Note: Descriptions are shown in the official language in which they were submitted.
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Improved Personal Care Formulations
Field and Background of the Invention
The present invention relates to new improved formulations fox application
to a mucosal tissue, and to methods of preparation of these formulations.
These
formulations are useful for oral administration, such as mouth wash or oral
rinse
formulations. More specifically, the present invention concerns improved
formulations including a lipid carrier and biologically active agent dispersed
in a
continuous aqueous phase. The lipid carrier is characterized by having high
to adhesive capabilities towards mucous membranes such as those of the gums,
tongue and palate. The lipid carrier also has a high load capacity for the
biologically active agent. As such, the lipid Garner can specifically target a
relatively large amount of the agent to these mucous membranes to ensure a
controlled and sustained release of the agent at the mucous surface.
~5 In the field of personal care and hygiene, many different formulations have
been designed and employed commercially in a wide variety of "over-the-
counter"
medications and products for a number of purposes including oral hygiene and
skin care. Many of these medications and products contain both a biologically
active agent such, as for example, an anti-microbial agent, and an inert
vehicle.
2o The particular choice of vehicle depends upon the desired properties of the
formulation.
However, the currently available formulations for personal care and
hygiene products suffer from a number of drawbacks, including lack of
suitability
of the carrier for its intended use. Most of these known formulations suffer
from
2s an inability to carry a large amount of the active agent and to ensure a
controlled
and prolonged release thereof at the desired site. This inability is
particularly
undesirable, since usually any biologically active agent must remain at the
desired
site for a prolonged period in order to be effective.
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Recently, liposome-based delivery systems have been developed in which
the active agent is encapsulated within a multiiamellar lipid vesicle or
liposome,
and is then released in a controlled fashion from the liposome. For example,
U.S.
Patent No. 4,588,578 discloses lipid vesicles in which the active ingredient
is
encapsulated, rather than being complexed with a lipid. However, such
liposomes
suffer from the drawback of having a limited load capacity for the active
agent.
Furthermore, many of these liposomes and related lipid particles are not
suitable for long term storage, particularly at ambient temperatures. An
example
of a liposome-based delivery system has been disclosed in U.S. Patent No.
to 4,767,615, in which specific modifications to the lipid structure enable
specific
targeting of the liposome to specific tissues, such as the enamel of the
teeth.
Conversely, the very specificity of such carriers limits them to tissues
covered by
an enamel layer. Furthermore, the maximum capacity for the active agent is
only
about 20% of the liposome volume of the disclosed prior art carrier.
is As another example, U.S. Patent No. 5,415,867 discloses lipid particles
with a relatively high ratio of agent to lipid. However, this reference does
not
teach or disclose the use of such particles for administration to a mucosal
tissue or
mucous membrane. Instead, the reference primarily teaches parenteral
administration. Similarly, PCT Application No. WO 92/03121 discloses only
2o colloidal particles for oral administration or for administration on the
intact skin.
Thus, the prior art does not teach the use of high ratio lipid particles for
administration to a mucous membrane or mucosal surface.
Furthermore, the known non-liposome, hydrophilic, water soluble
formulations also suffer from a very short retention time at the tissue to
which
2s they are applied, because they are readily washed away or degraded.
In view of the above drawbacks of the prior art carriers, there has been a
long-felt need to provide formulations for personal care and hygiene which are
multi-purpose and can be applied to a mucosal tissues. Such carriers must have
high adhesion capability to ensure contact for a prolonged time, and must be
able
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3
to carry a high amount of active agent to the site of adhesion for a
controlled and
prolonged release to the desired tissue.
Other aims and aspects of the present invention will be apparent from the
following description of the present invention.
s
Summar~r of the Invention
The present invention concerns new personal care and hygiene
formulations for topical application to mucosal surfaces. These formulations
include an amphiphilic lipid carrier in the form of a colloidal composition
which
can include a micellar aggregate or mixed micelles dispersed in a continuous
aqueous phase, or an emulsion of lipid droplets suspended in a continuous
aqueous phase, and an active agent which is an anti-microbial agent. The lipid
carrier has high adhesiveness to mucous membranes such as the soft tissues of
the
oral cavity. The lipid carrier also has a high load capacity for the active
agent to
is be carried to these tissues.
These formulations have the desirable properties of carrying a large amount
of active agent for controlled and prolonged release thereof at the desired
site,
such as mucous membrane surfaces and surrounding tissue. Accordingly, the
present invention provides a formulation for oral or topical application
including
2o an anti-microbial agent and a lipid. The agent is held by the carrier
through a
hydrophobic interaction and is released from the carrier in a controlled
manner
over a prolonged period of time. The lipid is also characterized by having a
high
adhesive capability towards mucous membrane surfaces. The lipid and the agent
are preferably present in a ratio in a range of from about 1:10 to about 10:1,
more
2s preferably from about 1:5 to about 5:1, and most preferably from about 1:3
to
about 3:1 in the formulation.
According to the present invention, there is provided a formulation for
topical application to a tissue selected from the group consisting of nasal,
ophthalmic, oral cavity, vaginal and rectal, the formulation including: {a) a
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4
biologically active agent selected from the group consisting of antibiotic,
antiviral
agent, antifungal agent, disinfectant, nutrient, anti-inflammatory agent,
local
anesthetic and essential oil; and (b) a lipid carrier, the lipid carrier
including at
least one lipid selected from the group of amphiphilic phospholipids
consisting of
s egg yolk lecithin, phosphatidic acid, alkylphosphates, phosphatidylglycerol,
Soya
lecithin and phosphatidyl choline, the lipid being characterized as a
colloidal
dispersion or as an emulsion of lipid droplets in suspension in an aqueous
medium, and the lipid and the active agent being present in a ratio of from
about
10:1 to about 1:10, such that the agent is carried by the lipid carrier and
the agent
to is released from the carrier in a controlled manner and over a prolonged
period of
time.
Hereinafter, the term "topical" refers to direct application to an external
surface or to a cavity of tissues of the body. The term "ophthalmic" refers to
the
tissue at the external surface of the eye or the external surfaces of
surrounding
is tissues. The term "oral cavity" includes the surface of the mouth, lips,
tongue and
gums.
Preferably, the antibiotic is selected from the group consisting of
erythromycin, tetracycline, and chloramphenicol. Preferably, the antiviral
agent is
selected from the group consisting of azothymidin, acyclovir, dideoxyuridine
and
zo amantadine. Preferably, the antifungal agent is selected from the group
consisting
of ketoconazole, fluconazole, miconazole, tolnaftate, amphotericin and
nystatin.
Preferably, the disinfectant is selected from the group consisting of
chlorhexidine
and salts thereof, triclosan, cetrimide and cetylpyridinium chloride.
Preferably,
the nutrient is selected from the group consisting of vitamin A, vitamin E,
vitamin
2s D, vitamin K, ascorbyl palmitate, coenzyme Q-10, coenzyme Q-50, lipoic,
biotin
and carnitine. Preferably, the anti-inflammatory agent is selected from the
group
consisting of non-steroidal and steroidal. More preferably, the non-steroidal
anti-
inflammatory agent is selected from the group consisting of indomethacin,
ketoprofen, diclofenol and acetylsalicylic acid. Alternatively and more
preferably,
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the steroidal anti-inflammatory agent is selected from the group consisting of
dexamethazone, prednisolone and fluoromethzolone acetonide. Preferably, the
local anesthetic is selected from the group consisting of lidocaine,
trimecaine and
benzocaine. Preferably, the essential oil is selected from the group
consisting of
s menthol, vanillin, peppermint oil, clove oil, eucalyptus oil and lavender
oil.
Preferably, the agent is further characterized by having activity in the oral
cavity for treatment of at least one condition selected from the group
consisting of
gum disease, caries, dry mouth, malodorous breath, and microbial infection.
More
preferably, the microbial infection includes an infection selected from the
group
consisting of bacterial, viral and fungal.
Alternatively and preferably, the agent is further characterized by having
activity on a tissue selected from the group consisting of vaginal and rectal,
the
activity being suitable for treatment of at least one condition selected from
the
group consisting of inflammation, irntation, dryness and microbial infection.
1s According to other preferred embodiments of the present invention, the
lipid and the agent are present in a ratio of from about S:1 to about 1:5.
More
preferably, the lipid and the agent are present in a ratio of from about 3:1
to about
1:3.
According to a preferred embodiment of the present invention, the
2o formulation preferably further includes a stabilizer, the stabilizer
including at least
one surfactant selected from the group consisting of non-ionic, anionic,
cationic
and amphiphilic. Preferably, the stabilizer is a non-ionic surfactant selected
from
the group consisting of polyethylene glycol derivatives and glycerol
derivatives.
More preferably, the polyethylene glycol derivative is selected from the group
2s consisting of Tweens, tritons, tyloxapol, pluronics, Brijes, Spans,
poloxamers and
emulphors. Also more preferably, the glycerol derivative is selected from the
group consisting of polyglycerines and polyalkylglycerides.
Alternatively and preferably, the stabilizer is an anionic surfactant selected
from the group consisting of alkyl and aryl sulphonates and phosphates. Also
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6
alternatively and preferably, the stabilizer is a cationic surfactant selected
from the
group consisting of cethyl pyridinium chloride or bromide, and cethyl
trimethylammonium bromide. Alternatively and preferably, the stabilizer is an
amphiphilic surfactant selected from the group consisting of alkyl betaine
s derivatives, cocoamphodiacetale derivatives, lauroamphoacetates and
phosphatidylglycerol.
According to another preferred embodiment of the present invention, the
formulation preferably also includes at least one lipid additive selected from
the
group consisting of triglycerides, alkyl esters, cholesterol, triolein, Soya
oil,
to medium chain glycerides, isopropylmyristate and cholesterol esters.
According to still another preferred embodiment of the present invention,
the formulation further includes at least one additive selected from the group
consisting of flavors, aroma modifiers, sweeteners, colors, and antioxidants.
According to yet another preferred embodiment of the present invention,
1s the formulation includes a lipid in a form selected from the group
consisting of
micelles, mixed micelles and micellar aggregates, the lipid having a particle
size
of from about 10 to about 300 nm. Alternatively and preferably, the lipid is
in a
form selected from the group consisting of an emulsion and a suspension, the
lipid
having lipid particles of size in the range of from about 50 to about 300 nm.
2o According to another embodiment of the present invention, there is
provided a method for the preparation of a formulation for topical application
to a
tissue selected from the group consisting of ophthalmic, oral cavity, vaginal
and
rectal, the method including the steps of (a) dissolving the lipid and the
agent in a
water-miscible solvent to form a solution; and (b) adding water to the
solution in
2s an amount sufficient to dilute the water-miscible solvent to form a diluted
solution. Preferably, the water-miscible solvent is selected from the group
consisting of ethyl alcohol, propylene glycol and polyethylene glycol (PEG).
Also
preferably, the method further includes the step of (c) passing the diluted
solution
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through a microporous membrane having a pore size selected from the group
consisting of 0.05 micron, 0.1 micron, 0.2 micron, 0.45 micron and 0.8 micron.
According to still another embodiment of the present invention, there is
provided a method for the preparation of a formulation for topical application
to a
s tissue selected from the group consisting of ophthalmic, oral cavity,
vaginal and
rectal, the method including the steps of (a) mixing the lipid and the agent
to form
a substantially clear solution; (b) mixing the clear solution with water to
form a
diluted suspension; and (c) sizing the diluted suspension to form a
homogenized
suspension. Preferably, the method further includes the step of (d) filtering
the
homogenized suspension with a microfilter.
According to yet another embodiment of the present invention, there is
provided a method of administering a formulation to a mucosal tissue selected
from the group consisting of nasal, ophthalmic, oral cavity, vaginal and
rectal,
comprising the steps of (a) providing the formulation, the formulation
featuring:
is (i) a biologically active agent selected from the group consisting of
antibiotic,
antiviral agent, antifungal agent, disinfectant, nutrient, anti-inflammatory
agent,
local anesthetic and essential oil; and (ii) a lipid carrier, the lipid
carrier including
at least one lipid selected from the group of amphiphilic phospholipids
consisting
of yolk lecithin, Soya lecithin, phosphatidylglycerol and analogs thereof, the
lipid
2o being characterized as a colloidal micellar dispersion or as an emulsion of
lipid
droplets dispersed in an aqueous medium, and the lipid and the agent being
present in a ratio of from about 10:1 to about 1:10, such that the agent is
carried by
the lipid of the lipid carrier and the agent is released from the lipid in a
controlled
manner and over a prolonged period of time, and such that the lipid carrier
has a
2s property of high adhesion to the mucosal tissue; and (b) administering the
formulation to the mucosal tissue. Preferably, the mucosal tissue is the oral
cavity
and the formulation is administered as a mouthwash.
Brief Description of Drawing
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The invention is herein described, by way of example only, with reference
to the accompanying drawing, wherein:
FIG. 1 is a graph of the effect of the formulation of the present invention.
Detailed Description of the Invention
The present invention concerns new improved formulations for local oral
and other topical mucosal applications which contain a biologically active
agent.
These formulations are therefore particularly useful for the purposes of oral
hygiene and for the purposes of antiseptic treatment of the mucosal surface.
to More specifically, the present invention concerns formulations containing
micelles or self emulsifying compositions having a biologically active agent,
which have a high adhesive capacity for mucous membranes such as those on the
outer surfaces of the gums. These colloidal compositions also have a large
capacity for the anti-microbial agent. The lipid components of the micelles or
~s emulsion interact with the agent through non-covalent hydrophobic
attraction.
The formulations of the present invention are particularly well suited for
administering the anti-microbial agent in effective amounts to rnucosal
surfaces
where the agent is released by a slow-release process over a prolonged period.
These formulations are useful as mouth wash formulations for oral hygiene.
After
2o contacting the oral cavity, the carrier with the anti-microbial agent will
first adhere
to the mucosal surface of the gums, and the agent will then be released to the
surrounding teeth and oral cavity in a substantially continuous manner over a
prolonged time. Indeed, effective amounts of the anti-microbial agent could
potentially be present for as long as 24 hours, requiring oral application of
the
2s formulation only about once a day. Such oral formulations are therefore
effective
for maintaining general oral hygiene and specifically to combat tooth decay,
gum
disease and malodorous breath.
These desirable characteristics of the formulations of the present invention
were achieved by preparing a formulation in which the ratio of lipid to
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9
biologically active agent was reduced from prior art formulations, which
relied
heavily on employing large amounts of lipid to carry effective amounts of the
active ingredient. In addition, the lipid carrier is needed to target the
active agent
and cause it to adhere to the desired tissue, and then to release this agent
in a
controlled manner. Prolonged, controlled release of the biologically active
agent is
especially important because such release of such a biologically active agent
provides for optimal biological effects and, at the same time, also reduces
the
absolute amount of the agent necessary for the desired effect. Reduction of
the
total amount of the active ingredient could decrease adverse side effects,
which
Io are usually dose dependent.
Although the Examples are drawn to specific active ingredients, namely
chlorhexidine and triclosan, these are for illustrative purposes only and are
not
meant to be limiting. It is anticipated that formulations according to the
present
invention would also be effective for a number of other active ingredients,
which
is can be divided into the following groups: antibiotic, antiviral agent,
antifungal
agent, disinfectant, nutrient, anti-inflammatory agent, local anesthetic and
essential oil.
Examples of each of these groups are listed herein, it being understood that
these examples are for illustrative purposes only and are not meant to be
limiting
2o in any way. Preferably, the antibiotic is selected from the group
consisting of
erythromycin, tetracycline, and chloramphenicol. Preferably, the antiviral
agent is
selected from the group consisting of azothymidin, acyclovir, dideoxyuridine
and
amantadine. Preferably, the antifungal agent is selected from the group
consisting
of ketoconazole, fluconazole, miconazole, tolnaftate, amphotericin and
nystatin.
2s Preferably, the disinfectant is selected from the group consisting of
chlorhexidine
and salts thereof, triclosan, cetrimide and cetylpyridinium chloride.
Preferably,
the nutrient is selected from the group consisting of vitamin A, vitamin E,
vitamin
D, vitamin K, ascorbyl palmitate, coenzyme Q-10, coenzyme Q-50, lipoic, biotin
and carnitine. Preferably, the anti-inflammatory agent is selected from the
group
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consisting of non-steroidal and steroidal. More preferably, the non-steroidal
anti-
inflammatory agent is selected from the group consisting of indomethacin,
ketoprofen, diclofenol and acetylsalicylic acid. Alternatively and more
preferably,
the steroidal anti-inflammatory agent is selected from the group consisting of
5 dexamethazone, prednisolone and fluoromethzolone acetonide. Preferably, the
local anesthetic is selected from the group consisting of lidocaine,
trimecaine and
benzocaine. Preferably, the essential oil is selected from the group
consisting of
menthol, vanillin, peppermint oil, clove oil, eucalyptus oil and lavender oil.
The formulations of the present invention preferably have a ratio of
to biologically active agent to lipid of from about 1:10 to about 10:1, more
preferably
of from about l: 5 to about S: l and most preferably from about 1:3 to about
3:1.
The high mucosal adhesive property of this delivery system is determined by
the
lipid molecules at the surface of the particles. Optionally and preferably,
there is
also included stabilizing agents, in the form of anionic and non-ionic
surfactants,
which serve to stabilize the lipid-biologically active agent complex at the
desired
ratio.
Preferred formulations of the present invention include those having
chlorhexidine or triclosan as the biologically active agent, which in their
case,
serve as anti-microbial agents. These preferred formulations are intended
2o primarily for personal hygiene products including mouth wash-formulations
and
chewing gum, and cosmetic products including various formulations and liquid
soaps.
In the preferred formulations of the invention, the lipid component is in the
form of micelles, mixed micelles or micellar aggregates, or in the form of
2s emulsions (lipid colloids with an inner lipid phase or fatty phase) which
provide
for only an external association between the lipid and the biologically active
agent, as opposed to iiposomes which have a structure consisting of an inner
hydrophilic core which contains the biologically active agent. The interaction
between the biologically-active agent and the lipid is via hydrophobic
interactions.
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Such interactions therefore enable the lipid to associate with a large amount
of
biologically active agent over the entire surface of the lipid micelle or
emulsion to
provide a high load capacity for the biologically active agent of at least
about 10%
and up to about 90%, more preferably at least 25% and up to about 80%, of the
s weight of the lipid phase. The lipid itself causes the strong adhesion of
the
dispersed formulation to the mucous membranes of the oral cavity and to other
mucosal tissues. Without wishing to be bound by a particular mechanism,
presumably the adhesive property of the formulation is due to the amiphiphilic
characteristics of the lipid.
to For example, in mouth wash formulations in accordance with the present
invention, the lipid-biologically active agent ratio is of such a nature that
a single
use of the mouth wash solution will provide gum and teeth protection, and
prevent
the occurrence of malodorous breath for approximately a full day (24 hours),
even
if the user eats and drinks during this period. In addition to the above
essential
is components of the formulations, stabilizers (preferably anionic and non-
ionic
surfactants) are also preferably employed to stabilize the interaction between
the
lipid and biologically active agent, which enables maximum loading of the
lipid
micelles or emulsions with the biologically active agent, as well as
stabilization of
the release of the biologically active agent at the desired site.
2o The lipid components of the formulations of the present invention,
whether in the form of micelles, mixed micelles or micellar aggregates, or
emulsions, are organized into aggregates of particular size distribution of
from
about 10 nm to about 300 nm, this providing the above noted high adhesion
capability of the lipid aggregates to mucosal membranes and enabling both a
high
2s load capability of the biologically active agent onto the lipid aggregates
and a
prolonged release period of the biologically agents from the lipid aggregates.
The
structure of the lipid aggregates includes hydrophobic hydrocarbon chains of
the
lipid molecules at the core and polar groups of the lipid molecules at the
surface,
thereby enabling these lipid aggregates to be formulated into the preferred
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aqueous formulations of the present invention. Also, the structure provides
for
effective interaction with the preferred biologically active agents of the
present
invention. The improved properties of this formulation over previously known
formulations are achieved by forming the suspension with lipid or lipophilic
s particles which are highly adhesive to mucosal membranes, and which permit
prolonged and controlled release of the biologically active agent from the
lipid
particles at the mucosal surface.
More preferably, the formulation is an aqueous lipid colloidal formulation
for application to a mucosal surface, in a particular, an oral mucosal
membrane
to surface as found on the gums. This formulation includes a pharmaceutically
acceptable anti-microbial agent that is distributed between an aqueous phase
and
suspended small water-insoluble particles in a colloidal dispersion.
The preparation of the formulations of the present invention includes well
known standard chemical techniques well known to those of skill in the art as
set
15 forth in a large number of chemical texts readily available to skilled
artisans.
As the formulations of the present invention are preferably non-medical
formulations intended for over-the-counter distribution to the public, the
ingredients of the formulations of the present invention have preferably been
approved for this purpose by the relevant health authorities. Examples of the
2o various components of the formulations of the present invention are the
following.
First, lipids which have high adhesive capability to mucosal membranes
include the various amphiphilic lipids such as the phospholipids, for example,
egg
yolk lecithin, Soya lecithin and phosphatidylcholine. Preferably such lipids
will be
used at a concentration of from about 0.1 to about S% in the formulations. At
this
25 concentration an optimally bioadhesive particle will be obtained.
Suitable biologically active agents include agents which can be used to
treat an existing condition of the skin, or of the rectal, vaginal or oral
cavities, or
to prevent such a condition from arising as a prophylactic measure. For
example,
preferably the agent is further characterized by having activity in the oral
cavity
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13
for treatment of at least one condition selected from the group consisting of
gum
disease, caries, dry mouth, malodorous breath, and microbial infection.
Hereinafter, any agent which is active against a microbe is referred to as an
"anti-
microbial agent". Hereinafter, the term "microbial infection" includes
bacterial,
viral and fungal infections.
Alternatively and preferably, the biologically active agent is suitable for
treatment of at least one condition selected from the group consisting of
inflammation, irritation, dryness and microbial infection on a tissue selected
from
the group consisting of vaginal and rectal.
io If an anti-microbial agent is to be used, suitable anti-microbial agents
include the known, approved, mufti-purpose agents included with various liquid
antiseptics and disinfectants, such as triclosan and chlorhexidine.
Preferably,
triclosan is used in a concentration of from about 0.01 % to about 2.0% in the
final
formulations, and chlorhexidine is used in a concentration of from about 0.001
~5 to about 2% in the final formulations, when these formulations are ready
for
administration.
It should be noted that the two essential ingredients are the lipid and the
biologically active agent. However, additional ingredients may be optionally
added to the formulation to achieve certain desired characteristics. According
to a
2o preferred embodiment of the present invention, a suitable stabilizer is
preferably
included. Stabilizers of the lipid and anti-microbial agent complex are
generally
surfactants which stabilize the interaction between the lipids and the anti-
microbial agent in the formulations. These stabilizers thus serve to increase
the
load capability of the lipids, control the release of the active agent from
the lipids
25 over a long period, and also improve the geological properties of the
formulations
(viscosity of the formulations). The surfactants may be of a number of types,
including non-ionic surfactants such as polyethylene glycol derivatives and
glycerol derivatives. The polyethylene glycol derivatives can be, for example,
polyoxyethylated including the various Tweens, tritons, tyloxapol; pluronics,
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14
Brijes, Spans, poloxamers and emulphors. The glycerol derivatives can be for
example, polyglycerines or polyalkylglycerides. When such non-ionic
surfactants
are used in the formulations, the concentration is preferably in the range of
from
about 0 to about 5%. These non-ionic surfactants are particularly useful for
s improving the reological properties (viscosity) and stability of the
formulations.
Suitable anionic surfactants include the various alkyl and aryl sulphonates
and phosphates such as, for example, the various stearates (e.g. sodium lauryl
sulfate), oleates or palmitates. When those are used in the formulations,
their
concentration is preferably in the range of from about 0 to about 0.5%. These
to anionic surfactants are particularly useful for improving the loading of
the anti -
microbial agent onto the lipid particles in the formulations. Furthermore, in
this
colloidal composition, the addition of anionic surfactants such as sodium
stearate
does not detract from the activity of chlorhexidine. Such a finding is
contrary to
the teachings of the prior art, in which the addition of anionic surfactants
to prior
15 art formulations of chlorhexidine resulted in a loss of activity.
Suitable cationic surfactants include cethyl pyridinium chloride or
bromide, or cethyl trimethylammonium bromide, preferably at a concentration in
the range of from about 0 to about 2%. These cationic surfactants are
particularly
useful for improving the antiseptic activities of triclosan or chlorhexidine
in the
2o formulations.
Suitable amphiphilic surfactants include the various alkyl betaines,
cocoamphodiacetales or lauroamphoacetates, as well as phosphatidylglycerol.
Preferably, the concentration is in the range of from about 0 to about 2%.
It should be noted that a mixture of two or more of the above surfactants
25 may be used in the formulations of the present invention, which is
preferred, each
surfactant improving the properties of the formulation in its own specific
way.
An additional optional ingredient is an additional lipid moiety. Suitable
lipid moities include the various triglycerides, alkyl esters and cholesterol,
such as,
for example, triolein, Soya oil, miglyol; isopropylmyristate; and cholesterol
esters.
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Preferably, the concentration is in the range of from about 0 to about 30%.
These
additives are particularly useful in the preparation of emulsions and serve to
increase the total amount of the active agent carried by the lipid particles.
Another optional but preferred ingredient is a flavor or aroma modifier.
Suitable flavor or aroma modifiers include the various approved natural or
synthetic flavoring or aroma substances such as, for example, vanillin,
menthol,
peppermint oil, thyme oil and the like. When used in the formulations, their
amount is that quantity specified by the manufacturer or as acceptable in the
art.
These additives are particularly useful in those formulations of the invention
to intended for use as oral formulations such as a mouth wash, oral rinse or
the like.
Still another optional ingredient is a sweetener. Suitable sweeteners
include the various food grade sweeteners such as aspartame, sorbitol,
glycerol,
mannitol, saccharine, cyclamates and the like. When used their amount is
usually
specified by the manufacturer or as acceptable in the art. These additives are
is particularly useful in the oral formulations of the invention.
Other optional ingredients include a coloring agent. Suitable coloring
agents include the various food grade colors, such as, for example, beta-
carotene,
methylene blue and the like. When used, their amount is that specified by the
manufacturer or as acceptable in the art. These additives are particularly
useful in
oral formulations of the invention,
Finally, another optional ingredient is an antioxidant. Suitable antioxidants
and other stabilizers include the various tocopherols, ascorbates, and helates
such
as EDTA. Preferably the concentration is in the range of from about 0.001 to
about 0.2%. These additives are particularly useful to improve the stability
of the
2s formulations during storage and to prolong shelf life.
As mentioned above, the various lipids, biologically active agents and
additives of the formulations of the invention are known and widely available
from a member of commercial suppliers. Methods of preparation are also known.
However, in accordance with the present invention there is also provided
specific
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16
preferred methods to prepare these formulations. These methods include
processes for the preparation of bioadhesive colloidal antiseptic
compositions,
which are particularly useful for preparing stable oral rinse formulations.
One
example of such a method starts with the dissolution of the biologically
active
s agent, the lipid, and any additional ingredients such as stabilizers and
antioxidants,
in a minimal amount of a water-miscible solvent, such as ethyl alcohol. Next,
the
ingredients are mixed with an appropriate amount of water.
This will provide the desired suspension of liquid particles as a colloidal
dispersion in the water phase with the antiseptic distributed between the
water
to phase and the suspended lipid particles. If necessary, the suspension can
be
filtered through a microporous membrane, preferably with a pore size of from
about 0.1 to about 0.45 microns, to improve the particle size distribution and
suspension stability. Alternatively, the raw, original suspension can be
treated in
any suitable known high pressure homogenizer to reduce particle size as is
well
is known in the art. Following this homogenization step, the suspension can be
optionally filtered through a microporous membrane as noted above.
In formulations containing lipid emulsions in which lipid additives are
also included, the same procedure as above may be employed to improve and
control particle size. In addition, in such formulations a self dispersion
process
2o may be used followed by homogenization of the coarse dispersion to yield
the
desired submicron colloidal formulation having improved stability.
It should be noted, however, that the optimal method for preparing each
formulation of the invention is dependent upon the choice of the ingredients
for
each formulation and the steps of the method will be chosen accordingly to the
2s properties of the various components, their behavior in solution or
suspension and
their concentration. Such modifications of the method are readily apparent to
those
of ordinary skill in the art.
The present invention will now be described in more detail with the
following non-limiting Examples.
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Example l:Chlorhexidine in colloidal composition
without additional surfactants
315 mg ( ~ 0.4 minol) of purified egg lecithin (E-80) and 115 mg (~ 0.18
s mmol) of chlorhexidine diacetate were dissolved together in 5 ml of ethyl
alcohol
while stirring to obtain a stock solution. The stock solution was diluted with
distilled water during intensive stirring until 45 ml of water was added, such
that
the final concentration of ethyl alcohol was 10% to obtain a suspension. The
suspension was further filtered through a microporous membrane filter of pore
to size 0.45 micron to form a stable suspension of uniformly sized particles.
The
mean particle size was 285 + 65 nm. About 50% of chlorhexidine was bound to
lipid particles, as determined by centrifugal ultrafiltration. The absence of
a
liposomal fraction in the suspension was determined by NMR.
The high density of lecithin molecules on the particle surface should
is increase the opportunity for the amphiphilic phosphatidylcholine molecules
to
interact with polar groups of mucosal tissues. Antimicrobial activity of
chiorhexidine was not altered (data not shown).
Example 2. Chlorhexidine colloidal formulation with anionic surfactant
20 580 mg (0.8 mmol) of lecithin (E-80), 250 mg of chlorhexidine diacetate
(0.4 mmol) and 235 mg (0.8 mmol) of sodium lauryl sulfate (SLS) were dissolved
in 4 ml of ethyl alcohol. After dilution with 96 ml of distilled water, the
resultant
suspension was filtered sequentially through membrane filters having a pore
size
of first 0.45 micron and then 0.22 micron. A stable suspension with particles
of a
2s size less than 200 nm was obtained. More than 70% of chlorhexidine was
associated with the lipid phase. The antimicrobial activity of chlorhexidine
in the
prepared colloidal formulation was tested "in vitro" by diffusion in agar
plates and
by serial dilution. The activity was in the same range as the activity of
chlorhexidine in solution.
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Example 3. Chlorhexidine colloidal formulation
with additional non-ionic surfactant
A formulation was prepared as in Example 2 with Lecithin E-80, but
instead of sodium lauryl sulfate (SLS), 100 mg of polyoxyethylene sorbitan
monooleate (Tween-80) was added to the alcohol solution. After dilution and
filtration through a 0.22 micron membrane filter, a fine suspension was
obtained,
with a mean particle size of about 60 nm. About 50% of the total chlorhexidine
was associated with lipid particles.
to
Example 4. Chlorhexidine colloidal formulation with
additional anionic and non-ionic surfactants.
treated with a high pressure homogenizer.
The formulation was prepared by dissolving 500 mg (0.68 mmol) of
is lecithin E-80, 125 mg (0.2 mmol) of chlorhexidine diacetate, 120 mg (0.4
mmol)
of SLS and 120 mg of Tween-80 in a mixture of 2 ml absolute ethyl alcohol and
3
ml 2-propanediol (propylene glycol) to form a stock solution. The stock
solution
was diluted with 95 ml of distilled water and 2 g of glycerol was added to
form a
suspension. The suspension was treated with a high pressure homogenizer
20 (EmulsiFlex~ C-S ,"Avestin", Ottawa, Canada), 6 cycles at 12000-15000 psi.
The
final particle size was about 50 nm with 85% of the drug bound to particles.
Example 5. Chlorhexidine mouthwash colloidal formulation
A mouthwash (oral rinse) formulation of the present invention was
2s prepared according to the following method. 7.5 g of Lecithin E-80, 625 mg
of
chlorhexidine diacetate, 525 mg of Tween-80, 250 mg of D,L-Menthol and 30 mg
of alpha-tocopherol acid succinate were dissolved in mixture of 20 ml of
absolute
ethyl alcohol and 10 ml of propylene glycol. The resultant stock solution was
mixed with vigorous stirring with 480 ml of distilled water and 10 g of pure
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glycerol was added as sweetener to obtain a suspension. The suspension was
then
filtered sequentially first through a 0.45 micron and then through a 0.22
micron
PTFE membrane.
s Example 6. Triclosan mouthwash formulation
300 mg of triclosan ( 1.05 mmol), 2000 mg (2.7 mmol) of
phosphatidylcholine, S00 mg (1.7 mmol) of SLS, 300 mg of D,L-Menthol and 42
mg of aspartame were dissolved in 20 ml of absolute ethyl alcohol with slight
heating (40 °C). After dissolution, 98 ml of purified water containing
20 mg of
to EDTA-Na (ethylenediamine tetraacetic acid sodium salt) was added slowly
with
vigorous stirring. The coarse suspension was treated with a high pressure
homogenizer ( 6 cycles at 800-900 bar, 12000-14000 psi) and then filtered
through
a 0.22 micron PTFE membrane filter.
About 95% of the total triclosan was found to be associated with lipid
is particles having a mean size of about 170 nm. The antiseptic activity was
unchanged.
Example 7: Non-medicated colloidal composition
for evaluation of bioadhesive behavior in the oral cavity
20 315 mg of pure phosphatidylcholine and 80 mg of polyoxyethylated
sorbitan monolaurate (Tween-20) were dissolved in 2 ml of ethyl alcohol to
form
a solution. The solution was diluted with purified water to a final volume of
100
ml and then passed through a 0.22 micron PTFE membrane filter. The resultant
colloidal carrier had a mean droplet size of about 185 nm.
2s The bioadhesive properties were examined according to the following
method, using the radioactive Tc99 label, which is safe and approved for human
use. The lipid colloidal particles were labeled with Tc99 by using potassium
pertechnate-Tc99, after reduction by Sn2+ so that substantially all
radioactivity was
completely associated with lipid aggregates. A water solution of Tc99
complexed
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with DTPA (Diethylenetriamine pentaacetic acid), in which all radioactivity
was
in the aqueous phase, was used as a control. 10 ml of either the labeled
colloidal
composition or the control solution was administered to the oral cavity of the
volunteer human subjecf, and was then expectorated by the subject after a
short
s rinse. As shown in Figure 1, more than 20% of the radioactive label
associated
with the colloidal carrier remained attached to gum and palate tissues over
2.5
hours after expectoration. By contrast, the radioactive label level for the
control
water solution dropped below 20% of its initial value after less than 20
minutes
following rinse, and the remaining radioactivity detected was extremely low
after
to this time.
Example 8. Chlorhexidine colloidal self emulsi , in a~ptic composition
450 mg (0.6 mmol) of purified egg lecithin, 150mg (0.25 mmol) of
chlorhexidine diacetate, 1 SO mg of PEG-10 laurate and 450 mg (0.5 mmol) of
~ s triolein were all mixed together and heated to 60°C for 20 minutes
until
dissolution. Water was then added to this solution with gentle stirring.
Immediately, a fine oil-in-water emulsion was formed. Such emulsions were
observed to be stable with final oil phase concentrations of S% - 25%. The
resultant emulsion can optionally be treated by sonication, extrusion or high-
2o pressure homogenization to standardize the size of emulsion droplets.
Example 9. Triclosan colloidal self emulsif~ng antiseptic cpmposition
A self emulsifying composition containing 0.03 - 0.2% triclosan was
prepared as described in example 8, except that triclosan was used instead of
2s chlorhexidine diacetate, and 150 mg of Tyloxapol was added instead of PEG-
10
laurate. After formation of the emulsion, the mixture was treated by high-
pressure
homogenization (6 cycles, 800 bar), producing a stable emulsion.
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It will be appreciated that the above descriptions are intended only to serve
as examples, and that many other embodiments are possible within the spirit
and
the scope of the present invention.
