U.S. patent number 3,786,813 [Application Number 05/318,798] was granted by the patent office on 1974-01-22 for drug delivery device with self actuated mechanism for retaining device in selected area.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Alan S. Michaels.
United States Patent |
3,786,813 |
Michaels |
January 22, 1974 |
DRUG DELIVERY DEVICE WITH SELF ACTUATED MECHANISM FOR RETAINING
DEVICE IN SELECTED AREA
Abstract
A device is disclosed for administering a drug at a controlled
rate for a prolonged period of time to a drug receptor area to
produce a nonsystemic or systemic physiological or pharmacological
effect. The device is comprised of a hollow deformable member that
is movable from a collapsed to an expanded position and returnable
to a collapsed position after an extended period of time. A housing
is attached to the deformable member and it is internally divided
into a first and second chamber with the chambers separated by an
impermeable, pressure responsive movable bladder. The first chamber
contains a drug and it has a discharge port for releasing the drug
to the exterior of the device. The second chamber contains a means
for generating pressure that is applied against the bladder. Drug
is released from the first chamber through the discharge port by
the bladder moving in response to pressure generated in the second
chamber to increase its volume while simultaneously reducing the
volume of the first chamber to release the drug at a controlled
rate over a prolonged period of time. The device is initially
optionally contained in a bioerodible container that erodes in the
area to release the container.
Inventors: |
Michaels; Alan S. (Atherton,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
23239608 |
Appl.
No.: |
05/318,798 |
Filed: |
December 27, 1972 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
300673 |
Oct 25, 1972 |
|
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Current U.S.
Class: |
604/892.1;
424/424; 206/522; 424/426 |
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
;119/1 |
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. 300,673
filed on Oct. 25, 1972, now abandoned.
Claims
What is claimed is:
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 an outer
housing defining an internal space including a first chamber and a
second chamber, the first chamber containing drug and having in
communication therewith discharge means for releasing the drug to
the environment of use, the second chamber containing means for
generating a pressure, with means for separating the chambers and
transmitting the pressure generated in the second chamber to the
drug in the first chamber being interposed between the two
chambers, the pressure thereby causing a therapeutically effective
amount of drug to be released from the first chamber 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 2 wherein the hollow
expandable member communicates with the second chamber, the means
for generating a pressure in the second chamber comprises a means
for producing a gas at physiological temperature, the gas expanding
the member and also producing a pressure which is transmitted to
the drug in the first chamber.
7. A drug delivery device for the controlled and continuous
administration of drug according to claim 1 wherein the means for
generating a pressure comprises means for generating an osmotic
pressure.
8. 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 in an environment of use, such as a biological drug receptor
site, at a controlled rate for a prolonged period of time to
produce a local or systemic physiological or pharmacological
effect. The drug delivery device optionally is comprised of a
bioerodible container housing a drug delivery device. The drug
delivery device is secured to a deformable hollow member, which
member is expandable from a collapsed state to an expanded state
and collapsable to a collapsed state after an extended period of
time. The device is comprised of a shell having a first and second
chamber with the chambers separated by an impermeable, pressure
responsive movable bladder. The first chamber contains a drug and a
discharge control means for releasing the drug from the chamber to
the exterior of the device. The second chamber contains a pressure
generating source such as a gas in liquified form and having a
vapor pressure greater than one atmosphere at the temperature of
use, or it can be an osmotically effective solute phase which has
an osmotic gradient in a fluid environment of use to allow a volume
increase that generates pressure against the bladder. Drug is
released from the first chamber through the discharge outlet by the
bladder moving in response to pressure generated in the second
chamber to increase its volume while simultaneously reducing the
volume of the first chamber to release drug at a controlled rate
over a prolonged period of time.
A critical need exists for a drug delivery device that can
effectively administer a drug to a preselected environment, such as
a body cavity or opening, for example the stomach, reliably at a
controlled rate over a prolonged period of time. In many instances,
such a rate of release of drug from a drug delivery device to the
environment should have a preferred zero order time dependence,
that is, the rate of drug release is independent of time. Different
approaches have been tried by the prior art to obtain such a drug
delivery device. However, the results obtained for these approaches
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 for administering a drug to the gastrointestinal
tract, is to mix a drug with a carrier material that is gradually
broken down by the gastrointestinal fliuds with the drug released
as the carrier disintegrates. Numerous drug carriers have been used
in such devices including waxes, oils, fats, soluble polymers, and
the like. While some of these devices have provided for a delayed
release of drug, the desired constant release rate for a prolonged
period has not been achieved. One reason for this is as the carrier
disintegrates the surface area of the dosage unit decreases,
concomitantly exposing increasingly smaller quantities of the
carrier to the surrounding fluids. This inherently results in a
decline in the release rate over time.
Another approach for administering a drug to a body cavity, for
example the gastrointestinal tract, has been to enclose the drug
within a single capsule having a permeable wall through which the
drug can pass, for example, by diffusion. An approach of this kind
is set forth in U.S. Pat. No. 3,279,996. These 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 because the only variable
parameter for the device is the thickness of the material used to
make the device. Additionally, these prior art devices 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 defeat the
primary object of an acceptable drug delivery device.
Another method widely used to obtain a necessary and beneficial
drug level in a drug recipient over a large number of hours
comprises orally 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 may be
rapidly cleared by muscular movement from the environment of use,
for example the gastrointestinal tract, before they are fully
utilized, or there can be an excessive amount of fluid present in
the environment that can unfavorably dilute the concentration of
the drug and prevent the reaching of 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
appearances of a series of peaks and valleys; and, often these
valleys may fall below the drug concentration needed to achieve the
desired effects.
One other approach used by the art to administer drugs to a drug
receptor and obtain controlled release over a prolonged period is
the coated slow release bead 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 is coated with a material
resistant to fluids present in the environment of use, such as
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 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 delivery device for the administration of locally active or
systemically active drugs to produce a physiologic or pharmacologic
effect which device essentially overcomes the aforesaid
disadvantages associated with the prior art modes of administration
devices.
Still another important object of the invention is to provide a
drug delivery for releasing drug at a controlled rate for a
prolonged period of time.
Still yet another object of this invention is to provide a reliable
and easily use drug delivery device for continuously administering
controlled quantities of drug to the environment of use, such as
body cavities and body opening.
A further object of this invention is to provide a complete dosage
regimen for administering a drug to a drug receptor site such as
the stomach, vagina or uterus for a particular time period, the use
of which requires intervention only for initiation of the regimen,
and in some instances removal of the device.
Still a further object of the invention is to provide a drug
delivery device suitable for continuously administering drug to a
body cavity such as the gastro-intestinal tract and remaining
therein until the desired dosage regimen is essentially complete
before the device is eliminated from the cavity, that is from the
gastro-intestinal tract.
Yet still a further object of the invention is to provide a drug
delivery device that is self-contained and self-powered and will
remain in a preselected area, such as in the stomach for an
extended time while administering drug from the device through a
drug flow control outlet in response to pressure produced in the
drug delivery device.
In attaining the objects, features and advantages of this
invention, a device is provided for the continuous dispensing of a
drug in the environment of use, such as the stomach, by using a
pressure differential as the driving force for dispensing the drug
from the device. The device is comprised of a first chamber and
second chamber with the chambers separated by a vapor and fluid
substantially impermeable, flexible bladder. The first chamber
contains at least one drug and a discharge passage for releasing
drug to the exterior of the device. The second chamber is in one
embodiment essentially impermeable to a fluid or vapor and it
contains a fluid with a vapor pressure in excess of one atmosphere
at the temperature of use. In another embodiment the second chamber
is comprised of a wall having controlled permeability to an
external fluid, such as water, and it contains a solution of an
osmotically effective solute which exhibits an osmotic pressure
gradient against the fluid. Drug is discharged from the device by
the bladder urging and exerting a pressure against the drug as the
bladder responds to pressure applied against it. The pressure
arises in the second chamber by either the vapor pressure in excess
of one atmosphere or by fluid diffusing into the chamber to
increase its volume and concurrently exert a force toward the
bladder to urge it to eject drug from the device. The device is
bonded to a deformable, hollow member that can either expand or
collapse. Optionally, the device is housed in a bioerodible
container that bioerodes to reduce the device 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.
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, top view of a drug delivery device of the
invention optionally housed in a bioerodible container.
FIG. 2 is an enlarged perspective view illustrating a drug delivery
device in a container with a section of the container removed, to
show a device in detail.
FIG. 3 is an enlarged view illustrating another drug delivery
device of the invention confined in a container with a section
removed.
FIG. 4 is an exploded view of a drug delivery device affixed to a
deformable member in expanded position. The device in this figure
is illustrated without a bioerodible container.
FIG. 5 is a view diagrammatically illustrating a contained drug
delivery device passing to the environment of use, that is, the
device is seen descending in the esophagus.
FIG. 6 is a view diagrammatically illustrating a drug delivery
device in an environment of use such as the stomach.
In the drawings and specification, like parts in related figures
are identified by like numbers. The items 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 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 in this embodiment is illustrated in side
perspective view and it is comprised of a bioerodible container 12
housing a device 14 afixed to a deformable hollow member 16. In
FIG. 1 drug delivery device 10 is depicted in miniature size to
simplify one operative embodiment of the invention. In this figure,
the device is illustrated within a container; however, it is to be
understood that the container is not critical to successfully
practice 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 removed to illustrate a
device 14 housed in container 12 and mounted onto a deformable
collapsed hollow bladder 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. Bioerodible container 12
in one embodiment is made from commercially available materials
such as gelatin preferably so it can move quickly and easily
through body passages such as the alimentary canal and quickly
disintegrates when it reaches a drug receptor site, such as the
stomach, wherein it frees the device 14. Containers made of other
bioerodible materials can also be used for initially containing and
subsequently releasing the device in animal, human or avian
cavities. Device 14 as initimately joined to a deformable hollow
member 16 and it is made of naturally occurring or synthetic
flexible, polymeric materials that lend themselves to changes in
shape and size. Member 16 in FIG. 2 is in the form of a completely
sealed envelope which is shown in collapsed state. The envelope is
sealed at its margins and folded in a number of staggered folds 18.
Member 16 contains a fluid that readily changes most of its volume
at the temperature of use to a gas to inflate member 16. Member 16
thus acts as a floating support for device 14 to keep it in a
preselected environment. Member 16 is equipped with a plug 20
formed of an erodible material that erodes after a predetermined
time to release gas from member 16, thereby deflating it to a
collapsed state so it can pass from the environment. In other
embodiments, flat bags, balloons, tubes, foldable bags and the like
can also be used as 16 for the purpose of the invention.
Drug delivery device 14, as seen in FIG. 2, is an osmotically
functioning device and it is comprised of a housing or shell 22
having an internal space and at least a portion of the housing
permeable to external fluids, such as water, gastric juice and the
like. Device 14 is comprised internally of a unitary chamber
divided into a first chamber 24 and a second chamber 26. A pressure
responsive movable bladder 25 separates the chambers and it
substantially defines and forms the first chamber 24. Bladder 25 is
formed of a material that is substantially impermeable to vapor and
fluid, and its geometric shape used for the drug delivery device is
any shape that forms a container for containing drug. In the
embodiment illustrated, bladder 25 defines chamber 25 in a balloon
like container 24 for housing drug 29. First chamber 24, which
serves as a drug reservoir for containing drug 29 is manufactured
with a discharge outlet 27 for releasing drug 29. Discharge outlet
27 is closed with an eordible plug 28 that quickly erodes after
device 14 is freed from container 22 upon its entry into the
environment of use, such as the stomach. Second chamber 26 is
occupied by a solution of an osmotically effective solute 30 which
exhibits an osmotic pressure gradient against an external
fluid.
Housing 22 which in at least a part exhibits controlled
permeability to fluids, such as water, gastric fluids or the like,
is made of a fluid permeable membrane adhesively secured, lined,
laminated or cast in place on housing or shell 22. In another
embodiment, all of shell 22 can be made of a fluid permeable
membrane. In device 14 of FIG. 2, the fluid permeable membrane is
cellulose acetate that is permeable to fluids but relatively
impermeable to salts, thus permitting fluids to enter chamber 26 in
an effort to reach osmotic equilibrium. Other materials such as
those used for reverse osmosis processes, typically anistropic
membranes that are permeable to fluids but relatively impermeable
to solute can optionally be used for the purpose of this
invention.
In operation, device 14 is administered in one application into the
stomach and after it is freed from container 12 and deformable
member 16 inflates in the stomach, fluids, which will be absorbed
from the body tissues or stomach, will diffuse through the reverse
osmosis membrane of shell 22 and mix with solute 30 in an effort to
establish osmotic equilibrium. As fluid enters chamber 26, the
volume of the solution contained therein is increased and pressure
is exerted against movable bladder 25 which urges drug 29 in
chamber 24 through discharge outlet 27 at a controlled and constant
rate into the external environment.
In FIG. 3 another embodiment of the invention is illustrated
comprised of an assembled drug delivery device 10 consisting of an
optionally used swallowable bioerodible container 12 made of two
telescopically associated non-toxic envelopes having an interior
cavity housing device 14. Container 12 is of standard
pharmaceutical or veterinary design and it has a size and shape for
swallowing and for passage by humans, farm animals such as cows,
steers, pigs and the like, houshold pets such as dogs and sport
animals such as horses to their stomach by normal peristalsis. In
the stomach container 12, which is made from gelatin or the like
pharmaceutically acceptable materials, quickly and easily
disintegrates to release device 14 for discharging a medicament,
not shown, into the stomach.
Device 14 of FIG. 3 is a vapor pressure activated device and it is
comprised of a shell 22 with an internal space defining a first
chamber 24 and a second chamber 26. Shell 22, in this embodiment,
is made from a material essentially impermeable to fluids and
gases, and it has a deformable hollow member 16 fixed to one end of
said shell 22. Deformable bladder member 16 is optionally
integrally formed, cemented or sealed to shell 22 and as shown it
is a collapsible bag folded or having a plurality of bellows like
folds made from a flexible or resilent material to allow it to
freely expand and return to a collapsed state. Member 16 is also
manufactured with both a bioerodible plug 20 that erodes after a
period of time and with a passageway 21 for communicating with
chamber 26. Chamber 24 is a means for storage of a drug, that is a
drug reservoir, and delivery of it, and it is a movable bladder 25
preferably a bellows like foldable bag secured to a part of shell
22. Movable bladder 25 is essentially impermeable to fluids and
gases and a flow control means 28 made of a porous inert material,
a calibtated aperture or the like vents chamber 24 through shell 22
to the exterior of the device. The flow control means acts to
release drug at a metered rate, for example, according to the
Hagen-Poiseuille equation, at a constant rate over a period of
time, despite its decreasing volume during the discharge of the
drug. Chamber 26 is a pressure generating chamber and it contains a
gas stored in liquified form for producing a vapor pressure in
excess of one atmosphere at the temperature of use, that is, for
example, the temperature of the stomach, to cause member 16 to
inflate to a predetermined size and shape. The dimensions of member
16 in the inflated state will of course be different for animals
but it should be large enough to retain the device in the stomach.
It is 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. Vapor pressures arising in
chamber 26 also exert their pressure against bladder 25 causing it
to fold, collapse and urge drug 29 (not seen in FIG. 3) through
flow control means 27 to the exterior of the device at a controlled
rate for a prolonged period of time. At the end of the prescribed
therapeutic regimen, bioerodible plug 20 erodes to vent chamber 26
into the stomach causing it to collapse to a size smaller than the
pyloric canal. Device 14 then passes through the alimentary tract
and out of the body.
FIG. 4 graphically represents an exploded view of a device of the
invention as seen from a top view. In FIG. 4 a drug delivery device
14 is seen mounted on top of an inflated, support member 16. Member
16 is a long balloon, a balloon of pillow shape or the like. It
serves as a floating dock for drug delivery device 14 in the
environment of use. Device 14 is illustrated in exploded view and
the features of its housing, for one embodiment of the invention,
are illustrated herein. Device 14 housing is comprised of a head 32
having a flow control opening 34 and internal threader 35 which
threads onto external threads 36 of shell 22. Shell 22 houses an
osmotically operated drug delivery system of the type seen in FIG.
2, and it has a fluid admitting head 33 and a holding member 37 to
help retain member 33 in shell 22.
FIG. 5 and FIG. 6 diagrammatically illustrate the use of the device
of the invention. In FIG. 5 there is seen the outline of a human 39
with a container 12 moving through the esophagus 40 and on into the
stomach 41. In FIG. 6 the device 14 is seen in the stomach 41
administering a drug.
DETAILS OF THE DISCLOSURE
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 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 oral administration into
body openings or cavities, such as 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 opening or exit of
the body cavity, such as the pyloric canal at the stomach's exit to
let the device stay in the stomach during the period of drug
release and on collapse of member 16 let it pass therefrom. The
dimensions of various animal openings or cavities are recorded in
standard anatomy textbooks. For example, for humans to retain the
device in the stomach the device will be larger than the pyloric
canal, that is, the inflated member will be about 3 cm in diameter
to about 10 cm in length, with a usual diameter range of 2 cm by 4
cm. 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.
Shell 22 of the device defining chamber 24 and 26 and confining the
solute and gas in liquefied form can be flexible, semi-flexible or
rigid or modifications thereof. Shell 22 is essentially impermeable
to the gas in liquefied form and to solute but when the device is
an osmotic actuated device it has at least one area permeable to
fluids. The shell can be made from a wide variety of commercially
available materials such as aluminum, teflon, poly(ethylene),
laminates of poly(propylene), poly(methlmethacrylate),
poly(formaldehyde), nylon, laminates of poly(styrene), metal foils
such as aluminim foil, tin foils, poly(vinylidene chloride),
copolymers of vinyldene chloride and vinyl chloride, or
acrylonitrile, 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 0.2 mils to 25 mils,
generally in the range of 0.5 mils to 10 mils and the like.
Pressure responsive bladder 25 positioned in shell 22 defining the
chambers and used to urge drug from the device is flexible,
collapsable, essentially impermeable to vapors and fluids and the
like, and it has a size and shape corresponding to the volume of
drug employed. The bladder is made from naturally occurring or
synthetic materials and it is about 0.2 mils to 100 mils thick, or
more, usually 0.4 to 20 mils and the like. The bladder can be made
of a single material, a combination of materials in laiminated
form, elastomeric materials bonded on foils and the like.
Illustrative materials include silicones, poly(urethanes),
poly(acrylonitriles), poly(ethylenes), poly(propylenes),
poly(vinylidene chlorides), copolymers of vinylidene chloride and
vinyl chloride or polyethylene terephthalate, poly(vinylidene
fluorides), acrylic elastomers, ethylene propylene terpolymers,
laminates such as poly(ethylene)-poly(vinylidene chloride),
nylon-poly(vinylidene chloride), poly(ethylene)-poly (vinylidene
chloride)-poly(ethylene), poly(ethylene)-poly(vinyl
alcohol)-poly(vinylidene)chloride, metal foils such as thin tin
foil, thin aluminum foil, plastic coated foils such as
poly(ethylene) on thin tin foil, poly(vinylidene chloride) on thin
stainless steel foil and the like.
Member 16 is generally made from naturally occurring or synthetic
materials that readily lend themselves to reversible change in size
and shape. 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
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
acrylonitrite, poly(ethylene terephthalate), acrylic elastomers,
laiminates such as poly(ethylene-poly(vinylidene chloride),
nylon-poly(vinylidene chloride), and the like.
The portion of shell 22 that has permeability to fluids, for
example, stomach juice, water or the like include a variety of
materials permeable or semi-permeable to solvent but not to solute
are suitable for construction of the osmotic power device. Typical
membranes include the membranes known to act as osmosis and reverse
osmosis membranes, such as unplasticized cellulose acetate,
plasticized cellulose acetate, reinforced cellulose acetate,
cellulose diacetate, cellulose triacetate, agar acetate, amylose
triacetate, beta glucan acetate, beta glucan triacetate, cellulose
acetate acetaldehyde dimethyl acetate, cellulose acetate ethyl
carbamate, cellulose acetate methyl carbamate, cellulose acetate
ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate
ethyl oxalate, cellulose acetate methyl sulfonate, cellulose
acetate propionate, cellulose acetate p-toluene sulfonate,
triacetate of locust gum bean, cellulose acetate with acetylated
hydroxyethyl cellulose, hydroxylized ethylenevinylacetate,
cellulose acetate butyrate having a viscosity of from about 10
seconds to about 50 seconds, cellulose acetate butyrate containing
about 17 percent of combined butyryl and about 29.5 percent acetyl
and the like. Generally membranes having a permeability of 0.01 to
5 cc/cm.sup.2 /hour/or day/or higher at atmospheric pressure
against a saturated salt solution to a changing concentration
solution of the temperature of use are within the spirit of the
invention.
Representative of solutes suitable for housing in chamber 26 of an
osmotically powered device include solutes, usually those soluble
in aqueous type fluids, acidic fluids, uterine fluids, vaginal
fluids, and the like. Various osmotically effective solutes include
organic and inorganic compounds such as magnesium sulphate,
magnesium chloride, sodium chloride, potassium sulphate, sodium
carbonate, sodium sulphite, calcium bicarbonate, potassium acid
phosphate, calcium lactate, magnesium succinate and the like. The
solid, present initially in excess, can be in any suitable physical
form such as particles, crystals, pellets and the like.
Exemplary materials suitable for exerting a vapor pressure against
pressure responsive bladder 25 when device 14 functions as a
constant rate vapor pressure powered device are inorganic and
organic compounds whose vapor is in equilibrium with its solid or
liquid phase or a mixture of phases 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. 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 useful for
inflating deformable hollow member 16 are halogenated hydrocarbons,
fluorochloronated 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, methyln-propyl
ether BP 39.1.degree. C, methyl-isopropyl ether BP 32.degree. C,
tetramethyl silane BP 26.5.degree. C, perfluoropentane isomers BP
31.0.degree. C, n-petane 36.0.degree. C, iso-pentane 27.9.degree.
C, mixtures thereof, and the like. Usually, the amount of gas
stored in the liquefied phase in the deformable hollow member 16 or
in chamber 26 will be about 0.2 cc to 10 cc or higher, depending on
the size of the device and the animal, generally 1 to 5 cc, and the
volume of the vapor phase will be sufficient to inflate member 16
to about 20 to 80 percent of the volume of the chamber, or
higher.
Materials suitable for use as bioerodible plug 20 are those
materials that are commercially available and that bioerode in the
environment of use, for example the stomach, at a predetermined
given time. The materials are those that erode by known 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 fluid, such as 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, 2 hours to 20 days, usually 8
hours to 5 days.
Representative materials for use of plug 20 comprise hydrophilic
polymers of uncross-linked hydroxylalkyl acrylates and
methacrylates, hydrolytically biodegradable poly(anhydride)polymers
as described in U.S. 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; U.S. 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, carobxyl 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 to 325,
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 anmial 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% 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; hetero-cyclic
hypnotics such as dioxopiperidines, and gluarimides; 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, ethotoin, pheneturide, ethosuximide and the like; muscle
relaxants and antiparkinson agents such as mephensin, methocarbmal,
trihexylphenidyl, biperiden, levo-dopa, also known as L-dopa and
L-.alpha.-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; antipasmodics and anti-ulcer 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, chlorotetracyline,
chloramphenicol, sulfonamides and the like; anti-malarials such as
4-aminoquinolines, 8-aminoquinolines, chloroquine and
pyrimethamine; hormonal agents such as prednisolone, cortisone,
cortisol and triamcinolone; antihistamines such as chlorpeniramine;
androgenic steroids, for example, methyltestosterone,
fluoximesterone and the like; estrogenic steroids, for example
17.alpha.-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,
trichloromethiazide, flumethiazide and the like; antiparasitic
agents such as bephenium hydroxynaphthoate and dichlorophen,
dapsone and the like; neoplastic agents such as mechlorethamine,
uracil mustard, 5-fluorouracil, 6-thioguanine, procarbazine and the
like; hypoglycemic drugs such as sulfonylureas such as tolbutamide,
acetohexamide, tolazamide, and chlorpropamide, the biguanides and
the like; nutritional agents such as vitamins, such as vitamin A,
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 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, the suitable pharmaceutical carriers
include sterile water; saline, dextrose; dextrose in water or
saline; condensation products of caster oil and ethylene oxide
combining about 30 to about 35 moles of ethylene oxide per mole of
caster oil; liquid gylceryl 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,
lectithin, 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 size of the device for a selected animal, 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 drag's physiological or
pharmacological local or systemic effects. For example, the amount
of drug present in the delivery device when the device is used for
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 240 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 400 to 600 mg; nylidrin
hydrochloride 12 to 48 mg; bethanechol chloride 120 to 480 mg;
phentolamine 100 to 400 mg; quanethidine 100 to 1,000 mg; methyl
dopa 3 to 12 gms; atropine 100 mcg to 1,250 mcg; and the like.
The discharge outlet 27 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 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 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 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 2 ml/hour, or more for
various times such as 8 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 drug delivery device is fabricated according to the
spirit of the invention as follows: first, a spherical collapsable
balloon of approximately 4 cm in diameter is made from commercially
available poly(ethylene terephthalate) by conventional 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.
Then, fabrication is continued by passing through the final heat
seal a water poly(urethane) erodible seal of 3 mm in length and a
poly(ethylene terephthalate)monofilament to which is secured an
osmotic delivery device. The device consists of a cylindrical
poly(ethylene) drug reservoir bag open at one end which is filled
with a drug formulation. In this device, 0.21 cm.sup.3 of a drug
formulation consisting of 50 percent chlorpheniramine maleate and
50 percent polyethylene glycol were charged into the reservoir.
This drug bag is then coated with 33 mg of potassium sulfate
containing 2 percent ethyl cellulose. The just applied salt layer
is then coated with 0.25 mm thick cellulose acetate having a degree
of acetylation of 2.5, which then has a total surface area of 1.7
cm.sup.2. At ambient temperature, 25.degree. C, the collapsable
balloon is easily folded around the osmotic delivery device and the
whole assembly is placed within a number 000 gelatin capsule. Upon
ingestion, the capsule dissolves, the poly(ethylene terephthalate)
balloon inflated as a consequence of vaporization of the
isopentane. The drug polyethylene glycol formulation melts at
physiological temperatures and it is pumped from the device as a
consequence of fluid, gastric juice, permeating through the
cellulose acetate membrane. The device delivers chlorophemiramine
maleate at a rate of 0.84 mg/hour for five days. The water soluble
poly(urethane) seal self-fails, that is, bioerodes, during the
fourth to fifth day releasing the gas from the balloon allowing it
to collapse. The spent device is then readily eliminated through
the lower gastrointestinal tract.
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 aminal 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 physically 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.
* * * * *