U.S. patent number 3,760,806 [Application Number 05/106,132] was granted by the patent office on 1973-09-25 for helical osmotic dispenser with non-planar membrane.
Invention is credited to Harold M. Leeper.
United States Patent |
3,760,806 |
Leeper |
September 25, 1973 |
HELICAL OSMOTIC DISPENSER WITH NON-PLANAR MEMBRANE
Abstract
An osmotic active agent dispenser is comprised of: (1) a first
helical compartment of relatively impervious material containing an
active agent and provided with a dispensing head for releasing
active agent to the exterior of the dispenser; (2) a second helical
compartment of controlled permeability to water containing a
solution of an osmotically effective solute which exhibits an
osmotic pressure gradient against water, the second compartment
being interconnected with said first compartment to define a
continuous helix therewith; 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 by osmosis therein;
whereby as water flows 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.
Inventors: |
Leeper; Harold M. (Lawrence,
KS) |
Family
ID: |
22309665 |
Appl.
No.: |
05/106,132 |
Filed: |
January 13, 1971 |
Current U.S.
Class: |
604/892.1;
222/386; 128/832 |
Current CPC
Class: |
B01D
61/002 (20130101); B01D 61/005 (20130101); A61F
6/142 (20130101); B01D 69/04 (20130101); A61K
9/0004 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61F 6/00 (20060101); A61F
6/14 (20060101); A61m 031/00 (); A61f 005/46 () |
Field of
Search: |
;128/260,127-131,172,213,261,272,271
;222/193,389,386.5,386,130,105,106,94,95,97 ;210/23 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Govidan and Sourirajan, "Reverse Osmosis Separation of Some
Inorganic Salts ...-Using...Membranes;" I & EC Process Design
and Development, Vol. 5, No. 4, Oct. 1966; p. 422-429..
|
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: McGowan; J. C.
Claims
What is claimed is:
1. An osmotic active agent dispenser comprising, (1) a first
helical compartment of relatively impervious material containing an
active agent and provided with means for releasing said active
agent to the exterior of the dispenser; (2) a second helical
compartment comprised of membrane material having controlled
permeability to water, being at least in part non-planar in
configuration, and containing an osmotically effective solute
which, in solution, exhibits an osmotic pressure gradient against
water, said second compartment being interconnected with said first
compartment to define a continuous helix therewith; means to
restrict substantial expansion of the helix due to internal
pressure and (3) a movable barrier member separating the said first
from the said second compartment and movably responsive to an
increase in volume in the said second compartment via absorption of
water by osmosis therein; whereby as water flows 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 same 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.
2. The osmotic dispenser as defined by claim 1, wherein the barrer
(3) defines a wall member common to each of said compartments (1)
and (2).
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 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 first
helical compartment (1) is comprised of a member selected from the
group consisting of polyethylene, metal-foil polyethylene laminate,
neoprene rubber, rubber hydrochloride, polystyrene, polypropylene,
polyethylene terephthalate, polyvinlyl chloride,
polymethylmethacrylate, sheet metal, galvanized pipe, reinforced
epoxy resin, natural gum rubber, and styreneacrylonitrile
copolymer.
8. The osmotic dispenser as defined by claim 1, wherein the second
helical compartment (2) is comprised of a member selected from the
group consisting of cellulose acetate, silicone rubber,
polyurethane, natural rubber and hydrolyzed ethylene/vinyl acetate
copolymer.
9. The osmotic dispenser as defined by claim 1, wherein the active
ingredient release means comprises a capillary tube forming an
extension of helical compartment (1).
10. The osmotic dispenser as defined by claim 1, wherein the
restricting means comprises a relatively rigid permeable housing
member enveloping the device.
11. The osmotic dispenser as defined by claim 10, wherein the
housing member is comprised of a member selected from the group
consisting of perforated polystyrene, perforated polyethylene,
perforated polypropylene, perforated polyethylene terephthalate,
perforated polyvinyl chloride, perforated polymethylmethacrylate,
perforated sheet metal, perforated reinforced epoxy resin,
perforated galvanized pipe, porous sintered brass tubing, porous
styrene/acrylonitrile polymer, and porous sintered
polyethylene.
12. The osmotic dispenser as defined by claim 1, wherein the
movable impervious barrier is a spherical body comprised of glass
or plastic.
13. The osmotic dispenser as defined by claim 1, further comprising
a ballast member to regulate the weight thereof.
14. 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 sulfite, sodium
sulphate, sodium bicarbonate, potassium acid phthalate, calcium
bicarbonate, potassium acid phosphate, raffinose, tartaric acid,
succinic acid, calcium succinate, calcium lactate, magnesium
succinate and mixtures thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
Takeru Higuchi copending application, Ser. No. 106,131, filed Jan.
13, 1971, assigned to the assignee of the present invention;
and
Takeru Higuchi and Harold M. Leeper copending application, Ser. No.
106,130, filed Jan. 13, 1971, also 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 environement,
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 by such means as
destroying a parasitic organism or limiting the effect of the
disease or abnormality by chemically altering the physiology of the
host or parasite;
2. Maintaining, increasing, decreasing, limiting or destroying a
physiologic body or plant function, e.g., vitamin compositions, sex
sterilants, fertility inhibitors, fertility promoters, 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 in a
remote and/or another environment, which need not be agueous, 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 semipermeable 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 osomotic
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 helical compartment of
relatively impervious material containing an active agent and a
second helical compartment containing a solution of an osmotically
effective solute which exhibits an osmotic pressure gradient
against water. The two helical compartments are interconnected so
as to define a continuous helix. Separating the first helical
compartment from the second helical compartment, and defining a
wall member common to each of said compartments, is a sliding or
movable barrier of impervious material, advantageously a plastic or
glass ball separator. 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 material 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 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
the same, and which sliding or rolling barrier in turn ejects the
active agent out of the apparatus at an osmotically controlled rate
over a prolonged period of time. For the purpose of permitting the
active agent to be squeezed out of the first compartment, the same
is provided at its terminal point with any suitable dispensing head
or active agent release means to the exterior of the device, for
example, a capillary duct therethrough.
A further feature of this invention resides in an osmotic active
agent dispenser comprised of a dispenser according to the foregoing
description enveloped by a relatively rigid, highly permeable
housing member. The housing member serves both as a protective
means for the dispenser and also to restrict expansion of the
dispenser due to internal pressure. Alternatively, such expansion
may be in and of itself restricted by means of any suitable band or
tie member.
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 fragmentary cross-sectional view of an osmotic
dispenser of this invention;
FIG. 2 is a top view of FIG. 1;
FIG. 3 is a fragmentary cross-sectional view of a modification in
the dispensing head of the osmotic dispenser of FIG. 1;
FIG. 3a is a fragmentary cross-sectional view of another
modification in the dispensing head of the osmotic dispenser of
FIG. 1; and
FIG. 4 is a fragmentary cross-sectional view of an osmotic
dispenser of this invention having a rigid housing member.
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 two helically
shaped compartments, a first compartment designated generally by
reference numeral 12 and the second compartment designated by
reference numeral 14. Each of the helical compartments is formed by
coiling a relatively flexible tubular material, the former
essentially being a continuation of the latter, although, as
hereinafter described, there are significant differences in the
types and properties of the tubular material used to fabricate each
of the helical compartments 12 and 14. The lower end or terminal
point of compartment 14 is sealed off, as, for example, by curved
plug member 16 of a rigid impervious material such as refractory
plastic. Optionally, plug member 16 may be fabricated from metal or
similar heavy material to additionally serve as a ballast member
for adjusting the specific gravity of the dispenser. The terminal
point of helical compartment 12 is provided with a short
continuation in the form of tubing 18 having a capillary duct or
opening 20 approximately 0.5 millimeters in diameter. Joints
between the respective components may be press-fits or may involve
use of an adhesive system. The device is preferably provided with
one or more bands or ties 22 which bind together each of the coils
in the helix and act as restraining means to prevent spreading of
the coils due to internal pressures developed in the dispenser. A
sliding barrier plug 24 of impermeable material compartmentalizes
the helix and thus defines the exact boundaries of the helical
compartments 12 and 14.
The first compartment 12 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. Compartment 12 is thus
fabricated from a material which is impermeable both to the drug
contained therein and also to all components of the dispenser
environment.
The second compartment 14 contains a solution of an osmotically
effective solute which exhibits an osmotic pressure gradient
against water; and the sliding barrier plug 24 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 compartment. Advantageously, and as illustrated, the barrier
is a plastic or glass ball separator. Without this tight barrier,
undesirable contamination could take place. Compartment 14 is
fabricated at least in part from a material which exhibits
controlled permeability to water, preferably a semi-permeable
membrane of the type used in reverse osmosis water desalination,
e.g., isotropic or anisotropic cellulose acetate. Obviously, the
tubing used to fabricate compartment 14 must be impermeable to the
osmotically active solute contained therein.
The capillary tube or active agent release means 18 provides
communication from the interior of the compartment 12 to the
exterior of the device 10, in this instance the said means being
comprised of capillary duct 20 formed at the terminal point of the
active agent containing helical compartment 12. See also FIG. 2.
The plug 24 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. Thus, an oil/water or other
interface can be said to exist at the point of the plug in the
device.
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 water permeable walls of compartment 14 in an effort to
reach osmotic equilibrium, i.e., a transition from hypertonicity to
isotonicity. As the water flows into the compartment 14 tending to
increase the volume of same corresponding pressure is built up
behind the sliding barrier plug 24. Such pressure serves to drive
the said barrier plug 24 forward at a constant rate thus forcing
the drug through the tube 18 and capillary duct 20 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 metal plug 16 in
FIG. 1. Suitable weights comprise steel plugs, iron plugs, 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 affect 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. In such
a configuration, as illustrated in FIG. 3, 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. 3a), to prevent
backflow of active agent or other materials from the external
environment into the device.
The design of a device in accordance with the present invention is
moreover unique in that it provides a simple means to control the
amount of surface area available for osmotic penetration. Thus, for
example, by decreasing the diameter of the tubing used to
manufacture the helical coils, or by increasing the number of turns
in the helix of compartment 14 a significant increase in the
surface area of the water-permeable material results, whereby such
a design provides for ready attainment of large exposure areas of
the water permeable membrane and thus takes advantage of the
availability of a far greater number of water-permeable materials
than the semi-permeable, anisotropic cellulose acetate membrane of
the type used in reverse osmosis water desalination. Isotropic
membranes have less water permeability than do the anisotropic
membranes. Use of the latter type of material, however, permits
significant decreases in the size of helical compartment 14.
In FIG. 4 there is depicted an osmotic active agent dispenser
generally of the type illustrated in FIG. 1, except that the same
is enveloped by a relatively rigid permeable housing member 26. The
porosity of the housing member readily permits contact of water
from the environment with the dispensing device, while at the same
time its relatively rigid characteristics afford a high degree of
protection from damage or puncturing to the dispenser. Moreover,
the housing member advantageously serves as a restraining means to
prevent spreading of the coils, etc., in the device due to internal
pressure, especially when a housing member having both ends capped
is provided for this purpose; and serves the furter purpose of
facilitating emplacement in a given host or environment.
Another salient feature of the osmotic active agent dispenser of
this invention resides in its simple means of construction, and
correlatively in the simple manner thereby provided for controlling
the dosage rate in a given dispenser device. In contradistinction
to other known types of active agent dispensing devices wherein a
device of different size is required for each dosage level to be
contained therein, the instant dispensing device may be designed to
contain and administer any desired quantity of active agent to
contain and administer any desired quantity of active agent by
merely increasing or decreasing the length of tubing which
constitutes the active agent containing helical compartment 12.
Moreover, a device according to this invention 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 agents
thereto at a carefully controlled rate. Other variations of 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 tubing employed to fabricate the osmotic solution containing
compartment 14 can be formed from the 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 material should be substantially impermeable to
passage of the osmotically effective solute so as to prevent losses
thereof. Same is also insoluble and chemically compatible with the
salt solution in the compartment 14. 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 such as
above have less water permeability than do the anisotropic
membranes. Also, with both types of materials, increasing the
acetate content of the cellulose acetate polymer decreases the
water permeability. Since, as previously described, the surface
area available for osmotic transfer may be widely varied, the
devices of this invention are not limited to any one class of water
permeable material, i.e., both those exhibiting high permeability
as well as those of lower permeability may be employed. Thus, a
cellulose acetate membrane suitable for a device designed with
limited surface area available for osmotic transfer 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. When the compartment
is fabricated from an anisotropic reverse osmosis type of membrane
it is possible to obtain a delivery rate of from 20 to 10,000 mg of
active agent per day. In general, the unplasticized membranes of
whatever type provide for a far greater rate of release per day
than do the plasticized membranes. The device of the above specific
embodiment, having a specific gravity of at least 1.5, is moreover
well suited for administration to the rumen of beef cattle, whereat
it is retained, via the gastrointestinal tract; and this is an
excellent way of treating, for example, a 500 pound calf with
anti-biotic. For drug depot applications as heretofore described,
the membranes are also biologically inert, non-irritating to body
tissues and non-allergenic. One specific embodiment of a dispenser
fabricated in accordance with the design illustrated in FIG. 1,
having compartment 14 fabricated of cellulose diacetate tubing
(degree of acetyl substitution = 2.4) and compartment 12 formed of
polyethylene tubing, and having the following dimensions:
Compartment 14 Compartment 12 Outer diameter of tubing 1.000 cm
0.976 cm Wall thickness 0.012 cm 0.050 cm Inner diameter of tubing
0.976 cm 0.876 cm Outer diameter of helix 3 cm 3 cm Number of turns
4 3 Uncoiled length 25.1 cm 18.8 cm Initial volume Osmotic
Solution.sup.1 18.75 cc .sup.1 Saturated aqueous solution of NaCl
containing sufficient excess solute in solid form to maintain
solution saturated over period of intended use.
Compartment 14 Compartment 12 Initial volume drug.sup.2 11.3 cc
Effective surface area 78.9 cm.sup.2 Final volume osmotic solution
30.0 cc Final volume drum 0.00 cc Overall size of device: Diameter
3.2 cm Height 7.5 cm .sup.2 Approximately 55 percent
oxytetracycline hydrochloride in 45 percent cocoa butter
medium.
is capable of delivering 20 to 300 mg of drug per day.
The impermeable plastic material used to fabricate compartment 12
of the device too is insoluble, is chemically compatible with the
active agent contained therein, and can be formed of polystyrene,
polyethylene, polypropylene, polyethylene terephthalate, polyvinyl
chloride, reinforced epoxy resin, polymethylmethacrylate, etc.,
metal foil polyethylene laminate, neoprene rubber, natural gum
rubber, rubber hydrochloride, sheet metal, 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 24 can be formed of materials
identical to those used for fabricating the impervious active agent
containing compartment 12, and additionally can be formed of glass.
Likewise with respect to the rigid housing member 26 of FIG. 4,
except in this instance the materials would be highly porous since
it is not intended that the housing member in any way act as a
barrier to or restrict the transport of water.
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 wall thicknesses of the various types of tubing
comprising the two compartments of the dispeners of the invention
can vary widely and are not limitations on the invention.
Typically, however, the impermeable tubing of compartment 12 has a
wall thickness of 0.5 to 50 mils, preferably of 5 to 50 mils, and
the water permeable tubing of compartment 14 has a wall thickness
of 1 to 10 mils.
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, dyphtheria toxoid,
tetanus toxoid, pigeon pox, whooping cough, influenzae, 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 flurophosphate, phospholine
iodide, and demercarium bromide;
9. Mydriatics such as atropine sulfate, cyclopentolate,
homatropine, scopolamine, tropicamide, eucatropine, and
hydroxyamphetamine;
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, 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-materials 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 trolnitrate;
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 compartment 14, 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 environment. Dimensions of the device can thus
vary widely and are not of controlling importance. The lower limit
of the size of the device is governed by the amount of the
particular active agent to be supplied to the environment to elicit
the desired response, as well as by the form the 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 materials, the pump can
deliver drug more slowly up to and in excess of one 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
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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