Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS AND TECHNIQUES FOR VAGINAL INSERTION
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional
Application No.
63/225,872, filed July 26, 2021; U.S. Provisional Application No. 63/285,447,
filed December 2,
2021; and U.S. Provisional Application No. 63/331,749, filed April 15, 2022,
the entire contents
of each of which is incorporated herein by reference in its entirety.
FIELD
The present disclosure generally relates to compositions and techniques for
vaginal
insertion.
BACKGROUND
In subjects having a vagina, the vagina represents an important route for drug
administration, e.g., due to its large surface area and blood supply. A
variety of materials
potentially can be applied to the vagina for delivery to a subject, including
both local and
systemic delivery. However, materials applied to the vagina may be expelled
relatively quickly,
e.g., due to gravity, as well as vaginal discharge. In addition, the mucosal
layer within the
vagina presents a significant challenge for drug entry. Accordingly,
improvements in vaginal
delivery techniques are needed.
SUMMARY
The present disclosure generally relates to the treatment of compositions and
techniques
for vaginal insertion. The subject matter of the present disclosure involves,
in some cases,
interrelated products, alternative solutions to a particular problem, and/or a
plurality of different
uses of one or more systems and/or articles.
In one aspect, the present disclosure is directed to a composition. The
composition, in
one set of embodiments, comprises a poloxamer and a stabilization polymer. The
composition
may have a viscosity at room temperature of at least 1.5 million cP.
According to another set of embodiments, the composition comprises a
poloxamer, and a
stabilization polymer. The composition may be made by a process comprising
forming a
composition comprising the poloxamer and the stabilization polymer, and
removing air from the
composition.
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The composition, in another set of embodiments, comprises a poloxamer and a
stabilization polymer. In some embodiments, the composition is made by a
process comprising
forming a composition comprising the poloxamer and the stabilization polymer,
and exposing
the composition to a pressure of less than 100 mbar (absolute) for at least 30
minutes.
In one set of embodiments, the composition comprises a poloxamer, a
stabilization
polymer, and an active ingredient for inducing cervical ripening. In some
cases, the composition
has a viscosity at room temperature of at least 1.5 million cP.
In another set of embodiments, the composition comprises a poloxamer, a
stabilization
polymer, and an active ingredient for inducing cervical ripening. In some
cases, the composition
is made by a process comprising forming a composition comprising the
poloxamer, the
stabilization polymer, and the active ingredient, and removing air from the
composition.
In yet another set of embodiments, the composition comprises a poloxamer, a
stabilization polymer, and an active ingredient for inducing cervical
ripening. In some cases, the
composition is made by a process comprising forming a composition comprising
the poloxamer,
the stabilization polymer, and the active ingredient, and exposing the
composition to a pressure
of less than 100 mbar (absolute) for at least 30 minutes.
In still another set of embodiments, the composition is a composition for
inducement of
cervical ripening. In some cases, at least 90 wt% of the composition consists
essentially of a
poloxamer, a stabilization polymer, an active ingredient for inducing cervical
ripening, and
water.
In one set of embodiments, the composition comprises a poloxamer, a
stabilization
polymer, and an active ingredient for treating dysmenorrhea. In some cases,
the composition has
a viscosity at room temperature of at least 1.5 million cP.
In another set of embodiments, the composition comprises a poloxamer, a
stabilization
polymer, and an active ingredient for treating dysmenorrhea. In some cases,
the composition is
made by a process comprising forming a composition comprising the poloxamer,
the
stabilization polymer, and the active ingredient, and removing air from the
composition.
In yet another set of embodiments, the composition comprises a poloxamer, a
stabilization polymer, and an active ingredient for treating dysmenorrhea. In
some cases, the
composition is made by a process comprising forming a composition comprising
the poloxamer,
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the stabilization polymer, and the active ingredient, and exposing the
composition to a pressure
of less than 100 mbar (absolute) for at least 30 minutes.
In still another set of embodiments, the composition is a composition for
treatment of
dysmenorrhea. In some cases, at least 90 wt% of the composition consists
essentially of a
poloxamer, a stabilization polymer, an active ingredient for treating
dysmenorrhea, and water.
In another aspect, the present disclosure is directed to a method. The method,
according
to one set of embodiments, comprises applying, to the vagina of a subject, a
gel having a
viscosity at room temperature of at least 1.5 million cP.
In another set of embodiments, the method comprises applying, to a vagina of a
subject, a
composition comprising a poloxamer and a stabilization polymer. In certain
embodiments, the
composition, as applied, has a viscosity of at least 1.5 million cP.
In another set of embodiments, the method comprises providing a composition
comprising a poloxamer and a stabilization polymer, and removing air from the
composition.
The method, in still another set of embodiments, comprises providing a
composition
comprising a poloxamer and a stabilization polymer, and exposing the
composition to a pressure
of less than 100 mbar (absolute) for at least 30 minutes to form a gel.
In one set of embodiments, the method comprises applying, to a vagina of a
subject, a
composition comprising a poloxamer, a stabilization polymer, and an active
ingredient for
inducing cervical ripening. In some cases, the composition, as applied, has a
viscosity of at least
1.5 million cP.
In another set of embodiments, the method comprises providing a composition
comprising a poloxamer, a stabilization polymer, and an active ingredient for
inducing cervical
ripening, and removing air from the composition.
In yet another set of embodiments, the method comprises providing a
composition
comprising a poloxamer, a stabilization polymer, and an active ingredient for
inducing cervical
ripening, and exposing the composition to a pressure of less than 100 mbar
(absolute) for at least
minutes to form a gel.
In one set of embodiments, the method comprises applying, to a vagina of a
subject, a
composition comprising a poloxamer, a stabilization polymer, and an active
ingredient for
30 treating dysmenorrhea. In some cases, the composition, as applied, has a
viscosity of at least 1.5
million cP.
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In another set of embodiments, the method comprises providing a composition
comprising a poloxamer, a stabilization polymer, and an active ingredient for
treating
dysmenorrhea, and removing air from the composition.
In yet another set of embodiments, the method comprises providing a
composition
comprising a poloxamer, a stabilization polymer, and an active ingredient for
treating
dysmenorrhea, and exposing the composition to a pressure of less than 100 mbar
(absolute) for at
least 30 minutes to form a gel.
Several methods are disclosed herein of administering a subject with a
compound for
prevention or treatment of a particular condition. It is to be understood that
in each such aspect
of the disclosure, the disclosure specifically includes, also, the compound
for use in the treatment
or prevention of that particular condition, as well as use of the compound for
the manufacture of
a medicament for the treatment or prevention of that particular condition.
In another aspect, the present disclosure encompasses methods of making one or
more of
the embodiments described herein, for example, a composition as described
herein. In still
another aspect, the present disclosure encompasses methods of using one or
more of the
embodiments described herein, for example, a composition for the treatment of
as described
herein, and other indications.
In some embodiments, the present disclosure provides kits comprising the
compositions
described herein, where the kit includes an applicator suitable for vaginal
application. In some
embodiments, the applicator is pre-filled with the compositions described
herein. In some
embodiments, the applicator is not pre-filled with the compositions described
herein.
In some embodiments, the kit includes one or more of instructions for
inserting the
applicator into the vagina and instructions for inducing cervical ripening,
for treating
dysmenorrhea, for treating menorrhagia or promoting cervical ripening by
applying the
applicator filled with the composition or gel.
In some embodiments, the composition is at a temperature of about 4 C for pre-
filling the
applicator.
In some aspects, provided herein is a method including for treating
menorrhagia, the
method including applying, to a vagina of a subject, a composition comprising
a poloxamer, a
stabilization polymer, and an active ingredient for treating menorrhagia,
wherein the
composition, as applied, has a viscosity of at least 1.5 million cP. In some
embodiments, the
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active ingredient is diclofenac. In embodiments, the subject has menorrhagia.
In some
embodiments, the subject is at risk of having menorrhagia. In some
embodiments, the subject is
human.
In some aspects, provided herein is a method including for treating pelvic
pain, the
method including applying, to a vagina of a subject, a composition comprising
a poloxamer, a
stabilization polymer, and an active ingredient for treating menorrhagia,
wherein the
composition, as applied, has a viscosity of at least 1.5 million cP. In some
embodiments, the
active ingredient is diclofenac. In some embodiments, the pelvic pain is
generalized pelvic pain,
acute pelvic pain or chronic pelvic pain. For example, pelvic pain can result
from endometriosis,
adenomyosis, ovulatory pain, ovarian cyst pain and/or pelvic muscle associated
pain. In some
embodiments, the subject is experiencing pelvic pain. In embodiments, the
subject is at risk of
pelvic pain. In embodiments, the subject has generalized pelvic pain. In
embodiments, the
subject has acute pelvic pain. In embodiments, the subject has chronic pelvic
pain. In
embodiments, the subject has endometriosis. In embodiments, the subject has
adenomyosis. In
embodiments, the subject has ovulatory pain. In embodiments, the subject has
ovarian cyst pain.
In embodiments, the subject has an ovarian cyst. In embodiments, the subject
has pelvic muscle
associated pain.
In some embodiments, the composition is a gel. In embodiments, the poloxamer
includes
poloxamer 407. In embodiments, the stabilization polymer is xanthan gum.
In embodiments, the composition has air at no more than 15 vol%.
In embodiments, the method includes applying the composition through an
applicator to
the vagina.
In aspects, provided herein is a method for treating menorrhagia, the method
including
providing a composition including a poloxamer, a stabilization polymer, and an
active ingredient
for treating menorrhagia; and removing air from the composition. In
embodiments, the active
ingredient is diclofenac.
In some embodiments, removing air includes exposing the composition to a
pressure of
less than 100 mbar (absolute). In some embodiments, removing air includes
exposing the
composition to a pressure of less than 50 mbar (absolute). In some
embodiments, removing air
includes exposing the composition to a pressure of less than 40 mbar
(absolute).
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In some embodiments, the method includes exposing the composition to the
pressure for
at least 30 min. In embodiments, removing air includes centrifuging the
composition at 100
RPM, for example centrifuging the composition for at least 30 min.
In some embodiments, the method includes removing air such that the
composition has
no more than 15 vol% air.
In some embodiments, the composition has a viscosity at room temperature of at
least 1.5
million cP. In some embodiments, the poloxamer is poloxamer 407. In
embodiments, the
stabilization polymer is xanthan gum.
In embodiments, provided herein is a method for treating menorrhagia, the
method
including providing a composition including a poloxamer, a stabilization
polymer, and an active
ingredient for treating menorrhagia; and exposing the composition to a
pressure of less than 100
mbar (absolute) for at least 30 minutes to form a gel.
In embodiments, the active ingredient is diclofenac.
In some embodiments, the gel has a viscosity at room temperature of at least
1.5 million
cP.
In some embodiments, the method includes exposing the composition to the
pressure of
less than 100 mbar until the gel comprises no more than 15 vol% air.
In some embodiments, the poloxamer is poloxamer 407. In some embodiments, the
stabilization polymer is xanthan gum.
In aspects, provided herein is a method for treating menorrhagia, the method
including
providing a composition having a poloxamer, a stabilization polymer, and an
active ingredient
for treating menorrhagia; and exposing the composition to a pressure of less
than 100 mbar
(absolute) for at least 30 minutes to form a gel.
In some embodiments, the active ingredient is diclofenac.
In some embodiments, the gel has a viscosity at room temperature of at least
1.5 million
cP.
In some embodiments, the method includes exposing the composition to the
pressure of
less than 100 mbar until the gel has no more than 15 vol% air.
In some embodiments, the poloxamer is poloxamer 407. In some embodiments, the
stabilization polymer is xanthan gum.
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Also provided herein are methods for treating menorrhagia in a subject
including
comprising administering any of the compositions described herein to the
vagina of the subject.
Other advantages and novel features of the present disclosure will become
apparent from
the following detailed description of various non-limiting embodiments of the
disclosure when
considered in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS
Non-limiting embodiments of the present disclosure will be described by way of
example
with reference to the accompanying figures, which are schematic and are not
intended to be
drawn to scale. In the figures, each identical or nearly identical component
illustrated is
typically represented by a single numeral. For purposes of clarity, not every
component is
labeled in every figure, nor is every component of each embodiment of the
disclosure shown
where illustration is not necessary to allow those of ordinary skill in the
art to understand the
disclosure. In the figures:
FIG. 1 illustrates the viscosity of a composition as a function of
temperature, in
accordance with one embodiment as described herein.
FIG. 2 is a graph showing in vitro release test (IVRT) comparison of drug
release versus
time (SQRT: square root).
FIG. 3 is a graph showing a regression model for release rate versus drug
load.
FIG. 4 is a graph showing a Release plot of a 1% gel composition.
FIG. 5 is a graph showing a linear time plot of a 1% gel composition.
FIG. 6 is a graph showing a Release plot of a 3% gel composition.
FIG. 7 is a graph showing a linear time plot of a 3% gel composition.
FIG. 8 is an image showing appearance results for Batch 178003-2201 (1%
diclofenac;
Left); Batch 178003-2202 (2% diclofenac; Middle); Batch 178003-2203 (3%
diclofenac; Right).
FIG. 9 are microscopy images at 200x magnification for Batch 178003-2201 (1%
diclofenac; Left); Batch 178003-2202 (2% diclofenac; Middle); Batch 178003-
2203 (3%
diclofenac; Right). The images indicated that the API (active pharmaceutical
ingredient) is
angular crystalline rod-shape material with low sphericity. Batches 178003-
2202 & 178003-2203
exhibited higher amounts of API agglomeration in the drug product. There was
no indication of
agglomeration reported in visual observations.
FIG. 10 is a graph showing a thermal viscosity profile comparison.
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FIG. 11A is a graph showing the thermal ramp at a 1% gel composition.
FIG. 11B is a table showing the data from the thermal ramp graph of FIG. 11A.
FIG. 12A is a graph showing the thermal ramp at a 2% gel composition.
FIG. 12B is a table showing the data from the thermal ramp graph of FIG. 12A.
FIG. 13A is a graph showing the thermal ramp at a 3% gel composition.
FIG. 13B is a table showing the data from the thermal ramp graph of FIG. 13A.
DETAILED DESCRIPTION
The present disclosure generally relates to compositions and techniques for
vaginal
insertion. In some embodiments, a composition such as a gel may be applied to
the vagina of a
subject that is relatively viscous, for example, with a viscosity at room
temperature of at least 1.5
million cP. The composition may also contain an active ingredient, e.g.,
dinoprostone,
diclofenac, and/or salts thereof. Compositions having such relatively high
viscosities may be
useful, for example, to prevent the composition from readily exiting the
vagina or degrading too
quickly. This may, for example, allow the composition to release the active
ingredient over a
relatively long period of time to the vagina. In some embodiments, such
compositions may be
prepared by removing air from the composition to increase its viscosity or
cause the composition
to form a gel, etc. In addition, certain embodiments as described herein are
generally directed to
techniques for making or using such compositions, kits including such
compositions, or the like.
Contrary to compositions for dermal or surface applications, the compositions
described
herein are formulated for vaginal application (e.g., a mucosal surface). The
vaginal epithelium
has completely different biophysical properties compared to other skin
surfaces. For example,
the inner lining of the vagina consists of multiple layers of (squamous)
cells. The basal
membrane provides the support for the first layer of the epithelium-the basal
layer. The
intermediate layers lie upon the basal layer, and the superficial layer is the
outermost layer of the
epithelium. In developing vaginal compositions, additional factors are
considered, including
viscosity. This is because materials applied to the vagina may be expelled
relatively quickly
(e.g., due to gravity or vaginal discharge) and thus the viscosity (thickness
or stickiness) of the
vaginal composition is particularly relevant. Also, the mucosal layer within
the vagina presents a
unique challenge for drug entry, and the vagina is designed to permit the
passage of normal
uterine secretions (e.g., flushing of the vaginal discharge). In light of
these challenges,
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developing vaginal compositions presents itself with unique hurdles as
compared to developing
compositions for other dermal uses. Moreover, advantages of preparing and
formulating
compositions for vaginal (local) delivery include lower systemic side effects
due to lower
systemic concentrations of the drug, but equivalent or better symptom relief
due to local delivery
of the drug to the affected tissue.
One aspect as discussed herein is generally directed to compositions having
relatively
high viscosities, or resistance to flow or deformation. In some embodiments,
such compositions
may have viscosities of, for example, at least 1 million cP, 3 million cP, or
more, or other
viscosities as discussed in more detail below. Fluids with such relatively
high viscosities do not
flow easily and may even resist flow due to gravity in some cases.
The compositions may contain a polymer, which can increase the viscosity of
the
composition. For example, the polymer may include a poloxamer, which may form
a gel in
some cases. In addition, in some cases, the composition may also contain
xanthan gum, e.g., that
can also act as a stabilizer or a thickening agent, which may help increase
viscosity. The
composition may also contain an active ingredient, such as dinoprostone,
diclofenac, etc., which
can be released from the composition over a suitable period of time. The
composition may be
applied to the vagina or another suitable body cavity of a subject, for
example, where release of
the active ingredient is desired, e.g., to treat or prevent an indication,
such as described herein.
More details of these and other compositions, in accordance with various
embodiments, are
provided below.
Such compositions containing relatively high viscosities may be particularly
useful, in
certain embodiments, to prevent the composition from readily exiting the
vagina (or other
cavity), and/or from degrading too quickly after application. This may be
used, for example, to
assist the delivery of an active ingredient to the subject, e.g., to the
vagina of the subject. For
instance, fluids with relatively high viscosities may release the active
ingredient more slowly
and/or uniformly, thereby allowing the active ingredient to be delivered to
the subject over a
longer period of time. Higher viscosities may also better resist the natural
function of the vagina
to discharge. Thus, as discussed in more detail herein, the active ingredient
may be delivered,
e.g., at suitably effective concentrations or amounts, for example, over a
period of at least a day,
a week, or even longer in some cases. In addition, in some embodiments, only a
single dose of
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the composition may be required to treat a subject, e.g., since the
composition does not readily
exit the vagina.
As a non-limiting example, in one set of embodiments, a composition may be
delivered
to a subject, such as a pregnant subject, to include cervical ripening in the
subject. In some
cases, the composition may be inserted into the vagina, and an active
ingredient such as
dinoprostone may be delivered, e.g., to the vagina. This may be useful, for
example, to facilitate
or induce cervical ripening, e.g., before or during labor. As another example,
in certain
embodiments, a composition may be delivered to a subject having or at risk of
dysmenorrhea,
menstrual cramps, menorrhagia, and/or pelvic pain. The composition may be
applied to the
vagina of the subject, and an active ingredient, such as diclofenac, may be
delivered to the
vagina.
Although other techniques for delivering active ingredients to the vagina (or
other body
cavity) may also involve the use of relatively high viscosities fluids, these
fluids are often
selected to have lower viscosities at room temperatures (e.g., about 25 C)
and higher viscosities
at body temperatures (e.g., 37 C). For example, they may be a liquid at room
temperature, but
become a gel at body temperature. In addition, they may not have viscosities
as high as 1 million
cP or more; as an example, such a composition may have a viscosity of 300,000
cP at room
temperature (and be relatively flowable), increasing to only about 800,000 cP
at body
temperature.
In contrast, the compositions as discussed herein may have relatively high
viscosities, for
instance, viscosities as high as 1 million cP, 1.5 million cP or more, even at
room temperature. It
should be noted that such compositions, due to their high viscosities, are
actually difficult to
manufacture; accordingly, most other techniques will use compositions with
either lower
viscosities, or viscosities that are at least low at room temperatures,
typically well below 1
million cP. However, without wishing to be bound by any theory, it is believed
that having a
high initial viscosity, e.g., upon application to the vagina, may be
surprisingly useful for rapid
symptom relief. A composition with a relatively high viscosity is less able to
lose the active
ingredient, i.e., prior to application to the vagina, and thus retains the
active ingredient for release
to the subject more readily than a liquid or less viscous composition. For
example, the
composition may at least partially seal the vagina better, e.g., to promote
treatment with the
active ingredient. In addition, a composition with a relatively high viscosity
may itself also stay
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within the vagina longer. Furthermore, in some embodiments, the presence of
the gel itself may
be beneficial, i.e., even without the presence of an active ingredient such as
dinoprostone,
diclofenac, etc. Thus, it should be understood that an active ingredient is
not always required.
Accordingly, such compositions may produce better symptom resolution, e.g., as
compared to
formulations with relatively low viscosities at room temperature.
Such high viscosities can be achieved, in various embodiments, using
techniques such as
removing air from the composition, which may increase its viscosity and/or
cause it to form a
gel. Other techniques may also be used, including any of those described
herein. For example,
in certain embodiments, a composition may be prepared, e.g., comprising
poloxamer, an active
ingredient, xanthan gum, water, etc., and the composition treated to remove
air from the
composition, for example, to reduce the composition to 15 vol% air, or less.
Techniques for
removing air include, but are not limited to, a variety of techniques, such as
centrifugation or
exposure to relatively high vacuums, e.g., less than 100 mbar. In addition, it
should be
understood that the composition need not be limited to those described above,
and in other
embodiments, other compositions may also be used. Examples of such
compositions follow.
For instance, in some aspects, a composition may include one or more
poloxamers,
xanthan gum, and/or another stabilization polymer, and an active ingredient
such as any of those
discussed herein. Water may be present in some cases, e.g., such that the
composition is a gel,
and/or has a relatively high viscosity at room temperature, such as is
described herein. Other
components may be present as well in certain embodiments, for instance,
citrate and/or a citrate
salt, benzyl alcohol, or the like. These may act, for example, as excipients,
preservatives,
antimicrobials, bulking agents, stabilizers, antioxidants, buffers, pH
regulating agents, or the like.
In addition, in some cases, other components that increase the viscosity of
the composition may
also be used, for example, hyaluronic acid, alginic acid, modified celluloses
such as
hydroxypropyl methylcellulose, in addition or instead of poloxomer.
As mentioned, the composition may include one or more poloxamers in one set of
embodiments. The poloxamer may be used to increase the viscosity of the
composition, e.g., as
described herein. In some cases, sufficient poloxamer may be present to cause
the composition
to form a gel, e.g., at room temperature (about 25 C) and/or body temperature
(about 37 C).
Furthermore, in some cases, the composition may have a gelling temperature,
but the gel
temperature may be in a range that is physiologically irrelevant. For
instance, the gelling
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temperature may be above 40 C, or below 25 C, and thus, the composition does
not change
phase or gel at normal physiological or body temperatures.
Poloxamers generally include any of a variety of polyoxyethylene-
polyoxypropylene
triblock copolymers. In some cases, the poloxamer may be a nonionic block
copolymer
composed of a central hydrophobic chain of polyoxypropylene (polypropylene
oxide) flanked by
two hydrophilic chains of polyoxyethylene (polyethylene oxide). In some
embodiments, the
poloxamers may be soluble in water and other polar and non-polar solvents.
Because the lengths of the polymer blocks can be independently customized,
many
different poloxamers exist that have slightly different properties. For
example, the polxoxamer
may have a structure:
HO¨[CH2¨CH2-0],[CH2¨CH(CH3)-0]b¨[CH2¨CH2-0]a¨H.
The structure includes a core of propylene oxide (represented by "b" in the
above figure),
flanked by ethylene oxide subunits (represented by "a" in the above figure),
typically on both
sides. The sum of the two a's may be, for example, from 50 to 500, from 100 to
300, from 150
to 250, or 200. As another example, a may be between 99 and 103, e.g., 101. In
embodiments, b
may be, for example, from 30 to 100, from 50 to 80, from 60 to 70, or 65. As
another example, b
may be between 54 and 58, e.g., 56.
In some embodiments, the ethylene oxide subunits forming the poloxamer may be
in
molar excess to the propylene oxide subunits. For example, in certain
embodiments, the ratio of
ethylene oxide subunits to propylene oxide subunits (i.e., a:b) may be, for
example, from 3:1 to
5:1, or from 2:1 to 4:1.
Several suitable poloxamers can be readily obtained commercially, including
poloxamer
407, Pluronic F-127, or the like. The composition may include a single
poloxamer, or more
than one type of poloxamer. In some cases, at least 50 wt%, at least 60 wt%,
at least 70 wt%, at
least 80 wt%, or at least 90 wt% of the poloxamer within the composition is a
single type of
poloxamer, for example, poloxamer 407 or Pluronic F-127.
The molecular weight of the poloxamer may be, in one embodiment, from 5 kDa to
25
kDa. In some instances, the molecular weight of the copolymer may be from 9
kDa to 16 kDa.
In some cases, the molecular weight of the poloxamer may be at least 1 kDa, at
least 2 kDa, at
least 3 kDa, at least 4 kDa, at least 5 kDa, at least 7 kDa, at least 9 kDa,
at least 10 kDa, at least
15 kDa, at least 16 kDa, at least 20 kDa, at least 25 kDa, at least 50 kDa,
etc. In addition, in
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certain embodiments, the molecular weight of the poloxamer may be no more than
50 kDa, no
more than 25 kDa, no more than 20 kDa, no more than 16 kDa, no more than 15
kDa, no more
than 10 kDa, no more than 9 kDa, no more than 5 kDa, no more than 4 kDa, no
more than 3 kDa,
no more than 2 kDa, no more than 1 kDa, etc. Combinations of any of these are
also possible.
For instance, the poloxamer may have a molecular weight of between 10 kDa and
15 kDa. As
other non-limiting examples, the molecular weight may be between 3 kDa and 5
kDa, between 2
kDa and 4 kDa, between 5 kDa and 20 kDa, between 9 kDa and 16 kDa, etc. The
molecular
weight, in some cases, may be determined as a weight average molecular weight.
In certain embodiments, the poloxamer may be present within the composition at
concentrations of at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 5
wt%, at least 7 wt%, at
least 10 wt%, at least 15 wt%, at least 20 wt%, at least 25 wt%, at least 30
wt%, at least 40 wt%,
or at least 50 wt%. In addition, in some embodiments, the poloxamer may be
present within the
composition at concentrations of no more than 50 wt%, no more than 40 wt%, no
more than 30
wt%, no more than 25 wt%, no more than 20 wt%, no more than 15 wt%, no more
than 10 wt%,
no more than 7 wt%, no more than 5 wt%, no more than 3 wt%, no more than 2
wt%, etc.
Combinations of any of these are also possible in other embodiments. For
example, the
poloxamer may be present in a composition at between 10 wt% and 20 wt%,
between 5 wt% and
15 wt%, between 15 wt% and 30 wt%, etc.
In one embodiment, the poloxamer used in the composition is Pluronic F-127.
In
Pluronic F-127, the sum of two a's in the above block polymer structure may
be 200, and b may
have a value of 65. In Pluronic F-127, the ratio of the sum of two a's to b
in the poloxamer (i.e.,
a:b) may be from 2:1 to 4:1. Tables 1 and 2 illustrate chemical composition
and specifications of
Pluronic F-127.
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TABLE 1
(: tQl, LTC Oa (U PiUr011iC-4, 1:-127
uttber average
Cohlein raoLxmlar Poly-
Number
Oethyt Moketz lar weight
ktver$ity repeating .
21Ltronic Pt'r!mwner h iet' Wekk w:mo1) index
1..t.ttite
1' 127 407 101 56 7L5-74.c 964(-14t.'
IOW) 2 EG:JigiV6s Pli 6
TABLE 2.
Spfo.liiieturoup Pluroruc.) 27
C Ethylene
Propylene 1 ,4
Physical (2.% plata, API-LA BET, tinsalurai ion
Oxide. Oxide, tlioicane,
crm in water) 10% eotor PPM
rrit:e;,g p 'OM pptI) PPM
Solal s' -,E0(r C i.rCaat solid u.4. 0)248 z 7
1 YlliOZ.
aka:, PrM
In addition, in one set of embodiments, the composition may comprise xanthan
gum,
and/or another stabilization polymer. Examples of other stabilization polymers
include
hyaluronic acid, alginic acid, modified celluloses such as hydroxypropyl
methylcellulose, or
others such as described herein. Xanthan gum generally refers to a high
molecular weight
polysaccharide used as a food additive and rheology modifier, as would be
known by those of
ordinary skill in the art. In addition, many such xanthan gums are readily
available
commercially. Xanthan gum may be produced, as a non-limiting example, by a
process
involving fermentation of glucose or sucrose by the Xanthomonas campestris
bacterium. In
some embodiments, the backbone of the polysaccharide chain may have two beta-D-
glucose
units linked through the 1 and 4 positions. The side chains are formed of two
mannose and one
glucuronic acid, so the chain has repeating modules of five sugar units. The
side chain is linked
to every other glucose of the backbone at the 3 position. About half of the
terminal mannose
units have a pyruvic acid group linked as a ketal to its 4 and 6 positions.
The other mannose unit
has an acetyl group at the 6 positions. Two of these chains may be aligned to
form a double
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helix, giving a rather rigid rod configuration that accounts for its high
efficiency as a viscosifier
of water.
However, it should be understood that not all xanthan gums have precisely the
above
molecular configuration or properties, and that xanthan gums may vary in
molecular
composition, e.g., depending on the source of the xanthan gum, especially
those arising from
different biological sources. In addition, other stabilization polymers
instead of (or in addition
to) xanthan gum can be used, for example, KELTROL BT and/or KELTROL RD,
KELZAN XC, KELZAN XCD, KELZAN D, KELZAN CC, XANTURAL 180,
XANTURAL 75, or the like, all of which can be obtained commercially from
various suppliers.
The molecular weight of the xanthan gum or other stabilization polymer can
vary. For
instance, the xanthan gum or other stabilization polymer may have any suitable
molecular
weight, for example, at least about 1 million, at least about 2 million, at
least about 5 million, at
least about 10 million, at least about 25 million, or at least about 50
million. In other
embodiments, the molecular weight can vary from about one million to 50
million, e.g.,
depending upon various factors such as how it is prepared. In some
embodiments, the molecular
weight can range from approximately 1 million to approximately 25 million,
e.g., as measured by
a Brookfield Viscometer or other suitable device. In yet other embodiments,
the molecular
weight may be, for example, 1, 2, 3, 4, or 5 (+/- 0.5) million, or 6, 7, 8, 9,
10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 19, 20, 21, 22, 23, 24, or 25 (+/- 2) million. Still other
molecular weights are also
possible.
The xanthan gum (and/or another stabilization polymer) may be present within
the
composition at concentrations of at least 0.1 wt%, at least 0.2 wt%, at least
0.3 wt%, at least 0.4
wt%, at least 0.5 wt%, at least 0.7 wt%, at least 1 wt%, at least 1.5 wt%, at
least 2 wt%, at least
2.5 wt%, at least 3 wt%, at least 3.5 wt%, at least 4 wt%, at least 4.5 wt%,
at least 5 wt%, at least
5.5 wt%, at least 6 wt%, at least 6.5 wt%, at least 7 wt%, at least 7.5 wt%,
at least 8 wt%, at least
8.5 wt%, at least 9 wt%, at least 9.5 wt%, at least 10 wt%, etc. In addition,
in some cases, the
xanthan gum and/or other stabilization polymer may be present at no more than
10 wt%, no more
than 9.5 wt%, no more than 9 wt%, no more than 8.5 wt%, no more than 8 wt%, no
more than
7.5 wt%, no more than 7 wt%, no more than 6.5 wt%, no more than 6 wt%, no more
than 5.5
wt%, no more than 5 wt%, no more than 4.5 wt%, no more than 4 wt%, no more
than 3.5 wt%,
no more than 3 wt%, no more than 2.5 wt%, no more than 2 wt%, no more than 1.5
wt%, no
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more than 1 wt%, no more than 0.8 wt%, no more than 0.6 wt%, no more than 0.4
wt%, no more
than 0.2 wt%, etc. In addition, in certain instances, combinations of any of
these ranges are also
possible. For example, the xanthan gum and/or other stabilization polymer may
be present at
between 1 wt% and 5 wt%, between 0.5 wt% and 2 wt%, between 0.5 wt% and 5 wt%,
between
0.5 wt% and 2 wt%, or the like.
In one set of embodiments, the composition may also comprise an active
ingredient. The
active ingredient may be one suitable for treating any of the conditions
described herein. For
instance, the active ingredient may be one suitable for treatment of a subject
for a condition
when the active ingredient is delivered to the vagina, or another suitable
body cavity. In some
embodiments, the active ingredient is present in a therapeutically effective
amount. One or more
than one active ingredient may be used, depending on the embodiment.
For example, in certain embodiments, the active ingredient may be one that is
suitable to
facilitate or induce cervical ripening, e.g., before or during labor. In some
embodiments, a
composition such as is described herein may be inserted into the vagina of a
subject, e.g., to
induce or facilitate opening of the cervix. In one embodiment, for example,
the composition may
contain dinoprostone and/or a salt thereof as an active ingredient. However,
in other
embodiments, other suitable active ingredients include, but are not limited
to, pro staglandins
such as misoprostol, mifepristone, relaxin, oxytocin, etc., and/or
pharmaceutically acceptable
salts thereof.
In another set of embodiments, the active ingredient may be one that is
suitable to treat a
subject having or at risk of dysmenorrhea or menstrual cramps. In some cases,
a composition
such as is described herein may be inserted into the vagina of a subject. An
active ingredient
may be released from the composition to treat the subject. In one embodiment,
for example, the
composition may contain diclofenac and/or a salt thereof as an active
ingredient, e.g., diclofenac
potassium, diclofenac sodium, etc. However, in other embodiments, other
suitable active
ingredients include, but are not limited to, ibuprofen, ketoprofen,
meclofenamate, mefenamic
acid, camylofm, celecoxib, dexibuprofen, estropipate, flurbiprofen,
levonorgesterel, naproxen,
nimesulide, norgestimate, and ethinyl estradiol, trolamine salicylate,
valdecoxib, valethamate,
etc., and/or pharmaceutically acceptable salts thereof.
In yet another set of embodiments, the active ingredient may include, but is
not limited
to, lincomycin, metronicla7ole, clotrimazole, secnicla7ole, ornida7ole,
tinidi7ole, probiotics, boric
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acid, etc., and/or pharmaceutically acceptable salts thereof. The
pharmaceutical formulation may
also include an antibiotic as an active ingredient in certain cases. In
another set of
embodiments, the active ingredient may be an ingredient that can be delivered
to the vaginal,
e.g., for local or systemic delivery to the subject. In some embodiments, the
active ingredient
may be any active ingredient that can be dissolved and/or suspended within a
composition as
described herein, for example, a gel. For example, the active ingredient may
be one that is at
least partially water soluble. The gel may be relatively viscous, e.g., as
discussed herein. Non-
limiting examples of suitable active ingredients include, but are not limited
to, lidocaine,
hydrocortisone, progesterone, misoprostol, metronidazole, ketoconazole,
clobetasol, acyclovir,
miconazole, nonoxyno1-9, lactobacilli, tinicla7ole, butoconazole, flucytosine,
glycerol
monolaurate (GML), or the like.
If a salt is present, the salt may be a pharmaceutically acceptable salt in
some
embodiments. Pharmaceutically acceptable salts include salts which are, within
the scope of
sound medical judgment, suitable for use in contact with the tissues of a
subject (e.g., a human)
without undue toxicity, irritation, allergic response, and the like, and are
commensurate with a
reasonable benefit/risk ratio. Pharmaceutically acceptable salts may also be
salts that are
generally safe, non-toxic and neither biologically nor otherwise undesirable
and includes that
which is acceptable for human pharmaceutical use. Pharmaceutically acceptable
salts are well
known in the art. Pharmaceutically acceptable salts of the compounds describe
herein include
those derived from suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid salts are salts of an amino group
formed with
inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid,
sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic
acid, tartaric acid,
citric acid, succinic acid, or malonic acid or by using other methods used in
the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate, alginate,
ascorbate,
aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate,
citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,
formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,
hexanoate, hydroiodide,
2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate,
malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate,
palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate,
picrate, pivalate,
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propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-
toluenesulfonate, undecanoate,
valerate salts, and the like. Salts derived from appropriate bases include
alkali metal, alkaline
earth metal, ammonium and I=r(C1_4alkyl).4 salts. Representative alkali or
alkaline earth metal
salts include sodium, lithium, potassium, calcium, magnesium, and the like.
Further
pharmaceutically acceptable salts include, when appropriate, quaternary salts.
In some cases, the active ingredient may be released from the composition over
any
suitable period of time. For example, a therapeutically effective amount of
the active ingredient
may be released from 1 to 21 days. In some instances, a therapeutically
effective amount of the
active ingredient may be released up to about 1 to 7 days, about 5 or 15 days,
or about 8 to 29
days following administration. As still other examples, the active ingredient
may be released at
therapeutically effective amounts from the composition, following application
to the subject, for
at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27,
28, 29, or 30 or more days. In some embodiments, only a single application of
the composition
to the subject may be needed. However, in other embodiments, the composition
may be applied
to the subject more than once, for example, in applications separated by any
of the lengths of
time discussed herein.
For example, in some cases, tmax, or the time at which the maximum
concentration of the
active ingredient is present in the vagina (due to release by the composition)
may be at least 1
day, at least 2 days, at least 3 days, etc., or other times such as those
described above. In
addition, in some embodiments, tmax may be less than 30, 29, 28, 27, 26, 25,
24, 23, 22, 21, 20,
19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 days.
Combinations of any of these
are also possible, e.g., tmax may be between 1 and 3 days, or between 4 and 6
days, etc. Without
wishing to be bound by any theory, it is believed that this may be due to the
relatively high
viscosity of the composition and/or slower release kinetics from the
composition.
The active ingredient may be present within the composition at any suitable
concentration. For example, the active ingredient may be present at at least
0.1 wt%, at least 0.2
wt%, at least 0.3 wt%, at least 0.4 wt%, at least 0.5 wt%, at least 0.7 wt%,
at least 1 wt%, at least
1.5 wt%, at least 2 wt%, at least 2.5 wt%, at least 3 wt%, at least 3.5 wt%,
at least 4 wt%, at least
4.5 wt%, at least 5 wt%, at least 5.5 wt%, at least 6 wt%, at least 6.5 wt%,
at least 7 wt%, at least
7.5 wt%, at least 8 wt%, at least 8.5 wt%, at least 9 wt%, at least 9.5 wt%,
at least 10 wt%, etc.
In addition, in some cases, the active ingredient may be present at no more
than 10 wt%, no more
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than 9.5 wt%, no more than 9 wt%, no more than 8.5 wt%, no more than 8 wt%, no
more than
7.5 wt%, no more than 7 wt%, no more than 6.5 wt%, no more than 6 wt%, no more
than 5.5
wt%, no more than 5 wt%, no more than 4.5 wt%, no more than 4 wt%, no more
than 3.5 wt%,
no more than 3 wt%, no more than 2.5 wt%, no more than 2 wt%, no more than 1.5
wt%, no
more than 1 wt%, no more than 0.8 wt%, no more than 0.6 wt%, no more than 0.4
wt%, no more
than 0.2 wt%, etc. In addition, in certain instances, combinations of any of
these ranges are also
possible. For example, the active ingredient may be present at between 1 wt%
and 5 wt%,
between 0.5 wt% and 2 wt%, between 0.5 wt% and 5 wt%, or the like.
In addition, in accordance with certain embodiments, the composition may
release the
active ingredient over an extended period of time. In some cases, this may be
determining by
determining a concentration of an active ingredient in the mucus of the vagina
after a certain
period of time, for instance, after 1 day, 2 days, 3 days, etc. For example,
in one set of
embodiments, the concentration of the active ingredient may be at least 100
micrograms/g, at
least 200 micrograms/g, at least 300 micrograms/g, at least 400 micrograms/g,
at least 500
micrograms/g, at least 600 micrograms/g, at least 700 micrograms/g, etc. The
mucus may be
sampled, for example, using a swab, or other techniques known to those of
ordinary skill in the
art.
In addition, in accordance with certain embodiments, the composition may
release the
active ingredient over an extended period of time. In some cases, this may be
determining by
determining a concentration of an active ingredient in the mucus of the vagina
after a certain
period of time, for instance, after 1 day, 2 days, 3 days, etc. For example,
in one set of
embodiments, the concentration of the active ingredient may be at least 100
micrograms/g, at
least 200 micrograms/g, at least 300 micrograms/g, at least 400 micrograms/g,
at least 500
micrograms/g, at least 600 micrograms/g, at least 700 micrograms/g, etc. The
mucus may be
sampled, for example, using a swab, or other techniques known to those of
ordinary skill in the
art.
Other components may be present as well within a composition. As a non-
limiting
example, in one set of embodiments, the composition may include citrate and/or
a citrate salt.
These may include, for example, citric acid, citric acid monohydrate, sodium
citrate, sodium
citrate dihydrate, or the like. Other examples include other suitable salts,
e.g., to make citrate
buffer such as sodium phosphate, potassium phosphate, or the like. Buffers
such as these may be
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used, for example, to maintain the pH of the composition (for example, at
around 4.5, or another
suitable pH). As another example, the composition may include benzyl alcohol.
Benzyl alcohol
may be useful, for example, as a solvent or a preservative.
Components such as these may each independently be present in any suitable
amount or
concentration. For example, a component may be present at at least 0.1 wt%, at
least 0.2 wt%, at
least 0.3 wt%, at least 0.4 wt%, at least 0.5 wt%, at least 0.7 wt%, at least
1 wt%, at least 1.5
wt%, at least 2 wt%, at least 2.5 wt%, at least 3 wt%, at least 3.5 wt%, at
least 4 wt%, at least 4.5
wt%, at least 5 wt%, at least 5.5 wt%, at least 6 wt%, at least 6.5 wt%, at
least 7 wt%, at least 7.5
wt%, at least 8 wt%, at least 8.5 wt%, at least 9 wt%, at least 9.5 wt%, at
least 10 wt%, etc. In
addition, in some cases, a component may be present at no more than 10 wt%, no
more than 9.5
wt%, no more than 9 wt%, no more than 8.5 wt%, no more than 8 wt%, no more
than 7.5 wt%,
no more than 7 wt%, no more than 6.5 wt%, no more than 6 wt%, no more than 5.5
wt%, no
more than 5 wt%, no more than 4.5 wt%, no more than 4 wt%, no more than 3.5
wt%, no more
than 3 wt%, no more than 2.5 wt%, no more than 2 wt%, no more than 1.5 wt%, no
more than 1
wt%, no more than 0.8 wt%, no more than 0.6 wt%, no more than 0.4 wt%, no more
than 0.2
wt%, etc. In addition, in certain instances, combinations of any of these
ranges are also possible.
For example, the component may be present at between 1 wt% and 5 wt%, between
0.5 wt% and
2 wt%, between 0.5 wt% and 5 wt%, between 0.5 wt% and 2 wt%, or the like.
In addition, in one set of embodiments, water may be present within the
composition.
Any suitable amount of water may be present, for example, such that the
composition forms a
gel, has a relatively high viscosity as discussed herein, or the like. For
example, in some cases,
at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt%, at least
70 wt%, at least 75
wt%, at least 80 wt%, at least 85 wt%, at least 90 wt%, or at least 95 wt% of
the composition
may be water.
In one set of embodiments, the composition is a gel. The can may be semi-solid
material
that includes a relatively large amount or concentration of water, e.g., as
noted above. In some
cases, the polymer (e.g., one or more poloxamers) may from a scaffold
structure that contains the
water within the gel.
The gel or other composition, e.g., as described herein, may have a relatively
high
viscosity, at least in one set of embodiments. Those of ordinary skill in the
art will be aware of
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techniques for determining viscosity of a sample, for example, using devices
such as a
rheometers, viscometers, etc.
In some cases, the composition may have a viscosity at room temperature of at
least 1
million cP, at least 1.1 million cP, at least 1.2 million cP, at least 1.3
million cP, at least 1.4
million cP, at least 1.5 million, at least 1.6 million cP, at least 1.8
million cP, at least 2 million
cP, at least 2.2 million cP, at least 2.4 million cP, at least 2.6 million cP,
at least 2.8 million cP, at
least 3 million cP, at least 3.5 million cP, at least 4 million cP, etc. In
addition, in certain
embodiments, the composition may have a viscosity of no more than 4 million
cP, no more than
3.5 million cP, no more than 3 million cP, no more than 2.8 million cP, no
more than 2.6 million
cP, no more than 2.4 million cP, no more than 2.2 million cP, no more than 2.0
million cP, no
more than 1.8 million cP, no more than 1.6 million cP, no more than 1.5
million cP, no more
than 1.4 million cP, no more than 1.3 million cP, no more than 1.2 million cP,
no more than 1.1
million cP, no more than 1.0 million cP, etc. Combinations of any of these are
also possible, for
example, the composition may exhibit a viscosity of between 1.5 million cP and
2 million cP,
between 1.8 million cP and 2.4 million cP, between 1.2 million cP and 3
million cP, etc.
In some cases, the composition may contain xanthan gum and/or another
stabilization
polymer, and a polymer such as a poloxamer, which may cause the composition to
have a
relatively high viscosity. In some embodiments, the composition may contain no
other
component that changes the viscosity of said composition at room temperature
by more than +/-
100,000 centipoise.
Due to the natural acidity of the vagina, vaginal compositions typically aim
for a pH of
about 4.5. In embodiments, the pH of the composition may be between about 4
and about 7. In
embodiments, the pH of the composition may be between about 4 and about 5.5.
In
embodiments, the pH of the composition may be between about 4 and about 5. In
embodiments,
the pH of the composition may be between about 4.5 and about 5.5. For example,
the
composition may have pH about 4, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or
4.9. In embodiments,
vaginal compositions as described herein (e.g., using diclofenac) have up to
about pH 5.5, for
example pH 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In embodiments, vaginal
compositions as described
herein (e.g., using diclofenac) have up to about pH 7, for example pH 5.6,
5.7, 5.8, 5.9, 6.0, 6.1,
6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7Ø
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In embodiments, a composition as described herein may release about 50% of the
drug
within the composition in about 1 hour to about 80 hours. In embodiments, a
composition as
described herein may release about 50% of the drug within the composition in
about 10 hours to
about 70 hours. In embodiments, a composition as described herein may release
about 50% of
the drug within the composition in about 20 hours to about 70 hours. In
embodiments, a
composition as described herein may release about 50% of the drug within the
composition in
about 10 hours to about 60 hours. In embodiments, a composition as described
herein may
release about 50% of the drug within the composition in about 10 hours to
about 50 hours. In
embodiments, a composition as described herein may release about 50% of the
drug within the
composition in about 10 hours to about 40 hours. In embodiments, a composition
as described
herein may release about 50% of the drug within the composition in about 10
hours to about 30
hours. In embodiments, a composition as described herein may release about 50%
of the drug
within the composition in about 15 hours to about 60 hours. In embodiments, a
composition as
described herein may release about 50% of the drug within the composition in
about 15 hours to
about 50 hours. In embodiments, a composition as described herein may release
about 50% of
the drug within the composition in about 15 hours to about 40 hours. In
embodiments, a
composition as described herein may release about 50% of the drug within the
composition in
about 15 hours to about 30 hours. In embodiments, a composition as described
herein may
release about 50% of the drug within the composition in about 20 hours to
about 60 hours. In
embodiments, a composition as described herein may release about 50% of the
drug within the
composition in about 20 hours to about 50 hours. In embodiments, a composition
as described
herein may release about 50% of the drug within the composition in about 20
hours to about 40
hours. In embodiments, a composition as described herein may release about 50%
of the drug
within the composition in about 20 hours to about 30 hours. The time may be
any value or
subrange within the recited ranges.
In embodiments, a composition as described herein may release about 80% of the
drug
within the composition in about 1 hour to about 80 hours. In embodiments, a
composition as
described herein may release about 80% of the drug within the composition in
about 10 hours to
about 70 hours. In embodiments, a composition as described herein may release
about 80% of
the drug within the composition in about 20 hours to about 70 hours. In
embodiments, a
composition as described herein may release about 80% of the drug within the
composition in
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about 10 hours to about 60 hours. In embodiments, a composition as described
herein may
release about 80% of the drug within the composition in about 10 hours to
about 50 hours. In
embodiments, a composition as described herein may release about 80% of the
drug within the
composition in about 10 hours to about 40 hours. In embodiments, a composition
as described
herein may release about 80% of the drug within the composition in about 10
hours to about 30
hours. In embodiments, a composition as described herein may release about 80%
of the drug
within the composition in about 15 hours to about 60 hours. In embodiments, a
composition as
described herein may release about 80% of the drug within the composition in
about 15 hours to
about 50 hours. In embodiments, a composition as described herein may release
about 80% of
the drug within the composition in about 15 hours to about 40 hours. In
embodiments, a
composition as described herein may release about 80% of the drug within the
composition in
about 15 hours to about 30 hours. In embodiments, a composition as described
herein may
release about 80% of the drug within the composition in about 20 hours to
about 60 hours. In
embodiments, a composition as described herein may release about 80% of the
drug within the
composition in about 20 hours to about 50 hours. In embodiments, a composition
as described
herein may release about 80% of the drug within the composition in about 30
hours to about 60
hours. In embodiments, a composition as described herein may release about 80%
of the drug
within the composition in about 40 hours to about 50 hours. The time may be
any value or
subrange within the recited ranges.
In embodiments, a composition as described herein may release about 100% of
the drug
within the composition in about 1 hour to about 80 hours. In embodiments, a
composition as
described herein may release about 100% of the drug within the composition in
about 10 hours to
about 70 hours. In embodiments, a composition as described herein may release
about 100% of
the drug within the composition in about 20 hours to about 70 hours. In
embodiments, a
composition as described herein may release about 100% of the drug within the
composition in
about 10 hours to about 60 hours. In embodiments, a composition as described
herein may
release about 100% of the drug within the composition in about 10 hours to
about 50 hours. In
embodiments, a composition as described herein may release about 100% of the
drug within the
composition in about 10 hours to about 40 hours. In embodiments, a composition
as described
herein may release about 100% of the drug within the composition in about 10
hours to about 30
hours. In embodiments, a composition as described herein may release about
100% of the drug
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within the composition in about 15 hours to about 60 hours. In embodiments, a
composition as
described herein may release about 100% of the drug within the composition in
about 20 hours to
about 60 hours. In embodiments, a composition as described herein may release
about 100% of
the drug within the composition in about 30 hours to about 60 hours. In
embodiments, a
composition as described herein may release about 100% of the drug within the
composition in
about 40 hours to about 60 hours. In embodiments, a composition as described
herein may
release about 100% of the drug within the composition in about 45 hours to
about 60 hours. The
time may be any value or subrange within the recited ranges.
In addition, in one set of embodiments, the composition may have a relatively
low
concentration or amount of air. For instance, in one embodiment, the
composition is
substantially free of air. In some cases, during manufacture, a large amount
of air may be
introduced into the composition, e.g., as foam or bubbles, etc. However, this
air may be
undesirable in accordance with certain embodiments, and accordingly, the
composition may be
prepared by also including a step of removing air from the composition that
has been introduced
during manufacture.
In some embodiments, the composition, after removing at least some of the air
may
contain no more than 20 vol%, no more than 15 vol%, no more than 12 vol%, no
more than 10
vol%, no more than 8 vol%, no more than 6 vol%, no more than 5 vol%, no more
than 4 vol%,
no more than 3 vol%, no more than 2 vol%, or no more than 1 vol%, etc. of air.
In some cases,
the air may be removed such that no air bubbles are visually present within
the composition.
Without wishing to be bound by any theory, it is believed that the presence of
air may
reduce the viscosity of the composition, e.g., making it easier for the
composition to flow.
Accordingly, in some embodiments, any air that is introduced may be removed,
thereby
increasing the viscosity of the composition, e.g., to at least 1 million cP,
or other ranges of
viscosities, such as any of those described herein. Furthermore, in some
cases, removing the air
may also increase the density of the final composition. For instance, the
density of the
composition may be at least 0.98 g/cm3, at least 0.99 g/cm3, at least 1 g/cm3,
at least 1.01 g/cm3,
at least 1.02 g/cm3, at least 1.03 g/cm3, at least 1.05 g/cm3, at least 1.1
g/cm3, etc. In some cases,
the density of the composition may be no more than 1.1 g/cm3, no more than
1.05 g/cm3, no
more than 1.03 g/cm3, no more than 1.02 g/cm3, no more than 1.01 g/cm3, etc.
Furthermore, in
some embodiments, combinations of any of these ranges are possible. For
example, the final
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density of the composition may be between 1.00 g/cm3 and 1.01 g/cm3, between
0.99 g/cm3and
1.02 g/cm3, etc.
In one embodiment, air may be removed from a composition, e.g., during or
after
formation, by applying a pressure less than atmospheric or ambient pressure to
the composition.
For instance, the pressure that is applied may be less than 1 bar, less than
800 mbar, less than 600
mbar, less than 500 mbar, less than 400 mbar, less than 300 mbar, less than
200 mbar, less than
100 mbar, less than 75 mbar, less than 60 mbar, less than 50 mbar, less than
40 mbar, less than
30 mbar, less than 20 mbar, less than 10 mbar, less than 5 mbar, less than 3
mbar, less than 2
mbar, less than 1 mbar, etc. It should be noted that 1 atmosphere is
approximately 1 bar, and that
these pressures are absolute pressures (i.e., a pressure of less than about 1
bar means a pressure
lower than atmospheric pressure, i.e., a vacuum pressure). Such pressures may
be applied for
any suitable length of time, e.g., at least 10 min, at least 20 min, at least
30 min, at least 45 min,
at least 1 h, at least 2 h, at least 3 h, at least 4 h, at least 6 h, at least
24 h, at least 1 day, etc. In
addition, in some cases, the pressure may be applied until the composition
comprises less than a
certain amount of air, e.g., less than 15 vol%, or other percentages such as
those described
herein. As yet another example, in some cases, a solution may be caused to
form a gel by
removing a certain amount of air from the solution.
In certain embodiments, as another example, the air may be removed from the
composition using a Versator or other deaerator, degas ser, and/or defoamer.
In a Versator, a
material such as a liquid is spread onto the inside of a rotating Versator
disc under vacuum
to remove entrapped air, foam, gas, etc. While the liquid travels across the
disc, the high vacuum
draws off the bubbles, etc., from the liquid. Versators may be obtained from
several commercial
sources. Accordingly, in some embodiments, a composition such as described
herein may be
treated using a Versator for any suitable length of time, e.g., at least 10
min, at least 20 min, at
least 30 min, at least 45 min, at least 1 h, at least 2 h, at least 3 h, at
least 4 h, at least 6 h, at least
24 h, at least 1 day, etc., and/or until the composition comprises less than a
certain amount of air,
e.g., less than 15 vol%, or other percentages such as those described herein
As yet another example, in some cases, the air may be removed from the
composition
using centrifugation. Without wishing to be bound by any theory, it is
believed that by
centrifuging the composition, air (being less dense) may be forced out of the
composition. Thus,
for example, the material may be centrifuged at any suitable speed, e.g., at
least at least 500
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RPM, at least 1,000 RPM, at least 2,000 RPM, at least 3,000 RPM, at least
5,000, at least 10,000
RPM, or the like, for any suitable length of time, e.g., at least 10 min, at
least 20 min, at least 30
min, at least 45 min, at least 1 h, at least 2 h, at least 3 h, at least 4 h,
at least 6 h, at least 24 h, at
least 1 day, etc., and/or until the composition comprises less than a certain
amount of air, e.g.,
less than 15 vol%, or other percentages such as those described herein.
Furthermore, it should be understood that these techniques are non-limiting,
and that
other methods of removing air, besides centrifuges or Versators, are also
possible in still other
embodiments.
In embodiments, the product can be manually or filled using an automated
filling
machine. In some embodiments, the automated filling machine (e.g., a Capmatic
automated
filing machine) is especially designed to fill applicator-based products, such
as vaginal
applicator-based products. As the viscosity of the product decreased at
refrigerated
temperatures, e.g., at temperatures of about 4 C. (e.g., a reduction in
viscosity of 2-3x), the
product may become suitable for automated filling into a vaginal applicator.
In some
embodiments, a cooled, jacketed vessel, feeding cooled product into the filler
hopper to fill the
applicators is used.
Methods of Use
Accordingly, as discussed above, a variety of compositions are covered in
various
embodiments, including any suitable combinations of any of the above-described
components,
such as poloxamer, xanthan gum and/or another stabilization polymer, an active
ingredient, and
water. For example, in one set of embodiments, at least 50 wt%, at least 60
wt%, at least 70
wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt% of
the composition
comprises or consists essentially of polymer such as a poloxamer, xanthan gum
and/or another
stabilization polymer, an active ingredient, and water. The active ingredient
may include any of
those described herein, for example, dinoprostone, diclofenac, etc., as well
as salts thereof.
Furthermore, as mentioned, certain aspects as described herein are generally
directed to
compositions and methods for applying such compositions for the treatment or
prevention of
indications such as any of those described herein, e.g., to the vagina of a
subject, such as a
human. The subject can also be a non-human animal. In embodiments, the subject
is female.
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In other embodiments, indications that can be treated with a composition such
as those
described herein include, but are not limited to, vulvovaginal candidiasis
(yeast infection),
vulvovaginal pain, cervical or vaginal cancer, hormone therapy, etc.
In one set of embodiments, a composition such as is described herein may be
used to
facilitate or induce cervical ripening in a subject, e.g., before or during
labor. In a subject about
to give birth, the cervix may open or dilate to allow the baby to be born.
However, in some
cases, cervical ripening does not occur, and/or occurs but at too slow of a
rate, and accordingly,
some intervention may be required to facilitate or induce cervical ripening.
In some cases, a
subject may be treated by applying a composition such as is described herein
to the vagina, e.g.,
to facilitate or induce cervical ripening. The composition may have a suitable
active ingredient,
such as dinoprostone and/or a salt thereof, and/or other active ingredients
such as those described
herein. After insertion, the active ingredient may be released, e.g., into the
vagina or cervix,
which may thus facilitate or induce cervical ripening.
In another set of embodiments, a composition such is described herein may be
used to
treat a subject having or at risk of dysmenorrhea or menstrual cramps. These
are often caused by
uterine contractions during menstruation. Although some menstrual pain is
normal, subjects
with dysmenorrhea often experience pain so severe that it prevents them from
doing normal
activities for several days, often lasting 3, 4, or more days. In some cases,
a subject may be
treated by applying a composition such as is described herein to the vagina to
treat the
dysmenorrhea. The composition may have a suitable active ingredient, such as
diclofenac and/or
a salt thereof, and/or other active ingredients such as those described
herein. After insertion, the
active ingredient may be released, e.g., into the vagina or cervix to treat or
prevent
dysmenorrhea.
In another set of embodiments, a composition such as described herein may be
used to
treat a subject having or at risk of having menorrhagia. Menorrhagia is heavy
menstrual
bleeding. It is a common disorder in adolescents and reproductive age women
and if untreated,
can result in anemia, work and school absenteeism and other disruptions to
activities of daily
living. Dysmenorrhea and menorrhagia are also common side effects of the
copper (Cu)
intrauterine device (IUD). First line, non-hormonal treatments of menorrhagia
include
administration of oral non-steroidal anti-inflammatory drugs (NSAlDs), such as
diclofenac.
Data support that oral NSAlDs reduce menorrhagia by similar mechanisms which
also result in
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reduced dysmenorrhea, including reduction in endometrial leukotrienes and
inflammation.
Tranexamic acid is also a non-hormonal medication which significantly reduces
menorrhagia,
however, this non-hormonal agent cannot be used long term due to the risk of
thrombosis.
The advantage of oral NSAIDs is that they are generally available over-the-
counter and
are effective in reducing menorrhagia and dysmenorrhea, even in Cu IUD users.
However,
common dose-dependent side effects of oral NSAIDs include gastrointestinal
bleeding, diarrhea,
and nausea. In addition, taking daily oral NSAIDs for several months to manage
menorrhagia
and or dysmenorrhea and or side effects of Cu IUDs requires high adherence,
especially difficult
in younger populations and most importantly long term systemic use of NSAIDs
can result in
renal damage. Oral NSAIDs are also a first line non-hormonal treatment for the
management of
generalized pelvic pain, acute pelvic pain and chronic pelvic pain, which can
result from
endometriosis, adenomyosis, ovulatory pain (Mittleschmirtz), ovarian cyst pain
and/or pelvic
muscle associated pain.
The oral NSAID dose and the frequency of oral dosing are the same for the
treatment of
menorrhagia, dysmenorrhea, generalized pelvic pain, acute pelvic pain,
ovulatory pain, ovarian
cyst pain and pelvic muscle associated pain. Oral NSAIDs are most commonly
given as needed
or "pm" for the treatment of pain. The duration of treatment for oral NSAIDs
is generally
shorter for acute pelvic pain, ovulatory pain, dysmenorrhea and menorrhagia.
Longer, chronic
administration of NSAIDs is generally required for chronic conditions such as
endometriosis,
adenomyosis, and generalized pelvic pain. It is expected that the treatment
duration for the
diclofenac vaginal hydrogel would follow the same flexible dosing schedule,
based on the
individual's specific pain levels and causative factors.
Local genital delivery of NSA1DS for dysmenorrhea and menorrhagia
Local delivery of active pharmaceutical ingredients through the vaginal mucosa
is ideal
because lower doses can be used to target local genital tissues and the
myometrium. Data
consistently support that drugs delivered vaginally concentrate 10¨ 100 times
higher in genital
tissues and fluids compared to systemic blood concentrations, which reduces
systemic side
effects. This is particularly important when the expectation is that a patient
will need longer
term or chronic NSAID therapy for conditions such as endometriosis or
generalized pelvic pain.
In another set of embodiments, a composition such as described herein may be
used to
treat a subject having or at risk of having generalized pelvic pain, acute
pelvic pain and chronic
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pelvic pain. Without wishing to be bound by theory, these can result from
endometriosis,
adenomyosis, ovulatory pain, ovarian cyst pain and or pelvic muscle associated
pain.
Dosing may or may not be different depending on the underlying cause. In some
embodiments, the only difference in dosing is the duration of treatment, e.g.,
where chronic
pelvic pain from chronic conditions (such as endometriosis) likely needs
longer durations of
treatment (e.g. weeks to months) whereas acute pain or pain flares (e.g.
dysmenoiThea, ovulatory
pain) likely requires a shorter duration of pain. Most of the time oral NSAIDs
are dosed as
needed, for example, for dysmenorrhea this is normally during the premenstrual
time, when
uterine contractions are beginning and for maybe the first few days of menses.
In embodiments, the composition is administered to a subject between one and
ten times.
In embodiments, the composition is administered to a subject between one and
ten times per
menstrual cycle. In embodiments, the composition is administered to a subject
between one and
five times per menstrual cycle. In embodiments, the composition is
administered to a subject
between one and three times per menstrual cycle. In embodiments, the
composition is
administered to a subject one time per menstrual cycle. In embodiments, the
composition is
administered to a subject twice per menstrual cycle.
In embodiments, the composition is administered daily. In embodiments, the
composition
is administered every two days. In embodiments, the composition is
administered every 3, 4, 5,
6, 7, 8, 9, 10, 20, 28, or 30 days. In embodiments, the composition is
administered as needed, for
example when the subject is in pain.
Terms such as "treat," "treatment," "treating," etc. comprise therapeutic
treatment of
subjects having already developed a disease, in particular in manifest form.
Therapeutic
treatment may be symptomatic treatment in order to relieve the signs and/or
symptoms of the
disease or causal treatment in order to reverse, partially reverse, stop, or
slow down the
progression of the disease. Thus, the compositions and methods of the present
disclosure may be
used, for instance, as therapeutic treatment (e.g., for acute or chronic
therapy).
Additionally, terms such as "prevent," "preventing," or "prevention" generally
refer to
the reduction of the occurrence of the disease, and/or a sign and/or symptom
thereof, in the
treated sample relative to an untreated control sample, or delays the onset of
one or more signs
and/or symptoms of the disease relative to the untreated control sample, in a
statistically
significant manner. Preventing the disease, and/or a sign and/or a symptom
thereof, includes
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preventing or delaying the initiation of the disease, sign, and/or symptom.
Prevention also
includes preventing a recurrence of the disease, sign, and/or symptom.
In certain aspects, the composition can be applied to a subject, e.g., to the
vagina of a
subject, and/or to another body cavity, for example, the mouth or the rectum.
Any suitable
technique may be used to apply the composition to the subject. For instance,
the composition
may be free or mass flowing, e.g., so that it may be administered through an
applicator or other
suitable device. Thus, in some embodiments, the composition may be contained
within
applicator, such as a vaginal applicator or a syringe, which can be applied,
e.g., by the subject, or
by another person.
The subject may be, but is not limited to, humans (i.e., a male or female of
any age group,
e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject
(e.g., young adult, middle-
aged adult, or senior adult)) and/or other non-human animals, for example,
mammals (e.g.,
primates (e.g., monkeys such as cynomolgus monkeys or rhesus monkeys,
chimpanzees, etc.);
commercially relevant mammals such as cattle, pigs, horses, sheep, rabbits,
mice, rats, goats,
cats, dogs, etc.) and birds (e.g., commercially relevant birds such as
chickens, ducks, geese,
turkeys, etc.). In certain embodiments, the subject is a mammal. The subject
may be a male or
female and at any stage of development. A non-human animal may be a trans
genie animal.
In one set of embodiments, as discussed, the composition is applied to treat
the subject
with a therapeutically effective amount of an active ingredient, such as any
of those described
herein. The therapeutically effective amount may be an amount which, when
administered to a
subject for treating or preventing a disease, is sufficient to effect such
treatment or prevention for
the disease, for example, any of those described herein. Examples include, but
are not limited to,
vulvovaginal candidiasis (yeast infection), vulvovaginal pain, cervical or
vaginal cancer,
hormone therapy, or the like, e.g., as discussed herein. The therapeutically
effective amount may
also be an amount sufficient to elicit a desired biological response, i.e.,
alleviating a symptom.
The therapeutically effective amount may vary depending on such factors as the
desired
biological endpoint, the mode of administration, and/or the age and health of
the subject.
Kits
Still another aspect of the present disclosure is directed to kits. The kit
may include a
package or an assembly including one or more of the compositions as described
herein, and/or
other compositions. Each of the compositions of the kit may be provided in
liquid form (e.g., in
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solution), or in solid form (e.g., a dried powder), or in gaseous form in some
cases. In certain
cases, some of the compositions may be constitutable or otherwise processable
(e.g., to an active
form), for example, by the addition of a suitable solvent or other species,
which may or may not
be provided with the kit. Examples of other components include, but are not
limited to, solvents,
surfactants, diluents, salts, buffers, emulsifiers, chelating agents, fillers,
antioxidants, binding
agents, bulking agents, preservatives, drying agents, antimicrobials, needles,
syringes, packaging
materials, tubes, bottles, flasks, beakers, dishes, fits, filters, rings,
clamps, wraps, patches,
containers, and the like, for example, for using, administering, modifying,
assembling, storing,
packaging, preparing, mixing, diluting, and/or preserving the compositions
components for a
particular use, for example, to a sample and/or a subject.
A kit may, in some cases, include instructions in any form that are provided
in connection
with the compositions described herein in such a manner that one of ordinary
skill in the art
would recognize that the instructions are to be associated with those
compositions. For instance,
the instructions may include instructions for the use, modification, mixing,
diluting, preserving,
administering, assembly, storage, packaging, and/or preparation of the
compositions and/or other
compositions associated with the kit. In some cases, the instructions may also
include
instructions for the delivery and/or administration of the compositions, for
example, for a
particular use, e.g., to a sample and/or a subject. The instructions may be
provided in any form
recognizable by one of ordinary skill in the art as a suitable vehicle for
containing such
instructions, for example, written or published, verbal, audible (e.g.,
telephonic), digital, optical,
visual (e.g., videotape, DVD, etc.) or electronic communications (including
Internet or web-
based communications), provided in any manner.
In an embodiments, provided herein are kits comprising the compositions and
gels
described herein. For example, the kit includes an applicator suitable for
vaginal application. In
other examples, the applicator is pre-filled with the compositions or the gels
described herein. In
other embodiments, the applicator is not-prefilled with the compositions or
the gels described
herein. In some embodiments, the compositions or gels described herein are at
refrigerated
temperatures (e.g., about 4 C) prior to pre-filling the applicator. In some
embodiments, the kit
includes an applicator that is pre-filled with the composition, where the
composition includes a
poloxamer, a stabilization polymer, and an active ingredient (e.g., diclofenac
or any other
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therapeutic agent for inducing cervical ripening or treating dysmenorrhea or
treating primary
dysmenorrhea).
In some embodiments, the kit further includes one or more instructions for
inserting the
applicator into the vagina. In other embodiments, the kit includes
instructions for inducing
cervical ripening, treating dysmenorrhea, treating primary dismenorrhea by
applying the
applicator filled with the compositions or gels described herein. In some
embodiments, the kit
further includes instructions for filling the applicator with the composition
or gel.
In some embodiments, the compositions described herein are stored at room
temperature
(either pre-filled in an applicator or a separate storage container). In some
embodiments, the
compositions can be stored for 1 day, 2 days, 10 days, 2 weeks, 1 month, 2
months, 3 months, 4
months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year,
or more at
room temperature.
EXAMPLES
The following examples are intended to illustrate certain embodiments of the
present
disclosure, but do not exemplify the full scope of the disclosure.
Example 1: Composition
In this prophetic example, a composition in accordance with one embodiment is
as
follows (all components USP grade). The active ingredient may be dinoprostone,
diclofenac, or
the like.
TABLE 3 - composition
Material g/100 g
Poloxamer 407 16.50
Xanthan gum 2.00
Active ingredient 2.00
Citric acid monohydrate 0.60
Sodium citrate dihydrate 0.55
Benzyl alcohol 1.00
Purified water (qs) 77.35
Total 100
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Example 2: Method of making the composition
This prophetic example illustrates a method of making the composition
described in
Example 1, in accordance with another embodiment.
Purified water is added to a kettle (or other suitable container), which is
placed under a
dissolver (30-60 HP) with a 12-inch stand dissolver blade. The dissolver is
started, and an active
ingredient is added to the kettle. The dissolver is allowed to mix for at
least 10 minutes, or until
the active ingredient has visually dissolved in the water.
Afterwards, mixing is continued while citric acid monohydrate and sodium
citrate
dihydrate are added to the kettle. The kettle is then cooled with chilled
cooling water, e.g., a
temperature of 8 C. Mixing is continued for at least 5 minutes, or until
these have visually
dissolved.
Mixing and cooling then continues while benzyl alcohol and poloxamer 407 is
added.
These are mixed until the water is clear and everything has visually
dissolved.
Mixing and cooling continues while xanthan gum is slowly added. Mixing of the
xanthan gum continues for at least 10 minutes, or until the composition is
visually uniform. The
speed of mixing may be adjusted, for example, as the composition thickens and
its viscosity
increases, and/or to avoid trapping too many air bubbles within the
composition.
Next, the composition is transferred into a round-bottom, jacketed, stainless
steel
pressure/vacuum kettle, or another suitable container. The kettle is cooled as
before, e.g., using
chilled cooling water at 8 C. Mixing in the kettle is started and the batch
is slowly recirculated
under a vacuum. Mixing, cooling with chilled cooling water, and recirculating
under vacuum
occurs for at least 30 minutes, or until the composition has been sufficiently
deaerated.
It should be understood that the above is by way of example only, and that
other
techniques for making the compositions described herein are also contemplated.
For example,
the addition sequence of poloxamer 407 and xanthan gum may be reversed, with
the poloxamer
going into the mixing first. Air may be removed using a centrifuge, a
Versator, or the like.
Example 3: Method of making the composition
This prophetic example illustrates a method of making a composition in
accordance with
another embodiment.
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The primary compounding phase in this example is prepared by adding 154 kg of
Purified Water USP to a 270 L kettle. The kettle is placed under a dissolver
equipped with a 10-
inch standard blade. Mixing commences at about 600 rpm. 4.86 kg of an active
ingredient is
added and mixed for 10 minutes until visually dissolved. Mixing continues and
1200 g citric
acid and 1100 g of sodium citrate are added and mixed for 6 min until visually
dissolved.
Cooling of the batch is started during this step by flowing chilled water
through the kettle jacket.
Mixing continues and 2000 g of benzyl alcohol and 33.0 kg of poloxamer 407 are
added.
Cooling and mixing continue until the solution is clear and the poloxamer is
visually dissolved.
The batch temperature reaches approximately 11 C during this step. This step
creates foam on
the surface of the batch and the mixing speed is decreased to allow the foam
to dissipate. Mixing
speed is then increased, eventually reaching 1200 rpm for addition of the 4.00
kg of xanthan
gum. After the addition of the xanthan gum, the product rapidly increases in
viscosity and the
original mixing blade size is switched to a 12-inch blade to better facilitate
mixing at this stage
of the process. A 14-inch blade may also be used at this scale.
After this step in the process, the product has generated a large amount of
foaming. The
foaming can be reduced by transferring the product into a cooling, jacketed
vacuum vessel and
recirculate the product for several passes to help remove the air. Another
approach is to use a
Versator, which is a device for removing air from liquids and semi-solids. The
product was
passed through the Versator several times until all air was removed.
Measurements of the
viscosity after Versator treatment rose to over 3 million cP, from 1.2 million
cP at room
temperature prior to using the Versator.
Example 4: Viscosity of the composition
The present example shows the viscosity of a composition in accordance with
one
embodiment as a function of temperature. It will be noted that, even at room
temperature (about
25 C), the composition has a viscosity of over 1 million cP.
Fig. 1 illustrates the viscosity (in mPA s, equilavent to cP) plotted as a
function of
temperature for the composition shown in Example 1. Viscosity was measured
using a
Brookfield Viscometer.
In this experiment, the viscosity at 25 C was found to be 1,798,000 cP, while
the
viscosity at 37 C (body temperature) was found to be 1,759,000 cP.
34
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Example 5: In vitro release testing (IVRT) results
In vitro release testing (IVRT) was evaluated for diclofenac sodium gel 1%,
2%, and 3%
at n=6 using a PION Rainbow in situ fiber optic probes with PDA (200-720 nm)
with 2 mm
stainless steel probes. The results for the average release and release rate
(slope) are presented in
Table 4 (below).
The release rate increased proportionally with the dose (FIG. 2 and FIG. 3).
The release
rate did not strictly follow the classical Higuchi model for drug release of
suspensions from the
matrix, which may be explained by the additional changes in the rheology which
correlate to the
increase solids content in the formulation. The result describes a more
complex relationship
between the formulation composition and the drug release.
Table 4: IVRT Results
Time Average Drug Release (ig/cm2)
SQRT Time
(hours) 1% Gel 2% Gel 3% Gel
1 1.00 46.4 142.5 316.6
2 1.41 89.9 250.0 507.5
3 1.73 133.6 346.6 668.4
4 2.00 168.9 436.7 806.6
5 2.24 203.9 521.1 928.3
6 2.45 237.9 598.3 1037.5
Slope (Rate) 132.6 316.2 500.2
R2 0.995 0.995 0.999
%RSD 2.2 4.3 2.5
The release rates obtained during IVRT for the three test batches were used to
calculate
the estimated time for 50, 80, and 100% drug release (Table 5, below) based on
a dose coverage
of -0.23g/cm2 assuming a constant release rate. Typically the release rate
slowed as the dose is
depleted so it would be expected that the actual times for 80% and 100% drug
release would be
longer than provided by this estimate.
There are at least two notable aspects of this release data. First, diclofenac
is in
suspension, not solution, within the gel. As compared to poloxamer gel
containing a solubilized
active agent (e.g., clindamycin), diclofenac would be expected to take longer
to release out of an
equivalent amount of gel matrix. Second, a relationship between pH and
diclofenac release rate
CA 03227295 2024- 1- 26
WO 2023/009461 PCT/US2022/038234
has been observed. It is implicit in the data in Table 4 showing a non-linear
variance in release
rate as the API concentration goes up. When combined with the data in Table 17
that the pH
goes up as the API concentration goes up, it supports the conclusion that
higher pH supports
faster release. Table 5 further supports this by showing that the 3% gel
releases 50%, 80% and
100% faster than 1% or 2% diclofenac compositions.
Table 5: Estimated time for diclofenac release
Time (hours)
Sample 50% Drug 80% Drug 100% Drug
Release Release Release
1% Gel 30 47 59
2% Gel 25 40 50
3% Gel 24 40 47
IVRT for diclofenac gel at 1% and 3% w/w
Additional IVRT was performed for diclofenac vaginal gel 1% and 3% w/w. For
this
analysis the receptor media was changed from phosphate buffer pH 7 to
simulated vaginal fluid.
Sampling was executed every 60 minutes for 6 hours, and a single point at T=24
hours. Total
volume replacement at each time point was implemented due the low solubility
of the drug
substance in the simulated vaginal fluid (-16 p,g/mL).
The results for both dose strengths followed the square root (t) model through
24 hours.
The drug release was linear with time through at least 6 hours, and then began
to taper off
slightly by 24 hours. This demonstrated a typical release profile for a drug
substance suspended
in a viscoelastic matrix. The vessel-to-vessel variance (%RSD) was <4% for
both runs, and the
R2 values for the SORT(t) was >0.99 through 24 hours.
From the data collected through 24 hours the drug release versus time for the
applied
dose (-0.4 g) was estimated according to the Higuchi square root equation
based on the total
surface area of the IVRT membrane, and the average surface area of the vagina
(see, P.
Pendergrass, M Belovicz. Surface Area of the Human Vagina as Measured from
Vinyl
Polysiloxane Casts. February 2003. Gynecologic and Obstetric Investigation
55(2):110-3,
incorporated herein by reference in its entirety). The percent drug release at
T=24 hours (4.3%
and 2.4% respectively) was included in the estimate for comparison to the
measured result to the
regression model. Tables 6 and 7 below show the estimated relates for the 1%
diclofenac gel and
3% diclofenac gel, respectively
36
CA 03227295 2024- 1- 26
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Table 6: Estimated Release for the 1% Diclofenac Vaginal Gel
Est. In
Total g IVRT hours
% Release Vivo hours
Release (1.77 cm^2)
(87.5 cm^2)
100 4000 10272.3 4.2
80 3200 6574.2 2.7
50 2000 2568.1 1.1
25 1000 642.0 0.3
4.3 174 19.4 0.0
Table 7: Estimated Release for the 3% Diclofenac Vaginal Gel
______________________________________________
ESL In
Total p,g IVRT hours "
P% Release Vivo hours
Release (1.77 cm^2)
(87.5
100 12000 46358.5 19.0
80 9600 29669.5 12.1
50 6000 11589.6 4.7
25 3000 2897.4 1.2
2.4 287 26.5 0.01
The estimated time assumes the parameters of the Higuchi model are maintained
throughout the drug release and do not account for total dose depletion, pH
changes, swelling of
the matrix, or dissolution of the gel. As an estimate the relationship between
the total dose and
drug release time can be modeled as the change in dose squared:
it22'µ:2
RT2 = (--- RT1
-Q1)
Where:
RT is the release time
Ql is the reference dose
Q2 is the new dose
Example: Change in 100% release time of a 1% gel for a 0.4g dose to a 1 g dose
based on a
surface area of 87.5 cm2.
1N:00
A .k A" 4. Maims - 26.3 hours
sANI:1380.0
37
CA 03227295 2024- 1- 26
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Table 8: IVRT Results for 1% w/w Diclofenac Gel (see also FIG. 4 and FIG. 5)
Hours sqrt ptg/cm2 Avg.
(hrs) 1 2 3 4 5 6 ptg/cm2
0.5 0.71 7.13 6.96 8.85 6.53 5.53 7.34
7.06
1.0 1.00 10.61 10.51 13.11 10.59 8.45
11.21 10.75
2.0 1.41 17.17 17.26 20.14 18.20 15.19 18.49 17.74
3.0 1.73 23.39 23.51 26.76 25.33 21.61 25.23 24.30
4.0 2.00 29.43 29.54 33.54 32.28 27.80 31.68 30.71
5.0 2.24 35.50 35.50 40.22 39.21 33.79 38.01 37.04
Avg.
6.0 2.45 41.78 41.37 46.71 45.84 39.58 44.12 43.23
Slop
(SQRT
24.0 4.90 96.08 93.23 100.52 103.37 95.95 100.18 98.22
(t)
Linear Slope 3.6 3.5 3.7 3.9 3.7 3.8 3.71
22.3
R2 0.967 0.962 0.956 0.958 0.970 0.962
SQRT (0 Slope 21.8 21.1 22.4 23.7 22.2 22.7
Linear Slope 3.8
%RSD
R2 0.995 0.996 0.996 0.996 0.994 0.996
SQRT(t) Slope 3.9
%RSD
Table 9: IVRT Results for 3% w/w Diclofenac Gel (see also FIGs. 6 and 7)
H sqrt ttg/cm^2
ours
(hrs) 1 2 3 4 5 6 Avg.
0.5 0.71 32.25 32.24 25.21 24.28 45.12 47.44 31.82
1.0 1.00 40.23 39.11 32.87 31.08 53.23
92.29 39.30
2.0 1.41 51.22 48.89 43.60 41.66 63.28 129.12 49.73
3.0 1.73 60.10 57.60 52.78 51_37 71.94 195.33 58.76
4.0 2.00 68.68 65.73 61.55 59.95 80.32 265.81 67.25
5.0 2.24 76.73 73.43 69.78 68.91 89.05 334.58 75.58
Avg.
6.0 2.45 84.76 81.15 77.64 77.22 97.69 407.06 83.69
SQRT(t)
24.0 4.90 161.91 154.95 159.56 162.58 171.88 532.51 162.18
Slope
Linear Slope 5.2 4.9 5.4 5.6 5.1 18.4 5.2
31.5
R2 0.958 0.962 0.965 0.969 0.956 0.709
SQRT (t) Slope 31.2 29.7 32.4 33.5 30.6 120.6
Linear Slope 5.1
%RSD
R2 0.999 0.998 0.997 0.996 0.998 0.873
SQRT(t) Slope 4.9
%RSD
Example 6: Release rate evaluation
This study evaluated the release rate of diclofenac by in-vitro release
testing of diclofenac
1% and 3% gel in simulated vaginal fluid. Two liters of simulated vaginal
fluid was prepared
and the release rate of diclofenac from 1% and 3% gels was evaluated. The
formulation
composition for simulated vaginal fluid is shown in Table 10 below. To prepare
the simulated
vaginal fluid, -1700 mL of purified water was transferred into a tared 2L
beaker with a stir bar,
38
CA 03227295 2024- 1- 26
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PCT/US2022/038234
the components were mixed until dissolved, the pH was adjusted to 4.5 with LON
HC1/Na0H,
the solution was transfer into a 2 L volumetric flask and diluted
volumetrically with purified
water and mix well, and the solution was degased for 30 minutes prior to use.
Table 10: Formulation Composition of Simulated Vaginal Fluid
Amount
Item Amount/Batch
Ingredient % w/w mg/mL
Weighed
(g)
1 Sodium Chloride 0.351 3.510 7.020
2 Potassium Hydroxide 0.140 1.400 2.800
3 Calcium Hydroxide 0.022 0.222 0.444
4 Bovine Serum Albumin 0.002 0.018 0.036
5 Lactic Acid 0.200 2.000 4.000
6 Acetic Acid 0.100 1.000 2.000
7 Glycerol 0.016 0.160 0.320
8 Urea 0.040 0.400 0.800
9 D(+)-Glucose 0.500 5.000 10.000
pH to 4.5 (HC1/Na0H) QS QS QS
11 Water 98.629 986.29 1972.580
Total 100.000 1000.000 2000.000
The results of the testing are shown in the tables below, where 178003-2201
corresponds to 1%
w/w diclofenac gel, and 178003-2203 corresponds to 3% w/w/ diclofenac gel.
39
CA 03227295 2024- 1- 26
n
>
o
L.
r.,
r.,
--4
Lo
u,
r.,
o
r.,
4.'
, Table 11: Release data for 178003-2201 (1% w/w diclofenac gel)
0
30 Minutes
240 Minutes 0
t.)
Cell mL of Total g Total
Cell mL of Total g Total =
Measured Measured
"
Cell Volume Sample Previously g/cmA2 Cell
Volume Sample Previously g/cm^2 w
,
gimL
(mL) collected Removed Released
(mL) Collected Removed Released
.1-
1 0.63 20.0 19.521 0.00 7.13 1 0.55
20.0 19.476 41.10 29.43 a
-,
2 0.62 20.0 19.353 0.00 6.96 2 0.55
20.0 19.368 41.27 29.54
3 0.78 20.0 19.666 0.00 8.85 3 0.61
20.0 19.472 47.08 33.54
4 0.58 20.0 19.427 0.00 6.53 4 0.63
20.0 19.484 44.50 32.28
0.49 20.0 17.948 0.00 5.53 5 0.56 20.0 19.682
38.06 27.80
6 0.65 20.0 19.407 0.00 7.34 6 0.59
20.0 19.461 44.36 31.68
60 Minutes
300 Minutes
Cell mL of Total g Total
Cell mL of Total g Total
Measured Measured
Cell Volume Sample Previously g/cm"2 Cell
Volume Sample Previously g/cm^2
pg/mL pg/mL
(mL) Collected Removed Released
(mL) Collected Removed Released
1 0.32 20.0 19.633 12.32 10.61 1 0.55
20.0 19.435 51.80 35.50
2 0.33 20.0 19.424 11.92 10.51 2 0.55
20.0 19.404 51.94 35.50
3 0.39 20.0 19.675 15.40 13.11 3 0.61
20.0 19.517 59.04 40.22
4 0.38 20.0 19.557 11.23 10.59 4 0.63
20.0 19.474 56.81 39.21
5 0.31 20.0 19.162 8.78 8.45 5 0.54
20.0 19.707 49.02 33.79
6 0.36 20.0 19.488 12.61 11.21 6 0.58
20.0 19.488 55.76 38.01
t
n
-i
;--.
5
cp
L.)
=
L.)
L.)
--
w
00
L.)
w
.1-
n
>
o
L.
r.,
r.,
--4
N,
Lo
u,
r.,
o
r.,
4.'
, Table 11, continued
0
o
t..)
120 Minutes
360 Minutes =
w
Cell mL of Total ng Total
Cell mL of Total ng Total ,
=
Measured Measured
Cell Volume Sample Previously pg/cm^2 Cell
Volume Sample Previously g/cm^2
g/mL ng/mL
.r..
a
(mL) Collected Removed Released
(mL) Collected Removed Released -,
1 0.59 20.0 19.589 18.66 17.17 1 0.57
20.0 19.300 62.52 41.78
2 0.61 20.0 19.371 18.41 17.26 2 0.54
20.0 19.435 62.52 41.37
3 0.63 20.0 19.568 23.07 20.14 3 0.59
20.0 19.566 70.90 46.71
4 0.68 20.0 19.473 18.58 18.20 4 0.60
20.0 19.523 69.08 45.84
0.61 20.0 19.450 14.70 15.19 5 0.52 20.0 19.714
59.64 39.58
6 0.65 20.0 19.565 19.65 18.49 6 0.56
20.0 19.524 66.99 44.12
180 Minutes
24 hours
Cell mL of Total ng Total
Cell mL of Total ng Total
Measured Measured
Cell Volume Sample Previously g/cm^2 Cell Volume Sample
Previously g/cm^2
g/mL
(mL) Collected Removed Released
(mL) Collected Removed Released
1 0.56 20.0 19.476 30.16 23.39 1 4.83
20.0 NA 73.54 96.08
2 0.57 20.0 19.412 30.17 23.51 2 4.61
20.0 NA 72.92 93.23
3 0.60 20.0 19.533 35.38 26.76 3 4.78
20.0 NA 82.43 100.52
4 0.65 20.0 19.466 31.86 25.33 4 5.11
20.0 NA 80.85 103.37
5 0.59 20.0 19.685 26.54 21.61 5 5.00
20.0 NA 69.91 95.95
6 0.61 20.0 19.501 32.45 25.23 6 4.98
20.0 NA 77.83 100.18 t
n
-i
;--.
cp
L.)
=
L.)
L.)
--
4,
00
L.)
4,
.1-
41
n
>
o
L.
r.,
r.,
--4
Lo
u,
r.,
o
r.,
4.'
, Table 12: Release data for 178003-2203(3% w/w diclofenac gel)
0
30 Minutes
240 Minutes 0
t.)
Cell mL of Total g Total
Cell mL of Total g Total =
Measured Measured
"
Cell Volume Sample Previously g/cm^2 Cell
Volume Sample Previously g/cm^2 w
,
ug/mL
(mL) collected Removed Released
(mL) Collected Removed Released
.1-
1 2.85 20.0 19.640 0.00 32.25 1 0.78
20.0 19.316 106.04 68.68 a
-,
2 2.85 20.0 19.336 0.00 32.24 2 0.74
20.0 19.407 101.48 65.73
3 2.23 20.0 19.496 0.00 25.21 3 0.80
20.0 19.126 93.05 61.55
4 2.15 20.0 19.559 0.00 24.28 4 0.79
20.0 19.530 90.32 59.95
3.99 20.0 19.154 0.00 45.12 5 0.76 20.0 19.614
126.97 80.32
6 4.20 20.0 19.231 0.00 47.44 6 6.39
20.0 19.770 342.62 265.81
60 Minutes
300 Minutes
Cell mL of Total lig Total
Cell mL of Total g Total
Measured Measured
Cell Volume Sample Previously g/cm^2 Cell
Volume Sample Previously g/cm^2
fig/mL pg/mL
(mL) Collected Removed Released
(mL) Collected Removed Released
1 0.76 20.0 19.628 56.05 40.23 1 0.74
20.0 19.519 121.03 76.73
2 0.70 20.0 19.380 55.17 39.11 2 0.70
20.0 19.464 115.89 73.43
3 0.73 20.0 19.621 43.50 32.87 3 0.76
20.0 19.136 108.26 69.78
4 0.65 20.0 19.399 42.03 31.08 4 0.81
20.0 19.544 105.74 68.91
5 0.89 20.0 19.644 76.48 53.23 5 0.79
20.0 19.817 141.88 89.05
6 4.13 20.0 19.410 80.73 92.29 6 6.16
20.0 19.651 469.01 334.58
t
n
-i
;--.
cp
L.)
=
L.)
L.)
--
4,
00
L.)
4,
.1-
42
n
>
o
L.
r.,
r.,
--4
N,
Lo
u,
r.,
o
r.,
4.'
, Table 12, continued
0
o
t.)
120 Minutes
360 Minutes =
w
Cell mL of Total pg Total
Cell mL of Total pg Total ,
=
Measured Measured
Cell Volume Sample Previously pig/cm^2 Cell
Volume Sample Previously g/cm^2
lig/mL
.r..
a
(mL) Collected Removed Released
(mL) Collected Removed Released
1 0.99 20.0 19.556 70.93 51.22 1 0.73
20.0 19.542 135.46 84.76
2 0.89 20.0 19.548 68.79 48.89 2 0.70
20.0 19.392 129.60 81.15
3 0.96 20.0 19.566 57.90 43.60 3 0.73
20.0 19.634 122.86 77.64
4 0.96 20.0 19.130 54.62 41.66 4 0.75
20.0 19.395 121.59 77.22
0.91 20.0 18.984 93.91 63.28 5 0.77 20.0 19.646
157.47 97.69
6 3.38 20.0 19.475 160.91 129.12 6 6.52
20.0 19.358 590.06 407.06
180 Minutes
24 hours
Cell mL of Total pg Total
Cell mL of Total itg Total
Measured Measured
Cell Volume Sample Previously pg/cm^2 Cell
Volume Sample Previously g/cm^2
14ml, Itg/mL
(mL) Collected Removed Released
(mL) Collected Removed Released
1 0.81 20.0 19.594 90.21 60.10 1 7.23
18.9 NA 149.69 161.91
2 0.79 20.0 19.401 86.13 57.60 2 6.94
18.9 NA 143.21 154.95
3 0.83 20.0 19.558 76.76 52.78 3 7.88
18.4 NA 137.15 159.56
4 0.90 20.0 19.317 72.91 51.37 4 8.31
18.2 NA 136.22 162.58
5 0.81 20.0 19.562 111.09 71.94 5 6.93
19.0 NA 172.64 171.88
t
6 5.95 20.0 19.476 226.76 195.33 6 12.07
18.8 NA 716.31 532.51 n
-i
;--.
cp
L.)
=
L.)
L.)
--
4,
00
L.)
4,
.1-
43
WO 2023/009461
PCT/US2022/038234
Example 7: Compatibility assay of diclofenac gel in Gel Formulation 1
The results of analysis for the compatibility of 1%, 2%, and 3% Diclofenac
Sodium Gel
in Gel Formulation 1 composition are provided herein. The formulation
composition of each
Diclofenac Sodium Gel is outlined in Tables 13-15 below.
Table 13: Composition of 1% Diclofenac Sodium Gel Batch 178003-2201
Item No. Ingredient % w/w mg/g
Amount/Batch
(g)
1 Poloxamer F127 16.50 165.00 82.50
2 Xanthan Gum, USP 2.00 20.00 10.00
3 Diclofenac Sodium 1.00 10.00 5.00
4 Citric Acid 0.60 6.00 3.00
Monohydrate
5 Sodium Citrate 0.55 5.50 2.75
Dihydrate
6 Benzyl Alcohol 1.00 10.00 5.00
7 Purified Water 74.35 743.50 371.75
8 Purified Water QS 4.00 40.00 20.00
9 Total 100.00 1000.00 500.00
Table 14: Composition of 2% Diclofenac Sodium Gel Batch 178003-2202
Item No. Ingredient % w/w mg/g
Amount/Batch
(g)
1 Poloxamer F127 16.00 160.00 80.00
(Portion A)
2 Poloxamer F127 0.50 5.00 2.50
(Portion B)
3 Xanthan Gum, USP 2.00 20.00 10.00
4 Diclofenac Sodium 2.00 20.00 10.00
5 Citric Acid 0.60 6.00 3.00
Monohydrate
6 Sodium Citrate 0.55 5.50 2.75
Dihydrate
7 Benzyl Alcohol 1.00 10.00 5.00
8 Purified Water 73.35 733.50 366.75
9 Purified Water QS 4.00 40.00 20.00
Total 100.00 1000.00 500.00
44
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Table 15: Composition of 3% Diclofenac Sodium Gel Batch 178003-2203
Item No. Ingredient % w/w mg/g
Amount/Batch
(g)
1 Poloxamer F127 16.00 160.00 80.00
(Portion A)
2 Poloxamer F127 0.5 5.00 2.50
(Portion B)
3 Xanthan Gum, USP 2.00 20.00 10.00
4 Diclofenac Sodium 3.00 30.00 15.00
Citric Acid 0.60 6.00 3.00
Monohydrate
6 Sodium Citrate 0.55 5.50 2.75
Dihydrate
7 Benzyl Alcohol 1.00 10.00 5.00
8 Purified Water 72.35 723.50 361.75
9 Purified Water QS 4.00 40.00 20.00
Total 100.00 1000.00 500.00
Viscosity
5 The viscosity was evaluated using a calibrated parallel plate
oscillating rheometer, model
MCR 102 by Anton Paar, and a PP 25 measuring device. A single point viscosity
was measured
in duplicate at 0.22 1/s for 60 seconds at 25 C and 37 C. Due to excessive air
in the drug product
a portion of each batch was centrifuged at 6,000 RPM for 10 minutes prior to
measuring
viscosity. The results outlined in 15 presents the average viscosity. Batches
178003-2201 and
10 178003-2202 exhibited a significant decrease in viscosity at 37 C
compared to the viscosity at
25 C. Batch 178003-2203 exhibited some thermo-reversible gel properties with a
17% increase
in viscosity at 37 C.
The relationship (correlation) between the temperature and viscosity of the
composition
was important. Normally, viscosity of poloxamer gels increases with
temperature. However,
with the compositions described herein, the viscosity levels off or decreases.
Without being
bound by theory, it is believed this may be related to viscosity at room
temperature (e.g., gel
having higher viscosity at room temperature is more likely to have velocity
decrease with
increased temperature).
CA 03227295 2024- 1- 26
WO 2023/009461
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Table 16: Results for Viscosity at 0.22 1/s
Batch No: Shear Rate Duration Average Viscosity at
Average Viscosity at
25 C 37 C
1/s Seconds M*Pas M*Pas
178003-2201 0.22 60.0 1,652,400 996,155
(1% diclofenac)
178003-2202 0.22 60.0 895,255 827,575
(2% diclofenac)
178003-2203 0.22 60.0 953,035 1,135,450
(3% diclofenac)
Qkf
Due to the viscous nature of the drug product, pH was evaluated by diluting a
portion of
the drug product with an equal amount by weight of Total Organic Carbon (TOC)
water and
mixed until uniform. The pH results for each prototype are presented in Table
17, below. These
results demonstrated a significant increase in pH with the increase in
diclofenac sodium
concentration. In some embodiments, this correlation may be due to the
chemical nature of the
ingredients.
Diclofenac solubility was shown to depend on pH, with higher solubility
correlated with
higher p11 of the gel.
Due to the natural acidity of the vagina, vaginal compositions typically aim
for a pH of
about 4.5. Vaginal compositions described herein (e.g., using diclofenac) may
have pH values
up to about 5.5. In some embodiments, gels described herein containing
diclofenac may require
additional buffer (e.g., increased sodium citrate concentration) as compared
to the gel containing
other active agents.
Table 17: Results for pH
Batch pH
178003-2201 5.04
(1% diclofenac)
178003-2202 5.84
(2% diclofenac)
178003-2203 6.54
(3% diclofenac)
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Appearance
Appearance was evaluated visually based on color and general physical
properties such
as absence of agglomerates and absence of particulate matter. The results for
appearance are
presented in Table 18 and FIG. 8 and FIG. 9.
Table 18: Appearance results
Appearance
Batch No. Color Absence of Absence of Particulate
Comments
Agglomerates Matter
178003-2201 Off White/Opaque Conforms Conforms
Contains excessive
(1% diclofenac)
amounts of air
178003-2202 White/Slightly Conforms Conforms
Contains excessive
(2% diclofenac) Opaque
amounts of air
178003-2203 White Conforms Conforms
Contains excessive
(3% diclofenac)
amounts of air
The rheological comparison between the three prototypes indicated that batch
178003-2203
exhibited some thermos-reversible gel properties with a 17% increase in the
average viscosity at
37 C. Variation in pH was reported between prototypes but was expected due to
the chemical nature
of the API. Appearance results indicated a slight difference in color between
prototypes with batch
178003-2203 exhibiting a more pronounced white due to the higher
concentrations of API.
Based on these data Diclofenac Sodium is compatible with the Gel Formulation 1
composition.
Example 8: Uniformity and Viscosity
The results for assay of diclofenac sodium and benzyl alcohol were within the
expected
range. Uniformity for batches 2201 (1% diclofenac gel) and 2203 (3% diclofenac
gel) was
similar to the values obtained for assay and were within 2% RSD which is the
verified precision
of the method. Changes were observed in the rheology which correlated to the
increased API
(diclofenac) concentration. Particularly, these effects were observed in the
shear stress of the
flow point and in the thermal viscosity. These changes may be due to
differences in the solids
content and/or the water in the formulation. Surprisingly, a composition
having diclofenac in
suspension (not solution), was expected to take longer to release an
equivalent amount of gel
matrix. Also, a pH effect on release rate described herein. It is implicit in
the data in Table 4
showing a non-linear variance in release rate as the API concentration goes
up. When combined
with the data in Table 17 that the pH goes up as the API concentration goes
up, it supports the
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conclusion that higher pH supports faster release. Table 5 further supports
this by showing that
the 3% gel releases 50%, 80% and 100% faster than 1% or 2% diclofenac
compositions.
Uniformity
Uniformity was evaluated and the results are provided in Table 19 below
Table 19: uniformity results
Assay of Assay of
% Related
Batch Number Diclofenac Uniformity Benzyl
Compounds PH
Sodium Alcohol
96.0%
178003-2201 99.4% 95.6% Inclv. Imp: ND
105.5%
5.0
(1% diclofenac) 95.6% Total Imp: ND
%RSD 0.2%
90.4%
178003-2202 97.0% 99.0% Inclv. Imp: ND
102.6%
5.8
(2% diclofenac) 91.3% Total Imp: ND
%RSD 5.1%
96.3%
178003-2203 96.7% 97.5% Indy. Imp: ND
102.4%
6.5
(3% diclofenac) 95.3% Total Imp: ND
%RSD 1.1%
Rheology
Testing was performed at 25 C, 10 racVs, from 0.1-100% amplitude (logarithmic
ramp)
and results are shown in Table 20, below.
Table 20: Rheology
LVER G' LVER Flow Point (Pa)
Batch Number
(Pa) G'/G" (Pa) Tau (Pa) G' (Pa)
178003-2201
8790 9.1 307 2286
(1% diclofenac)
178003-2202
10100 9.1 276 2294
(2% diclofenac)
178003-2203
9930 11.0 215 2304
(3% diclofenac)
Thermal Viscosity
Thermal viscosity testing was performed at 0.221/s, 5 C-45 C, at 1 minute
intervals, pre
shear 3 1/s at 60 seconds and results are shown in FIG X and Table 21 below.
Thermal ramp up
reports are shown in FIGs 11A-11B, 12A-12B, and 13A-13B.
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Table 21: Thermal viscosity
mPas
C
1% 2% 3%
4.9 216,800 33,509 2,808
13.2 262,850 45,200 544,330
21.1 1,713,300 1,068,200 1,196,500
29.0 1,583,600 1,088,500 1,178,600
36.9 1,237,200 997,950 961,980
44.8 1,015,300 941,560 228,600
Example 9: Air removal
In this example, a manufacturing process is outlined describing air removal
from the
composition, as well as filing the composition into vaginal applicators is
provided.
During mixing, 2000 g of benzyl alcohol and 33.0 kg of poloxamer 407 were
added.
Cooling and mixing continued until the solution was clear and the poloxamer
was visually
dissolved. The batch temperature reached approximately 11 C during this step.
This step created
foam on the surface of the batch and the mixing speed was decreased to allow
the foam to
dissipate. Mixing speed was then increased, eventually reaching 1200 rpm for
addition of the
4.00 kg of xanthan gum. After the addition of the xanthan gum, the product
rapidly builds
viscosity and the original mixing blade size proved inadequate. A switch was
made to a 12-inch
blade to better facilitate mixing at this stage of the process.
After this step in the process, the product generated a large amount of
foaming. Initially,
the product was transferred into a cooling, jacketed vacuum vessel and
recirculated the product
for several passes to help remove the air. A second approach used a Versator,
which is a device
especially designed to remove air from liquids and semi-solids. The product
was passed through
the Versator several times until all air was removed. Measurements of the
viscosity after
Versator treatment rose from 1.2 Cp (prior to use of the Versator) to over 3M
Cp at room
temperature.
Following this step, the product can be manually or filled using an automated
filling
machine. In some embodiments, the automated filling machine (e.g., a Capmatic
automated
filing machine) is especially designed to fill vaginal applicator-based
products. As the viscosity
of the product decreased at refrigerated temperatures, e.g., at temperatures
of about 4 C. (e.g., a
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reduction in viscosity of 2-3x) provides a product suitable for automated
filling into a vaginal
applicator. In some embodiments, a cooled, jacketed vessel, feeding cooled
product into the
filler hopper to fill the applicators is used.
Example 10: pH effects on release rate
The purpose of this study is to evaluate effect of the matrix pH on the
release rate
(diffusion) of diclofenac from the drug product.
Objectives
= Prepare 3x 100g batches of Diclofenac 3% Gel at pH 3.5, 5.5, and 6.5
= Evaluate the release rate of each plI adjusted batch by IVRT as per the test
method
RD-0240 over 24 hours.
= Perform IVRT in simulated vaginal fluid for pH 3.5 and 5.5 over 24 hours
= Determine the effects of pH on the release rate of Diclofenac Vaginal
Gel.
Study Design
S I. ID# Receptor Media Drug Product pH
2215-01 50 mM Phosphate Buffer pH 7.0 3.5
2215-02 50 mM Phosphate Buffer pH 7.0 5.5
2215-03 50 mM Phosphate Buffer pH 7.0 6.5
2215-04 Simulated Vaginal Fluid pH 4.5 3.5
2215-05 Simulated Vaginal Fluid pH 4.5 6.5
Testing
Assay of Diclofenac: 90.0 - 110.0% of LC
IVRT: Report Release Rate pg/hr/cm2
Rheology: Thermal Rheology, Amplitude Sweep, Flow Curve
pH: Report Results
Appearance: Report Results
It was expected that the 2% diclofenac composition would release about 2x the
amount of
drug at a given time compared to the 1%, or conversely 3x that of the 3%.
Surprisingly, however
this was not observed. The higher concentration released much faster, and in
fact the 2%
diclofenac composition released all the active component faster than the 1%
diclofenac
composition released all of its active component. Without wishing to be bound
by theory, it is
contemplated that increases in pH increase the release rate of diclofenac.
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Definitions
While several embodiments of the present disclosure have been described and
illustrated
herein, those of ordinary skill in the art will readily envision a variety of
other means and/or
structures for performing the functions ancVor obtaining the results and/or
one or more of the
advantages described herein, and each of such variations and/or modifications
is deemed to be
within the scope of the present disclosure. More generally, those skilled in
the art will readily
appreciate that all parameters, dimensions, materials, and configurations
described herein are
meant to be exemplary and that the actual parameters, dimensions, materials,
and/or
configurations will depend upon the specific application or applications for
which the teachings
of the present disclosure is/are used. Those skilled in the art will
recognize, or be able to
ascertain using no more than routine experimentation, many equivalents to the
specific
embodiments of the disclosure described herein. It is, therefore, to be
understood that the
foregoing embodiments are presented by way of example only and that, within
the scope of the
appended claims and equivalents thereto, the disclosure may be practiced
otherwise than as
specifically described and claimed. The present disclosure is directed to each
individual feature,
system, article, material, kit, and/or method described herein. In addition,
any combination of
two or more such features, systems, articles, materials, kits, and/or methods,
if such features,
systems, articles, materials, kits, and/or methods are not mutually
inconsistent, is included within
the scope of the present disclosure.
In cases where the present specification and a document incorporated by
reference
include conflicting and/or inconsistent disclosure, the present specification
shall control. If two
or more documents incorporated by reference include conflicting and/or
inconsistent disclosure
with respect to each other, then the document having the later effective date
shall control.
All definitions, as defined and used herein, should be understood to control
over
dictionary defmitions, definitions in documents incorporated by reference,
and/or ordinary
meanings of the defined terms.
The indefmite articles "a" and "an," as used herein in the specification and
in the claims,
unless clearly indicated to the contrary, should be understood to mean "at
least one."
The phrase "and/or," as used herein in the specification and in the claims,
should be
understood to mean "either or both" of the elements so conjoined, i.e.,
elements that are
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conjunctively present in some cases and disjunctively present in other cases.
Multiple elements
listed with "and/or" should be construed in the same fashion, i.e., "one or
more" of the elements
so conjoined. Other elements may optionally be present other than the elements
specifically
identified by the "and/or" clause, whether related or unrelated to those
elements specifically
identified. Thus, as a non-limiting example, a reference to "A and/or B", when
used in
conjunction with open-ended language such as "comprising" can refer, in one
embodiment, to A
only (optionally including elements other than B); in another embodiment, to B
only (optionally
including elements other than A); in yet another embodiment, to both A and B
(optionally
including other elements); etc.
As used herein in the specification and in the claims, "or" should be
understood to have
the same meaning as "and/or" as defined above. For example, when separating
items in a list,
"or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion
of at least one, but also
including more than one, of a number or list of elements, and, optionally,
additional unlisted
items. Only terms clearly indicated to the contrary, such as "only one of' or
"exactly one of," or,
when used in the claims, "consisting of," will refer to the inclusion of
exactly one element of a
number or list of elements. In general, the term "or" as used herein shall
only be interpreted as
indicating exclusive alternatives (i.e. "one or the other but not both") when
preceded by terms of
exclusivity, such as "either," "one of," "only one of," or "exactly one of"
As used herein in the specification and in the claims, the phrase "at least
one," in
reference to a list of one or more elements, should be understood to mean at
least one element
selected from any one or more of the elements in the list of elements, but not
necessarily
including at least one of each and every element specifically listed within
the list of elements and
not excluding any combinations of elements in the list of elements. This
definition also allows
that elements may optionally be present other than the elements specifically
identified within the
list of elements to which the phrase "at least one" refers, whether related or
unrelated to those
elements specifically identified. Thus, as a non-limiting example, "at least
one of A and B" (or,
equivalently, "at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in
one embodiment, to at least one, optionally including more than one, A, with
no B present (and
optionally including elements other than B); in another embodiment, to at
least one, optionally
including more than one, B, with no A present (and optionally including
elements other than A);
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in yet another embodiment, to at least one, optionally including more than
one, A, and at least
one, optionally including more than one, B (and optionally including other
elements); etc.
When the word "about" is used herein in reference to a number, it should be
understood
that still another embodiment of the disclosure includes that number not
modified by the
presence of the word "about."
"Solution" according to the current disclosure is a clear, homogeneous liquid
dosage
form that contains one or more chemical substances dissolved in a solvent or
mixture of mutually
miscible solvents. A solution is a liquid preparation that contains one or
more dissolved chemical
substances in a suitable solvent or mixture of mutually miscible solvents.
Because molecules of a
drug substance in solution are uniformly dispersed, the use of solutions as
dosage forms
generally provides assurance of uniform dosage upon administration and good
accuracy when
the solution is diluted or otherwise mixed.
"Suspension" as used herein is a liquid dosage form that contains solid
particles dispersed
in a liquid vehicle.
When ranges are given by specifying the lower end of a range separately from
the upper
end of the range, it will be understood that the range can be defined by
selectively combining any
one of the lower end variables with any one of the upper end variables that is
mathematically
possible. Where ranges are recited, it will be understood that any subrange or
value within the
recited ranges, including endpoints, is contemplated.
It should also be understood that, unless clearly indicated to the contrary,
in any methods
claimed herein that include more than one step or act, the order of the steps
or acts of the method
is not necessarily limited to the order in which the steps or acts of the
method are recited.
In the claims, as well as in the specification above, all transitional phrases
such as
"comprising," "including," "carrying," "having," "containing," "involving,"
"holding,"
"composed of," and the like are to be understood to be open-ended, i.e., to
mean including but
not limited to. Only the transitional phrases "consisting of" and "consisting
essentially of" shall
be closed or semi-closed transitional phrases, respectively, as set forth in
the United States Patent
Office Manual of Patent Examining Procedures, Section 2111.03.
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