U.S. patent application number 11/636743 was filed with the patent office on 2007-04-19 for osmotic implant with membrane and membrane retention means.
Invention is credited to James E. Brown, Scott J. Gilbert, John R. Peery.
Application Number | 20070087058 11/636743 |
Document ID | / |
Family ID | 23159679 |
Filed Date | 2007-04-19 |
United States Patent
Application |
20070087058 |
Kind Code |
A1 |
Peery; John R. ; et
al. |
April 19, 2007 |
Osmotic implant with membrane and membrane retention means
Abstract
An osmotic delivery system for controlled delivery of a
beneficial agent includes an implantable capsule containing a
beneficial agent and an osmotic engine that swells on contact with
water, thereby causing the release of the beneficial agent over
time. The osmotic delivery system has a membrane material that
allows a controlled amount of fluid to enter from an exterior of
the capsule, while preventing the compositions within the capsule
from passing out of the capsule. The osmotic delivery system is
designed to meet at least the operating pressures of 1000 psi. The
membrane material is cast, calendered or extruded followed by
machining (i.e., die-cutting, stamping or otherwise cutting to
shape) to provide a uniform nonribbed membrane material. The
capsule also includes a membrane material-retaining means that is
positioned at a fluid uptake end to retain the membrane material
within the capsule, even under periods of high pressure.
Inventors: |
Peery; John R.; (Stanford,
CA) ; Gilbert; Scott J.; (Menlo Park, CA) ;
Brown; James E.; (Los Gatos, CA) |
Correspondence
Address: |
TRASK BRITT
P.O. BOX 2550
SALT LAKE CITY
UT
84110
US
|
Family ID: |
23159679 |
Appl. No.: |
11/636743 |
Filed: |
December 11, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10173992 |
Jun 18, 2002 |
7163688 |
|
|
11636743 |
Dec 11, 2006 |
|
|
|
60300575 |
Jun 22, 2001 |
|
|
|
Current U.S.
Class: |
424/473 ;
604/890.1 |
Current CPC
Class: |
A61K 9/0004
20130101 |
Class at
Publication: |
424/473 ;
604/890.1 |
International
Class: |
A61K 9/24 20060101
A61K009/24; A61K 9/22 20060101 A61K009/22 |
Claims
1. A delivery system for controlled delivery of a beneficial agent,
the system comprising: an implantable capsule having a beneficial
agent delivery end and a fluid uptake end, wherein the implantable
capsule comprises one or a plurality of inwardly protruding ridges
circumferentially arrayed near the fluid uptake end of the
implantable capsule to securingly grip an outer surface of a
membrane material; a beneficial agent reservoir positioned within
the implantable capsule for delivery of the beneficial agent at a
predetermined delivery rate; the membrane material received in the
fluid uptake end of the implantable capsule and providing a fluid
permeable barrier between an interior and an exterior of the
implantable capsule; and a frit positioned at the fluid uptake end
of the implantable capsule, for preventing the membrane material
from being ejected out of the fluid uptake end of the implantable
capsule.
2. A delivery system for controlled delivery of a beneficial agent,
the system comprising: an implantable capsule having a beneficial
agent delivery end and a fluid uptake end, wherein the implantable
capsule comprises one or a plurality of inwardly protruding ridges
circumferentially arrayed near the fluid uptake end of the
implantable capsule to securingly grip an outer surface of a
membrane material; a beneficial agent reservoir positioned within
the implantable capsule for delivery of the beneficial agent at a
predetermined delivery rate; the membrane material received in the
fluid uptake end of the implantable capsule and providing a fluid
permeable barrier between an interior and an exterior of the
implantable capsule; and a sintered powdered metal structure
including porous capillaries positioned at the fluid uptake end of
the implantable capsule for preventing the membrane material from
being ejected out of the fluid uptake end of the implantable
capsule.
3. The delivery system according to claim 2, wherein a diameter of
the porous capillaries is between about 0.5 microns and about 10
microns.
4. An osmotic system for controlled delivery of a beneficial agent
comprising: an implantable capsule having a beneficial agent
delivery end and a fluid uptake end; a beneficial agent reservoir
positioned adjacent the beneficial agent delivery end for housing
the beneficial agent; a piston positioned between the beneficial
agent reservoir and the fluid uptake end; an osmotic engine
positioned between the piston and the fluid uptake end; a membrane
material received in the fluid uptake end and providing a fluid
permeable barrier between an interior and an exterior of the
capsule; one or a plurality of inwardly protruding ridges
circumferentially arrayed near the fluid uptake end of the capsule
to securingly grip an outer surface of the membrane material; a
membrane material-retaining means positioned at the fluid uptake
end, the membrane material-retaining means including at least one
opening for allowing passage of fluid, the membrane
material-retaining means preventing the membrane material from
being ejected out of the fluid uptake end of the capsule; and
wherein the osmotic engine is expandable at a controlled rate and
when expanded, applies a pushing force against the piston which
applies a pushing force against the beneficial agent, such that the
beneficial agent is released through the beneficial agent delivery
end at a predetermined rate.
5. The osmotic system of claim 4 wherein the material-retaining
means comprises a perforated disc.
6. The osmotic system of claim 4, wherein the membrane
material-retaining means comprises a frit.
7. The osmotic system of claim 4, wherein the membrane
material-retaining means comprises a sintered powdered metal
structure including porous capillaries.
8. The osmotic system of claim 7, wherein the diameter of the
porous capillaries is between about 0.5 and about 10 microns.
9. The osmotic system of claim 4, wherein the membrane
material-retaining means comprises a flange.
10. The osmotic system of claim 4, wherein the membrane
material-retaining means comprises a flange with a frit.
11. The osmotic system of claim 4, wherein the membrane
material-retaining means comprises a flange with a sintered
powdered metal structure including porous capillaries.
12. The osmotic system of claim 4, wherein the membrane
material-retaining means comprises a flange that is a separate
member attached to the capsule.
13. The osmotic system of claim 4, wherein the membrane
material-retaining means comprises a flange that is attached to the
capsule by welding, press fit, or screw means.
14. The osmotic system of claim 4, wherein the membrane
material-retaining means has a flat, rounded, or contoured surface
on at least one surface thereof.
15. The osmotic system of claim 4, wherein the membrane
material-retaining means includes at least one opening for allowing
passage of fluid.
16. The osmotic system of claim 4, wherein the membrane material
comprises a generally smooth, cylindrical shape having a diameter
between about 0.040 inch and about 0.250 inch.
17. The osmotic system of claim 4, wherein the membrane material
comprises a generally smooth, cylindrical shape having a length or
thickness between about 0.010 inch and about 0.350 inch.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of application Ser. No.
10/173,992, filed Jun. 18, 2002, pending, which claims the priority
of U.S. application Ser. No. 60/300,575 filed Jun. 22, 2001, which
is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to osmotically controlled
implantable delivery devices, and more particularly to a delivery
system having a membrane material that controls the delivery rate
of a beneficial agent from the delivery system, in which the
membrane material is cast, calendered or extruded, then machined
(i.e., stamped, die cut or otherwise cut to shape), and the
membrane material is maintained within the delivery device by a
retaining means.
[0004] 2. Description of the Related Art
[0005] Controlled delivery of beneficial agents, such as drugs, in
the medical and veterinary fields, has been accomplished by a
variety of methods, including implantable delivery devices such as
implantable osmotic delivery devices and implantable diffusion
controlled delivery systems. Osmotic delivery systems are very
reliable in delivering a beneficial agent over an extended period
of time called an administration period. In general, osmotic
delivery systems operate by imbibing fluid from an outside
environment and releasing corresponding amounts of beneficial agent
from the delivery system.
[0006] Representative examples of various types of delivery devices
are disclosed in U.S. Pat. Nos., 3,732,865; 3,987,790; 4,865,845;
5,059,423; 5,112,614; 5,137,727; 5,213,809; 5,234,692; 5,234,693;
5,308,348; 5,413,572; 5,540,665; 5,728,396; and 5,985,305, all of
which are incorporated herein by reference. All of the above-cited
patents generally include some type of capsule having at least a
portion of a wall that selectively passes water into the interior
of the capsule containing a water-attracting agent (also called an
osmotic agent, an osmopolymer or osmoagent). The absorption of
water by the water-attracting agent within the capsule reservoir
creates an osmotic pressure within the capsule which causes a
beneficial agent within the capsule to be delivered. The
water-attracting agent may be the beneficial agent being delivered
to the patient. However, in most cases, a separate 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, such as a piston. The structure of the
capsule is generally rigid such that as the osmotic agent takes in
water and expands, the capsule does not expand. As the osmotic
agent expands, the agent causes the movable dividing member to
move, discharging the beneficial agent through an orifice or exit
passage of the capsule. The beneficial agent is discharged through
the exit passage at the same volumetric rate that water enters the
osmotic agent through the semipermeable wall portion of the
capsule.
[0008] The rate at which the beneficial agent is discharged from
the delivery device is determined by many factors, including the
type of water-attracting agent or osmotic agent, the permeability
of the semipermeable membrane wall, and the size and shape of the
exit passage. One manner in which the back diffusion of
environmental fluid into the beneficial agent reservoir is
controlled is by a flow moderator in the exit passage of the
capsule, with the flow moderator generally consisting of a tubular
passage having a particular cross-sectional area and length.
[0009] In known osmotic delivery systems, an osmotic tablet, such
as salt, is placed inside the capsule and a membrane plug is placed
in an open end of the capsule to provide a semipermeable barrier.
The membrane plug seals the interior of the capsule from the
exterior environment, permitting only certain liquid molecules from
the environment to permeate through the membrane plug and into the
interior of the capsule. The membrane plug is impermeable to items
within the capsule including the osmotic agent and the beneficial
agent. The rate at which the liquid permeates the membrane plug and
enters the capsule varies depending upon the type of membrane
material and the size and shape of the membrane plug. Further, the
rate at which the liquid passes through the membrane plug controls
the rate at which the osmotic agent expands to thereby drive the
beneficial agent from the delivery system through the exit passage.
Accordingly, the rate of delivery of the beneficial agent from the
osmotic delivery system is controllable by varying the permeability
coefficient of the membrane plug and/or the size of the membrane
plug.
[0010] Some known osmotic delivery systems use injection molded
membrane plugs featuring protruding circumferential sealing ribs
that fit into matching circumferential grooves on the inside of the
capsule (U.S. Pat. No. 6,113,938, which is incorporated herein by
reference). The membrane plug is retained in the capsule by the
sealing ribs, which usually requires the membrane to be inserted
from the membrane end of the reservoir. Injection molded
semipermeable membranes may be difficult to manufacture without
internal stresses; thus performance may vary slightly from plug to
plug. An additional drawback of known osmotic delivery systems is
that the membrane plug itself is required to withstand the
pressures created by the expansion of the osmotic engine. Other
known osmotic delivery systems use membrane plugs with protruding
circumferential sealing ribs but no matching circumferential
grooves inside of the capsule. Still other known osmotic delivery
systems use membrane plugs with no circumferential sealing ribs
that fit into the capsule by friction fit. Still other known
osmotic delivery systems use membrane plugs without any
circumferential sealing ribs but with holes in the capsule into
which the membrane plug can expand (WO99/33446, which is
incorporated herein by reference). Known delivery systems preclude
the use of a capsule having a pre-installed retaining feature
covering or partially covering the membrane plug end of the capsule
for keeping the membrane plug sealed in position. Consequently, in
these systems, if a retaining feature other than the capsule
grooves and matching ribs of the membrane plug is to be used, it
must be assembled to the main capsule body, after the membrane plug
is inserted. This requirement tends to increase the cost and
complexity of a high pressure osmotic delivery system.
[0011] Accordingly, it is desirable to provide a delivery device
that provides improved consistency and performance of the membrane
material and also provides a feature for retaining the membrane
material within the capsule under high pressure.
SUMMARY OF THE INVENTION
[0012] In accordance with the present invention, a delivery system
for controlled delivery of a beneficial agent includes an
implantable capsule having a beneficial agent delivery end and a
fluid uptake end. The capsule also includes a beneficial agent
reservoir positioned within the capsule for housing the beneficial
agent. A membrane material is received in the fluid uptake end of
the capsule and provides a fluid permeable barrier between an
interior and an exterior of the capsule. A membrane
material-retaining means is positioned at the fluid uptake end of
the capsule and includes at least one opening for allowing passage
of fluid. The membrane material-retaining means also prevents the
membrane material from being ejected out of the fluid uptake end of
the capsule.
[0013] In another aspect, the present invention is directed to a
delivery system for controlled delivery of a beneficial agent in
which the membrane material-retaining means includes a retention
flange positioned along a proximal end of the fluid uptake end of
the capsule.
[0014] In accordance with another aspect, the present invention
pertains to a delivery system, in which the membrane
material-retaining means includes a screen, a grate, a perforated
disk, a frit, or a sintered powdered metal structure including
porous capillaries. If the membrane material-retaining means
includes porous capillaries, the capillaries can have diameters
between about 0.5 and about 10 microns. The membrane
material-retaining means can be flat or have a rounded or contoured
surface on at least one surface thereof.
[0015] In a further aspect, the present invention pertains to a
delivery system for controlled delivery of a beneficial agent, in
which the membrane material has a generally smooth, cylindrical or
disc shape.
[0016] In yet another aspect, the present invention is directed to
a delivery system for controlled delivery of a beneficial agent, in
which the membrane material is extruded, cast, or calendered and
then machined (i.e., die-cut, stamped, or otherwise cut into
shape).
[0017] In another aspect, the present invention pertains to a
delivery system for controlled delivery of a beneficial agent, in
which the capsule includes one or a plurality of inward protruding
ridges and in which the inward protruding ridges securely grip an
outer surface of the membrane material. Note that the word "ridges"
as used herein can indicate one or more ridges. Additionally, the
inwardly protruding ridge or plurality of inwardly protruding
ridges are shaped to accommodate insertion of the membrane material
from the beneficial agent delivery end of the capsule while
inhibiting withdrawal of the membrane material from the beneficial
agent delivery end of the capsule.
[0018] In a further aspect, the present invention is directed to a
delivery system for controlled delivery of a beneficial agent, in
which an osmotic engine is positioned between the beneficial agent
delivery end and the membrane material.
[0019] In a further aspect, the present invention pertains to a
delivery system for controlled delivery of a beneficial agent and
includes a piston positioned between the beneficial delivery end
and the osmotic engine for transmitting a pushing force created by
the osmotic engine to the beneficial agent.
[0020] According to a further aspect of the present invention, a
method of forming a beneficial agent delivery device includes the
steps of providing an implantable capsule having an open delivery
end, an open fluid uptake end and a membrane material-retaining
means. A membrane material is inserted into the capsule from the
open agent delivery end and positioned such that an end surface
thereof is in contact with an inside surface of the membrane
material-retaining means. The osmotic agent is inserted into the
capsule, followed by a movable dividing means or piston. The
capsule is then filled with a beneficial agent, and the agent
delivery end is closed while providing a controlled outlet for the
beneficial agent to escape when sufficient pressure is applied to
the beneficial agent.
[0021] In a further aspect, the present invention pertains to an
osmotic system for controlled delivery of a beneficial agent
including an implantable capsule having a beneficial agent delivery
end and a fluid uptake end. The capsule includes a beneficial agent
reservoir positioned adjacent the beneficial agent delivery end for
housing the beneficial agent. A piston is positioned between the
beneficial agent reservoir and the fluid uptake end. An osmotic
engine is positioned between the piston and the fluid uptake end.
The osmotic engine is expandable at a controlled rate and when
expanding, applies a pushing force against the piston which applies
a pushing force against the beneficial agent, such that the
beneficial agent is released through the beneficial agent delivery
end at a predetermined rate. A membrane material is received in the
fluid uptake end and provides a fluid permeable barrier between an
interior and an exterior of the capsule. A membrane
material-retaining means is positioned at the fluid uptake end,
with the membrane material-retaining means including at least one
opening for allowing passage of fluid. The membrane
material-retaining means also prevents the membrane material from
being ejected out of the fluid uptake end of the capsule by osmotic
pressure.
[0022] The present invention provides the advantage of consistent
and predictable delivery rate of a beneficial agent by allowing the
use of extruded, cast, or calendered and then machined (i.e., die
cut, stamped or otherwise cut to shape) membrane materials, whose
consistency is more homogeneous when produced on a highly
controlled machining or extrusion line as compared to the
part-to-part consistency of injection molded membrane plugs.
[0023] The present invention also provides the advantage of
allowing the sealing of a cast, calendered, or extruded membrane
material that has been machined (i.e., die cut, stamped or
otherwise cut to shape) in place in an implantable osmotic delivery
device while reducing the expulsion of the membrane from the
implantable device under high pressure conditions (greater than
1,000 psi), such as those encountered in the case of a blocked exit
passage.
[0024] In addition, the present invention allows for the membrane
material-retaining means to be formed integrally with the
implantable capsule or attached thereto during assembly of the
delivery device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The invention will be described in greater detail with
reference to the accompanying drawings in which like elements bear
like reference numerals, and wherein:
[0026] FIG. 1 is a cross-sectional side view of an osmotic drug
delivery device including a capsule, a piston, an osmotic engine, a
membrane, and an exit passage;
[0027] FIG. 2 is a cross-sectional side view of a portion of an
implantable capsule;
[0028] FIG. 3 is a front view along line 3-3 of the implantable
capsule of FIG. 2;
[0029] FIG. 4 is a side view of a membrane plug;
[0030] FIG. 5 is a front view along line 5-5 of the membrane plug
of FIG. 4;
[0031] FIG. 6 is a cross-sectional side view of a portion of an
implantable capsule according to a second embodiment of the
invention;
[0032] FIG. 7 is a front view taken along line 7-7 of the
implantable capsule of FIG. 6;
[0033] FIG. 8 is a cross-sectional side view of a portion of an
implantable capsule according to a third embodiment of the
invention;
[0034] FIG. 9 is a front view taken along line 9-9 of the
implantable capsule of FIG. 8; and
[0035] FIG. 10 is an enlarged view of the detail A of FIG. 1.
[0036] FIG. 11 is a cross-sectional side view of a portion of an
implantable capsule according to a fourth embodiment of the
invention.
[0037] FIG. 12 is a cross-sectional side view of a portion of an
implantable capsule according to a fifth embodiment of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0038] The present invention relates to an osmotic delivery system
10 having a membrane material 30 for controlling a delivery rate of
a beneficial agent from the osmotic delivery system.
Definitions
[0039] The term "active agent" or "beneficial agent" intends the
active agent(s) optionally in combination with pharmaceutically
acceptable carriers and optionally additional ingredients such as
antioxidants, stabilizing agents, permeation enhancers, etc.
[0040] The term "impermeable" intends that the material is
sufficiently impermeable to environmental fluids as well as
ingredients contained within the dispensing device such that the
migration of such materials into or out of the device through the
impermeable device is so low as to have substantially no adverse
impact on the function of the device during the delivery
period.
[0041] The term "semipermeable" intends that the material is
permeable to external fluids but substantially impermeable to other
ingredients contained within the dispensing device and the
environment of use.
[0042] The term "membrane material" intends that the semipermeable
membrane is in the form of a sheet or plug. The membrane material
preferably has a diameter between about 0.040 inch and about 0.250
inch and preferably has a length or thickness between about 0.010
inch and about 0.350 inch. The diameter and thickness of the
membrane material are determined by such considerations as desired
rate of delivery of the beneficial agent, desired duration of
delivery of the beneficial agent, the device size, the material
used for the semipermeable membrane, the retention means for the
semipermeable membrane, the beneficial agent formulation, and/or
the osmotic pressure generated during operation of the device.
[0043] FIG. 1 shows that the osmotic delivery system 10 generally
includes a first chamber 50 which contains a beneficial agent, a
piston 54 and a second chamber 40 containing an osmotic agent, all
of which are enclosed within an elongated substantially cylindrical
capsule 12.
[0044] The capsule 12 must be sufficiently strong to ensure that it
will not leak, crack, break or distort so as to expel its active
agent contents under stresses it would be subjected to during use.
In particular, it should be designed to withstand the maximum
osmotic pressure that could be generated by the osmotic agent in
chamber 40. Capsule 12 must also be chemically inert,
biocompatible, and impermeable, that is, it must be nonreactive
with the active agent formulation as well as the body and must
isolate the beneficial agent during the delivery process. Suitable
materials generally comprise a nonreactive polymer or a
biocompatible metal or alloy. The polymers include acrylonitrile
polymers such as acrylonitrile-butadiene-styrene terpolymer, and
the like; halogenated polymers such as polytetrafluorethylene,
polycholortrifluoro-ethylene, copolymer tetrafluoroethylene and
hexafluoropropylene; polyimide; polysulfone; polycarbonate;
polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;
polycarbonate-acrylonitrile-butadiene-styrene; polystyrene;
polyether ether ketone (PEEK); liquid crystal polymer (LCP); and
the like. The water vapor transmission rate through compositions
useful for forming the reservoir are reported in J. Pharm. Sci.,
Vol. 29, pp. 1634-37 (1970); Ind. Eng. Chem., Vol. 45, pp.
2296-2306 (1953); Materials Engineering, Vol. 5, pp. 38-45 (1972);
Ann. Book of ASTM Stds., Vol. 8.02, pp 208-211 and pp. 584-587
(1984); and Ind. and Eng. Chem., Vol. 49, pp. 1933-1936 (1957).
Metallic materials useful in the invention 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.
A reservoir made from titanium or a titanium alloy having greater
than 60%, often greater than 85%, titanium is particularly
preferred.
[0045] The capsule 12 has a delivery end 70 with an exit passage 72
in it at the beneficial agent delivery end 70 and an opening 62 at
the fluid uptake end of the capsule 12. The exit passage 72 may
take any convenient form such as straight, circular, spiral, etc.
The exit passage 72 is made of an inert and biocompatible material
selected from, but not limited to, metals, including, but not
limited to, titanium, stainless steel, platinum and their alloys
and cobalt-chromium alloys and the like, and polymers, including,
but not limited to, polyethylene, polypropylene, polycarbonate and
polymethyl-methacrylate and the like.
[0046] The fluid uptake end 60 of the capsule 12 is closed by the
membrane material 30. In FIG. 2 the membrane material is in the
form of a plug. Materials from which the membrane materials are
made are those that are semipermeable and that can conform to the
shape of the capsule 12 upon wetting and sealing to the rigid
surface of the capsule 12. The semipermeable membrane material 30
expands as it hydrates when placed in a fluid environment so that a
seal is generated between the mating surfaces of the membrane
material and the capsule. The diameter of the membrane material is
such that it will sealingly fit inside the reservoir prior to
hydration as a result of sealing contact at one or more
circumferential or axial zones and will expand in place upon
wetting to form an even tighter seal with the capsule. The membrane
material must be able to imbibe between about 0.1% and 200% by
weight of water. The polymeric materials from which the
semipermeable membrane material may be made vary based on the
pumping rates and the device configuration requirements and
include, but are not limited to, plasticized cellulosic materials,
enhanced polymethylmethacrylate such as hydroxyethylmethacrylate
(HEMA) and elastomeric materials such as polyurethanes and
polyamides, polyether-polyamide copolymers, thermoplastic
copolyesters and the like.
[0047] The membrane material 30 closes the fluid uptake end 60 from
the second chamber 40 containing the osmotic agent.
[0048] The osmotic agent or osmotic engine may include, for
example, a nonvolatile water soluble osmoagent, an osmopolymer
which swells on contact with water, or a mixture of the two.
Osmotic agents, such as NaCl with appropriate tabletting agents
(lubricants and binders) and viscosity modifying agents, such as
sodium carboxymethylcellulose or sodium polyacrylate are preferred
water-swellable agents. Other osmotic agents useful as the
water-swellable agent include osmopolymers and osmoagents and are
described, for example, in U.S. Pat. No. 5,413,572, which is
incorporated by reference herein. The water-swellable agent
formulation can be a slurry, a tablet, a molded or extruded
material or other form known in the art. A liquid or gel additive
or filler may be added to chamber 40 to exclude air from spaces
around the osmotic engine.
[0049] Fluid passes through the membrane material 30 from an
exterior of the capsule 12 and into the second chamber 40, while
the membrane material 30 prevents the compositions within the
capsule 12 from passing out of the capsule 12.
[0050] As seen in FIG. 1, the first chamber 50, containing the
beneficial agent, is separated from the second chamber 40,
containing the osmotic agent, by a separating member, such as the
movable piston 54. The movable piston 54 is a substantially
cylindrical member configured to fit within the interior diameter
of the capsule 12 in a sealing manner and to slide along a
longitudinal axis inside the capsule 12. The piston 54 provides an
impermeable barrier between the beneficial agent contained in the
first chamber 50 and the osmotic agent contained in the second
chamber 40. The materials from which the piston are made are
preferably elastomeric materials that are impermeable and include,
but are not limited to, polypropylene, rubbers such as EPDM,
silicone rubber, butyl rubber, and the like, perfluoro-elastomers,
such as Kalrez.RTM. and Chemrez.RTM., fluorocarbons such as
Viton.RTM., and thermoplastic elastomers such as plasticized
polyvinylchloride, polyurethanes, Santoprene.RTM., C-Flex.RTM. TPE,
a styrene-ethylene-butylene-styrene copolymer (Consolidated Polymer
Technologies Inc.), and the like.
[0051] As seen in FIGS. 2 and 3, the capsule 12 includes a smooth,
generally cylindrical shape having a hollow interior. The capsule
12 is provided with a membrane material-retaining means having a
retention flange 20 positioned along an outer periphery of the
fluid uptake end 60 and includes an opening 62 to allow for the
passage of fluid into the capsule 12. The membrane retention flange
20 can have a flat, rounded, or contoured surface on the exterior
side. The retention flange 20 of the membrane material-retaining
means should be long enough to retain the membrane material 30
under full osmotic pressure, yet the opening 62 needs to maximize
the exposed surface of the membrane material. The capsule 12 also
includes one or a plurality of inwardly protruding annular ribs or
ridges 14 which provide fluid sealing between the interior surface
of the capsule 12 and the outer surface of the membrane material 30
and prevent fluid from leaking around the membrane material. The
ribs or ridges 14 are also formed to grippingly engage the outer
surface of the membrane material 30 and prevent the membrane
material 30 from moving in a lateral direction towards the
beneficial agent delivery end 70. In this respect, the diameter of
the membrane material 30 is substantially equal to the inner
diameter of the capsule 12. Moreover, the diameter of the membrane
material 30 is larger than the inner diameter of the ribs or ridges
14. The capsule may be provided with between about 1 to 8 ribs or
ridges, but is preferably provided with about 1 to 4 ribs or
ridges. Any reference to the word "ribs" is intended to include a
single rib as well as a plurality of ribs. Any reference to the
words "ridge" or "ridges" is intended to be a reference to the
words "rib" or "ribs," and vice versa.
[0052] Although FIG. 2 depicts the retention flange 20 as being
formed integrally with the capsule 12, it will be understood that
the retention flange may alternatively be a separate member
attached to the capsule. For example, the membrane retention flange
20 may be welded, pressed, screwed or the like to the end of the
capsule 12.
[0053] The opening 62 is sufficiently small that the membrane
material 30 cannot distort and pass through the opening under high
operating pressures, such as about 5000 psi.
[0054] The membrane material 30, as seen in FIGS. 4 and 5, includes
a substantially smooth cylindrical body. As seen in FIGS. 4 and 5,
the membrane material 30 is devoid of any protrusions, ribs, or
abscesses. Thus, the membrane material 30 is simpler to manufacture
than known membrane plugs. The membrane material 30 may be produced
by casting, calendering, or extrusion, then machining (i.e.,
die-cutting, stamping or otherwise cutting to shape), thereby
yielding a membrane of superior consistency compared with injection
molded membrane materials of known systems. The membrane material
30 may be made of any suitable biocompatible membrane material.
[0055] As seen in FIG. 10, the inwardly protruding ridges 14
include a sloped wall 16 and a vertical wall 18. The ridges 14
extend a distance from the inner wall 22 of the capsule 12, about
the entire circumference of the inner wall. The height h of
vertical wall 18 preferably is about 0.002'' to about 0.020''. In
addition, the sloped wall 16 is provided at an angle .alpha. from
the inner wall 22. The angle of the sloped wall 16 can be chosen to
be any suitable angle that allows for the membrane material 30 to
be easily inserted over the ridges 14. The vertical wall 18 of the
ridges 14 prevents the membrane material 30 from moving laterally
towards the beneficial agent delivery end 70. In use, the ridges 14
and the membrane retention flange 20 act together to restrict any
lateral movement of the membrane material 30.
[0056] Although FIG. 10 does not show any clearance between the
membrane material 30 and the ridges 14, it is within the scope of
the present invention that gaps may exist therebetween and between
the inner wall 22 of the capsule 12 and the membrane material
30.
[0057] FIGS. 6 and 7 show a portion of a second preferred
embodiment of an osmotic delivery system 150. In this embodiment,
the membrane material-retaining means comprises a perforated disk
120. The perforated disk 120 includes a plurality of openings 122
which allow fluid to pass therethrough and subsequently through the
membrane material 30 and into the interior of the capsule. As can
also be seen in FIG. 6, the perforated disk 120 acts together with
the ridges 114 to restrict the lateral movement of the membrane
material 30 within the capsule 112. Thus, ridges 114 function in
the same manner as the ridges 14 of the first embodiment. In this
embodiment, the perforated disk 120 is affixed by welding,
pressing, screwing or the like, to the fluid uptake end of the
capsule 112.
[0058] FIGS. 8 and 9 illustrate a portion of a third preferred
embodiment of an osmotic delivery device 250. In this embodiment, a
screen or a grate 220 having a plurality of openings 222 is affixed
to the fluid uptake end 60 (see FIG. 2) of the capsule 212. As in
the previous embodiment, the screen or grate 220 may be welded,
pressed, screwed, or otherwise affixed to the fluid uptake end 60
(see FIG. 2) of the capsule 212. The screen or grate 220 may be
affixed to the capsule 212 either before or after insertion of the
membrane material 230. Although a screen or grate 220 has been
illustrated, other structures that allow passage of water and
prevent the membrane material 230 from being expelled may also be
used.
[0059] As also seen in FIG. 8, the capsule 212 is provided with a
plurality of inward protruding, circumferentially extending,
sealing ribs or ridges 214 having a smaller inner diameter than the
inner diameter of the capsule 212. The ridges 214 include sloped
walls 16 and vertical walls 18 (see FIG. 10). The sloped walls 16
allow for the easy insertion of the membrane material 230 into the
capsule 212 while the vertical walls 18 prevent the transverse
movement of the membrane material 230 in the direction of the
beneficial agent delivery end 70 (see FIG. 1).
[0060] FIG. 11 shows a portion of a fourth preferred embodiment of
an osmotic delivery system 350. In this embodiment, the fluid
uptake end 160 comprises the membrane material perforated disk 120
and a frit or sintered powdered metal structure 320. The frit 320
includes a plurality of capillaries having diameters between about
0.5 and 10 microns which allow fluid to pass therethrough and
subsequently through the membrane material 30 into the interior of
the capsule. In FIG. 11, the membrane material 30 is of sufficient
length to include at least one rib or ridge 314. As can also be
seen in FIG. 11, the frit 320 acts together with the ridges 314 to
restrict the lateral movement of the membrane material 30 within
the capsule 112. Thus, ridges 314 function in the same manner as
the ridges 14 of the first embodiment. In this embodiment, the frit
320 is affixed, by welding, pressing, screwing or the like, to the
membrane material perforated disk 120 of the capsule 112.
[0061] FIG. 12 shows a portion of a fifth preferred embodiment of
an osmotic delivery system 350. This embodiment is similar to the
embodiment shown in FIG. 11 except that the membrane material 30 is
located between the first rib or ridge 314 and the membrane
material perforated disk 120. Movement of the membrane material 30
is restricted within the capsule 112 by both the ridge 314 and the
membrane material perforated disk 120.
[0062] The membrane material can be prepared by casting,
calendering, or extrusion. Casting comprises pouring the membrane
material onto a flat surface. Calendering comprises forming a sheet
of membrane material by pressing or rolling. Extrusion comprises
pushing the membrane material through a die form to form a rod
shape. Once the sheet or rod is prepared, the plug or disc shape is
prepared by cutting or machining the sheet or rod. The cutting or
machining can be accomplished, for example, by die-cutting or
stamping the shape.
[0063] The devices of the invention are useful to deliver a wide
variety of active agents. These agents include, but are not limited
to, pharmacologically active peptides and proteins, genes and gene
products, other gene therapy agents, and other small molecules. The
polypeptides may include, but are not limited to, growth hormone,
somatotropin analogues, somatomedin-C, Gonadotropic-releasing
hormone, follicle-stimulating hormone, luteinizing hormone, LHRH,
LHRH analogues such as leuprolide, nafarelin and goserelin, LHRH
agonists and antagonists, growth hormone-releasing factor,
calcitonin, colchicine, gonadotropins, such as chorionic
gonadotropin, oxytocin, octreotide, somatotropin plus an amino
acid, vasopressin, adrenocorticotrophic hormone, epidermal growth
factor, prolactin, somatostatin, somatotropin plus a protein,
cosyntropin, lypressin, polypeptides such as thyrotropin-releasing
hormone, thyroid stimulation hormone, secretin, pancreozymin,
enkephalin, glucagon, endocrine agents secreted internally and
distributed by way of the bloodstream, and the like. Further agents
that may be delivered include .alpha..sub.1 antitrypsin, factor
VIII, factor IX and other coagulation factors, insulin and other
peptide hormones, adrenal cortical-stimulating hormone,
thyroid-stimulating hormone and other pituitary hormones,
interferon (for example, alpha, beta, gamma, and omega),
erythropoietin, growth factors such as GCSF, GMCSF, insulin-like
growth factor 1, tissue plasminogen activator, CD4, dDAVP,
interleukin-1 receptor antagonist, tumor necrosis factor,
pancreatic enzymes, lactase, cytokines, interleukin-1 receptor
antagonist, interleukin-2, tumor necrosis factor receptor, tumor
suppresser proteins, cytotoxic proteins, and recombinant antibodies
and antibody fragments, and the like.
[0064] The above agents are useful for the treatment of a variety
of conditions including, but not limited to, hemophilia and other
blood disorders, growth disorders, diabetes, leukemia, hepatitis,
renal failure, HIV infection, hereditary diseases such as
cerebrosidase deficiency and adenosine deaminase deficiency,
hypertension, septic shock, autoimmune diseases such as multiple
sclerosis, Graves disease, systemic lupus erythematosus and
rheumatoid arthritis, shock and wasting disorder, cystic fibrosis,
lactose intolerance, Crohn's disease, inflammatory bowel disease,
gastrointestinal and other cancers.
[0065] The active or beneficial agents may be anhydrous or aqueous
solutions, suspensions or complexes with pharmaceutically
acceptable vehicles or carriers such that a flowable formulation is
produced that may be stored for long periods on the shelf or under
refrigeration, as well as stored in an implanted delivery system.
The formulations may include pharmaceutically acceptable carriers
and additional inert ingredients. The active agents may be in
various forms, such as uncharged molecules, components of molecular
complexes or pharmacologically acceptable salts. Also, simple
derivatives of the agents (such as prodrugs, ethers, esters,
amides, etc.) which are easily hydrolyzed by body pH, enzymes, etc.
can be employed.
[0066] It is to be understood that more than one active agent may
be incorporated into the active agent formulation in a device of
this invention and that the use of the term "agent" in no way
excludes the use of two or more such agents. The dispensing devices
of the invention find use, for example, in humans or other animals.
The environment of use is a fluid environment and can comprise any
subcutaneous position or body cavity, such as the peritoneum or
uterus. Ultimate delivery may be systemic or targeted and may or
may not be systemic delivery of the beneficial agent. A single
dispensing device or several dispensing devices can be administered
to a subject during a therapeutic program. The devices are designed
to remain implanted during a predetermined administration period.
If the devices are not removed following the administration, they
may be designed to withstand the maximum osmotic pressure of the
water-swellable agent or they may be designed with a bypass to
release the pressure generated within the device.
[0067] The devices of the present invention are preferably rendered
sterile prior to use, especially when such use is implantation.
This may be accomplished by separately sterilizing each component,
e.g., by gamma radiation, steam sterilization or sterile
filtration, then aseptically assembling the final system.
Alternatively, the devices may be assembled, then terminally
sterilized using any appropriate method.
[0068] The assembly of the osmotic delivery device will be
described below with reference to the embodiment of FIGS. 1-3,
however, it should be understood that the embodiments of FIGS. 6-9
and 11 and 12 may be assembled in a similar manner.
[0069] According to a preferred embodiment, the capsule is
assembled with the membrane retention flange 20 fixed to the
capsule. The membrane material 30 is preferably inserted from the
beneficial agent delivery end 70 of the capsule 12. The membrane
material 30 is then slid through the length of the capsule 12,
towards the direction of the fluid uptake end of the capsule 12
until it abuts a membrane material retention flange 20. The
membrane material 30 may be inserted by, for example, compressed
gas. In addition, as seen in FIG. 1, after the membrane material 30
has been fully inserted, the osmotic engine or osmotic agent may
then be inserted into chamber 40 from the beneficial agent delivery
end 70. Once the osmotic engine has been inserted, the piston 54
may then be inserted into the capsule. After insertion of the
piston 54, the beneficial agent can be inserted into the first
chamber 50 configured as a beneficial agent reservoir. Finally, the
exit passageway or diffusion moderator is inserted into the
beneficial agent delivery end 70.
[0070] Alternatively, the membrane retention flange 20 can be
attached to the capsule after one or more of the membrane material
30, osmotic engine, piston 54, or beneficial agent has been
inserted into the capsule 12.
[0071] If a screen, grate, or frit is present in opening 62, such
screen, grate, or frit can be attached to capsule 12 before or
after the membrane material 30 is placed in capsule 12.
[0072] Once all of the components of the osmotic delivery system 10
have been assembled, the beneficial agent delivery end 70 can be
closed in a known manner, such as providing a cap with an exit
passage 72. For example, the beneficial agent delivery end may be
closed in the manner disclosed in commonly owned and assigned U.S.
Pat. No. 5,728,396, issued to Peery et al., which is incorporated
herein by reference.
[0073] Thus, the present invention provides a more consistent and
predictable delivery rate of a beneficial agent by allowing for the
use of cast, calendered or extruded membrane materials that are
machined (i.e., die-cut, stamped or otherwise cut to shape), in
which the permeability of the membrane materials are more
homogeneous because they are produced on a highly controlled
extrusion or machining line as compared to the part-to-part
homogeneity of injection molded plugs.
[0074] According to other embodiments of the present invention, the
delivery system may take different forms. For example, the piston
may be replaced with a flexible member such as a diaphragm,
partition, pad, flat sheet, spheroid, or rigid metal alloy, and may
be made of any number of other materials. Furthermore, the osmotic
device may function without the piston, having simply an interface
between the osmotic agent/fluid additive and the beneficial agent
or having the osmotic agent incorporated in the beneficial agent.
In addition, the capsule of the present invention may be provided
with a more rounded shape along its edges in order to make
insertion of the capsule within the patient simpler.
[0075] The above-described exemplary embodiments are intended to be
illustrative in all respects, rather than restrictive, of the
present invention. Thus the present invention is capable of many
variations and detailed implementation that can be derived from the
description contained herein by a person skilled in the art. All
such variations and modifications are considered to be within the
scope and the spirit of the present invention as defined by the
following claims.
* * * * *