Note: Descriptions are shown in the official language in which they were submitted.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
"Poloxamer Emulsion Preparations"
Field of the Invention
This invention relates to microemulsions and compositions useful in a variety
of
pharmaceutical and personal care products and applications. In particular, it
provides microemulsions and compositions useful for topical and/or mucosal
application of water insoluble or sparingly soluble active agents to
oesophageal,
otic, vaginal, rectal or ophthalmic surfaces or for application to the
epidermis of an
animal (such as skin in human) and/or to treat disorders and imperfections of
the
skin. It also provides a method for making the microemulsions and compositions
comprising water insoluble or sparingly soluble active agents.
Background Art
Many of the active agents in pharmaceutical and cosmetic preparations comprise
oils or are immiscible or insoluble in water. It can be difficult to deliver
an effective
amount of these active agents in order to provide the desired therapeutic
effect,
due to their lack of water solubility. It is therefore often desirable to
provide such
agents in water-based compositions (eg. for oral administration, topical
application, intravenous injection, intramuscular injection, subcutaneous
injection
etc). One of the methods for preparing such compositions is to form an
emulsion.
An emulsion is a heterogeneous system consisting of at least two immiscible
liquids (such as a water phase and an oil phase), one of which is dispersed in
the
other in the form of droplets, with continuous and discontinuous phases. The
discontinuous phase is referred to variously as the dispersed or internal
phase,
whereas the phase in which the dispersion occurs is referred to as the
continuous
or external phase. When water is the continuous phase, the emulsion is
referred
to as oil-in-water (OM), and when oil is the continuous phase, the emulsion is
referred to as water-in-oil (WIO). OM emulsions are the most frequently used
emulsions. However, W/O emulsions are desirable for many applications and
would be more, extensively used if problems with instability could be
overcome.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-2-
Macroemulsions are defined as being formed by high shear mixing and normally
having particles of 1 micron to 10 microns in size. Such emulsions are
difficult to
achieve and possess minimal stability, as the oil and water components
separate
into distinct phases over time. In addition, the droplet size of the
macroemulsion
increases with time. Various methods have been developed to stabilize such
emulsions, such as the addition of additives such as emulsifiers and finely
divided
solids.
In contrast, microemulsion systems consisting of oil, water, and appropriate
emulsifiers can form spontaneously (i.e. form with minimal agitation) and are
therefore thermodynamically stable. This level of thermodynamic stability is
highly
desirable, but seldom achieved. Microemulsion systems theoretically have an
infinite shelf life under normal conditions -without separating, in contrast
to the
limited life of macroemulsions. In addition, the size of the droplets in such
microemulsions remains constant and is typically less than 150 nm (in general
between 10-50 nm) and the microemulsion has very low oil/water interfacial
tension.
Emulsions such as microemulsions are important for the development of new and
effective active agent delivery systems that allow water insoluble or
sparingly
soluble active agents to be provided in aqueous solutions appropriate for
human
use. The preparation of such microemulsions represents a major technological
hurdle for pharmaceutical delivery systems as one must choose materials that
are
biocompatible, non-toxic, clinically acceptable and form stable
microemulsions.
Furthermore, many of the known emulsion formulations suffer from an inability
to
ensure a controlled and prolonged release of the active agent at the desired
site
as they have a very short retention time at the tissue to which they are
applied,
due to being readily washed away or degraded. This inability is particularly
undesirable, since most biologically active agents must remain at the desired
site
for a prolonged period in order to be effective.
In view of the above, there is a need to provide emulsion formulations for
delivery
of active agents that are multi-purpose and can be applied to, for example,
topical
or mucosal tissues. Such emulsions should preferentially have high bioadhesion
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-3-
capability to ensure contact for a prolonged time. Further they should
preferentially be able to carry a high amount of active agent to the site of
application for a controlled and prolonged release to the desired tissue.
Although stable emulsion preparations have been described, these compositions
typically require the use of high temperatures to melt all ingredients of the
oil
phase to uniformly disperse the particles of one phase through the particles
of the
other one. Microemulsions are usually formed at temperatures in excess of 75
C,
typically about 90 C, and the composition is then cooled slowly over a period
of
hours or days to room temperature in order to create the emulsion. For large
batches this is a costly and time consuming procedure. There is also the risk
that
the emulsions will be overheated resulting, for example, in the degradation of
some of the ingredients.
Another method by which stable emulsions may be prepared is via the use of
surfactants or emulsifiers. Typically, surfactants and emulsifiers for the
preparation of emulsions are selected from the group consisting of hydrophilic
surfactants and mixtures thereof. To function as a surfactant, a compound must
necessarily include polar or charged hydrophilic moieties as well as non-polar
lipophilic (hydrophobic) moieties; that is, a surfactant compound must be
amphiphilic. An empirical parameter commonly used to characterize the relative
hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the
hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB
values
are more lipophilic or hydrophobic, and have greater solubility in oils, while
surfactants with higher HLB values are more hydrophilic, and have greater
solubility in aqueous solutions. Hydrophilic surfactants are generally
considered
to be those compounds having an HLB value greater than about 10, as well as
anionic, cationic, or zwitterionic compounds for which the HLB scale is not
generally applicable. It should be appreciated that the HLB value of a
surfactant
is merely a rough guide generally used to enable formulation of industrial,
pharmaceutical and cosmetic emulsions.
A group of compounds that have been successfully used as surfactants in the
production of macro- and microemulsions are the block copolymers of ethylene
oxide and propylene oxide, the poloxamers. A number of these compounds have
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-4-
the unusual property that they become liquid when chilled, but harden when
warmed, a characteristic known as thermo-reversibility. Such thermo-
reversibility
is useful in pharmaceutical compounding wherever it is desirable to handle a
material in a fluid state, but performance is preferably in a gelled or more
viscous
state. Such compounds can be drawn into a syringe for accurate dose
measurement or easily applied from a bottle or squirted from a dispenser when
cold. When the poloxamer warms to body temperature (eg. when applied to skin
or mucosal surfaces) it thickens to a suitable consistency to facilitate
proper
inunction and adhesion.
The desired gelling temperature can be regulated by adjusting the
concentration
of the block copolymer, with the lower copolymer concentrations giving higher
gelling temperatures. Concentrations of the copolymer of at least 18% to 20%
by
weight are needed to produce a composition which exhibits such a transition at
commercially or physiologically useful temperatures. However, it has been
found
that incorporating high concentrations of copolymer causes the composition to
become extremely viscous or "gelatinised" and solutions containing 18% to 20%
by weight of poloxamer typically have high viscosity even in the "liquid"
phase, so
that these solutions can not function under conditions where low viscosity,
free-
flowing is required prior to transition. For this reason, typical copolymer
emulsions
usually contain less than 10% copolymer.
Active Agents
Active agents are chemical materials or compounds which, when administered to
an organism (human or animal, generally human) induce a desired pharmacologic
effect. Many of the active agents in pharmaceutical and cosmetic preparations
comprise oils or are immiscible or insoluble in water. An example of such an
active agent is Tea Tree Oil (TTO).
TTO is isolated by distilling the oil from the stems and leaves of the
paperbark
tree Melaleuca alternafolia. TTO has medicinal properties including
antimicrobial,
antiviral, anti-inflammatory and antifungal characteristics. Additionally, TTO
provides a soothing sensation when in contact with a person's skin. However,
the
properties of TTO can only be exploited by formulating delivery systems
suitable
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-5-
to the various conditions required. When TTO products, in the form of aqueous
creams, are exposed to air, the TTO component oxidates and some of the
chemical components can change their characteristics, affecting the
medicament's effectiveness and safety. The presence of many of the emulsifying
agents used to solubilize TTO in water also inhibit or inactivate the activity
of TTO.
As a gel suspension, TTO tends to separate from the gel base formula,
particularly when the suspension contains concentrations of TTO higher than
2%,
a process accentuated by changes in temperature (eg. temperatures over 30 C)
and/or applying physical shear forces, such as kneading the gel suspension.
To deliver an effective amount of TTO, it is desirable to apply the oil in a
form that
will both remain in contact with the skin for an extended period of time and
deliver
the highest concentration of TTO possible. Microemulsion formulations are
therefore highly desirable as they are thermodynamically stable.
This invention has as its objective the formation of safe and effective
pharmaceutical microemulsion delivery systems that can be manufactured without
the need for the high temperature preparation. Other aims and aspects of the
present invention will be apparent from the following description of the
present
invention.
Summary of the Invention
According to the present invention there is provided a composition or more
specifically a microemulsion for delivery of water-insoluble active agents,
comprising: an aqueous component and a non-ionic block copolymer, and at least
an oil that is the active agent or has a water-insoluble active agent
dissolved
therein.
In the present invention, the term "emulsion" includes both macroemulsions and
microemulsions.
Compositions of the present invention will desirably possess bioadhesive or
mucoadhesive properties. Preferentially, the composition will be in the form
of a
liquid or a gel. Most preferably, the microemulsion composition will exist as
a gel
CA 02516863 2009-02-12
-6-
or will be a liquid that is capable of gelatinising upon contact with dermal
or
mucosal tissue.
According to a second embodiment, the invention provides a microemulsion or a
composition for delivery of water-insoluble active agents, comprising an
aqueous
component and a non-ionic block copolymer, a hydrophilic, non-ionic short
chain
fatty acid emulsifier, and at least a oil that is the active agent or has a
water
insoluble active agent dissolved therein.
According to a third embodiment, the invention provides a method for preparing
the microemulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature
to substantially dissolve the copolymer in the aqueous solution; and
(b) Mixing, at cold temperature, an oil that is the active agent or has a
water-insoluble active agent dissolved therein, with the aqueous
copolymer solution prepared in step (a) to form a microemulsion.
According to a fourth embodiment, the invention provides a method for
preparing
the microemulsion composition, comprising the steps of.
(a) Mixing a copolymer with an aqueous solution at a suitable temperature
to substantially dissolve the copolymer in the aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an
oil that Is the active agent or has a water-insoluble active agent
dissolved therein, at a low temperature to form an oil mixture; and
(c) Mixing the solution prepared in step (a) with the solution prepared in
step (b) at a low temperature to form a microemulsion.
Also provided herein are microemulsion compositions formed by the above
methods.
According to another aspect of the present invention, there Is provided an
emulsion composition comprising: an aqueous component, a non-ionic block
copolymer, and an oil wherein the copolymer comprises at least 10% by weight
of the composition, and wherein the composition is thermoreversibie.
CA 02516863 2009-02-12
-6a-
According to a further aspect of the present invention, there is provided an
emulsion composition comprising: an aqueous component, a non-ionic block
copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and an
oil
wherein the copolymer comprises at least 10% by weight of the composition, and
wherein the composition is thermoreversible.
According to another aspect of the present invention, there is provided a
method
for preparing an emulsion composition, comprising the steps of.
(a) Mixing a copolymer with an aqueous solution at a suitable
temperature to substantially dissolve the copolymer in the
aqueous solution; and
(b) Mixing, at cold temperature, an oil that is an active agent or has
a water-Insoluble active agent dissolved therein, with the
aqueous copolymer solution prepared in step (a) to form an
emulsion;
wherein said composition comprises at least 10% by weight of the
copolymer.
According to a further aspect of the present invention, there is provided a
method for preparing an emulsion composition, comprising the steps of.
(a) Mixing a copolymer with an aqueous solution at a suitable
temperature to substantially dissolve the copolymer in the
aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier
with an oil that is an active agent or has a water-insoluble active
agent dissolved therein, at a low temperature to form an oil
mixture; and
(c) Mixing the aqueous solution prepared in step (a) with the oil
mixture prepared in step (b) at a low temperature to form an
emulsion;
wherein said composition comprises at least 10% by weight of the
copolymer.
CA 02516863 2010-01-13
-6b-
According to another aspect of the present invention, there is provided a
method
for preparing an emulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable
temperature to substantially dissolve the copolymer in the
aqueous solution; and
(b) Mixing, at a temperature less than about 15 C, an oil that is an
active agent or has a water-insoluble active agent dissolved
therein, with the aqueous copolymer solution prepared in step (a)
to form an emulsion;
wherein said composition comprises at least 10% by weight of the
copolymer.
According to a further aspect of the present invention, there is provided a
method for preparing an emulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable
temperature to substantially dissolve the copolymer in the
aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier
with an oil that is an active agent or has a water-insoluble active
agent dissolved therein, at a low temperature to form an oil
mixture; and
(c) Mixing the aqueous solution prepared in step (a) with the oil
mixture prepared in step (b) at a temperature less than about
60 C to form an emulsion;
wherein said composition comprises at least 10% by weight of the
copolymer.
According to another aspect of the present invention, there is provided an
emulsion composition comprising: an aqueous component, a non-ionic block
copolymer, and an oil wherein the copolymer comprises at least 15% by weight
of the composition.
CA 02516863 2010-01-13
-6c-
According to a further aspect of the present invention, there is provided an
emulsion composition comprising: an aqueous component, a non-ionic block
copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and an
oil
wherein the copolymer comprises at least 15% by weight of the composition.
Composition of the invention will have a wide variety of applications. When
applied topically to the dermal layer of an animal the compositions may
include
agents to promote bodily attractiveness or to mask the physical manifestations
of
a disorder or disease, in lieu or in addition to the treatment of a physical
disorder.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-7-
The same agent may have either a cosmetic or pharmaceutical effect, depending
upon the amounts used and the manner of administration.
In another aspect of the invention, compositions of the invention may be
incorporated into other compositions to impart thickening properties to the
final
composition. Such thickening properties include enhanced overall viscosity, as
well as a desirable viscosity response with temperature. The composition may
be
useful as a thickener in pH ranges where other thickeners are not effective.
In addition, compositions of the invention may be incorporated into other
compositions to impart emolliency to the composition. In this respect the
composition may also act as a film-forming bioactive agent after it has been
applied to the skin or other mucosal membrane. This film-forming bioactive
agent
may be used as a barrier to prevent water loss from the skin while treating
biological challenges.
Other aspects and advantages of the invention will become apparent to those
skilled
in the art from a review of the ensuing description.
Detailed Description of the Invention
General
Those skilled in the art will appreciate that the invention described herein
is
susceptible to variations and modifications other than those specifically
described.
It is to be understood that the invention includes all such variation and
modifications. The invention also includes all of the steps, features,
compositions
and compounds referred to or indicated in the specification, individually or
collectively and any and all combinations or any two or more of the steps or
features.
The present invention is not to be limited in scope by the specific
embodiments
described herein, which are intended for the purpose of exemplification only.
Functionally equivalent products, compositions and methods are clearly within
the
scope of the invention as described herein.
CA 02516863 2009-02-12
No admission is made that any of the references cited herein constitute prior
art
or are part of the common general knowledge of those working in the field to
which this invention relates.
Throughout this specification, unless the context requires otherwise, the word
"comprise", or variations such as "comprises" or "comprising", will be
understood
to imply the inclusion of a stated integer or group of integers but not the
exclusion of any other integer or group of integers.
Other definitions for selected terms used herein may be found within the
detailed
description of the invention and apply throughout. Unless otherwise defined,
all
other scientific and technical terms used herein have the same meaning as
commonly understood to one of ordinary skill in the art to which the invention
belongs.
Description of the Preferred Embodiment
The present invention provides a microemulsion composition comprising at least
10% by weight of a copolymer that preferentially has thermo-reversible
properties. Copolymer levels of this magnitude exceed, to the best of the
applicant's knowledge, those found in other oil-copolymer based microemulsion.
When the copolymer used in the microemulsion is thereto-reversible, oil-
copolymer combinations may be prepared at a cold temperature. The applicant
has found, however, that the combination of an emulsifier with the oil before
addition of the copolymer surprisingly allows the microemulsion to be prepared
at a low temperature,
According to the present invention there is provided a composition or more
specifically a microemulsion for delivery of water-insoluble active agents,
comprising: an aqueous component and a nonionic block copolymer, and at
least an oil that is the active agent or has a water-insoluble active agent
dissolved therein.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-9-
Microemulsions as described herein will comprise an amount by weight of block
copolymer of about 10% to about 50% by weight, more preferably the amount by
weight block copolymer will be between about 10.1% and 40% by weight of the
emulsion while an amount by weight of the block copolymer between any of the
following ranges will be highly desirable: 10.5% to 35%, 11% to 30%, 12% to
25%, 13% to 20% or 14% to 18% by weight of the emulsion. Thus, as an
illustration of the invention, the block copolymer may comprise 15% by weight
of
the emulsion.
In addition to the block copolymer being present in the aforementioned weight
ranges in the microemulsion, it will also desirably be a thermo-reversible
copolymer.
In a preferred embodiment of the invention, the microemulsion or composition
will
possess bioadhesive or mucoadhesive properties. Such properties will be
consistent with the microemulsion or composition being prepared in either a
liquid
or more preferably a gel form. When prepared in this manner the microemulsion
or composition will be useful for topical and/or mucosal application of water
insoluble or sparingly soluble active agents to oesophageal, otic, vaginal,
rectal or
ophthalmic surfaces, or for application to the epidermis of an animal (such as
skin
in human) and/or to treat disorders and imperfections of the skin. Desirably,
the
microemulsion or composition will either exist as a gel or will be prepared in
such
a manner that it is capable of gelatinising upon contact with dermal or
mucosal
tissue.
When. preparing a microemulsion in accordance with the first embodiment of the
invention, ideally, the oil and the thermo-reversible copolymer will be mixed
at a
cold temperature. When this is done at a cold temperature at the weight ranges
specified herein the composition forms a stable microemulsion capable of
application to dermal or mucosal tissue.
In a second embodiment, the invention provides a composition or more
specifically a microemulsion for delivery of water-insoluble active agents,
comprising: an aqueous component and a non-ionic block copolymer, a
CA 02516863 2009-02-12
-10-
hydrophilic non-ionic short chain fatty acid emulsifier and at least an oil
that is the
active agent or has a water-insoluble active agent dissolved therein.
When preparing a microemulsion in accordance with the second embodiment of the
invention, ideally, the oil and the emulsifier will be mixed and then applied
to the
thermo-reversible copolymer. When this is done at a low temperature at the
weight
ranges specified herein the composition rapidly forms a stable microemulsion
capable of application to dermal or mucosal tissue.
The copolymer for use In the present invention is preferably a block copolymer
of
ethylene oxide and propylene oxide (poloxamer) preferably those represented by
the formula:
HO(C2H4O)a(C3HSO)b(C2H40)aH
Where 'b' is between 15 and 67 and 'a' is between 2 and 130, and the total
proportion of 'a' units amounts to from 20% to 90% by weight of the poloxamer.
The molecular weight of the poloxamer ranges from preferably about 1,000 to
20,000 and it will preferentially have thermo-reversible properties. By way of
example only the block copolymer may be poloxamer 407, such as that sold as
Pluronico F127 (BASF Corporation) or Synperonic''M PE/F127 (Unigema).
According to the invention the preferred emulsifier is a fatty acid component
with a
polyethoxylated side chain. For example, suitable emulsifiers might be Laureth-
4,
Laureth-9, Laureth-23, PPG-26-Buteth-26/PEG-40 Hydrogenated castor oil or PEG-
40 Hydrogenated castor oil. When such emulsifiers are used in the invention
the
amount by weight of the emulsifier will vary generally from about 0.5% to
about
50% by weight of the microemulsion.
The physico-chemical characteristics of the present invention make the
microemulsion suitable as a delivery vehicle for water insoluble or sparingly
soluble
active agents. It is particularly welt-suited for transdermal or transmucosal
delivery.
In this respect the oil phase may comprise oils commonly used in the food,
cosmetic and pharmaceutical industries for example, oils of natural or
synthetic
origin, long chain alcohols, glyceryl esters of fatty acids or fatty esters of
monohydric alcohols. The esters and alcohols can be straight or branch
chained,
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-11-
saturated or unsaturated and liquids at room temperature. The oil phase may
also contain active agents that are soluble in or miscible with the oil phase.
The oil of the present invention may have inherent pharmaceutical properties
and
constitute the active agent of the microemulsion and/or may contain dissolved
active agents that are soluble or miscible in the oil. The active agents may
include, but are not limited to, antimicrobials (such as antibiotics,
antifungals and
antivirals), anti-inflammatories, antihistaminics, antidepressants,
anaesthetics
antineoplastics, enzymes, cardiovascular agents, polynucleotides, genetic
material, viral vectors, immunoactive agents, imaging agents,
immunosuppressive
agents, peptides, proteins etc and combinations thereof. Pharmaceutically
effective amounts of the selected active agents may be determined using
techniques well known in the art.
Preferentially the amount by weight of the oil used in the microemulsion will
comprise from about 0.1% to about 80% by weight of the emulsion, more
preferably 1% to 30% by weight of the emulsion, with a range of 3% to 15% by
weight of the emulsion being highly desirable. In an illustration of the
invention
the oil will constitute about 6% of the total weight of the emulsion.
In a highly preferred form of the invention the oil is tea tree oil (TTO).
Where the
active agent is TTO the microemulsion will have microbicide activity. Such a
composition can be used to treat for example; diseases such as sexually
transmitted disease (eg. HIV) by vaginal delivery; impetigo and cold sores by
topical preparation, elimination of MRSAs by intranasal application and
diseases
such as otitis media, otitis externa, acne, periodontitis, gingivitis,
paronychia,
onychomycosis and secondary infections in connection with operations,
dermatitis, burns, etc.
According to a third embodiment, the invention provides a method for preparing
the microemulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature
to substantially dissolve the copolymer in the aqueous solution; and
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-12-
(b) Mixing, at cold temperature, an oil that is the active agent or has a
water-insoluble active agent dissolved therein, with the aqueous
copolymer solution prepared instep (a) to form a microemulsion.
According to step (a) in the method the co-polymer is mixed with an aqueous
solution at a suitable temperature to substantially dissolve the copolymer in
the
aqueous solution. Dissolution of the co-polymer with an aqueous solution will
occur almost instantaneously at temperatures of around 6 C. Alternatively, the
co-polymer may be mixed with the aqueous solution at room temperature if left
over night with semi-continuous or continuous stirring.
As used herein "cold temperature" refers to temperatures less than about 15 C,
preferably from about 4 C to about 12 C and most preferably less than about
10 C.
According to a fourth embodiment, the invention provides a method for
preparing
the microemulsion composition, comprising the steps of:
(a) Mixing a copolymer with an aqueous solution at a suitable temperature
to substantially dissolve the copolymer in the aqueous solution;
(b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an
oil that is the active agent or has a water-insoluble active agent
dissolved therein, at a low temperature to form an oil mixture; and
(c) Mixing the solution prepared in step (a) with the solution prepared in
step (b) at a low temperature to form a microemulsion.
As used herein "Low temperature" refers to temperatures less than about 60 C,
preferably from about 15 C to about 40 C, more preferably from about 20 C to
about 30 C and most preferably at about room temperature. The ability to
manufacture microemulsions of the present invention at these temperatures is
highly significant as it provides a distinguishing feature from most other
methods
of manufacture of microemulsions which demand the microemulsions be made at
about 90 C.
It has been found that a microemulsion composition prepared according to the
present invention has the surprising feature that the addition of the
oil/emulsifier
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-13-
mixture to the aqueous poloxamer solution at room temperature changes the
thermo-reversible nature of the poloxamer by altering the temperature at
which.
solidification occurs. This effect is most evident at high ratios of poloxamer
to oil.
Microemulsion compositions of the present invention provide clear, colourless
gels that are particularly well suited to pharmaceutic and personal care
applications. For example, very little residue is formed upon dehydration,
which
may be important in some applications, such as in optically applied
pharmaceutics. An additional advantage of the microemulsion composition of the
invention is that they remain clear and translucent before and after the
triggering
environmental change. These characteristics of the reversibly gelling
microemulsion composition make it well suited for use in pharmaceutic
compositions.
The practical advantage of this behaviour of the microemulsion composition is
that
the formulation can be administered as a flowing liquid at ambient
temperatures.
Upon contact with body tissues it viscosifies, thus changing its flow
properties,
and more importantly, its clearance from the site of application is
dramatically
reduced.
Those skilled in the art will appreciate that microemulsion composition of the
present invention may be utilized for a wide variety of pharmaceutic and
personal
care applications. To prepare a pharmaceutic composition, an effective amount
of
pharmaceutically active agent(s) which imparts the desirable pharmaceutic
effect
is incorporated into the reversibly gelling composition of the present
invention.
When prepared according to the method of the invention the microemulsion
composition can further include one or more pharmaceutically acceptable
additives, excipients carriers and diluents. Such additives, excipients
carriers and
diluents include, without limitation, water, saline, ethanol, dextrose,
glycerol,
lactose, dextrose, sucrose sorbitol, mannitol, starches, gum acacia, calcium
phosphates, alginate, tragacanth, gelatine, calcium silicate, microcrystalline
cellulose, polyvinylpyrrolidone, cellulose,, water syrup, methyl cellulose,
methyl
and propylhydroxybenzoates, talc, magnesium stearate and mineral oil or
combinations thereof. The formulations can additionally include lubricating
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-14-
agents, pH buffering agents, wetting agents, emulsifying and suspending
agents,
preserving agents, sweetening agents or flavouring agents, antifoaming agents,
polymers, antioxidants, chelating agents, viscomodulators, tonicifiers,
flavorants,
colorants, odorants, opacifiers, suspending agents, binders, fillers,
plasticizers,
lubricants, and mixtures thereof. The particular selection of constituent that
can
be included in the compositions described herein will generally depend on the
type of preparation.
In addition, an acid or a base may be incorporated into the microemulsion
composition to facilitate processing, to enhance stability, or for other
reasons.
Examples of pharmaceutically acceptable bases include amino acids, amino acid
esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium
hydrogen carbonate, aluminium hydroxide, calcium carbonate, magnesium
hydroxide, magnesium aluminium silicate, synthetic aluminium silicate,
synthetic
hydrocalcite, magnesium aluminium hydroxide, diisopropylethylamine,
ethanolamine, ethylenediamine, triethanolamine, triethylamine,
triisopropanolamine, trimethylamine, tris (hydroxymethyl) aminomethane (TRIS)
and the like. Also suitable are bases that are salts of a pharmaceutically
acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid,
alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid,
butyric
acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid,
gluconic acid,
hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic
acid,
para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,
salicylic
acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic
acid,
toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such
as
sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen
phosphate can also be used. When the base is a salt, the cation can be any
convenient and pharmaceutically acceptable cation, such as ammonium, alkali
metals, alkaline earth metals, and the like. Preferred cations include sodium,
potassium, lithium, magnesium, calcium and ammonium.
Suitable acids are pharmaceutically acceptable organic or inorganic acids.
Examples of suitable inorganic acids include hydrochloric acid, hydrobromic
acid,
hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and
the like.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-15-
Examples of suitable organic acids include acetic acid, acrylic acid, adipic
acid,
alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid,
boric
acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid,
fumaric acid,
gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic
acid,
methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic
acid,
p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic
acid,
tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the
like.
When the hydrophilic active agent is subject to enzymatic degradation, the
present compositions can also include an enzyme inhibiting agent. Enzyme
inhibiting agents are shown for example, in Bernskop-Schnurch (1998),"The use
of inhibitory agents to overcome enzymatic barrier to perorally administered
therapeutic peptides and proteins," Controlled Release 52: 1-16.
Generally, inhibitory agents can be divided into the following classes:
inhibitors
that are not based on amino acids (such as P-aminobenzamidine, FK-448,
camostat mesylate and sodium glycocholate); amino acids and modified amino
acids (such as aminoboronic acid derivatives and n-acetylcysteine); peptides
and
modified peptides (such as bacitracin, phosphinic acid dipeptide derivatives,
pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin,
hosphoramindon,
puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin);
polypeptide protease inhibitors (such as aprotinin, Bowman-Birk inhibitor,
soybean
trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor,
and
human pancreatic trypsin inhibitor); complexing agents (such as EDTA, EGTA,
1,10-phenanthroline and hydroxychinoline); and mucoadhesive polymers and
polymer-inhibitor conjugates (such as polyacrylate derivatives, chitosan,
celluiosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-
bacitracin,
carboxymethyl cellulose-pepstatin and polyacrylic acid-Bowman-Birk inhibitor).
The choice and levels of the enzyme inhibitor are based on toxicity,
specificity of
the proteases and the potency of inhibition.
A discussion of particular applications and formulations follows.
Esophageal, oral cavity and buccal applications: One indication for the use of
this
microemulsion composition would be to provide a suitable vehicle for
delivering a
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-16-
pharmaceutic effect within the oesophageal lining. In this respect the
mucoadhesive properties of the microemulsion composition of the invention make
that composition desirable for controlling and facilitating a pharmaceutic
effect to
the oesophageal lining. The shear sensitivity of the microemulsion composition
could also be taken advantage of in applications in which a liquid treatments
is
sprayed under high shear conditions onto the oral cavity, where the solution
adheres and viscosifies to provide a reservoir for antibacterial agents, such
as
chlorohexadine, or a breath freshener.
Ophthalmic applications: Most ophthalmic drugs are applied to the eye,
typically
to the precorneal area. The most common dosage form is a liquid drop. Drug
bioavailability is generally low because liquid formulations are quickly
cleared from
the eye by tearing and blinking, resulting in the need for frequent dosing and
uneven drug delivery.
The microemulsion composition described herein provides a new vehicle for
achieving greater bioavailability of topically administered insoluble or
partially
soluble ophthalmic active agents. Formulations containing such active agents
can
be applied as drops that viscosify or gel upon contact with eye. Since gelling
can
be accomplished with low concentrations of the polymer, blurring can be
minimized upon drop instillation.
When used in this manner the microemulsion composition would preferentially be
used for delivering bioactive materials, such as anaesthetics, mydriatics and
cycloplegics, antimicrobial agents (antibacterial, antifungal, antiviral),
anti-
inflammatory agents, agents for the treatment of glaucoma, ocular
decongestants,
diagnostic agents, and wound healing agents.
Nasal applications: Microemulsion compositions of the invention may also be
used for delivery of drugs to the nasal cavity. Nasal drug delivery has been
considered as an alternative to parenteral routes of administration of drugs
that
demonstrate low oral bioavailability. In order to increase the bioavailability
of
nasally administered drugs, efforts have been made to increase the residence
time of formulations in the nasal cavity. Nasal delivery of drugs can offer
advantages over other methods of delivery, including rapid systemic
absorption,
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-17-
lower dosing, more rapid onset of desired therapeutic effects, and improved
pharmacokinetics. In addition, it provides an alternative route for
administering
peptide drugs, which generally have low bioavailability via the oral route and
are
normally administered parenterally.
Microemulsion composition would potentially be useful for delivering agents
such
as decongestants, antihistamines, anti-osteoporosis agents, hormones,
antineoplastic agents, Parkinsonism drugs, etc. The composition may also be
used for the application of vaccines, such as those against the influenza
virus.
Vaginal/rectal applications: Microemulsion compositions of the invention are
also
indicated for the delivery of bioactive agents (such as TTO) to the vaginal or
the
rectal cavity. These delivery routes have been considered as an alternative to
parenteral routes of administration of bioactive agents that demonstrate low
oral
bioavailability. In order to increase the bioavailability of vaginally or
rectally
administered bioactive agents, efforts have been made to increase the
residence
time of formulations in these cavities. These routes offer advantages over
other
methods of delivery, including rapid systemic absorption, lower dosing, more
rapid
onset of desired therapeutic effects, and improved pharmacokinetics.
Veterinary applications: Microemulsion compositions of the invention may also
be
useful in the treatment of not only human conditions but in providing
treatments
for animal care. For veterinary products, the microemulsion compositions is
indicated for the preparation of topical dermal products, such as
antibacterials,
antifungals, antipruritics, and antiseborrheia, antiodor, and antiseptic/wound
healing preparations. Otic products would include ear cleaners with or without
actives, such as, antifungals. Ophthalmic products would include eye
moisturizers or antimicrobial preparations.
Personal Care Applications: Microemulsion compositions of the invention may
also be particularly well suited for cosmetic applications. For example, very
little
residue is formed upon dehydration, which may be important in some
applications, such as in topically applied cosmetics. An additional advantage
of
the composition of the invention is that it remains clear and translucent
above and
CA 02516863 2009-02-12
-18-
below the critical temperature or pH. These characteristics of the
microemulsion
compositions make it well suited for use in cosmetic compositions.
To prepare a cosmetic composition, an effective amount of cosmetically active
agent(s) that imparts the desirable cosmetic effect is incorporated into the
microemulsion composition of the present invention. Preferably the selected
agent
lends itself to a homogeneous dispersion through out the microemulsion
composition. It is contemplated as within the scope of the invention that the
reversibly gelling composition compositions of the present invention may be
prepared under sterile conditions.
Exemplary cosmetic and personal care applications, in which the microemulsion
composition may be used include, but are not limited to, baby products, bath
preparations, eye makeup preparations, fragrance preparations, noncolouring
hair
preparations, colour cosmetics, hair colouring preparations, makeup
preparations,
manicuring preparations, oral hygiene products, shaving preparations, skin
care
preparations, and suntan preparations such as suntan creams, gels and lotions,
indoor tanning preparations.
The cosmetic composition may be in any form. Suitable forms include but are
not
limited to lotions, creams, sticks, roll-ons formulations, mousses, aerosol
sprays,
pad-applied formulations, and film-forming formulations.
Preparation of the above-named cosmetic compositions and others may be
accomplished with reference to any of the cosmetic formulation guidebooks and
industry journals which are available in the cosmetic industry. These
references
supply standard formulations which may be modified by the addition or
substitution
of the microemulsion composition of the present invention into the
formulation.
Suitable guidebooks include Cosmetics and Toiletries Magazine, Vol. 111
(March,
1996); Formular Ideas for Personal Care; Croda, Inc, Parsippany, N. J. (1993);
and
Cosmeticon: Cosmetic Formular, BASF.
Preparation of pharmaceutic compositions may be accomplished with reference to
any of the pharmaceutic formulation guidebooks and industry journals which are
CA 02516863 2009-02-12
-19-
available in the pharmaceutic industry. These references supply standard
formulations which may be modified by the addition or substitution of the
microemulsion compositions of the present invention. Suitable guidebooks
include Pharmaceutics and Toiletries Magazine, Vol. 111 (March, 1996);
Formular Ideas for Personal Care; Croda, Inc, Parsippany, N. J. (1993); and
Pharmaceuticon: Pharmaceutic Formular, BASF.
Exemplary drugs or therapeutics delivery systems which may be administered
using the aqueous responsive compositions of the invention include, but are in
no
way limited to, mucosal therapies, such as esophageal, otic, rectal, buccal,
oral,
vaginal; and urological applications; topical therapies, such as wound care,
skin
care and teat dips; and intravenous/subcutaneous therapies, such as
intramuscular, intrabone (e.g., joints), spinal and subcutaneous therapies,
tissue
supplementation, adhesion prevention and parenteral drug delivery.
The term "animal" used herein Is taken to mean mammals, such as primates,
including humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice; It also
includes, birds, reptiles, and fish.
As will be understood by those skilled in the art, two or more pharmaceutical
agents may be combined for specific effects. The necessary amounts of active
ingredient can be determined by simple experimentation.
The Invention is now described with reference to the following examples which
are
presented for the purpose of illustration only and are not limiting of the
invention.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-20-
Best Mode(s) for Carrying Out the Invention
Example 1 -- Manufacture of Vaginal gel B
Part A
Add 15.6 g Lutrol F127 to 84.4 g deionised water, which is held at a
temperature
of 60C. Combine with slow mixing to reduce air entrapment and place under
vacuum for a few minutes to remove any trapped air after Lutrol F127 is
dissolved.
PartB
Add 0.20 g fumaric acid to 5.0 g alcohol by stirring until dissolved. Cool the
solution to 10 C.
Part C
Combine 3.0 g Tea Tree oil, 5.0 g propylene glycol and 2.0 g undecylenic acid
and mix to dissolve all ingredients. Cool the solution to 100C.
Gel preparation
Place 84.8 g of the Lutrol F127 solution of Part A in a vessel and hold at
100C.
Slowly add 5.2 g of the fumaric acid solution of Part B and mix well,
maintaining
the solution at 100C. Slowly add 10.0 g of the Tea Tree oil solution of Part C
with
gentle stirring and whilst maintaining the solution at 100C. If necessary,
remove
any aeration by placing the gel under vacuum. Allow the gel to warm to room
temperature.
Example 2 -- Manufacture of Poloxamer gel 8C
Part A
Heat 76.3 g deionised water to 60-65 C, slowly add 16.7 g poloxamer 407 and
stir
gently for approximately 2 hours or until all the poloxamer is dissolved and
the
solution thickens. Allow the solution to cool to room temperature and leave
overnight. Adjust the pH of the solution to 4.2-5.0 with potassium hydroxide.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-21-
Part B
Combine 3.0 g of PPG-26-Buteth-26/PEG-40 Hydrogenated castor oil, 3.0 g Tea
Tree oil and 1.0 g d-alpha tocopheryl acetate with gentle mixing.
Gel Preparation
Add 7.0 g of the Tea Tree oil solution of Part B to 93.0 g of the room
temperature
poloxamer solution of Part A. Mix with gentle stirring until the solution
thickens.
Example 3 -- Manufacture of Poloxamer gel 8E
Part A
Heat 73.4 g deionised water to 60-65 C, slowly add 16.0 g poloxamer 407 and
stir
gently for approximately 2 hours or until all the poloxamer is dissolved and
the
solution thickens. Allow the solution to cool to room temperature and leave
overnight. Adjust the pH of the solution to 4.2-5.0 with potassium hydroxide.
Part B
Combine 2.0 g Laureth-4, 1.0 g of Laureth-23, 6.0 g Tea Tree oil and 1.0 g d-
alpha tocopheryl acetate, 0.1 g of 1.0 M (1 U/g) retinyl palmitate and 0.5 g
panthenol. Heat solution to 40-45 C with gentle mixing to dissolve all
components.
Gel Preparation
Add 10.6 g of the Tea Tree oil solution of Part B to 89.4 g of the room
temperature
poloxamer solution of Part A. Mix with gentle stirring until the solution
thickens.
Example 4 -- Testing of gel formulations against microorganisms
The products were tested using macrodilution and microdilution methods, using
a
96-well microtitre tray. The highest concentration of gel tested was 50%
product.
The test organisms were Staphylococcus aureus NCTC 6571, Escherichia coli
NCTC 10418, Pseudomonas aeruginosa NCTC 10662 and the yeast Candida
albicans ATCC 10231.
CA 02516863 2005-08-23
WO 2004/076561 PCT/AU2004/000218
-22-
Inocula were prepared in double strength Mueller Hinton broth, resulting in a
final
concentration of single strength broth and organisms at a final concentration
of
approximately 5 x 105 cfu/mL. Tests were incubated at 37 C for 24 hours. After
this time, trays were subcultured by removing 5 L from tray wells and spot
inoculating onto Mueller Hinton agar. All subcultures were incubated for 24
hours
and the colonies counted.
The minimum inhibitory concentration (MIC) was defined as the lowest
concentration of product resulting in the maintenance or reduction of the
inoculum. The minimum cidal concentration (MCC) was defined as the lowest
concentration of product resulting in the death of 99.9% of the inoculum.
MIC/MCC
Product TTO%
C. albicans S. aureus E. coil P. aeruginosa
Vaginal gel B 3.0 <0.78/<0.78 <2.1/<2.1 4.2/4.2 33.0/33.0
Poloxamer gel 8C 3.0 -- >1.5/>1.5 -- >1.5/>1.5
Poloxamer gel 8E 6.0 0.38/0.38 0.75/0.75 <0.19/<0.19 >3.0/>3.0
