U.S. patent application number 10/885828 was filed with the patent office on 2004-12-02 for osmotic delivery device with membrane plug retention mechanism.
Invention is credited to Ayer, Rupal.
Application Number | 20040243106 10/885828 |
Document ID | / |
Family ID | 22085978 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040243106 |
Kind Code |
A1 |
Ayer, Rupal |
December 2, 2004 |
Osmotic delivery device with membrane plug retention mechanism
Abstract
An osmotic delivery device includes a delivery device body
having a first end with a beneficial agent delivery orifice and a
second open end. An expandable, semipermeable membrane plug is
secured in an open end of the delivery device body by a plurality
of holes formed in the delivery device body around the open end of
the delivery device body.
Inventors: |
Ayer, Rupal; (Santa Clara,
CA) |
Correspondence
Address: |
TRASK BRITT
P.O. BOX 2550
SALT LAKE CITY
UT
84110
US
|
Family ID: |
22085978 |
Appl. No.: |
10/885828 |
Filed: |
July 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10885828 |
Jul 7, 2004 |
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09858631 |
May 17, 2001 |
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09858631 |
May 17, 2001 |
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09217823 |
Dec 22, 1998 |
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6270787 |
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60068987 |
Dec 29, 1997 |
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Current U.S.
Class: |
604/892.1 ;
424/422 |
Current CPC
Class: |
A61K 9/0004
20130101 |
Class at
Publication: |
604/892.1 ;
424/422 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. An osmotic delivery device comprising: a delivery device body
comprising a first end having a beneficial agent delivery orifice,
and a second open end; and an expandable, semipermeable membrane
plug secured in an open end of the delivery device body by a
plurality of holes formed in the delivery device body around the
open end of the delivery device body.
2. The osmotic delivery device according to claim 1, wherein the
delivery device body further comprises a movable piston separating
a first reservoir containing the beneficial agent from a second
reservoir containing an osmotic agent and causing the beneficial
agent to be delivered through the delivery orifice when the osmotic
agent draws the external liquids through the expandable,
semipermeable membrane plug.
3. The osmotic delivery device according to claim 1, wherein
external liquid is drawn into the delivery device body through the
expandable, semipermeable membrane plug by way of the open end of
the delivery device body and the plurality of holes.
4. The osmotic delivery device according to claim 1, wherein the
plurality of holes are cylindrical bores.
5. The osmotic delivery device according to claim 1, wherein the
plurality of holes are spaced in an annular manner around a side
wall of the delivery device body adjacent the open end of the
delivery device body.
6. The osmotic delivery device according to claim 1, wherein the
delivery device body has a substantially cylindrical side wall and
the plurality of holes are formed in the substantially cylindrical
side wall.
7. The osmotic delivery device according to claim 6, wherein the
substantially cylindrical side wall includes an inwardly directed
annular lip at the open end of the delivery device body which
provides additional retention of the expandable, semipermeable
membrane plug in the delivery device body.
8. The osmotic delivery device according to claim 2, wherein the
movable piston is movable longitudinally in a direction defined by
a longitudinal-axis of the osmotic delivery device.
9. The osmotic delivery device according to claim 1, wherein the
expandable, semipermeable membrane plug provides a semipermeable
closure of the open end of the delivery device, the expandable,
semipermeable membrane plug allowing fluid to pass into the osmotic
engine and preventing the osmotic engine from passing out of the
capsule.
10. The osmotic delivery device according to claim 6, wherein the
plurality of holes is cylindrical bores spaced in an annular manner
around the side wall.
11. An osmotic delivery device comprising: a delivery device body
comprising a first end having a beneficial agent delivery orifice,
a second open end, a beneficial agent, and an osmotic agent for
drawing external liquids into the delivery device body to cause the
beneficial agent to be delivered; and an expandable, semipermeable
membrane plug secured in an open end of the delivery device body by
a plurality of holes formed in the delivery device body around the
open end of the delivery device body.
12. The osmotic delivery device according to claim 11, wherein the
delivery device body further comprises a movable piston separating
a first reservoir containing the beneficial agent from a second
reservoir containing the osmotic agent and causing the beneficial
agent to be delivered through the delivery orifice when the osmotic
agent draws the external liquids through the expandable,
semipermeable membrane plug.
13. The osmotic delivery device according to claim 11, wherein
external liquid is drawn into the delivery device body through the
expandable, semipermeable membrane plug by way of the open end of
the delivery device body and the plurality of holes.
14. The osmotic delivery device according to claim 11, wherein the
plurality of holes are cylindrical bores.
15. The osmotic delivery device according to claim 11, wherein the
plurality of holes are spaced in an annular manner around a side
wall of the delivery device body adjacent the open end of the
delivery device body.
16. The osmotic delivery device according to claim 11, wherein the
delivery device body has a substantially cylindrical side wall and
the plurality of holes are formed in the substantially cylindrical
side wall.
17. The osmotic delivery device according to claim 16, wherein the
substantially cylindrical side wall includes an inwardly directed
annular lip at the open end of the delivery device body which
provides additional retention of the expandable, semipermeable
membrane plug in the delivery device body.
18. The osmotic delivery device according to claim 12, wherein the
movable piston is movable longitudinally in a direction defined by
a longitudinal axis of the osmotic delivery device.
19. The osmotic delivery device according to claim 1 wherein the
expandable, semipermeable membrane plug provides a semipermeable
closure of the open end of the delivery device, the expandable,
semipermeable membrane plug allowing fluid to pass into the osmotic
engine and preventing the osmotic engine from passing out of the
capsule.
20. The osmotic delivery device according to claim 16, wherein the
plurality of holes is cylindrical bores spaced in an annular manner
around the side wall.
Description
[0001] This application is a continuation of application Ser. No.
09/858,631, filed May 17, 2001, pending, which is a divisional of
application Ser. No. 09/217,823, filed on Dec. 22, 1998, now U.S.
Pat. No. 6,270,787, issued Aug. 7, 2001, which claims the benefit
under Title 35, United States Code, .sctn. 119(e) of U.S.
Provisional Application No. 60/068,987 filed on Dec. 29, 1997.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to osmotic delivery systems
for delivering beneficial agents, and more particularly, to an
osmotic delivery system having an osmotic engine and a membrane
plug allowing fluid to pass into the osmotic engine.
[0004] 2. State of the Art
[0005] Controlled delivery of beneficial agents, such as drugs, in
the medical and veterinary fields has been accomplished by a
variety of methods. One method for controlled prolonged delivery of
beneficial agents involves the use of osmotic delivery systems.
These systems can be implanted within a body of a human or animal
to release beneficial agents in a controlled manner over a
preselected time or administration period. In general, osmotic
delivery systems operate by imbibing liquid from the outside
environment and releasing corresponding amounts of the beneficial
agent.
[0006] A known osmotic delivery system, commonly referred to as an
"osmotic pump," generally includes some type of a capsule or
enclosure having a semipermeable portion which selectively passes
water into an interior of the capsule containing a water-attracting
osmotic agent. In one known osmotic delivery system, the walls of
the capsule are substantially impermeable to items within and
outside the capsule. A membrane plug is inserted into one end of
the capsule and acts as the semipermeable portion to allow water to
pass into the interior of the capsule. The difference in osmolarity
between the water-attracting osmotic agent and the environment
surrounding the capsule causes water to pass through the membrane
plug into the capsule which in turn causes the beneficial agent
within the capsule to be delivered through a delivery orifice. The
water-attracting osmotic agent may be the beneficial agent
delivered to the patient; however, in most cases, a separate
osmotic agent is used specifically for its ability to draw water
into the capsule.
[0007] When a separate osmotic agent is used, the osmotic agent may
be separated from the beneficial agent within the capsule by a
movable dividing member or piston. The structure of the capsule is
such that the capsule does not expand when the osmotic agent takes
in water and expands. As the osmotic agent expands, it causes the
piston to move and the beneficial agent to be discharged through
the delivery orifice at the same rate as the liquid (which is
typically water) enters the osmotic agent by osmosis. Osmotic
delivery systems may be designed to deliver a beneficial agent at a
controlled constant rate, a varying rate, or in a pulsatile
manner.
[0008] In the known osmotic delivery systems, an osmotic tablet is
generally used as the osmotic agent and is placed inside the
capsule adjacent the piston. The membrane plug is placed in an
opening in the capsule through which the tablet and piston are
inserted. Known membrane plugs are typically cylindrical members
which seal the interior of the capsule from the exterior
environment, permitting only certain liquid molecules from the
environment of use to permeate through the membrane plug into the
interior of the capsule. The rate that the liquid permeates through
the membrane plug controls the rate at which the osmotic agent
expands and drives the beneficial agent from the delivery system
through the delivery orifice. The rate of delivery of the
beneficial agent from the osmotic delivery system may be controlled
by varying the size of the beneficial agent delivery orifice, the
osmotic material, a size and shape of the membrane plug, or the
permeability coefficient of the membrane plug.
[0009] The permeability coefficient of a membrane plug is dependent
on the particular material or combination of materials used in the
plug. Thus, the delivery rate of the beneficial agent may be
controlled by forming the same configuration membrane plug from
different semipermeable materials, these materials having
permeability coefficients which result in delivery of the
beneficial agent at a desired delivery rate. One problem associated
with obtaining different permeation rates in this manner is that a
different membrane material must be used for every system which has
a different desired beneficial agent delivery rate, thus requiring
the purchase of many different membrane materials and the
manufacture of many different membrane plugs.
[0010] Many osmotic delivery systems which use membrane plugs have
problems with expulsion of the membrane plug from the capsule.
Expulsion may occur after the beneficial agent has been completely
delivered while the osmotic agent continues to draw water into the
capsule and forces the membrane plug out of the capsule. Some
osmotic delivery systems use glues or adhesives to prevent the
capsule from leaking and to ensure that the membrane plug remains
in place in order to prevent harmful materials from the interior of
the capsule from leaking into the surrounding environment. In
addition to adding a manufacturing step and increasing costs,
applying an adhesive to the membrane plugs may affect the rate of
permeation.
[0011] Membrane plugs used in systems which are designed to deliver
a beneficial agent at delivery rates which allow complete delivery
of the beneficial agent in time periods from about 1 day to 2 weeks
are particularly susceptible to membrane expulsion problems. These
rapid delivery membranes swell due to water uptake within hours of
implantation and become slippery and sponge-like. The rapid
swelling of such membranes tends to cause the membranes to be
expelled from the capsule.
[0012] Because of the above-identified problems associated with
current osmotic delivery system membrane plugs, it is difficult and
expensive to provide osmotic delivery systems which administer
beneficial agents at different desired delivery rates and prevent
expulsion of the membrane plug.
BRIEF SUMMARY OF THE INVENTION
[0013] In accordance with the present invention, an osmotic implant
has a membrane plug which swells into holes in the side wall of the
capsule to lock the membrane in place.
[0014] According to one aspect of the present invention, an osmotic
delivery device includes a delivery device capsule having a
substantially cylindrical side wall, a first end having a
beneficial agent delivery orifice, and a second open end. A
separating member is positioned within the delivery device capsule
and is movable in a longitudinal direction within the delivery
device capsule to dispense the beneficial agent. An osmotic engine
is positioned adjacent one side of the separating member. A
plurality of openings is formed in the substantially cylindrical
side wall adjacent the second open end of the delivery device
capsule. A membrane plug is positioned within the second open end
of the delivery device capsule and covers each of the plurality of
openings in the substantially cylindrical side wall. The membrane
plug is retained in the capsule by the plurality of openings.
[0015] In accordance with a further aspect of the invention, the
membrane plug is formed of a material which swells causing a
portion of the membrane plug to extend into the openings in the
side wall increasing friction between the membrane plug and the
delivery device capsule and preventing expulsion of the membrane
plug from the delivery device capsule.
[0016] In accordance with another aspect of the present invention,
an osmotic delivery device includes a delivery device body
containing a beneficial agent to be delivered through a delivery
orifice of the delivery device body and an osmotic agent for
drawing external liquids into the delivery device body to cause the
beneficial agent to be delivered. A membrane plug is secured in an
open end of the delivery device body and allows the external
liquids to pass through the membrane plug into the delivery device
body. The membrane plug is secured in the open end of the delivery
device body by a plurality of holes formed in the delivery device
body around the open end of the delivery device body. The membrane
plug is expandable to extend into the plurality of holes to prevent
expulsion of the membrane plug from the delivery device body.
[0017] According to an additional aspect of the present invention,
an implantable osmotic beneficial agent delivery device with a
controllable beneficial agent delivery rate includes a
substantially cylindrical body having a beneficial agent delivery
orifice and an open end. A plurality of openings is formed in a
side wall of the substantially cylindrical body at the open end.
The plurality of openings is of a size and number determined to
achieve a predetermined beneficial agent delivery rate. A membrane
plug is received in the open end of the body and covers the
plurality of openings.
[0018] In accordance with another additional aspect of the present
invention, a method of retaining a membrane plug in an implantable
osmotic device includes steps of forming a substantially
cylindrical membrane plug; forming holes in the side wall of a
capsule adjacent an open end of the capsule; inserting the
substantially cylindrical membrane plug into the open end of the
capsule such that the membrane plug covers the holes formed in the
side wall; and causing the membrane plug to swell into the holes in
the side wall to retain the membrane plug in the capsule.
[0019] The present invention provides the advantages of improved
membrane retention and the ability to achieve a desired beneficial
agent delivery rate by varying a number and size of the membrane
retention openings.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0020] The invention will be described in greater detail with
reference to the accompanying drawings in which like elements bear
like reference numerals, and wherein:
[0021] FIG. 1 is a side cross-sectional view of an osmotic drug
delivery device according to the present invention;
[0022] FIG. 2 is a side elevational view of the osmotic drug
delivery device of FIG. 1;
[0023] FIG. 3 is a side cross-sectional view of an osmotic drug
delivery device having an alternate embodiment of a membrane plug;
and
[0024] FIG. 4 is a graph comparing the beneficial agent delivery
rate of the osmotic drug delivery device according to the present
invention to an osmotic drug delivery device with a conventional
capsule.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention relates to an osmotic delivery system
for controlled delivery of a beneficial agent. The osmotic drug
delivery device 10, as illustrated in FIG. 1, includes an elongated
substantially cylindrical enclosure or capsule 12 having an open
end 14. An end of the capsule 12 opposite the open end 14 has one
or more delivery ports 16 for delivering a beneficial agent
contained within a first chamber 18 of the osmotic delivery device
10. The elongated capsule 12 is formed of a material which is
sufficiently rigid to withstand expansion of an osmotic agent
contained within a second chamber 20 of the delivery device 10
without changing size or shape. The elongated capsule 12 is
preferably substantially impermeable to fluids in the environment
as well as to ingredients contained within the osmotic delivery
device 10 such that the migration of such materials into or out of
the device through the impermeable material of the capsule is so
low so as to have substantially no adverse impact on the function
of the osmotic delivery device.
[0026] The osmotic agent in the second chamber 20 of the capsule 12
is separated from the beneficial agent in the first chamber 18 by a
movable separating member or piston 22. The movable separating
member or piston 22 is a substantially cylindrically member which
is configured to fit within the capsule 12 in a sealed manner which
allows the piston to slide along a longitudinal direction within
the capsule. The piston 22 preferably is formed of a resilient
material which is impermeable to the compositions within the
capsule and includes annular protrusions 24 which form a seal with
the inner surface of the capsule 12.
[0027] As illustrated in FIG. 1, the drug delivery device 10 of one
embodiment of the present invention includes a membrane plug 26,
which is inserted in the open end 14 of the capsule 12 after
placing the osmotic agent within the second chamber 20 of the
capsule. The membrane plug 26 allows liquid to pass from an
environment of use into the capsule 12 to cause the osmotic agent
to swell. However, the material forming the semipermeable membrane
plug 26 is largely impermeable to the materials within the capsule
12 and to other ingredients within the environment of use.
[0028] The configuration of the osmotic delivery system membrane
plug 26 according to the present invention dictates the liquid
permeation rate through the membrane plug, which, in turn, controls
the delivery rate of a beneficial agent from the osmotic delivery
system. The liquid permeation rate of a particular membrane plug
depends on both the membrane material and the membrane shape.
[0029] FIG. 2 illustrates a side view of an osmotic drug delivery
device 10 according to one embodiment of the present invention
having a membrane plug 26 and a plurality of holes 30 in the
capsule 12 for retaining the membrane plug 26 and controlling the
beneficial agent delivery rate. The semipermeable membrane plug 26
is cylindrically shaped, and has a tight interference fit between
an outer sealing surface of the membrane plug 26 and the capsule
12. In accordance with alternative embodiments of the invention,
the membrane plug 26 may also include ribs extending from an outer
surface of the membrane plug 26, or may include other
configurations such as threads, glue, adhesives, ridges, lips, or
other devices which seal the membrane plug to the interior walls of
the capsule 12 to prevent leakage. The ribs may engage
correspondingly shaped grooves in the interior walls of the capsule
12. The fit between the membrane plug 26 and the capsule 12 is
preferably an interference fit which prevents significant salt
leakage.
[0030] An inwardly directed annular lip may also be provided on the
interior wall of the capsule 12 at the open end 14 to provide
additional retention of the membrane. The membrane plug 26 is
intended for at least partial insertion into the open end 14 of the
capsule 12, and the tight interference fit prevents liquid and
other substances in the environment of use, besides the permeation
liquid, from entering the osmotic delivery device 10 while also
preventing materials from the inside of the delivery system from
leaking or escaping to the use.
[0031] The membrane plug 26 includes a stop surface 32 which
extends radially from the plug and abuts the end wall of the
capsule 12 when the membrane plug is fully inserted. Alternatively,
the membrane plug 26 need not have a stop surface 32 and the plug
may be inserted entirely within the open end 14 of the capsule 12
of an osmotic delivery system. Likewise, the membrane plug 26 may
be partially inserted into the open end 14 of the osmotic Delivery
system capsule 12.
[0032] Because at least a portion of the membrane plug 26 is within
the capsule, only a portion of the membrane plug 26 is exposed to
liquids in the environment of use. In the embodiment of the present
invention illustrated in FIGS. 1 and 2, an end surface 34 of the
semipermeable membrane is exposed to liquids in the environment of
use. In addition, the portions of the membrane adjacent the holes
30 in the side wall of the capsule 12 are exposed to liquids in the
environment. The end surface 34 preferably has smoothed or curved
corners which are more acceptable for implantation than sharp
edges. The outer diameter of the end surface 34, measured
perpendicular to the longitudinal center axis of the delivery
device 10, is approximately equal to that of an external diameter
of the osmotic delivery device 10, such that the interface between
the capsule and the liquid surface of the body 32 is void of abrupt
edges, ridges, or sharp corners.
[0033] As shown in FIG. 2, the plurality of holes 30 is spaced
around the open end 14 of the capsule 12. The holes 30 allow the
membrane plug 26 to swell into the holes creating a large
frictional force between the membrane plug and the interior capsule
walls which prevents membrane plug expulsion. The frictional force
between the capsule 12 and the membrane plug 26 is directly related
to the number, placement, and shapes of the holes 30 in the capsule
wall and the mount the plug material expands into the holes. The
plurality of holes 30 may be sized and arranged to achieve a
desired frictional force, however, each of the holes should be
entirely covered by the membrane plug 26 so that osmotic agent
leakage cannot occur. For example, between two and twenty holes may
be provided of varying diameters. The number of holes 30 may also
be greater than 20 for large diameter capsules 12 as long as the
integrity of the capsule is maintained.
[0034] The plurality of holes 30 in the capsule wall also increases
the exposed membrane plug surface area, thus increasing the liquid
permeation rate through the membrane plug. The increased exposed
area of the membrane plug will shorten the start-up period for
beginning beneficial agent delivery over an identical system
without the holes 30.
[0035] The liquid permeation rate dV/dt through a semipermeable
membrane in an osmotic delivery system depends on the liquid
permeability and shape of the membrane. The liquid permeation rate
dV/dt for a conventional capsule without holes is determined by the
formula: 1 V / t = k ( A t ) Where , A = D m 2 4
[0036] D.sub.m is the diameter of the exposed end surface 34 of the
membrane plug and k is a constant which takes into account the
liquid permeation rate and thickness of a membrane wall in a hollow
membrane plug or the length for a solid membrane plug.
[0037] For an osmotic delivery device according to the present
invention with a plurality of circular holes 30, the liquid
permeation rate dV/dt is determined by the formula: 2 V / t = k ( A
t ) Where , A = D m 2 4 + # of holes ( D h 2 4 )
[0038] D.sub.m is the diameter of the exposed membrane plug end
surface 34, D.sub.h is the diameter of the holes 30, and k is the
constant taking into account the membrane plug material and
thickness or length.
[0039] In the embodiment of FIG. 1, the liquid permeation rate
dV/dt is also affected by the longitudinal position of the holes 30
on the capsule. The shorter the distance the liquid must travel
through the membrane, the faster the liquid will permeate the
membrane. Accordingly, the closer the holes 30 are to the end of
the membrane plug adjacent to second Chamber 20, the faster the
release rate.
[0040] As can be seen from the foregoing, the liquid permeation
rate, and thus, the beneficial agent delivery rate, can be
controlled by changing the diameter and/or number of the holes 30
without the need to change the overall geometry of the osmotic
delivery device 10 or the membrane plug 26. The delivery rate can
also be controlled by varying the longitudinal position of the
holes.
[0041] An alternative embodiment of the invention illustrated in
FIG. 3 includes a membrane plug 26a having a hollow interior and a
substantially constant thickness cylindrical side wall 40 and end
wall 42. The hollow membrane plug 26a is particularly useful in
rapid delivery systems for delivery of a beneficial agent over a
short period of time such as 1 to 42 days. In the embodiment, the
beneficial agent delivery rate can be controlled by changing the
diameter and/or number of the holes 30. However, the delivery rate
generally does not change when the longitudinal position of the
holes 30 is varied because the distance that the permeating liquid
travels through the constant thickness side wall 40 is the
same.
[0042] In the above-described manner, the liquid permeation rate
dV/dt through the membrane plug 26 can be controlled simply and
efficiently by forming holes 30 in the side walls of the capsule
12. This is advantageous because the same membrane plug 26 can be
used to form osmotic delivery systems with different liquid
permeation rates. A different membrane material need not be used
for every system which has a different desired beneficial agent
delivery rate, and biocompatibility and toxicity tests need only be
performed on one semipermeable material.
[0043] The semipermeable membrane plug 26 is preferably injection
molded. However, the semipermeable body may be fashioned by a
different process. For example, the semipermeable body may also be
made from extrusion, injection molding, rotational molding,
thermoforming, compression molding, and other known casting
processes.
[0044] FIGS. 1-3 illustrate two examples of osmotic delivery
devices 10 according to the present invention. The configurations
illustrated in the figures are examples of osmotic delivery devices
and are not to be construed as limiting the present invention. The
present invention is generally applicable to all osmotic delivery
devices having any number of shapes, and to all such devices
administered in humans and animals in any variety of methods such
as oral, ruminal, and implantable osmotic delivery techniques.
[0045] FIG. 4 shows the beneficial agent release rate for osmotic
delivery devices having a conventional barrel without holes
compared to the release rate for the osmotic delivery devices
according to the present invention. As shown in FIG. 4, the release
rate is increased by between approximately 1 and 10 ml/hr by the
addition of 10 circular holes around the perimeter of the capsule's
open end. The diameters of the holes 30 in the delivery device
tested were approximately 14 percent of the diameter of the
membrane. The amount of increase in the release rate depends in
part on the diameter of the membrane retention holes.
[0046] Semipermeable compositions suitable for the semipermeable
membrane plug 26 are well known in the art, examples of which are
disclosed in U.S. Pat. No. 4,874,388, the entire disclosure of
which is incorporated herein by reference. Such possible
semipermeable materials from which the membrane plug 26 can be made
include, but are not limited to, for example, Hytrel.RTM. polyester
elastomers (DuPont), cellulose esters, cellulose ethers, and
cellulose ester-ethers, water flux-enhanced ethylene-vinyl acetate
copolymers, semipermeable membranes made by blending a rigid
polymer with water-soluble low molecular weight compounds, and
other semipermeable materials well known in the art. The above
cellulosic polymers have a degree of substitution, D.S., on the
anhydroglucose unit, from greater than 0 up to 3 inclusive. By
"degree of substitution" or "D.S." is meant the average number of
hydroxyl groups originally present on the anhydroglucose unit
comprising the cellulose polymer that are replaced by a
substituting group. Representative materials include, but are not
limited to, one selected from the group consisting of cellulose
acylate, cellulose diacylate, cellulose triacylate, cellulose
acetate, cellulose diacetate, cellulose triacetate, mono-, di-, and
tricellulose alkanylates, mono-, di-, and tricellulose aroylates,
and the like. Exemplary cellulosic polymers include cellulose
acetate having a D.S. up to 1 and an acetyl content up to 21%;
cellulose acetate having a D.S. of 1 to 2 and an acetyl content of
21% to 35%; cellulose acetate having a D.S. of 2 to 3 and an acetyl
content of 35% to 44.8%, and the like. More specific cellulosic
polymers include cellulose propionate having a D.S. of 1.8 and a
propionyl content of 39.2% to 45% and a hydroxyl content of 2.8% to
5.4%; cellulose acetate butyrate having a D.S. of 1.8 and an acetyl
content of 13% to 15% and a butyryl content of 34% to 39%;
cellulose acetate butyrate having an acetyl content of 2% to 29%, a
butyryl content of 17% to 53%, and a hydroxyl content of 0.5% to
4.7%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl
content of 4%, and a butyryl content of 51%; cellulose triacylates
having a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose
trilaurate, cellulose tripalmitate, cellulose trisuccinate, and
cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2
to 2.6 such as cellulose disuccinate, cellulose dipalmitate,
cellulose dioctanoate, cellulose dipentate; coesters of cellulose
such as cellulose acetate butyrate and cellulose, cellulose acetate
propionate, and the like.
[0047] Other materials for the membrane plug 26 are polyurethane,
polyetherblockamide (PEBAX.RTM., commercially available from ELF
ATOCHEM, Inc.), and injection-moldable thermoplastic polymers with
some hydrophilicity such as ethylene vinyl alcohol (EVA). In
general, the membrane plug 26 is made from semipermeable materials
having a water uptake ranging from 1% to 80% but preferably less
than 50%. The composition of the semipermeable membrane plug 26 is
permeable to the passage of external liquids such as water and
biological liquids, and it is substantially impermeable to the
passage of beneficial agents, osmopolymers, osmagents, and the
like.
[0048] Materials which may be used for the capsule 12 must be
sufficiently strong to ensure that the capsule will not leak,
crack, break, or distort under stresses to which it is subjected
during implantation or under stresses due to the pressures
generated during operation. The capsule 12 may be formed of
chemically inert and biocompatible, natural or synthetic materials
which are known in the art. The capsule material is preferably a
non-bioerodible material which remains in the patient after use,
such as titanium or a titanium alloy, and is largely impermeable to
materials within and outside the capsule. However, the material of
the capsule 12 may alternatively be a bioerodible material which
bioerodes in the environment after dispensing of the beneficial
agent. Generally, preferred materials for the capsule 12 are those
acceptable for animal and human implants.
[0049] In general, typical materials of construction suitable for
the capsule 12 according to the present invention include
non-reactive polymers or biocompatible metals or alloys. The
polymers include acrylonitrile polymers such as
acrylonitrile-butadiene-styrene terpolymer, and the like;
halogenated polymers such as polytetrafluoroethylene,
polychlorotrifluoroethylene, copolymer tetrafluoroethylene and
hexafluoropropylene; polyimide; polysulfone; polycarbonate;
polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;
polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and the
like. Metallic materials useful for the capsule 12 include
stainless steel, titanium, platinum, tantalum, gold, and their
alloys, as well as gold-plated ferrous alloys, platinum-plated
ferrous alloys, cobalt-chromium alloys and titanium nitride coated
stainless steel.
[0050] The capsule 12 may be formed from any of the wall-forming
materials disclosed above by the use of a mold, with the materials
applied either over the mold or inside the mold, depending on the
mold configuration. Any of the wide variety of techniques known in
the pharmaceutical industry may be used to form the capsule 12.
[0051] In general, materials suitable for use in the movable
separating member or piston 22 are elastomeric materials including
the non-reactive polymers listed above, as well as elastomers in
general, such as polyurethanes and polyamides, chlorinated rubbers,
styrene-butadiene rubbers, and chloroprene rubbers.
[0052] The osmotic agent is a liquid-attracting agent used to drive
the flow of the beneficial agent. The osmotic agent may be an
osmagent, an osmopolymer, or a mixture of the two. Species which
fall within the category of osmagent, i.e., the non-volatile
species which are soluble in water and create the osmotic gradient
driving the osmotic inflow of water, vary widely. Examples are well
known in the art and include magnesium sulfate, magnesium chloride,
potassium sulfate, sodium chloride, sodium sulfate, lithium
sulfate, sodium phosphate, potassium phosphate, d-mannitol,
sorbitol, inositol, urea, magnesium succinate, tartaric acid,
raffinose, and various monosaccharides, oligosaccharides and
polysaccharides such as sucrose, glucose, lactose, fructose, and
dextran, as well as mixtures of any of these various species.
[0053] Species which fall within the category of osmopolymer are
hydrophilic polymers that swell upon contact with water, and these
vary widely as well. Osmopolymers may be of plant or animal origin,
or synthetic, and examples of osmopolymers are well known in the
art. Examples include: poly(hydroxy-alkyl methacrylates) with
molecular weight of 30,000 to 5,000,000, poly(vinylpyrrolidone)
with molecular weight of 10,000 to 360,000, anionic and cationic
hydrogels, polyelectrolyte complexes, poly(vinyl alcohol) having
low acetate residual, optionally cross-linked with glyoxal,
formaldehyde, or glutaraldehyde and having a degree of
polymerization of 200 to 30,000, a mixture of methylcellulose,
cross-linked agar and carboxymethylcellulose, a mixture of
hydroxypropl methylcellulose and sodium carboxymethylcellulose,
polymers of N-vinyllactams, polyoxyethylene-polyoxypropylene gels,
polyoxybutylene-polyethylene block copolymer gels, carob gum,
polyacrylic gels, polyester gels, polyuria gels, polyether gels,
polyamide gels, polypeptide gels, polyamino acid gels,
polycellulosic gels, carbopol acidic carboxy polymers having
molecular weights of 250,000 to 4,000,000, Cyanamer.RTM.
polyacrylamides, cross-linked indene-maleic anhydride polymers,
Good-Rite.RTM. polyacrylic acids having molecular weights of 80,000
to 200,000, Polyox.RTM. Polyethylene oxide polymers having
molecular weights of 100,000 to 5,000,000, starch graft copolymers,
and Aqua-Keeps.RTM. acrylate polymer polysaccharides.
[0054] The osmotic agent may be a solid osmotic tablet or a fluid
osmotic agent. The osmotic tablet may be formed in many different
conceivable shapes, textures, densities, and consistencies and
still be within the confines of the present invention. The osmotic
agent may be manufactured by a variety of techniques, many of which
are known in the art. In one such technique, the osmotically active
agent is prepared as solid or semisolid formulation and pressed
into pellets or tablets whose dimensions correspond to slightly
less than the internal dimensions of the respective chambers which
they will occupy in the capsule interior. Depending on the nature
of the materials used, the agent and other solid ingredients which
may be included may be processed prior to the formation of the
pellets by such procedures as ballmilling, calendaring, stirring,
or rollmilling to achieve a fine particle size and hence fairly
uniform mixtures of each.
[0055] In assembling the osmotic delivery device 10 according to
one preferred embodiment of the present invention, the capsule 12
is prepared by forming the plurality of holes 30 around the open
end 14 of the capsule. The holes 30 may be formed by mechanical
drilling, laser drilling, molding, or any other known method. Once
the capsule 12 has been prepared with a plurality of holes 30
having a number and size to achieve a desired delivery rate of the
beneficial agent, the piston 22 is inserted into the capsule 12.
Once the osmotic agent pellet(s) or tablet(s) have been formed,
they are placed inside the pre-formed capsule in the second chamber
20 on top of the piston 22. Then the membrane plug 26, according to
one embodiment of the present invention, is placed into the open
end 14 of the capsule 12 to close off and seal one end of the
osmotic delivery system.
[0056] The delivery port 16 is an orifice formed by conventional
techniques which are known in the art. Included among these methods
are mechanical drilling, laser drilling, and molding. The capsule
12 contains at least one such delivery port 16, and in most
configurations, one delivery port will suffice. However, two or
more delivery ports 16 may be present without departing from the
present invention. The dimensions of the port 16 in terms of both
diameter and length will vary with the type of beneficial agent,
the rate at which the beneficial agent is to be delivered, and the
environment into which it is to be delivered. The considerations
involved in determining the optimum dimensions of the delivery port
for any particular capsule 12 or beneficial agent and the selection
of the appropriate dimensions will be readily apparent to those
skilled in the art.
[0057] According to one embodiment of the present invention, the
beneficial agent contained in the first chamber 18 of the capsule
12 is a flowable composition such as a liquid, suspension, or
slurry, and is typically poured into the first chamber 18 of the
capsule after the osmotic agent and the piston 22 have been
inserted. However, the first chamber 18 may also be filled through
the open end prior to insertion of the piston.
[0058] The present invention applies to the administration of
beneficial agents in general, which include any physiologically or
pharmacologically active substance. Drug agents which may be
delivered by the present invention include drugs which act on the
peripheral nerves, adrenergic receptors, cholinergic receptors, the
skeletal muscles, the cardiovascular system, smooth muscles, the
blood circulatory system, synoptic sites, neuroeffector junctional
sites, endocrine and hormone systems, the immunological system, the
reproductive system, the skeletal system, autacoid systems, the
alimentary and excretory systems, the histamine system and the
central nervous system. Suitable agents may be selected from, for
example, proteins, enzymes, hormones, polynucleotides,
nucleoproteins, polysaccharides, glycoproteins, lipoproteins,
polypeptides, steroids, analgesics, local anesthetics, antibiotic
agents, anti-inflammatory corticosteroids, ocular drugs and
synthetic analogs of these species.
[0059] Examples of drugs which may be delivered by devices
according to this invention include, but are not limited to,
prochlorperzine edisylate, ferrous sulfate, aminocaproic acid,
mecamylamine hydrochloride, procainamide hydrochloride, amphetamine
sulfate, methamphetamine hydrochloride, benzamphetamine
hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride,
bethanechol chloride, methacholine chloride, pilocarpine
hydrochloride, atropine sulfate, scopolamine bromide, isopropamide
iodide, tridihexethyl chloride, phenformin hydrochloride,
methylphenidate hydrochloride, theophylline cholinate, cephalexin
hydrochloride, diphenidol, meclizine hydrochloride,
prochlorperazine maleate, phenoxybenzamine, thiethylperzine
maleate, anisindone, diphenadione erythrityl tetranitrate, digoxin,
isofluorophate, acetazolamide, methazolamide, bendroflumethiazide,
chloropromaide, tolazamide, chlormadinone acetate, phenaglycodol,
allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole,
erythromycin, hydrocortisone, hydrocorticosterone acetate,
cortisone acetate, dexamethasone and its derivatives such as
betamethasone, triamcinolone, methyltestosterone, 17-S-estradiol,
ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,
17-.alpha.-hydroxyprogest- erone acetate, 19-nor-progesterone,
norgestrel, norethindrone, norethisterone, norethiederone,
progesterone, norgesterone, norethynodrel, aspirin, indomethacin,
naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,
isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,
cimetidine, clonidine, imipramine, levodopa, chlorpromazine,
methyldopa, dihydroxyphenylalanine, theophylline, calcium
gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin,
haloperidol, zomepirac, ferrous lactate, vincamine, diazepam,
phenoxybenzamine, diltiazem, milrinone, capropril, mandol,
quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen,
fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuinal,
nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,
lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine,
lisinolpril, enalapril, enalaprilat, captopril, ramipril,
famotidine, nizatidine, sucralfate, etintidine, tetratolol,
minoxidil, chlordiazepoxide, diazepam, amitriptyline, and
imipramine. Further examples are proteins and peptides which
include, but are not limited to, insulin, colchicine, glucagon,
thyroid stimulating hormone, parathyroid and pituitary hormones,
calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone,
follicle stimulating hormone, chorionic gonadotropin, gonadotropin
releasing hormone, bovine somatotropin, porcine somatotropin,
oxytocin, vasopressin, GRF, prolactin, somatostatin, lypressin,
pancreozymin, luteinizing hormone, LHRH, LHRH agonists and
antagonists, leuprolide, interferons, interleukins, growth hormones
such as human growth hormone, bovine growth hormone and porcine
growth hormone, fertility inhibitors such as the prostaglandins,
fertility promoters, growth factors, coagulation factors, human
pancreas hormone releasing factor, analogs and derivatives of these
compounds, and pharmaceutically acceptable salts of these
compounds, or their analogs or derivatives.
[0060] On the molecular level, the various forms of the beneficial
agent may include uncharged molecules, molecular complexes, and
pharmaceutically acceptable acid addition and base addition salts
such as hydrochlorides, hydrobromides, acetate, sulfate, laurylate,
oleate, and salicylate. For acidic compounds, salts of metals,
amines or organic cations may be used. Derivatives such as esters,
ethers and amides can also be used. A beneficial agent can be used
alone or mixed with other agents. The beneficial agent may
optionally include pharmaceutically acceptable carriers and/or
additional ingredients such as antioxidants, stabilizing agents,
permeation enhancers, etc.
[0061] According to other embodiments of the present invention, the
capsule 12 may take different forms. For example, the delivery port
16 may be formed in a soft impermeable material delivery plug
inserted into the capsule 12. In addition, the movable separating
member or piston 22 may be a flexible member such as a diaphragm,
partition, pad, flat sheet, spheroid, or rigid metal alloy, and may
be made of any number of inert materials. Furthermore, the osmotic
device may function without the piston 22, having simply an
interface between the osmotic agent and the beneficial agent.
[0062] Animals to whom beneficial agents may be administered using
systems of this invention include humans and other animals. The
invention is of particular interest for application to humans and
household, sport, and farm animals, particularly mammals. For the
administration of beneficial agents to animals, the devices of the
present invention may be implanted subcutaneously or
intraperitoneally wherein aqueous body fluids are available to
activate the osmotic agent. Devices of the invention may also be
administered to the rumen of ruminant animals, in which embodiment
the devices may further comprise a density element for maintaining
the device in the rumen for extended periods of time of up to 120
days or longer. Density elements are well known in the art of drug
delivery devices.
[0063] The delivery devices of this invention are also useful in
environments outside of physiological or aqueous environments. For
example, the delivery devices may be used in intravenous systems
(attached to an IV pump or bag or to an IV bottle, for example) for
delivering beneficial agents to an animal, primarily to humans.
They may also be utilized in blood oxygenators, kidney dialysis and
electrophoresis, for example. Additionally, delivery devices of the
present invention may be used in the biotechnology area, such as to
deliver nutrients or growth-regulating compounds to cell cultures.
In such instances, activating mechanisms such as mechanical
mechanisms are particularly useful. The beneficial agent may be any
of the agents which are known to be delivered to the body of a
human or an animal such as medicaments, vitamins, nutrients, or the
like. The beneficial agent may also be an agent which is delivered
to other types of aqueous environments such as pools, tanks,
reservoirs, and the like. Included among the types of agents which
meet this description are biocides, sterilization agents,
nutrients, vitamins, food supplements, sex sterilants, fertility
inhibitors and fertility promoters.
[0064] While the invention has been described in detail with
reference to preferred embodiments thereof, it will be apparent to
one skilled in the art that various changes can be made, and
equivalents employed without departing from the invention.
* * * * *