U.S. patent number 3,760,984 [Application Number 05/293,551] was granted by the patent office on 1973-09-25 for osmotically powered agent dispensing device with filling means.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Felix Theeuwes.
United States Patent |
3,760,984 |
Theeuwes |
September 25, 1973 |
OSMOTICALLY POWERED AGENT DISPENSING DEVICE WITH FILLING MEANS
Abstract
A device is disclosed comprised of a wall formed of a material
collapsable in response to mechanical force and surrounding a
closed compartment for containing an agent, a dispensing passageway
communicates with the compartment and the exterior of the device
for dispensing agent therefrom, a filling passageway communicates
with the exterior of the device and the compartment for filling the
device, a layer of an osmotically effective solute is deposited on
the collapsable wall's outer surface, said solute capable of
exhibiting an osmotic pressure gradient against an external fluid
and increasing its volume as fluid diffuses by osmosis into the
solute, an outer wall surrounding the layer of solute formed of a
material having shape retaining properties, permeable to the fluid
and substantially impermeable to solute, and wherein the filling
passageway houses a material penetrable to a means for filling the
compartment which material self closes on removal of the means to
maintain the compartment in closed condition for subsequent
collapsing thereof in response to mechanical or hydrostatic force
generated by osmotic pressure arising in the solute layer, as fluid
diffuses therein to increase its volume and generate forces that
are exerted between the collapsable wall of the agent containing
chamber and the more rigid outer semi-permeable wall, which
collapsing force in turn dispenses an agent through the dispensing
passageway when the compartment is charged with drug and the device
is positioned in the environment of use.
Inventors: |
Theeuwes; Felix (Los Altos,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
23129540 |
Appl.
No.: |
05/293,551 |
Filed: |
September 29, 1971 |
Current U.S.
Class: |
222/95;
222/386.5; 222/389; 604/892.1 |
Current CPC
Class: |
B01D
61/002 (20130101); A61K 9/0004 (20130101); B01D
61/005 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); B65d 035/28 () |
Field of
Search: |
;222/94,95,190,386.5,389,394 ;129/213,214R,218R,218A,260,272
;141/3,30 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
australian Journal Experimental Biology (1955), 33, pp.
415-420..
|
Primary Examiner: Reeves; Robert B.
Assistant Examiner: Martin; Larry
Claims
What is claimed is:
1. An osmotic dispenser for dispensing an active agent, wherein
said dispenser comprises:
a. an inner wall formed of a flexible material essentially
impermeable to solute and external fluid, the wall surrounding and
forming,
b. a compartment defined by the inner surface of the wall as a
means for housing an active agent,
c. a layer of an osmotically effective solute deposited on the
inner wall's outer surface, said solute capable of exhibiting an
osmotic pressure gradient against an external fluid when the
dispenser is positioned in the environment of use,
d. an outer wall surrounding the layer of solute, said outer wall
formed of a material having shape retaining properties and at least
a part of the wall is permeable to external fluid and impermeable
to solute,
e. a dispensing passageway communicating with the compartment and
the exterior of the device for dispensing an agent from the
device,
f. a filling passageway communicating with the exterior of the
device and the compartment as a means for charging agent into the
compartment,
g. a means positioned in the filling passageway for closing the
passageway, said means formed of a material that automatically
closes after agent is charged into the compartment through the
filling passageway.
2. An improved osmotic dispenser for dispensing an active agent
according to claim 1 wherein the inner wall material is a heat
shrinkable polymeric material.
3. An improved osmotic dispenser for dispensing an active agent
according to claim 1 wherein the automatic closing material is an
elastomeric material.
4. An improved osmotic dispenser for dispensing an active agent
according to claim 1 wherein the filling passageway is formed of a
heat shrinkable polymer in intimate contact with the automatic
closing material formed of an elastomeric material.
5. An improved osmotic dispenser for dispensing an active agent
according to claim 1 wherein in operation in the environment of
use, agent is dispensed from the dispensor by external fluid
permeating from the exterior through the permeable outer wall
continuously dissolving the solute in a tendency toward osmotic
equilibrium with the environment to continually increase the volume
between the outer wall and the compartment generating a mechanical
or hydrostatic force to cause the compartment to continuously
collapse and dispense agent from the device at a controlled rate
over a prolonged period of time through the dispensing passageway
with essentially no agent dispensed through the filling passageway.
Description
AREA OF THE INVENTION
This invention pertains to both a novel and useful device for
dispensing a useful agent. More particularly, the invention relates
to a dispensing device for the controlled and continuous dispensing
of an agent over a prolonged period of time to produce a desired
result. Specifically, the invention concerns an osmotic dispenser
manufactured with a minimum number of components wherein one of the
components is a filling port with a means for self-closing the port
to maintain the sterility and operability of the device after the
device is charged with agent.
BACKGROUND OF THE INVENTION
Osmotic dispensing devices for the delivery of active agent are
well known to the prior art. These devices are of assorted designs
and generally have a plurality of similar structural components.
For example, the devices usually have an external wall or housing
for containing an internal collapsable chamber for containing an
agent. The chamber in the device is surrounded by an osmotically
effective solute that is capable of exhibiting a pressure gradient
against an external fluid and increasing its volume as external
fluid diffuses into the solute to generate a force that is exerted
against the chamber causing it to collapse. As the chamber
collapses, it ejects agent through a passageway that leads to the
exterior of the device.
While these osmotic devices are useful for dispensing agent, they
have certain disadvantages that restrict or tend to defeat their
use for many applications. For example, the presently available
devices are prefilled with a drug which often looses its sterility
prior to use of the drug. Also, some drugs have a short shelf life
and these drugs tend to deteriorate during storage and diminish the
usefulness of the drug. Additionally, the prior art devices lacked
a port for filling the chamber, and if they were filled by
puncturing with a hollow needle, the device failed to function
either because of osmotic pressure leakage at the puncture site or
the device became contaminated resulting from mixing of solute and
agent arising at the site the inner wall was pierced. Thus, it will
be appreciated by those skilled in the art that while the prior art
devices made a valuable contribution to the art, the above
mentioned disadvantages tended to restrict their use to a few
environments.
OBJECTS OF THE INVENTION
Accordingly, it is an immediate object of this invention to provide
a novel dispensing device for the dispensing of agent to produce a
beneficial effect, which device overcomes the aforesaid
disadvantages associated with the prior art devices.
Still another object of the invention is to provide a novel osmotic
dispensing device for dispensing an agent at a controlled rate for
a prolonged period of time.
Yet still another object of this invention is to provide a novel
and useful osmotic dispensing device that is simple in
construction, designed with a minimum number of parts, easy to use,
and in operation is practical and useful for the controlled,
continuous, long-term administration of an agent.
Still another object of the invention is to provide an osmotic
dispensing device that has a separate port for filling the device
which is self closing to maintain the integrity of the device.
Yet still another object of the invention is to provide an osmotic
dispensing device that can be filled with agent when needed from a
separate source through a self closing port integral in the
device.
Still a further object of the invention is to provide an osmotic
dispensing device that is empty until charged and then can
administer a complete pharmaceutical dosage regimen for a period of
time, the use of which requires intervention only for initiation
and termination of the regimen.
Yet another immediate object of this invention is to provide a
dispensing device that can be filled with drug at the time of use
for administering a drug to produce a locally acting or
systemically acting drug to produce a physiologic or pharmacologic
effect which device can release the drug at a rate that does not
vary with time.
Other objects, features, and advantages of the invention will be
apparent to those skilled in the art, from the detailed description
of this specification, taken in conjunction with the drawings and
the accompanying claims.
SUMMARY OF THE INVENTION
The invention concerns a device comprised of an outer wall
surrounding an inner wall that defines a compartment as a means for
containing an agent. A layer of an osmotically effective solute
capable of exhibiting an osmotic pressure gradient against an
external fluid is housed between th outer and inner wall. A
dispensing passageway leads from the compartment to the exterior of
the device for releasing agent from the device. A filling
passageway leads from the exterior of the device to the compartment
and it houses a means for closing the passageway. The outer wall of
the device is formed of a material having shape retaining
properties and it is permeable to an external fluid and
substantially impermeable to solute. The inner wall is formed of a
material essentially impermeable to external fluid and solute and
collapsable when force is exerted thereon. In operation, external
fluid permeates at a rate controlled by the wall permeability, wall
dimensions, and osmotic pressure gradient into the solute causing
it to increase in volume. The increased volume generates a
mechanical or hydrostatic compressing or deflating pressure on the
collapsable wall, which pressure, negligible to the equilibrium in
osmotic pressure of the fluid, in turn ejects the active agent out
of the chamber at an osmotic-permeation controlled rate over a
prolonged and continuous period of time.
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 an elevated illustration of an osmotic dispenser of the
invention.
FIG. 2 is a cross-sectional view of FIG. 1 through 2--2
illustrating the structure of the device of FIG. 1.
FIG. 3 is a perspective, top view of a dispensing device of the
invention illustrating another embodiment of the invention.
FIGS. 4 through 7 represent a graphic illustration of osmotic pumps
showing their release rate from the devices over a prolonged period
of time.
In the drawings and specification, like parts in related figures
are identified by like numbers. The terms appearing earlier in the
specification and in the description of the drawings, as well as
embodiments thereof, are further described elsewhere in the
disclosure.
DETAILED DESCRIPTION OF THE DRAWINGS
Turning now to the drawings in detail, which are examples of
various delivery devices of the invention, and which examples are
not to be construed as limiting, one embodiment of a novel osmotic
delivery device is indicated in FIG. 1 by the number 10. Delivery
device 10 is comprised of a body portion 11, a discharge passageway
12 and a filling passageway 13 integrally formed with device 10. A
means 14 for self closing filling passageway 13 is seen in broken
lines in passageway 13.
Device 10 of FIG. 1 is seen in FIG. 2 in open section through 2--2
of FIG. 1. In FIG. 2, device 10 is comprised of a body 11 formed of
an inner wall 15 formed of a flexible material collapsable in
response to pressure and relatively impervious to fluid as osmotic
solute, the wall surrounds and forms a compartment 16 defined by
wall 15's inner surface. Compartment 16 is a means for containing
an active agent and it is proVided with a means 17 for dispensing
the agent to the exterior of device 10. COmpartment 16 is further
provided with a means 18 for filling compartment 16. Means 18, also
referred to as filling port or filling passageway is Provided with
a means 14 for self closing passageway 18. Closing means 14 is made
from a material that is essentially impermeable and inert to agent
and pierceable by a filling needle and self closes after the needle
is removed therefrom. Distant from inner wall 15 is positioned
outer wall 20. Wall 20 is formed in at least a part of a material
permeable to the passage of external fluid. Wall 20 can be of unit
construction, or composite construction with a section of a
semi-permeable membrane either formed integral in wall 20 or
optionally lined or laminated to wall 20. Wall 20 can be formed of
a semi-permeable material that has uniform properties across all
its dimensions, that is, it is substantially imperforate or
substantially homogenous, or wall 20 can be formed of a material
that is microporous.
In FIG. 2, positioned between wall 20 and wall 15 is a layer 21 of
an osmotically effective solute that exhibits an osmotic pressure
gradient against an external fluid, when the device is positioned
in the environment of use. In operation, these solutes osmotically
attract fluid through the semi-permeable membrane 20 to produce a
solution of the solute which increases in volume while
simultaneously generating mechanical or hydrostatic force that is
exerted against wall 15 to cause it to correspondingly collapse. As
wall 15 collapses it ejects active agent out of chamber 16 through
dispensing passageway 17 to the exterior of device 10 at an
osmotically membrane controlled rate over a prolonged period of
time.
FIG. 3 illustrates another embodiment of the invention. In FIG. 3,
device 10 is illustrated comprised of a body 11 having a pair of
ports 22 each distant from the other. Ports 22 can be optionally
used as filling ports or discharge ports and each houses a material
14 for closing the port after penetrated by a needle. Additionally,
either port can be equipped with a needle for discharging agent
from device 10.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the practice of the present invention, it has
now been found that the osmotic delivery device of the invention
provides many important advantages over previously known
osmotically operated delivery devices. One advantage of the device
is the ease of construction of the drug delivery device by standard
manufacturing techniques into devices of various shapes and forms
for delivering agent to recipient or environment. A more important
advantage of the claimed delivery device is that it can be
manufactured comprised of a minimum number of parts.
Another important advantage for osmotic delivery device 10 is the
device and its agent can be separately stored and the device
charged with agent at the time of use. This feature prevents or
substantially reduces deterioration of the agent since agents
susceptible to deterioration can be stored in glass containers and
charged into the device at the time of use. Yet another important
advantage for the devices of this invention resides in the users
option to formulate special agents or compositions of agents that
can be charged into the compartment at the time of use and at the
environment of use. Another important advantage for the device
resides in the device entering the commerical stream uncharged with
agent in a simple sterile package. The feature enhances the utility
of the device and simultaneously makes it possible to design
special devices for special application that can be charged with
agent at the environment of use. These features and other
advantages are made available to the art by the invention providing
the device with a filling port generally positioned distant from
the discharge port. The filling port is equipped with a self
sealing or self closing stopper or bung that fills the internal
space of the filling port and can be repeatedly penetrated and
closed following withdrawal by a penetrating instrument. The
filling port housing the bung is constructed with the wall in
intimate contact with the bung by shrinking the wall to the bung
during fabrication of the device. This unique feature of the device
also makes it possible to fill the device with agent without
developing air pockets in the compartment and without penetrating
the device's walls which could lead to a loss of osmotic pressure
and leakage. Additionally, another advantage for the novel osmotic
pump is that pumps made with a long and narrow catheter which could
not be filled heretofore can now be filled by entering the chamber
through filling port equipped with the bung.
Wall 20 of the device is a material that is semi-permeable, for
example a material that is permeable to an external fluid such as
water and the like while essentially impermeable to a selected
product or to other compounds in the device. The material forming
the wall can be non-erodible or bioerodible after a predetermined
period of time and in each instance it is semi-permeable to
external fluid but not to solute and is suitable through its shape
retaining properties during its useful life for construction of the
osmotic powered device. Typical materials for forming the wall
include membranes known to the art as osmosis and reverse osmosis
membranes such as commercially available unplasticized cellulose
acetate, plasticized cellulose acetate, reinforced cellulose
acetate, cellulose nitrate with 11 percent nitrogen, 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 phthalate, cellulose acetate methyl carbamate,
cellulose acetate succinate, cellulose acetate dimethaminoacetate,
cellulose acetate ethyl carbonate, cellulose acetate chloroacetate,
cellulose acetate ethyl oxalate, cellulose acetate methyl
sulfonate, cellulose acetate butyl sulfonate, cellulose acetate
propionate, cellulose acetate p-toluene sulfonate, triacetate of
locust gum bean, cellulose acetate with acetylated hydroxyethyl
cellulose, hydroxylated ethylene-vinylacetate, 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 permselective,
aromatic nitrogen-containing polymeric membranes that exhibit water
permeability and essentially no solute passage, osmosis membranes
made from polymeric epoxides, osmosis membranes made from
copolymers of an alkylene oxide and alkyl glycidyl ether,
semi-permeable polyurethanes, semi-permeable polyglycolic or
polylactic acid and derivatives thereof, thin film membranes as
disclosed by Loeb and Sourirajan in U. S. Pat. No. 3,133,132, the
membranes of ionically associated polyelectrolytes, the polymers
formed by the coprecipitation of polycation and a polyanion as
described in U. S. Pat. Nos. 3,276,586; 3,541,005; 3,541,006;
3,546,142; 3,173,876; derivatives of polystyrene such as
poly(sodium styrenesulfonate) and poly(vinylbenzyltrimethylammonium
chloride), and the like. Generally, membranes having a fluid
permeability of 0.01 to 10 cc/cm.sup.2 /hour or day or higher at
atmosphere pressure against a saturated product solution or
saturated solute solution to a changing concentration at the
temperature of use while simultaneously possessing a high degree of
impermeability to the product or solute are useful and within the
spirit of the invention.
Wall 15, or the inner wall of the device that defines the
compartment and is in intimate contact with bung 14 is a heat
shrinkable, polymeric material that collapses on the application of
force thereto and simultaneously maintains the self sealing bung in
the filling port. The polymeric membrane is selected from the class
of heat shrinkable polymeric films in the form of tubes, spheres,
ellipsoids, envelopes, films, laminates, and other geometric shapes
and fabricated structures is in one embodiment a material that has
been prepared by inducing strong molecular orientation by
uni-axially or bi-axially stretching of the film, which operation,
preferably, can be preceded by the introduction of inter-molecular
primary valence cross-linkage by chemical or radiation processes.
The degree of cross-linking, when employed, should be sufficient to
impart to the film a thermoset character, which can be conveniently
defined as the ability to exhibit a minimum tensile strength of
about 50 lbs./in..sup.2 at a temperature of 300.degree.F. By "heat
shrinkable" is meant in this embodiment that the film can contract
by at least 10 percent and typically from about 25 percent tO 75
percent of its stretched dimension in one or more directions upon
heating. The material is expanded or stretched mechanically,
hydraulically, or pneumatically, either uni-axially or bi-axially,
at room temperature or elevated temperatures, and then is set or
fixed, or "frozen", into this expanded, high energy state.
Procedures for accomplishing this are well known in the polymer
fabrication art. For example, in the manufacture of bi-axially
oriented, heat shrinkable flim, the film is prepared by extrusion
through a shaping die with a long, narrow horizontal slit of such
width as to give the desired film thickness. As the hot ribbon of
polymeric material issues from the die, it is gripped along its two
edges by tenter hooks which tend to stretch the film along its
width and to stretch it in a forward direction at the same time.
This operation imparts bi-axial orientation and yields a film with
equal shrinkage along both axes. Typically, such a film will have a
potential shrinkage of 50 percent in both directions. Not only is
the rate of stretching important in achieving this result, but the
rate of cooling and the temperature profile during the stretching
are important. As described here, this operation is done in-line
with extrusion, but it can also be done on preformed film by
heating and stretching the film.
In the manufacture of one type of heat shrinkable tubing for use in
the present invention, the polymer is first prepared in tubular
shape, preferably by extrusion through a die of the desired
cross-sectional configuration. The tubing can then be subjected to
ionizing radiation consisting of a stream of high energy electrons
as delivered by a van de Graaff generator or other electron
accelerating equipment. Or the tubing can be treated with gamma
rays as emanating from cobalt-60. The dosage delivered can vary,
depending upon the polymer system, from 0.5 to 100 megarads to
achieve the desired degree of intermolecular cross-linkage. The
tubing is then subjected to uni-axial molecular orientation by
drawing it, optimally in a warm or heated condition, over an
appropriately shaped mandrel, which increases the cross-sectional
area by a factor of 2 to 16. The polymer, having been selected from
classes which tned to have high intermolecular attraction, will
tend to remain in the high energy, stretched state until heated
above a temperature at which these intermolecular attractions are
melted or released. The "memory" or tendency to recover back to the
unstretched state is encouraged by the cross-linkage which was
introduced by the earlier radiation treatment.
Polymeric membranes preferably are cross-linked prior to stretching
and using to form the inner wall. The chemical cross-linking of
these polymers can be achieved by incorporation of various
cross-linking agents such as peroxides, sulfur, metallic oxides,
selenium, tellerium, diamines, diisocyanates, alkyl phenol
disulfides, p-quinone dioxime, tetra-chloro-p-benzoquinone, tetra
alkyl thiuram disulfides, 4,4'-dithiomorpholine, sulfur dichloride,
and the like, into the polymer followed by a period of heating.
Alternatively, cross-linking or vulcanization can be achieved by
use of high energy electron-beam radiation such as is provided by a
van de Graaff generator or other types of electron accelerators, or
by gamma ray emitters, or by X-ray generators.
In another embodiment pre-oriented shrinkable materials suitable
for forming the chamber and housing the self sealing bung by
engaging the bung when the film is exposed to heat comprise
oriented film of vinyl chloride polymer which has a Young's modulus
of elasticity in both directions of at least 200,000 p.s.i. (14,000
kg/cm.sup.2) at 23.degree.C, a shrinkage of at most 35 percent at
150 p.s.i. (10.5 kg/cm.sup.2) at any temperature. The films
preferably have shrink tensions not exceeding 100 p.s.i. (7
kg/cm.sup.2) at any temperature. The most preferred film is a rigid
(i.e. unplasticized) polyvinyl chloride film which is 0.01 to 0.95
mm thick and has been bi-axially oriented so that it has a
shrinkage in both directions of at most about 20 percent,
especially 15 to 20 percent, e.g. about 20 percent. Films having
low degrees of orientation or shrink in one direction only, such as
are produced directly by some extrusion methods, can be used in
accordance with the invention, but require the use of rather high
film temperatures, near the melting point of the polymer, in order
sufficiently to shrink the film. Accordingly it is preferred to use
films which have been bi-axially oriented so that they have percent
shrinkages at 100.degree.C in both directions of 5 to 35 percent,
especially 15 to 25 percent, particularly 15 to 20 percent, and
have shrink tensions not exceeding 150 p.s.i. (10.5 kg/cm.sup.2)
and preferably not exceeding 100 p.s.i. (7.0 kg/cm.sup.2) at any
temperature; such films are believed to be novel. They can be very
satisfactorily used in shrink packaging procedures in which the
film only has to reach a maximum temperature of 120.degree.C and
for regular objects 100.degree.C or even less.
The vinyl chloride polymer shrinkable materials used herein include
homopolymers and copolymers such as vinyl chloride and vinyl
acetate, styrene, acrylonitrite, dialkyl fumarate or maleate, or
alkyl acrylate or methacrylate, vinyl acetate and vinylidene
chloride, blends of polyvinyl chloride with chlorinated
polyethylene or terpolymer, and the like. Other heat shrinkable
materials include vinylidene chloride, copolymers of vinylidene
chloride of 20 to 80 percent vinylidene chloride, copolymers of
vinylidene chloride and vinyl chloride and the like. Heat
shrinkable materials are set forth in U.S. Pat. Nos. 3,022,543;
3,419,421; 3,459,582; 3,614,852; 3,627,116; and the like.
Various osmotically effective solutes including organic and
inorganic compounds are advantageously used for coating on the
exterior surface of the inner wall to act as a means for generating
osmotic pressure. Suitable solutes exhibit an osmotic pressure
gradient against an external fluid across the semi-permeable
membrane which membrane is substantially impermeable to the passage
of the osmotically effective solute to prevent loss thereof through
the membrane. Various osmotically effective solutes include
compounds such as magnesium sulfate, magnesium chloride, sodium
chloride, lithium chloride, potassium sulfate, sodium carbonate,
sodium sulfite, lithium sulfate, calcium bicarbonate, sodium
sulfate, calcium sulfate, potassium acid phosphate, calcium
lactate, magnesium succinate, tartaric acid, soluble carbohydrates
such as raffinose, glucose, mixtures thereof and the like.
Additionally, the solute can be used in a mixed form by mixing the
compound with a binder. The solute in powdered, granular, piece and
the like form, is homogenously or heterogenously dispersed in the
binder which binder is soluble or insoluble but will release the
solute on contact with wall material. Typical binders include
polyethylene glycol, gelatin, agar, carboxycellulose,
ethylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone,
soluble starch derivatives and the like. Typical binders that can
comprise about 1 to 50 percent of the composition include cellulose
acetate, polyurethane, epoxides, and other binders that permit the
free movement of fluid into the solute of the layered structure to
permit the solute to increase in volume and generate osmotic
pressure.
The stopper or bung, as confined in the filling passageway, is
comprised of naturally occurring or synthetic material that
possesses self closing or self sealing properties following the
withdrawal therefrom of a piercing instrument. These materials are
generally known to the art as elastomers, and they include the
commercially available carboxylated butadiene acrylonitrile
copolymers, butadiene vinylpyridine copolymers, polychloroprene,
isoprene, copolymerized with piperylene, polyisoprene,
poly(butadiene-co-styrene), poly(butadiene-co-acrylonitrile),
natural rubber, poly(isobutylene-co-isoprene), silicones,
fluroelastomers, butyl rubber, halogenated butyl rubber,
poly(butadiene-styrene-vinylpyridine) acrylic rubbers,
butadiene:acrylonitrite 80/20, 73/27, 68/32, 61/39, free radical
cross-linked silicone elastomers, and the like.
The phrase "active agent" and the term "agents" as used throughout
the specification and the accompanying claims comprises any
compound, or mixture of compounds, composition of matter or mixture
thereof that can be dispensed from the device to produce a
predetermined beneficial and useful result. The active agents
include pesticides, germicides, biocides, algicides, rodenticides,
fungicides, insecticides, anti-oxidants, plant growth promoters,
plant growth inhibitors, preservating agents, surfactants,
disinfectants, sterilization agents, catalysts, chemical reactants,
fermentation agents, cosmetics, foods, nutrients, food supplements,
drugs, vitamins, sex sterilants, fertility inhibitors, fertility
promotors, air purifiers, microorganism attenuators, and other like
agents that benefit the environment, surroundings, and habitat
including animals, mammals, man, valuable farm animals, household
animals, sport animals, and the like.
In a presently preferred embodiment the active agent is a drug that
will produce a local or systemic physiologic or pharmacologic
response when administered to animals, including humans, avians,
and the like. Suitable drugs that are dispensed in conventional,
standard dosage amounts as known to the art comprise desensitizing
agents such as ragweed pollen antigens, hay fever pollen antigens,
dust antigen and milk antigen; vaccines such as small pox, yellow
fever, distemper, hog cholera, fowl pox, antivenom, scarlet fever,
diphtheria toxoid, tetanus toxoid, pigeon pox, whooping cough,
influenzae, rabies, mumps, measles, poliomyelitis, Newcastle
disease, etc; anti-infectives, such as antibiotics, including
penicillin, tetracycline, chlortetracycline, bacitracin, nystatin,
streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline,
chloramphenicol, and erythromycin; sulfonamides, including
sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine,
sulfamerazine, and sulfisoxazole; anti-virals including
idoxuridine; and other anti-infectives including nitrofurazone and
sodium propionate; anti-allergenics such as antazoline,
methapyrilene, chlorpheniramine, pyrilamine and prophenpyridamine;
anti-inflammatories such as hydrocortisone, cortisone,
hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,
fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone
21-phosphate, and prednisolone acetate; decongestants such as
phenylephrine, naphazoline, and tetrahydrozoline; miotics and
anticholinesterases such as pilocarpine, eserine salicylate,
carbachol, di-isopropyl fluorophosphate, phospholine iodide, and
demecarium bromide; mydriatics such as atropine sulfate,
cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine,
and hydroxy-amphetamine; sympathomimetics such as epinephrine;
sedatimes and hypnotics such as pentobarbital sodium,
phenobarbital, secobarbital sodium, codeine,
(.alpha.-bromo-isovaleryl) urea, carbromal; psychic energizers such
as 3-(2-aminopropyl) indole acetate and 3-(2-aminobutyl) indole
acetate; tranquilizers such as reserpine, chlorpromazine, and
thiopropazate; androgenic steroids such as methyltestosterone and
fluoxymesterone; estrogens such as estrone, 17 .beta.-estradiol,
ethinyl estradiol, and diethyl stilbesterol; progestational agents
such as progesterone, megestrol, melengestrol, chlormadinone,
ethisterone, norethynodrel, 19-nor-progesterone, norethindrone,
medroxyprogesterone and 17 .alpha.-hydroxyprogesterone; humoral
agents such as the prostaglandins, for example PGE.sub.1,
PGE.sub.2, and PFD.sub.2 ; antipyretics such as aspirin, sodium
salicylate, and salicylamide; anti-spasmodics such as atropine,
methantheline, papaverine, and methscopolamine bromide;
anti-malarials such as the 4-aminoquinolines, 8-aminoquinolines,
chloroquine, and pyrimethamine; antihistamines such as
diphenhydramine, dimehydrinate, tripelennamine, perphenazine, and
carphenazine; cardioactive agents such as hydrochlorothiazide,
flumethiazide, chlorothiazide, and trolnitrate; nutritional agents
such as vitamins, essential amino acids and essential fats;
anti-Parkinsonism agents such as L-dopa,
(L-3,4-dihydroxyphenylalanine); investigative antihypotensive
agents such as dopamine, 4-(2-aminoethyl) pyrocatechol. Other
agents having the same or different physiological activity as those
recited above can be employed in osmotic dispensers within the
scope of the present invention. Suitable mixtures of drugs can, of
course, be explained with equal facility as with single component
systems.
The agent can be in various forms, such as unchanged molecules,
components of molecular complexes, or non-irritating
pharmacologically acceptable salts such as hydrochloride,
hydrobromide, sulphate, phosphate, nitrate, borate, acetate,
maleate, tartrate, salicylate, and the like. For acidic drugs,
salts of metals, amines, or organic cations, for example,
quaternary ammonium can be employed. Furthermore, simple
derivatives of the drugs such as ethers, esters, amides, and the
like which have desirable retention and release characteristics but
which are easily hydrolyzed by body pH, enzymes and the like can be
employed. The amount of agent incorporated in the osmotic dispenser
varies widely depending on the particular agent, the desired
therapeutic effect, and the time span for which it takes the agent
to be released. Since a variety of dispensers in a variety of sizes
and shapes are intended to provide complete dosage regimens for
therapy for a variety of maladies, there is no critical upper limit
on the amount of drug incorporated in the dispenser. The lower
limit too will depend on the activity of the drug and the time span
of its release from the dispenser. Thus it is not practical to
define a range for the therapeutically effective amount of drug to
be released by the dispenser. Thus, the amount dispensed for active
agents such as drug will be the standard amount as described in
Pharmacology in Medicine, edited by DiPalma, J.R.., 1965,
McGraw-Hill Book Company, New York; The Pharmacological Basis of
Therapeutics, Fourth Edition, by Goodman, L.S. and Gilman, A.,
1970, The Macmillian Co., New York; Remington's Pharmaceutical
Sciences, Fourteenth Edition, 1970, Mack Publishing Company,
Easton, Penn.; and the like. Additionally, the drug can be charged
into the device in known forms such as solution, dispersion, cream,
emulsion, suspensions, fine powders, and the like. Generally, the
device will contain about 0.01 to 90 percent or higher of an agent
or a mixture of agent and carriers based on the weight of the agent
or agent carriers composition solute to the volume of the device,
and the like. Typically, the device can be of such size and shape
to release 0.01 cc to 5 cc or higher of agent, usually contained in
a pharmaceutical carrier, per hour, day or longer, such as 1 cc to
10 cc of agent composition for 1 to 10 days, and the like.
The expressions "passageway" and "passageway communicating with" as
used herein are comprised of those means and methods suitable for
releasing the product from the device under the pumping rate of the
device. The expression includes an aperture, orifice, bore,
stainless steel needles, hollow cellulose acetate tubes, polyolefin
tubes, capillary tubes suitable for passing the agent, tubes and
conduits of various inside diameters, closed passageways containing
a bioerodible material that erodes in the environment of use to
produce an open passageway. Typical bioerodible materials include
erodible polyglycolic and polylactic fibers, erodible gelatinous
filaments, polyvinyl alcohol, and the like.
The following 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.
An osmotic dispensing device for the continuous release of active
agent and having a diameter volume of 100 microliters was
manufactured as follows: first, a section of commerically available
heat shrinkable poly(olefin) such as poly(vinylidene chloride)
having an internal diameter three thirty-seconds inches was cut
into a 5 cm section. Next, a plug of commerically available
Silastic silicone rubber was cut from a rod, with the plug having
the following dimensions 3 mm long .times. 3 mm O.D. wherein O.D.
is outside diameter. Then, the plug was inserted into the heat
shrinkable tubing and held in position between two solid steel
rods. One rod entered the tubing from each of its entrances. The
unit was heated at 100.degree.C in water and pulled longitudinally
until the gap between the plug and the rod was 2 mm longer than a
mold cavity used for the pulling step. The mold cavity was 7 mm
long.
The tubing containing the plug was cooled to room temperature and
clamped into a second mold with a milled cavity and a clamping
means for confining the encapsulated silicone rubber. The mold was
closed and heated at 100.degree.C in water with pressure applied
for 30 seconds through one opening of the tubing to expand the
tubing to the dimensions of the cavity. The mold was next cooled
and tubing housing the plug and having a cavity was removed from
the mold.
Next, an osmotic solute slurry was prepared by mixing 500 grams of
analytical reagent grade K.sub.2 SO.sub.4 powder with 200 ml of 2
wt percent ethyl cellulose in ethanol in a Waring blender at the
highest speed for about 2 minutes. The appropriate amount of solute
was deposited on 15 chambers by 5 dips in the cooled solute slurry
with 15 minute intervals between dips. The slurry coated chambers
were placed in a near zero humidity dry box to prevent water
absorption during evaporation of solvent. A few of the chambers
were optionally dipped in gelatin to smooth any pores and add
strength to the solute deposit. When gelatin was applied, the
gelatine dip was 15 g in 100 ml of distilled water at 60.degree.C.
All the coated chambers were dried at least 2 hours. The total
solute coat thickness was measured at about 0.27 mm.
Next, the dry solute coated chambers were placed in a dipping box
containing an acetone atmosphere for dipping in a freshly prepared
cellulose acetate membrane solution comprised of 15 wt percent
cellulose acetate and 85 wt percent acetone. The chambers were
dipped 14 times with 15 minute intervals between dips to deposit a
membrane about 14 mils thick.
Four osmotic dispensing devices manufactured according to the above
description were changed with a blue dye solution and the dye
release rate measured and charted in accompanying FIGS. 4, 5, 6 and
7. The osmotic pumps were placed in an environment of water which
was an external fluid. The dispensed blue dye is measured
volumetrically or by using standard otpical laboratory measuring
instruments. The results obtained show that after a short start-up
period, the osmotic devices uniformly dispense about 0.6 .mu.l/hr.
The prolonged and constant pumping rate is obtained to exhaustion
of the chamber, or for about 150 hours, and the total volume
dispensed from the devices was about 92 .mu.l. The results for the
devices measured as shown in FIGS. 4 - 7 are seen as evidencing the
useful operability of the device for its application in industry
and commence.
The novel, osmotic product delivery device of this invention
employs a unique means which facilitates the obtainment of
precisely conducted agent release rates in the environment of use.
While there has been described and pointed out the fundamental
novel features of the invention as applied to the presently
preferred embodiments, those skilled in the art will appreciate
that various modifications changes and omissIons in the osmotic
agent devices illustrated and described can be made without
departing from the spirit of the invention.
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