U.S. patent number 3,604,417 [Application Number 05/024,136] was granted by the patent office on 1971-09-14 for osmotic fluid reservoir for osmotically activated long-term continuous injector device.
This patent grant is currently assigned to American Cyanamid Company, Wayne Henry Linkenheimer. Invention is credited to Sidney Joseph Stolzenberg.
United States Patent |
3,604,417 |
Stolzenberg |
September 14, 1971 |
**Please see images for:
( Certificate of Correction ) ** |
OSMOTIC FLUID RESERVOIR FOR OSMOTICALLY ACTIVATED LONG-TERM
CONTINUOUS INJECTOR DEVICE
Abstract
An improved osmotic pressure actuated injection device for long
term continuous injection which has a chamber filled with the
medicament to be injected and a suitable injection orifice, with a
piston or similar device, the other side of he piston being a
concentrated solution, such as a saturated solution, caPped with a
semipermeable membrane and exposed to a second chamber having the
solvent for the solution, and a freely movable piston exposed on
its other side to atmospheric pressure or similar source so that
the solvent moves through the semipermeable membrane increasing the
osmotic pressure and so forcing the piston in the first chamber to
discharge a small amount of medicament. The pressure in the solvent
chamber is maIntained constant, thus preventing formation of air
pockets therein.
Inventors: |
Stolzenberg; Sidney Joseph
(Yardley) |
Assignee: |
Linkenheimer; Wayne Henry
(Upper Makefield Township, Bucks County, PA)
American Cyanamid Company (Stamford, CT)
|
Family
ID: |
21819040 |
Appl.
No.: |
05/024,136 |
Filed: |
March 31, 1970 |
Current U.S.
Class: |
604/131; 222/389;
604/143 |
Current CPC
Class: |
A61M
5/145 (20130101); A61M 5/14526 (20130101); A61M
3/00 (20130101); A61M 2005/14513 (20130101) |
Current International
Class: |
A61M
3/00 (20060101); A61M 5/145 (20060101); A61m
005/00 () |
Field of
Search: |
;128/213,214,215,216,218R,218A,218P,225,260,261,1 ;222/389,399
;169/7,27,32,33 ;3/1 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Truluck; Dalton L.
Claims
We claim:
1. In a continuous, long-term injector device, which comprises a
hollow member with injection orifice at one end adapted for
connection with body tissue, a slidable piston in the member
dividing it into first and second chambers and a semipermeable
membrane across the end of said second chamber, the second chamber
being filled with an osmotic pressure developing solution and the
69 chamber containing a medicament, the improvement which
comprises,
a. a second hollow member serving as a reservoir for osmotic
pressure solvent and provided with a freely sliding piston,
b. screw-threaded means securing the reservoir onto the hollow
member of the injector device to maintain continuous contact of the
osmotic pressure solvent with the semipermeable membrane, and
c, means for exposing the side of the sliding piston in the
reservoir out of contact with solvent to a source of at least
ambient pressure.
2. A injector device according to claim 1 in which the source of at
least ambient pressure is the atmosphere.
Description
BACKGROUND OF THE INVENTION
Long-term, continuous injector devices have been developed for
gradual administration of medicaments over a considerable time,
such as the administration of anticancer agents, long continued
administration of contraceptive drugs, and like, using gas pressure
from electrolytic decomposition of water, which is not accurate,
and also those that have been actuated by osmotic pressure.
Normally the osmotic pressure devices have been supplied with
flexible reservoirs, such as plastic bags and the like, and this
has caused considerable problems, not only from the standpoint of
size which makes it unsuitable for implanting in a patient and
particularly in veterinary cases in an animal, but also, the
tendency of air or gas bubbles to form as the solvent flows out of
the reservoir into the concentrated or saturated solution has
resulted in a lowering of pressure so that the final pressure on
the medicament became insufficient.
SUMMARY OF THE INVENTION
The present invention utilizes an orifice, chamber with a piston in
it containing medicament, and on the other side of the piston a
concentrated or saturated solution as has been used before.
However, instead of a bag containing the osmotic solvent, this is
contained in another chamber which screws onto the first chamber,
of course being separated from the osmotic pressure solution by a
conventional semipermeable osmotic membrane, and it also contains a
piston which can freely slide, the other side of the piston either
being connected to atmospheric pressure or to some other constant
gentle pressure so that as the osmotic solvent gradually passes
through the semipermeable membrane the piston slides and prevents
formation of any gas voids. Atmospheric pressure is a very
desirable and simple form of maintaining the piston in continuous
contact with the osmotic solvent; however, other things, such as
springs or other devices, may be used.
Since the two chambers are rigid, usually of a metal or strong
plastic, the operation is independent of movements of a human or
animal in whom it is implanted or to whom it is attached, and this
is a very important characteristic, which maintains the pressure on
the osmotic solution constant for long periods of time (for example
as long as 1 month or more). This assures a continuous maintenance
of an unbroken layer of osmotic solvent across the membrane surface
regardless of the position of the subject and no gas voids can form
in the reservoir, which automatically and continuously adjusts its
volume by the movement of the piston to compensate for the
diminishing volume of reservoir solvent during operation of the
device. A long continued, gradual release of medicament, which can
be at a rate as low as 0.12 ml. per day, can be maintained, and the
device of the present invention therefore avoids all of the
disadvantages or drawbacks of the osmotic pressure actuated
injectors used hitherto.
The nature of the material of which the two chambers are formed and
of the pistons is not critical. Of course the chambers must be of a
material which is compatible with mammalian tissue if it is to be
implanted, but otherwise any material which is sufficiently strong
to maintain its shape and free-sliding fits for the two pistons may
be used. For many uses, particularly where the device is attached
to the patient or animal, atmospheric pressure to maintain a
constant pressure on the osmotic solvent is the simplest and
cheapest.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a section through a chamber containing the osmotic
pressure solvent, and
FIG. 2 is a similar section showing the osmotic solvent chamber
screwed onto the medicament dispensing chamber.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The preferred embodiments will be described first generally in
conjunction with the drawing followed by some specific examples
giving the details of the loading and use of the instrument.
FIG. 1 shows the osmotic pressure solvent chamber at 1 with one
chamber 2 filled with the osmotic pressure solvent and a sliding
free piston 4 which is capable of sliding in the circular device.
Lips 3 prevent the piston from leaving the chamber.
The chamber 2 has a threaded outlet 5 at one end, and in the
modification shown in FIG. 1 an outlet to the atmosphere on the
other end of the device, the chamber 6, which is on the other side
of the piston 4. Connection to the atmosphere can be through any
suitable conduit, such as a flexible elastomer if the device is
embedded in the patient or animal. If it is desired to have a
closed device, the end of the chamber 3 is closed, as is shown in
dashed lines as an optional structure 7.
FIG. 2 shows the threaded opening 5 from the chamber 2 screwed onto
external threads on a medicament dispensing vessel 8. This
dispensing vessel contains a freely sliding piston 10, and a
dispensing orifice 9 to which can be connected a short piece of
hypodermic needle, a plastic or silastic tubing or similar device.
The piston divides the device into two chambers, 11 and 12. The
former is filled with the medicament which is to be gradually
injected over a long period and the chamber 12 contains a
concentrated solution of a suitable osmotic pressure developing
solution, for example one constituting a saturated solution of the
dyestuff Congo Red, (3,3'-[ 4,4' -biphenylenebis (azo)] bis (4
-amino-1-naphthalene sulfonic acid, disodium salt). Continued
saturation is provided by having some of the material present in
solid form, not shown.
The chamber 12 at the end opposite the piston 10 is closed by a
semipermeable membrane 14 which is clamped tightly against the end
of the chamber by the clamping member 15 which shows onto a
threaded shoulder 16. In the chamber 2 there is the same solvent
which is used to form the solution in the chamber 12. The nature of
the particular solvent is not critical as it is not contacted with
the medicament or with the tissues of the patient or animal, and it
may be any suitable, stable liquid. In the case of the Congo Red
solution, water is a very suitable solvent. In chamber 2 water is
present or, if desired, a much more dilute solution of the Congo
Red. In addition to the solids mentioned above in the chamber 12, a
ball of metal or noncorrodible material, such as ceramic, 17 may be
provided, which will keep the saturated Congo Red solution
dispersed as a result of the normal movements of the patient or
animal which causes the ball to move around and to stir the
solution in chamber 12 gently.
As osmotic pressure slowly and gradually builds up in chamber 12,
the piston 10 moves and displaces an equal amount of medicament in
chamber 11 through the orifice 9. The volume of chamber 12 of
course increases as a result of the osmotic flow of solvent from
chamber 2 through the semipermeable membrane 14, and a constant
gentle pressure is therefore maintained on the piston 10, which
results in a very slow and continuous injection of the medicament.
As solvent, such as water, passes out from chamber 2 through the
semipermeable membrane 14, the piston 4 moves in slightly, under
atmospheric pressure in the case of this modification, or under
pneumatic pressure where a closed chamber is utilized. The chamber
2, therefore, cannot develop any gas voids and there is maintained
therein a gentle pressure suitable for continuous passage of
solvent through the membrane. It will be noted that the piston 4
always assures that there is a constant liquid layer at the
interface between the semipermeable membrane 14 and the osmotic
pressure solvent in the chamber 2, and this is maintained
regardless of the position of the patient or the animal in or on
which the injection device is mounted.
After a long period of continuous injection, the medicament in the
chamber 11 becomes exhausted and the device can then be removed
from the patient or animal and after suitable cleaning and
resterilizing, refilled with medicament and osmotic pressure
solvent.
Where the host is immobilized it may be desirable to actuate the
magnetized balls in the Congo Red compartment 12. To this end there
may be provided a microtiming device, connected to two small
magnets spaced exteriorly of the injector and at opposite ends of
compartment 12, shown in FIG. 2. At timed intervals the balls are
thus caused to roll from one end of the compartment to the other
causing agitation of the Congo Red solution suspension.
EXAMPLE 1
A 2 1/2 cc. plastic disposable syringe manufactured by
Becton-Dickinson, was cut off at the 2 cc. mark. The plastic handle
of the piston was removed and the remaining rubber plug was placed
so that the syringe would hold a volume of 1 cc. of medicament. The
remainder of the syringe contained about 0.8 gm. Congo Red and two
stainless steel balls. This was covered by a sheet of semipermeable
membrane obtained from a Visking dialysis sac. The membrane covered
this opening tightly and the ends were folded back securely. A
hollow cylinder obtained from a 5 cc. syringe of the same type, cut
between the 0 and 3 cc. marks, was inserted over the ends of the
semipermeable membrane. An airtight seal was made between the two
plastic syringes with Dow-Corning medical grade Elastomer. The
Elastomer hardened with a few minutes and supported the
semipermeable membrane as well. At the other end of the cylinder
the rubber plug from the 5 cc. syringe was inserted and the opening
behind the plug was covered with a plastic cap with a small opening
in the center. The plastic cap was sealed in place behind the 5 cc.
syringe with Elastomer.
To activate the device, two hypodermic needles were inserted
through the plastic walls on each side of the semipermeable
membrane. These were filled with distilled water so as to exclude
air bubbles on either side. The holes caused by the hypodermic
needles were sealed with elastomer. The compartment designed to
hold the medicament was filled with a 0.1 percent methylene blue
solution by means of a thin caliber hypodermic needle inserted
through the opening.
The device successfully constructed was tested in an in vitro
system. It was warmed at 37.degree. C. in a water bath contained in
a Dubnoff shaker. The entire 1 cc. of methylene blue was expelled
within 2 3/4 to 3 hours. When a plastic ring was glued next to the
semipermeable membrane such that the diameter of the membrane
exposed to fluids was about 3 mm., less than 1 cc. of the methylene
blue solution was injected after a week. It was about 0.12 cc. of
solution was expelled per day. The decline in volume of methylene
blue could be observed from day to day.
EXAMPLE 2
It should be emphasized that a high purity Congo Red, free of
contaminating ions or compounds of low molecular weight, is
essential, Contaminating molecules diffuse across the semipermeable
membrane and nullify or reduce the effective osmotic gradient.
The device is constructed as shown in FIG. 2 However, a 15 percent
solution suspension of Congo Red is used. In our recent experiments
higher concentrations tended to congeal and eventually appeared
gelatinous. The Congo Red compartment was filled and five stainless
steel balls of about 1.5 mm. diameter were added. The compartment
was covered with a Visking semipermeable membrane with a thickness
of 0.0008 inch. The water compartment obtained from a 5 cc. syringe
was sealed in place as previously described, using Caulk Grip
dental cement instead of Elastomer. Two drops of distilled water
was added and the water compartment was covered with the rubber
plunger from the 5 cc. syringe for storage before use.
To activate an injector device, the rubber plunger was removed and
the water compartment filled with distilled water. A 24-gauge
hypodermic needle was inserted through the plunger. The plunger was
reinserted into the 5 cc. syringe, allowing the excess water to
flow out through the hypodermic needle. Both the Congo Red and
water compartments were free of air bubbles. The opening behind the
plug was covered with a snugly fitting plastic cap with an opening
in the center measuring about 3 mm. in diameter. The medicament
compartment was filled with water.
Two in vitro experiments were carried out in a Dubnoff shaker by
placing the devices in a water bath at 37.degree. with mild but
continuous agitation. The results obtained with six injector
devices are listed in table 1. Two injector devices were fastened
on the backs of two sheep in an area previously shaved to remove
the wool. The devices were held in place with adhesive tape and
branding cement. The results are shown in table 2. ##SPC1##
##SPC2##
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