U.S. patent number 3,732,865 [Application Number 05/106,130] was granted by the patent office on 1973-05-15 for osmotic dispenser.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Takeru Higuchi, Harold M. Leeper.
United States Patent |
3,732,865 |
Higuchi , et al. |
May 15, 1973 |
OSMOTIC DISPENSER
Abstract
An osmotic active agent dispenser is comprised of (1) a first
compartment of relatively impervious material containing an active
agent and provided with an aperture for releasing said active agent
to the exterior of the dispenser; (2) a second compartment of
controlled permeability to water containing a solution of an
osmotically effective solute which exhibits an osmotic pressure
gradient against water; and (3) a movable barrier member separating
the first from the second compartment. The barrier member is
slidably responsive to an increase in volume in the second
compartment via absorption of water therein; whereby as water flows
by osmosis into the compartment (2) of the dispenser in a tendency
towards osmotic equilibrium with its environment, corresponding
pressure is exerted behind the barrier (3) driving it into and
diminishing the volume of the compartment (1), in turn continuously
ejecting active agent thereout at an osmotically controlled rate
over a prolonged period of time. In a specific embodiment, the
dispenser is comprised of a plurality of capsule half shells one of
which compartmentalizing and being free to move within the device,
thereby defining a closure for both the active agent compartment
and the solution compartment.
Inventors: |
Higuchi; Takeru (Lawrence,
KS), Leeper; Harold M. (Lawrence, KS) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
22309650 |
Appl.
No.: |
05/106,130 |
Filed: |
January 13, 1971 |
Current U.S.
Class: |
604/892.1;
424/433; 424/453; 424/436; 424/455 |
Current CPC
Class: |
A61K
9/0004 (20130101); A61F 6/14 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61F 6/00 (20060101); A61F
6/14 (20060101); A61m 007/00 (); A61m 031/00 () |
Field of
Search: |
;128/127-131,172,213,218M,260,272,271,261
;222/193,389,386.5,130,105,106,94-97 ;424/15-21 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: McGowan; J. C.
Claims
What is claimed is:
1. An osmotic active agent dispenser, comprised of a plurality of
capsule half shells, with a first and a second half shell securedly
affixed in capsular configuration, and a third half shell
frictionally disposed in such capsule but free to slidably move
therein, the said capsule being thereby divided into two
compartments, an active agent compartment containing active agent
and provided with release means therefor to the exterior of the
dispenser and a second compartment containing a solution of an
osmotically effective solute which exhibits an osmotic pressure
gradient against water; the shell of the capsule comprising the
solution compartment is rigid, resistant and water pervious; the
shell of the capsule comprising the active agent compartment is
rigid, resistant and water impervious; and the interior half shell
is rigid, resistant and water impervious, the open end of which is
in communicating relationship with the said second compartment;
whereby as water flows by osmosis into the solution compartment in
a tendency towards osmotic equilibrium with its environment the
said solution compartment expands by forcing the interior shell
further into and diminishing the volume of the active agent
compartment, thus continuously squeezing active agent thereout at
an osmotically controlled rate over a prolonged period of time.
2. The osmotic dispenser as defined by claim 1, further comprising
a rapidly soluble fourth half shell capping the active agent
release means of the capsule.
3. The osmotic dispenser as defined by claim 1, wherein the active
agent is selected from the group consisting of a drug and a
bio-affecting composition.
4. The osmotic dispenser as defined by claim 1, wherein the active
agent contained therein is in the form of a semisolid
formulation.
5. The osmotic dispenser as defined by claim 1, wherein the
solution of an osmotically effective solute exhibiting an osmotic
pressure gradient against water is a saturated aqueous salt
solution.
6. The osmotic dispenser as defined by claim 5 wherein the
saturated salt solution contains excess solute in solid form.
7. The osmotic dispenser as defined by claim 1, wherein the said
second compartment is comprised of a membrane selected from the
group consisting of cellulose acetate, silicone rubber,
polyurethane, natural rubber and hydrolyzed ethylene/vinyl acetate
copolymer.
8. The osmotic dispenser as defined by claim 7, wherein the
membrane is anisotropic.
9. The osmotic dispenser as defined by claim 1, wherein the
osmotically effective solute is selected from the group consisting
of magnesium sulphate, magnesium chloride, sodium chloride,
potassium sulphate, sodium carbonate, sodium sulphite, sodium
sulphate, sodium bicarbonate, potassium acid phthalate, calcium
bicarbonate, potassium acid phosphate, raffinose, tartaric acid,
succinic acid, calcium succinate, calcium lactate and magnesium
succinate.
Description
CROSS-REFERENCE TO RELATED APPLICATION
Takeru Higuchi copending application, Ser. No. 106,131 filed Jan.
13, 1971, assigned to the assignee of the present invention.
FIELD OF THE INVENTION
This invention relates to an osmotic dispenser, and, more
especially, to an osmotic dispenser, simple in construction,
capable of releasing to its outside environment concentrations of
active agent at an osmotically controlled rate over a prolonged
period of time.
DEFINITION OF TERMS
The expression "active agent" as used herein denotes any drug (as
defined, infra); composition in any way affecting 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
substance having any other effect on any other environment,
especially any aqueous environment.
Therefore, 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 of 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, growth
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.
The terms "environment," "surroundings" and "habitat" as used
hereinabove and herein denote any prospective situs for the osmotic
dispenser of this invention which is comprised of or will provide
sufficient water for absorption into the device to develop the
needed osmotic pressure on which its motive force depends; and
implicit in the foregoing definition of "active agent" -- one that
will develop its action in the presence of such environment,
surroundings or habitat, or one that will develop its action on a
remote and/or another environment, which need not be aqueous, as
hereinafter described and illustrated.
BACKGROUND OF THE INVENTION
Many and varied compositions, products, appliances, depositors,
applicators, dispensers, injectors and devices are well known in
the art in which the timing or spacing of administration or
absorption of an active agent is regulated by the structure or
physical arrangement of elements so that a single administration
provides a gradual but continuous or sustained feeding of the
active agent to a system by slow or differential release. All of
such prior art devices and the like, however, are characterized by
at least one feature which adversely affects control over their
rate of sustained or differential release or which detracts from
the practical benefits attendant the long-term continuous
administration of various active agents both to humans, animals,
and into other environments.
An osmotic dispenser too has been proposed which is capable of
delivering drug solution at a relatively constant rate. See Rose
and Nelson, Austral. J. Exp. Biol., 33 pp. 415 - 420 (1955). The
Rose et al. injector consists of three compartments and a clamp to
hold a semi-permeable membrane. The motive force of the injector
depends on the osmotic pressure developed by a saturated aqueous
solution of Congo red against water. This solution is contained in
a partially collapsed rubber compartment and is separated from a
second water compartment by the semi-permeable cellophane membrane.
The partially collapsed bag is placed in a glass ampoule, with the
drug compartment of the device being defined by the space between
the Congo red bag and the glass ampoule. The ampoule is also
provided with drug release means and when the drug compartment is
charged with a drug solution by osmosis water will move into the
Congo red solution thus expanding the rubber compartment and
providing the mechanical force to eject the drug out of the
apparatus.
The Rose et al. device, however, has substantial inherent
disadvantages which has prevented its wide acceptance by the
medical community. In the first place, the use of a solution as the
drug vehicle (1) will not permit high concentration of drug to be
embodied within the device; (2) such solutions exhibit the
deleterious tendency to be released from the device by simple
leaching; and (3) many chemical substances on prolonged storage in
a dissolved state undergo chemical deterioration. The reference
injector is moreover cumbersome in that it depends for its motive
force on a separate water compartment rather than its environment.
In addition, the Rose et al. device is essentially only a research
or experimentation tool, is complex in construction and is at least
literally restricted to a Congo red solution to produce the osmotic
driving force and to a cellophane osmotic membrane. See also Rose
and Nelson, Austral. J. Exp. Biol., 33 pp. 411 - 414 (1955).
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of this invention to provide an
osmotic dispenser, simple in construction, which exhibits all of
the practical benefits of long-term continuous administration of
various active agents both to animals, humans, and into other
environments.
Another object of this invention is to provide an improved osmotic
dispenser which overcomes problems inherent in related devices
heretofore proposed.
Another object of this invention is to provide an improved osmotic
dispenser which will permit high concentrations of active agent to
be embodied therein, and which high concentrations of active agent
will not exhibit the tendency to be leached from the device nor be
decreased in potency by chemical breakdown.
Another object of this invention is to provide an osmotic active
agent dispenser which depends for its motive force on its
environment.
Still another object of this invention is to provide an osmotic
dispenser, the osmotic membrane of which can be fabricated from
many and varied suitable materials, and which is capable of using a
variety of solutions of osmotically effective solutes to produce
the osmotic driving force.
Yet another object of this invention is to provide an osmotic
dispenser of simple design which will release active agent
solution, or gel, or semisolid active agent formulation, at a
controlled rate over a prolonged period of time.
In attaining the objects of this invention, one feature resides in
an osmotic dispenser comprised of a first compartment of relatively
impervious material containing an active agent and a second
compartment containing a solution of an osmotically effective
solute which exhibits an osmotic pressure gradient against water.
Separating the said first from the said second compartment, and
defining a wall member common to each of said compartments, is a
sliding or movable barrier of impervious material. The enclosure,
whether of integral construction or not, defining the remainder of
the second compartment, wherein the osmotic motive force of the
dispenser is developed, is at least in part comprised of membrane
which exhibits controlled permeability to water. When placed in a
hypotonic aqueous environment, water, by osmosis, is absorbed
therefrom through the membrane and diffuses into the solution
contained in the said second compartment. As the water flows into
the second compartment, the solution contained therein increases in
volume exerting corresponding pressure behind the movable barrier
divider. Such pressure serves to drive the said barrier forward and
into the active agent compartment thus diminishing the volume of
same and which sliding barrier in turn ejects the active agent out
of the apparatus at an osmotically controlled rate over a prolonged
period of time. For purposes of permitting the active agent to be
squeezed out of the first compartment, same is provided with any
suitable dispensing head or active agent release means to the
exterior of the device, for example, capillary ducts
therethrough.
A further feature of this invention resides in an osmotic active
agent dispenser comprised of a plurality of capsule half shells,
similar in shape to pharmaceutical hard gelatin half shells, with a
first and a second half shell being securedly affixed in capsular
configuration, and a third half shell frictionally disposed in such
capsule but free to slidably move therein. The said capsule is
thereby divided into the two compartments with the third half shell
defining the wall member common to each of same. Optionally, a
fourth half shell defines capping means for the dispensing head of
the capsule.
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
In the drawings:
FIG. 1 is a cross-sectional view of an osmotic dispenser of this
invention;
FIG. 1a is a fragmentary cross-sectional view of a modification in
the dispensing head of the osmotic dispenser of FIG. 1;
FIG. 1b is a fragmentary cross-sectional view of another
modification in the dispensing head of the osmotic dispenser of
FIG. 1;
FIG. 2 is a cross-sectional view of another osmotic dispenser of
this invention;
FIG. 3 is a cross-sectional view of yet another osmotic dispenser
of this invention;
FIG. 4 is a cross-sectional view of still another osmotic dispenser
of this invention; and
FIG. 5 is an exploded view of the dispenser of FIG. 4.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment in accordance with this invention as illustrated
in FIG. 1 an osmotic dispenser 10 is comprised of a rigid,
impervious housing member or plastic shell 12, capsule-shaped and
having a thickened rounded end and bored with one or more capillary
ducts or openings 14 approximately 0.5 mm in diameter. The open end
of the plastic shell 12 is sealed or closed off with a membrane 16
which exhibits controlled permeability to water, advantageously a
semi-permeable, anisotropic cellulose acetate membrane of the type
used in reverse osmosis water desalination. The membrane 16 is
backed up by and supported by a stiff water-porous disc 18 which is
advantageously cemented in place in the said shell 12 and is
fabricated from such materials as, for example, a ceramic frit. A
sliding barrier plug, disc or seal 20, of impermeable barrier
material compartmentalizes the shell 12 into an active agent
compartment 22 and a compartment 24 wherein the motive force of the
dispenser is developed. The said first compartment 22 contains the
active agent, advantageously a drug, in a gel, paste or other
semisolid state (albeit a solution or concentrated solution of
active agent will sometimes suffice), and the active agent, if a
drug, is preferably normally carried in an oil phase, such as cocoa
butter. The said compartment 24 contains a solution of an
osmotically effective solute which exhibits an osmotic pressure
gradient against water; and the sliding barrier plug 20 is so
constructed as to movably provide and maintain a tight barrier
between the active agent phase in the first compartment and the
osmotic fluid in the second. Without this tight barrier undesirable
contamination could take place. The capillary ducts or active agent
release means 14 provide communication from the interior of the
compartment 22 to the exterior of the device 10, in this instance
the said means being comprised of one or more of said capillary
ducts 14 drilled in the thickened rounded end or dispensing head of
the said shell 12. The plug 20 is frictionally disposed but is free
to move within the device by sliding while at the same time
maintaining an impenetrable or contamination preventing barrier
between the active agent phase and the osmotic fluid.
To use the osmotic active agent dispenser of FIG. 1, the device,
when the active agent is a drug or other agent for treating, etc.,
a living organism, is either physically inserted or surgically
implanted in the body of the organism, typically a mammal, or is
administered via the gastrointestinal tract. Once in place, water
will be absorbed therein from either body tissues or body fluids
through the stiff porous support 18 and through the water permeable
membrane 16 in an effort to reach osmotic equilibrium, i.e., a
transition from hypertonicity to isotonicity. As the water flows by
osmosis into the compartment 24 tending to increase the volume of
same corresponding pressure is built up behind the sliding barrier
plug 20. Such pressure serves to drive the said barrier plug 20
forward at a constant rate thus forcing the drug through the
capillaries 14 at an osmotically controlled and constant rate into
the external environment. 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. Moreover, the use of any semisolid drug vehicle will reduce
the tendency to release the drug, or any other active agent for
that matter, by leaching and will permit high concentrations
thereof to be embodied within the device.
In some instances, the dispenser is 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 the device, such as the steel ball 26 of
FIG. 1. Other suitable weights comprise iron plugs, iron ore
tablets, brass plugs, ceramic plugs, or 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 aqueous 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 an aqueous
reaction medium.
If desired, long flexible tubing of polythene or the like can be
extended from the dispensing head of the device of FIG. 1. See FIG.
1a. In such manner the device can be deposited at a site remote
from the desired point of application and still release its active
agent contents through the dispensing head and then through the
tube directly to said point. This permits placement of the
dispenser in an aqueous environment and release of the active agent
into another environment which need not be aqueous. The dispensing
head can also be provided with a check valve, for example, a one
way ball valve (see FIG. 1b), to prevent back flow of active agent
or other materials from the external environment into the
device.
The design of the FIG. 1 device is moreover unique in that it
requires a membrane of but limited surface area. This because of
the ready availability of the highly water-permeable cellulose
acetate membranes designed for use in reverse osmosis processes for
water desalination. These membranes, typically and preferably
anisotropic membranes, are highly permeable to water (allow
relatively rapid rates of water transmission) but are relatively
impermeable to salt, thus permitting their use in relatively small
exposure area devices.
In FIG. 2 there is depicted an osmotic active agent dispenser 10
which allows for higher available exposure area of the membrane 16
and, accordingly, which design takes advantage of the availability
of a far greater number of membranes than the semi-permeable,
anisotropic cellulose acetate membranes of the type used in reverse
osmosis water desalination. In this embodiment, both the membrane
16 and the stiff water porous support 18 are cup shaped rather than
a flat disc, with the former being adhered or cemented to the
latter. The designs of both FIG. 1 and FIG. 2 are also such that
the porous disc or cup 18/membrane 16 assembly can alternatively
merely be snapped or press-fit into the porous shell 12 and be
there secured without the need for added adhesive or cement, and in
such manner this mechanical lock in and of itself prevents any
leakage. Optionally, in another alternative embodiment, a separator
of porous paper, fabric or the like can conveniently be disposed
between the support 18 and membrane 16. This prevents the membrane
from being punctured or drawn into too tight a contact with the
casing, thereby assuring that the entire membrane is exposed to the
aqueous environment. Also in FIG. 2 it is depicted that the
separator 20 may take the configuration of a capsule half shell,
rather than a plug or disc (as in, for example, the design of FIG.
3).
FIG. 3 illustrates another embodiment of this invention wherein an
osmotic active agent dispenser 30, similar to that of FIG. 1, is
comprised of three, and optionally four capsule half shells,
similar in shape to pharmaceutical hard gelatin half shells. The
shell 32 is optional and designed to rapidly dissolve in the
aqueous environment in which the device is intended to be placed,
for example, is designed to rapidly dissolve in body fluids (when
the active agent is a drug or other agent for treating, etc., a
living organism). Shell 32 thus provides a capping means for the
release port 44 of the capsule. Contrariwise, the shells 34 and 36
are rigid and resistant to dissolution and degradation in the
aqueous environment or body fluids, but exhibit controlled
permeability to moisture. The shells 34 and 38 are cemented tightly
on manufacture, in capsular configuration, with shell 36 being free
to move or slide in response to water flowing into the compartment
40, which compartment contains the solution of the osmotically
effective solute exhibiting an osmotic pressure gradient against
water, and said compartment 40 being defined by the walls of the
said shells 36 and 38 and to some extent by the walls of the said
shell 34. The active agent, advantageously a drug, is contained in
the compartment 42 which is defined by the space between the walls
of the shells 34 and 36. Shell 34 is provided with an aperture or
orifice 44 from which the active agent or drug exits upon expansion
of the solution compartment 40 which forces the shell 36 further
into the active agent compartment 42, thus diminishing the active
volume of the latter. The shell 36 is frictionally set into the
shells 34 and 38 to such an extent (1) that it is free to move in
response to absorption of water through the permeable shell 38 and
concomitant increase in volume of the said compartment 40 but (2)
the fit is tight enough as to prevent commingling and contamination
of the contents of the several compartments 40 and 42 by leakage.
It can be seen that, in use, as water flows into the solution
compartment in a tendency towards osmotic equilibrium with the
environment, the said solution compartment expands or increases in
volume by forcing the interior shell further into the active agent
compartment, thus continuously ejecting or squeezing active agent
thereout at an osmotically controlled rate over a prolonged period
of time. Thus, it will be appreciated that, mechanism-wise, the
dispenser of FIG. 3 is functionally equivalent to those of FIGS. 1
and 2. The shell 38 most preferably is a composite comprised of a
rigid, highly porous half shell 46 lined with membrane 48 which is
controlledly permeable to water. Such composite is readily
fabricated by either lining or laminating the membrane 48 to the
porous half shell 46, or by casting a film of the said membrane 48
onto and preferably within the said shell 46. The aforementioned
casting about the porous shell is advantageously perfected by
depositing the film from a solution of membrane forming material in
a solvent, e.g., a 20 percent solution of cellulose acetate in an
acetone-ethanolethyl lactate mixed solvent, 65 percent - 20 percent
- 15 percent. In casting the film, care should be taken that the
pores of the shell 46 do not become clogged.
Moreover, a device of either FIG. 1, FIG. 2 or FIG. 3 type is
admirably suited for the continuous administration of the
antibiotic oxytetracycline to beef cattle from the rumen. This
because such devices can easily be fabricated of a size, weight and
shape as to be retained in the rumen of polygastric animals to
release drug or similar agent thereto at a carefully controlled
rate. Other variations on the basic theme would be readily apparent
to the skilled artisan. Although particular configurations may be
designed for specific body uses, each of these configurations is
applicable to use in other environments.
The membrane 16 of FIGS. 1 and 2 and the half shell lining 48 of
FIG. 3 can be formed from a wide variety of materials permeable or
semi-permeable to solvent (water) but not to solute, i.e., those
suitable for the construction of an osmotic cell. For best results,
the membrane should be substantially impermeable to passage of the
osmotically effective solute so as to prevent loss thereof. Typical
membranes are isotropic membranes such as unplasticized cellulose
acetate, plasticized cellulose acetate, reinforced cellulose
acetate, cellulose di- and triacetate, ethyl cellulose; anisotropic
reverse osmosis membranes which typically are made of cellulose
acetate; silicone rubbers, polyurethanes, natural rubber, and
hydrolyzed ethylene/vinyl acetate copolymers. Isotropic membranes
have less water permeability than do the anisotropic membranes.
Also, with both types of membranes, increasing the acetate content
of the cellulose acetate polymer decreases the water permeability.
Since, as previously described, the surface area of the membrane is
relatively limited in a device of FIG. 1 type, it will be preferred
to use semi-permeable membranes allowing relatively rapid water
transmission in this general category of dispensers. Thus, in such
embodiments the anisotropic membranes are the preferred. A
cellulose acetate membrane suitable for this limited surface area
application is Eastman Chemical Products Type RO 97, which is rated
to be permeable to 1.5 to 2 cc/cm.sup.2 /day at atmospheric
pressure, against a saturated solution of K.sub.2 SO.sub.4 at
39.degree. C. A specific example of the design of FIG. 1
constructed with polymethylmethacrylate dispensing head, separator
and tubing having an inner diameter of 1.9 cm, is capable of
delivering 4 to 6 cc of active agent, advantageously a drug, per
day. In one specific embodiment of a dispenser of FIG. 2 type, the
membrane used was an isotropic cellulose acetate membrane, with no
plasticizer, having an acetate substitution of 2.4, being 3 mils
thick, and passing water at the rate of 70 mg/cm.sup.2 per day
against a saturated magnesium sulfate solution at 39.degree. C. The
membranes too are insoluble, and chemically compatible with the
salt solution and any excess solute therein. For drug depot
applications as heretofore described, the membranes are also
biologically inert, non-irritating to body tissues and
non-allergenic. For devices designed to deliver active agents
relatively rapidly for a limited period, membranes of controlled
high water permeability are indicated; membranes of lower water
permeability are used to provide slower and more prolonged
delivery.
The impermeable plastic shell 12 of FIGS. 1 and 2 and the half
shell 34 of FIG. 3 too are insoluble and can be formed of
polystyrene, polyethylene, polypropylene, polyvinyl chloride,
reinforced epoxy resin, polymethylmethacrylate, etc., sheet metal
(e.g., aluminum, copper, steel, etc.), galvanized pipe, or
styrene/acrylonitrile copolymer. It is of course intended that such
casing or shell act as a barrier to the transport of water. Again,
for drug depot applications the same are advantageously
biologically inert, non-irritating to body tissues and
non-allergenic. The barrier plug 20 and the half shell 36 can be
formed of materials identical to those used for fabricating the
shells 12 and 34. Especially preferred of the above are the
impermeable or refractory plastics. Likewise with respect to the
porous disc or cup 18 of FIGS. 1 and 2, and the half shell 46 of
FIG. 3, except in this instance the materials would be highly
porous since it is not intended that the member 18 and the half
shell 46 in any way act as a barrier to or restrict the transport
of water.
Half shell 32 of the FIG. 3 dispenser can be formed from any
material which will rapidly dissolve in the aqueous environment in
which the device is intended to be placed, such as gelatin and such
material again being biologically inert, non-irritating to body
tissues and non-allergenic when the device is designed for
placement in the body.
Many other materials including those which are biologically
acceptable 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 have previously been
described as being insoluble under the conditions and 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 situs 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.
It is further within the scope of the invention to optionally
provide the subject dispenser with a self-contained water supply or
separate water compartment, as in the first mentioned Rose and
Nelson publication, supra.
The relative thicknesses of the various membranes comprising the
dispensers of the invention, as well as the relative thickness of
the various shells and half shells can vary widely and are not
limitations on the invention. Typically, however, each shell and
half shell has a wall thickness of 0.5 to 50 mils, preferably of 5
to 50 mils, and the water permeable membranes have a wall thickness
of 1 to 10 mils.
One specific embodiment of a dispenser fabricated in accordance
with the invention, and as illustrated in FIG. 4 and 5, fitted with
a 3 mils thick semi-permeable membrane 16, and having the following
dimensions and specifications:
Outer diameter of dispenser 1.125 inch
Wall thickness of shell 12 0.125 inch
Inner diameter of dispenser 0.875 inch
Overall length 2.5 inch
External volume 2.45 inch.sup.3
Internal volume 1.24 inch.sup.3
Overall dispenser density .gtoreq. 1.5
Available membrane area 0.44 inch.sup.2
Active agent volume 0.94 inch.sup.3
Active agent density 1.2
Active agent: Approximately 60 percent tetracycline hydrochloride
dispersed in 40 percent cocoa butter medium;
Osmotic solution: Saturated aqueous solution of K.sub.2 SO.sub.4
containing sufficient excess solute in solid form to maintain
solution saturated over a period of at least 3 days;
Water permeable membrane: Cellulose diacetate, with a degree of
acetyl substitution of 2.4;
Shell 12: Soft polyethylene;
Threaded end cap 50: Soft polyethylene;
Delivery cap 52: Soft polyethylene;
Barrier member 20: Soft polyethylene;
Chamfered ring 54: Polycarbonate;
Membrane support 18: Polystyrene;
Diameter of delivery port 14: 0.0625 inch;
Diameter of orifices in cap 50: 0.0625 inch;
Diameter of orifices in support 18: 0.1250 inch;
is capable of delivering 5 gm of the active drug per day, over a
period of 3 days, when administered to the rumen of a 500 pound
calf, whereat it is retained, via the gastrointestinal tract. It
will be appreciated that the design of the FIG. 4 and FIG. 5 device
is quite similar to that of FIG. 1, with the most salient
distinctions therebetween residing, in the FIGS. 4 and 5 device, in
the separate rather than integral delivery cap 52; the chamfered
polycarbonate retaining ring 54 which aids in maintaining a tight
seal between the shell 12 and cap 52; and the perforated end cap
construction 50 which is threaded onto the shell 12 and fitted with
a rubber O-ring 56 to prevent leakage at the point of the thread
fit. The cap 50 houses the membrane 16 and the membrane support 18.
Of course, the greater the free space or total open surface area of
the plurality of ducts bored into the end cap 50, the greater the
amount of the membrane 16 which is exposed to the aqueous
environment. Likewise, the greater the open surface area of the
plurality of ducts bored into the membrane support 18, the more
readily the water diffuses into the compartment 24. As in the
designs of FIGS. 1 and 2, it is again optional that a separator of
porous paper, fabric or the like can be placed between either or
both of the membrane support 18 and end cap 50 and the
semi-permeable membrane 16. Same, as heretofore mentioned, prevents
the membrane from being punctured or drawn into too tight a contact
with its housing, thereby additionally assuring that the entire
membrane is exposed to the aqueous environment.
Any of the drugs used to treat the body, both topical and systemic,
can be compartmentalized as the active agent in any of the osmotic
dispensers of this invention. "Drug" is used herein in its broadest
sense as including any composition of substance that will produce a
pharmacological or biological response.
Suitable drugs for use in therapy with the dispenser of the
invention include without limitation:
1. Protein drugs such as insulin;
2. Desensitizing agents such as ragweed pollen antigens, hay fever
pollen antigens, dust antigen and milk antigen;
3. Vaccines such as small pox, yellow fever, distemper, hog
cholera, fowl pox, antivenom, scarlet fever, diphtheria toxoid,
tetanus toxoid, pigeon pox, whooping cough, influenza, rabies,
mumps, measles, poliomyelitis, Newcastle disease, etc.;
4. 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;
5. Anti-allergenics such as antazoline, methapyrilene,
chlorpheniramine, pyrilamine and prophenpyridamine;
6. Anti-inflammatories such as hydrocortisone; cortisone,
hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,
fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone
21-phosphate, and prednisolone acetate;
7. Decongestants such as phenylephrine, naphazoline, and
tetrahydrozoline;
8. Miotics and anticholinesterases such as pilocarpine, eserine
salicylate, carbachol, di-isopropyl fluorophosphate, phospholine
iodide, and demecarium bromide;
9. Mydriatics such as atropine sulfate, cyclopentolate,
homatropine, scopolamine, tropicamide, eucatropine, and
hydroxy-amphetamine;
10. Sympathomimetics such as epinephrine;
11. Sedatives and Hypnotics such as pentobarbital sodium,
phenobarbital, secobarbital sodium, codeine,
(.alpha.-bromoisovaleryl) urea, carbromal;
12. Psychic Energizers such as 3-(2-aminopropyl) indole acetate and
3-(2-aminobutyl) indole acetate;
13. Tranquilizers such as reserpine, chlorpromazine, and
thiopropazate;
14. Androgenic steroids such as methyltestosterone and
fluoxymesterone;
15. Estrogens such as estrone, 17 .beta. -estradiol, ethinyl
estradiol, and diethyl stilbesterol;
16. Progestational agents such as progesterone, megestrol,
melengestrol, chlormadinone, ethisterone, norethynodrel,
19-nor-progesterone, norethindrone, medroxyprogesterone and 17
.alpha.-hydroxy-progesterone;
17. Humoral agents such as the prostaglandins, for example,
PGE.sub.1, PGE.sub.2, and PGF.sub.2 ;
18. antipyretics such as aspirin, sodium salicylate, and
salicylamide;
19. Antispasmodics such as atropine, methantheline, papaverine, and
methscopolamine bromide;
20. Anti-malarials such as the 4-aminoquinolines,
8-aminoquinolines, chloroquine, and pyrimethamine;
21. Antihistamines such as diphenhydramine, dimenhydrinate,
tripelennamine, perphenazine, and carphenazine;
22. Cardioactive agents such as hydrochlorothiazide, flumethiazide,
chlorothiazide, and aminotrate;
23. Nutritional agents such as vitamins, essential amino acids and
essential fats;
24. Anti-Parkinsonism agents such as L-dopa,
(L-3,4-dihydroxyphenylalanine);
25. Investigative antihypotensive agents such as dopamine,
4-(2-aminoethyl) pyrocatechol.
Other drugs 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 dispensed with equal facility as with single
component systems.
Drugs can be in various forms, such as uncharged molecules,
components of molecular complexes, or non-irritating
pharmacologically acceptable salts such as hydrochloride,
hydrobromide, sulphate, phosphate, nitrate, borate, acetate,
maleate, tartrate, salicylate, etc. For acidic drugs, salts of
metals, amines, or organic cations (e.g., quaternary ammonium) can
be employed. Furthermore, simple derivatives of the drugs (such as
ethers, esters, amides, etc.) which have desirable retention and
release characteristics but which are easily hydrolyzed by body pH,
enzymes, etc., can be employed.
The amount of drug incorporated in the osmotic dispenser varies
widely depending on the particular drug, the desired therapeutic
effect, and the time span for which it takes the drug to be
released. Since a variety of dispensers in a variety of sizes and
shapes are intended to provide complete dosage regimes 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.
The motive force of the dispenser of this invention depends on the
osmotic pressure generated by the solution of the osmotically
effective solute contained in the compartments 24 and 40, which
solution exhibits an osmotic pressure gradient against water. Said
solution is most preferably a saturated aqueous salt solution. To
maintain the solution saturated and therefore to achieve a constant
osmotic pressure throughout operation of the dispenser, the
compartment containing the solution also contains excess solute in
solid form. Various osmotically effective solutes can be used.
These include magnesium sulphate, magnesium chloride, sodium
chloride, potassium sulphate, sodium carbonate, sodium sulphite,
sodium sulphate, sodium bicarbonate, potassium acid phthalate,
calcium bicarbonate, potassium acid phosphate, raffinose, tartaric
acid, succinic acid, calcium succinate, calcium lactate, and
magnesium succinate. The excess solid solute can be in the form of
dispersed particles or preferably in the form of a pellet. The
solution can initially be a solution of the same or of a
osmotically effective solute different than the solid excess
solute.
The osmotic dispenser can be fabricated in any convenient shape for
either physical insertion or implantation in the body, or for
administration via the gastrointestinal tract, or for introduction
into any desired aqueous 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 aqueous environment
to elicit the desired response, as well as by the form the dosage
unit takes, for example, in cases of specific body uses,
implantate, bolus, IUD, IVD, vaginal ring, uterine capsule for
fertility suppression, artificial gland, pessary, prosthesis,
suppository, and the like. Likewise with respect to the upper limit
on the size of the device. In one specific embodiment, the
dispenser can be of such size as to deliver 1 to 2 cc of drug
formulation per day and to deliver a total of 5 to 10 cc of drug
formulation over a 5 to 10 day period. With alternate choice of
slower permeation membranes, the pump can deliver drug more slowly
up to and in excess of 1 year. It is preferred that the
construction of the several compartments and of the active agent
release means be such that the osmotic driving pressure developed
is at least 10 times greater than the back pressure generated by
the active agent formulation.
Thus, the invention provides, in an osmotic dispenser, a reliable
means for releasing effective concentrations of active agent
contained therein to the body of a living organism, or to any other
aqueous environment, at an osmotically controlled rate and over a
prolonged period of time. In addition, prime advantages of the
dispenser of the invention are that it is simple in construction
and exhibits all of the practical advantages of the long-term
continuous administration of various active agents both to humans,
animals, and into other environments, and that the active agent
contained therein will not exhibit the tendency to be leached
therefrom.
While the invention has been described and illustrated with
reference to certain preferred embodiments thereof, those skilled
in the art will appreciate that various modifications, changes,
omissions, and substitutions can be made without departing from the
spirit of the invention. It is intended, therefore, that the
invention be limited only by the scope of the following claims.
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