U.S. patent application number 11/856050 was filed with the patent office on 2008-03-20 for osmotic delivery system flow modulator apparatus and method.
This patent application is currently assigned to ALZA CORPORATION. Invention is credited to Craig R. Davis, Houdin Dehnad, Lawton Hom, Fred H. Maruyama, John R. Peery, Lewis L. Peterson, Kevin S. Sly.
Application Number | 20080071253 11/856050 |
Document ID | / |
Family ID | 21985903 |
Filed Date | 2008-03-20 |
United States Patent
Application |
20080071253 |
Kind Code |
A1 |
Peterson; Lewis L. ; et
al. |
March 20, 2008 |
Osmotic Delivery System Flow Modulator Apparatus and Method
Abstract
An osmotic delivery system flow modulator assembly, an osmotic
delivery system with a flow modulator assembly, and a method of
assembling an osmotic delivery system. The osmotic delivery system
flow modular assembly includes a body having a hole located through
the body and communicating two opposing ends of the body. The use
of the osmotic delivery system flow modulator assembly lessens the
chance that air or gas pockets will form in the enclosure of the
osmotic delivery system during assembly of the system. Because less
air is within the osmotic delivery system, performance of the
system is enhanced. Use of the flow modulator assembly also lessens
the chance that beneficial agent will be wasted during assembly of
the osmotic delivery system.
Inventors: |
Peterson; Lewis L.;
(Woodside, CA) ; Maruyama; Fred H.; (San Jose,
CA) ; Dehnad; Houdin; (El Granada, CA) ; Hom;
Lawton; (San Jose, CA) ; Sly; Kevin S.; (San
Jose, CA) ; Davis; Craig R.; (Newark, CA) ;
Peery; John R.; (Stanford, CA) |
Correspondence
Address: |
DEWIPAT INCORPORATED
P.O. BOX 1017
CYPRESS
TX
77410-1017
US
|
Assignee: |
ALZA CORPORATION
1900 Charleston Rd Patent Law Department
Mountain View
CA
94043
|
Family ID: |
21985903 |
Appl. No.: |
11/856050 |
Filed: |
September 16, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10994615 |
Nov 22, 2004 |
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11856050 |
Sep 16, 2007 |
|
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|
10279957 |
Oct 25, 2002 |
6840931 |
|
|
10994615 |
Nov 22, 2004 |
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|
09122073 |
Jul 24, 1998 |
6524305 |
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10279957 |
Oct 25, 2002 |
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60053690 |
Jul 25, 1997 |
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Current U.S.
Class: |
604/892.1 ;
29/890.09 |
Current CPC
Class: |
A61M 5/14526 20130101;
A61M 5/14276 20130101; Y10T 29/494 20150115; A61M 5/16813 20130101;
A61K 9/0004 20130101; A61M 5/141 20130101 |
Class at
Publication: |
604/892.1 ;
029/890.09 |
International
Class: |
A61K 9/22 20060101
A61K009/22; B21D 51/16 20060101 B21D051/16 |
Claims
1. An osmotic delivery system comprising: an enclosure having an
opening and an interior for holding a liquid swellable osmotic
agent and a beneficial agent, the enclosure provided with a
semipermeable portion, the liquid swellable osmotic agent for
imbibing liquid from a surrounding environment through the
semipermeable portion and causing a delivery rate of the beneficial
agent from the enclosure; an osmotic delivery system flow moderator
assembly having a flow moderator body at least partially positioned
in the opening of the enclosure, the body having two opposing ends
and means for venting the osmotic delivery system when the
beneficial agent is inserted into the osmotic delivery system; a
delivery path located separate from the venting means for
delivering the beneficial agent from the osmotic delivery system,
the delivery path being formed in at least one of the enclosure and
the flow moderator assembly; and a check valve located between the
surrounding environment and the interior of the enclosure, the
check valve including a surface of a partition which abuts against
a surface of the enclosure, wherein the surface of the enclosure is
an exterior surface of the enclosure.
2. A method of assembling an osmotic delivery system having an
enclosure, the enclosure having an opening, and the osmotic
delivery system having a semipermeable portion, the method
comprising the steps of: positioning an osmotic agent in an
interior of the enclosure; inserting an osmotic delivery system
flow moderator body at least partially in the opening of the
enclosure to at least partially seal the opening; and delivering a
beneficial agent into the enclosure through a fill hole in the flow
moderator body.
3. The method according to claim 2, further comprising the step of
sealing the fill hole.
4. The method according to claim 2, further comprising the step of
venting the interior of the enclosure through an additional hole in
the flow moderator body to reduce the amount of gas within the
enclosure.
5. The method according to claim 2, wherein the step of delivering
of the beneficial agent into the enclosure through the fill hole is
achieved with one of a pipette and a syringe.
6. The method according to claim 2, further comprising the step of
inserting a semipermeable plug into a second opening of the
enclosure.
7. The method according to claim 6, further comprising the step of
sealing the additional hole.
8. The method according to claim 6, wherein the fill hole is sealed
with a cap.
9. The method according to claim 2, further comprising the step of
venting the interior of the enclosure through the fill hole in the
flow moderator body while delivering the beneficial agent into the
enclosure to reduce an amount of gas within the enclosure.
10. A method of delivering a beneficial agent into an osmotic
delivery system, comprising the steps of: inserting the beneficial
agent through a hole in a flow moderator body inserted in an
opening of the osmotic delivery system; and venting gas from the
osmotic delivery system through the hole while inserting the
beneficial agent through the hole.
11. The method according to claim 10, further comprising the step
of creating a vacuum adjacent to the flow moderator body to reduce
an amount of gas within the osmotic delivery system.
12. The method according to claim 10, further comprising the step
of sealing an interior of the hole from a surrounding
environment.
13. A method of assembling an osmotic delivery system having an
enclosure, the enclosure having an opening, and the osmotic
delivery system having a semipermeable portion, comprising the
steps of: positioning an osmotic agent into an interior of the
enclosure; inserting an osmotic delivery system flow moderator body
at least partially in the opening of the enclosure; delivering a
beneficial agent into the enclosure through the hole in the flow
moderator body; and creating a vacuum adjacent to the flow
moderator body to reduce an amount of gas within the osmotic
delivery system.
14. The method according to claim 13, further comprising the step
of sealing the hole.
15. The method according to claim 14, wherein the hole is sealed
with a stopper.
16. The method according to claim 14, further comprising the step
of attaching to the inserted flow moderator body means for
preventing a liquid external of the osmotic delivery system from
entering the interior of the osmotic delivery system, the
preventing means allowing the beneficial agent to exit the osmotic
delivery system to a surrounding environment.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 10/994,615, filed Nov. 22, 2004, which is a divisional of U.S.
application Ser. No. 10/279,957, filed Oct. 25, 2002, which is a
divisional of U.S. application Ser. No. 09/122,073, filed Jul. 24,
1998, now U.S. Pat. No. 6,524,305, which claims the benefit of U.S.
Provisional Application No. 60/053,690 filed Jul. 25, 1997,
pursuant to 35 U.S.C. .sctn.119(e), all of which are hereby
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to osmotic delivery systems
for delivering beneficial agents, and more particularly, to an
osmotic delivery system flow modulator.
[0003] Controlled delivery of beneficial agents, such as drugs, in
the medical and veterinary fields is accomplished by a variety of
methods. One method of 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 pre-selected time or administration period. In
general, osmotic delivery systems operate by imbibing fluid from
the outside environment and releasing corresponding amounts of the
beneficial agent.
[0004] Osmotic delivery systems, commonly referred to as "osmotic
pumps," generally include some type of a capsule or enclosure
having a wall which selectively permits liquid to enter the
interior of the enclosure which contains a liquid attracting
osmotic agent. The absorption of liquid by the osmotic agent within
the enclosure creates osmotic pressure within the enclosure which,
in turn, causes the beneficial agent to be delivered from the
enclosure. The osmotic agent may be the beneficial agent and/or a
formulation containing the same delivered to the patient. However,
in many cases, a separate osmotic agent is used specifically for
its ability to draw liquid into the enclosure.
[0005] When a separate osmotic agent is used, the osmotic agent may
be separated from the beneficial agent within the osmotic delivery
system enclosure by a dividing member or movable piston. The
structure of the osmotic delivery system does not permit the
enclosure to expand when the osmotic agent takes in water and
swells. As the osmotic agent expands, it causes the beneficial
agent to be discharged through an orifice or delivery port in the
enclosure at generally the same rate as a 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 some known osmotic delivery systems, the osmotic agent is
typically shaped as an osmotic tablet, and is placed inside the
enclosure. A semipermeable membrane plug is then typically placed
in an opening in the enclosure through which the tablet was
inserted. The semipermeable membrane plug acts as the wall which
selectively permits liquid to enter the interior of the enclosure.
Known semipermeable membrane plugs are typically a cylindrical
member with ribs, and operate in the same manner as a cork. These
semipermeable membrane plugs seal the interior of the enclosure
from the exterior environment of use, only permitting certain
liquid molecules from the environment of use to permeate through
the semipermeable membrane plug into the interior of the enclosure.
The rate that the liquid permeates through the semipermeable
membrane plug controls the rate at which the osmotic agent expands
and drives a desired concentration of beneficial agent from the
delivery system through the delivery port. Osmotic delivery systems
may control the rate of delivery of the beneficial agent by varying
the permeability coefficient of the semipermeable membrane
plug.
[0007] In known osmotic delivery systems, the beneficial agent
exits the osmotic delivery system enclosure through a delivery
port. Such delivery ports are typically fashioned in a plug-like
member which is inserted into an opening of the osmotic delivery
system enclosure. The opening of the enclosure into which the
delivery plug is inserted is typically opposite the end of the
enclosure which holds the semipermeable membrane plug. Thus, in
assembling these osmotic delivery systems, the dividing member is
first inserted into the enclosure. Then the osmotic agent or agents
are inserted into the enclosure, and the semipermeable membrane
plug is inserted into the opening through which the dividing member
and osmotic agents where inserted. Thereafter, if the osmotic
delivery system enclosure includes two openings located opposite
from each other, the system is rotated 180.degree., and the
beneficial agent is inserted into the enclosure through the opening
through which the delivery plug is to be inserted. After the
desired amount of beneficial agent has been inserted into the
enclosure, the delivery plug having the delivery port is then
inserted into the opening through which the beneficial agent was
inserted. The delivery plug effectively seals the enclosure from
the exterior environment, except for the delivery port.
[0008] When the osmotic delivery system with the delivery plug is
placed in the environment of use, liquid is imbibed through the
semipermeable membrane plug by osmosis, causing the osmotic agent
to expand and causing the beneficial agent to flow through the
delivery port in the delivery plug. Thus, the beneficial agent
exits the enclosure of the osmotic delivery system through the
delivery port, and is delivered to the environment of use.
[0009] One problem associated with the above-described osmotic
delivery system, is that air or gas is frequently trapped above the
beneficial agent as the delivery plug is inserted into the osmotic
delivery system enclosure. When liquid begins to be imbibed by the
osmotic agent through the membrane plug, the osmotic agent expands
and drives the dividing member, compressing the beneficial agent to
be delivered through the delivery port. Because of air pockets
trapped in the compartment or within the beneficial agent
formulation itself, the osmotic pressure must compress the air
pockets before the incompressible beneficial agent will be
delivered through the delivery channel in the delivery plug. This
is problematic because the start-up period to delivery of the
beneficial agent is delayed by the amount of time during which the
air pockets are compressed. The time to "start-up" of delivery
generally refers to the time from insertion into the environment of
use until the beneficial agent is actually delivered at a rate not
less than approximately 70% of the intended steady-state rate. The
start-up period may be delayed up to several days or weeks,
depending upon the size of the air gaps and the flow rate of the
system. Delayed start-up of beneficial agent delivery is a
significant problem in osmotic delivery systems. Furthermore, air
might be expelled from the osmotic delivery system and cause
serious health risks to, for example, humans having implanted
osmotic delivery systems, depending on where the system is
implanted.
[0010] If the osmotic delivery system includes a delivery plug with
a very small delivery path or channel, the trapped air may
completely prevent the flow of beneficial agent from the delivery
channel and/or cause the beneficial agent to be delivered in
sporadic bursts.
[0011] Another problem associated with the above-described osmotic
delivery system is that surplus beneficial agent is typically
expelled from the enclosure when the delivery plug is inserted into
the enclosure which contains the beneficial agent. Surplus
beneficial agent is necessary to ensure that as much air as
possible escapes the delivery enclosure. This expelled beneficial
agent must be cleaned from the osmotic delivery system enclosure,
and makes it difficult to precisely determine the amount of
beneficial agent within the osmotic delivery system and the amount
of beneficial agent eventually delivered. This wasted agent problem
is even more dramatic because most beneficial agents are extremely
expensive, and the surplus agent cannot be recovered for re-use. In
some instances, as much as forty microliters of beneficial agent
may be expelled during the insertion process.
[0012] The delivery channel or orifice in the delivery plug which
has been inserted in the above-described osmotic delivery systems
is the site of interaction between the beneficial agent and the
external environment of use. One constraint of certain delivery
paths of known delivery plugs is that they must be small enough,
either in length and/or interior cross-sectional area, such that
the average velocity of active agent out of the delivery system
enclosure is higher than the inward flow of liquid into the
delivery system from the environment of use. Thus, these delivery
channels or orifices in the delivery plug serve the important
function of isolating the beneficial agent from liquids and
particulate in the external environment of use, since any
contamination of the beneficial agent by such external substances
may adversely affect the utility of the beneficial agent. For
example, the inward flux of materials from the environment of use
due to diffusion through the delivery orifice may contaminate the
interior of the capsule, destabilizing, diluting, or otherwise
altering the beneficial agent formulation. It has been particularly
problematic to prevent the diffusion of liquids from the
environment of use through the delivery orifice of known osmotic
delivery systems such that the utility of the beneficial agent is
not impaired, while also obtaining the desired delivery rate of
beneficial agent from the osmotic delivery system.
[0013] Still another problem associated with the above-described
osmotic delivery system is that after the delivery plug has been
inserted into the enclosure of the osmotic delivery system, the end
of the system with the delivery plug inserted therein must be
capped. This capping process is necessary to prevent the beneficial
agent from evaporating through the delivery channel or orifice in
the delivery plug during the period of time before the osmotic
delivery system is inserted into its environment of use. Thus,
during the implantation procedure, the cap must be removed prior to
implantation of the unit, further complicating the implantation
process and the assembly process of the osmotic delivery
system.
[0014] Because of the above-identified problems associated with
current osmotic delivery systems, it is costly and particularly
difficult to administer beneficial agents from osmotic delivery
systems at controlled delivery rates.
SUMMARY OF THE INVENTION
[0015] A primary object of the present invention is to provide an
osmotic delivery system flow modulator assembly which enhances
performance of osmotic delivery systems.
[0016] Another object of the present invention is to provide an
osmotic delivery system flow modulator assembly which can reduce
the start-up time before delivery of the beneficial agent from an
osmotic delivery system.
[0017] Still another object of the present invention is to provide
an osmotic delivery system flow modulator assembly which simplifies
the assembly of osmotic delivery systems.
[0018] Another object of the present invention is to provide an
osmotic delivery system flow modulator assembly which reduces back
diffusion of substances from the external environment into the
osmotic delivery system.
[0019] Yet another object of the present invention is to provide an
osmotic delivery system which has a reduced start-up time as
compared to conventional osmotic delivery systems.
[0020] Another object of the present invention is to provide an
osmotic delivery system that does not require a cap on the osmotic
delivery system after assembly to prevent beneficial agent
evaporation from the system.
[0021] Another object of the present invention is to provide a
method of assembling an osmotic delivery system which reduces the
amount of wasted beneficial agent.
[0022] Still another object of the present invention is to provide
a method of assembling an osmotic delivery system which reduces the
possibility of gas or air trapped therein.
[0023] Another object of the present invention is to provide a
method of delivering a beneficial agent into an osmotic delivery
system which permits air or gas to escape the enclosure of the
osmotic delivery system while the beneficial agent is delivered
into the enclosure.
[0024] The present invention addresses the disadvantages of known
osmotic delivery systems by providing embodiments of an osmotic
delivery system flow moderator or modulator body, an osmotic
delivery system flow modulator assembly, an osmotic delivery system
incorporating the flow modulator assembly, a method of assembling
an osmotic delivery system, and a method of delivering a beneficial
agent into an osmotic delivery system. As used herein, "modulator"
and "moderator" are used interchangeably. The osmotic delivery
system flow modulator body or assembly reduces the occurrence of
air pockets within the beneficial agent or between the beneficial
agent and the flow modulator, reduces the amount of beneficial
agent wasted when assembling the delivery system, and, according to
another embodiment of a flow modulator assembly, minimizes the back
diffusion of substances from the external environment of use.
[0025] According to one aspect of the present invention, an osmotic
delivery system includes a semipermeable portion, and an enclosure
having an opening and an interior for holding a liquid swellable
osmotic agent and a beneficial agent. The liquid swellable osmotic
agent imbibes liquid from a surrounding environment through the
semipermeable portion to cause delivery of the beneficial agent
from the enclosure. Also included is an osmotic delivery system
flow modulator body at least partially positioned in the opening of
the enclosure. The body has two opposing ends and means for venting
the osmotic delivery system when the beneficial agent is inserted
into the osmotic delivery system. A delivery path is located
separate from the venting means, and is for delivering the
beneficial agent from the osmotic delivery system. The delivery
path is formed in at least one of the enclosure and the body.
[0026] According to another aspect of the present invention, an
osmotic delivery system flow modulator assembly includes a flow
modulator body constructed and arranged for at least partial
positioning in an opening of an enclosure of an osmotic delivery
system. The body includes two opposing ends, and a vent hole
located through the body communicates the opposing ends. A delivery
path is formed in the body, and is located separate from the hole
for delivering a beneficial agent from the osmotic delivery
system.
[0027] According to another aspect of the present invention, an
osmotic delivery system flow modulator assembly includes a flow
modulator body constructed and arranged for at least partial
positioning in an opening of an enclosure of an osmotic delivery
system. The body includes two opposing ends, a first hole located
through the body, and a second hole located through the body. The
first hole and the second hole each communicate the opposing ends.
The flow modulator body includes a delivery path for delivering a
beneficial agent from the osmotic delivery system. The flow
modulator assembly includes means for sealing at least one of the
first and second holes.
[0028] According to another aspect of the present invention, an
osmotic delivery system includes a semipermeable portion and an
enclosure having an opening and an interior for holding a liquid
swellable osmotic agent and a beneficial agent. The liquid
swellable osmotic agent imbibes liquid from a surrounding
environment through the semipermeable portion to cause delivery of
the beneficial agent from the enclosure. The delivery system
includes an osmotic delivery system flow modulator assembly having
a body at least partially positioned in the opening of the
enclosure. The body has two opposing ends, a first hole located
through the body, and a second hole located through the body. The
first and second holes each communicate the opposing ends. The flow
modulator assembly includes at least one cap positioned in one of
the first and second holes, and at least one of the body and the
enclosure include a delivery path for delivering a beneficial agent
from the osmotic agent delivery system.
[0029] According to another aspect of the present invention, an
osmotic delivery system flow modulator assembly includes a body
constructed and arranged for at least partial positioning in an
opening of an enclosure of an osmotic delivery system. The body has
two opposing ends, and a hole located through the body. The hole
communicates the opposing ends. The body has a delivery path for
delivering a beneficial agent from the osmotic delivery system. A
stopper has a head, a shaft, and a tip located opposite from the
head. The stopper is at least partially positioned in the hole to
seal the hole, and a partition secured to the body with the stopper
so that the partition is secured between the body and the head of
the stopper.
[0030] According to another aspect of the present invention, an
osmotic delivery system includes a semipermeable portion, and an
enclosure having an opening and an interior for holding a liquid
swellable osmotic agent and a beneficial agent. The liquid
swellable osmotic agent imbibes liquid from a surrounding
environment through the semipermeable portion to cause delivery of
the beneficial agent from the enclosure. An osmotic delivery system
flow modulator body is at least partially positioned in the opening
of the enclosure. The body has two opposing ends, and a hole
located through the body communicating the opposing ends. A
delivery path is located separate from the hole and formed in at
least one of the body and the enclosure for delivering the
beneficial agent from the osmotic delivery system. Also included
are means for substantially preventing a liquid external from the
osmotic delivery system from entering the interior of the osmotic
delivery system. The preventing means allows the beneficial agent
to exit the osmotic delivery system to the surrounding
environment.
[0031] According to another aspect of the present invention, a
method of assembling an osmotic delivery system includes the steps
of: positioning an osmotic agent in an interior of the enclosure;
inserting an osmotic delivery system flow modulator body at least
partially in the opening of the enclosure to at least partially
seal the opening, one of the flow modulator body and the enclosure
having a delivery path for delivering a beneficial agent from the
osmotic delivery system; and delivering a beneficial agent into the
enclosure through a fill hole in the flow modulator body.
[0032] According to another aspect of the present invention, a
method of delivering a beneficial agent into an osmotic delivery
system includes the steps of inserting the beneficial agent through
a hole in a flow modulator body inserted in an opening of the
osmotic delivery system, and venting a gas from the osmotic
delivery system through the hole while inserting the beneficial
agent through the hole.
[0033] According to another aspect of the present invention, a
method of assembling an osmotic delivery system includes the steps
of positioning an osmotic agent into an interior of the enclosure;
inserting an osmotic delivery system flow modulator body at least
partially in the opening of the enclosure, the flow modulator body
having a hole and a delivery path located separate from the hole;
delivering a beneficial agent into the enclosure through the hole
in the flow modulator body; and creating a vacuum adjacent to the
flow modulator body to reduce an amount of gas within the osmotic
delivery system.
[0034] Still other objects and advantages of the present invention
will become readily apparent to those skilled in the art from the
following detailed description, which illustrates and describes the
preferred embodiment of the present invention. As will be realized,
the invention is capable of modification in various obvious
aspects, all without departing from the invention. Accordingly, the
drawings and description are to be regarded as illustrative in
nature, and not restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] The invention will be described in greater detail with
reference to the accompanying drawings in which like elements bear
like reference numerals, and wherein:
[0036] FIG. 1 is a side view of an osmotic delivery system flow
modulator according to one embodiment of the present invention.
[0037] FIG. 2 is an end view of an osmotic delivery system flow
modulator according to one embodiment of the present invention.
[0038] FIG. 3 is a cross-sectional side view of the osmotic
delivery system flow modulator according to one embodiment of the
present invention taken along the line 3-3 of FIG. 2.
[0039] FIG. 4 is a cross-sectional side view of an osmotic delivery
system according to one embodiment of the present invention.
[0040] FIG. 5 is an end view of an osmotic delivery system flow
modulator according to one embodiment of the present invention.
[0041] FIG. 6 is a cross-sectional side view of the osmotic
delivery system flow modulator according to one embodiment of the
present invention taken along the line 6-6 of FIG. 5.
[0042] FIG. 7 is a cross-sectional side view of an osmotic delivery
system flow modulator according to one embodiment of the present
invention.
[0043] FIG. 8 is a cross-sectional side view of an osmotic delivery
system flow modulator according to one embodiment of the present
invention.
[0044] FIG. 9 is a cross-sectional side view of the assembly of an
osmotic delivery system according to one embodiment of the present
invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0045] The present invention relates to osmotic delivery system
flow modulator assemblies which enhance the start-up and
performance of osmotic delivery systems which incorporate the flow
modulator. FIGS. 1, 6, and 8 illustrate osmotic delivery system
flow modulator assemblies 20, 120, 220 according to embodiments of
the present invention. The osmotic delivery system flow modulator
assemblies 20,120, 220 will be described in reference to exemplary
osmotic delivery systems 40, 140, 240 according to embodiments of
the present invention. The osmotic delivery systems 40, 140, 240
include the respective flow modulator assemblies 20,120, 220.
[0046] The osmotic delivery system flow modulator assemblies 20,
120, 220 include a flow modulator body 21,121, 221 having venting
means or holes 24,124, 224 located through the bodies of the flow
modulator assemblies and communicating the opposing ends of the
bodies. The flow modulator body 21 also includes a second,
additional hole or fill hole 22 also communicating the two opposing
ends 37, 38. The osmotic delivery system flow modulator assemblies
20,120, 220 lessen the chance that air or gas pockets will form in
the enclosures 42, 142, 242 of the osmotic delivery systems 40,
140, 240 during assembly of the system, specifically during the
delivery of the beneficial agent 44,144, 244 into the enclosure of
the system through the holes 22, 124, 224. Because use of the
osmotic delivery system flow modulator assemblies 20, 120, 220 with
the osmotic delivery systems 40, 140, 240 lessens the chance of air
or gas formations within the enclosures 42,142, 242, the time to
start-up of delivery of the beneficial agent 44, 144, 244 and
performance of the system is enhanced. Use of the flow modulator
assemblies 20, 120, 220 also lessens the chance that beneficial
agent 44, 144, 244 will be wasted during assembly of the osmotic
delivery systems 40, 140, 240.
[0047] FIG. 1 illustrates a side view of the exemplary osmotic
delivery system flow modulator assembly 20. The body 21 of the flow
modulator assembly 20 is constructed and arranged for at least
partial positioning in the second opening 39 of the enclosure 42.
The flow modulator body 21 illustrated in FIGS. 1-4 is generally
cylindrically shaped, and is intended for insertion or positioning
into the second opening 39 of the enclosure 42 of the exemplary
osmotic delivery system 40. Because the enclosure 42 and opening 39
therein are cylindrical, the flow modulator body 21 is also
cylindrical such that it is at least partially positionable in the
second opening of the enclosure. Of course, the flow modulator body
21 may be other different shapes and sizes, which generally
correspond to that of the second opening 39 in the enclosure 42 of
the osmotic delivery system 40, such that the body 21 of the flow
modulator assembly 20 is constructed and arranged for at least
partial positioning in the opening. For example, if the second
opening 39 of the enclosure 42 were square, the flow modulator
would also be configured in a square shape.
[0048] The osmotic delivery system flow modulator body 21 is formed
from an inert and, preferably, biocompatible material. Exemplary
biocompatible and inert materials include, but are not limited to,
metals such as titanium, stainless steel, platinum and their
alloys, and cobalt-chromium alloys and the like. Other compatible
materials include polymers such as polyethylene, polypropylene,
polycarbonate, polymethylmethacrylate, and the like.
[0049] As illustrated in FIG. 1, the flow modulator body 21 of the
osmotic delivery system flow modulator assembly 20 may include the
delivery path 32. In the embodiment of the present invention
illustrated in FIG. 1, the delivery path 32 is helical shaped. This
helical delivery path 32 permits the beneficial agent 44 located
within the enclosure 42 of the osmotic delivery system 40 to travel
from the interior of the enclosure to the exterior environment of
use. The helical delivery path 32 is formed between the threads 36
which are located on the elongated portion of the osmotic delivery
system flow modulator body 21.
[0050] Once the flow modulator body 21 is inserted into the second
opening 39 of the enclosure 42 above the beneficial agent 44, the
interior surface 43 or wall of the enclosure will abut against the
threads 36 such that the only area through which the beneficial
agent may travel is the delivery path 32 formed between the
threads. So configured, the helical delivery path 32 begins at the
delivery entrance 28 which intersects the first opposing end 37,
and ends at the delivery orifice 30. Once the osmotic agent 47
generates osmotic pressure within the delivery system, the
beneficial agent 44 within the enclosure 42 will travel into the
delivery entrance 28, flow along the helical delivery path 32, and
finally exit the delivery orifice 30 to the environment of use.
[0051] The pitch, the amplitude, cross-sectional area, and the
shape of the helical path 32 formed between the abutting surfaces
of the threads 36 and the interior surface 43 of the enclosure 42
are factors that affect both the back pressure within the osmotic
delivery system 40 and the possibility of back diffusion through
the delivery path 32. In general, the geometry of the delivery path
32 is such that it reduces back diffusion of liquid from the
environment of use into the enclosure 42. However, as further
described below, a flow modulator assembly 120 according to another
embodiment of the present invention may be used to mechanically
minimize back flow or back diffusion. The geometry of the osmotic
delivery system flow modulator body 21 illustrated in FIG. 1 is
such that the length of the helical flow path 32 and the velocity
of flow of beneficial agent 44 therethrough is sufficient to
prevent back diffusion of external liquid through the flow path 32
without significantly increasing the back pressure within the
enclosure 42. Thus, following start-up of the osmotic delivery
system 40, the release rate of the beneficial agent 44 is governed
by the osmotic pumping rate of the system. Factors to be considered
in sizing the delivery path 32 are disclosed in U.S. patent
application Ser. No. 08/595,761, the entire disclosure of which is
incorporated herein by reference.
[0052] The size of the flow modulator body 21 is such that a seal
is formed between the interior surface 43 of the enclosure 42 and
the outer surface of the threads 36 on the flow modulator body 21.
The seal formed between the modulator 20 and the enclosure 42
preferably may withstand the maximum osmotic pressure generated
within the osmotic delivery system 40, or to fail safe if the
pressure within the system exceeds a predetermined threshold. In
the embodiment of the present invention depicted in FIGS. 1-4, the
flow modulator fits tightly into the second opening 39 of the
enclosure 42, forming a seal between the threads 36 of the body 21
and the inner surface 43 of the enclosure. However, the seal may be
formed by other techniques well known in the art.
[0053] The delivery path 32 of the beneficial agent 44 is formed
between the threads 36 of the modulator 20 and the enclosure 42.
The delivery path length, interior cross-sectional shape, and area
of the path are chosen such that the average linear velocity of the
beneficial agent 44 through the path is higher than that of the
linear inward flux of materials in the environment of use due to
diffusion or osmosis, thereby attenuating or moderating back
diffusion and its deleterious effects of contaminating the interior
of the osmotic delivery system 40, destabilizing, diluting, or
otherwise altering the beneficial agent formulation. The release
rate of the beneficial agent 44 can be modified by modifying the
delivery pathway 32 geometry, as described below.
[0054] The convective flow of beneficial agent 44 out of the
delivery orifice 30 is set by the pumping rate of the osmotic
delivery system 40 and the concentration of beneficial agent in the
enclosure 42, which can be represented as follows: Q.sub.ca=(Q)(Ca)
(1) where [0055] Q.sub.ca is the convective transport of beneficial
agent 44 in mg/day [0056] Q is the overall convective transport of
the beneficial agent formulation in cm.sup.3/day [0057] C.sub.a is
the concentration of beneficial agent 44 in the formulation within
enclosure 42 in mg/cm.sup.3
[0058] The diffusive flow of agent 44 through the delivery orifice
30 is a function of agent concentration, cross-sectional
configuration of delivery path 32, agent diffusivity, and length of
delivery path, which can be represented as follows:
Q.sub.da=D.pi.r.sup.2.DELTA.C.sub.a/L (2) where [0059] Q.sub.da is
the diffusive transport of agent 44 in mg/day [0060] D is the
diffusivity through the delivery path 32 in cm.sup.2/day [0061] r
is the effective inner radius of the delivery path in cm [0062]
.DELTA.C.sub.a is the difference between the concentration of
beneficial agent 44 in the enclosure 42 and in the environment of
use outside of the delivery orifice 30 in mg/cm.sup.3 [0063] L is
the length of the delivery path in cm
[0064] In general, the concentration of beneficial agent 44 in the
enclosure 42 is much greater than the concentration of agent in the
environment of use such that the difference, .DELTA.C.sub.a can be
approximated by the concentration of agent within the enclosure,
C.sub.a. Thus: Q.sub.da=D.pi.r.sup.2C.sub.1/L (3)
[0065] It is generally desirable to keep the diffusive flux of
agent at less than 10% of the convective flow. This is represented
as follows:
Q.sub.da/Q.sub.ca=D.pi.r.sup.2C.sub.a/QC.sub.aL=D.pi.r.sup.2/QL.ltoreq.0.-
1 (4) Equation 4 indicates that the relative diffusive flux
decreases with increasing volumetric flow rate and path length,
increases with increasing diffusivity and channel radius, and is
independent of beneficial agent concentration.
[0066] The diffusive flux of water where the orifice 30 opens into
the enclosure 42 can be approximated as:
Q.sub.wd(res)=C.sub.OQe.sup.(-QL/DwA) (5) where [0067] C.sub.o is
the concentration profile of water in mg/cm.sup.3 [0068] Q is the
mass flow rate in mg/day [0069] L is the length of the delivery
path in cm [0070] D.sub.w is the diffusivity of water through the
material in the delivery path in cm.sup.2/day [0071] A is the
cross-sectional area in the delivery path in cm.sup.2
[0072] The hydrodynamic pressure drop across the delivery orifice
can be calculated as follows: .times. .DELTA. .times. .times. P = 8
.times. .times. QL .times. .times. .mu. .pi. .times. .times. r 4 (
6 ) ##EQU1## Simultaneously solving equations (4), (5), and (6)
gives the values shown in Table 1 for a series of different
effective delivery orifice diameters where:
[0073] Q=0.38 .mu.l/day
[0074] C.sub.a=0.4 mg/.mu.l
[0075] L=5 cm
[0076] D.sub.a=2.00 E-06 cm.sup.2/sec
[0077] .mu.=5.00 E+02 cp
[0078] C.sub.wo=0 mg/.mu.l
[0079] D.sub.w=6.00 E+06 cm.sup.2/sec TABLE-US-00001 TABLE 1 Drug
Diffusion & Pumping Water Intrusion Effective Cross Pump Rate
Diffusion Diff/Conv Q.sub.dw Q.sub.dw Pressure Drop Orifice dia Sec
area Q.sub.ca Q.sub.da Q.sub.da/ mg/ mg/ delta P (mil) (mm.sup.2)
mg/day mg/day Q.sub.ca day year psi 1 0.00051 0.152 0.0001 0.0005 0
0 1.55800 2 0.00203 0.152 0.0003 0.0018 1.14E-79 4.16-E-77 0.09738
3 0.00456 0.152 0.0006 0.0041 4.79E-36 1.75E-33 0.01923 4 0.00811
0.152 0.0011 0.0074 8.89E-21 3.25E-18 0.00609 5 0.01267 0.152
0.0018 0.0115 1.04E-13 3.79E-11 0.00249 6 0.01824 0.152 0.0025
0.0166 7.16E-10 2.61E-07 0.00120 7 0.02483 0.152 0.0034 0.0226
1.48E-07 5.4E-05 0.00065 8 0.03243 0.152 0.0045 0.0295 4.7E-06
0.001715 0.00038 9 0.04105 0.152 0.0057 0.0373 5.04E-05 0.018381
0.00024 10 0.05068 0.152 0.0070 0.0461 0.000275 0.100263 0.00016 11
0.06132 0.152 0.0085 0.0558 0.000964 0.351771 0.00011 12 0.07298
0.152 0.0101 0.0664 0.002504 0.913839 0.00008 13 0.08564 0.152
0.0118 0.0779 0.005263 1.921027 0.00005 14 0.09933 0.152 0.0137
0.0903 0.00949 3.463836 0.00004 15 0.11402 0.152 0.0158 0.1037
0.015269 5.573195 0.00003 16 0.12973 0.152 0.0179 0.1180 0.022535
8.225224 0.00002 17 0.14646 0.152 0.0202 0.1332 0.031114 11.35656
0.00002 18 0.16419 0.152 0.0227 0.1493 0.040772 14.88166 0.00001 19
0.18295 0.152 0.0253 0.1664 0.051253 18.70728 0.00001 20 0.20271
0.152 0.0280 0.1844 0.062309 22.7427 0.00001
[0080] In the embodiment of the flow modulator 20 illustrated in
FIG. 1, the delivery path 32 may be between about 0.5 and 20 cm
long, preferably between about 1 and 10 cm long and between about
0.001 and 0.020 inches in diameter, preferably between about 0.003
and 0.015 inches to allow for a flow of between about 0.02 and 50
.mu.l/day, usually 0.2 to 10 .mu.l/day and often 0.2 to 2.0
.mu.l/day. Additionally, a catheter or other system may be attached
to the end of the flow modulator delivery orifice 30 to provide for
delivery of the beneficial agent formulation at a site removed from
the implantable osmotic delivery system. Such systems are known in
the art and are described, for example, in U.S. Pat. Nos. 3,732,865
and 4,340,054, the disclosures of which are incorporated herein by
reference.
[0081] Although preferred, the delivery path 32 need not be formed
in the exterior surface of the flow modulator body 21. The flow
modulator body 21 need not have the delivery path 32. For example,
the interior surface 43 of the cylindrical enclosure 42 may include
threads of a predetermined pitch, amplitude, and cross-sectional
area. Such threads formed within the interior surface 43 of the
enclosure 42 may function as the delivery path 32 for the
beneficial agent 44. In such an embodiment, the flow modulator body
21 may have a smooth cylindrical outer surface which seals the
second opening 39 in the enclosure 42, except for the delivery path
32 formed in the interior surface 43 of the enclosure. In such an
embodiment, the flow modulator assembly 20 will continue to
modulate flow because the outer surface continues to define the
cross-sectional area of the delivery path 32. Alternatively, the
interior surface 43 of the enclosure 42 and the outer cylindrical
surface of the flow modulator body 21 each may have female threads,
male threads, or any combination thereof to form a delivery path 32
of predetermined size. Furthermore, the delivery path 32 need not
be a single helically shaped channel, it may be a straight or
curved channel or series of channels.
[0082] As illustrated in FIG. 3, the exemplary osmotic delivery
system flow modulator assembly 20 includes a first hole or vent
hole 24 and a second, additional hole or fill hole 22. The vent
hole 24 and the fill hole 22 are elongated, straight, and run
longitudinally and parallel through the body 21 of the osmotic
delivery system flow modulator assembly 20. In other words, the
longitudinal axis of the fill hole 22 and the longitudinal axis of
the vent hole 24 are substantially perpendicular to at least one of
the opposing ends 37, 38 of the flow modulator. Because the flow
modulator body 21 is preferably cylindrical such that it is
constructed and arranged for at least partial positioning in the
second opening 39 of the cylindrical enclosure 42, the vent hole 24
and fill hole 22 are parallel with the interior surface 43 and
cylindrical outer surface of the enclosure 42.
[0083] The vent hole 24 and the fill hole 22 run or extend
completely through the body of the flow modulator, and communicate
the first opposing end 37 with the second opposing end 38 of the
cylindrical flow modulator body 21. As illustrated in FIG. 2, the
vent hole 24 and the fill hole 22 each have a circular
cross-sectional shape of the same diameter. Although the
cross-sectional shape of the vent hole 24 and the fill hole 22 is
preferably circular, other shapes for the holes are contemplated.
For example, square, triangular, or oval cross-sectional shaped
holes 22, 24 would all be within the confines of the present
invention. Furthermore, the longitudinal axis of the holes 22, 24
need not be parallel with the longitudinal axis of the flow
modulator body 21. For example, the holes 22, 24 may be located at
an angle with respect to the longitudinal axis of the modulator
body 21, or spiral through the flow modulator body 21.
[0084] The flow modulator assembly 20 is best described in
reference to the osmotic delivery system 40 according to another
embodiment of the present invention.
[0085] FIG. 4 illustrates an example of an osmotic delivery system
40 according to the present invention. The configuration
illustrated in FIG. 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.
[0086] The osmotic drug delivery system 40, as illustrated in FIG.
4, includes an elongated substantially cylindrical enclosure 42
having a second opening 39 for receiving the osmotic delivery
system flow modulator 20, and a first opening 45 located opposite
the flow modulator opening or second opening 39 for receiving the
semipermeable plug 48. The delivery orifice 30 of the osmotic
delivery system flow modulator assembly 20 is for delivering the
beneficial agent 44 from the osmotic delivery system 40.
[0087] The elongated and cylindrical enclosure 42 is formed of a
material which is sufficiently rigid to withstand expansion of the
osmotic agent 47 without changing size or shape. The elongated
enclosure 42 is preferably substantially impermeable to fluids in
the environment of use as well as to ingredients contained within
the delivery system 40 such that the migration of such materials
into or out of the system through the impermeable material is so
low as to have substantially no adverse impact on the function of
the osmotic delivery system.
[0088] Materials which may be used for the enclosure 42 must be
sufficiently strong to ensure that the enclosure 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. The enclosure 42 may be
formed of chemically inert and biocompatible, natural or synthetic
materials which are known in the art. The enclosure material is
preferably a non-bioerodible material which remains in the patient
after use, such as titanium. However, the material of the enclosure
may alternatively be a bioerodible material which bioerodes in the
environment after dispensing of the beneficial agent. Generally,
preferred materials for the enclosure 42 are those acceptable for
human implantation.
[0089] In general, typical materials of construction suitable for
the enclosure 42 according to the present invention include
non-reactive polymers or biocompatible metals or alloys. The
polymers include acrylonitrile polymers such as
acrylonitrile-butadiene-styrene terpolymer, and the like;
halogenated polymers such as polytetraflouroethylene,
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 enclosure 42 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.
[0090] An enclosure 42 made from the titanium or a titanium alloy
having greater than 60%, often greater than 85% titanium is
particularly preferred for the most size-critical applications, for
high payload capability and for long duration applications, and for
those applications where the formulation is sensitive to body
chemistry at the implantation site or where the body is sensitive
to the formulation. In certain embodiments, and for applications
other than the fluid-imbibing devices specifically described, where
unstable beneficial agent formulations are in the enclosure 42,
particularly protein and/or peptide formulations, the metallic
components to which the formulation is exposed must be formed of
titanium or its alloys as described above.
[0091] Within the enclosure 42 is a beneficial agent 44 to be
delivered. Such a beneficial agent 44 may optionally include
pharmaceutically acceptable carriers and/or additional ingredients
such as anti-oxidants, stabilizing agents, permeation enhancers,
etc.
[0092] The present invention applies to the administration of
beneficial agents 44 in general, which include any physiologically
or pharmacologically active substance. The beneficial agent 44 in
the osmotic delivery system 40 may be any of the agents which are
known to be delivered to the body of a human or an animal such as
medicaments, vitamins, nutrients, or the like. The beneficial agent
44 may also be an agent which is delivered to other types of
aqueous environments such as pools, tanks, reservoirs, and the
like. Included among the types of agents which meet this
description are biocides, sterilization agents, nutrients,
vitamins, food supplements, sex sterilants, fertility inhibitors
and fertility promoters.
[0093] Drug agents which may be delivered by the present invention
include drugs which act on the peripheral nerves, adrenergic
receptors, cholinergic receptors, the skeletal muscles, the
cardiovascular system, smooth muscles, the blood circulatory
system, synoptic sites, neuroeffector junctional sites, endocrine
and hormone systems, the immunological system, the reproductive
system, the skeletal system, autacoid systems, the alimentary and
excretory systems, the histamine system and the central nervous
system. Suitable agents may be selected from, for example,
proteins, enzymes, hormones, polynucleotides, nucleoproteins,
polysaccharides, glycoproteins, lipoproteins, polypeptides,
steroids, analgesics, local anesthetics, antibiotic agents,
anti-inflammatory corticosteroids, ocular drugs and synthetic
analogs of these species.
[0094] Examples of drugs which may be delivered by devices
according to this invention include, but are not limited to
prochlorperzine edisylate, ferrous sulfate, aminocaproic acid,
mecamylamine hydrochloride, procainamide hydrochloride, amphetamine
sulfate, methamphetamine hydrochloride, benzamphetamine
hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride,
bethanechol chloride, methacholine chloride, pilocarpine
hydrochloride, atropine sulfate, scopolamine bromide, isopropamide
iodide, tridihexethyl chloride, phenformin hydrochloride,
methylphenidate hydrochloride, theophylline cholinate, cephalexin
hydrochloride, diphenidol, meclizine hydrochloride,
prochlorperazine maleate, phenoxybenzamine, thiethylperzine
maleate, anisindone, diphenadione erythrityl tetranitrate, digoxin,
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.alpha.-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, dihydroxyphenylalanine, theophylline, calcium
gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin,
haloperidol, zomepirac, ferrous lactate, vincamine, diazepam,
phenoxybenzamine, diltiazem, milrinone, capropril, mandol,
quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen,
fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuinal,
nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,
lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine,
lisinolpril, enalapril, enalaprilat, captopril, ramipril,
famotidine, nizatidine, sucralfate, etintidine, tetratolol,
minoxidil, chlordiazepoxide, diazepam, amitriptyline, and
imipramine. Further examples are proteins and peptides which
include, but are not limited to, insulin, colchicine, glucagon,
thyroid stimulating hormone, parathyroid and pituitary hormones,
calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone,
follicle stimulating hormone, chorionic gonadotropin, gonadotropin
releasing hormone, bovine somatotropin, porcine somatotropin,
oxytocin, vasopressin, GRF, prolactin, somatostatin, lypressin,
pancreozymin, luteinizing hormone, LHRH, LHRH agonists and
antagonists, leuprolide, interferons, interleukins, growth hormones
such as human growth hormone, bovine growth hormone and porcine
growth hormone, fertility inhibitors such as the prostaglandins,
fertility promoters, growth factors, coagulation factors, human
pancreas hormone releasing factor, analogs and derivatives of these
compounds, and pharmaceutically acceptable salts of these
compounds, or their analogs or derivatives.
[0095] The beneficial agent 44 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, 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 44 can be used alone or
mixed with other beneficial agents.
[0096] The enclosure 42 receives the osmotic agent 47, which in the
embodiment of the present invention depicted in FIG. 4 is two
osmotic tablets. Osmotic agents 47, specifically the osmotic
tablets illustrated in FIG. 4, drive the osmotic flow of the
osmotic delivery system 40. However, the osmotic agent 47 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. For example, the osmotic agent 47 may be in
the form of a powder. The osmotic tablet is preferably and
initially non-flowable and solid, but upon insertion of the osmotic
delivery system 40 into the environment of use, an external liquid
permeates through the semipermeable plug 48, causing the osmotic
tablets to assume a flowable form.
[0097] The embodiment of the present invention illustrated in FIG.
4 includes a dividing member 46, which may be movable or stationary
within the enclosure 42. The osmotic agent 47 within the enclosure
42 is separated from the beneficial agent 44 by the dividing member
46. The dividing member 46 may be in the form of a slidable or
movable partition or a stationary and stretchable partition member.
The dividing member 46 is preferably movable and is formed from an
impermeable resilient material that includes annular ring shape
protrusions which form a seal with the inner surface 43 of the
enclosure 42.
[0098] The dividing member 46 is a substantially cylindrical member
which is configured to fit within the enclosure 42 in a sealing
manner which also allows the dividing member to slide along the
longitudinal direction of the enclosure. The dividing member 46
isolates the beneficial agent 44 from the environmental liquids
that are permitted to enter enclosure 42 through the semipermeable
plug 48 such that in use, at steady-state flow, the beneficial
agent is expelled through the delivery orifice 30 at a rate
corresponding to the rate at which liquid from the environment of
use flows into the osmotic agent 47 through the semipermeable plug.
As a result, the flow modulator assembly 20 and the beneficial
agent 44 will be protected from damage and their functionality will
not be compromised even if the enclosure 42 adjacent the osmotic
agent becomes deformed.
[0099] The dividing member 46 is preferably made of a material that
is of lower hardness than the enclosure 42 and will deform to fit
the lumen of the enclosure to provide a fluid tight compression
seal with the enclosure. The materials from which the dividing
member 46 may be 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,
and thermoplastic elastomers such as plasticized polyvinylchloride,
polyurethanes, Santoprene.RTM., C-flex TPE (Consolidated Polymer
Technologies, Inc.), and the like. The dividing member 46 may be a
self-loading or a compression-loaded design. Other materials
suitable for the dividing member 46 are elastomeric materials
including the non-reactive polymers listed above, as well as
elastomers in general, such as polyurethanes and polyamides,
chlorinated rubbers, styrene-butadiene rubbers, and chloroprine
rubbers.
[0100] However, the present invention need not include the dividing
member 46. In such an embodiment, the beneficial agent 44 and the
osmotic agent 47 may be separated by an interface between the
osmotic agent and the beneficial agent or the may together form a
homogeneous mixture.
[0101] As illustrated in FIG. 4, the osmotic delivery system 40
includes the semipermeable membrane plug 48 which is inserted into
the first opening 45 within the enclosure 42. The semipermeable
membrane plug 48 allows liquid to pass from an environment of use
into the enclosure 42 to cause the osmotic agent 47 to swell. The
semipermeable material forming the plug 48 is largely impermeable
to materials within the enclosure 42 and other ingredients within
the environment of use. Materials from which the semipermeable
membrane plug 48 may be fabricated are well known within the art.
The semipermeable membrane plug 48 is of a lower hardness material
and will conform to the shape of the enclosure 42 to produce a
liquid-tight seal with the interior of the enclosure 42 upon
wetting. Materials from which the semipermeable membrane plug 48
are made are those that are semipermeable, can conform to the shape
of the enclosure 42 upon wetting, and adhere to the rigid interior
surface 43 of the enclosure.
[0102] The polymeric materials from which the semipermeable plug 48
may be made vary based on the pumping rates and system
configuration requirements, and include, but are not limited to,
plasticized cellulosic materials, enhanced polymethylmethacrylates
such as hydroxyethylmethacrylate (HEMA), and elastomeric materials
such as polyurethanes and polyamides, polyether-polyamide
copolymers, thermoplastic copolyesters, and the like.
[0103] The osmotic tablets are osmotic agents 47 which are liquid
attracting agents used to drive the flow of the beneficial agent
44. The osmotic agent 47 may be an osmagent, an osmopolymer, or a
mixture of the two. Species which fall within the category of
osmagent, i.e., the non-volatile species which are soluble in water
and create the osmotic radiant 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.
[0104] Species which fall within the category of osmopolymer are
hydrophilic polymers that swell upon contact with water, and these
vary widely as well. Osmopolymers may be of plant or animal origin,
or synthetic, and examples of osmopolymers are well known in the
art. Examples include: poly(hydroxy-alkyl methacrylates) with
molecular weight of 30,000 to 5,000,000, poly(vinylpyrrolidone)
with molecular weight of 10,000 to 360,000, anionic and cationic
hydrogels, polyelectrolyte complexes, poly(vinyl alcohol) having
low acetate residual, optionally cross-linked with glyoxal,
formaldehyde or glutaraldehyde and having a degree of
polymerization of 200 to 30,000, a mixture of methyl cellulose,
cross-linked agar and carboxymethylcellulose, a mixture of
hydroxypropl methycellulose 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 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.
[0105] In assembling the osmotic delivery device 40 according to
one embodiment of the present invention, the movable dividing
member 46 is first inserted into the first opening 45 of the
enclosure 42. The osmotic agent 47 is then positioned or placed
through the same first opening 43 such that it is adjacent to the
movable dividing member 46. Thereafter, the semipermeable plug 48
is inserted into the same first opening 43, effectively sealing
this opening. Thus, the osmotic agent 47 is adjacent to the
semipermeable plug 48 and, preferably, in fluid communication with
the semipermeable plug 48 such that fluids may flow through the
semipermeable portion to the osmotic agent. The osmotic delivery
system 40 is then preferably rotated such that the second opening
39 of the enclosure 42 located opposite the semipermeable plug 48
faces vertically upward.
[0106] In previous osmotic delivery systems, the beneficial agent
is next measured and inserted into an opening of the system such
that it is located above the dividing member. Ordinarily, the last
step in assembling these systems is to insert a delivery plug into
the this opening. However, the osmotic delivery system 40 according
to one embodiment of the present invention includes the osmotic
delivery system flow modulator assembly 20 illustrated in FIG. 4.
The beneficial agent 44 may be delivered to the interior of the
enclosure through the fill hole 22 in the flow modulator body
21.
[0107] Thus, when assembling the osmotic delivery system 40
according to the present invention, the flow modulator body 21 is
first inserted at least partially into the second opening 39 of the
enclosure 42 opposite the semipermeable plug 48 before the
beneficial agent 44 is delivered into the system. The flow
modulator body 21 is preferably inserted into the enclosure 42 such
that the head surface 34 abuts against the enclosure 42. Thus, the
head surface 34 controls the depth that the flow modulator may be
inserted into the second opening 41 in the enclosure 42. The head
surface 34 preferably extends perpendicularly from the longitudinal
axis of the flow modulator body 21 such that it extends radially
away from the threads 36. The delivery path 32, in the embodiment
of the flow modulator assembly 20 depicted in FIG. 1, ends at the
delivery orifice 30, which is located on or near the head surface
34.
[0108] Thereafter, a pipette, syringe, or other similar device,
preferably filled with the beneficial agent 44, is arranged above
or within the fill hole 22, and the beneficial agent is released
into the fill hole at a predetermined rate, delivering the
beneficial agent into the interior of the enclosure 42 through the
fill hole. The fill hole 22 may be sized to matingly receive a fill
tube of a syringe, or may also be larger than the diameter of the
fill tube of the syringe such that the fill hole also permits
venting like the vent hole 24. The predetermined rate of release of
beneficial agent 44 from the pipette is such that a gas, such as
air, within the beneficial agent or the enclosure 42 has the
opportunity to escape through the vent hole 24 as the incoming
beneficial agent is delivered through the fill hole 22 and fills
the interior of the enclosure. Thus, it is apparent that the vent
hole 24, and all of its possible configurations discussed above,
acts as means for venting the osmotic delivery system 40 when the
beneficial agent 44 is inserted into the osmotic delivery system.
The beneficial agent 44 is delivered for a predetermined period of
time such that the beneficial agent fills the enclosure 42, and at
least partially fills the fill hole 22 and the vent hole 24.
Finally, the caps 26, illustrated in FIG. 3 are inserted into the
vent hole 24 and fill hole 22, capping or sealing the holes such
that beneficial agent 44 located within the delivery system 40 will
not escape from the enclosure 42, save from the delivery orifice
30.
[0109] The caps 26, or means for sealing the holes 22, 24 from the
surrounding environment, may be fashioned from a material similar
to that of the osmotic delivery system flow modulator body 21, and
should sufficiently seal the fill hole 22 and vent hole 24 from the
environment of use such that external liquids from the environment
of use do not substantially leak or diffuse into the osmotic
delivery system 40, and such that pressures generated from the
osmotic agent 47 within the osmotic delivery system 40 do not
substantially cause the beneficial agent 44 to leak out from the
fill hole 22 or vent hole 24. The caps 26 may press fit or thread
into the holes 22, 24. However, the fill hole 22 and vent hole 24
need not be sealed by the caps 26. Plugs, inserts, molten plastics,
rods, and other devices or items may also be used to cap the fill
hole 22 and the vent hole 24 such that they also function as means
for sealing. Likewise, one cap may be used to cover and seal both
holes 22, 24.
[0110] The fill hole 22 and the vent hole 24 are sized to
accommodate the predetermined rate that beneficial agent 44 is
delivered into the fill hole. If this delivery rate is relatively
slow, the fill hole 22 may have a smaller diameter and/or a longer
length. If the predetermined rate of delivery of beneficial agent
44 into the fill hole 22 is relatively fast, the fill hole 22 must
have a larger diameter and/or a shorter length such that the
beneficial agent does not overflow the fill hole 22 as it is
delivered through the hole. The fill hole 22 may have sufficient
volume to accommodate the rate of beneficial agent 44 delivered
through the fill hole such that there is relatively little pressure
drop across the fill hole during delivery of the beneficial agent
through the fill hole.
[0111] Alternatively, the beneficial agent 44 may be forced into
and through the fill hole 22 such that there is a significant
pressure drop across the fill hole, which also forces air quickly
out of the enclosure 42 through the vent hole 24.
[0112] The preferred size of the fill hole 22 is also dependent
upon the size of the vent hole 24. Because the flow modulator forms
a seal with the interior surface of the enclosure, the vent hole 24
should be sufficiently large to accommodate the rate of escaping
air or gas from within the enclosure 42, which roughly equals the
rate that beneficial agent 44 is pipetted into the fill hole 22,
depending upon the amount of gas allowed to escape through the fill
hole 22. Because air is compressible, the vent hole 24 may be
smaller than the fill hole, yet accommodate the same rate of
escaping air as entering beneficial agent 44. However, once the
enclosure 42 is sufficiently full of beneficial agent 44 such that
the agent begins to rise into the fill hole 22 and vent hole 24,
the rate that the beneficial agent rises in the vent hole
preferably matches that of the rising rate in the fill hole. Thus,
the fill hole 22 and vent hole 24 preferably have the same volume,
which in the embodiment of the present invention illustrated in
FIG. 3, is obtained by matching the diameters and lengths of the
cylindrical fill and vent holes.
[0113] However, if the flow moderator body 21 is made from a
resilient material, the fill hole 22 and vent hole 24 must not be
overly large such that the sealing capacity of the threads 36
against the interior surface 43 is compromised.
[0114] As shown in FIGS. 3 and 4, the fill hole 22 and the vent
hole 24 are preferably located separate from the delivery path 32
such that the holes and the path are not integral. This is
preferred because, although some venting may occur in the delivery
path 32, it is typically too small to effectively vent the osmotic
delivery system 40 without the assistance of a vacuum during the
beneficial agent filling process.
[0115] Assembling the osmotic delivery system 40 in the above
described manner is advantageous because the amount of wasted
beneficial agent 44 is reduced. Beneficial agent 44 is preferably
delivered into the enclosure 42 through the fill hole 22 until the
fill hole and the vent hole 24 are both substantially filled with
beneficial agent. Thereafter, the fill hole 22 and the vent hole 24
are capped with the caps 26. When the holes 22, 24 are capped with
the caps 26, a minute amount of surplus beneficial agent 44 is
expelled from the flow modulator. This reduced amount of beneficial
agent expelled when assembling an osmotic delivery system 40, as
compared to past assembly methods, reduces the costs of assembly.
Because the amount of expelled and wasted beneficial agent is
reduced, it is also easier to determine the precise amount of
beneficial agent 44 remaining in the osmotic delivery system.
[0116] As described above, when delivering the beneficial agent 44
into the osmotic delivery system 40, the vent hole 24 permits gas
within the enclosure of the osmotic delivery system to escape from
the system. Thus, when the osmotic delivery system 40 is completely
assembled, the amount of gas within the system is reduced. This
reduction of trapped air or gas within the system 40 is
advantageous because the time to start-up of delivery of beneficial
agent 44 from the delivery system to the environment of use is
reduced.
[0117] When the osmotic delivery system 40 is eventually placed
into an environment of use, the osmotic agent 47 imbibes fluid
through the semipermeable plug 48 and expands, creating osmotic
pressure within the enclosure 42. This osmotic pressure forces the
beneficial agent 44 through the delivery path 32. Because the
amount of gas or air within the enclosure 42 is reduced during
assembly of the osmotic delivery system 40, the osmotic agent 47
need not first compress air within the beneficial agent or interior
of the delivery system before forcing the beneficial agent into the
delivery entrance 28. Hence, the start-up period to delivery of the
beneficial agent 44 is not delayed by the amount of time which
would ordinarily be required to compress air pockets within the
osmotic delivery system 40. Furthermore, the chance that
significant amounts of air or gas may expel from the system,
causing possible health risks, is reduced.
[0118] FIGS. 5-8 illustrate osmotic delivery system flow modulator
assemblies 120, 220 according to further embodiments of the present
invention. The osmotic delivery system flow modulator assemblies
120, 220 will be described in reference to exemplary osmotic
delivery systems 140, 240 according to further embodiments of the
present invention illustrated in FIGS. 7 and 8. Each of the osmotic
delivery systems 140, 240 includes the respective flow modulator
assemblies 120, 220. Features on the flow modulator assemblies 120,
220, and osmotic delivery systems 140, 240 that are similar to
features on the flow modulator assembly 20 and osmotic delivery
system 40 are assigned corresponding reference numbers, increased
by 100's. Thus, the above description of the benefits and functions
of the different components of the flow modulator assembly 20,
osmotic delivery system 40, and methods of assembling associated
therewith also apply to the flow modulator assemblies 120, 220 and
osmotic delivery systems 140, 240. However, the flow modulator
assemblies 120, 220 and the osmotic delivery systems 140, 240
include additional features and inherent functions, as described
below.
[0119] As shown in FIGS. 5 and 6, the osmotic delivery system flow
modulator assembly 120 includes a flow modulator body 121 having a
filling and venting hole 124 located through the body of the flow
modulator and communicating the opposing ends 137, 138 of the body.
The osmotic delivery system flow modulator assembly 120, similar to
the osmotic delivery system flow modulator assembly 20, lessens the
chance that air or gas pockets will form in the enclosure 142 of
the osmotic delivery system 140 during assembly of the system,
specifically during the delivery of the beneficial agent 144 into
the enclosure of the system through the hole 124 in the flow
modulator body 121. Because use of the osmotic delivery system flow
modulator assembly 120 with the osmotic delivery system 140 lessens
the chance of air or gas formations within the enclosure 142, the
time to start up of delivery of the beneficial agent 144 and
performance of the system is enhanced. Use of the flow modulator
assembly 120 also lessens the chance that beneficial agent will be
wasted during assembly of osmotic delivery system 140, and also
reduces back diffusion of substances from the external environment
into the osmotic delivery system.
[0120] FIGS. 5 and 6 illustrate an exemplary osmotic delivery
system flow modulator assembly 120 according to one embodiment of
the present invention. Like the osmotic delivery system flow
modulator assembly 20 depicted in FIG. 1, the body 121 of the flow
modulator assembly 120 is constructed and arranged for at least
partial positioning in the osmotic delivery system enclosure 142.
The osmotic delivery system flow modulator assembly 120 may also be
made from the materials from which the osmotic delivery system flow
modulator 20 assembly may be made. Likewise, the delivery path 132
of the osmotic delivery system flow modulator assembly 120 may also
be configured like the delivery path 32 of the flow modulator
assembly 20. Thus, it is apparent that the flow modulator 120 is
similar in many aspects to the flow modulator 20. However, the flow
modulator body 121 of the flow modulator assembly 120, as shown in
FIGS. 5 and 6, only includes one hole 124 which communicates the
opposing ends 137, 138 of the flow modulator body 121. As described
below, the hole 124 may function as both a fill hole and a vent
hole.
[0121] In assembling the osmotic delivery system 140, the movable
dividing member 146 is first inserted into a first opening of the
enclosure 142. The osmotic agent 147 is then positioned or placed
through the same first opening such that is adjacent to the movable
dividing member 146. Thereafter, the semipermeable plug 148 is
inserted into the same first opening, effectively sealing this
opening. The osmotic delivery system 140 is then preferably rotated
such that the second opening of the enclosure 142 located opposite
from the semipermeable plug 148 faces vertically upward.
[0122] At this point, the beneficial agent 144 may be delivered to
the interior of the enclosure 144 through the hole 124 in the flow
modulator body 121. Thus, when assembling the osmotic delivery
system 140 according to the present invention, the flow modulator
body 121 may be inserted at least partially into the second opening
of the enclosure 142 opposite the semipermeable plug before the
beneficial agent 144 is delivered into the system. The flow
modulator body 121 is preferably inserted in the enclosure 142 such
that both ends 137, 138 of the flow modulator body are within the
interior of the enclosure 142.
[0123] Thereafter, a pipette, syringe, or other similar filling
device, preferably filled with the same beneficial agent 144, is
arranged above the hole 124 and the beneficial agent is released
into the hole at a predetermined rate, delivering the beneficial
agent into the interior of the enclosure 142 through the hole 124.
The predetermined rate of release of beneficial agent 144 from the
pipette is such that air or gas within the beneficial agent and the
enclosure 142 has the opportunity to escape through the hole 124 as
incoming beneficial agent is delivered through the hole 124 and
fills the interior of the enclosure 142. Thus, it is apparent that
the hole 124, and all of its possible configurations such as that
discussed above in regard to the holes 22, 24 acts as means for
venting the osmotic delivery system 140 when the beneficial agent
144 is inserted into the osmotic delivery system. Hence, the hole
124 functions as both a fill hole and a vent hole. The beneficial
agent 144 is delivered for a predetermined period of time such that
the beneficial agent fills the enclosure 142 and the hole 124 of
the flow modulator body 121.
[0124] Alternatively, a portion of the beneficial agent 144 may be
first delivered into the enclosure 142, and then the flow modulator
body 121 may be at least partially inserted into the second opening
of the enclosure such that the remainder of the beneficial agent
may be delivered into the enclosure through the hole 124.
[0125] After the beneficial agent has been delivered into the
enclosure 142, the stopper 170 illustrated in FIGS. 5-7 is inserted
into the hole 124. As illustrated in FIG. 6, the stopper 170 is a
pin-like member having a tip 173 and a head 175 located opposite
from one another. The stopper 170 also includes a shaft 171 located
between the tip 173 and the head 175. The shaft 171 is configured
and sized to fit in the hole 124 of the flow modulator 120 such
that a seal is formed between the exterior surface 179 of the shaft
171 and the interior surface of the hole 124. Thus, the stopper 170
functions similar to the caps 26 depicted in FIG. 3. As such, the
stopper 170 may be fashioned from a material similar to that of the
osmotic delivery system flow modulator 120, and should sufficiently
seal the hole 124 from the environment of use such that external
liquids from the environment of use do not leak into the osmotic
delivery system, and such that pressures generated from the osmotic
agent 147 within the osmotic delivery system 140 do not cause the
beneficial agent 144 to leak out from the hole 124. Thus, the
stopper 170 may press fit, thread into the hole 124, and/or be
fixedly adhered within the hole with the assistance of an adhesive.
However, the stopper 170 need not be a pin-shaped member. A plug,
cork, peg, pin, insert, molten plastic, rod, check valve, lid, top,
cap or other device or item(s) may be used to stop or close the
hole 124 such that the hole is sealed. However, as described below,
the stopper 170 is preferably shaped as described below such that
it attaches or secures a partition 160 to the flow modulator body
121.
[0126] The stopper 170 may be made from any chemically inert and
biocompatible, natural, or synthetic material which is known in the
art. The stopper material is preferably a non-bioerodible material
which remains in the patient after use, such as titanium. The
preferred titanium for the stopper 170 is similar or equal to that
from which the enclosure 142 may be made from. However, the
material of the stopper 170 may alternatively be a bioerodible
material which bioerodes in the environment after the osmotic
delivery system has dispensed the beneficial agent 144. Generally,
preferred materials for the stopper 170 are those acceptable for
human implantation. Furthermore, the exterior surface 179 of the
shaft 171 may be coated with a material which will help form a seal
between the exterior surface 179 and the interior surface of the
hole 124, such as a gold plating.
[0127] As shown in FIGS. 5 and 6, the shaft 171 of the stopper 170
is cylindrical and elongated and sized to matingly fit within the
hole 124 of the flow modulator body 121. Located opposite from the
tip 173 and adjacent to the head 175 is a tapered section 176 which
has a smaller diameter than that of the shaft 171. After the
exterior surface 179 of the shaft 171 tapers to the smaller
diameter of the tapered section 176, it curvingly angles at
approximately 45 from the tapered section to form the arcuate
surface 177 and to define the head 175 of the stopper 170. The
arcuate surface 177 of the stopper 170 ends at a diameter which is
larger than that of the shaft 171 and the tapered section 176.
[0128] After the beneficial agent 144 has been inserted into the
enclosure 142 through the hole 124 in the flow modulator 120, the
stopper 170 is inserted into the hole 124 to seal the hole in the
manner described above. However, before the stopper 170 is inserted
into the hole 124, the stopper is fitted with the partition 160
illustrated in FIGS. 5 and 6.
[0129] In the embodiment illustrated in FIGS. 5-7, the partition
160 is a disc-shaped member having a predetermined thickness and
smooth exterior surface 161. The partition 160 is preferably made
from an elastomeric material, which may be similar or equal to that
of the flow modulator body 121. Two preferred materials for the
partition 160 are silicone and C-Flex, manufactured by Consolidated
Polymer Technologies.
[0130] The above-described preferred materials for the partition
160 are sufficiently soft and flexible such that the tip 173 of the
stopper 170 may pierce through the thickness of the partition 160
and such that the partition 160 flexes as the shaft 171 is forced
through a pierced slit, cut, or rip created with the tip 173. Thus,
the partition 160 illustrated in FIG. 6 preferably does not include
a preformed hole for receiving the stopper 170, such that the tip
173 of the stopper 170 must be forcibly pierced through the
partition 160 so that the partition 160 is slidable up the shaft
171 of the stopper.
[0131] After the partition 160 has been pierced by the tip 173, the
partition 160 is slid along the shaft 171 until it reaches the
tapered section 176 of the stopper 170. Because the tapered section
176 of the stopper 170 is a smaller diameter than that if the shaft
171, it is adapted to receive the partition 160 such that the
partition is attached to the stopper 170 and will not easily slide
down the shaft 171 toward the tip 173. However, the stopper 170
need not include the tapered section 176. Although the material for
the partition 160 is sufficiently elastomeric to allow the
partition to slide along the shaft 171 after it is pierced by the
tip 173, it is also sufficiently rigid such that it will not easily
slide beyond the head 175 which has a greater diameter than that of
the shaft 171 and tapered section 176. That is, the head 175 is
configured to prevent the partition 160 from being removed from the
head end of the stopper 170, as shown in FIG. 7. The head 175 may
also be other configurations such as the top of a "T", a retaining
ring, nut, bolt, item fastened to the shaft 176, or other device
which prevents the partition 160 from being removed from the head
end of the shaft 171. Thus, after the partition 160 has been fitted
on the shaft 171 and the stopper 170 has been inserted into the
hole 124, the partition is secured to the flow modulator body 121,
between the flow modulator body and the head 175 of the
stopper.
[0132] Although the partition 160 depicted in FIGS. 5-7 is formed
from a solid and integral piece, it need not be so configured. The
partition 160 may also include an opening, slit, cut, or a hole for
receiving the stopper shaft 171. Thus, with such an embodiment, the
tip 173 of the stopper 170 need not be sharp or pin-like to pierce
the partition 160. Likewise, the partition 160 may have an
indentation located at or near the center of the partition 160 to
define a predetermined location where the tip 173 of the stopper
170 should pierce the partition upon application of force to the
stopper.
[0133] FIG. 7 illustrates the flow modulator assembly 120
positioned in an opening of the osmotic delivery system 140. Once
the partition 160 has been positioned on the tapered section 176 of
the stopper 170, and the flow modulator body 121 has been press-fit
into the opening of the enclosure 142, the top 178 of the head 175
of the stopper 170 may be pressed into the hole 124 such that the
stopper 170 and partition 160 attached thereto are received by the
opening in the enclosure 142. The stopper 170 is preferably
inserted into the hole 124 until the partition 160 abuts against a
surface of the enclosure 142. In this manner, the partition 161 and
the surface of the enclosure 142 define a one-way seal or check
valve 141 which substantially prevents liquids external of the
osmotic delivery system from the entering the interior of the
enclosure 142, but which also permits the beneficial agent 144
within the enclosure 142 to exit the osmotic delivery system 140.
Once the stopper 170 has been inserted into the hole 124, it is
apparent that the osmotic delivery system flow modulator assembly
120 is at least partially within the interior of the enclosure
142.
[0134] As shown in FIG. 7, the partition 160 abuts against the
interior surface 143 of the enclosure 142 to define the check valve
141 between the exterior surface 161 of the partition 160 and the
interior surface 143. Thus, when the osmotic delivery system 140 is
eventually placed into an environment of use, the osmotic agent 147
imbibes fluid through the semipermeable plug 148 and expands,
creating osmotic pressure within the enclosure 142. This osmotic
pressure forces the beneficial agent 144 through the delivery path
132 and eventually through the check valve 141 between the exterior
surface of the partition 161 and the interior surface 143 of the
enclosure 142.
[0135] As shown in FIG. 7, the stopper 170 and the partition 160
attached thereto are at least partially inserted into the enclosure
142 of the osmotic delivery system 140. In the embodiment shown in
FIG. 7, the flow modulator assembly 120 is fully inserted within
the enclosure 142 such that the partition 160 is also fully within
the enclosure 142. Thus, as described above, the partition surface
161 abuts against the interior surface 143 of the enclosure 142 to
define the check valve 141. Because the check valve 141 is formed
between the exterior surface 161 of the partition 160 and the
interior surface 143 of the enclosure 142, it is necessary that the
partition 160 be sufficiently large such that it will abut against
the interior surface 143 when the flow modulator assembly 120 is
inserted into the opening of the delivery system 140. Thus, in the
embodiment of the flow modulator assembly 120 depicted in FIGS.
5-7, the partition 160 has a greater diameter than that of the flow
modulator body 121 to assure that the outer surface 161 of the
partition 160 will abut against the interior surface 143 of the
enclosure 142 when the flow modulator 120 is inserted into the
enclosure.
[0136] The diameter, thickness, and material of the partition 160
control the amount of pressure required to "open" the check valve
141 so as to allow the beneficial agent 144 to flow past or through
the check valve after it has travelled through the delivery channel
132.
[0137] For example, the diameter or thickness of the partition 160
may be increased such that the amount of pressure required to
"open" the check valve 141 is increased. The size of the head 175
of the stopper 170 may also be varied and/or have differently
shaped surfaces so as to control the "opening" check valve
pressure. Furthermore, the delivery path 132 may be located
elsewhere in the flow modulator assembly 120. For instance, a
portion of the delivery path 132 may also be defined by the check
valve 141 of the partition 160.
[0138] FIG. 8 depicts another embodiment of an osmotic delivery
system 240 which includes another embodiment of a flow modulator
assembly 220. The flow modulator assembly 220 is similar to the
flow modulator assembly 120, and the above description of the
benefits and function of the different components of the flow
modulator assembly 120 also applies to the flow modulator assembly
220. Thus, features on the flow modulator assembly 220 that are
similar to features on the flow modulator assembly 120 are assigned
corresponding reference numbers, increased by 100. However, the
stopper 270 and the partition 260 are shaped differently than that
of the stopper 170 and partition 160 depicted in FIGS. 5-7. The
stopper 270 and the partition 260 have larger dimensions than the
stopper 170 and partition 160 such that the amount of osmotic
pressure required to "open" the check valve 241 so as to allow the
beneficial agent 144 to flow past or through the check valve is
increased.
[0139] More specifically, the diameter and thickness of the
partition 260 is greater than that of the partition 160. Because of
these increased dimensions, the exterior surface 261 of the
partition 260 abuts against the exterior surface of the osmotic
delivery system enclosure 242 to define the check valve 241.
Contrary to the check valve 141 shown in FIG. 7, the check valve
241 illustrated in FIG. 8 is formed between the exterior surface of
the enclosure 242 of the osmotic delivery system 240. Thus, in this
embodiment of the present invention, the head 275 of the stopper
270 and the partition 260 are not completely within the interior of
the enclosure 242, but are only partially located therein such that
at least a portion of the exterior surface of the partition 260
abuts against the exterior surface of the enclosure 242. However,
the partition 260 may be a greater diameter such that the head 275
may be located completely within the enclosure 242 and the exterior
surface of the partition may still abut against an exterior surface
of the enclosure. In an alternative embodiment, not shown, the
partition 160, 260 does not form a check valve. That is, the
partition 160, 260 need not abut against a surface of the enclosure
142, 242, but may assist in sealing the hole 124, 224.
[0140] In reference to either of the osmotic delivery systems 140,
240, after the hole 124, 224 has been filled to a predetermined
level with the beneficial agent 144, 244, the stopper 170, 270 with
the partition 160,260 attached thereto in the manner described
above, is inserted into the hole 124, 224 capping or sealing the
hole 124, 224 such that the beneficial agent 144, 244 located
within the delivery system 140, 240 will not escape from the
enclosure 142, 242 save from the delivery orifice formed in the
flow modulator body 121, 221.
[0141] The hole 124, 224 may be sized to accommodate the
predetermined rate that beneficial agent 144, 244 is delivered into
the hole and to accommodate any gas exiting the enclosure 142, 242
through the hole. Alternatively, the beneficial agent may be
delivered into the enclosure with a fill tube that is received by
the hole, requiring that the hole 124, 224 be larger than the
diameter of the fill tube to accommodate the escaping gas. If the
delivery rate of the beneficial agent 144, 244 is relatively slow,
the hole 124, 224 may have a smaller diameter and/or a longer
length. If the predetermined rate of delivery of beneficial agent
144, 244 into the hole 124, 224 is relatively fast, the hole 124,
244 must have a larger diameter and/or a shorter length such that
the beneficial agent 144, 244 does not overflow the hole 124, 224
as it is delivered through the hole. The level that the beneficial
agent 144, 244 reaches within the hole 124, 224 at the end of the
filling process may be selected such that when the stopper 170, 270
is inserted into the hole, little or no beneficial agent is
expelled from the top of the hole 124, 224 due to the stopper 170,
270 occupying a portion of the space of the fill hole 124, 224.
[0142] Alternatively, the beneficial agent 144, 244 may be forced
into and through the hole 124, 224 such that gas or air is forced
out of the enclosure 142, 242 through the delivery path 132,
232.
[0143] Because the flow modulator assembly 120, 220 forms a seal,
except for the delivery path 132, 232, with the interior surface
143, 243 of the enclosure 142, 242 the hole 124, 224 should be
sufficiently large to accommodate the rate of escaping air or gas
from within the enclosure 142, 242, which roughly equals the rate
that the beneficial agent 144, 244 is delivered into the fill hole
124, 224.
[0144] Assembling the osmotic delivery system 142, 242 in the
above-described manner is advantageous because the amount of
beneficial agent 144, 244 which may be wasted is reduced. When the
stopper 170, 270 is positioned within the flow modulator body 121,
221, only a minute amount of surplus beneficial agent 144, 244 is
expelled from the enclosure of the osmotic delivery system 140,
240. This reduced amount of beneficial agent 144, 244 expelled when
assembling an osmotic delivery system 140, 240, as compared to past
assembly methods, reduces the cost of assembly. Because the amount
of wasted beneficial agent is reduced, it is also easier to
determine the precise amount of beneficial agent 144, 244 remaining
in the osmotic delivery system 140, 240 for eventual delivery.
[0145] As described above, when delivering the beneficial agent
144, 244 into the osmotic delivery system 140, 240, the hole 124,
224 permits gas within the enclosure of the osmotic delivery system
to escape from the system. Thus, when the osmotic delivery system
140, 240 is completely assembled, the amount of gas within the
system is reduced. This reduction of trapped air or gas within the
system is advantageous because the time to start-up of delivery of
beneficial agent 144, 244 from the delivery system to the
environment of use is reduced.
[0146] When the osmotic delivery system 140, 240 is eventually
placed into an environment of use, the osmotic agent 147, 247
imbibes fluid through the semipermeable plug 148, 248 and expands,
creating osmotic pressure within the enclosure 142, 242. This
osmotic pressure forces the beneficial agent 144, 244 through the
delivery path 132, 232. Because the amount of gas or air within the
enclosure 142 is reduced during assembly of the osmotic delivery
system, the osmotic agent 147, 247 need not first compress air
within the beneficial agent before forcing the beneficial agent
into the delivery path 132, 232. Hence, the start-up period to
delivery of the beneficial agent 144, 244 is not delayed by the
amount of time which would ordinarily be necessary to compress air
pockets within the osmotic delivery system 140, 240. Furthermore,
the chance that significant amounts of air or gas may expel from
the system, causing possible health risks, is reduced.
[0147] The check valve 141, 241 defined by the partition 160, 260
and a surface of the enclosure 142, 242 is advantageous because it
reduces the possibility of the inward flux of materials from the
environment of use into the osmotic delivery system 140, 240. That
is, the check valve 141, 241 reduces the chances of contaminants
from entering the interior of the enclosure 142, 242, possibly
destabilizing, diluting, or altering the beneficial agent
formulation 144, 244. The check valve 141, 241 permits the desired
rate of beneficial agent 144, 244 to exit from the osmotic delivery
system 140, 240, while also controlling the diffusion of liquids
from the environment of use into the system. This is further
advantageous because the delivery path 132, 232 may be made larger
such that it can accommodate difficult-to-deliver viscous or
multi-phased beneficial agent formulations without a substantial
risk of back diffusion of substances into the osmotic delivery
system 140, 240. Thus, the delivery path 132, 232 need not be sized
such that the average linear velocity of the beneficial agent 144,
244 through the path is higher than that of the linear inward flux
of materials in the environment of use due to back diffusion
because the check valve 141, 241 substantially prevents liquids
external of the osmotic delivery system from entering the osmotic
delivery system.
[0148] A further advantage of the osmotic delivery system 140, 240
having the flow modulator assembly 120, 220 is that the system does
not need to be capped to prevent evaporation of the beneficial
agent 144 from the delivery path 132, 232 of the system because the
partition 160 acts as a cap or seal to prevent such evaporation.
Accordingly, the osmotic delivery system 140, 240 is simpler to
manufacture than conventional osmotic delivery systems while
substantially preventing evaporation of the beneficial agent 144
from the system.
[0149] FIG. 9 illustrates that the hole 124 of the flow modulator
body 121 may also be used in conjunction with a vacuum creating
means 605, such as a vacuum pump to further remove gas from the
osmotic delivery system. As shown in FIG. 9, the vacuum fixture 600
includes a first opening 608 for receiving a delivery tube 508 of a
beneficial agent delivery device 500. The vacuum fixture 600 also
includes a second opening 604 for connecting the interior of the
vacuum fixture to the vacuum creating means 600.
[0150] The vacuum fixture 600 includes a third opening formed by
the wall 602 of the vacuum fixture which is sized and shaped to
form a seal with the exterior surface of the enclosure 142 when the
enclosure is received by the third opening.
[0151] After the flow modulator body 121 has been inserted into the
enclosure 142, the third opening of the vacuum fixture 600 may be
snugly pressed over the second opening of the enclosure 142 such
that at least a portion of the enclosure is within the vacuum
fixture 600. Thereafter, the delivery tube 508 is inserted into the
first opening 608 and the vacuum means 606 is connected to the
second opening 604. Preferably, the vacuum means 606 is initiated
before any beneficial agent 144 is delivered or inserted into the
enclosure 142. The initiated vacuum means 606 creates a vacuum
adjacent to the flow modulator body 121, defining the vacuum area
601 within vacuum fixture 600. For example, a vacuum of
approximately 27 inches of mercury may be created by the vacuum
means 606. Hence, it is preferable that the first opening 608 form
a seal with the delivery tube 508 and that the wall 602 form a seal
with the exterior surface of the enclosure 142.
[0152] Because a vacuum exists within the vacuum area 601, adjacent
the flow modulator body 121, the interior of the osmotic delivery
system enclosure 142 is also vented or evacuated via the hole 124
in the flow modulator body 121 such that the amount of gas within
the osmotic delivery system is substantially reduced. After the gas
has been removed from the osmotic delivery system 140 in the
above-described manner, the beneficial agent 144 is preferably
delivered into the enclosure 142 through the hole 124 in the flow
modulator body 121 via the delivery tube 508 of the beneficial
agent delivery device 500. Once the beneficial agent 144 has been
delivered into the enclosure 142 and has at least partially filled
the hole 124, the vacuum means may be shut-off and the vacuum
fixture 600 removed from the enclosure. Thereafter, the assembly of
the osmotic delivery system 140 may be completed by inserting the
stopper 170 into the hole 124.
[0153] By creating a vacuum adjacent to the flow modulator body 121
before delivery of the beneficial agent 144 into the enclosure 142
and/or while inserting the beneficial agent 144 through the hole
124, the amount of gas within the osmotic delivery system is
reduced. In addition, even if a small amount of gas bubbles were
somehow trapped within the enclosure 142 of the osmotic delivery
system 140, such gas bubbles will collapse after the vacuum has
been removed and the system is exposed to atmospheric pressure such
that the collapsed bubbles dissolve into the beneficial agent
formulation 144. Hence, after the assembly of the delivery system
140 is completed and the system is eventually placed into an
environment of use, the start-up period to delivery of the
beneficial agent 144 is not delayed by the amount of time
ordinarily required to compress gas pockets within the osmotic
delivery system 140.
[0154] The above-described process may also be advantageously
performed during the assembly of the osmotic delivery system 40
illustrated in FIG. 4. It will also be realized that other methods
and apparatus may be used to create a vacuum adjacent to the flow
modulator body 121 within the knowledge of those skilled in the
art. For example, the vacuum may be created by directly applying
vacuum creating means to the hole 124 of the flow modulator body
121, rather than the enclosure 142.
[0155] The above description of the preferred and alternative
embodiments of the present invention must be considered as
illustrative only of the principle of the invention and not
limitative. Indeed, it may be easily understood that numerous
modifications could be made by those skilled in the art without
departing from the spirit of the invention as defined in the claims
below.
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