Note: Descriptions are shown in the official language in which they were submitted.
7~7
BACKG~OUND OF THE INVENTION
.
The present invention encompasses devices which are
used in the vagina to deliver spermicidal surfactants. By
virtue of their unique construct:ion and shape, the devices
remain in position, even during intercourse, so that delivery
of the spermidical surfactant is not interrupted.
The devices of this invention are designed for use
in the vagina, can be inserted by the user, and do not require
insertion by a physician as, for example, in the case of intra-
uterine contraceptive devices. The devices are designed to
remain in the vagina during the time between menstrual periods
to provide desirable, prolonged release of a spermicidal sur-
factant, and their construction and shape facilitate retention
therein. An effective between-period contraceptive device is
thereby provided.
SUMMARY OF THE INVENTION
The present invention combines the desirable features
of devices which provided prolonged release of medicaments,
e.g., spermicides, or the like, into the vaginal area with the
added advantages that the unique construction and shape of
the present devices allows them to be worn comfortably in the
vagina for periods of several weeks and to remain substantially
undisturbed within the vaginal cavity during sexual inter-
course.
Most importantly, the construction of the present
devices allows them to be positioned in the vagina in such a
way that maximum contraceptive protection is secured. As can
be seen by reference to the Figures herein, the highly pre-
ferred devices of the present type for use within the vaginal
cavity are characterized by a dome-shaped construction and
~, - 2 -
o~
comprise one or more containers, said containers having walls
which allow passage of spermicidal surfactant monomers from
within the containers into the vagina. The configuration of
the devices allows them to be placed in the closest possible
proximity to the cervical os, and this feature contributes
importantly to their contraceptive efficacy. Indeed, the
highly preferred dome-shaped devices herein substantially
surround the "cap" the cervical os.
The contraceptive devices of this invention make use
of the association colloid nature of solutions of certain
spermicidal surfactants to provide a reservoir from which
spermicide is released in a controlled manner through the
semi-permeable membrane which comprises at least a portion of
the wall of the container. Surfactant micelles, as is, cannot
diffuse through the semi-permeable membrane; they must first
dissociate, at or remote from the membrane, to individual
surfactant molecules which then dissolve in the membrane
material and diffuse therethrough to its outer surface, where-
upon the surfactant monomers are free to dissolve in the
surrounding vaginal fluid to provide their contraceptive effect.
Since the predominant driving force for diffusion is the
concentration difference between unassociated li.e., monomeric)
surfactant molecules in the solution inside and outside the
contraceptive device, the rate of transport will slow drastic-
ally when the exterior surfactant monomer concentration ap-
proaches that on the interior of the device, thus producing
a desirable controlled release behavior of the surfactant
through the membrane. In the present devices, the bulk of the
surfactant remains in micellar form, where it resides in
reserve to provide a source of monomers over a long period of
time, thereby delivering continuous contraceptive protection
to the user for a time period of 20-30 days.
~ . ~
As will be seen from the following disclosure, the
present invention encompasses contraceptiye devices which are
especially adapted for use within the vaginal cavity at a
position posterior to the introitus and in close proximity
to the cervical os, characterized by: vaginal retaining means
having affixed thereto one or more containers having walls,
at least a portion of the walls comprising a substantially
non-porous, semi-permeable membrane, said containers holding
a reservoir of spermicide comprising an aqueous solution of
a micelle-forming spermicidal surfactant compound at a con-
centration at or above the critical micelle concentration of
said surfactant compound, said membrane-walled containers
being maintained in position in the device by positioning
means, thereby providing a transport surface on the face of
the device~ Preferred devices are those wherein the transport
surface extends substantially across the face of the device.
Domed or "cup-shaped" devices which can be positioned to sub-
stantially cap the cervical os are an especially preferred
embodiment of the invention.
Devices according to this invention wherein the con-
tainer walls which face the cervical os comprise the substanti-
ally non-porous, semi-permeable membrane transport surface
are preferred, inasmuch as the spermicidal surfactant is there-
by delivered directly to its prime situs of action. Moreover,
delivery of excess surfactant to the general vaginal cavity is
thereby avoided. However, devices wherein all container walls
comprise the substantially non-porous, semi-permeable membrane
transport surEace are also useful and are encompassed by this
lnvent lon .
The most highly preferred embodiment of the present
eontraeeptive deviees eomprises: a double-walled, dome-shaped
dise suitable for eapping the eervieal os, at least one wall
-- 4
~ . . .
~,. .
- ,
of said disc comprising a non-porous, semi-permeable membrane
having a thickness in -the range of from about 0.1 mm to about
~ 0.4 mm, said walls being sealed together to provide containers,
said containers holding an aqueous solution comprising from
about 10% to about 50~ by weight of C1oEO5 or C10~O6. Such
devices wherein the walls are sealed together around their
peripheral edges to provide a container with a dimensionally-
stable rim as the retaining means, and especially those
devices wherein only the transport surface facing the cervical
os comprises the semi-permeable membrane, are especially useful
and preferred herein.
Another preferred embodiment comprises a double-
walled, dome-shaped device wherein the outer dome-shaped wall
comprises a dimensionally-stable, non-permeable retaining
means and wherein the inner wall (facing the cervical os)
comprises the non-porous, semi-permeable membrane transport
surface.
This invention also provides a method for achieving
contraception in the vagina, comprising: inserting within
the vaginal cavity at a position posterior to the introitus
and in close proximity to the cervical os a device characterized
by: vaginal retaining means having affixed thereto one or
more containers having walls, at least a portion of the walls
comprising a substantially non-porous, semi-permeable membrane,
said containers holding a reservoir of spermicide comprising
an aqueous so:Lution of a micelle-forming spermicidal surfact-
ant compound at a concentration at or above the critical
micelle concentration of said surfactant compound, said mem-
brane-walled containers being maintained in position in the
device by pos:itioning means, thereby providing a transport
surface on the device, and placing the device so that the
~r
transport surface substantially covers or "blocks" the cervical
os, whereby surfactant monomers diffuse from the device
through the membrane transport surface and substantially bathe
the cervical os with surfactant in the vaginal fluids to pro-
vide a spermicidal effect on sperm coming in contact there-
with.
The devices herein are prepared from components
which are described in detail hereinafter.
DESCRIPTION OF THE DRAWINGS
Figure 1 is an exploded view of the highly preferred
dome-shaped device of the present type. The device comprises
two dome-shaped discs which are assembled into a "double-domed"
structure.
As seen from Figure 1, the first, or inner, disc
comprises a membrane 11 which is permeable to surfactant
monomers but which is not permeable to the passage of sur-
factant micelles therethrough, and a seal rim 10. Conveniently,
seal rim 10 is fashioned from the same material used to pre-
pare semi-permeable membrane 11 during the molding process.
The second, or outer, dome-shaped half of the
preferred device comprises a toxicologically-acceptable mate-
rial 13 and a seal rim 12. The toxicologically-acceptable
material used to fashion the dome on this portion of the
article need not be a semi-permeable membrane material.
Figure 1 depicts the halves of the device in proper
juxtaposition for assembling. To assemble the device, the seal
rims can be heat-sealed or sealed by an adhesive, thereby
leading to the assembled device depicted in Figure 2.
Figure 3 is a section view of the assembled dome-
shaped device showing the relationship of the semipermeable
membrane 11, the outer dome material 13, seal rims 10 and 12
- 6 -
sealed with an adhesive 15. The container formed by joining
the two halves of the device is substantially filled with an
aqueous solu-tion of spermicidal surfactant 14.
In use, the dome-shaped device is inserted in-to the
vagina posterior to the introitus to substantially "cap" the
cervical os such that semi-permeable membrane 11 is in the
closest possible proximity to the os.
It will be appreciated that other configurations for
the present devices can be used, if desired, to provide vaginal
contraceptives. Devices of such alternate configurations are
also encompassed by this invention.
For example, the devices herein can be in the con-
figuration of a flat, rather than dome-shaped, disc. The
walls of the flattened disc are assembled to provide a con-
tainer for the surfactant solution. At least one wall of
the container is made from a membrane material of the type
disclosed hereinafter which will allow passage of surfactant
monomers therethrough, but which substantially retains surfact-
ant micelles and water within the container. In use, such
a device is positioned with the semi-permeable membrane
facing the cervical os, whereby the os is substantially
bathed in spermicidal surfactant as monomers are released
through the membrane.
In another, alternate structure, flat or dome-shaped
devices are compartmentalized into muliple containers, the
walls of said containers comprising the semi-permeable membrane
and positioned so that they face the cervical os. Such
devices having a plurality of containers offer the advantage
that, in case of accidental rupture of some con-tainers in use,
other containers remain intact to continue delivering sperm-
iàidal surfactant monomers to the area surrounding the cerival
os .
~ ~,
.~ ~
As shown in the Figures, seal rim 12 depicted in the
preferred, double~domed disc structure provides a positioning
means which serves to join the halves of the device and to
maintain the membranous container in the proper position to
provide a transport surface for the spermicidal surfactant.
Moreover, the seal rim is thicker and more resilient than
other parts of the device, and thus also provides the vaginal
retaining means which holds the device in place with the
vagina during use. It will be appreciated that vaginal retain-
ing means other than a seal rim can be employed for these
purposes. For example, a disc-shaped device of the type
depicted in the Figures can be prepared using a relatively
thick, pliable, yet resilient and comfortable outer dome posi-
tioning means with a semi-permeable membrane inner dome af-
fixed thereto. The resilience of the outer dome also provides
the retaining means. Thus, this single structural member
both holds the inner domed membrane in the device, and provides
the means whereby the device, itself, is retained in the
vagina.
Other alternate configurations for the vaginal retain-
ing means in disc-shaped devices include, for example, tri-
lobal discs and multi-lobal discs suc~h as hexa-lobal and octa-
lobal discs. In such devices, the rim or edge around their
periphery is characterized by a plurality of soft, comfortable,
yet resilient lobes which promote retention of the device in
the vagina.
ETAILED DESCRIPTION OF THE INVENTION
By the present invention, devices which deliver
metered doses of spermicidal surfactants to the vaginal cavity
are constructed to provide a shape or configuration whereby
said devices can remain in the vagina during intercourse.
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G ~ ~
The configuration of the devices herein is designed
to provide a semi-permeable membrane as a transport surface
for the surfactant monomers, said transport surface extending
across the entire surface of the cervix (i.e., substantially
covering the o~cal os). This elminates problems occasioned
by small lateral movements of the device associated with
muscular contractions/exertions of the user during wear.
Most importantly, by providing a transport surface which is
in the closest possible proximity to the cervix, the surfact-
ant has the shortest possible path to the cervical os. Since
conception is associated with transmittal of sperm into the
os, it will be appreciated that, by delivering surfacant mono-
mers in the most efficient manner to this point in the vagina,
the most efficient and effective contraceptive protection is
provided.
The configuration of the present devices allows
them to be positioned in close proximity to the cervical os
(i.e., actually touching or within a distanc~e of ca. 1 mm
to 10 mm) or, in the case of the preferred dome-shaped device,
substantially enveloping and capping the cerv cal os. Thus,
the present devices deliver the spermicidal surfactants more
efficiently and effectively than the devices disclosed in
the following patents of Gougeon and Drobish: U.S. Patent
3,995,634 issued December 7, 1976; U.S. Patent 3,991,760,
issued November 16, 1976; and U.S. Patent 3,995,633, issued
December 7, 1976.
The desirability of providing metered dosage forms
of various biolQgically active or medicinal agents has long
been recognized. Metered dosages can be manifest either as
"controlled release" or "sustained release" of a given mate-
rial. The distinction between controlled release and sus-
tained or prolonged release has been recognized; see Cowsar,
in "Advances in Experimental Medicine and Biology", Vol. 49,
"Controlled Release of Biologically Active Agentsl!~ Ed.
Tanquary and Lacey, Plenum Press, New York 1974.
Briefly stated, con-trolled release devices of the
present type respond rapidly to changes such as dilution
effects in the environment external to the article, e.g., by
body fluid changes, whereas sustained release articles do not.
The net result is that devices based on the principle of
controlled release are capable of rapidly establishing an
effective level or concentration of a medicament or other
agent in a selected environment, and then substantially
shutting off release to maintain the concentration at that
level. In constrast, sustained release articles dispense
an agent at a constant rate and do not display the feedback
regulation of release that a controlled release article
displays.
It will be appreciated that devices operating by
the controlled release mechanism provide substantial advan-
tages over sustained release articles for certain uses. For
example, placement of a properly formulated controlled
release medicament system in an animal's body cavity in con-
tact with body fluids establishes and maintains an effective
concentration of the medicament in the fluids. The system
responds to dilution or depletion as additional fluids are
secreted, or the medicament is bound to tissue, absorbed,
etc., thereby automatically maintaining the concentration of
medicament at *he proper level.
As disclosed by Laughlin in German OLS 2,610,880,
open to inspection October 7, 1976, solutions of micelle-form-
ing surfactant compounds can be releasably enclosed in a
container comprising a microporous membrane. Articles thus
prepared are stable and do not suffer osmotic rupture when
-- 10 --
placed in body cavities in contact with body fluids. Rather,
the stable articles provide controlled release of the sur-
factant into the body fluids. The proper selection of mem-
brane and surfactant provides a means for achieving various
biological ef~ects, e.g., antim:icrobial activity, spermicidal
activity, and the like. Laughlin teaches the use of porous
membranes such as cellulose. However, cellulose is fragile
and is quite difficult to fashion into controlled release
devices.
By the present invention, it has been discovered that
various non-porous elastomers can be fashioned into membranes
which allow passage of spermicidal surfactant monomers there-
through in a controlled manner. Such membranes are not
fragile; accordingly, stable controlled release articles with
optimal shapes for providing vaginal contraceptive protection
are readily made therefrom.
Moreover, the membranes used in the present devices
are substantially impervious to liquid water. In use, the
monomers of spermicidal surfactant diffuse through the membrane
into the vagina (presumably by virtue of their solubility in
the membrane), whereas the surfactant micelles do not. Since
the membranes are non-porous and are substantially impervious
to bulk water and body fluids, they do not undesirably develop
an internal pressure in an aqueous environment.
In contrast, osmotic pressure causes some rigidity
in the devices of Laughlin, which can aid in their retention
in the vagina. However, development of internal hydrostatic
pressure due t:o osmotic effects can cause at least two dis-
advantages in the Laughlin devices: (1) this pressure stresses
the membrane structural components of the device making them
more prone to rupture under the influence of more external
force then they would be otherwise; and (2) this pressure
~`,
~ Ei7~7
precludes the use of products having relatively broad unsup-
ported membrane areas in the present vaginal contraceptive
application. Products so designed would undesirably inflate
to uncomfortable and potentially contraceptively ineffective
shapes. In any case, osmotic pressure is not, per se, the
force which moves surfactant out of either the Laughlin
devices or the devices disclosed herein. Rather, in both
cases, it is the trans-membrane chemical potential (i.e.,
substantially the surfactant monomer concentration) ~ifference
which causes release of spermicidal surfactant monomers from
the device. However, as noted above, Laughlin employs micro-
porous membranes, such as swollen cellulose, which comprise
microporous, water-filled channels through which the monomers
are transported. In contrast, the present devices are non-
porous membrane materials through which the surfactant mono-
mers migrate by first dissolving therein then diffusing there-
through.
Moreover, the devices herein do not operate by an
osmotic pressure mechanism and are thus entirely different
from that of art-disclosed, osmotically-actuated "pump"
devices for delivering drugs.
Highly preferred devices are those opera-ting by a
controlled release mechanism. However, devices operating by
a sustained release mechanism can also be constructed in the
manner disclosed herein so that they can be retained in the
vagina during intercourse. Accordingly, sustained release
devices of the unique construction and shape of the devices
herein are fully contemplated by this invention.
_ntainer
Broadly, the present devices comprise a container,
or multiple containers, said container being insoluble in
vagina fluids, in a total device ofthe configuration described
- 12 -
. . .
hereinabove. The container has the surfactant solution en-
closed therein. At least one portion of the container com-
prises a non~porous polymeric membrane which permits the
release of surfactant monomers into the vagina, but which
substantially prevents the transport of the larger surfactant
micelles. In short, the membrane is the transport surface
which selectively discriminates between passage of monomers
; and micelles.
Containers used in the present devices can be partly
made of any stable material such as glass, plastic, etc.,
which is not permeable, even to surfactant monomers. Of
course, the containers should be made from a material which is
inert to the surfactant solutions being used, as well as to
the vaginal tissues, but selection of inert container materials
is not a problem. At least some portion of the container used
in the present devices must comprise a non-microporous poly-
meric membrane which allows diffusion of the spermicidal
surfactant monomers therethrough and into the vaginal cavity.
For the reasons disclosed above, at least that wall of the
container which faces the cervical os comprises the controlled
release membrane. Alternatively, the entire device can be
made of the membrane material.
Preferred controlled release devices are those where-
in the container comprises a dome-shaped envelope of the con-
trolled release membrane.
The membranes used in the controlled release devices
are characterized by parameters which reflect their strength,
integrity and ability to pass surfactant monomers and to
retain surfactant micelles, as follows.
The membranes should be substantially water-insoluble
so that they maintain their strength and integrity when in
contact with body fluids.
- 13 -
Since the devices are to be used in contact with
body fluids and tissues, the membranes (and total container
and device) should be toxicologically acceptable. Moreover,
the membrane material will most preferably be immunologically
acceptable and will not be rejected by the body's natural
defense mechanisms nor have any untoward effect on the rate
of antibody formation, and the like.
The membrane must possess the ability to provide
metered release of the surfactant monomers in order to pro-
vide the prolonged contraceptive benefit of the article.
The membrane must be sufficiently strong, yet flex-
ible, so that it can be fashioned into the highly preferred
shape of the devices disclosed herein.
The membranes employed herein comprise non-porous
elastomers, preferably silicone polymers or latex rubbers,
either natural or synthetic. The membranes generally have
a thickness in the range from about 0.02 mm to about 0.6 mm,
preferably about 0.1 mm to about 0.4 mm. By selecting a
membrane thickness within this range, stable, non-fragile,
yet flexible and comfortable articles which effectively
transport surfactant monomers to the vagina are provided.
The s-iliconè polymers used in preparing the membranes
for use in the present devices are preferably polydimethyl-
siloxanes, i.e., silicone polymers which contain the repeat-
ing unit
CH3
~--si~
Y
CH3
wherein y is an integer in the range of about lO0-100,000.
- 14 -
,
. ~
U~ ~ ~
Repeating units of the silicone polymer can contain
side-chain branching and cross~linking, e.g.,
H3C Si-- CH3
CH3 0
~ ~ si ~
Y
O CH3
3 S i--CH 3
CH
Various functional groups may be present in the basic
silicone polymer structure to facilitate cross-linking/curing.
Silicone polymers suitable for use herein can be pre-
pared, for example, by hydrolyzing dimethyldichlorosilane or
mixtures of dimethyldichlorosilane, trichloromethylsilane and
chlorotrimethylsilane with water, in well-known fashion.
Alternatively, siloxane "oligomers" can be polymerized and
"cured" in various ways well known in`the art. Sll~cpne poly-
mers suitable for prepaing the membranes for use in the pre-
sent invention are also available, commercially, from suppliers
such as the Dow Corning Corporation and the General Electric
Corporation.
The latex rubbers which can be used in the present
invention can be either the natural or synthetic latex rubber
polymers which are commercially available. Such materials
include, for example, the neoprene-type rubbers, the Buna ~ -
type rubbers, and the like. Natural or synthetic rubber
~0 which is calendered or molded can also be used.
Other types of non-porous polymers which can be used
to fashion membranes for use with devices of the present type
- 15 _
- . .
~ 7
comprise, for example, mixtures of silicone polymers and latex
rubbers; copolymers of silicone polymers and various other
polymeric materials such as the polycarbonates, and the like;
elastomers such as the well-known styrene/butadiene block
copolymers; ethylene-vinyl acetate copolymers, etc.
Various polymeric membranes suitable for use in the
contraceptive devices of the present invention can be deter-
mined easily using the Surfactant Transport Procedure, dis-
closed hereinafter.
Highly preferred membranes for use herein are the
non-porous membranes comprising silicone polymers, especially
the polydimethylsiloxanes manufactured under "clean" condi-
tions and marketed for various medical uses. Such materials
are safe for prolonged use in contact with human tissues and
provide excellent transport of surfactant monomers, especially
the preferred, nonionic spermicidal surfactants of the type
CloEO5 and CloEO6, as described hereinafter. These silicone
polymers can readily be fashioned into membranes for use in
devices having the preferred dome-shaped configuration dis-
closed herein. Typical examples of such silicone materials
include Silastic ~ 382 and Dow Corning ~ MDX 4-4210, MDX 4-
4515, MDX 4-4516 and Q 7-2213, available from the Dow Corning
Corporation.
Spermidical Surfactant
The use of micelle-forming surfactant solutions in
the present contraceptive devices results in several important
advantages over other types of metered dosage systems.
First:, the surfactants employed as the active agent
of the contraceptive devices of the present invention appear
to function by an entirely localized effect on motile sperm.
(The terms "spermicide" and "spermicidal" as employed herein
encompass surfactants which truly "kill" animal, including
- 16 -
,.
J~'7
human, sperm as well as those which immobllize or otherwise
render sperm cells inactive.) Accordingly, undesirable side-
effects which can accompany the prolonged use of systemic
contraceptive drugs such as hormones are avoided.
Moreover, the use of safe, effective surfactants as
the spermicide permits the formulator of the present devices
to employ a large excess of the spermicide therewith. The
controlled release feature allows formulation of devices con-
taining more spermicide (surfactant) than the usual expected
need but (1) reduces the probability of side-effects by
regulating the concentration to a minimum level, and (2)
allows for unusual variations in the amount of spermicide
required or in the time period over which it might be needed.
Accordingly, a "safety factor" of the order of several-fold
vis-a-vis prolonged contraceptive efficacy is provided by the
present devices.
The devices herein can be somewhat flaccid, rather
than turgid. Accordingly, the pressure differential across
the enclosing container is small, or zero~ and the container
is stable and is not subject to hydrostatic rupture. This
desirable attribute of the present devices is to be contrasted
with the situation which occurs when a similarly concentrated
solution of a non-micelle-forming solute of similar molecular
weight is enclosed by a water-permeable diffusion membrane,
whereupon internal hydrostatic pressures of tens or hundreds
of atmospheres can be developed due to osmotic effects,
thereby leading to rupture of the membrane.
The surfactants employed in the present devices and
processes are characterized by several parameters. In general,
the surfactants are selected from those which, in combination
with the semi-permeable membrane described hereinabove, pro-
vide an appropriate relationship between release and the
- 17 -
:
.
desired contraceptive end use of the devices.
The surfactants herein are characterized by their
ability to dissolve ~n a sol~ent (normally, water) and to
form an association colloid, or micelles, therein. It has now
been discovered that the surfactant micelles do not penetrate
the walls of the membranous containers used herein. However,
surfactant monomers do diffuse through the membranous walls
and into the vagina. Thus, by virtue of the equilibrium be-
tween micellar and monomeric surfactant, the solution of
surfactant micelles provides a reservoir for the controlled
delivery of spermicidal surfactant monomers to the environment
external to the device, i.e., the vagina, especially the area
immediately around the cervical os. In a surfactant solution
which is sufficiently concentrated to form true micelles, the
concentration of monomer in equilibrium with the micellar
surfactant remains substantially constant at the so-ealled
"critical micelle concentration" (cmc) over a wide range of
total surfactant concentration. In order to realize fully
the unique advantages of surfactants in devices of the present
type, it is preferred to use those spermicidal surfactants
having a cmc of at most about 5xlO Molar (M). In particular,
by choosing surfactants with this low cmc, the user of the
present devices is exposed to only minimum amounts of surfact-
ant, thereby minimizing any possible toxicological hazards.
It is to be appreciated that "neat" surfactantsl i.e.,
not in solutionl are not in the form of micellar aggregates
andl accordinglyl simply pass through the walls of the mem-
branes in an undesirablel uncontrolled mannerl thereby ellm-
inating the reservoir effect provided by surfactant micelles.
When used as between-period contraceptivesl it is,
of course, necessary to select surfactants which produce the
desired spermicidal response. Moreover, to secure the benefits
18 -
,, ~
~,
. . .
3L7
of controlled release~ it is necessary also to select surfact-
ants whose monomers are rapidly transported through the mem-
branous ~alls of the container to establish an effective con-
centration of surfactant in the vaginal area.
From the foregoing considerations it will be appre-
ciated that various surfactants can be tested in vitro in a
simple medium which approximates various body fluids (such as
physiological saline or distilled water) to determine the~ con-
centration at which the surfactant must be present in such
medium to provide spermicidal efficacy. Surfactants whose
monomers are transported through the enclosing membrane of
the device to provide at least the aforesaid effective concen-
tration in the medium are useful herein. Upon immersion in
an external solvent (e.g., vaginal fluids) the controlled
release devices herein deliver surfactant monomers to the
external solvent in the rapid, or "primary", transport process.
After this external concentration reaches, approximately, the
cmc of the surfactant, monomer transport slows drastically,
since monomer concentration on both sides of the semi-permeable
membrane is nearly equal. Slower, "secondary" transport
processes may carry a bit more of the surfactant through the
membrane to the vagina, but this does not substantially deplete
the surfactant reservoir in the present devices.
From the foregoing, it follows that, for the desired
spermicidal effect to be realized, the ratio, R, of the cmc of
the surfactant to its spermicidally-effective concentration,
Csperm.~ e-g-~ in saline~ i.e.,
cmc
R =C
sperm.
should be greater than or equal to about 1. Similar considera-
tions hold for external media other than saline, i.e., fluid
media such as vaginal fluids, water, etc., in which the present
.... -- 1 9
~' ~
surfactant monomers are soluble. Accordingly, the preferred
compounds for use in the devices described herein have values
of R which are greater than or equal to ca 1, i.e.,
R > ca~ 1.
A variety of surfactants exhibit a cmc less than about
5xlO 3M and meet this criteria for use in the preferred con-
trolled release devices herein. Several surfactant types
having this preferred cmc provide a desirable spermicidal res-
ponse. Moreover, several surfactants exhibit the requisite
relationship, R 2 ca. 1, between cmc and spermicidal activity.
Based solely on the foregoing considerations, repre-
sentative examples of surfactants useful herein include non-
ionic surfactants such as n-ClOH21(0CH2CH2)50H (abb. CloE05)
10 21( 2CH2)60H (CloE06); semipolar surfactants such
as C12H25S(NH)2CH3 and C12H25(CH3)2Aso; and cationic surfact-
16 33N (CH3)3,CL and C16H33N+C5H ,Cl- These
surfactants are characterized by R >~ and cmc < 10 3M.
It is to be understood that other surfactants having
a cmc of about 10 M, or less, but which exhibit somewhat
lower activity as spermicidal agents, i.e., surfactants wherein
ca. 1 > R > 2, can be employed in controlled release articles.
However, the biological response to these latter surfactants
is somewhat less than that of the preferred group, and the
efficacy margin, i.e., R-l, is not as great. Included among
this group of surfactants are n-C12E09; n-C16EOlS04 ,Na ;
C H (CH ) P0; n-ClOE4; C12H25(C2H5)2P0; 16 33
sulfonate; and nonylphenol nonaethoxylate.
As can be seen from the foregoing, various surfactant
types are usefu~ in controlled release contraceptive devices of
the present type. However, when devices designed for use as
between-period contraceptives in humans are being prepared,
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6~7
additional physio-chemical properties of the surfactants must
be considered. For example~ the surfactants should be toxico-
logically acceptable for use in the body over extended time
periods. The surfactants should also be non-irritating to
the delicate tissues of the vagina and uterus. The preferred
surfactants should not substantially bind serum proteins found
in the vaginal area between periods of menstrual flow, inasmuch
as the bound surfactant-protein moiety does not function as a
spermicide and accelerates the depletion of surfactant from
the reservoir (micelles) within the device. The surfactant
monomers must be able to dissolve or partition into the en-
closing membrane of the device and diffuse through the membrane
in an efficient and effective manner. Finally, the surfactant
should be selected from those which do not bind to charged
sites in the enclosing diffusion membrane, since binding in-
hibits the passage of the surfactant monomers through the
membrane. In particular, ionic surfactants are troublesome
in this regard. Moreover, some ionic surfactants are too polar
to partition into and diffuse through the preferred silicone
membranes efficiently.
Based on the foregoing factors, and considering the
high spermicidal activity of the compounds, the alkylene oxide
nonionic surfactants, especially the well-known condensation
products of ethylene oxide with aliphatic alcohols or alkyl
phenols, are preferred for use herein. In particular, CloEO5
and CloEO6 surfactants are most preferred for use in the pre-
sent controlled rel~ase contraceptive devices. As between
these latter compounds, CloEO5 has the advantage of the lower
molecular weight, and therefore provides more spermicidal
monomer per given weight of compound. Accordingly, CloEO5 is
most preferred for use in the between-period, controlled
release contraceptive devices of this invention.
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,
.
The surfactants disclosed hereinabove are all well
known from the detergency arts and can be made by various
art-disclosed processes.
Sur~actant Transport Procedure
A cell for testing transport of surfactant monomers
through me~branes is as follows. A 40 mm (diameter) x 50 mm
(length) poly-methylmethacrylate rod is halved and each half
is suitably machined to provide cavities 16 mm (diameter) x
10 mm (depth), such that the cavities abut when the rod halves
are reassembled. Each cavity is provided with two inlet holes
for filling and sampling. A brass clamp is used to hold the
two cell halves firmly together.
The surfactant transport testing is carried out in
the following manner. A disc 3 cm in diameter of the membrane
material to be tested is sandwiched between the cell halves,
enclosing a 3 mm glass bead on each side of the membrane to
provide stirring. One half of the cell is filled with distilled
water and the other half is filled with an aqueous solution of
a radiolabeled surfactant. The inlet holes are sealed with
waterproof tape and the cell is placed in a 37C bath in a
device which allows the cell to be rotated axially at approxi-
mately 50 rpm. Periodically, the cell is raised from the
bath and the solution in the desired compartment sampled.
A typical procedure using a membrane of polydimethyl-
siloxane (Dow Corning ~ MDX 4-4210) is as follows. After
; charging the cell, the cell is maintained in the 37C bath for
varying time periods, after each of which the tape is removed
from the inlet holes and duplicate 10 microliter (~Q) samples
are removed by syringe and expressed into a counting vial. In
the subsequent scintillation counting, each sample vial is
charged with 10 ~IQ of a solution of 0.8% 2-diphenyloxazole and
0.01% of 1,4-bis-[2-(4-methyl-5-phenyloxazolyl~-benæene in a 1:1
``~'
:
~i67~
ethanol/toluene mixture. The vials (two for each time period)
are then placed in the refrigerator compartment of a counting
; instrument and cooled to 4C before bein~ counted for 5 minutes
each. The counts per minute are converted to ppm by applying
a factor found by counting one or more standard samples. By
taking samples at regular intervals, a curve plotting the
surfactant concentration in the initially surfactant-free side
of the cell versus the time of sampling can be drawn which
describes the transport of the surfactant across the membrane.
Following the Surfactant Transport Procedure set forth
hereinabove, the cell cavity designated (A) is charged with
surfactant solution and the cavity designated (B) is charged
with distilled water. The cell cavities are separated by the
test membrane, e.g., polydimethylsiloxane. The concentration
of surfactant transported to cavity (B) is determined in the
foregoing manner, and the graph of the concentration of
surfactant in (B) versus time is plotted.
This graph describes a monomer transport curve which
at the outset rises at a high rate (primary slope) and beyond
a certain time rises at a much lower rate (secondary slope).
The monomer transport curve has the general form C=C2(1-e t/T)
+S2t, where C=surfactant concentration in cavity (B), C2= the
zero time intercept of the secondary slope, t=time, ~=the time
constant, and S2=the secondary slope. The primary slope, Sl,
is the slope of the curve at t=0 and is given by
Sl= 2+S .
The controlled release devices of the present type,
the combination of surfactant and a suitable membrane should
yield a monomer transport curve wherein Sl is relatively large,
S2 is relatively small, and C2 is about equal to the cmc of the
~! - 23 -
.
surfactant being tested. The ratio of S2/Sl is from 0 to
about 0.1. Sl should genexally be no less than about 10 ppm/
hr. and preferably will be in the range of about 100 ppm/hr.
to about 200 ppm/hr.
sased on the foregoing, surfactant/membrane combina-
tions can be selected which will provide controlled release
articles of the present type. A highly preferred article herein
which is particularly useful as a vaginal contraceptive com-
prises from about a 5~ to about a 50~ (wt.) aqueous solution of
CloEO5 enclosed within a polydimethylsiloxane membrane.
Method of Manufacture
The following describes a typical method of manufactur-
ing a preferred, double-domed article of the type disclosed
herein. While the description relates to a preferred and
convenient process for preparing the articles from a silicone
polymer, various methods of manufacture can be employed to
prepare other devices encompassed by the present invention.
Dow Corning ~ MDX 4-4210 Clean Grade Elastomer (Dow
Corning Corporation, Midland, Michigan) is supplied in two
parts: an elastomer base and a curing agent which, when mixed
and cured, form the finished silicone polymer membrane. In
practice, about 10 parts of elastomer base are mixed with
about 1 part of curing agent. The mixture is deaerated in a
vacuum chamber until no more entrapped air can be seen. The
deaerated mixture is then injected into mold cavities of
appropriate dimensions for the halves of the dome-shaped device.
The silicone halves are cured by heating in the mold at ca.
125C for at least about 15 minutes. It will be appreciated
that the mold dimensions can be adjusted to provide the desired
thickness of the resulting silicone membrane.
The choice of curing agent for silicone polymers is
not critical to the operation of the devices prepared in the
~' 24
~ .
manner of this in-~ention. Depending on the particular sili-
cone polymer chosen, various platinum-based, tin-based and
peroxide~based catalysts or curing agents for silicones well
known in the art are suitable for use in preparing silicone
membranes. However, it has now been discovered that, in pro-
longed use in the vagina, some curing agents can cause the
silicone membrane to become discolored. While this discolora-
tion does not deleteriously affect the operation of the device$,
they are rendered unsanitary in appearance. Apparently, some
naturally-occurring sulfur and/or amino compounds present in
vaginal fluids somehow interact with tin-based curing agents
such as stannous octoate to cause the discoloration. Whatever
the cause, it is preferable, from an aesthetic standpoint, to
avoid the use of tin-based curing agents and curing~gents which
form colored complexes with the components of vaginal fluids
in the preparation of optimized articles of the present type.
Accordingly, peroxide-based or, preferably, platinum-based
silicone curing agents are preferred for use herein. Such
materials are well known in the art and can be selected from
listings in standard texts. Alternatively, suitable polymers
substantially free from color-forming curing agents can be
selected by preparing and curing silicone polymers in standard
fashion and incubating the polymers in the vaginas of live
laboratory animals to determine their propensity for discolora-
tion.
After having prepared the two halves of the double
dome-shaped device, a uniform layer of silicone adhesive (e.g.,
Silastic ~ Medi.cal Adhesive Silicone Type A, Dow Corning
Corporation) is placed around the periphery of the upper half
of the dome. The upper half and lower half are joined and
pressed to squeeze out any excess adhesive from the seal area.
The excess adhesive is removed and the adhesive which seals
- 25 -
'~' .
the double dome-shaped device is allowed to cure for 24 hours,
or longer.
An aqueous solution of the spermicidal surfactant is
prepared. The solution is taken up in a syringe fitted with a
25 gauge needle. The surfactant solution is injected into the
free space within the double dome-shaped device through the
peripheral rim. With the needle still in place, any air
remaining inside the device is removed. (Needle holes from
this procedure do not leak with pressures encountered in
use.)
In an alternative filling procedure, the upper dome
half of the device is positioned downwardly, the surfactant
solution is poured into this half, and the bottom dome half
of the device is sealed thereto while in a downward position.
After filling, the sealed device is placed in a
vial and covered with approximately 50 mls of water. The vial
is loosely covered and placed in an autoclave at 15 psig
(121C) for 30 minutes. After cooling, the autoclave is opened
and the closure on the vial is tigh-tened to provide individu-
ally packaged, sterile contraceptive devices suitable for
distribution to users.
The following examples illustrate the practice of
this invention, but are not intended to be limiting thereof.
EXAMPLE I
A device of the type depicted in Figure 2 is prepared
from Dow Corning ~ MDX 4-4210 Clean Grade Elastomer using the
methods described hereinabove. The device is in the form of a
disc having a double dome of the silicone membrane. The thick-
ness of the membrane is ca. 0.25+0.15 mm. The base of the
device has an outside diameter of ca. 55-~10 mm and an inside
diameter of ca. 50+15 mm. The height of the upper membrane of
the double dome from the base of the device is ca. 25+5 mm,
- 26 -
. ~ ., ~
whereas the height of the lower membrane of the double dome
from the base of the device is ca, 18+5 mm, whereby the total
volume of the dome~shaped container resulting from sealing the
edges of the device is ca~ 5 cc.
__
A device of the foregoing type is substantially filled
with a 25% (wt.~ aqueous solution of the CloEO5 surfactant.
Excess air is removed. The device is autoclaved and is ready
for use as a vaginal contraceptive.
The device is placed in the vagina posterior to the
introitus in a manner such that the concavity of the dome sub-
stantially covers and "caps" the cervical os. The device is
worn during the time between menses and safely and continuously
delivers a spermicidally effective amount of CloEO5 surfactant
to the vaginal area. In particular, the positioning and shape
of the device bathes the cervical os with the spermicidal sur-
factant. The device is quite comfortable and remains in place
during intercourse.
In the device of Example I, the CloEO5 surfactant is
replaced by an equivalent amount of CloEO6 surfactant and
excellent spermicidal results are secured.
EXAMPLE II
A device of the configuration depicted in Figure 2 is
prepared as follows. The internal portion of the device (i.e.,
the portion to be placed in close proximity to the cervical os)
is prepared from Dow Corning ~ MDX 4-4210 Clean Grade Elastomer
using the methods described in Example I. The thickness of
the silicone membrane is ca. 0.25*0.15 mm.
The other half of the device is prepared from a sub-
stantially non-permeable, polyethylene terephthalate (PET)
plastic having a thickness of ca. 0.6_0.1 mm.
The two halves are assembled in the manner described
above to provide a "double-domed" shaped device. The inner
- 27 -
X
: .:
concavity of the device comprises the semi-permeable silicone
membrane. The base o~ the device has an outside diameter of
ca. 55+10 mm and an inside diameter of ca. 50+15 mm. The height
of the outer PET half portion of the double dome from the base
of the device is ca. 25+5 mmr whereas the height of the inner,
silicone membrane of the double dome from the base of the
device is ca. 18+5 mm, whereby the total volume of the dome-
shaped container resulting from sealing the edges of the
device is _. 5 cc.
A device of the foregoing type is substantially filled
with a 25% (wt.) aqueous solution of the CloEO5 surfactant.
Excess air is removed. The device is autoclaved and is ready
for use as a vaginal contraceptive.
The device is placed in the vagina posterior to the
introitus in a manner such that the concavity of the dome
substantially covers and "caps" the cervical os. The device
is worn during the time between menses and safely and effec-
tively delivers a spermicidal amount of CloEO5 surfactant to
the vaginal area. In particular, the positioning and shape
of the device bathes the cervical os with the spermicidal
surfactant via the inner silicone membrane. Substantially none
of the surfactant migrates through the PET outer dome into
the general vaginal cavity. Thus, substantially all of the
surfactant is delivered to the intended situs, i.e., the
cervical os and immediate surrounding area. The device is
quite comfortable and remains in place during intercourse.
In the device of Example II, the CloEO5 surfactant
is replaced by an equivalent amount of CloEO6 surfactant and
excellent spermicidal results are secured.
EXAMPLE III
A flat, disc-shaped silicone device is prepared in
the manner described hereinabove by appropriate selection of
- 2~ -
~;
die configuration. The device has the general dimensions of
the device of Example I, with the exception that the container
formed by the membranes is flat, rather than domed.
The disc~shaped device is substantially filled with
a 50~ (wt.) aqueous solution of the CloEO5 spermicidal sur-
factant. Excess air is removed. The device is autoclaved in
the manner described hereinabove and is xeady for use as a
vaginal contraceptive.
The device is placed in the vagina posterior to the
introitus and in a manner such that the central portion of the
disc (which comprises the membranous container) is in the
closest possible proximity to the cervical os. The device is
worn during the time between menses and safely and effectively
delivers the spermicidal surfactant to the vaginal area
during that time. The device is quite comfortable and remains
in place during intercourse.
The device of Example III is prepared using synthetic
rubber and excellent spermicidal results are secured.
The device of Example III is prepared from the
following polymeric materials: polycarbonate; styrene/buta-
diene block copolymers; and ethylene-vinylacetate copolymers,
said polymeric materials being used in combination with both
CloEO5 and CloEO6. Excellent spermicidal results are secured.
EXAMPLE IV
A device of the general double-domed disc configura-
tion depicted in the ~'igures is prepared as follows.
The inner dome which comprises the 0.25 mm thick
membranous transport surface is prepared from Dow Corning ~
MDX 4-4210 Clean Grade Elastomer using the methods described
hereinabove.
The outer dome disc is prepared from non-permeable
PET plastic having a thickness of ca. 0.55 mm.
- 29 -
-. ~. .
7~
The inner and outer discs are sealed together around
their peripheral edges, but without formin~ a retaining rim.
The domed configuration is maintained by virtue of the dimen-
sional stability of the relatively thiek, resilient, yet com-
fortable outer PET dome.
A device of the foregoing type having the approximate
dimensions of the article of Example I provides a dome-shaped
container having a volume of ca. 5 cc.
A device of the foregoing type substantially filled
with ca. 30% (wt.~ aqueous solution of CloEO5 surfactant is
used as a vaginal contraceptive. The device is placed in the
vagina posterior to the introitus in a manner such that
the concavity of the dome, i.e., the inner, silicone membrane,
substantially covers and "caps" the cervical os. The device
is worn during the time between menses and safely and con-
tinuously delivers a spermicidally effective amount of CloEO5
surfactant to the vaginal area. In particular, the positioning
and shape of the deviee bathes the cervical os with the sperm-
icidal surfactant. The device is quite comfortable and remains
in place during intercourse.
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. . . ~
