Note: Descriptions are shown in the official language in which they were submitted.
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DELIVERY SYSTEM
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical delivery system including an
applicator that demonstrates controlled release of active agents, that has a
high
internal to external phase ratio value, and that is suitable for use in the
vaginal cavity.
BACKGROUND OF THE INVENTION
Medical treatment of the female reproductive system for the prevention,
control, diagnosis, and cure of disease typically involves the delivery of
pharmaceutically active agents to the vaginal cavity and proximal organs.
Generally,
agents are put in the form of gels, foams, creams, suppositories, and
dissolving
tablets, or other forms generally known in the art. However, these forms of
delivery
have not demonstrated the ability to deliver active agents to the vaginal
cavity in a
controlled manner, particularly for periods of three hours or longer, while
providing a
high level of bioadherence and a high level of stability in environments
having either
high or low temperatures.
The biological characteristics of the vagina and proximal areas make it
difficult to treat and deliver agents to the vaginal cavity. For example, the
vaginal
cavity exhibits an aqueous environment, with fluids having a pH in the range
of 4.5 to
5.5 and an internal temperature of approximately 98.6 F (37 C). The
environment of
the vaginal cavity is also conducive to the growth of microorganisms, such as
bacteria
and fungi, including yeast, and the retention of foreign particulates, such as
seminal
fluid resulting from intercourse, and menstrual debris. The vaginal cavity is
also
characterized by the ability for considerable physical deformation, such as
that
resulting from sexual intercourse or insertion of tampons.
Agents, such as fungicides, have typically been used to treat ailments and
afflictions in the vaginal cavity. However, the pharmaceutical and chemical
activity
of these agents has not reached an optimal level of effectiveness. This
limitation in
effectiveness is due, in part or in whole, to the inadequacy of the currently
available
delivery systems. In fact, the currently available delivery systems have not
shown the
ability to release a pharmaceutically active agent in an optimally safe manner
for
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periods of three hours or greater, without encountering problems related to
bioadherence or excessive release of the active pharmaceutical ingredient. For
instance, delivery systems that are available generally begin to either
solubilize,
disperse or liquefy almost immediately following insertion into the vaginal
cavity.
Thus, these delivery systems typically have minimal bioadherence to the
vaginal
walls.
Conventional delivery systems having a large proportion of propylene glycol
in the formulation have been used to enhance the availability of the
incorporated drug.
The advantage being taken of both the potential solubilization of the active
pharmaceutical compound in a solvent like molecule such as propylene glycol
and the
increased penetration potential afforded by propylene glycol through
biological
membranes. This extrapolation to delivery systems for mucosal membranes can be
overstated, particularly when used in the vaginal cavity. The aqueous nature
of the
environment provides optimum conditions for systemic absorption of solubilized
active pharmaceutical compounds. Inclusion of high concentrations of compounds
which solubilize active pharmaceutical agents can increase the systemic
absorption
potential of that agent. Though in some instances this is a desired effect, in
the
treatment of local mucosal infections the removal of the beneficial drug from
the
immediate area can prolong the treatment regime, and in some cases may cause
systemic absorption of active pharmaceutical compounds to reach levels that
are not
beneficial.
In addition there can be physical aspects of the delivery system that are
compromised by the inclusion of moderate to excessive amounts of propylene
glycol.
For conventional emulsions, moderate to excessive amounts propylene glycol can
add
to the solubilization and liquification of the delivery system in the
hydrophilic
environment of the vaginal cavity. For more unique emulsion systems the
inclusion
of higher levels of propylene glycol can lead to physical instability at both
ambient
and elevated temperatures.
As a result, the emulsions of conventional and unique delivery systems may
not provide optimal treatment in the vaginal cavity. There is an unmet need in
the art
for a controlled release delivery system providing optimal treatment of
vaginal
ailments and afflictions. Accordingly, there is an unmet need for a delivery
system
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providing a consistent release of a pharmaceutically active agent to the
vaginal cavity,
specifically a system allowing pharmaceutical activity for an extended period
of time,
such as at least three hours, and providing high levels of bioadherence.
Furthermore,
there is an unmet need in the art for a delivery system that reduces the
proportion of
propylene glycol in the formulation.
SUMMARY OF THE INVENTION
The present invention overcomes the above-mentioned problems, as well as
others, by providing a delivery system for the vaginal cavity having increased
effectiveness over the delivery systems currently available. In particular, a
first
embodiment of the present invention provides a delivery system for the
treatment of
fungal infections of the human female vaginal cavity comprising an effective
amount
of imidazole derivative active agent and one or more pharmaceutically
acceptable
excipients which allow the active agent to be released in a controlled manner
to a site
in the vaginal cavity, wherein the delivery system is an emulsion that
exhibits an
internal to external phase ratio of greater than 70%. A second embodiment of
the
present invention is a method of treating a vaginal fungal infection in a
female human,
comprising administering to the vaginal cavity a delivery system having an
effective
amount of an imidazole derivative active agent and one or more
pharmaceutically
acceptable excipients which allow the active agent to be released in a
controlled
manner to a site in the vaginal cavity, wherein the delivery system is an
emulsion that
exhibits an internal to external phase ratio of greater than 70%.
More specifically, the delivery system comprises a compact, prefilled, ready-
to-use, applicator for dispensing a medicament to a body cavity includes an
elongated
body having a proximal dispensing end and a distal grasping end. The body is
of a
sufficient length to dispense medicament to a desired location within a
selected body
cavity. A proximal portion of the elongated body forms a reservoir adapted to
contain
a predetermined amount of medicament. A distal portion of the elongated body
forms
a plunger housing. Closure means are disposed at the dispensing end of the
reservoir,
and impeller means are disposed at its distal end, at the junction of the
reservoir and
plunger assembly housing. A telescoping plunger rod assembly, having stop
means
associated therewith for limiting telescopic extension and preventing
telescopic
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collapse of the plunger rod assembly, is connected to the impeller means.
Grasping
means are provided for operating said telescoping plunger rod assembly. The
applicator is operated by holding it at the grasping end and inserting it,
closure end
first, into the desired cavity. The plunger assembly is drawn back via the
grasping
means to the limit of the stop means, and then the plunger assembly is pushed
proximally relative to the elongated body, thereby creating pressure to open
the
closure member and dispense the medicament from the reservoir
Other features of the present invention will become apparent connection with
the accompanying drawings. Additional advantages and novel features of the
invention will also become more apparent to those skilled in the art upon
examination
of the following or upon learning by practice of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the accompanying sheet of drawing:
FIG. 1 is a side elevational view of a medicament applicator illustrating the
principles of the present invention, shown in the compact, ready-to-use
position;
FIG. 2 is an exploded view of the medicament applicator of FIG. 1, showing a
closure portion, a cylindrical body portion, a first plunger member and second
plunger
member (together forming a plunger assembly), and a grasping member;
As illustrated in FIGS. 1 and 2 a medicament applicator 20 has a dispensing
end 22 and a grasping end 24. A cylindrical member 26 serves as the main body
of the
applicator, having a medicament reservoir portion, a plunger assembly housing
portion, and a grasping surface portion 32. A closure member 34 is slidingly
received
over a reduced outer diameter portion 36 of the cylindrical member 26. A
plunger
assembly 38, having a first plunger member 40 with a piston portion 42 and a
second
plunger member 44, is slidingly received within cylindrical member 26; the
piston
portion 42 being disposed within the medicament reservoir portion 28 and the
rest of
the plunger assembly 38 being disposed within the plunger assembly housing
portion
30. A grasping member 46 is provided for the second plunger member 44.
The present invention provides a delivery system that provides an emulsion
that exhibits a high internal to external phase ratio between 70% to 90%,
preferably
wherein the nonlipoidal phases comprise from about 70% to 90% by volume of the
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system. The formulations of the present invention reduce the amount of
propylene
glycol from commercially available bioadhesive systems, preferably by about
20% to
about 80%, more preferably about 25%, compared to the formulations in the
prior art,
while still maintaining the same high internal emulsion ratio of 70% to 90%.
5 Additionally, the present invention can sustain a temperature of 86 F for at
least one month, preferably greater than one month, more preferably greater
than two
months, more preferably greater than six months, and more preferably greater
than
one year, for example three to five years. The increased stability allows the
present
invention to be stored in environinents susceptible to climate changes or
temperature
extremes. This improvement is generally known as "improved shelf life."
This invention provides a delivery system for the vaginal cavity, wherein the
system delivers pharmaceutically active agents to the vaginal cavity in a
controlled
manner over an extended period of time. In one variation of the present
invention, the
extended period of time is at least three hours, and in most cases, the period
of time
can last as long as ten days or more. The delivery system is characterized by
a high
internal emulsion ratio. The delivery system is preferably an emulsion
comprised of
at least 70% hydrophilic constituents by volume of the system.
The delivery system provides agents that restore and maintain a healthy
vaginal environment, and cure ailments or afflictions affecting the vaginal
cavity.
The "vaginal cavity" also includes proximal areas, e.g., it includes the
vagina, female
urinary tract, such as the ostium of the urethra, organs and tissues at the
opening of
the vaginal cavity, as well as reproductive organs accessible through the
cavity. The
delivery system is also characterized by a capability to adhere (otherwise
known as
"bioadhere") to the walls of the vaginal cavity and proximal areas, including
epithelial
cells, tissue and organs.
The delivery system not only releases an active agent, but it releases the
agent
in a controlled manner to obtain optimal absorption. Thus, the active agent is
made
available for absorption, pharmacological or other effect at a site of
absorption or
action in an amount sufficient to cause a desired response consistent with the
intrinsic
properties of the agent and which provides for maintenance of this response at
an
appropriate level for a desired period of time. The delivery system of the
present
invention is preferably characterized by the controlled release of the active
agent to a
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receptor site, site of action, site of absorption, or site of use and the
achievement of
the desired effect at that site. The delivery system is preferably not
miscible in water
and is not harmful for use in the vaginal cavity.
The delivery system of the present invention can comprise a combination of
active and non-active pharmaceutical ingredients (also known generally herein
as
"excipients"). Non-active ingredients, for example, serve to solubilize,
suspend,
thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and
fashion the
active ingredients into an applicable and efficacious preparation that is
safe,
convenient, and otherwise acceptable for use. Active ingredients, which, for
example,
can constitute 1.0% to 10% of the total weight percent of the delivery system,
preferably from about 1.5% to 2.5%, more preferably about 2.0%, provide
medicinal
or chemical treatment of the vaginal cavity. These active ingredients are
formulated
to be released in a controlled manner. Active ingredients comprising the
active agent
may be any of those ingredients that are approved for or are used for the
treatment,
prophylaxis, cure, or mitigation of any disease of the vaginal cavity. The
primary
active ingredients of the delivery system of the present invention are
imidazole
derivatives, which are antifungal and antibacterial in nature. The imidazole
derivatives may be present in the form of pharmaceutically acceptable salts,
such as
nitrates. Examples of imidazole derivatives that can be used in this invention
include
miconazole nitrate, butoconazole nitrate, oxiconazole nitrate, metronidazole
nitrate,
terconazole nitrate, and clotrimazole nitrate, among others known in the art.
A
preferred imidazole derivative in the delivery system of the present invention
is
butoconazole nitrate.
The delivery system can be comprised of internal phase unit cells. These unit
cells are the basic, nondivisable, repeating unit of the systems. The internal
phase
may be nonlipoidal, i.e., miscible with water, and may comprise water,
glycerine, or
combinations thereof. The internal phase may be multiphasic and may be a
solution,
suspension, emulsion, or combination thereof, and may contain at least a
portion of
the active agent. The external phase may be a continuous phase and lipoidal,
i.e.,
containing organic compounds comprising the neutral fats, fatty acids, waxes,
phosphatides, petrolatum, fatty acid esters of monoprotic alcohols and mineral
oils
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that are insoluble in water but soluble in alcohol, ether, chloroform or other
fat
solvents.
The delivery system may be classified conventionally, for example, as
emulsions, emulsions/dispersions, double emulsions, suspensions within
emulsions,
suppositories, foams, or another classification known in the art. Accordingly,
in
embodiments of the invention, the delivery systems can vary in form. In one
embodiment of the present invention, the system is an emulsification of
ingredients in
a cream form. Other embodiments of the present invention include lotions,
gels,
foams, and various emulsifications. The preferred embodiment has a viscosity
range
from about 5,000 to 2,000,000 centipoise. Additionally, other embodiments of
the
present invention include liquids, semi-solids and solids having a viscosity
range from
about 5,000 to 750,000 centipoise, preferably 350,000 to 650,000 centipoise.
Optimizing viscosity can allow the system of delivery to achieve maximum
bioadherence on the vaginal cavity.
The delivery system is preferably in the form of an emulsion of medium or
high internal phase ratio, which is the ratio between the external phase and
the
internal phase. The ratio value represents how much the internal phase
comprises of
the system in terms of percent by volume of the system. In embodiments of this
invention, the ratio can be at least 70% by volume, preferably at least 75%,
more
preferably at least 80% and even more preferably up to about 90%.
The controlled release feature of the present invention is a product of the
high
internal phase emulsion exhibited by the present invention. Emulsifiers,
auxiliary
agents, emulsifying agents or other excipients, such as glycerol monostearate,
glycerol monoisostearate, methylparaben, propylparaben, and generally oils,
glycerides, sucrose esters, sorbitan esters, polysorbates, stearoyl
lactylates, lecithin
and other like compounds, create emulsified globules comprised of non-active
ingredients. The globules contain reservoirs of the active agents. These
globules
slowly disperse upon application, i.e., the globules tend to seek the
containing
surfaces or membranes, and the globules spread locally (i.e., in the vaginal
cavity),
thereby forming a "film" containing globules that releases the active agent,
in a
controlled release fashion, over time. This process occurs over a period of
time, such
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as, for example, three hours to up to ten days or more, and is therefore
generally
known as "controlled release."
The bioadherence feature of the present invention is a product of the high
internal phase emulsion exhibited by the present invention. The emulsified
globules,
which are comprised of excipients (examples of which are listed above), are
small in
volume, but have a relatively high surface area. The surface area and nature
of the
surfaces allows the globules to interact with human tissue through a number of
physical binding molecular forces such as Van der Waals forces or hydrogen
bonding.
These binding forces are intensified due to the high internal phase ratio of
the
emulsion, there being such a large number of these very small globules as
compared
to the small volume of the continuous or external phase comprising the
emulsion.
The present application incorporates by reference in its entirety U.S. Patent
No. 5,266,329 which issued on November 30, 1999 to Riley, Jr. ("Riley."). At
least
one change between the delivery system of the present invention and
conventional
delivery systems, including those disclosed in Riley, is the stability of the
delivery
system. Propylene glycol can affect the stability and diffusion rate of the
delivery
system. Propylene glycol can be included in the formulation of the delivery
system to
serve as a solvent that helps to dissolve the active ingredient of the
delivery system,
e.g., the imidazole, such as butoconazole nitrate. It has been known in
conventional
formulations to use propylene glycol at 5.00 weight percent.
In embodiments of the present invention, the propylene glycol can be present
in an amount from about 1.0 to about 4.0 weight percent, more preferably from
about
3.5 to about 3.85 weight percent, and most preferably about 3.75 weight
percent, i.e.,
the amount of propylene glycol is reduced by about 25% as compared to the 5.00
weight percent believed to be required in prior delivery systems.
An exemplary embodiment for the delivery system of the present invention is
as follows:
Butoconazole Nitrate Cream, 2.0%
Ingredients Wt %
Water Purified, USP 39.069
Sorbitol Solution, USP 39.978
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Propylene Glycol, USP 3.75
Edetate Disodium, USP 0.050
Butoconazole Nitrate, USP 2.000
Mineral Oil, USP 8.032
Polyglyceryl-3-Oleate 2.713
Glyceryl Monisostearate 2.713
Microcrystalline Wax, NF 0.452
Silicon Dioxide, 1.013
Hydrophobic
Methylparaben, PF 0.180
Propylparaben, NF 0.050
The delivery system of at least some embodiments of the present invention
improves upon the delivery systems known in the art by reducing the amount of
propylene glycol in the formulation. The reduction of propylene glycol does
not
affect the internal phase emulsion ratio, which is greater than 70%, nor does
it
preclude the formation of an emulsion. Moreover, the reduction of propylene
glycol
used achieves unexpected results that are highly advantageous and beneficial
to the
pharmaceutical and medicinal arts.
The delivery system of the present invention overcomes the limitations of the
prior art. For example, reducing the amount of propylene glycol improves the
diffusion rate of the active pharmaceutical agent in the delivery system while
maintaining its beneficial pharmaceutical properties and effectiveness.
Additionally, the delivery system of embodiments of the present invention has
demonstrated physical attributes such as bioadherence and potentially
increased
physical stability in relation to phase separation and the ability to remain
in place
resisting dispersion for extended periods of time. The overall increased
physical
attributes of the delivery system of the present invention provides a more
effective
product for the consumer and a more optimal treatment in the vaginal cavity,
i.e., the
emulsion is stable and has improved control over diffusion rates of the active
pharmaceutical ingredient thus is more effective. Finally, the increased
stability
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provides increased shelf life in areas where temperatures may be uncontrolled,
further
allowing the delivery system to be used by a greater number of people.
Exemplary embodiments of the present invention have now been described in
accordance with the above advantages. It will be appreciated that these
examples are
5 merely illustrative of the invention. Many variations and modifications will
be
apparent to those skilled in the art.
