U.S. patent number 3,845,761 [Application Number 05/281,445] was granted by the patent office on 1974-11-05 for intrauterine contraceptive anti-fertility device for the management of reproduction.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Alejandro Zaffaroni.
United States Patent |
3,845,761 |
Zaffaroni |
November 5, 1974 |
INTRAUTERINE CONTRACEPTIVE ANTI-FERTILITY DEVICE FOR THE MANAGEMENT
OF REPRODUCTION
Abstract
An intrauterine contraceptive delivery device for administering
an anti-fertility agent at a controlled rate for a prolonged period
of time is comprised of a shaped body having a cross member and a
depending member defining a "T." The body is comprised of a wall
surrounding at least one reservoir containing an anti-fertility
agent. The reservoir is formed of a liquid carrier permeable to the
passage of the agent and in which the agent has limited solubility.
The wall surrounding the reservoir is formed in at least a part of
a release rate controlling material permeable to the passage of the
agent, but the rate of passage of the agent through the wall is
lower than the rate of passage through the carrier so that release
by the wall is the release rate controlling step for releasing the
anti-fertility agent from the "T" shaped intrauterine contraceptive
anti-fertility delivery device.
Inventors: |
Zaffaroni; Alejandro (Atherton,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
27366210 |
Appl.
No.: |
05/281,445 |
Filed: |
August 17, 1972 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
185208 |
Sep 9, 1971 |
|
|
|
|
42786 |
Jun 2, 1970 |
|
|
|
|
Current U.S.
Class: |
128/833; 424/432;
604/57; 604/515 |
Current CPC
Class: |
A61M
31/002 (20130101); A61F 6/144 (20130101); A61F
9/0017 (20130101); A61K 9/0004 (20130101); A61K
9/0092 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61F 6/00 (20060101); A61F
6/14 (20060101); A61F 9/00 (20060101); A61M
31/00 (20060101); A61f 005/46 () |
Field of
Search: |
;128/127,128,129,130,131,260 ;424/19,20,21,22 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Kinel & Rudel, Sustained Release Hormonal Preparation, ACTA
Endocrinologica, The Population Council, Rockerfeller Univ., 1971.
.
Chang and Kinel, Sustained Release Hormonal Preparation: Biologic
Effectiveness of Steroid Hormones, Fertility and Sterility, Vol.
21, No. 2, Feb. 1972..
|
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: Dunne; G. F.
Attorney, Agent or Firm: Sabatine; Paul L. Mandell; Edward
L. Benz; William H.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of copending patent
application U.S. Ser. No. 185,208 filed on Sept. 9, 1971, which is
a contination-in-part of copending U.S. Pat. application Ser. No.
42,786 filed on June 2, 1970, and assigned to the same assignee of
the present patent application.
Claims
I claim:
1. A method of interfering with the reproductive process of a
female mammal by continuously administering a contraceptive agent
within the uterine cavity of said female over a prolonged period of
time by the steps of: (a) inserting into the uterine cavity an
intrauterine device comprising a reservoir containing dissolved
agent and undissolved replacement agent in a liquid core material
permeable to the passage of the agent, the undissolved replacement
agent being present in an amount in excess of its solubility in the
core and sufficient to maintain the dissolved agent during the
prolonged period substantially equal to the amount of dissolved
agent originally present in the core, the reservoir confined within
an enveloping shape membrane substantially in the shape of a T
comprised of a biologically acceptable material insoluble in
mammalian body fluid, and formed at least in part of a material
permeable by diffusion to passage of said agent at a rate which is
lower than the rate of permeability of said agent through said
core, (b) releasing said agent from said reservoir into the uterine
cavity at a controlled, continuous, contraceptively effective rate
by diffusional passage through said shaped membrane, and (c)
continuously replacing the dissolved agent released from the
reservoir by continuously dissolving said undissolved replacement
agent in the core so as to substantially maintain the amount of
dissolved drug at its originally present amount.
2. An intrauterine device for the administration of an
anti-fertility agent at a controlled and continuous rate over a
prolonged period of time to effect contraception, said device
comprising: (a) a reservoir comprising both dissolved
anti-fertility agent and undissolved replacement anti-fertility
agent in a liquid core material permeable to the passage of the
agent, with anti-fertility agent having limited solubility in the
liquid core, the undissolved replacement anti-fertility agent being
present in an amount in excess of its solubility in the core and in
amounts sufficient to maintain the dissolved drug in an amount
substantially equal to the amount of dissolved drug originally
present in the core material during the prolonged period of time,
said reservoir surrounded by, (b) a wall of a configuration which
is substantially in the shape of a T, the wall made of a material
insoluble in body fluid, and formed in at least a part of a release
rate controlling material permeable to the passage of the
anti-fertility agent, with the permeability of the wall to
anti-fertility agent lower than the permeability of the liquid core
material to anti-fertility agent, and (c) wherein the device when
placed in the uterus continuously releases anti-fertility agent
from the reservoir in a contraceptively effective amount by metered
passage through the wall, with released anti-fertility agent being
continuously replaced in the liquid core by replacement
anti-fertility agent to substantially maintain the amount of
dissolved anti-fertility agent at its initial present amount in the
liquid core.
3. An intrauterine contraceptive device for the administration of
an anti-fertility agent at a controlled and continuous rate over a
prolonged period of time, said device comprising: (a) a reservoir
comprising both dissolved anti-fertility agent and undissolved
replacement anti-fertility agent in a liquid core permeable to the
passage of the agent, with the anti-fertility agent having limited
solubiltiy in the liquid core, the undissolved replacement
anti-fertility agent contained in the liquid core in an excess
amount to continuously replenish and maintain dissolved
anti-fertility agent substantially at its original amount in the
liquid core during the prolonged period of time, said reservoir
surrounded by (b) a wall of a configuration which is substantially
in the shape of a T, the wall made of a material insoluble in body
fluid, and formed in at least a part of a release rate controlling
material permeable to the passage of the anti-fertility agent, with
the permeability of the wall to anti-fertility agent lower than the
permeability of the liquid core to anti-fertility agent, and (c)
wherein the intrauterine device when placed in the uterus releases
dissolved anti-fertility agent from the reservoir in an effective
amount for contraception by metered passage through the release
rate controlling wall, with released anti-fertility agent
continously replaced in the liquid core by replacement
anti-fertility agent simultaneously dissolving to substantially
maintain the amount of dissolved anti-fertility agent in the liquid
core for release at a controlled and continuous rate over a
prolonged period of time.
4. An intrauterine contraceptive device for the administration of
an anti-fertility agent at a controlled and continuous rate for a
prolonged period of time according to claim 3 wherein the release
rate controlling material is a substantially homogenous material
permeable to anti-fertility agent, the liquid core is a liquid
medium containing anti-fertility agent that constantly bathes the
inner surface of the release rate controlling material and is
permeable to the passage of anti-fertility agent, and the
anti-fertility agent is a progestogen.
5. An intrauterine contraceptive device for the administration of
an effective amount of an anti-fertility agent at a controlled and
continuous rate over a prolonged time according to claim 3 wherein
the release rate controlling material is ethylene vinyl acetate
copolymer, the liquid core is silicone oil and the anti-fertility
agent is progesterone.
6. An intrauterine contraceptive device for the administration of
an effective amount of an anti-fertility agent at a controlled and
continuous rate over a prolonged period of time according Jo claim
3 wherein the liquid core is a mixture permeable to the passage of
anti-fertility agent comprised of an oil, a liquid prepolymer and
an anti-fertiltiy agent which is a progestational agent.
7. An intrauterine contraceptive device for administration of an
anti-fertility agent at a controlled and continuous rate for a
prolonged period of time according to claim 3 wherein the
anti-fertility agent is a progestational agent.
8. An intrauterine contraceptive device for the administration of
an anti-fertility agent at a controlled and continuous rate over a
prolonged period of time according to claim 3 wherein said agent
release rate controlling material is permeable to passage of
dissolved anti-fertility agent by diffusion.
9. An intrauterine contraceptive device for the administration of
an anti-fertility agent at a controlled and continuous rate over a
prolonged period of time according to claim 3 wherein said release
rate controlling material is a microporous material having its
pores filled with a liquid medium permeable to passage of the
anti-fertility agent by diffusion.
10. An intrauterine contraceptive device for the administration of
an anti-fertility agent at a controlled and continuous rate over a
prolonged period of time according to claim 3 wherein the liquid
core is permeable to the passage of dissolved anti-fertility agent
by diffusion.
11. An intrauterine contraceptive device for the administration of
an anti-fertility agent at a controlled and continuous rate over a
prolonged period of time according to claim 3 wherein the liquid
core is an oil and the anti-fertility agent is a diffusible
estrogenic agent.
12. An improved process of contraception wherein an intrauterine
contraceptive device for the administration of an anti-fertility
agent at a controlled and continuous rate over a prolonged period
of time is placed within a fertile uterus, the improvement
comprised of using an intrauterine contraceptive device having (a)
a reservoir comprising a liquid core, liquid core containing, (b)
both diffusible anti-fertility agent dissolved in the liquid core
and undissolved replacement anti-fertility agent in the liquid
core, the liquid core permeable to the passage of anti-fertility
agent with the anti-fertility agent having limited solubility in
the liquid core, the undissolved replacement anti-fertility agent
contained in an amount sufficient to continuously dissolve to
replenish and substantially maintain dissolved anti-fertility agent
in the core for continuous availability at substantially the same
rate to the wall during the prolonged period of time, the reservoir
surrounded by (c) a wall of a configuration substantially in the
shape of a T, the wall made of a material insoluble in body fluid,
and formed of a release rate controlling material permeable to the
passage of a diffusible anti-fertility agent with the permeability
of the wall to the anti-fertility agent lower than the permeability
of the liquid core to the anti-fertility agent, and (d) wherein
during the process of contraception when the intrauterine device is
placed in the uterus, the intrauterine device releases dissolved
anti-fertility agent from the reservoir in an effective amount for
contraception by metered passage through the release rate
controlling wall, with released anti-fertility agent continuously
replaced in the liquid core by replacement anti-fertility agent
simultaneously dissolving to substantially maintain dissolved
anti-fertility agent in the liquid core for release at a controlled
and continuous rate over a prolonged period of time to produce
contraception.
13. A process of contraception according to claim 12 for the
controlled and continuous rate of release over a prolonged time
wherein the reservoir consists of an oil and the anti-fertility
agent is a diffusible estrogenic anti-fertility agent, or a
diffusible progestational anti-fertility agent.
14. An intrauterine contraceptive device for administering a member
selected from the group of anti-fertility agents consisting of
progestational, estrogenic and mixtures thereof at a controlled and
constant rate over a prolonged period of time up to three years
comprising: (a) a wall substantially in the shape of a T comprising
the anti-fertility device and formed of a release rate controlling
material permeable to the passage of the anti-fertility agent by
diffusion, the material insoluble in body fluid, and capable of
substantially maintaining the device's shape throughout the
prolonged period of time, said wall surrounding (b) at least one
reservoir defined by the wall's inner surface with the reservoir
comprising a liquid core, containing up to 10 grams of both
dissolved anti-fertility agent and undissolved replacement
anti-fertility agent with the liquid core permeable to the passage
of the anti-fertility agent and having limited solubility for the
anti-fertility agent, the undissolved replacement anti-fertility
agent in the liquid core present in an excess amount to
continuously replenish and maintain a substantially constant supply
of dissolved anti-fertility agent in the liquid core during the
prolonged period of time, with the permeability of the wall to the
anti-fertility agent lower than the permeability of the core to the
agent, (c) and wherein anti-fertility agent administered from the
intrauterine device is effected by releasing dissolved
anti-fertility agent with such released agent being replaced by
undissolved replacement agent to continuously maintain dissolved
anti-fertility agent in the liquid core for supplying the
anti-fertility agent at substantially the same rate to the wall so
that anti-fertility agent is metered at a controlled and
substantially constant rate from the reservoir by passage through
the wall over the prolonged period of time.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to both a novel and useful intrauterine
contraceptive anti-fertility delivery device for releasing an
anti-fertility agent at a controlled rate for a prolonged period of
time. The intrauterine device is comprised of a wall substantially
in the shape of a "T," and a reservoir defined by the inner surface
of the wall. The reservoir is comprised of an anti-fertility agent
in a liquid carrier permeable to the passage of the agent and in
which the agent has limited solubility. The wall of the
intrauterine device is comprised in at least a part of a release
rate controlling material permeable to the passage of the
anti-fertility agent. Both the carrier and the wall are permeable
to the passage of the agent, as by diffusion, but the permeability
of the wall to the agent is lower that the permeability of the
carrier to the agent. Accordingly, the release of anti-fertility
agent through the wall is the release rate controlling step for
releasing the agent from the intrauterine contraceptive
anti-fertility devices of the invention.
2. Description of the Prior Art
Intrauterine contraception devices formed of an integral, solid
filamentary body in one of several well known configurations have
become an increasingly popular method of birth control. One of the
most notable configurations formed in accordance with the prior art
practice that is relatively inexpensive to manufacture and
seemingly does not require the daily attention of the host is the
"T" type configuration as described in U.S. Pat. No. 3,533,406.
While it was initially thought that an intrauterine device of this
shape would provide satisfactory uterine retention properties and
prevent pregnancy, the recorded medical history of this device has
demonstrated that this is not the case. For example, the patent
reports a high incident of pregnancy and expulsion of 12.4 and 5.2
percent respectively. Similar statistical results for the T
configuration as reported in Am J. Obstet Gynec., Vol. 109, pages
771 to 774, 1971 show 18.3 pregnancies per 100 users and 5.9
expulsions per 100 users. Thus, the actual medical history of this
device with its high incidents of involuntary expulsion and
pregnancy has discouraged the use of the "T" as an acceptable
intrauterine contraceptive device.
The prior art attempted to overcome those disadvantages in
similarly designed and constructed devices by using several
techniques. One technique used was to design and manufacture a
large number of solid, intrauterine devices of varying sizes and
assorted configurations for use in all types of uterine cavities.
However, this attempt has not been successful because of the large,
natural variations in size and contour of the uterine cavity. This
makes it virtually impossible to effectively design a device that
is satisfactory with a wide range of users for preventing
spontaneous involuntary expulsion and a high pregnancy rate. Also,
varying the size of the device has been found to be inappropriate
because of the lack of reliable techniques for determining the size
of the uterine cavity resulting in many instances in the wrong
choice of device for insertion into the uterine cavity.
Other attempts by the prior art to avoid the recurrent problems
discussed above consist in tying to an intrauterine device a
capsule containing a progressional agent, or charging an
intrauterine device with a progestional agent that is releasable
therefrom for reducing uterine contractility and the accompanying
expulsion of the device, and seemingly the incidents of pregnancy
and uterine endometritis. However, this approach, as with previous
approaches, has been fraught with many problems. One problem
associated with this type of device in the past has been the
unpredictable and variable release pattern for the progestional
agent from the device to the uterus over prolonged periods of time.
This has inherently prevented the prior art from becoming reliable
sustained release birth control devices with a continued ability to
overcome the mentioned disadvantages.
These, and other unacceptable results can be attributed to the fact
that the art has not had available a satisfactory means of
carefully administering controlled amounts of an anti-fertility
agent, at a constant rate and over a prolonged period of time, for
example, periods of a year or more. Exemplary of the unsatisfactory
release pattern encountered by the art is the use of devices filled
with milled crystals or dry powdered progestional agents. With
these devices, there is a decrease in the release rate of the
progestional agent from the device which defeats the critical need
for a sustained controlled and constant or zero order release rate,
which release rate is critical in order to provide an effective
means of contraception. Accordingly, it was reported that this type
of device does not lend itself for use as a sustained hormonal
device for intrauterine application. Fertility and Sterility, Vol.
22, No. 10, pages 671 to 676, 1971. This pattern also can arise in
another embodiment wherein a beneficial drug, agent or the like is
dispersed in a solid matrix permeable to passage of the drug and
surrounded by a membrane, also permeable to passage of the drum but
at a lower rate than through the matrix. The device has proven
itself capable of zero order drug release and represents a
substantial improvement over previously proposed drug delivery
devices. However, in some instances, when zero order release is
required for long periods of time, on the order of several months
to a year or more, it may not be attained with this type of device.
For example, it has been found that as drug is released by that
device there is created over time a space in the solid matrix drug
carrier which if not occupied by more drug can result in the
carrier contracting and moving away from the membrane. The loss of
intimate contact between the carrier and the membrane at the
carrier/membrane interface tends to decrease the availability of
drug at the interface for release by the membrane. Thus, since the
amount of drug available to the membrane is no longer constant,
drug is released from the device at a continually reduced rate and
the device does not maintain a constant zero order release rate.
For applications in which controlled release is demanded for very
long periods, this can be a problem.
One other modification suggested by the prior art is to prepare a
plastic intrauterine device into which a contraceptive drug has
been incorporated, that is, dispersed in the plastic for subsequent
release therefrom. However, it is now known that this type of
device has not met with acceptance by the art. Generally, the art
has not accepted this type of anti-fertility delivery device
because it has proven itself incapable of providing a sustained,
zero order release rate, because of the drawback that the release
rate (dM/dt) instead of being zero order (dM/dt = constant)
decreases with time (dM/dt = constant x t.sup..sup.-1/2) during
much of the drug release history of the device. J. Pharm. Sci.,
Vol. 52, pages 1,145 to 1,149, 1963; and, U.S. Pat. No.
3,533,406.
OBJECT OF THE INVENTION
Accordingly, it is an immediate object of this invention to provide
a shaped intrauterine contraception device for the administration
of an anti-fertility agent which device overcomes the aforesaid
disadvantages associated with the prior art intrauterine
contraceptive devices.
Still another important object of the invention is to provide an
intrauterine contraception device for releasing an anti-fertility
agent at a controlled and constant rate for a prolonged period of
time, for example, for periods of a year or longer.
Yet still another object of the invention is to provide a reliable
and easily used intrauterine contraceptive device suitable for
continuously administering controlled quantities of an
anti-fertility agent within uteri of various sizes and contours
while substantially remaining free of the tribulations of the prior
art.
It is also an object of the invention to provide an intrauterine
contraceptive device that can be inexpensively fabricated in mass
quantities and essentially painlessly and simply inserted through
the normal cervical canal.
Another object is to provide an intrauterine device for releasing
an anti-fertility agent at a constant rate for a prolonged and
predictable period of time.
Still yet another object of the invention is to provide a new and
useful intrauterine contraceptive anti-fertility delivery device
that is essentially insoluble in body fluids, is essentially
nonbiodegradable and can be used for a prolonged period of time in
contact with animal fluids and membranes.
Another object of the invention is to provide an intrauterine
contraceptive anti-fertility dispensing device with improved
properties for substantially lessening the incident of expulsion
and pregnancy.
Yet another object of the invention is to provide an intrauterine
contraceptive anti-fertility delivery device that essentially has a
constant or zero order rate of release and can be used as a
sustained release delivery device.
Still a further object of the invention is to provide an
intrauterine contraceptive device that releases anti-fertility
progestational and estrogenic agents.
Other objects, features and advantages of the invention will be
apparent to those skilled in the art from the detailed description
of the invention which follows, taken in conjunction with the
drawings, and the accompanying claims.
SUMMARY OF THE INVENTION
This invention concerns, in its broadest aspects, a novel
intrauterine contraceptive anti-fertility delivery device
comprising a wall enclosing a drug reservoir. The wall is
substantially in the shape of a "T" having a top cross member and a
depending member. The wall is comprised of a flexible, release rate
controlling material permeable to the passage of an anti-fertility
agent. The reservoir is defined by inner surface of the wall of the
cross or depending member or both, and it is comprised of an
anti-fertility agent and a liquid core, which core is permeable to
the passage of the anti-fertility agent and having limited
solubility therefore. Both the wall and the liquid core are
permeable to the passage of the agent, as by diffusion, but the
permeability of the wall to the passage of the agent is at a lower
rate than through the liquid core. Since the permeability of the
wall to the passages of the anti-fertility agent is lower than the
permeability of the liquid core to the passage of the agent, the
passage of the agent through the wall of the intrauterine "T"
device is the rate determining step for releasing the agent from
the intrauterine contraceptive anti-fertility "T" shaped dispensing
device.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, which are not drawn to scale, but rather are set
forth to illustrate various embodiments of the invention, the
drawings are as follows:
FIG. 1 is a side, elevational view of a "T" shaped intrauterine
contraceptive anti-fertility releasing device of the invention;
FIG. 2 is a cross-sectional view of the intrauterine contraceptive
device of FIG. 1 through 2--2 depicting the reservoir of the
device; and
FIG. 3 is a side, fragmetary view of a uterine cavity illustrating
an anti-fertility releasing intrauterine "T" shaped device
positioned in the uterus.
In the specification and drawings, like parts in related figures
are identified by like numbers. The terms appearing earlier in the
specification and in the description of the drawings, as well as
embodiments thereof, are further discussed elsewhere in the
disclosure.
DETAILED DESCRIPTION OF THE DRAWINGS
Turning now to the drawings in detail, which are examples of
various intrauterine contraceptive anti-fertility devices of the
invention, and which examples are not to be construed as limiting
the invention, one embodiment of a novel intrauterine contraceptive
device is indicated in FIG. 1 by the number 20. Intrauterine
contraceptive 20 can be generically defined as a shaped body
defining a "T." Device 20 is comprised of a cross member 21, also
known as cross bar or top cross bar and a depending member 22, also
known as the depending leg. Intrauterine device 20 is made of a
biologically acceptable flexible material and it can be temporarily
deformed by moving member 21 toward member 22. While device 20 is
deformable, it retains its memory and returns to define the T. The
device's ability to temporarily deform conveniently aids in its
insertion into a uterus, while the device's memory insures its
return to the desired shape in the uterus. Generally, device 20 can
be manufactured in different sizes to accommodate all uteri; for
example, member 21 can have a length of about 2 cm to 4 cm which
length approximates the width of the fundal region of the uterus,
and member 22 can have a length of about 2 cm to 4 cm to extend
towards the cervical os when member 21 is positioned in the fundal
region. Generally, the diameter of either member is the same or
different and it is about 0.1 cm to 0.5 cm and the like.
Device 20 is comprised of a wall 23 surrounding a reservoir 24, not
shown in FIG. 1, but illustrated in FIG. 2 in cross-section through
2--2 of FIG. 1. Wall 23 of FIGS. 1 and 2 is formed of an
anti-fertility release rate controlling material and reservoir 24
is defined by wall 23's inner surface. Reservoir 24 is comprised of
an anti-fertility carrier 25 containing an anti-fertility agent 26,
or a mixture of anti-fertility agents. Carrier 25 can be a liquid,
gel, sol or the like and it is permeable to the passage of
anti-fertility agent 26, as by diffusion, or by convection, or by
an occurrence of both. The carrier medium confined in the reservoir
serves several purposes for effectively releasing drug from the
device. First, it is permeable to the passage fo an anti-fertility
agent so that it can migrate to wall 23. Secondly, the carrier
contacts and bathes the inner surface of wall 23 for facilitating
anti-fertility agent transfer from the carrier to the wall so that
molecules can dissolve in and migrate through the wall to the outer
surface thereof. Thirdly, the carrier acts as a constant source of
anti-fertility agent as it has a limited, or varying degree of
solubility for the anti-fertility agent or a mixture of agents. The
carrier is formulated to contain both dissolved and undissolved
anti-fertility agent and to act as a constant source of
anti-fertility agent, because as dissolved agent transfers from the
carrier to the wall, undissolved agent dissolves in the carrier to
insure a constant and uniform supply of agent until essentially all
the agent has been released by the device. This mechanism of
continually replenishing the agent enables the device to achieve a
uniform release rate for the device throughout its use. A detailed
description of the carrier is presented later in the
disclosure.
Wall 23 of device 20 of FIGS. 1 and 2 is also permeable to the
passage of the anti-fertility agent 26, as by diffusion, but the
rate of passage of the anti-fertility agent through wall 23 is
lower than the rate of passage of the anti-fertility agent through
the carrier 25. In operation, carrier 25 serves as a reservoir by
supplying dissolved anti-fertility agent 26 to wall 23 as
anti-fertility molecules move through carrier 25 to bathe the inner
surface of wall 23. Anti-fertility agent 26 present at the
anti-fertility carrier/wall interface dissolve in and migrate
through wall 23, ultimately reaching the outer surface of wall 23
for release in the uterine cavity. As anti-fertility agent 26
leaves carrier 25, undissolved agent present in reservoir 24
dissolve in carrier 25 to maintain a constant supply of dissolved
anti-fertility agent in the carrier for continuously supplying it
at substantially the same rate to wall 23. Wall 23 operates to
effectively control the rate of release of anti-fertility agent
throughout the useful period of birth control by the device. Thus,
a zero order anti-fertility release rate can be obtained.
Wall 23 is made from a material that can have uniform properties
across all its dimensions, or it can be microporous, or it can be a
material possessing both of these properties. When wall 23 is made
from the former material, that is, a material that is substantially
imperforate, molecules of anti-fertility agent 26 dissolve in an
diffuse through wall 23 by the process of diffusion. When wall 23
is made from the latter material, that is, a material having
microporous properties, molecules of anti-fertility agent 26
diffuse through a liquid phase, not shown, present in the minute
pores, pinholes or cracks, for example, by absorption of uterine
fluids by a hydrophilic microporous material, as of uterine fluids
by a hydrophilic microporous material, as by diffusion. When wall
23 is made from a material having both of these properties,
anti-fertility agent 26 can be released by intrauterine device 20
through wall 23 by a concurrent operation of both of these
mechanisms, that is, by diffusion through wall 23 and by diffusion
through liquid in the pores of wall 23. In the specification, the
permeation mechanism of drug release through the drug release rate
controlling material is generically described as "by diffusion" for
both types of materials used to fabricate wall 23. The permeability
of wall 23 to the diffusion of anti-fertility agent 26 is always
lower than the permeability of liquid carrier 25 to the diffusion
of anti-fertility agent 26 and accordingly, passage through wall 23
thus acts as the rate limiting step for agent 26 release from
intrauterine contraceptive device 20.
In FIG. 3 there is graphically depicted an intrauterine
contraceptive anti-fertility delivery device 20 prepared according
to the spirit of the invention. Device 20 is of T configuration and
it is adapted to be located within a uterine cavity 27, wherein it
optionally contacts sides 28 as well as fundus uteri 29 of uterus
27. Deivce 20 is preferably designed with rounded, non-traumatising
ends and a thread 30 is attached to trailing end 31, distal from
lead or inserting end 32, for manually removing device 20 from
uterus 27. Thread 30 can be any suitable material, for example,
nylon, surgical thread having a thickness of about 0.002 to 0.020
inches, and the like.
Device 20 of FIG. 3 is formed of a release rate controlling
material 23 to continuously meter the flow of an effective amount
of an agent from the reservoir, not shown in FIG. 3, within the
uterus. Material or wall 23 thus has three functions: first, it has
a memory for retaining the shape of the device, secondly, the
material forming the wall has a memory for releasing the agent at a
controlled rate throughout the device's history, and third, the
inner surface of the wall surrounds a reservoir formed of a hollow
space defined by the inner surface of wall 23 as described for FIG.
2 through cross-section 2--2 of FIGS. 1 and 2. These operate in
unity to form the novel device of the invention. Reservoir 24, not
illustrated in FIG. 3, is comprised of top member 21, or depending
member 22 or both members 21 and 22 for housing and releasing
antifertility agent 26. Device 20 can be integral or comprised of
members 21 and 22 serving as an integral unit device 20. Thus, with
either embodiments, wall 23 of device 20 acts as the rate limiting
barrier for releasing anti-fertility agent 26 from the device to
the uterine cavity 27 at a constant and uniform rate for producing
the desired result.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the practice of the present invention, it has
now been found that the intrauterine contraceptive device 20 of
this invention provides many important advantages over the prior
art. One advantage of device 20 is the ease of construction of the
antifertility delivery device by standard manufacturing techniques
into devices acceptable to the uterine cavity. A more important
advantage of the claimed intrauterine contraceptive device is to
provide devices having a reservoir containing a liquid carrier or a
mixture of liquid carriers permeable to the passage of an
anti-fertility agent and having limited solubility for an agent or
a mixture of agents; and, where the carrier simultaneously releases
drug and dissolves replacement drug to maintain a constant supply
of drug for release by the intrauterine contraceptive device. Thus,
the invention contributes to the art a sustained release
intrauterine drug delivery device.
Another important advantage of the invention resides in the
intrauterine contraceptive device's memory to effectively control
the rate of release of an antifertility agent from the device by
providing a zero order rate of agent release and also this memory
ability to act in concert with the device's memory to substantially
maintain the device's shape throughout the major portion of the
device's medical history. Another important advantage of the
intrauterine contraceptive devices of this invention is their
improved property for uniformly and continually releasing
anti-fertility steroid agents while simultaneously decreasing the
incidence of spontaneous expulsion and pregnancy.
The above advantages and objects are achieved by the unique
construction and operation of the intrauterine contraceptive device
and its ability to transfer anti-fertility agent to the recipient.
In construction, the device can be viewed as a single unit
constructed device comprising two structures acting in combination
for effective anti-fertility administration to a host. One
structure pertains to a wall comprising the device and formed of an
anti-fertility release rate controlling material permeable to the
passage of the agent and the other structure relates to a reservoir
comprising a liquid carrier phase formed of a material permeable to
the passage of an anti-fertility agent and having limited
solubility for the agent. The materials forming the wall and the
carrier phase comprising the device are chemically and structurally
different within a single device and the rate of anti-fertility
release through the wall is lower than the rate of passage in the
carrier phase.
These two structures, comprising the unit intrauterine
contraceptive device 20, operate to effectively transfer
anti-fertility agent from the device by first transferring the
agent from the carrier to the wall, and secondly, by transferring
the agent through the wall to a uterus. The transfer of agent
through the wall can occur by two different processes or transfer
mechanisms. These transfer processes are the diffusion of an agent
through a uniform material, and by diffusion of an agent through
the media present in the micropores of a material, as hereinafter
described. Thus, for example, an agent can be transferred from the
carrier to the wall and then through the wall by diffusion to the
recipient, or the agent can be transferred from the carrier to the
wall and then through the media in micropores of the wall by
diffusion to the recipient. With the contraceptive devices of this
invention, an anti-fertility agent can be transferred by using a
combination of these mechanisms for transferring the agent through
the wall. Thus, by fabricating devices having different kinds of
walls made from different materials, the device can provide for
transfer of an agent through the wall by either diffusion in a
substantially homogenous material or by diffusion through the media
in a microporous wall. The wall of the delivery device is made from
a material that has a lower agent release rate than the rate of
passage of the agent through the carrier phase to ensure that
release kinetics of the device are controlled by the release rate
of agent through the wall. Thus, by choosing the wall, a zero order
release of an anti-fertility agent or a time release pattern of an
agent to the body site can be achieved.
In the diffusion process, wall 23 is formed of an anti-fertility
agent release rate controlling material that is permeable to the
agent to permit passage of the agent by diffusion through the
material at predetermined rates. In this process, the agent
dissolves and equilibrates in the wall surface, and then diffuses
in the direction of lower chemical potential. At the second
boundary equilibrium is again established. When the boundary
conditions on both sides of the wall are maintained constant, a
steady state flux of the agent will be established which can be
described by Fick's First Law of Diffusion. The rate of passage of
the agent through the wall is generally dependent, in the case of
diffusion, on the solubility of the agent therein, as well as on
the thickness of the material. This means that selection of
appropriate materials for fabricating the wall will be dependent on
the particular agent to be used. By varying the composition and
thickness of the wall, the dosage rates per area of the device can
be controlled for this material acts to meter the diffusion of the
agent from the reservoir. In the devices of this invention, the
materials comprising the wall are chemically and/or structurally
different than the material comprising the carrier of the
reservoir. The carrier of the reservoir is permeable to the passage
of the agent, but the rate of diffusion or passage through the wall
is lower than the rate of diffusion or passage through the carrier,
so that the rate of passage of the agent through the wall is the
rate release controlling step for the device. Thus, through this
invention, devices of the same surface area, functioning by
diffusion, can give different dosages of the agent by varying the
characteristics of wall to give controlled administration of the
agent.
In the devices of the invention, when the wall is formed from a
release rate controlling microporous material that is permeable to
the agent, the agent transfer mechanism is by diffusion through a
medium contained in the micropores of the material at a controlled
and predetermined rate. That is, in this material, the rate of
passage or the rate of agent release through the wall is governed
by diffusion of the agent through a diffusive medium present in the
pores, microholes and cracks of the material forming the wall. The
diffusive medium, in one embodiment, is a liquid phase comprised of
a solution, a colloidal solution, a suspension, or a sol, and the
solution can be polar, semi-polar or non-polar. In these diffusive
mediums, the agent can have different degrees of solubility, such
as fully soluble, partially soluble and the like, to act in
cooperation with the material for achieving a controlled release
rate.
The diffusive medium can be added to the microporous material by
methods well known to the art, for example, by immersion of the
material in a bath containing the medium to let the medium
partially fill or fully saturate the micropores of the material.
Another method for charging the micropores with a diffusive medium
is to first add to the reservoir a diffusive medium, or a mixture
of diffusive media so that the medium can flow from within the
reservoir into the pores and remain therein to permit diffusion of
later added agent, but not its solubilizing limited carrier, to
pass therethrough. The media suitable for the immersion purpose are
those well known to the art such as water, glycerin, ethylene
glycol, propylene glycol, castor oil, olive oil, alcohols of two to
10 carbon atoms, halogentated hydrocarbons having two to 20 carbon
atoms, aldehydes, and ketones having four to 10 carbon atoms,
syrups and the like. Additionally, the medium can be emulsifying
and suspending agents such as methyl cellulose mixed with water,
mixtures of propylene glycol monostearate and oils, gum tragacanth
and water, assorted waxes and the like. Representative mediums are
set forth in Remington's Pharmaceutical Science, pages 246 to 269
and 1,338 to 1,380, 1970, published by Mack Publishing Company,
Easton, Pa.
In another embodiment, the medium can be added to the pores and
cracks of the material forming the wall by locating the wall in a
fluid environment, for example, by contacting the device with a
body tissue, for example, the mucous membranes of the uterus, that
can make available its intracellular and/or extra-cellular fluid
for subsequent transfer into the micropores of the wall for
functioning as a medium for the drug. In another embodiment, the
pores can be filled with plasticizer by immersing the wall in a
plasticizer solvent composition, and removing the solvent in vacuo
after the filling of the pores. Exemplary plasticizers suitable for
employment of the present purpose are the commercially available
plasticizers conventionally used for the manufacture of polymeric
materials such as diethyl adipate, di-isobutyl adipate, di-n-hexyl
adipate, di-isooctyl adipate, di-n-hexyl azelate,
di-2-ethylhexylazelate, ethylene glycol dibenzoate, acetyl
tri-n-butyl citrate, epoxidized soy bean oil, glycerol monoacetate,
diethylene glycol dipelargonate, propylene glycol diluarate,
isooctyl palmitate, tripehnyl phosphate and the like.
The materials comprising the wall are chemically and/or
structurally different than the materials comprising the carrier.
Both of the materials are permeable to the passage of the
anti-fertility agent but the rate of flow through the wall is lower
than the rate through the carrier. Thus, the rate of passage of the
agent through the wall is the rate release controlling step for the
device. Generally, for the practice of this invention, the ratio of
the agent release rate through the carrier of the reservoir to the
agent release rate through the wall should be from 100:1 to 2:1 and
preferably from 10:1 to 2:1. Of course, the invention is not
limited to these release rates as the invention comprises lower or
higher release rates from the carrier and lower and higher rates
through the wall with the release rate of the wall lower than the
release rate of the carrier. Thus, the invention provides that
devices of the same surface area, activated by diffusion, can give
different dosages of a drug by varying the characteristics of the
wall material to give controlled administration of an
anti-fertility agent; Encyclopedia of Polymer Science and
Technology, Vol. 9, pages 794 to 807, 1968.
For either of the above discussed mechanisms, diffusion through a
homogenous material, or diffusion through a medium present in the
micropores and cracks of a material, the transfer or rate of
release of the anti-fertility agent through the wall is at a lower
rate than the rate of release of the agent from the carrier of the
reservoir for administration to the receptor site. Thus, the
passage of the agent through the wall is the release rate
controlling step for the agent delivery system. In addition,
because the reservoir serves to transfer anti-fertility molecules
to all areas of the wall, the wall of the delivery device housing
the reservoir remains substantially at the thermodynamic activity
corresponding to that of the agent until substantially all of the
agent has been released from the reservoir. Ordinarily, one would
expect migration of anti-fertility agent from the reservoir to
cease when sufficient agent has entered the wall to establish an
equilibrium; however, when the delivery device is in situ,
molecules are continuously removed from the outer surface of the
wall. For optimum results, the rate of release of the agent through
the wall should be less than the rate of clearance of migrated
agent from the external surface of the device. This ensures that
the agent administration rate is dependent on the rate of release
of the agent through the wall which can be controlled, rather than
upon clearance of the agent from the device in vivo, which can
vary. Thus, in contrast to previously proposed intrauterine
contraceptive delivery devices, the rate of release of the agent
from the device of the invention can remain essentially constant
until the intrauterine contraceptive device has substantially
completed its useful function.
The term "reservoir" as used in the specification and the
accompanying claims generally refers to a "carrier" or to a "medium
containing the anti-fertility agent," that constantly bathes the
inner surface of the release rate controlling wall and supplies
agent thereto. That is, the reservoir is comprised of a carrier
material containing dissolved agent, and/or undissolved agent,
and/or a mixture of both, and it is a material that is permeable to
the passage of the agent as by diffusion or convection. The carrier
medium used for the purpose of the invention is a liquid, and it
can be inorganic or organic, and of naturally occurring or
synthetic origin. Examples of carries comprised within the terms
liquid are, for example, solutions, immiscible liquids,
suspensions, dispersions, liquid pre-cured polymers, liquid
polymers, liquid plasticizers, liquid thixotropic agents, polar
solvents, semipolar solvents, nonpolar solvents, liquid-like
mediums, mixturs thereof, and the like. Further, for the purpose of
this invention, the terms liquid and the examples thereof are
deemed as functional equivalents and they can be generically termed
"liquid carriers."
The carrier medium comprising the reservoir, also has in addition
to the properties described supra, limited solubility for the
contained anti-fertility agent or for a mixture of agents. By
"limited solubility" is meant that the agent is soluble in given
amounts in the carrier, that is, it comprises varying concentration
of the agent dissolved in the carrier. Essentially, there is also
an excess amount of undissolved drug present in the carrier. These
varying limited solubility concentrations include solubilities such
as, soluble, sparingly soluble, slightly soluble, very slightly
soluble, and almost practically insoluble. Generally, on a weight
basis at 25.degree.C, the amount of the agent dissolved in a
carrier that is termed a soluble carrier is about 1 part of agent
to about 10 to 25 parts of carrier, the amount of agent dissolved
in a carrier that is sparingly soluble for the agent is 1 part of
agent to about 25 to 100 parts of carrier, from 100 to 1,000 parts
of carrier for 1 part of agent when the agent is slightly soluble
in the carrier, from 1,000 to 10,000 parts of carrier for 1 part of
agent when the agent is very slightly soluble in the carrier, and
from 10,000 to 15,000 parts of carrier for 1 part of agent in a
carrier that is almost practically insoluble for the drug. Hence,
the term limited solubility comprises a range of solubility of the
agent in a carrier of 1 part of agent to about 10 to 15,000 parts
of carrier on a weight basis at 25.degree.C. The above ranges are
set forth to aid in defining the invention, and they should not be
considered as limiting as other ranges at higher or lower
temperatures are embraced within the above presentation are also
included herein. The amount of undissolved antifertility agent
incorporated in the reservoir will vary depending on the type of
materials and design of the device, the particular agent, the
length of time the device is used, and the rate of release of
desired agent from the reservoir. That is, there is no critical
upper limit on the amount of undissolved agent incorporated in the
reservoir, since, it serves as a reserve source of agent for
replacing released agent by dissolving in the carrier to make the
agent continually available from the carrier to the wall during the
history of the device, or until the device is no longer used. The
lower limit will depend on the activity of the particular agent and
the time span of its release from the device. Generally, the amount
of undissolved drug initially present in the reservoir will range
from about 90 percent by weight to about 99.9 percent by weight, of
the total amount of agent present in the reservoir.
The materials suitable for fabricating the wall of the intrauterine
device are generally those materials capable of forming walls, with
or without micropores, through which the agent can pass at a
controlled rate of release by diffusion. Such materials are
referred to in this specification and the appended claims as
"release rate controlling materials." Suitable materials for
forming the wall are naturally occurring or synthetic materials,
preferably materials that are biologically compatible with body
fluids, and uterine tissues, and essentially insoluble in body
fluids with which the device will come in contact. The use of
rapidly dissolving materials or materials highly soluble in natural
body fluids is to be avoided since dissolution of the wall of the
device would affect the constancy of the drug release, as well as
the capability of the system to remain in place for certain uses
for prolonged periods of time.
Exemplary naturally occurring or synthetic materials suitable for
fabricating the wall are release rate controlling materials such as
poly(methylmethracrylate), poly(butylmethacrylate), plasticized
poly(vinylchloride), plasticized nylon, plasticized soft nylon,
plasticized poly(ethylene terephthalate), natural rubber,
poly(isoprene), poly(isobutylene), poly(butadiene), poly(ethylene),
poly(tetrafluoroethylene), poly(vinylidene chloride),
poly(acrylonitrile), cross-linked poly(vinylpyrrolidone),
poly(trifluorochloroethylene), blends of poly(ethylene) and
ethylene vinyl acetate copolymer, poly(4,4'-isopropylidene
diphenylene carbonate), and the like. Also, by way of non-limiting
example, copolymers such as ethylene-vinylacetate, vinylidene
chloride acrylonitrile, vinyl chloride diethyl fumarate and the
like. Examples of other materials include silicone rubbers,
expecially the medical grade poly(dimethylsiloxanes), and
siliconecarbonate copolymers; modified insoluble collagen,
cross-linked insoluble poly(vinylalcohol), cross-linked partially
hydrolyzed insoluble poly(vinylacetate), and surface treated
silicone rubbers as described in U.S. Pat. No. 3,350,216. Other
polymeric membranes that are biologically compatible and do not
adversely affect the drugs can be used.
Additionally, other materials permeable to the passage of the
anti-fertility agent that are suitable for the present purpose
include copolymers such as acrylonitrile dithioglycidol,
acrylonitrile ethylene oxide, poly(vinyl butyral) comprised of 11
to 45 percent free hydroxyls, anisotropic permeable microporous
membranes of ionically associated polyelectrolytes, the microporous
polymers formed by the coprecipitation of a polycation and a
polyanion as described in U.S. Pat. Nos. 3,276,589; 3,541,005;
3,541,006; 3,546,142; and the like; treated aliphatic polyamide
membranes as in U.S. Pat. Nos. 2,071,253; 2,966,700; 2,999,296; and
the like; vinylidene chloride vinyl chloride copolymer 40/60 and
10/90; vinyl chloride acrylonitrile copolymer 80/20, 75/25, 50/50
and the like; vinylidene chloride acrylonitrile copolymer 60/40 and
12/88; water insoluble natural gums, and the like. Also, materials
such as regenerated cellulose diacetate, cellulose triacetate,
poly(urethanes), poly(arylenes), poly(carbonates) and the like.
Materials having a pore size of several hundredth microns or
larger, or down to several angstroms or smaller. For example, the
wall can comprise regenerated insoluble, nonerodible cellulose,
poly(electrolytes) with a pore size of 7 to 50A, epoxy resins,
poly(olefins), poly(vinylchlorides) with a pore size of about 50A
or less to 150 microns or larger as conventionally made by leaching
out incorporated salts, soap micelles, starch or the like materials
to give a microporous membrane. Also, the materials that can be
used include these materials having homogenous properties and
microporous properties, such as cross-linked gelatinous membranes;
and the like.
The carrier used to form the reservoir containing the
anti-fertility agent is comprised of materials of natrually
occurring or synthetic origin, of the inorganic or organic types
that do not adversely affect the agent, or the mixture of agents
contained therein and which are permeable to the passage of the
agent. Generally, the carrier used does not substantially diffuse
from the reservoir, but if the carrier does diffuse from the
reservoir, for example if the carrier is an aqueous medium, it
would be replaced by a corresponding amount of medium diffusing
inward from the exterior of the device when the device is
positioned in an aqueous type environment. Representative liquid
carriers include ethylene glycol, diethylene glycol, triethylene
glycol, propylene glycol, dipropylene glycol, thiodiethylene
glycol, ethylene glycol monomethyl ether, ethylene glycol
mono-n-butyl ether, ethylene glycol diethyl ether, propylene glycol
mono-propyl ether, liquid polyethylene glycols having a molecular
weight of 200, 300, 400 and 600, 1,3-butylene glycol; solvent
system like ethyl acetate-ethyl alcohol-water 10:83:7; isobutyl
acetate-isobutyl alcohol-water 24:46:30; mixed binary liquid
systems such as methanol:water, ethyl alcohol:water, n-amyl
alcohol:ethyl acetate; mixed tertiary liquid systems such as
n-butyl acetate-butyl alcohol-water 27:27:46; esters such as liquid
methyl propionate, methyl isobutyrate, butyl stearate, dibutyl
fumerate; fats and oils of plant, animal and marine origin such as
almond oil, babassu oil, corn oil, eucalyptus oil, cottonseed oil,
olive oil, palm oil, peanut oil, rapeseed oil, soybean oil, tung
oil, whale oil, herring oil; saturated, unsaturated, straight and
branched chain liquid fatty acids such as caproic, lauric,
arachidic, oleic, linoleic, etc.; emulsions of the single phase and
two phase types such as oil in water; water in oil,
lipophilic-liquid-in-hydrophilic-liquid emulsions with or without
suspending ingredients; emulsions of castor oil in aqueous solution
of pigskin gelatin, emulsion of gum arabic, water and ethyl
cellulose, halogenated hydrocarbons having two to 10 carton atoms,
aldehydes and ketones having four to 10 carbon atoms, syrups, and
the like. Other carries include silicone oil, medical oil, sterile
water; saline, dextrose; dextrose in water or saline; condensation
products of castor oil and ethylene oxide combining about 30 to
about 35 moles of ethylene oxide per mole of castor oil; liquid
glyceryl triester of a lower molecular weight fatty acid; oils with
emulsifiers such as mono- or di-glyceride of a fatty acid, or a
phosphatide, e.g., lecithin, and the like; aqueous media in the
presence of a suspending agent for example, sodium
carboxymethylcellulose; sodium alginate; poly (vinylpyrrolidone);
and the like, alone, or with suitable dispensing agents such as
lecithin; polyoxyethylene stearate; and the like, carriers such as
acetamide; N,N-dimethyl acetamide, N-(2-hydroxyethyl) acetamide,
and the like. The carrier can also contain adjuvants such as
preserving, stabilizing, or wetting agents, and the like.
The rate of release of an agent through various materials can
easily be determined by those skilled in the art by standard
procedures. In this manner, particular materials used as the device
wall as the drug release rate controlling barrier for release of
drug from the reservoirs can be selected. Various techniques, such
as the transmission method, the sorption desorption method, and the
like, can be used as measurers of permeability. One technique that
has been found to be eminently well suited is to cast or hot press
a film of the material to a thickness in the range of 2 to 60 mils.
The film is used as a barrier between a rapidly stirred (e.g., 150
r.p.m.) saturated solution of the drug and a rapidly stirred
solvent bath, both maintained at constant temperature (typically
37.degree.C). Samples are periodically withdrawn from the solvent
bath and analyzed for drug concentration. By plotting the agent's
concentration in the solvent bath versus time, the permeability
constant P of the material is determined by the Fick's First Law of
Diffusion.
Slope of plot = (Q.sub.1 - Q.sub.2)/(t.sub.1 - t.sub.2) = p
AC/h
wherein
Q.sub.1 = cumulative amount of drug in solvent in micrograms at
t.sub.1
Q.sub.2 = cumulative amount of drug in solvent in micrograms at
t.sub.2
t.sub.1 = elapsed time to first sample, i.e., Q.sub.1
t.sub.2 = elapsed time to second sample, i.e., Q.sub.2
a = area of membrane in cm.sup.2
C = initial concentration of drug
h = thickness of membrane in cm.
By determining the slope of the plot, i.e., Q.sub.1 - Q.sub.2
/t.sub.1 - t.sub.2 and solving the equation using the known or
measured values of A, C, and h, the permeability P constant in
cm.sup.2 /time of the material for a given drug is readily
determined.
Using the above technique, the permeability constant P of the
anti-fertility progesterone from isotonic solution through
different materials into isotonic solution at 37.degree.C was found
to be:
Permeability Constant Membrane (cm.sup.2 /hr)
______________________________________ Poly(dimethylsiloxane) 8.0
.times. 10.sup..sup.-2 Poly(ethylene) 4.7 .times. 10.sup..sup.-4
Ethylene vinyl acetate copolymer 9% vinyl acetate 3.8 .times.
10.sup..sup.-3 Silicone-polycarbonate copolymer, General Electric
Mem 213 12.6 .times. 10.sup..sup.-3
______________________________________
Using the above technique and data to design a device of the
invention to release the anti-fertility agent progesterone, one
would employ poly(ethylene) as the release rate controlling
material as the wall if a slow rate of release is desired, and the
cured poly(dimethylsiloxane) membrane as the wall if a faster rate
of release is desired. If a faster rate of release than the rate of
release through poly(ethylene) but slower than the rate of release
through poly-(dimethylsiloxane) is preferred for progesterone,
either the copolymer ethylene vinyl acetate or the silicone
polycarbonate can be used as the release rate controlling material.
The poly(ethylene), the poly(dimethylsiloxane), the ethylene vinyl
acetate copolymer and the siliconepolycarbonate copolymer are
commercially available products. The poly(dimethylsiloxane) used
above is commercially available Silastic 340 of the Dow Corning
Co., and the poly(ethylene) is low density with a metl index of
0.85. These examples and like examples can be used to determine the
rate of drug release through different drug release controlling
materials by easily ascertained standard techniques known to the
art as recorded in J. Pharm. Sci., Vol. 52, pages 1,145 to 1,149,
1963; ibid. Vol. 53, pages 798 to 802, 1964; ibid. Vol. 54, pages
1,459 to 1,464, 1965; ibid. Vol. 55, pages 840 to 843, and 1,224 to
1,239, 1966; Encyl. Polymer Sci. Technol., Vol. 5 and 9, pages 65
to 82 and 794 to 807, 1968; the references cited therein, and the
like.
The rate of solubilitzation, or the rate at which the
anti-fertility agent will go into solution is quantitaively
governed by physico-chemical principles. For an example, a particle
of an agent dispersed in a solvent is surrounded by a thin layer of
solvent having a finite thickness l in cm. This layer is considered
as an integral part of the agent and it is characteristically
referred to as the "stagnant layer." The stagnant layer remains a
part of the surface of the agent, moving wherever the agent moves.
Using Fick's First Law of Diffusion, the rate of solution is the
rate at which a dissolved agent diffuses through the stagnant layer
for supplying agent to the reservoir's inner wall. The driving
force behind the movement of the agent through the stagnant layer
is the difference in concentration of the agent, C.sub.1, in the
stagnant layer at the surface of the agent and the concentration
C.sub.2 on the farthest side of the stagnant layer. The difference
in concentration C.sub.1 - C.sub.2 determines the rate at which
agent is solubilized in the carrier. Hence, if the carrier on the
farthest side contains its optimum concentration because of a low
release by the agent release rate controlling wall, the rate of
solubilization of new agent will be low. Correspondingly, as agent
leaves the carrier, new agent is solubilized to establish a steady
state within the carrier.
The rate of diffusion of the anti-fertility agent in a solubilizing
limiting carrier is broadly determined by measuring the rate an
agent transfers from one chamber through a sintered glass filter of
known pore size and thickness into another chamber at atmospheric
pressure and room temperature about 25.degree.C, or body
temperature 37.5.degree.C, and calculating from the obtained data
the agent's transfer rate. The method is carried out by adding to a
first conical flask equipped with a ground glass stopper and a
stirring bar, a measured amount of carrier and simultaneously, the
agent in the same carrier is added to a second conical flask
similarly equipped while keeping the level of the carrier in the
two flasks the same. Next, the flasks are stirred, and samples
drawn at various time intervals for analysis. The measured rate of
agent transport through the sintered glass filter, and the
concentration difference of the agent in the two flasks is then
calculated. These procedures are known to the art in Proc. Roy.
Sci. London, Ser. A, Vol. 148, page 1,935; J. Pharm. Sci., Vol. 55,
pages 1,224 to 1,229, 1966; and references cited therein. The
diffusion coefficient of an agent can also be experimentally
determined by using the above apparatus and references, or similar
apparatus and procedures as described in Diffusion in Solids,
Liquids and Gases, by W. Jost, Chapter XI, pages 436 to 488, 1960,
Revised Edition, Academic Press Inc., New York.
Also, according to Fick's Law, the rate of an agent's solution is
directly proportional to the area of the agent, A in cm.sup.2, as
exposed to carrier and inversely proportional to the length of the
path through which the dissolved agent molecule must diffuse. Then,
the rate of solution of the agent is given by
R = DA/l (C.sub.1 - C.sub.2)
wherein R is the rate of solution, D is a proportionality constnat
called diffusion coefficient in cm.sup.2 /sec, and C.sub.1,
C.sub.2, and l are as previously defined. See Remington
Pharmaceutical Science, 14th Ed., pages 246 to 269, 1970, Mack
Publishing Company.
The solubility of the anti-fertility agent in the release rate
controlling material comprising the wall of a device broadly is
determined by preparing a saturated solution of a given
anti-fertility agent and ascertaining, by analysis, the amount
present in a definite area of the material. For example, the
solubility of the agent in the wall is determined by first
equilibrating the wall material with a measured saturated solution
of the agent at a known temperature and pressure, for example
37.degree.C and one atmosphere. Next, agent is desorbed from the
saturated wall material with a suitable solvent for the agent. The
resultant solution for the agent then is analyzed by standard
techniques such as ultraviolet, visible spectrophotometry,
refractive index, polarography, electrical conductivity and the
like, and calculating from the data the concentration, or
solubility of the agent in the material.
The solubility of an anti-fertility agent in a liquid carrier can
be determined by various, conventional known techniques. One
technique consists in preparing a solution, for example, a carrier
plus agent and ascertaining by analysis the amount of agent present
in a definite quantity of the carrier. A simple apparatus for this
purpose consists of a test tube of medium size fastened upright in
a water bath maintained at constant temperature and pressure, for
example, 37.5.degree.C and 1 atmosphere. The carrier and agent are
placed in the tube and stirred by means of a motor driven rotating
glass spiral. After a given period of stirring, a definite weight
of the carrier is analyzed and the stirring continued for an
additional period of time. If the analysis shows no increase of
dissolved substance after the second period of stirring, the
results are taken as the degree of solubility of the agent in the
carrier. Numerous other methods are available for the determination
of the degree of solubility of an agent in a liquid carrier.
Typical methods used for the measurement of solubility are chemical
analysis, measurement of density, refractive index, electrical
conductivity, and the like. Details of various methods for
determining solubilities are described in United States Public
Health Service Bulletin No. 67 of the Hygienic Laboratory;
Encyclopedia of Science and Technology, Vol. 12, pages 542 to 556,
1971 McGraw-Hill, Inc.; Encyclopaedic Dictionary of Physics, Vol.
6; pages 545 to 557, 1962, Pergamon Press, Inc.; and the like.
Using the procedures and formulas above described, one skilled in
the art can design an intrauterine contraceptive anti-fertility
dispensing device according to the invention by ascertaining the
properties of the wall and carrier forming material and then
fabricating the intrauterine contraceptive device by selecting a
carrier in which the agent has limited solubility and which is
permeable to the agent but at a higher rate than the permeability
of the wall. For example, by using the permeability coefficient,
which is determined by using the above procedures and formulas, and
which permeability coefficient is defined as the product of the
diffusion coefficient, D.sub.w, of the agent in the wall and a
distribution coefficient, K, which is a ratio of the solubility of
the agent in the wall to the solubility of the agent in the
saturated solution, the selection of materials for forming the wall
and the carrier can be made for making a device according to the
invention. For purposes of comparing the permeability of the wall
to that of the liquid carrier, it is convenient to define the
permeability as follows: P.sub.w = PC = D.sub.w S.sub.w wherein P,
C and D.sub.w have the meaning as above described and S.sub.w is
the solubility of the agent in the wall. The permeability of the
carrier to the agent can similarly be defined as P.sub.c = D.sub.c
S.sub.c wherein D.sub.c and S.sub.c are the diffusion coefficient
and the solubility of the agent in the liquid core carrier. The
solubility, S.sub.c, can be determined by cited methods. The
diffusion coefficients of the anti-fertility agent in liquid
carriers will be in the range of 10.sup..sup.-7 to 10.sup..sup.-5
cm.sup.2 /sec. The diffusion coefficient of the antifertility agent
in the wall will be in the range of 10.sup..sup.-10 to
10.sup..sup.-8 cm.sup.2 /sec. Thus, a selection of carrier
materials such that P.sub.c > than P.sub.w, preferably P.sub.c
.gtoreq. 5 P.sub.w, is ascertained for preparting an intrauterine
contraceptive anti-fertility delivery device. The symbols used
herein have then conventional meaning, for example, the symbol
">" means greater than and the symbol ".gtoreq." means greater
than or equal to.
In the specification and the accompanying claims, the phrase
"anti-fertility agent" and the term "agent" are used
interchangeably and they broadly include progestational substances
that have anti-fertility properties and estrogenic substances that
have anti-fertility properties. These substances can be of
naturally occurring or synthetic origin and they generally possess
a cyclopentanophenanthrene nucleus. The term progestational
substance as used herein embraces "progestogen" which term is used
in the pharmaceutically acceptable steroid art to generically
describe steroids possessing progestational activity, and the
former also includes "progestins," a term widely used for synthetic
steroids that have progestational effects. The active
anti-fertility progestational agents that can be used to produce
the desired effects in mammals, including humans, and primates,
include without limitations: pregn-4-ene-3,20-dione, also known are
progesterone; 19-nor-pregn-4-ene-3,20-dione;
17-hydroxy-19-nor-17.alpha.-pregn-5(10)-3n3-20-yn-3-one;
d1-11.alpha.-ethyl-17-ethinyl-17-.alpha.-hydroxygon-4-ene-3-one;
17ethinyl17-hydroxy-5(10)-estren-3-one;
17.alpha.-ethyinyl-19-norestosterone;
6-chloro-17-hydroxypregna-4,6-diene-3,20-dione;
17.alpha.-hydroxy-6.alpha.-methyl-17(-1-propynyl)androst-4-ene-3-one;
9.alpha.,10.alpha.-pregna-4,6-diene-3,20-dione;
17-hydroxy-17.alpha.-pregn-4-en-20-yne-3-one;
19-nor-17.alpha.-preg-4-3n-20-yen-3.alpha.,17-dial;
17-hydroxy-pregn-4-ene-3,20-dione; 17.alpha.-hydroxyprogesterone;
17-hydroxy-6.alpha.-methylpregn-4-ene-3,20-dione; mixtures thereof,
and the like.
The term estrogenic and estrogenic anti-fertility gents as used
herein also includes the compounds known as estrogens, and the
metabolic products thereof that possess anti-fertility properties
or are converted to active anti-fertility agents in the preselected
biological environment. Exemplary estrogenic compounds include
.alpha.-estradiol, .alpha.-estradiol 3-benzoate,
17-.alpha.-cyclopentanepropionate estradiol,
1,3,5(10)-estratriene-3,17.alpha.-diol dipropionate,
estra-1,3,5(10)-triene 3,17-.alpha.-diol valerate, estrone, ethinyl
estradiol, 17-ethinyl estradiol-3-methyl ether, 17-ethinyl
estradiol-3-cyclopentoether, estriol, mixtures thereof, and the
like.
Additionally, the above progestational and estrogenic agents can be
in the form of their pharmacologically accepted derivatives, such
as their hydroxy or keto groups can be in a derivative form for the
present purpose. The progestational or estrogenic derivative used
should easily convert to the parent agent upon its release from the
device by biological activities such as enzymatic transformation,
pH assisted hydrolysis in uteri, tissue and metabolism and the
like. The derivative can also be used to control the solubility of
the agent in the liquid core and to assist in metering the agent
from the device. Suitable derivatives include without limitation,
esters with pharmaceutically acceptable acids such as acetate,
glucuronate, benzoate, propionate, butyrate, valeroate, hexanoate,
heptanoate, maleate, citrate, succinate, tartrate, fumarate,
malate, ascorbate, sulphate, phosphate and the like; ethers such as
lower alkoxy-tetrahydropyran-yl, unsubstituted tetrahydropyran-yl,
silyl moieties, trifluoromethyloxy, cyclopentyl enol ethers and
other functional groups such as ureido, and the like.
The degree of solubility of various progestational and
anti-fertility agents in various liquid cores, is ascertained by
using the above techniques. Typical examples of solubilites are as
follows: 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione acetate
practically insoluble in water;
17.alpha.-hydroxy-6.alpha.-methyl-17-(1-propynyl)-androst-4-en3-3-one
slightly soluble in acetone;
9.alpha.,10.alpha.-pregna-4,6-diene-3,20-dione slightly soluble in
distilled water; 17-hydroxy-17.alpha.-pregn-4-en-20-yn-3-one
slightly soluble in alcohol and slightly soluble in vegetable oil,
19-nor-17.alpha.-pregn-4-en-20-yne-3.alpha.-17-dioldiacetate
sparingly soluble in fixed oils,
17-hydroxy-6.alpha.-methylpregn-4-ene-3,20-dione acetate sparingly
soluble in methanol,
17-hydroxy-19-nor-17.alpha.-pregn-4-en-20-yn-3-one sparingly
soluble in vegetable oil, 17-.alpha.-estradiol sparingly soluble in
vegetable oil, ethinyl estradiol soluble in various vegetable oils,
and the like.
The amount of anti-fertility agent present in the reservoir,
whether dissolved, partially dissolved or undissolved is generally
non-limited and it is an amount equal to or larger than the amount
of an agent that on its release from the device is effective for
being about the agnet's anti-fertility effect. For example, the
amount of agent present in the reservoir of an intrauterine device
when the device is used for a predetermined period of time to
achieve an anti-fertility effect in a potential child-bearing woman
is for .DELTA..sup.4 -pregene-3,20-dione, progesterone, for a year
supply wherein a year is 400 days, and the rate of release from the
device is 25.mu.g/day is 10 mg in the reservoir, at the same rate
of release for 2 years a reservoir supply of 20 mg and for 3 years
30 mg. If the rate of release for the same progestational agent is
100 .mu.g/day and the length of the year is as before, the
reservoir concentration for 1 year is 40 mg, for 2 years 80 mg and
for 3 years 120 mg. The amount of progestational agent present in
the reservoir for 1 year, 2 year and 3 year device is 80 mg, 160 mg
and 240 mg respectively when the rate of release is 200 .mu.g/day.
The amount of estrogenic agent present in the reservoir will also
vary dependingon the size of the device and the capacity of its
reservoir. Generally, the reservoir will contain from 50 mg to 250
mg of estogenic agent for release for1 to 3 years or longer. For
these devices, the estrogenic anti-fertility agent is released from
the device at a rate of release of about 1 microgram to 100
micrograms per day, and the like. Of course, for shorter periods or
longer periods smaller amounts or larger amounts will be present in
the reservoir, and the amount will also vary relative to the degree
of activity of the progestational agent or the estrogenic agent, or
mixtures thereof, Generally the intrauterine contraceptive device
will contain from about 0.1 mg to 10 g of a progestational or
estrogenic agent for releasing it at a controlled rate of from
about 1 microgram to 300 micrograms of agent, or larger amounts per
day. Of course, devices containing different amounts of agent for
use for different time periods such as week, month, and the like,
are also readily made by the invention.
The reservoir comprising the liquid core and the agent is
fabricated by standard techniques. For example, in one embodiment
the liquid can be mixed with the anti-fertility agent in solid,
semi-solid or liquid forms at the time of mixing, and then
distributed therethrough by conventional methods, such as
ballmilling, calendering, stirring, shaking, rollmilling, and the
like. The liquid core anti-fertility agent composition is then
charged into the lumen of the device formed from release rate
controlling material and sealed therein. In another embodiment the
liquid core and the agent are mixed and then charged into a highly
permeable tube that is positioned within a drug release rate
controlling material. The wall material forming the anti-fertility
dispensing device and having the reservoir contained therein can be
formed to a given intrauterine contraceptive device's design by
molding, casting, pressing, extruding, drawing, rotational molding,
compression and transfer molding, or like standard processes of
manufacture. Also, depending on the material used to form the wall,
a monomers may be cured at this stage of manufacture. The ability
to design and shape the wall into devices of highly reproducible
shapes of controlled composition, readily results in fabrication of
intrauterine contraceptive device with controlled characteristics
and thus overcome a significant disadvantage of previously
described devices.
The intrauterine device can be fabricated as an integral unit
device by using the above, art known techniques. For example, the
device can be fabricated by blow molding into a parison whose
shaped cavity is the predesigned device, by extrusion molding,
casting, vacuum forming and the like. The device can also be
manufactured from two members suitably joined into a unit article
of manufacture by conventional techniques. For example, two members
positioned in assembly relation can be joined by dielectric
heating, radiant heating, or hot iron pressed heating and the like.
Also, two members can be joined by solvent welding employing a
mixture of solvent and polymer that is painted onto the joinable
areas and then the solvent evaporated, such as using a sealing
composition of methylene chloride containing 10 to 15 percent
ethylene vinyl acetate copolymers for joining like copolymer parts.
Additionally, members can be united by friction welding, ultrasonic
welding, insert injection molding, radiant heat and the like. Other
standard procedures, as described in Modern Plastics Encyclopedia,
Vol. 46, pages 62 to 70, 1969, well known to those skilled in the
art can be used to fabricate the drug delivery device of the
invention.
The following examples are merely illustrative of the present
invention and they should not be considered as limiting the scope
of the invention in any way, as these examples and other
equivalents thereof will become apparent tho those versed in the
art in the light of the present disclosure, drawings and the
accompanying claims.
EXAMPLE 1
An intrauterine anti-fertility dispensing device shaped like a T
having a reservoir comprised of a liquid core containing an
anti-fertility agent and permeable to the passage of the agent is
surrounded by a wall of a biologically acceptable anti-fertility
release rate controlling material permeable to the agent is
manufactured as follows: first, a liquid core consisting of 11
percent by weight of progesterone and 10 percent by weight of
barium sulfate in a mixture of 3 parts by weight of Dow-Corning
Silastic 382 elastomer resin liquid silicone oil and 1 part by
weight of Dow-Corning 360 medical grade fluid silicone oil is
thoroughly mixed in a standard laboratory v-blender to yield a
liquid core. The progesterone is sparingly soluble in the liquid
core. Next, an aliquot of the liquid core is injected into a
section of medical grade polyethylene tubing having an outside
diameter of 0.110 inches and an inside diameter of 0.070 inches and
the ends of the tubing heat sealed with a standard, hand heater.
The filled polyethylene tubing, about 3.6 cm in length is placed
into the lower half of a two piece T shaped mold in the depending
position of the mold's T. The top cross position of the mold's T is
previously charged with a 3.2 cm section of unfilled polyethylene
tubing having its ends previously heat sealed as described above.
Next, the upper half of the mold is placed threon and the mold
electrically heated to yield a T shaped anti-fertility device. The
device will release 15 micrograms of progesterone per day for
controlling fertility in an adult woman.
EXAMPLE 2
An intrauterine contraceptive anti-fertility administrating device
having the shape of a T with the wall of the T formed of a release
rate controlling material permeable to the passage of the agent and
surrounding a reservoir comprised of a liquid core containing the
agent is fabricated as follows: first, a section of medical grade
polyethylene tubing is washed with methanol for at least 72 hours,
rinsed with water, and then air dried. Next, a core material is
prepared as a homogenous mixture consisting of 11 percent by weight
of progesterone, N.F., 10 percent by weight of barium sulfate,
U.S.P., 19 percent by weight of Dow-Corning 360 Medical Fluid, a
water white polydimethylsiloxane fluid, and 59.25 percent by weight
of Dow-Corning Silastic 382 Medical Grade Elastomer, a fluid
polysiloxane polymer by thoroughly blending the ingredients for
about 10 to 12 hours. Next, the bore material is injected into two
precut lengths of the washed polyethylene and the devices formed by
placing the filled polyethylene length in a T molh having a female
portion containing a cavity which corresponds to the shape of the
device. When the mold is closed, the male portion of the mold forms
the top of the device. The clearance between the male member and
the female member is sufficiently small, so that closing the molds
and applying heat thereto forms the predetermined device by heat
joining the two sections at their point of contact. The device
contains 20 mg of progesterone for releasing it at a rate of 25
.mu.g/day for 2 years.
EXAMPLE 3
An intrauterine contraceptive anti-fertility device comprised of a
release rate controlling wall permeable to the passage of a
therapeutically acceptable anti-fertility agent and surrounding a
reservoir comprised of an agent and a liquid core for releasing the
agent is manufactured as follows: a liquid carrier is prepared by
intimately contacting and blending in a rotating mill 25 percent by
weight of progesterone and 10 percent by weight of barium sulfate
with 65 percent by weight of Dow-Corning 360 medical fluid silicone
oil to yield a liquid carrier. The liquid carrier is permeable to
the progesterone and the progesterone is sparingly soluble therein.
Next, the liquid carrier is injected into a length of ethylene
vinyl acetate copolymer tubing comprised of 9 percent by weight of
vinyl acetate having an inside diameter of 0.090 inches and an
outside diameter of 0.110 inches. The ends of tubing are heat
sealed and the tubing is then formed into a T device by joining it
to a like length of ethylene vinyl acetate copolymer tubing in a
heated mold. The device releases 65 to 70 micrograms of
progesterone per day.
EXAMPLE 4
Following the procedure set forth in Example 1, except that the
members of the T are joined at their perpendicular point of contact
by heating with a heating iron, a device having a reservoir
comprised of a liquid core containing aqueous poly(vinyl
pyrrolidone) and progesterone housed within a poly(ethylene)
barrier is prepared by generally following the example. The
progesterone is sparingly soluble in the aqueous poly-(vinyl
pyrrolidone) and both the poly(vinyl pyrrolidone) and the
poly(ethylene) are permeable to the passage of the steroid, but the
rate of passage is lower for the poly(ethylene). The poly(ethylene)
barrier has a thickness of 50 microns, and it releases about 33
micrograms per square centimeter per day of progesterone to a
progesterone receptor site.
EXAMPLE 5
An intrauterine contraceptive anti-fertility drug delivery device
shaped like a T and comprised of a liquid carrier of aqueous
carboxymethylcellulose containing progesterone laminated between
two sections of poly(ethylene) half tubes, hermetically heat sealed
at their end and contacting surfaces and where the cross member and
the depending member meet in T fashion, is generally prepared
according to the procedure of Example 1. The poly(ethylene) had a
thickness of 50 microns. The steroid is sparingly soluble in the
carrier, and both the carrier and the poly(ethylene) are permeable
to the passage of the steroid, with the rate of passage for the
former higher than the rate of passage of the latter. The use of
this device results in a controlled rate of release of progesterone
over a prolonged period of about 1 year at the rate of 33
micrograms per sq. cm. per day.
EXAMPLE 6
Repeating the general procedure as described in Example 1, an
intrauterine contraceptive device is made of a permeable, release
rate controlling wall of ethylene vinylacetate copolymer of 91
percent ethylene and 9 percent vinyl acetate of about 50 microns
thick and surrounding a reservoir comprised of progesterone in
water is made by substituting the ingredients of this example for
those set forth above. A drug delivery device made according to
this procedure will release about 230 micrograms of progesterone
per sq. cm. per day.
EXAMPLE 7
Repeating the general procedures as described in Examples 1 through
6, an intrauterine contraceptive device is made of a permeable,
release rate controlling wall of a biologically acceptable material
and surrounds a reservoir comprised of an estrogenic agent admixed
in a liquid core. The device is substantially in the shape of a T
and will release the agent at a controlled rate for a prolonged
period of time.
In Table 1, immediately below, the rate of release obtained with an
intrauterine contraceptive device shaped like a T and having a wall
of ethylene vinyl acetate copolymer with 9 percent vinyl acetate
and a reservoir comprising liquid core of silicone oil and
progesterone is measured and compared with the rate of release
obtained for an intrauterine device shaped like a "T" with the
upright of the T made of cured silicone tubing filled within its
lumen with dry, powdered progesterone. The release rates for these
delivery devices is determined by agitating each device in separate
isotonic saline baths at 37.degree.C, and determining the optical
absorbance of the test saline solution at 248 nm using 10 cm cells
in a double-beam ultraviolet spectrophotometer with isotonic saline
in the reference cell. The concentration of progesterone in the
test solution is determined by comparing the absorbance value at
248 nm with the values obtained at 248 nm for various known
progesterone concentrations in isotonic saline. The results are
expressed in micrograms per day for devices of like surfaces. In
the table, the release rate for the liquid core T is the measured
rate for 10 devices. Two identical sets of 10 devices are presented
in the table.
TABLE 1 ______________________________________ Release Rates of
Intrauterine Devices Release Rate .mu.g/day Release Rate .mu.g/day
Time "T" device - liquid core "T" device - dry Days Range Run 1 Run
2 ______________________________________ Start 687 727 1 74 - 92
485 497 2 415 415 3 80 - 88 330 320 4 71 - 76 7 68 - 74 8 68 - 76 9
215 134 10 69 - 72 11 70 - 77 14 66 - 71 15 68 - 74 173 121 18 67 -
71 21 193 150 23 66 - 71 30 64 - 68 38 62 - 68 40 63 - 70
______________________________________
It will be understood to those versed in the art in the light of
the present specification, drawings and accompanying claims that
the invention makes available to the art both a novel and useful
intrauterine contraceptive anti-fertility delivery device for
administering an anti-fertility agent to produce the desired
effect; and, that the rate of release from the device can be
controlled to produce these effects, while simultaneously lessening
or overcoming the undesirable effects frequently associated with
the prior art methods. It will be further understood to those
versed in the art that different embodiments of this invention can
be made without departing from the spirit and the scope of the
invention. Accordingly, it is to be understood that the invention
is not to be construed as limited, but it embraces all equivalents
inherent herein.
* * * * *