U.S. patent number 3,840,009 [Application Number 05/212,140] was granted by the patent office on 1974-10-08 for self-powered vapor pressure delivery device.
This patent grant is currently assigned to ALZA Corporation. Invention is credited to Richard G. Buckles, Alan S. Michaels, Su Il Yum.
United States Patent |
3,840,009 |
Michaels , et al. |
October 8, 1974 |
SELF-POWERED VAPOR PRESSURE DELIVERY DEVICE
Abstract
A self-powered vapor pressure delivery device for the controlled
and continuous dispensing of an active agent employing in a
preferred embodiment outer and inner chambers in functional
relationships. The inner chamber is a sealed bag comprised of a
flexible and substantially vapor and fluid impermeable material.
The bag is freely positioned within an outer casing. The bag is
filled with a volatile propellant and is expandably responsive to
the vapor pressure of the propellant at the temperature of use,
such as to cause the bag to distend so as to reduce the volume of
the outer chamber. The active agent in the outer chamber is thereby
caused to flow through a flow resistive means which is provided in
the outer chamber.
Inventors: |
Michaels; Alan S. (Atherton,
CA), Buckles; Richard G. (Menlo Park, CA), Yum; Su Il
(Mountain View, CA) |
Assignee: |
ALZA Corporation (Palo Alto,
CA)
|
Family
ID: |
22789727 |
Appl.
No.: |
05/212,140 |
Filed: |
December 27, 1971 |
Current U.S.
Class: |
604/892.1 |
Current CPC
Class: |
A61K
9/0004 (20130101); A61M 37/00 (20130101); A61M
31/002 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 37/00 (20060101); A61M
31/00 (20060101); A61m 031/00 () |
Field of
Search: |
;128/260,272,261
;222/491,189 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: Recla; Henry J.
Attorney, Agent or Firm: Ciotti; Thomas E. Sabatine; Paul L.
Mandell; Edward L.
Claims
What is claimed is:
1. A self-powered dispenser for administering an active agent
internally to a mammal consisting essentially of:
a. a hollow casing whose inner surface defines an active agent
impermeable chamber and whose outer surface defines the exterior of
the dispenser;
b. an outlet in said casing communicating from said chamber to said
exterior of the dispenser;
c. a bladder positioned within said chamber the inner surface of
said bladder defining a sealed inner chamber, the active agent
being contained in said chamber externally of said bladder and in
contact with the outer surface of said bladder, said bladder being
formed of a flexible material and being expandable in response to a
pressure increase within the inner chamber from an initial state in
which the volume defined by the outer surface of the bladder is
less than the volume of said chamber to an expanded state in which
the outer surface of the bladder conforms approximately to the
shape of said chamber and the volume defined thereby is
approximately the volume of said chamber;
d. a self-actuated active agent flow resisting means within said
outlet for metering the discharge of agent from said chamber at a
substantially constant rate; and
e. a liquified gas propellant having a vapor pressure greater than
one atmosphere at the physiological temperature of the mammal
contained within said inner chamber;
whereby when said dispenser is placed internally of the mammal said
propellant vaporizes in response to said physiological temperature
causing said bladder to expand continuously from said initial state
to said expanded state and thereby concurrently and continuously
displace active agent from said chamber via said outlet and said
means in vivo at a controlled rate.
2. The dispenser of claim 1 wherein the outer surface of the
bladder in said expanded state is substantially contiguous with the
inner surface of the casing.
3. The dispenser of claim 1 including:
f. an inlet in said casing communicating from said exterior to said
chamber for charging active agent to said chamber.
4. The dispenser of claim 1 wherein the casing is constructed of a
flexible material.
5. The dispenser of claim 1 wherein the same has a specific gravity
of at least 1.5 and is of a size, weight and shape which enables it
to be retained in the rumen of polygastric mammals.
6. The dispenser of claim 1 wherein the bladder is comprised of a
polymeric film material.
7. The dispenser of claim 6 wherein the polymeric film is a
laminate.
8. The dispenser of claim 6 wherein the bladder is in the form of a
pleated accordian bellows.
9. The dispenser of claim 6 wherein the bladder is comprised of a
metal foil.
10. The dispenser of claim 1 wherein the bladder is comprised of
polyethylene, polyvinylidene, polyvinylidene chloride, aluminum
foil, polypropylene, nylon, polytrifluorochloroethylene,
polytetrafluoroethylene, polyvinylacetate, polyvinylchloride, or
combinations thereof.
11. The dispenser of claim 1 including:
f. a conduit connected to said outlet and leading to the
administration site of the agent.
12. The dispenser of claim 1 wherein the active agent substantially
fills that portion of the volume of said chamber not occupied by
said bladder in its initial state.
Description
BACKGROUND OF THE INVENTION
This invention relates to a delivery device or pump and, more
particularly, to a self-powered delivery pump which operates
without any external energy source and which is capable of
dispensing an active agent at a controlled rate over a prolonged
period of time. The device employs vapor pressure as the motive
force and it may be employed, in a preferred aspect, for internally
administering medicants in the body of an animal or human.
There is an increasing interest and expansion of activity in the
art, directed to the development of devices which can provide a
continuous and sustained feeding of an active agent to a system.
One field of endeavor to which such devices have applicability
pertains to therapeutic programs relating to the management of
health and disease wherein it is desirable to use a delivery device
to provide a slow release of drug to a recipient at a controlled
rate over a relatively prolonged period of time in order to achieve
a desired physiologic or pharmacologic effect. Such prolonged and
continuous medication gives results which are far superior to
periodic or intermittent administration that may be dangerous
because of the high concentration of medicament at the time of
administration or of no therapeutic value because of a low
concentration of medicament between the periods of administration.
Frequently, it is advantageous to implant or insert such devices
within the recipient at or near the area to be treated in order to
avoid systemic administration of the drug. Further, in many
instances, such a rate of release of the drug from a drug delivery
device should have a zero order time dependence, that is, the rate
of drug release is independent of time.
Different approaches have been tried by the prior art to obtain
such devices. One approach has been to enclose the drug within a
capsule having a polymeric wall through which the drug can pass at
a controlled rate by diffusion. An approach of this kind is set
forth in U.S. Pat. No. 3,279,996. However, this type of delivery
device has inherent shortcomings. For example, one difficulty is
that release rates cannot readily be varied with a given polymeric
material other than by changing the thickness of the material used
to make the device which may cause fabrication difficulties in
cases wherein very thin or very thick walls are required to achieve
the desired release rate. Further, there are restrictions on the
physical form of the active agent in that suspensions or the like
cannot be delivered by a polymeric diffusion system. Additionally,
few materials are satisfactory for the obtainment of desired
release rates for relatively high molecular weight materials such
as insulin.
Another approach has also been proposed in the form of a delivery
device which is powered by vapor pressure. See Medical World News,
Oct. 16, 1970, "A Lifetime Infusion Pump to Call His Own". The
device is disclosed to be implantable within a human body and
consists of a double walled chamber, containing a volatile liquid
in the outer chamber. Liquid drug is placed within the innermost
chamber formed by the inner walls of the double wall cylinder and
is in the form of a collapsible, but rigid, accordion-type bellows
made of stainless steel. For proper operation of the device, the
chambers must be hermetically sealed from each other. Evaporation
of the liquid in the outer chamber provides pressure so as to push
the drug out from the innermost chamber. Other delivery devices
comprised of cooperative chambers are known to the art, which also
utilize a volatile material placed in an outer chamber as the
motive force to dispense a liquid composition of matter placed in a
collapsible inner chamber; see for example Krizka, U.S. Pat. No.
3,433,391 and Schultz, U.S. Pat. No. 2,876,768.
These prior art pressure-operated devices, however, have inherent
disadvantages. These disadvantages result in part from the spatial
relationship of volatile liquid and the composition of matter to be
dispensed; that is, the former is placed in the annular space
between the inner chamber and casing, whereas the latter is placed
within the collapsible inner chamber, such that the pressure
generates a mechanical deflating force on the inner chamber to
thereby dispense the composition. In order to prevent the vapor
from pinching the inner chamber and thus preventing the dispensing
of the product, it is necessary to employ means so as to maintain
the inner chamber in an erect position. Although this can
satisfactorily be accomplished in a manner known to the art by the
use of rigid supports or materials and the like, the resulting unit
is relatively bulky and cumbersome. Moreover, the aforesaid
described spatial relationship of volatile liquid and product to be
dispensed in the prior art pressure-operated devices, necessitates
inclusion of a discharge passageway from the inner chamber to the
exterior of the device or alternatively, the mechanical securing in
some manner of a part of the structure of the inner chamber to the
outer casing, which in either case requires costly and difficult to
make liquid-vapor seals between the chambers. Consideration of
these factors will indicate that the usefulness of devices
constructed in the manner so described are seriously limited for
many applications.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to provide a
self-powered vapor-pressure delivery device, simple in
construction, inexpensive to manufacture, and therefore suitable
for disposal after relatively short periods of use without undue
economic hardship, and which exhibits all of the practical benefits
of a constant continuous administration of various active agents
both to animals and humans, and into other environments.
Another object of this invention is to provide an improved
self-powered vapor-pressure delivery device which is suitable to be
implanted or inserted in an animal or human.
Still another object of this invention is to provide a self-powered
delivery device which is suitable to dispense, for prolonged
periods of time, active agents having a wide variety of chemical
and physical properties and over a wide range of release rates.
A further object of this invention is to provide a delivery device
which depends on vapor pressure for its motive force and which is
particularly adapted to miniaturization so as to be suitable for
installation at a wide range of sites with reasonable ease.
Yet another object of this invention is to provide an improved
self-powered activated dispenser which overcomes problems inherent
in related devices heretofore proposed.
Another object of this invention is to provide an improved method
of administering an active agent to a recipient.
In attaining the objects of this invention, one preferred aspect of
this invention resides in a self-powered device for the controlled
and continuous dispensing of an active agent, employing a pressure
differential as the motive force, which comprises:
a casing housing therein outer and inner chambers in functional
operative relationship, the chambers being partitioned and sealed
from each other by a bladder; the bladder comprised of a flexible
and substantially vapor and fluid impermeable material and being
freely positioned within the casing, the bladder being expandably
responsive to an applied pressure emanating from the inner chamber
at the temperature of use and being adapted to approximately
conform to the shape and size of the inner surface of the
casing;
and
the outer chamber communicating with a discharge port having a flow
resistive means therein.
Other objects, features and advantages of this invention will
become more apparent from the following description when taken in
conjunction with the accompanying drawings, and wherein like
reference numerals are used to indicate like or equivalent
parts.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross-sectional view of an embodiment of a self-powered
vapor-pressure delivery device of this invention.
FIG. 2A is a perspective view of the bladder element or inner
chamber illustrated in FIG. 1, removed from the outer casing and
containing a propellant therein. The bag is also shown inflated, in
phantom position in the drawing.
FIG. 2B is a cross-sectional view through 2B--2B of FIG. 2A.
FIG. 3 is a perspective view of the device illustrated in FIG. 1,
depicting the inner chamber in a collapsed condition before any of
the active agent has been dispensed.
DETAILED DESCRIPTION OF THE INVENTION
Generally, the device can be viewed as a single unit comprising
outer and inner chambers acting in a functional relationship for
effective administration of agent. The outer chamber contains the
active agent and an inner chamber containing the propellant, and is
provided with a flow resistive means for releasing the active agent
at a controlled rate to the exterior of the device. The inner
chamber comprises a flexible and substantially impermeable bag
which contains a volatile propellant and provides the power or
energy for the device. The chambers are advantageously separated
and sealed from each other by a wall or bladder which forms a part
of the structure of the inner bag. The bladder is of such size and
configuration that in its distended condition all, or substantially
all, of the active agent will be discharged from the device.
Operation of the delivery device of the invention makes use of the
scientific principle that a vapor in equilibrium with its liquid
phase exhibits a constant pressure at a given temperature,
irrespective of volume occupied by the vapor.
A preferred embodiment of the self-powered vaporpressure delivery
device, in accordance with this invention, is illustrated in FIGS.
1, 2A, 2B and 3, wherein the device 20 comprises casing 22
containing an inner sealed bag therein so as to define inner
chamber 10, outer chamber 21 and bladder 12. Thus, the bladder is
advantageously an integral part of the structure of the outer wall
of the inner chamber and the inner wall of the outer chamber. More
specifically, device 20 is comprised of hollow casing 22, housing
bag 10 which is comprised of a flexible and impermeable material
12, termed a "bladder" herein. The space within bag 10 defines the
inner chamber of the device and contains volatile propellant 18
therein, having a vapor pressure greater than that of the
environment external to the device 20 at the temperature of use. It
is freely positioned within casing 22. The volume of casing 22,
other than that occupied by bag 10, defines the outer chamber 21 of
the device 20 and is occupied by active agent 28. The wall of bag
10 is expandably responsive to the vapor pressure of the propellant
18 at the temperature of use and is adapted to approximately
conform to the shape and size of the inner surface of casing 22 and
preferably be substantially contiguous therewith when in a fully
expanded condition.
Casing 22 is comprised of a rigid (or flexible, as described
hereinafter), impervious structure having a removable bottom member
27 which is so provided for insertion of bag 10 and active agent
28. Member 27 can be threaded as shown or, alternatively, can be
adhesively sealed or press-fit into place after insertion of the
power source 10 and active agent 28. As an aid in maintaining a
tight barrier between active agent 28 and the external environment
of the device, a resilient O-ring 25 may be included. Discharge
port 23 is bored into casing 22. Flow resistive metering means 24
snugly fits into discharge port 23 and is preferably adhesively
secured or bonded therein. Alternatively, non-integral threaded
member 27 can be eliminated entirely from casing 22 by employing
port 23 as a means of ingress to the casing prior to assembling of
flow resistive means 24. Thus, bag 10 can be temporarily folded up
or otherwise compressed to a small object and inserted into casing
22 via port 23. In like manner, active agent 28 can be so
incorporated into casing 22.
Optionally, casing 22 can be provided with an access port (not
shown) to provide entry into the device 20 for purposes of
refilling chamber 21 with active agent. The access port can be
comprised of self-sealing needle penetrable material such as rubber
and the like, or a suitable valve.
Bag 10 is easily fabricated, for example, by employing a
rectangular piece of film sheeting 12 which is folded over and
sealed with an appropriate sealant along its sides 14 and 16.
Propellant 18 may then be introduced into bag 10 through side 17,
and the bag sealed along side 17. Where the propellant has a vapor
pressure of about one atmosphere at or below room temperature, the
propellant is preferably introduced at reduced temperatures so that
it does not vaporize. The inner chamber 10 is susceptible of
embodiment in many different forms, other than that illustrated in
FIG. 3, and can assume any shape when expanded, such as elliptical,
spherical, tapered, barrel, tubular, arcuate, and the like, with
the proviso that such shape be substantially identical with the
inner surface of casing 22. Additionally, it is preferred that
inner chamber 10 be constructed such that it can be folded or
compressed, or otherwise oriented in its initially collapsed state,
to occupy only a small percentage of the total volume of the
casing.
As described above, since bag 10 is comprised of a flexible
material and is only partially filled with volatile propellant 18,
bag 10 can be folded up so as to occupy a very small volume,
compared to the total expanded volume when bag 10 is distended.
Usually, the volume of propellant which is required will not be
more than about 5 percent of the volume of the bag 10 when
expanded. Bag 10 with propellant 18 therein can be so constructed
in most cases so as to initially occupy less than 10 percent of the
effective internal volume of casing 22, advantageously resulting in
the ability to substantially fill chamber 21 entirely with active
agent 28. Additionally, it has been found to be desirable, in order
to promote complete discharge of agent 28, to pre-form or pre-mold
bag 10 such that it will conform with the shape and size of the
internal surface of casing 22 and will be substantially contiguous
therewith after the dispensing of active agent 28. This insures
that no active agent is wasted by remaining in device 20 after use.
Further, bag 10 can be independently manufactured so as to be
available as required. That is, the bag can be fabricated, filled
with a propellant or mixtures of propellants, depending on the
particular requirements, and stored until required for use in the
subject device. This provides for economical manufacturing
procedures and low unit cost.
In assembling device 20, either bag 10 or active agent 28 can be
first incorporated into casing 22, although it is preferred to
initially incorporate bag 10 pre-cooled so that the propellant 18
is in a condensed state. Agent 28 may now be introduced to fill
substantially all of the remaining volume within casing 22.
Metering of agent 28 from the device 20 is accomplished by flow
resistive means 24 (more fully described hereinafter). Such
metering element, in its preferred form, consists of a porous plug
24 inserted in discharge port 23. The element is preferably of a
uniform porosity so as to function to control the flow rate of
agent. The metering operation is preferably carried out in
conjunction with highly permeable filter (not shown) disposed in
port 23 in spaced relationship to plug 24, on the upstream side
thereof. The calibration of the porous plug is a function of its
built-in porosity, as well as its diameter and length, and these
parameters and materials may be varied to meet required dispensing
rate, as hereinafter more fully described. The function of the
filter is to assure that the fluid passing through the flow
resistive means shall be entirely free of sediment or precipitates
which might otherwise clog the flow resistive means and alter the
calibration value thereof. The filter element should be of greater
size than the resistive element.
Device 20 may be stored at reduced temperature until ready for use
or, alternatively, a cover or cap placed over porous element 24 to
prevent the unwanted premature release of agent 28, if stored at
higher temperatures. Device 20 is now ready for introduction into
the environment in which it is to operate. A critical requirement
of the environment is that it have a temperature at which the vapor
pressure of the volatile propellant is greater than the pressure of
the environment.
To use the delivery device of the invention, for example in cases
wherein the active agent is a drug or other agent for treating a
living organism, it is either physically inserted, orally ingested
or surgically implanted in the body of the organism, typically a
mammal. The particular method of introduction or retention of the
device in the environment is not an aspect of this invention and is
well known to those skilled in the art. Once in place, due to the
heat transfer from the environment to the device 20, volatile
propellant 18 will begin to vaporize and exert a pressure in excess
of the environment causing the wall 12 (bladder) of bag 10 to
expand. Because of the increase in volume of bag 10 suggested by
the broken lines illustrated in FIG. 1, agent 28 will slowly begin
to flow through porous plug 24 at a controlled rate into the
external environment. As agent 28 is discharged, bag 10 will
further distend to fill the space, the volatile liquid 18
vaporizing to maintain a constant pressure in bag 10. Bag 10 is of
such a size, configuration and contour, so that when completely
distended it will substantially fill the inner volume of casing 22.
There is accordingly provided the gradual and controlled constant
release of drug or similar agent directly to the body or affected
organ thereof over a prolonged period of time.
In connection with the many uses of the present invention in the
medical field and in other applications, it is quite important that
the flow rate in the discharge line shall be steady and at a low
and constant pressure. An important feature of the present
invention accordingly lies in the ability to realize a discharge
having these characteristics, and these ends are effected through
the development of a device which will discharge at a substantially
constant rate over a period of time. The constant discharge flow
rate of agent 28 is achieved due to the fact that the vapor
pressure of the propellant providing the motive operating force
remains constant under the isothermal conditions of the
environment. Additionally, the viscosity of the active agent must
be stable during storage and use.
In some instances the devices of this invention are of insufficient
specific gravity to maintain placement at the desired location. For
example, for use in the rumen of polygastric animals, the weight
should be sufficient to provide a specific gravity of at least 1.5.
In those instances of insufficient specific gravity, therefore, a
weight or ballast can be placed in or attached to the device. Other
suitable weights comprise iron plugs, iron ore tablets, brass
plugs, ceramic plugs, or the like.
The devices of this invention need not have any particular shape.
The devices in their original form ready for use may be
cylindrical, oblong, oblate, prolate, spherical, polyhedral, etc.
The shape of the device is primarily one of convenience, both as to
manufacturing and the site of use. Moreover, the devices can be
fabricated in shapes suitable for either physical insertion or
implantation in the body, or for insertion via the gastrointestinal
tract, or for introduction into any other desired environment.
Dimensions of the device can thus vary widely and are not of
controlling importance. The lower limit of the size of the device
is governed by the amount of the particular active agent to be
supplied to the environment to elicit the desired response, as well
as by the form the unit takes, e.g., implant, bolus, suppository,
and in cases of specific body use, the location therein, e.g.,
uterus, stomach, ear and the like, and may be miniaturized if
desired to a size, for example, of that of a Number 00 conventional
pharmaceutical capsules.
The outer casing of the device can be of either a rigid or flexible
but, preferably, not of an elastomeric material. The casing must be
substantially impermeable to the active agent and compatible
therewith. Also, the casing should be compatible with the
environment in which the device operates. The casing can be
prepared from a wide variety of materials, such as metal, e.g.,
aluminum; plastics, such as poly(vinyl chloride), teflon,
polyethylene, polypropylene, poly(methyl methacrylate),
polyformaldehyde, nylon, poly(vinylidene chloride), polystyrene,
copolymers and laminates of these polymers; metal foils, e.g.,
aluminum foil, etc. Since, in a preferred aspect, the devices of
this invention are to be used as single-use-discard units, it is
preferred to construct the casing (and bladder as described
hereinafter) from plastic materials which are relatively
inexpensive. The thickness of the outer wall may be varied over a
wide range, with the caution that the insulating effect of the wall
is not excessive and it is sufficiently strong to withstand the
pressure. Therefore, depending on the function of the wall and the
material employed, the wall thickness may vary, for example, from
0.5 mil to 2,000 mils, usually being in the range of 100 to 1,000
mils. The casing wall may be of uniform thickness or varying
thicknesses, as required. By choice of material one can enhance or
diminish the heat transfer qualities of the device. In some
instances, it may be desirable that heat be transferred slowly from
the environment to the volatile propellant. In most instances,
however, relatively rapid heat transfer will be desired so that the
material and thickness of the casing wall will be chosen to
minimize insulation and provide good heat conduction.
As previously indicated, the outer wall of the device may be of
flexible or rigid material and in certain instances, it may be
desirable to employ a flexible wall for the outer casing. In this
regard, the device can be introduced into an area or organ by
initially folding or otherwise making the device more suitable for
entry. In cases where the openings for egress are smaller than the
size of the casing when returned to its initial configuration, the
device will be trapped within that area so as to advantageously be
secured in place for the administration period.
The bladder employed to transmit the propellant pressure to the
active agent must be flexible, at least in part, and be
substantially impermeable both to the active agent and to the
propellant employed. Further, the bladder must be of a size and
configuration such that it can be distended sufficiently to force
substantially all of the active agent from the device. It is
advantageous to make the bladder as thin as possible, e.g., a film,
consistent with the obtainment of satisfactory permeability
properties and proper operation of the device, although the
thickness can vary widely and is not a limitation on the invention.
Typically, however, the bladder wall thickness is in the range of
0.5 to 50 mils, usually 1.0 to 20 mils. With regard to fabrication,
the bladder is comprised of a flexible, either inherently so or by
mode of construction, preferably non-elastomeric material or a
laminate of materials. Elastomeric materials are suitable so long
as they remain substantially impermeable to both the active agent
and propellant when distended. The choice of materials, either
individually or in combination, will be chosen in reference to the
compositions contained in the chambers. Where a single material is
not impervious to one or both of the active agent and the
propellant, by using coatings or laminates of two or more
diffferent materials, substantial impermeability can be achieved.
Illustrative materials include nylon, polyacrylonitrile,
polyethylene, polypropylene, polyvinylidene chloride, e.g. Saran,
cellophane, polyvinyl alcohol, etc. Laminates may be prepared, such
as nylon-Saran, polyethylene-Saran-polyethylene,
polyethylenepolyvinyl alcohol-polyethylene,
Mylar-aluminum-polyethylene, polyethylene-polyvinyl alcohol-Saran;
etc. In cases where the intended use is such that the overall size
or cost of the device is not of controlling importance, rigid-type
materials, e.g., thin metals such as stainless steel or the like,
can be used. Flexibility can be imparted in these instances by
employing a pleated accordion-type bellows construction. The choice
of materials is further governed by its ability to retain the above
discussed properties under the conditions of storage and use.
Many other materials are suitable for fabrication of the several
component parts of the device of this invention. While the said
several component parts of the device of the invention are
preferred to be insoluble under the conditions are in the
environment of intended use, it is also within the scope of the
invention that such materials be insoluble only during the period
of said intended use; thereafter dissolving away in the environment
of the device. Thus, a dispenser is here contemplated which is
unaffected by its environment, solubility-wise, at the site of use,
or which is only slightly soluble during the period of intended
use, such that once its active agent content has been discharged it
will then dissolve or erode away leaving no objectionable residue
or empty container at the said situs of use.
The term "active agent" as used herein denotes any drug (as
exemplified, infra); composition in any way effecting any
biological entity; substance having a nutrient or stimulating
action, or growth inhibiting, destroying or any regulating action
on plant growth, controlled or otherwise; substance to be
assimilated by any organism, e.g., human being, animal, or lower
order organism, for its nourishment or for regulating its growth;
substance exhibiting any of the above activities to be directly
applied to the habitat, surroundings, or environment of any of the
above organisms; and substances having any other effect on any
other environment.
The device of the invention is suitable for delivering active
agents which are fluids or which can be fluidized by use of mediums
such as carriers, solvents, emulsifying agents, or adjuvant
materials, and the like, and include compositions which are
liquids, emulsions, gels, sols, suspensions, foams, gels, pastes,
and the like.
Suitable active agents for use with the dispenser of this invention
include, without limitation, those which are generally capable
of:
1. Preventing, alleviating, treating or curing abnormal and
pathological conditions of the living body by such means as
destroying a parasitic organism or limiting the effect of the
disease or abnormality by chemically altering the physiology of the
host or parasite;
2. Maintaining, increasing, decreasing, limiting or destroying a
physiologic body or plant function, e.g., vitamin compositions, sex
sterilants, fertility inhibitors, fertility promoters, and the
like;
3. Diagnosing a physiological condition or state;
4. Controlling or protecting an environment or living body by
attracting, disabling, inhibiting, killing, modifying, repelling,
or retarding an animal or microorganism, such as food and non-food
baits, attractants and lures, biocides, pesticides, algicides,
parasiticides, rodenticides, insecticides, fungicides, and the
like;
5. Preserving, disinfecting or sterilizing; and
6. Controlling or affecting generically an environment, as by
introducing a catalyst or metering a reactant into a reacting
chemical system, or by effecting any chemical process therein, such
as a fermentation, including propagation and/or attenuation of a
microorganism.
As indicated, of particular interest are active agents which are
drugs. Any of the drugs used to treat the body, both topical and
systemic, can be compartmentalized as the active agent in any of
the devices of this invention. "Drug" is used herein in its
broadest sense as including any composition or substance that will
produce a pharmacological or biological response.
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, include, without limitation: for
example, drugs acting on the central nervous system such as
hypnotics and sedatives such as pentobarbital sodium,
phenobarbital, secobarbital, thiopental, etc.; heterocyclic
hypnotics such as dioxopiperidines, and glutarimides; hypnotics and
sedatives such as amides and ureas exemplified by
diethylisovaleramide and .alpha.-bromoisovaleryl urea and the like;
hynotics 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, diphenyl-dantoin, ethotoin, pheneturide, 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.1.sub..alpha., PGF.sub.2.sub..alpha., PGA and
the like; anti-microbials such as penicillin, tetracycline,
oxytetracycline, chlorotetracycline, chloramphenicol, sulfonamides
and the like; anti-malarials such as 4-amino-quinolines,
8-aminoquinolines and pyrimethamine; hormonal agents such as
prednisolone, cortisone, cortisol and triamcinolone; androgenic
steroids, for example, methyl-testosterone, 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-thioguanine,
procarbazine and the like; hypoglycemic drugs such as insulins,
protamine zinc insulin suspension, globin zinc insulin, isophane
insulin suspension, and other art known extended insulin
suspensions, sulfonylureas such as tolbutamide, acetohexamide,
tolazamide, and chlorpropamide, the biguanides and the like;
nutritional agents such as vitamins, essential amino acids,
essential fats and the like; and other physiologically or
pharmacologically active agents. Also, the drugs can be present as
the pharmacologically acceptable derivatives, such as ethers,
esters, amides, acetals, etc. that lend themselves to passage into
the circulatory system. These derivatives can be prepared by art
known techniques and then used in the practice of the invention. Of
course, the drug derivative should be such as to convert to the
active drug within the body through the action of body enzymes
assisted transformations, pH, specific organ activities, and the
like.
When the active agent is other than a drug or similar agent, or is
intended for use other than in a living organism, the device is
introduced into the desired environment to produce the desired
effect exactly as would be any of the known means for accomplishing
a like result. And this is generally a mere physical insertion,
such as by placing a pesticide containing device in a river or
stream, or a catalyst containing device in a reaction medium.
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,
in cases wherein the active agent is a drug, suitable
pharmaceutical carriers include sterile water; saline, dextrose,
dextrose in water or saline; condensation products of castor oil
and ethylene oxide combining about 30 to about 35 moles of ethylene
oxide per mole of castor oil; liquid glyceryl triester of a lower
molecular weight fatty acid; lower alkanols; oils such as corn oil;
peanut oil; sesame oil and the like, with emulsifiers such as mono-
or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin,
and the like; glycols; polyalkylene glycols; aqueous media in the
presence of a suspending agent, for example, sodium
carboxymethylcellulose; sodium alginate; poly(vinylpyrrolidone);
and the like, alone or with suitable dispensing agents such as
lecithin; polyoxyethylene stearate; and the like. The carrier may
also contain adjuvants such as preserving, stabilizing, wetting,
emulsifying, viscosity modifying agents, and the like.
It is essential to the successful practice of the invention that
the flow resistive means be self-actuated when the device is to be
employed from continuous in vivo administration from within
internal body passages, although the flow resistive element can be
a conventional-type valve when the device is not so employed. By
the term "self-actuated" is meant that there is no requirement for
external manipulation to initiate the flow of agent. Numerous types
of flow self-actuated resistive elements are available, such as
porous plugs, microporous membranes, capillary tubes, etc. The flow
resistive element may be of a wide diversity of materials, such as
etched or perforated polymers, e.g., polyethylene, nylon, teflon,
poly(vinyl chloride), poly(vinyl chloride), poly(methyl
methacrylate), epoxy resin; sintered metals or ceramics. By proper
selection of the flow resistive element, i.e., materials, diameter,
length, pore size, and the viscosity of the medium for the active
agent, a wide range of dispensing rates can be obtained, as well
known to those skilled in the art. Rates may vary, for example,
from 0.01 ml per hour to 1,000 mls per hour, as desired, and for
periods, for example, such as one day up to and in excess of one
year. For satisfactory discharge rates, viscosities of the medium
employed with the active agent can be in the range, for example, of
from 1 to 10,000 centipoise at the temperature of use, with the
exact selection depending on the other fluid flow parameters and
the desired delivery rate.
The flow resistive element 24 can be inserted into port 23 by any
convenient means which provides a non-leaking seal. For example,
the means employed may be adhesives, mechanical means, e.g.,
threading, heat sealing or, alternatively, by making flow resistive
element 24 an integral member of the casing structure.
The amount of active agent incorporated in the device varies widely
depending on the particular agent, the desired effect, and the time
span over which it is desired to have the agent released. Since a
variety of devices in a variety of sizes and shapes are intended,
and in the case of drugs, to provide complete dosage regimen for
therapy for a variety of maladies, there is no critical upper limit
on the amount of drug incorporated in the device. The lower limit,
too, 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 when the
device is used for a period of time to achieve local or systemic
effect is for various drugs, such as 11-desmethoxyreserpine, about
5 to 40 mg in the device; for acetophenazine, an amount in the
device of 100 to 200 mg; for methoxypromizine, about 600 to 750 mg
in the device. Additionally, the amount of drug in the device can
be 100 to 300 mg of thiopropzate for releasing 15 to 30 mg over a
24 hour period; 200 to 400 mg in the device of phenyltoloxamine for
a release of 150 to 200 mg per day; 100 to 200 mg of papaverine in
the device for a topical release of 30 to 75 mg over a 24 hour
period; 2.5 g to 4.0 g of mephenoxalone for a release of 1.0 to 1.5
g per day; 15 to 25 mg of tranylcypromane for a release of 10 to 15
mg as the standard dose; 1 to 2 gm of trimethadione present in the
device for a release administration of 0.5 to 1.0 g per day;
prostaglandins, for example PGE.sub.1, PGE.sub.2, PGA.sub.1,
PGF.sub.2.sub..alpha., in amounts of 0.5 mg to 10 mg for release of
1 ng to 100 ng, and the like; for progestogen, progesterone, an
amount of 0.01 to 20 mg; and the like.
Suitable volatile propellants for use in devices of the invention
are well known in the art. A critical factor in selection of the
propellant employed is that its vapor pressure at the temperature
of use is greater than the pressure external to the device to
ensure that a pressure differential will exist to provide the
motive operating force for the device. Additionally, if the device
is employed for internal drug administration, the propellant should
be non-toxic and exhibit a pressure which is preferably not in
excess of about 2 atmospheres at the temperature of use.
Additionally, it is critical for this use that the propellant be
such that activation is not required from an extracorporeal
position. Exemplary of materials useful as propellants are
liquified gases. Suitable non-toxic gases are generally
fluorochlorinated lower saturated aliphatic hydrocarbons, suitably
halogenated lower alkanes containing one to four carbon atoms,
preferably one or two carbon atoms, and at least one fluorine atom,
including propellants such as dichlorodifuloromethane ("Freon 12"),
dichlorotetrafluoroethane ("Freon 114"), and
trichloromonofluoromethane ("Freon 11"). These propellants, or
suitable mixtures thereof, will produce a propellant vapor pressure
between about 1 and about 60 pounds per square inch at room
temperatures (20.degree.-25.degree.C). Suitable mixtures of the
propellants can be employed to give a preferred vapor pressure
between about 1 and about 10 pounds per square inch at these
temperatures.
When the device is to be employed for internal drug administration
in mammals, the propellant should have a vapor pressure which is in
excess of about one atmosphere at a temperature of about
37.degree.C or physiological temperatures. Preferred propellants
for this use include ethyl ether, Freon 11, n-pentane, butane,
dimethyl ether, isobutane, etc. Further, for this use it is
preferred that the volatile liquid have a vapor pressure of one
atmosphere at a temperature above -10.degree.C, more usually above
15.degree.C, and most preferably in the range of about 15.degree.
to 40.degree.C. Generally, the volatile liquid should have a vapor
pressure of one atmosphere at a temperature at least about
5.degree.C lower than the temperature of use and usually not more
than about 40.degree.C lower than the temperature of use. However,
this is not critical, but is primarily a matter of convenience in
handling and storage.
In order to achieve greater versatility as well as lower cost,
propellant blends have been developed as known to the art. These
blends consist of mixtures of fluorinated hydrocarbons and
hydrocarbons. Blends are used for a variety of reasons, including
(1) obtaining a preferred vapor pressure, (2) reduction of cost,
and (3) proper density. Further, blends of propellants can be
prepared wherein the changes in vapor pressure with temperature are
small.
If desired, long flexible tubing of polyethylene or the like can be
extended from the discharge port 23 of the device. In such manner
the device can be deposited at a site remote from the desired point
of application and still release the active agent contents through
the tube or conduit directly to said point. A modification of this
aspect permits placement of the dispenser in an environment at one
temperature to release the active agent into another environment
which can be at a lower temperature, for example, at a temperature
which is below the boiling point of the propellant. The dispenser
can also be provided with a check valve, for example, a one-way
ball valve, to prevent back flow of active agent or other materials
from the external environment into the device.
The subject device can be suitably modified for the independent
concurrent administration of more than one active agent. This can
be accomplished by employing a plurality of agent containing
chambers within the same device separated and/or sealed from each
other with each chamber having the same or separate flow resistive
elements. Each agent containing chamber is placed in operative
relation with the same or a pluraility of pressure driven
distendable bladders so as to discharge the agents as a mixture or
separately, but concurrently.
The following in vitro examples are merely illustrative of the
present invention and they should not be considered as limiting the
scope of the invention in any way, as these examples and other
equivalents thereof will become apparent to those versed in the art
in the light of the present disclosure, drawings and the
accompanying claims.
EXAMPLE 1
Stainless steel shells utilizing a single small bore exit tube are
employed; the exit tube functions as a flow resistent element.
Propellant bags are made by heat sealing plastic film into a
"pillow-type" structure of the type illustrated in FIG. 2 with
propellant inserted before closing the final seal. The bags are
made of one mil Capran 77 K film (Allied Chemical Co., nylon-six
coated with Saran on one side), and reagent grade ethyl ether is
employed as the volatile liquid.
Three difference sizes of bags are used, with 0.02 to 0.5 cc of
propellant being introduced into the bags. The amount of air
retained in the bags varies with the size of the bags. The largest
sized bag has a diameter of two centimeters and a length of about
five centimeters. The middle sized bag has an expanded volume
approximately 1/16th of the full size bag and has a diameter of
about 0.9 centimeters and a length of about 2.0 centimeters. The
smallest bag has an expanded volume of about 1/32nd of the full
size bag and has a diameter of 0.5 centimeters and a length of
about 1.4 centimeters.
The volume of the steel cylinder is varied by use of a plug or a
syringe so that the size of the cell is the same dimension as the
length of the bag. After placing the bag in the cylindrical
stainless steel tube, the tube is then filled with Dow Corning 200
fluids per milliliter containing 5 percent by weight of
progesterone.
The pump is tightly sealed and connected to an inverted graduated
pipette through a stainless steel capillary tube by using Silastic
tubing. Different sizes of capillary tube are employed. The pump
and inverted pipette are immersed completely in a constant
temperature bath, except for the short portion of the pipette tip.
The pumping rate is determined from the rising level with respect
to time of the Dow Corning fluid in the measuring pipette. For the
"three-equilibrated" runs, the entire system is thermostated for 15
minutes, and then the fluid is released to be pumped out. For the
"non-equilibrated" runs, the measurement of the pumping rate is
started right after the pump is placed in the bath water. The
measurements of the pumping rate are performed either by using a
different bag for each run or by using the same bag for a number of
runs.
The following table indicates the results of the test.
__________________________________________________________________________
Dimensions of Viscosity Size of Net Pumping Capillary Tubing of
Fluid Temp. Bag Q (exptal) Time length (cm) Q (expt) (cp).sup.(1)
(.degree.C) Used.sup.(4) (cc/min).sup.(2) (min).sup.(3) Int. radius
(cm) Q (calc).sup.(5)
__________________________________________________________________________
65.10 37 F/16 0.117 .+-. 0.0202 7.0 .+-. 1.0 8 0.84 2.477 .times.
10.sup.-.sup.2 653.54 37 F/16 0.0133 .+-. 0.0025 62 .+-. 8.0 8 0.78
2.477 .times. 10.sup.-.sup.2 6797.64 37 F/16 0.0038 .+-. 0.0005
161.25 .+-. 22.6 4 1.12 2.477 .times. 10.sup.-.sup.2 65.10 37 F/32
0.185 .+-. 0.0035 1.44 .+-. 0.216 8 0.76 2.477 .times.
10.sup.-.sup.2 653.54 37 F/32 0.031 .+-. 0.0037 8.25 .+-. 1.46 8
1.14 2.477 .times. 10.sup.-.sup.2 6797.64 37 F/32 0.0029 .+-.
0.00046 83.33 .+-. 6.40 8 1.07 2.477 .times. 10.sup.-.sup.2 6797.64
37 F 0.002 .+-. 0.00047 5061.7 .+-. 295 7.95 1.11 2.477 .times.
10.sup.-.sup.2 56.40 40 F 1.98 .+-. 0.16 7.25 .+-. 0.5 7.95
.sup.(6) -- 4.19 .times. 10.sup.-.sup.2 606.20 40 F 0.332 .+-.
0.021 36 .+-. 3.16 7.95 0.93 4.19 .times. 10.sup.-.sup.2 6198.8 40
F 0.0305 .+-. 0.0005 367.5 .+-. 17.5 7.95 0.87 4.19 .times.
10.sup.-.sup.2
__________________________________________________________________________
Notes: 1. Measured values with the Rotovisco Viscometer. 2. The
data are obtained by the pumping system which is at room
temperature until it is placed into bath water to start the pumping
test. Q (exptal) is the over-all average slope of the line
representing the accumulative volume of fluid pumped out versus
time. 3. 95 percent of the time at which the release rate goes to
zero. 4. F -- Full size bag. It is the largest bag used in this
program. Dia. .about. 2 cm and length .about. 5 cm. F/16 --
Expanded volume of this bag is approximately 1/16 of the full size
bag. Dia. .about. 0.9 cm and length .about. 2.0 cm. F/32 --
Expanded volume is about 1/32 of the full size bag. Dia. .about.
0.55 cm and length .about. 1.4 cm. 5. Q (calc) are based on the
Hagen-Poiseuille law. 6. Incomplete because of the lack of data for
the temperature history inside the pump, and therefore, the vapor
pressure of ether cannot be estimated accurately.
A number of conclusions are obvious from the above table. First, an
extremely wide range of fluids of different viscosities may be
employed in the subject invention with controlled release of the
fluid. Secondly, very small bags may be used having extremely small
amounts of a volatile liquid. Thirdly, long periods of time of
continuous discharge of the fluid can be achieved, although the
test is terminated after three and one-half days. Furthermore, good
reproducibility is obtained, in that the results are amenable to
mathematical analysis and predictability based on empirical
formulations.
EXAMPLE 2
A self-powered delivery device for the controlled and continuous
administration over a period of three days of tetracycline
hydrochloride to the rumen of a cow weighing 1,000 pounds is
prepared having the following dimensions and specifications:
Casing
High density rigid polyethylene Inside diameter 2.3 cm Wall
thickness 0.2 cm Inside length 5.0 cm Inner volume 21 cc
Inner bag
Polyethylene-polyvinyl alcohol-polyethylene laminate film, 1 mil
thick charged with 0.2 cc of propellant; propellant mixture of
Freon 11 and Halothane (2-bromo-2-chloro-1,1,1-trifluoroethane);
mole fraction of Freon 11 is 0.5; vapor pressure of propellant is
900 mm Hg at 38.degree.C; the bag is of the type illustrated in
FIG. 2A, having dimensions, when flat, 5 cm .times. 3.14 cm.
Active agent
15 grams of tetracycline HC1 in suspension medium of polyethylene
glycol 200 (40 weight percent). Concentration of drug is 0.75
gram/cc, having a particle size of less than one micron; viscosity
of formulation at 38.degree.C is 10,000 centipoise.
Flow Control Element
The flow control element is comprised of five stainless steel
hollow capillary tubes sealed in discharge port of the pump. The
dimension of each tube is as follows: length - 0.5 cm; diameter of
the lumen - 20 micron.
The device prepared above is inserted into the rumen of a cow and
will continuously administer the agent at a controlled rate over
approximately a 3 day period.
EXAMPLE 3
A self-powered delivery device for the controlled and continuous
administration of digitoxin to a human adult patient over a one day
period is prepared having the following dimensions and
specifications:
Casing
High density rigid polyethylene shell Inner volume 0.4 cm.sup.3
Inside diameter 0.6 cm Inside length 1.4 cm Wall thickness 0.1
cm
Inner bag
Polyethylene-polyvinyl alcohol-polyethylene laminate film 0.5 mil
thick charged with 0.05 cc of propellant mixture of Freon 11 -
Halothane; mole fraction of Freon 11 equal to 0.5; vapor pressure
of the propellant mixture is 850 mm Hg at 37.degree.C; the bag is
of the type illustrated in FIG. 2A, having dimensions, when flat,
of 1.4 cm .times. 0.9 cm.
Active agent
0.1 mg of digitoxin in carrier medium of ethyl alcohol (17 weight
percent) and sodium carboxyl methyl cellulose (1.5 weight percent).
Concentration of drug is 17 mg/cc; viscosity of drug carrier
formulation is 10,000 centipoise at 37.degree.C.
Flow Control Element
The flow control element is 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
The device prepared above is inserted in a conventional
pharmaceutical gelatin capsule, size 00, and sealed therein. When
orally ingested, the device prepared above will continuously
dispense the drug at a constant rate over approximately a one day
period.
It can be noted that among the advantages of the device herein
described is the ease of construction by standard manufacturing
techniques into units of various sizes, especially those which are
miniaturized, shapes and forms suitable for delivering an active
agent internally to an animal or human or other environment.
Another important advantage of the claimed delivery device is to
dispense at controlled rates, active agents having a wide variety
of chemical and physical properties and over a wide range of
release rates. This can conveniently be accomplished by appropriate
selection of the flow resistive means. Still another important
advantage of the invention resides in the ability to effectively
control the rate of release of the agent from the device throughout
the major portion of the administration period in a substantial
zero order manner. 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, e.g., a day
or week, without undue economic hardship on the user, and which
provides a continuous and controlled administration of an active
agent without employing any external energy source. Still another
advantage resides in the simplified manner of sealing the liquid
and vapor containing chambers from each other. Further, the chamber
containing the volatile liquid has a large surface area in contact
with the chamber containing the active agent, so that small changes
in pressure exerted against the bladder translate into relatively
large increases in force. Thus, the device can be constructed, if
desired, so as to have a relatively sensitive response to
temperature. However, the sensitivity of the rate of discharge to
temperature can be minimized, if preferred, by employing mixtures
of volatile liquids having a flat pressure-temperature response, as
known to those skilled in the art. The above advantages are
achieved by the unique combination of design, materials and
operation of the device.
Although the foregoing invention has been described in some detail
by way of illustration of a preferred embodiment and examples for
purposes of clarity of understanding, it will be understood that
certain changes and modifications may be practiced within the scope
and spirit of the invention, as defined in the appended claims.
* * * * *