U.S. patent application number 11/743185 was filed with the patent office on 2007-08-30 for osmotic delivery system having space efficient piston.
This patent application is currently assigned to ALZA CORPORATION. Invention is credited to Bonnie Burdett Dennis, Ben Eckenhoff, Felix Theeuwes.
Application Number | 20070203476 11/743185 |
Document ID | / |
Family ID | 22355938 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070203476 |
Kind Code |
A1 |
Theeuwes; Felix ; et
al. |
August 30, 2007 |
Osmotic Delivery System Having Space Efficient Piston
Abstract
An osmotic delivery system having a space-efficient piston is
provided. The enclosure has an interior holding the piston, a
protein or polypeptide, and an osmotic agent. The piston is movable
with respect to an interior surface of the capsule, and defines a
movable seal with the interior surface of the capsule. The movable
seal separates the osmopolymer from the protein or peptide. The
piston has a recess that receives at least a portion of the osmotic
agent. The osmotic agent imbibes liquid from a surrounding
environment to cause the piston to move and in turn cause delivery
of the beneficial agent from the capsule.
Inventors: |
Theeuwes; Felix; (Los Altos
Hills, CA) ; Eckenhoff; Ben; (Los Altos, CA) ;
Dennis; Bonnie Burdett; (Los Altos, CA) |
Correspondence
Address: |
DEWIPAT INCORPORATED
P.O. BOX 1017
CYPRESS
TX
77410-1017
US
|
Assignee: |
ALZA CORPORATION
Mountain View
CA
|
Family ID: |
22355938 |
Appl. No.: |
11/743185 |
Filed: |
May 2, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11353842 |
Feb 14, 2006 |
7235068 |
|
|
11743185 |
May 2, 2007 |
|
|
|
10959489 |
Oct 5, 2004 |
6997922 |
|
|
11353842 |
Feb 14, 2006 |
|
|
|
10354142 |
Jan 30, 2003 |
6872201 |
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|
10959489 |
Oct 5, 2004 |
|
|
|
09472600 |
Dec 27, 1999 |
6544252 |
|
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10354142 |
Jan 30, 2003 |
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60114548 |
Dec 31, 1998 |
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|
Current U.S.
Class: |
604/892.1 |
Current CPC
Class: |
A61K 9/0004
20130101 |
Class at
Publication: |
604/892.1 |
International
Class: |
A61K 9/22 20060101
A61K009/22 |
Claims
1. An osmotic delivery system comprising: an enclosure having an
interior for holding a protein or peptide, an osmotic agent located
in the enclosure, and a semipermeable body in liquid communication
with the enclosure for permitting liquid to permeate through the
semipermeable body to the osmotic agent; and a piston located
within the enclosure, the piston defining a movable seal with the
enclosure that separates the osmotic agent from the protein or
peptide, the piston having a recess that receives a sleeve having
an interior that receives at least a portion of the osmotic agent,
the osmotic agent located between the piston and the semipermeable
body, the osmotic agent for imbibing liquid from a surrounding
environment through the semipermeable body to cause the piston to
move and, in turn, cause delivery of the protein or peptide from
the enclosure.
2. The osmotic delivery system according to claim 1, wherein the
osmotic agent comprises an osmagent or an osmopolymer.
3. The osmotic delivery system according to claim 1, wherein the
osmotic agent comprises a semisolid or a solid.
4. The osmotic delivery system according to claim 1, wherein the
osmotic agent is 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, sucrose,
glucose, lactose, fructose, dextran, poly(hydroxy-alkyl
methacrylates) with molecular weight of about 30,000 to about
5,000,000, poly(vinylpyrrolidone) with molecular weight of about
10,000 to about 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 about 200
to about 30,000, a mixture of methyl cellulose, cross-linked agar
and carboxymethylcellulose, a mixture of hydroxypropyl
methylcellulose and sodium carboxymethylcellulose, a polymer of
N-vinyllactams, polyoxyethylene-polyoxypropylene gels, a
polyoxybutylene-polyethylene block copolymer gel, carob gum,
polyacrylic gel, polyester gel, polyurea gel, polyether gel,
polyamide gel, polypeptide gel, polyamino acid gel, polycellulosic
gel, carbopol acidic carboxy polymer having a molecular weight of
about 250,000 to about 4,000,000, Cyanamer polyacrylamide,
cross-linked indene-maleic anhydride polymer, polyacrylic acid
having a molecular weight of about 80,000 to about 200,000, Polyox
Polyethylene oxide polymer having a molecular weight of about
100,000 to about 5,000,000, starch graft copolymer, or an acrylate
polymer polysaccharide.
5. The osmotic delivery system according to claim 1, wherein the
osmotic agent is in the form of a tablet, pellet, or powder.
6. The osmotic delivery system according to claim 1, wherein the
protein is interferon.
7. The osmotic delivery system according to claim 1, wherein the
protein is omega interferon.
8. The osmotic delivery system according to claim 1, wherein the
protein is leuprolide.
9. The osmotic delivery system according to claim 1, wherein the
enclosure includes an opening and the semipermeable body includes a
semipermeable membrane, the semipermeable membrane located at least
partially within the opening.
10. The osmotic delivery system according to claim 1, wherein the
recess is a concave indentation, square cavity, conical pit, gouge,
or depression.
11. The osmotic delivery system according to claim 1, wherein the
piston includes at least one rib for effecting a movable seal with
the enclosure.
12. The osmotic delivery system according to claim 1, wherein the
protein or peptide is located in the interior of the enclosure, the
protein or peptide being delivered from the enclosure when the
piston moves.
13. The osmotic delivery system according to claim 1, wherein the
protein or peptide is located in the interior of the enclosure, the
piston defining the movable seal that separates the osmotic agent
from the protein or peptide.
14. An osmotic delivery system comprising: a piston located within
an enclosure, the piston having a recess and at least one rib for
effecting a movable seal with the enclosure; and an osmotic agent
located within the recess, the osmotic agent for imbibing liquid
from a surrounding environment to cause the piston to move within
the enclosure and displace the contents of the enclosure.
15. The osmotic delivery system according to claim 14, wherein the
piston comprises an elastomeric material.
16. The osmotic delivery system according to claim 14, wherein the
piston comprises a material selected from the group consisting of
polyurethanes, polyamides, chlorinated rubbers, styrene-butadiene
rubbers, and chloroprene rubbers.
17. A piston for use in an osmotic delivery system having an
enclosure and a semipermeable body in communication with the
enclosure, the piston comprising: a sleeve located within a recess
in the piston, the sleeve having an interior; an osmotic agent at
least partially contained in the sleeve, the osmotic agent located
between the piston and the semipermeable body, the osmotic agent
for imbibing liquid from a surrounding environment through the
semipermeable body to cause the piston to move and cause delivery
of the beneficial agent from the enclosure.
18. The osmotic delivery system according to claim 17, wherein the
piston includes at least one rib for effecting a movable seal with
the enclosure.
19. The osmotic delivery system according to claim 17, wherein the
piston comprises an elastomeric material.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
11/353,842, filed Feb. 14, 2006, which application is a
continuation of application Ser. No. 10/959,489, filed Oct. 5,
2004, now U.S. Pat. No. 6,997,922, issued Feb. 14, 2006, which
application is a continuation of application Ser. No. 10/354,142,
filed Jan. 30, 2003, now U.S. Pat. No. 6,872,201, issued Mar. 29,
2005, which is a continuation of, and claims priority from U.S.
patent application Ser. No. 09/472,600, filed Dec. 27, 1999, now
U.S. Pat. No. 6,544,252, issued Apr. 8, 2003, which claims the
benefit of U.S. Provisional Application Ser. No. 60/114,548, filed
on Dec. 31, 1998, the entire disclosures of which are hereby
incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to osmotic delivery systems
for delivering beneficial agents, and more particularly, to an
osmotic delivery system having a piston with a recess for receiving
an osmotic agent.
BACKGROUND OF THE INVENTION
[0003] Description of the Related Art: 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 devices can be implanted 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.
[0004] A known osmotic delivery system, commonly referred to as an
"osmotic pump," generally includes some type of capsule or
enclosure having a semipermeable portion that may selectively pass
water into an interior of the capsule that contains a
water-attracting osmotic agent. In such a known osmotic delivery
system, the walls of the capsule are substantially impermeable to
items within and outside the capsule, and a plug acts as the
semipermeable portion. The difference in osmolarity between the
water-attracting agent and the exterior of the capsule causes water
to pass through the semipermeable portion of the capsule, which in
turn causes the beneficial agent to be delivered from the capsule
through the delivery port. The water-attracting 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.
[0005] In some instances, a piston is required to separate the
beneficial agent from the osmotic agent to prevent the osmotic
agent from mixing with or contaminating the beneficial agent. 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, pressure 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.
[0006] In those osmotic delivery systems that require the use of a
piston to separate the beneficial agent and the osmotic agent, the
piston necessarily occupies space in the capsule. Hence, if the
piston is needed to separate the beneficial agent and the osmotic
agent, and the size of the capsule is not changed, the amount of
beneficial agent or osmotic agent that can be held within the
capsule decreases as compared to another osmotic delivery system
having the same size capsule that does not include a piston.
Decreasing the amount of beneficial agent within the capsule
detrimentally decreases the net amount of beneficial agent that can
be delivered over a sustained period of time. Decreasing the amount
of osmotic agent within the capsule detrimentally decreases the
sustained period of time through which continuous delivery of the
beneficial agent can be obtained.
[0007] But if the specific application requires a specific amount
of beneficial agent or osmotic agent that cannot be varied and a
piston must be used to separate the beneficial agent from the
osmotic agent, the size of the capsule must be increased to
accommodate for the extra space occupied by the piston such that
the amount of osmotic agent or beneficial agent in the capsule does
not vary. While simply increasing the size or volume of the capsule
to accommodate for the extra volume occupied by the piston may
appear to be a simple solution, because many osmotic delivery
systems are destined for implantation in humans or animals, it is
especially desirable to decrease the size of the osmotic delivery
system as much as possible, while still allowing the osmotic
delivery system to deliver the beneficial agent over a prolonged
period of time. Additionally, simply increasing the size of the
capsule for those applications requiring a piston that separates
the beneficial agent from the osmotic agent is inexpedient as it is
desirable to use one capsule for multiple osmotic delivery system
applications. Moreover, it has been particularly problematic to
increase the amount of time over which steady state release of the
beneficial agent may be obtained with current osmotic delivery
systems incorporating conventional pistons, without increasing the
size of the capsule to hold more beneficial agent or osmotic agent.
These problems associated with current osmotic delivery systems
having known pistons have created a need for a solution.
BRIEF SUMMARY OF THE INVENTION
[0008] In accordance with one aspect of the present invention, an
osmotic delivery system includes an enclosure having an interior
for holding a protein or peptide. An osmotic agent is located in
the enclosure, and a semipermeable body is in liquid communication
with the enclosure for permitting liquid to permeate through the
semipermeable body to the osmotic agent. The system also includes a
piston located within the enclosure, the piston defining a movable
seal with the enclosure that separates the osmotic agent from the
protein or peptide. The piston has a recess that receives a sleeve.
The sleeve has an interior that receives at least a portion of the
osmotic agent. The osmotic agent is located between the piston and
the semipermeable body, the osmotic agent adapted to imbibe liquid
from a surrounding environment through the semipermeable body to
cause the piston to move and cause delivery of the protein or
peptide from the enclosure.
[0009] In accordance with another aspect of the present invention,
an osmotic delivery system includes a piston located within an
enclosure, the piston having a recess. The system also includes an
osmotic agent located within the recess, the osmotic agent adapted
to imbibe liquid from a surrounding environment to cause the piston
to move within the enclosure and displace the contents of the
enclosure.
[0010] According to another aspect of the present invention, a
piston for use in an osmotic delivery system that has an enclosure
and a semipermeable body in communication with the enclosure
includes a sleeve located within a recess in the piston, the sleeve
having an interior. An osmotic agent is at least partially
contained in the sleeve and is located between the piston and the
semipermeable body. The osmotic agent is adapted to imbibe liquid
from a surrounding environment through the semipermeable body to
cause the piston to move and cause delivery of the beneficial agent
from the enclosure.
[0011] Other objects, advantages and features associated with the
present invention will become readily apparent to those skilled in
the art from the following detailed description. As will be
realized, the invention is capable of other and different
embodiments, and its several details are capable of modification in
various obvious aspects, all without departing from the invention.
Accordingly, the drawings and the description are to be regarded as
illustrative in nature, and not limiting.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0012] The invention will be described in greater detail with
reference to the accompanying drawings in which like elements bear
like reference numerals, and wherein:
[0013] FIG. 1 is a sectional view of an osmotic delivery system
according to one embodiment of the present invention;
[0014] FIG. 2 is a sectional view of an osmotic delivery system
according to the present invention taken along the line 2-2 of FIG.
1;
[0015] FIG. 3 is a perspective view of a piston according to one
embodiment of the present invention;
[0016] FIG. 4 is an exploded perspective view of an osmotic
delivery system according to one embodiment of the present
invention;
[0017] FIG. 5 is a sectional view of another osmotic delivery
system according to the present invention;
[0018] FIG. 6 is a perspective view of a cup-shaped sleeve for
insertion into a recess of a piston in accordance with another
embodiment of the present invention;
[0019] FIG. 7 is sectional view of the sleeve of FIG. 6 taken along
the line 7-7 of FIG. 6.
DETAILED DESCRIPTION OF THE INVENTION
[0020] As shown in FIGS. 1-4, the present invention relates to an
osmotic delivery system 20 for delivering a beneficial agent 24.
The osmotic delivery system 20 includes a "space-efficient" piston
30. The piston 30 includes a recess 34 that receives an osmotic
agent 26. The osmotic delivery system 20 also includes an enclosure
21 that encloses the piston 30 and the osmotic agent 26. The piston
30 is movable within the enclosure 21 and defines a movable seal
that substantially prevents the osmotic agent 26 and the beneficial
agent 24 from adversely affecting one another. A semipermeable body
28 is in liquid communication with the osmotic agent 26 and permits
liquid to permeate through the semipermeable body to the osmotic
agent 26. The osmotic agent 26 imbibes the liquid from a
surrounding environment and causes the piston 30 to move, which, in
turn, causes the beneficial agent 24 to be released from the
osmotic delivery system 20.
[0021] The configuration of the osmotic delivery system 20
according to the present invention illustrated in FIGS. 1-4 is one
example of an osmotic delivery device and is 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 any variety of
methods, such as oral, ruminal, and implantable osmotic delivery
techniques. Such devices may also be placed in reservoirs, tanks,
or pools.
[0022] The enclosure 21 of the osmotic delivery system 20 encloses
or contains the osmotic agent 26 and the body 32 of the piston 30
(shown in FIG. 3). The enclosure 21 includes a tubular or elongated
and substantially cylindrical capsule 22 illustrated in FIGS. 1 and
4. The capsule 22 has a first opening 51 at a first end 50 and a
second opening 53 at a second end 52 opposite the first end 50. The
enclosure 21 also includes the semipermeable body 28 that
obstructs, blocks, closes-off, or plugs the first opening 51 in the
capsule 22 to enclose the osmotic agent 26 and body 32 of piston
30. Thus, the first opening 51 receives the semipermeable body
28.
[0023] The enclosure 21 also includes a delivery port 44 located at
the second end 52 of the capsule 22. The delivery port 44 delivers
the beneficial agent 24 from the osmotic delivery system 20.
According to other embodiments of the present invention, the
capsule 22 may take different forms and shapes. For example, the
capsule 22 can be tablet-shaped, have an elliptical cross-section,
and can be formed from multiple piece tubes or cylinders, or two
spheroidal sections. Additionally, the second opening 53 of the
capsule 22 can define the delivery port 44, and the first opening
51 can define a channel for communicating a liquid, such as water,
from a semipermeable body external of the capsule 22 to an osmotic
agent within the capsule. The first opening 51 can also define a
channel for communicating a liquid from an external environment to
a semipermeable body within the capsule 22.
[0024] The delivery port 44 is an orifice formed by conventional
techniques. Included among these methods are mechanical drilling,
laser drilling, and molding. The enclosure 21 will contain at least
one such delivery port 44, and in most configurations, one delivery
port will suffice. However, two or more delivery ports 44 may be
present without departing from the present invention. The delivery
port 44 may be formed in the capsule 22 itself, such as in the
embodiment illustrated in FIG. 5 (shown as 144 and 122,
respectively), or may be formed in a separate and distinct
plug-like member 42 having means for sealing or ribs 48 extending
outwardly from the outer surface thereof for insertion into the
second opening 53 of the capsule 22. The delivery port 44 can be
other configurations. For example, the delivery port 44 can be a
slit orifice, such as that disclosed in U.S. application Ser. No.
09/045,944, now U.S. Pat. No. 5,997,527, the entire disclosure of
which is hereby incorporated herein by reference, or a spiral
orifice, such as that disclosed in U.S. application Ser. No.
08/595,761, the entire disclosure of which is hereby incorporated
herein by reference.
[0025] The dimensions of the port 44 in terms of both diameter and
length will vary with the type of beneficial agent 24, 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 44 for any
particular enclosure or beneficial agent 24 are the same as those
for delivery ports or orifices of enclosures of the prior art, and
selection of the appropriate dimensions will be readily apparent to
those skilled in the art.
[0026] The capsule 22 is formed of a material that is sufficiently
rigid to withstand expansion of an osmotic agent 26 without
changing size or shape. The capsule 22 is preferably substantially
impermeable to fluids in the environment as well as to ingredients
contained within the osmotic delivery system 20 such that the
migration of such materials into or out of the capsule through the
impermeable material of the capsule is so low as to have
substantially no adverse impact on the function of the osmotic
delivery system 20.
[0027] Materials that can be used for the capsule 22 are preferably
sufficiently strong to ensure that the capsule will not leak,
crack, break, or distort under stresses to which it would be
subjected during implantation or under stresses due to the
pressures generated during operation of the osmotic delivery system
20.
[0028] The capsule 22 can be formed of chemically inert and
biocompatible, natural or synthetic materials that are known in the
art. The capsule material is preferably a non-bioerodible material
that can remain in a patient after use, such as titanium or a
titanium alloy, and is largely impermeable to materials within and
outside the capsule 22. However, the material of the capsule 22 can
alternatively be a bioerodible material that bioerodes in the
environment after dispensing the beneficial agent 24. Generally,
preferred materials for the capsule 22 are those acceptable for
human implants.
[0029] In general, typical materials of construction suitable for
the capsule 22 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 22 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. The capsule 22 can be formed from any of the
above-mentioned wall-forming materials by the use of a mold, with
the materials applied either over the mold or inside the mold,
depending on the mold configuration. Additionally, the capsule 22
can be formed by machining. Any of the wide variety of techniques
known in the pharmaceutical industry can be used to form the
capsule 22.
[0030] The interior of the capsule 22 receives the osmotic agent
26, which in the embodiment of the present invention depicted in
FIGS. 1 and 4 is an osmotic tablet. The osmotic agent 26,
specifically the osmotic tablet of the embodiment of the present
invention illustrated in FIG. 1, drives the osmotic flow of the
osmotic delivery system 20. The osmotic agent 26 need not be a
tablet; it may be other conceivable shapes, textures, densities,
and consistencies and still be within the confines of the present
invention. Additionally, more than one osmotic tablet may be used
to drive the osmotic flow of the osmotic delivery system 20. When
the osmotic delivery system 20 is assembled, the capsule 22
contains the osmotic agent 26.
[0031] The osmotic agent 26 is a liquid-attracting agent used to
drive the flow of the beneficial agent 24 from the osmotic delivery
system 20. The osmotic agent 26 may be an osmagent, an osmopolymer,
or a mixture of the two. Species that 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.
[0032] Species that 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 methyl cellulose,
cross-linked agar and carboxymethylcellulose, a mixture of
hydroxypropyl methylcellulose and sodium carboxymethylcellulose,
polymers of N-vinyllactams, polyoxyethylene-polyoxypropylene gels,
polyoxybutylene-polyethylene block copolymer gels, carob gum,
polyacrylic gels, polyester gels, polyurea 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
polyacrylamides, cross-linked indene-maleic anhydride polymers,
Good-Rite.RTM. polyacrylic acids having molecular weights of 80,000
to 200,000, Polyox Polyethylene oxide polymers having molecular
weights of 100,000 to 5,000,000, starch graft copolymers, and
Aqua-Keeps acrylate polymer polysaccharides.
[0033] The osmotic agent 26 may be manufactured by a variety of
techniques, many of which are known in the art. In one such
technique, an osmotically active agent is prepared as solid or
semi-solid formulations 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 that may be included, can 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.
[0034] The beneficial agent 24 may optionally include
pharmaceutically acceptable carriers and/or additional ingredients
such as antioxidants, stabilizing agents, permeation enhancers,
etc. In other embodiments of this invention, the beneficial agent
24 contained in the capsule 22 may include flowable compositions
such as liquids, suspension, or slurries, which are typically
poured into the capsule after the osmotic agent 26 and the body 32
of the piston 30 have been inserted in the capsule.
[0035] Patients to whom beneficial agents 24 may be administered
using systems of this invention include humans and 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, the devices of the present
invention may be implanted subcutaneously or intraperitoneally
wherein aqueous body fluids or liquids are available to activate
the osmotic agent 26. Devices of the invention may also be
administered to the rumen of humans and ruminant animals, in which
embodiment the devices may further comprise a conventional density
element for maintaining the device in the rumen for extended
periods of time of up to 120 days or longer.
[0036] The present invention applies to the administration of
beneficial agents in general, which include any physiologically or
pharmacologically active substance. The beneficial agent 24 may be
any of the agents that 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 24 may also be an agent that is
delivered to other types of aqueous environments such as pools,
tanks, reservoirs, and the like. Included among the types of agents
that meet this description are biocides, sterilization agents,
nutrients, vitamins, food supplements, sex sterilants, fertility
inhibitors and fertility promoters.
[0037] Drug agents that 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.
[0038] Examples of drugs that 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, isoflurophate, 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-.varies.-hydroxyprogesterone 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, dihydroxyphenylalaline, 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.
[0039] The beneficial agent 24 can be present in this invention in
a wide variety of chemical and physical forms, such as solids,
liquids and slurries. On the molecular level, the various forms 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.
[0040] Osmotic delivery systems according to the present invention
are also useful in environments outside of physiological or aqueous
environments. For example, the osmotic delivery system 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
or human. Osmotic delivery systems according to the present
invention may also be utilized in blood oxygenators, kidney
dialysis and electrophoresis, for example. Additionally, devices or
systems 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.
[0041] The osmotic delivery system 20 also includes the
aforementioned semipermeable body 28, such as the semipermeable
plug illustrated in FIGS. 1 and 4. The semipermeable body 28 is
formed of a semipermeable material that allows liquid to pass from
an exterior environment of use into the capsule 22 to cause the
osmotic agent 26 to swell. But the material forming the
semipermeable body 28 is largely impermeable to the materials
within the enclosure 21 and other ingredients within the
environment of use. As illustrated in FIG. 1, the semipermeable
body 28 is in the shape of a plug that is inserted into the first
opening 51 of the capsule 22 at the first end 50. The semipermeable
body 28 defines part of the enclosure 21 because it closes-off the
first opening 51 of the capsule 22. Alternatively, the
semipermeable body 28 may be located distant from the enclosure 21,
but communicate liquid from a surrounding environment of use to the
osmotic agent 26 through a tube in liquid communication with the
capsule 22 or through other means for communicating liquid. The
semipermeable body 28 may also be a membrane coating on the
exterior surface of the capsule 22 or a sleeve or cap that slides
over a portion of the capsule 22 to enclose the osmotic agent
26.
[0042] As shown in FIG. 1, the osmotic delivery system 20 includes
the semipermeable body 28, such as the semipermeable plug
illustrated. The semipermeable body 28 is typically cylindrically
shaped, and has means for sealing or ribs 46 extending outwardly
from the outer surface of the semipermeable body 28. The ribs 46
are the means by which the semipermeable plug operates like a cork
or stopper, obstructing and plugging the opening 51 in the capsule
22 of the osmotic delivery system 20 illustrated in FIG. 1. The
means for sealing 46 may be the exemplary ribs, or may be other
configurations such as threads, a tight interference fit between an
outer sealing surface of the plug and the capsule 22, glue,
adhesives, ridges, lips, or other devices which join the
semipermeable body 28 with the capsule 22 to prevent leakage. The
semipermeable body 28 is, therefore, intended for at least partial
insertion into an opening of the capsule 22, and the means for
sealing 46 the environment of use from an inside of the capsule 22
prevents liquid and other substances in the environment of use,
besides the permeation liquid, from entering the osmotic delivery
system 20 while also preventing materials from the inside of the
delivery system from leaking or escaping to the environment of
use.
[0043] The semipermeable body 28 is made from a semipermeable
material. The semipermeable material of the body 28 allows liquids,
especially water, to pass from an exterior environment of use into
the capsule 22 to cause the osmotic agent 26 to swell. However, the
semipermeable material forming the semipermeable body 28 is largely
impermeable to the materials within the capsule 22 and other
ingredients within the fluid environment.
[0044] Semipermeable compositions suitable for the semipermeable
body 28 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 body 28 can be made include, but are not
limited to, for example, Hytrel 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 is replaced by a substituting group.
Representative materials include, but are not limited to, one
selected from the group consisting of cellulose acylate, 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, and acetyl
content of 4 average weight percent 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.
[0045] Other materials for the semipermeable body 28 are
polyurethane, polyetherblockamide (PEBAX, commercially available
from ELF ATOCHEM, Inc.), injection-moldable thermoplastic polymers
with some hydrophilicity such as ethylene vinyl alcohol (EVA). The
composition of the semipermeable body 28 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.
[0046] The osmotic delivery system 20 also includes the movable
space-efficient piston 30. The piston 30 is a member that is
matingly received by the hollow interior of the capsule 22 and
moves when subjected to pressure from the osmotic agent 26 to
displace or move the beneficial agent 24. The piston 30 forms a
movable seal with the interior surface of the capsule 22. The
movable seal formed by the piston 30 separates the osmotic agent 26
and the beneficial agent 24 such that the osmotic agent 26 does not
substantially leak or seep past the piston seal and adversely
affect the function of the beneficial agent 24. Hence, the osmotic
agent 26 is separated from the beneficial agent 24 by the movable
piston 32.
[0047] As illustrated in FIG. 3, the body 32 of the piston 30 is a
substantially cylindrical member that is configured to fit in the
capsule 22 in a sealing manner that allows the piston 30 to slide
within the capsule 22 in the longitudinal direction of the capsule
22. That is, the exterior surface of the piston body 32 abuts
against and slides relative to the interior cylindrical surface of
the capsule 22. Because the semipermeable body 28 is lodged within
the first opening 51, the piston 30 also moves relative to the
semipermeable body 28.
[0048] The piston body 32 includes annular ring-shaped protrusions
or ribs 38 that define the movable or sliding seal with the inner
surface of the capsule 22. The ribs 38 are the most outwardly
radial surface of the piston body 32. The ribs 38 are the means by
which the piston 30 forms a seal with the interior surface of the
capsule 22. Thus, the outermost radial diameter of the piston body
32 is greater than the inner diameter of the capsule 22. Although
the piston body 32 illustrated in FIG. 3 includes two ribs, other
pistons according to the present invention may include one or more
ribs. Additionally, the piston body 32 need not include ribs. For
example, the exterior surface of the piston body can be entirely
cylindrical such that the entire cylindrical exterior surface of
the piston body effects a seal with the interior surface of the
capsule 22. However, the ribs 38 are preferred as they effect a
better movable seal with the interior surface of the capsule 22, as
compared to a piston body having an exterior surface that is
entirely cylindrical. The piston body 32 is preferably formed of an
impermeable resilient and inert material. In general, materials
suitable for the piston body 32 are elastomeric materials including
the non-reactive polymers listed above in reference to the
materials for the capsule 22, as well as elastomers in general,
such as polyurethanes and polyamides, chlorinated rubbers,
styrene-butadiene rubbers, and chloroprene rubbers.
[0049] As illustrated in FIG. 3, the piston body 32 includes a
hollow interior portion or recess 34, such as the cylindrical
cavity illustrated. The recess 34 can be other configurations such
as a square cavity, concave indentation, conical pit, cup, gouge,
depression, or similar space adapted to receive the osmotic agent
26. The recess 34 has a cylindrical and longitudinal interior
surface 33 that begins at an insert opening 31 formed by the recess
34 in the first end 35 of the piston body 32, and ends at a depth
surface 36 within the piston body 32 close to the second end 37 of
the piston body 32. Because of the general cylindrical shape of the
outer surface of the piston body 32 and the cylindrical shape of
the recess 34, the piston is thimble or cup-shaped such that a
"bottom of the cup" has a thickness. Because the piston 30
separates the beneficial agent 24 and the osmotic agent 26, the
recess 34 preferably does not pierce completely through the piston
body 32. The piston body 32 is cup-shaped because the recess 34
defines a hollow area within the piston body 32.
[0050] The longitudinal axis of the recess 34 is approximately
parallel to the longitudinal axis of the capsule 22, and is
preferably coincident with the longitudinal axis of the capsule 22.
Additionally, the opening 31 of the recess 34 faces away from the
delivery port 44, i.e., toward the semipermeable body 28. The depth
surface 36 of the recess preferably extends past the median of the
piston body 32 along the longitudinal axis of the piston as
measured from the first end 35. The diameter of the recess 34 is
typically 50%, preferably greater than 60%, and preferably less
than 80% of the inner diameter of the capsule 22. By increasing the
diameter of the recess 34, the wall thickness of the piston body 32
decreases. It is preferable that the recess 34 occupy as much
internal volume of the piston 30 as possible without destroying the
effectiveness of the piston seal when the piston 30 is inserted
into the capsule 22. Additionally, the exterior surface of the
piston body 32 can take other shapes, such as a chevron or
cantilever shape.
[0051] Although the cylindrical configuration of the recess 34 is
preferred, other configuration recesses fall within the confines of
the present invention. For example, the recess 34 or hollow
interior portion may be square, rectangular, octagonal, triangular,
oval, half-circular, circular, or a shape that matches the shape of
the exterior surface of the piston body 32. Likewise, the hollow
interior portion 34 may be a series or plurality of recesses,
tubes, slots, or gaps within the interior of the piston body 32.
All of the above, and other configurations, would function to
receive a portion of the osmotic agent 26 such that the piston 30
occupies less space within the capsule 22.
[0052] The recess 34 of the piston body 32 receives the osmotic
agent 26, such as the osmotic tablet illustrated in FIG. 1.
Additionally, the recess 34 also matingly receives an insert or
sleeve 40, such as the cylindrical tube illustrated in FIGS. 1 and
2. The sleeve 40 is preferably made from a rigid and impermeable
material such as that used for the capsule 22, and helps effect a
movable seal between the piston and the interior surface of the
capsule 22. For example, the sleeve 40 can be formed from
polycarbonate, polysulfone, polystyrene, or an acetal such as
DELRIN.RTM. (DuPont). The sleeve 40 also can be made out of an
inert metal such as stainless steel or titanium. The sleeve 40 is
inserted into the recess 34 and has an outer diameter that at least
matches the diameter of the recess 34. Because the recess 34
receives the sleeve 40, it is preferable that the shape of the
exterior surface of the sleeve 40 matches or corresponds to the
shape of the recess 34. For example, the recess 34 and the sleeve
40 are both cylindrical. It is also preferable that the
wall-thickness of the sleeve 40 be thin so as to occupy little
space within the recess 34. In general, the wall-thickness of the
sleeve 40 must be thick enough to impart enough rigidity to the
sleeve to maintain the piston seal with the interior surface of the
capsule 22.
[0053] The sleeve 40 is sized such that the recess 34 matingly
receives the sleeve 40. In instances where it is desirable to
increase the outer diameter of the piston body 32, if the piston
body 32 is formed of a resilient material, the outer diameter of
the sleeve 40 may be greater than the diameter of the recess 34
such that the piston body 32 deflects radially and outwardly when
the sleeve 40 is inserted therein. In the embodiment illustrated in
FIG. 1, the longitudinal length of the sleeve 40 is substantially
equal to the longitudinal depth of the recess 34 in the piston body
32.
[0054] It will be appreciated that the sleeve 40 may be in any
number of different shapes and sizes, but preferably matches the
shape and size of the recess 34 into which the sleeve 40 is
inserted. For example, the sleeve 40 may be cup-shaped or shaped
like a chevron. In general, the sleeve 40 stabilizes the dimensions
and sealing forces of the piston body 32 as the piston moves,
especially if an osmotic tablet is used that dissolves into a fluid
during operation of the osmotic delivery system 20. Additionally,
the sleeve 40 helps prevent the beneficial agent 24 from diffusing
into the osmotic agent 26 during storage of the osmotic delivery
device 20.
[0055] The sleeve 40 is preferably inserted into the recess 34 for
assisting the piston body 32 in effecting a movable seal with the
interior surface of the capsule 22. Because the piston body 32 is
preferably flexible and resilient, the wall of the piston body 32
flexes toward the interior of the recess 32 after the piston body
32 is inserted into the capsule 22. By inserting the preferably
rigid sleeve 40 into the opening 31 of the recess 34 such that the
sleeve 40 is matingly received, the wall of the piston body 32 will
not overly flex inwardly toward the recess 34, and the seal formed
between the outer surface of the piston 30 and the interior surface
of the capsule 22 is maintained.
[0056] FIGS. 6 and 7 illustrate another embodiment of a sleeve. As
shown by FIGS. 6 and 7, the sleeve 240 is in the shape of cup, such
as a cap or thimble. The sleeve 240 is inserted into the piston
232, and the osmotic agent 226 is inserted in the recess formed by
the cup-shaped sleeve 240. The sleeve 240 may be fabricated from an
inert and rigid material to ensure that the piston is
impermeable.
[0057] Although the piston 30 illustrated in FIG. 1 includes the
sleeve 40, in some instances, it may not be necessary to include
the sleeve 40 in the recess 34 as the material of the piston body
32 is sufficiently rigid to effect a satisfactory seal between the
interior surface of the capsule 22 and the piston body 32. In this
case, the sleeve 40 need not be inserted into the recess 34.
Generally, the wall thickness and the structural characteristics of
the piston body 32 determine whether or not a rigid sleeve 40 is
needed to assist in defining the seal, which is determinable by
experimental methods.
[0058] The osmotic agent 26 is at least partially located within
the recess 34. Preferably, the majority of the total weight of the
osmotic agent 26 is located within the recess 34. The osmotic agent
26 may be completely located within the recess 34, or may extend
partially from the recess 34. As illustrated in FIG. 1, the volume
of the osmotic agent 26 is greater than that of the recess 34 such
that the osmotic agent extends from the recess 34 and into a gap or
space 54 located between the piston 30 and the semipermeable body
28. The osmotic agent 26 may completely fill the gap 54 such as
shown in FIG. 5, or only partially fill the gap 54, as shown in
FIG. 1.
[0059] The piston body 32 is preferably injection molded. However,
the piston body 32 may be fashioned by a different process. For
example, the piston body 32 may also be made from extrusion,
reaction injection molding, rotational molding, thermoforming,
compression molding, and other known processes. If an injection
molding process is used to form the piston body 32, the ejector pin
or core may be used to form the recess 34, and different length and
sized ejector pins or cores may be easily changed to fashion
different size recesses 34 to controllably vary the amount of
osmotic agent that is received by the recess 34 of the piston 30.
Additionally, the recess 34 may be formed in the piston body 32
after the piston body has been formed without a recess. For
example, a cylinder of material may be fabricated and sliced into
smaller cylinders. Thereafter, a cylindrical section may be removed
from the piston body to form the recess 34 in the piston body
32.
[0060] Furthermore, the piston body 32 need not be the unitary
structure illustrated in FIG. 3. A cylindrical tube may be attached
to a flat circular disk to define the cup-shape of the piston 30.
Additionally, the sleeve 40 may be cup-shaped, and a resilient tube
with ribs may wrap around an outer cylindrical surface of the
sleeve to define the piston 30.
[0061] It is preferable that the piston body 32 be substantially
impervious to liquids, such that the osmotic agent and the liquid
that permeates through the semipermeable body 28 does not diffuse
through the piston body 32 and affect the beneficial agent 24
located on the side of the piston 30 opposite from that of the
osmotic agent 26, and such that the beneficial agent does not
diffuse through the piston body 32 and affect the performance of
the osmotic agent 26.
[0062] Because the recess 34 of the piston body 32 at least
receives a portion of the osmotic agent 26, the total volume of the
osmotic delivery system 20, as compared to past systems, may be
efficiently utilized. That is, rather than locating the osmotic
agent 26 entirely between a semipermeable body and a known piston
having no recess, the osmotic agent is at least partially located
within the piston such that the space within the capsule 22 is
efficiently utilized. The space-efficient piston 30 occupies less
space in the capsule 22 of the osmotic delivery system 20, as
compared to conventional pistons. Because the piston 30 occupies
less space within the capsule 22, the internal volume of the
interior of the capsule 22 need not be overly increased, if
increased at all, to accommodate for the extra space occupied by
the piston such that the amount of osmotic agent or beneficial
agent in the capsule does not excessively vary when the piston 30
is used. This characteristic of the osmotic delivery system 20
increases the amount of time over which steady-state release of the
beneficial agent 24 may be obtained as compared to past osmotic
delivery systems that include conventional pistons. Additionally,
because the piston 30 occupies less volume than past pistons, the
total internal volume of the capsule 22 of the osmotic delivery
system 20 can be decreased to provide an enclosure that is more
suitable for human or animal implantation.
[0063] The piston 30 can also be used with existing osmotic
delivery systems that utilize conventional pistons to increase the
duration of continuous or pulsatile delivery of a beneficial agent
from the osmotic delivery system. This is because the recess 34 can
receive additional osmotic agent or because the existing osmotic
agent can be located within the recess 34 so that the delivery
system can hold additional beneficial agents. The factors that
determine how much osmotic agent is needed to obtain sustained
release of beneficial agents from osmotic delivery systems are
described in a publication by F. Theeuwes and S. I. Yum, Principles
of the Design and Operation of Generic Osmotic Pumps for the
Delivery of Semisolid or Liquid Drug Formulations, ANNALS OF
BIOMEDICAL ENGINEERING 41, 1976, at 343-353, the entire disclosure
of which is hereby incorporated herein by reference.
[0064] In assembling the osmotic delivery system 20 according to
one embodiment of the present invention, the sleeve 40 is first
inserted into the recess 34 of the piston 30. Then, the piston 30
is inserted into the first opening 51 of the capsule 22. Once the
osmotic agent pellet or tablet has been formed, it is placed inside
the recess 34 such that the hollow interior 41 of the sleeve 40
receives the osmotic agent 26. If the osmotic agent is a powder
formulation, it can be poured into the recess 34. After the osmotic
agent is located within the capsule 22, the semipermeable body 28
is inserted into the first opening to close-off the first end 50 of
the enclosure 21. At this stage of the assembly process, the
osmotic agent 26 is located between the semipermeable body 28 and
the piston body 32. The beneficial agent 24 is then inserted into
the second opening 53 of the capsule 22 such that the beneficial
agent is directly adjacent to the piston 30. Thereafter, the
plug-like member 42 having means for sealing or ribs 48 extending
outwardly from the outer surface thereof is inserted into the
second opening to close-off the second end of the enclosure 21 and
complete the osmotic delivery system 20.
[0065] FIG. 5 illustrates an alternative embodiment of an osmotic
delivery system 120 according to the present invention. The
foregoing and following discussion of the benefits and function of
the osmotic delivery system 20 also applies to the osmotic delivery
system 120. Thus, the osmotic delivery system illustrated in FIG. 4
has been assigned corresponding reference numbers as the osmotic
delivery system 20, increased by 100. The osmotic delivery system
120 illustrated in FIG. 4 also includes many additional features
and inherent functions as described further below.
[0066] As illustrated in FIG. 5, the osmotic delivery system 120
includes an elongated substantially cylindrical capsule 122 having
an opening through which a semipermeable body 128 has been
inserted. The semipermeable body 128 is a cup-shaped membrane that
has been inserted into an opening in the first end 150 of the
capsule 122.
[0067] Also located within the capsule 122 is the osmotic agent
126, which is a powder formulation. The osmotic agent 126 is
received by the recess of the piston body 132, as is the sleeve
140. Because the osmotic agent 126 is a powder formulation, it
generally occupies the entire space or gap between the piston body
132 and the semipermeable body 128. Thus, the powder formulation of
the osmotic agent efficiently utilizes the space between the piston
body 132 and the semipermeable body 128.
[0068] The capsule 122 of the osmotic delivery system 120 defines a
delivery port 144 at the second end 152. Attached to the delivery
port 144 is a catheter or tube 160 that delivers the beneficial
agent 124 dispensed from the capsule 122 to a remote location.
Hence, the osmotic delivery system 120 does not include a plug-like
member having a delivery port such as the plug-like member 42 shown
in FIG. 1. Protrusions or ribs 138 of the piston body 132 seal the
beneficial agent 124 from the osmotic agent 126.
[0069] While the invention has been described in detail with
reference to a preferred embodiment thereof, it will be apparent to
one skilled in the art that various changes can be made, and
equivalents can be employed without departing from the spirit and
scope of the invention.
* * * * *