and easily through body passages such as the alimentary
canal and also because it can quickly disintegrate when it reaches
a drug receptor area such as the stomach to free device 14.
Containers made of other non-toxic bioerodible materials can also
be used for releasing the device in animals, humans, avians and the
like. Drug delivery device 14 is comprised of a wall 15 surrounding
an internal space divided into a product chamber 11 and a
propellant chamber 17. Propellant chamber 17 is suitably joined to
a collapsed balloon 16 that communicates through a passageway 19
with propellant chamber 17. Product chamber 11 is separated from
propellant chamber 17 by a valve 20 for directing the flow of a
propellant from chamber 17 into product chamber 11 and also to
prevent a product in chamber 11 from moving into propellant chamber
17.
Drug delivery device 14 as seen in FIG. 2 is made of materials that
are essentially impermeable to fluids and gases in the environment
of use such as water, gastric juice, carbon dioxide and the like.
Device 14 is made by conventional manufacturing techniques, such as
casting, lamination and interface sealing, stamping accompanied
with adhesive or thermal joining of parts into a composite device
and the like. Device 14 can be made of naturally occurring or
synthetic materials of the kinds commerically available to the art.
Device 14 can be made of rigid, semi-rigid or flexible materials
and they can be non-biodegradable or biodegradable. In one
embodiment a part of device 14 can be made of bioerodible material
that bioerodes in the environment of use to facilitate removal from
the environment. In another embodiment, all of device 14 including
wall 15 can be made of bioerodible material that bioerodes in the
environment of use, such as the stomach, to facilitate the passage
of the device from the stomach through the gastrointestinal
tract.
Collapsed balloon 16 in sealed relation with drug delivery device
14 is in one embodiment suitably joined to device 14 by sealing
balloon 16 with an adhesive, such as an epoxy,
.alpha.-cyanoacrylic, polyvinyl chloride adhesives or the like to
device 14, or balloon 14 can be heat sealed or cast on device 14.
in another embodiment it can be fitted over a communicating conduit
12a integrally formed on one end of device 14. Collapsable balloon
16 is made of naturally occurring or synthetic flexible, polymeric
materials that lend themselves to changes in shape and size, that
is, changes in volume from collapsed to inflated and returnable to
collapsed position after a prolonged period of time. Balloon or
member 16 can in one embodiment be made of a material that is
biodegradable in the environment of use, or in another embodiment
member 16 can be made of a material that is permeable to a gas at a
slow rate, or member 16 can be equipped with an erosion plug, not
shown in FIG. 2, that erodes after a predetermined time to release
gas from an inflated balloon thereby deflating it to a collapsed
state to let it pass from the environment of use, such as the
stomach. In other embodiments, member 16 can have other designs and
shapes such as flat bags, tubes, foldable bags and the like, which
can be used for the purpose of the invention.
Drug delivery device 14 consists of a product chamber 16 that
contains a product 22 such as a drug or the like and a propellant
chamber 17 that contains a means for producing a gas, such as a gas
stored in liquified form at ambient temperatures but a gas at
physiological temperature. The two chambers communicate through a
valve 20 that is a conventional self actuated valve, or a one way
flap valve or the like. Valve 20 is a unidirectional valve that
suitably guides the flow of propellant into the product chamber,
and it is suitably positioned between product chamber 16 and
propellant chamber 17. Valve 20 is positioned by adhesively or
thermally joining it to wall 15 or a wall 15a that separates the
chambers prior to the closure of device 14. Valve 20 is made of
commerically available plastics, metals, laminates of plastics and
metals or the like. In FIG. 2, valve 20 is a one way flap valve,
and it is sealed on the product side of the device. Valve 20 acts
to tightly close and substantially prevent the backflow of gas that
passed into product chamber 11 back into chamber 17. It also serves
to prevent the movement of product 22 in product chamber 11 into
propellant chamber 17; and, it further serves to guide the flow of
gas from the propellant chamber 17 into the product chamber 11
where the gas functions as the pressure driving force for moving
product 22 from chamber 11 through a metering outlet 21 for
releasing product 22 to the environment of use. Metering outlet 21
is initially closed with an erodible plug, not shown in FIG. 2,
that quickly erodes after device 14 is freed from container 12 upon
its entry into the environment of use, such as the stomach.
In operation, in one example of the invention that is not to be
construed as limiting the scope of the invention, device 10 is
orally administered through the esophagus into the stomach where
drug delivery device 14 is freed from container 12. Next, collapsed
balloon 16 inflates in the stomach to keep drug delivery device 14
therein during the period of drug administration. Drug
administration is affected by the production of a gas in propellant
chamber 17 that inflates collapsed balloon 16 and also moves
through valve 20 into product chamber 11 to urge drug 22 through
discharge outlet 21 at a controlled and constant rate into the
external environment, the stomach. At the end of the drug
administration period, inflated balloon 16 collapses by erosion of
its plug, of the whole device biodegrades to permit passage of
device 14 from the stomach.
In FIG. 3, another embodiment of the invention is illustrated
comprised of an assembled drug delivery device 10 consisting of a
swallowable bioerodible container 12 made of two telescopically
associated non-toxic envelopes having an interior cavity housing a
drug delivery device 14. Container 12 has a size and shape for
swallowing and for passage by humans, farm animals such as cows and
steers, household pets such as dogs and sport animals to their
stomach by normal peristalsis. In the stomach container 12 is made
from gelatin, gelatin cocoa butter mixtures or the like, and it
quickly and easily disintegrates to release drug delivery device 14
for discharging a medicament 22, a mixture of medicaments, or a
beneficial agent such as a vitamin, nutrient or the like into the
stomach.
Device 14 of FIG. 3 is a self actuated, self powered vapor pressure
activated device and it is comprised of an outer wall 15
surrounding an internal space defining a product chamber 11 and a
propellant chamber 17. Wall 15, optionally called a housing or
shell, in this embodiment is made from a material essentially
impermeable to fluids and gases, preferably biodegradable and
digestable, and it has a deformable hollow member 16 fixed to one
end of said shell 15. Deformable bladder member 16 is optionally
integrally formed, cemented or sealed to shell 15 at a passageway
24 that connects with propellant chamber 17. A one way valve 20
allows gas to enter collapsed bag 16 and it also acts to
essentially prevent the flow back of gas into propellant chamber
17. The inflated size of deformable member 16 is controlled by
predetermined dimension that corresponds to the size of the
environment of use, or of the host and also to limit its expansion
to assure a flow of gas into product chamber 11. Deformable member
16, as shown in FIG. 3, is a collapsed bag folded or having a
plurality of staggered folds 18a and it is made from a flexible,
elastic material to allow it to freely expand and then return to a
collapsed state. Member 16 is manufactured with a bioerodible plug
23 that erodes to vent the gas or it is made of a material
permeable to gas to allow the gas to slowly diffuse therethrough
over a period of time to deflate member 16 to let it pass from the
environment of use, such as the stomach. Product chamber 11 is a
means for storage of drug 22, that is, a drug reservoir, and it
also functions as a chamber for communicating with propellant
chamber 17 through valve 20 for receiving gas for moving drug 22
through a flow control means 21 to the exterior of the device. Flow
control means 21 can be of different structures, such as a porous
inert plate, sintered ceramics, a calibrated aperture, a capillary,
a hollow stainless steel tube having an internal diameter
corresponding to 15 gauge to >30 gauge surgical needles, or the
like for conveying a drug 22 through shell 15 to the exterior of
the device. In another embodiment element 21 can be made of a
material that is essentially impermeable to a selected gas but
permeable as by diffusion to a selected drug. Element 21 can also
be of pores of minute diameter that gas cannot pass through under
normal presure, but readily let drug diffuse threrethrough. Valve
20 can also operate in cooperation with element 21 by valve 20
extending to the wall of the device to move drug into element 21.
The flow control means acts to release drug at a metered rate, for
example, according to the Hagen-Poiseuille equation, and at a
constant rate over a period of time, despite the decreasing volume
of drug 22 in chamber 11 during the discharge of the drug.
Propellant chamber 17 is a vapor pressure generating chamber and it
contains a gas stored in a chemical state, for example, a solid or
liquified form that produces a gas with a vapor pressure in excess
of one atmosphere at the temperature of use, that is, the
temperature of the stomach, to cause collapsed member 16 to inflate
to a predetermined size and shape by the movement of gas into it.
The dimension of inflated balloon 16 in the inflated state will of
course be different for different animals but it should be large
enough to retain the device, for example, in the selected drug
receptor area, such as the stomach. Generally, the dimensions of
the device are slightly larger than the diameter of the body cavity
or opening which dimensions are of recorded size in standard
textbooks. The device will be slightly larger than the pyloric
canal which is about 1 cm to 4 cm, usually 2 cm in humans, and the
device maintains these dimensions until completion of the
prescribed therapeutic regimen. Vapor pressures arising in
propellant chamber 17 also exert their pressure against drug 22 in
product chamber 11 to urge drug 22 through flow control means 21 to
the exterior of the device at a controlled rate for a prolonged
period of time. At the end of the pressurized therapeutic regimen,
bioerodible plug 23 erodes to vent balloon 16 into the stomach
causing it to collapse to a size smaller than the pyloric canal.
Device 14 then passes through the lower gastrointestinal tract and
out of the body. Alternatively, drug delivery device 14 can
bioerode or be digested by the action of gastric juices, enzymes
and the like into fragments that pass from the stomach.
FIG. 4 represents another novel and useful drug delivery device of
the invention. In FIG. 4 there is seen a device 14 structurally
similar to device 14 of FIG. 3 with the device of FIG. 4
illustrated free of the optional container 12. Device 14 of FIG. 4
is manufactured with a piston 30 positioned between propellant
chamber 17 and drug reservoir chamber 11. Piston 30 is made from a
material that is essentially impermeable to gas and drug and one of
its functions is to keep propellant in the propellant chamber for
propellant to exert energy against it to push it against drug to
urge drug from the device. Piston 14 is slidably mounted and it can
be a sliding barrier, a disk or sliding seal so constructed as to
movably provide and maintain a gas drug barrier between the
compartments. Piston 30 is substantially frictionally disposed and
it is free to move within the device by sliding while maintaining
an impenetrable barrier therebetween. The size of the balloon to
the device can vary depending on the mass of the product charge,
and generally, the size may be alike, or the size of the balloon
may be the larger size. The desired size can easily be determined
by test floating various devices in known liquids and then
selecting the appropriate size and shape for the particular drug
regimen.
FIG. 5 and FIG. 6 diagrammatically illustrate the use of the drug
delivery device 14 of the invention. In FIG. 5 there is seen a
device being administered into an environment of use, such as, the
outline of a human 39 with a container 12 moving through the
esophagus 40 and on into a drug receptor area, the stomach 41. In
FIG. 5 the device 14 is seen in operation in the drug receptor
site, the stomach 41 administering a drug at a controlled and
continuous rate for a prolonged period of time to the stomach.
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 animal, human or avian 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 such as oral administration into
the stomach and the size of the deformable hollow member 16 of the
device in the inflated state will be slightly larger than the
diameter of the body passageway or cavity to maintain the device in
a drug receptor area. The size of various body cavities are
recorded in standard medical references, and for the purpose of
illustrating the spirit of the invention the size of the device
needed in the inflated state to keep the device in a human stomach
will be slightly larger than the size of the pyloric canal. For
example, for humans the size of the inflated member will be in the
range of 3 cm in diameter to about 10 cm in length, usually about 2
cm by 4 cm. Of course, the devices of various sizes such as 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 manner of the invention.
Wall 15 of the device defining chambers 11 and 17 and housing the
drug and gas in liquified form can be flexible, semi-flexible or
rigid or modifications thereof. Wall 15 is initially essentially
impermeable to the gas in liquified form and to the drug, and it
can be made from a wide variety of materials commercially available
such as thin aluminum, teflon, poly(ethylene), laminates of
poly(propylene), poly(methylmethacrylate); poly(formaldehyde),
nylon, laminates of polystyrene, thin metal foils such as thin
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 whole range,
usually from 0.2 mils to 200 mils, generally in the range of 1 mil
to 10 mils and the like.
Collapsable bag 16 attached to housing 15 at propellant chamber 17
is made from flexible, polymeric materials. In one embodiment the
material can be substantially impermeable to gases. In the
embodiment wherein the material is impermeable to gas, an erodible
plug is used to deflate an inflated member, and it has a size and
shape corresponding to the volume of gas employed and to the
animal's stomach. In another embodiment the material can be
permeable to gas to let gas slowly diffuse through the material to
collapse an inflated balloon to let the device pass from the
environment of use. The bag 16 is made from commercially available
naturally occurring or synthetic materials and it is about 0.2 mils
to 20 mils thick, or more, usually 0.4 to 2.0 mils and the like.
Bag 16 can be made of a single material, a combination of materials
in laminated form such as elastomric materials bonded on foils and
the like. Illustrative materials include commercially available
materials such as natural rubber, silicones, poly(urethanes),
poly(acrylonitriles), poly(ethylene), poly(propylene),
poly(vinylidene chloride), poly(vinylidene fluoride), acrylic
elastomers, ethylene propylene terpolymers, laminates such as
poly(ethylene)-poly(vinylidene chloride), nylon- poly(vinylidene
chloride), nylon-poly(vinylidene chloride),
poly(ethylene)-poly(vinylidene)-poly(ethylene),
poly(ethylene)-poly(vinyl alcohol)-poly(vinylidene)chloride, other
laminates such as extra thin metal foils such as tin foil coated on
a polymer, aluminum foil coated on a polymer, plastic coated foils
such as poly(ethylene) on tin foil, poly(vinylidene chloride) on
stainless steel foil and the like.
Exemplary materials suitable for exerting a vapor pressure to
inflate a collapsed bag and to act as the driving power to enable
the device to function as a constant rate vapor pressure powered
device are inorganic and organic compounds whose vapor is in
equilibrium with its liquid phase to exert a constant pressure at a
given temperature regardless of volume. Representative of compounds
are those that are liquids at ambient temperatures, usually
20.degree.C 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. Exemplary materials
useful for exerting a vapor pressure and also for inflating
deformable hollow member 18 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, isopentane BP
27.9.degree.C, tetramethyl silane BP 26.5.degree.C,
perfluoropentane isomers BP 31.0.degree.C, n-pentane 36.0.degree.C,
diethenyl ether 28.degree.C, mixtures thereof and the like.
Usually, the amount of gas stored in the liquified phase in the
propellant chamber 18 will be about 0.2 cc to 5.0 cc or higher, and
the volume of the vapor phase will be from 40 percent to 100
percent of the inflated member or the volume of the chamber.
Materials suitable for use as bioerodible plug 23 or for forming
bioerodibles when the device is erodible in the environment of use,
are those materials that bioerode in the environment of use, such
as the stomach, at a predetermined given time or over a period of
time. The materials are those that erode by known biological
processes, such as chemical degradation, acidic hydrolysis,
enzymatic action, oxidation, 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 body
juice, such as gastric juice 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 making plug 23 and wall 15 comprise
hydrophilic polymers of uncross-linked hydroxylalkyl acrylates and
methacrylates, hydrolytically biodegradable poly(anhydride)polymers
as described in United States Pat. Nos. 2,073,799; 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; United States Pat. 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 hydrocolloides of animal and
plant origins such as modified collagen, elastin, keratin, fibrin,
karaya, algin, pectin, carrageenin, chitin, heparin, locust bean
gum and the like. Also, synthetic polymers such as poly(ethylene
oxide), poly(vinylpyrrolidone), poly(ethyleneimine), poly(acrylic
acid) copolymers of acrylamide and methacrylamide up to 40 percent
by weight of N-methylene bisacrylamide or N,N-dimethylol urea,
synthetic poly amino acid polymers, and the like.
The active product or agent that can be released by the device are
those that give a beneficial effect to an animal, human, and the
like including the environment. The term product and agent are
considered equivalents for the purpose of this invention and it
includes active drugs that can be administered with the delivery
device of the invention. These drugs are administered 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 exemblified 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 urethanes, 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
chloridiazepoxide, and the like; anticonvulsants such as primidone,
diphenylhydantoin, ethotoin, pehneturide, ethosuximide and the
like; muscle relaxants and anti-parkinson 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-ulcer agents such as atropine, scopolamine, methscopolamine,
oxyphenonium, papaverine, prostaglandins such as PGE.sub.1,
PGE.sub.2, PGF.sub.2.alpha., PGA and the like; anti-microbials such
as penicillin, tetracycline, oxytetracycline, chlorotetracycline,
chloramphenicol, sulfonamides and the like; anti-malarials such as
4-aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal
agents such as prednisolone, cortisone, cortisol and triamcinolone;
androgenic steroids, for example, methyltestosterone,
fluoximesterone and the like; estrogenic steroids, for example,
17.beta.-estradiol and ethinyl estradiol; progestational steroids,
for example 17.alpha.- hydroxyprogesterone acetate,
19-nor-progesterone, norethindrone and the like; sympathomimetic
drugs such as epinephrine, amphetamine, ephedrine, norepinephrine
and the like; cardiovascular drugs, for example, procainamide, amyl
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-thioquanine, procarbazine and the like;
hypoglycemic 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 and the like 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 activites
and the like. Other agents that can be released by the device
include without limitation insecticides, bactericides, germicides,
animal feeds, cosmetics, fish pond foods, perfumes and like agents
that can be charged into the reservoir and metered at a controlled
rate from the device to the environment of use.
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
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, for example, 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
of drug present in the delivery device for large farm animals will
vary with the size of the animal, while the amount in the device
when it is used for adult humans for a period of time of 4 hours to
6 days to achieve local or system 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 50 to 300 mg; for
pargyline hydrochloride 50 to 100 mg; for erythrityl tetranitrate
50 to 100 mg; mannitol hexanitrate 75 to 100 mg; ephedrine sulfate
40 to 500 mg; nylidrin hydrochloride 12 to 48 mg; bethanechol
chloride 120 to 480 mg; phentolamine 100 to 400 mg; guanethidene
100 to 1000 mg; methyl dopa 3 to 12 gms; atropine 100 mcg to 1250
mcg; and the like.
The discharge outlets 21 suitable for the purpose of the invention
include flow resistive means for the continuous administration of
the drug in the environment of use, such as in the body, is
comprised of flow resistive elements that 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, expoxies, 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 disk 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 = .pi.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 varied 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.sup.6 centipoise at physiological
temperature for administering a drug to a host.
A typical example of a novel and useful product delivery device for
the administration of drug is prepared by first manufacturing a
device comprised of a spherical collapsable balloon approximately 4
cm in diameter fabricated from commercially available poly(ethylene
terephthlate) by standard vacuum forming and heat sealing
processes. Passing through one place of the balloon at the point of
a final heat seal is a water solubel poly(urethane) erodible seal.
Next, a housing formed of polymeric material of tubular shape is
divided into two compartments with one compartment adhesively
sealed by means of a cyanoacrylate adhesive to the collapsed
balloon. The two compartments are separated by a sliding pistion,
and the compartment communicating with the balloon is charged with
1.25 cm.sup.3 of isopentane. The compartment distant from the
balloon is charged with drug and it is closed and equipped with a
flow control means consisting of a porous poly(ethylene) 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. The device is filled with 1 cm.sup.3 of drug formulation
containing 16 mg of the commercially available 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 porous flow control element is sealed with the
water soluble commercially available polymer, sodium poly(styrene
sulfonate). The collapsed balloon is folded around the delivery
device and the whale assembly is placed in a two piece gelatin
capsule. On ingestion, the capsule freely dissolves and the balloon
self inflates by virtue of vaporization of the isopentane at the
physiologic temperature. The sodium poly(styrene sulfonate) seal is
dissolved and the device delivers 2 mg of bendroflumethiazide per
day for seven days. At the end of the continuous, controlled and
prolonged drug delivery period, the dissolution of the water
soluble poly(urethane) seal is completed which allows for collapse
of the poly(ethylene 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 technique 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 materials for the power, and
for the device to give a unit suitable for disposal, after
comparatively short periods of use, for example, eight hours, 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.
* * * * *