Note: Descriptions are shown in the official language in which they were submitted.
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METHOD FOR WETTING A POWDER CONTAINING BENZOYL PEROXIDE
Field of the Invention
The invention pertains to the field of formulating
stable dispersions and microdispersions of benzoyl peroxide.
Background of the Invention
Benzoyl peroxide is used extensively in dermatologic
pharmaceutical compositions. Many compositions for the
treatment of acne vulgaris and acne rosacea, for example,
contain between 2.5% and 10% benzoyl peroxide. The
effectiveness of benzoyl peroxide in treating these and other
dermatologic conditions is its usefulness as a keratolytic
agent, thereby increasing skin turnover and clearing pores.
Benzoyl peroxide additionally has direct antibacterial
activity as well.
A serious difficulty in obtaining stable dispersions
of benzoyl peroxide in aqueous f__uids is that benzoyl peroxide
is a highly hydrophobic organic compound and is not readily
wetted by water. This problem has been dealt with by the
prior art in one or more ways.
Benzoyl peroxide may be dissolved in an organic
solvent, thus avoiding the problem of preparing a stable,
homogeneous, cosmetically elegant and efficacious dispersion
of benzoyl peroxide for topical administration for treating a
skin affliction. Early products containing benzoyl peroxide in
solution for topical use were gels in which the benzoyl
peroxide was dissolved in an organic solvent such as acetone
or a combination of alcohol and acetone. These products proved
to be efficacious, however they suffered from several
disadvantages including flammability, over-drying the skin,
and causing frank skin irritation in many acne sufferers.
More recent developments have used other organic solvents to
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solubilize benzoyl peroxide. However these compositions do
not solve the problem of severe skin irritation in a
significant number of subjects due to the problem of bolus
delivery of solubilized benzoyl peroxide into the pilo-
sebaceous apparatus of the skin.
For these and other reasons, including increased
production of degradation products that occurs with solutions,
suspensions of benzoyl peroxide are preferred over solutions.
Micro-suspensions, that is suspensions containing micronized
benzoyl peroxide, are preferred to standard or non-micronized
suspensions of benzoyl peroxide for several reasons, including
the following exemplary reasons. First, micronized
suspensions provide effective delivery of small particles of
benzoyl peroxide into the infundibulum of the pilo-sebaceous
apparatus, in which they lodge and from which they provide
non-bolus delivery of drug into the sebum and pilo-sebaceous
tissue. This delivery provides a proper balance of optimal
efficacy and reduction of skin irritation reactions. Second,
cosmetic elegance and patient acceptance is improved with the
smooth, homogeneous gels, creams or lotions containing
suspended benzoyl peroxide. Particularly in treating facial
conditions of the skin such as acne or acne rosacea, cosmetic
elegance is an important factor in obtaining good patient
compliance with treatment instructions. For chronic diseases
with ongoing topical drug management, good patient compliance
is essential in obtaining overall treatment success.
Surfactants are often utilized as wetting agents to
help disperse benzoyl peroxide in aqueous fluids and to
maintain benzoyl peroxide in suspension. Surfactants,
however, are often irritating to damaged or diseased skin and,
when applied to intact skin repeatedly, surfactants are known
to disrupt the normal skin barrier function as evidenced by an
increase in trans-epidermal water loss from the skin.
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Therefore it is desirable to formulate pharmaceutical
compositions, particularly those that will be used daily over
extended periods for treating chronic skin conditions, with
minimal or no surfactants. In order to facilitate dispersion
of benzoyl peroxide and to maintain the dispersion of benzoyl
peroxide in suspension, a micronized form of benzoyl peroxide
is often utilized, sometimes in conjunction with a surfactant.
Cox, U.S. Patent No. 3,535,422, discloses a stable
emulsion containing benzoyl peroxide. Cox discloses two
methods to obtain the emulsion containing benzoyl peroxide in
suspension. In a first method, Cox forms an emulsion
containing water, a surfactant, and up to 25% of a saturated
organic compound emollient. Dry micronized benzoyl peroxide
is then blended into this emulsion to obtain the composition.
In a second method, utilizing non-micronized benzoyl peroxide,
coarse crystals of benzoyl peroxide in the form of a powder
packaged wet with water are combined with a previously made
emulsion containing all of the components of the composition,
including a surfactant and a saturated organic compound
emollient. The resulting composition is then milled in order
to obtain a composition containing micronized benzoyl
peroxide.
Young, U.S. Patent No. 4,056,611, discloses a
single-phase composition containing benzoyl peroxide in
suspension. The composition of Young contains an alcoholic
solvent, water, and a surfactant as necessary components.
Like Cox, Young discloses that the composition may be made by
using dry micronized benzoyl peroxide crystals. Preferably,
Young utilizes, as does Cox, a wet-packed powder of coarse
crystals of benzoyl peroxide, which powder contains 70%
benzoyl peroxide and 30% w/w water. All of the components of
the composition are mixed together and then this mixture is
milled to obtain a composition containing micronized benzoyl
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peroxide in suspension. Young further discloses that the
compositions may advantageously contain a suspending agent to
maintain the benzoyl peroxide particles in suspension and a
viscosity building (gelling) agent.
The Cox and Young methods and compositions contain
several disadvantages pertaining to compositions containing
benzoyl peroxide. In both Cox and Young, surfactants are
utilized, which are often irritating to damaged or diseased
skin. Further, both Cox and Young disclose combining together
all constituents of their compositions containing coarse, non-
micronized benzoyl peroxide to form a mixture and then milling
this mixture to obtain a composition containing micronized
benzoyl peroxide. Although Young discloses that a gelling
agent may be combined in the composition, it is well known
that the mechanical milling forces used in to micronize
benzoyl peroxide will likewise tend to disrupt the polymers
utilized as gelling agents. Thus, the milling process results
in a reduction of the ability of the gelling agents to provide
the viscosity that is desired.
Klein, U.S. Patent No. 4,387,107, discloses gel
compositions containing benzoyl peroxide. Klein avoids the
problem of milling a composition containing benzoyl peroxide
by using benzoyl peroxide that is pre-micronized prior to
combining with the remaining ingredients. In order to make
the composition of Klein, water is combined with a gelling
agent to make a first mixture. To this mixture is optionally
added an alcohol vehicle and other components such as a
perfume and other therapeutic agents such as methyl
salicylate. Finally, a second mixture containing micronized
benzoyl peroxide, a surfactant, and water is added to the
first mixture to obtain the composition. Because micronized
benzoyl peroxide is used, there is no need to mechanically
mill the composition. Thus, the polymeric gelling agents are
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not disrupted. However, the method of Klein requires the use
of pre-micronized benzoyl peroxide and the presence of a
surfactant.
The use of micronized benzoyl peroxide, as disclosed
in Klein, provides advantages, particularly regarding the
formation of semi-solid compositions containing one or more
polymeric gelling agents. Micronized, as opposed to non-
micronized benzoyl peroxide, is more readily suspended in a
hydrophilic fluid and such suspensions are more physically
stable than are similar suspensions made with non-micronized
benzoyl peroxide. However, micronized benzoyl peroxide,
particularly as pharmaceutical grade material, is often
difficult to obtain and, when it is obtainable, micronized
benzoyl peroxide is expensive.
It would, therefore, be advantageous to be able to
purchase non-micronized benzoyl peroxide, which is readily
available and is much less expensive than micronized benzoyl
peroxide, and to then be able to micronize the benzoyl
peroxide for use in manufacturing pharmaceutical formulations.
As disclosed in both the Cox and Young patents,
benzoyl peroxide, in solid crystalline form, is stable at room
temperature but is flammable and capable of exploding when
subjected to temperatures associated with grinding.
Consequently, dry milling of benzoyl peroxide is not
preferred. Rather, it is preferred to wet-mill benzoyl
peroxide in order to obtain benzoyl peroxide in a micronized
form. Benzoyl peroxide in the presence of water, which is
utilized in the preferred wet milling processes, is much safer
to process as the risk of fire and explosion is minimized.
One difficulty encountered in wet-milling benzoyl
peroxide, as mentioned above, is that benzoyl peroxide is
highly hydrophobic and resists wetting with water. Further,
the strong attractive forces between benzoyl peroxide
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particles create a problem of aggregation which compromises
both the manufacturing process and the quality of the final
pharmaceutical formulation. Surfactants have been utilized
for this purpose and to maintain a stable-non-agglomerated
micro-suspension of benzoyl peroxide, as disclosed in each of
Cox, Young, and Klein patents, but surfactants are not
preferred due to their tendency to irritate damaged or
diseased skin. Therefore, a method in which benzoyl peroxide
may be readily wetted, and preferably placed into suspension,
in a hydrophilic or aqueous fluid, and preferably without the
use of surfactants, would be of great benefit.
Description of the Invention
It has been unexpectedly discovered that a benzoyl
peroxide powder is readily wetted, and a benzoyl peroxide
suspension with minimal or no aggregation may be obtained, by
combining the benzoyl peroxide, with or without mechanical
agitation, with a wetting fluid, preferably aqueous-based,
containing a water-soluble organic solvent dissolved in the
water-containing fluid at a concentration that is sufficient
to decrease the surface tension to about 64 dynes/cm or less.
It has further been discovered that this wetting may be
obtained without the use of wetting agents, such as a
surfactant.
As used herein, the term "benzoyl peroxide powder"
means any particulate form of benzoyl peroxide. Examples of
such particulate forms include granules, crystals, and
amorphous powder, whether coarse, fine, or ultrafine such as a
nanoparticulate powder.
As used herein, the term "powder containing benzoyl
peroxide" refers to a powder containing a benzoyl peroxide
powder and optionally a particulate form of one or more
materials other than benzoyl peroxide. For example, a powder
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containing benzoyl peroxide may contain particles of benzoyl
peroxide and one or more other particles, wherein the
concentration of particles other than benzoyl peroxide in the
powder is 50% w/w or less. A powder containing benzoyl
peroxide may contain a concentration of benzoyl peroxide
between 50% and 100%, for example between 50% and 60%, between
60% and 70%, between 70% and 80%, between 80% and 90%, or
between 90% and 100%.
As used herein, the term "non-micronized," when used
in reference to a benzoyl peroxide powder, means a powder in
which the average benzoyl peroxide particle is 50 microns or
greater in size. Conversely, the term "micronized," when used
in reference to a benzoyl peroxide powder, means a powder in
which the average benzoyl peroxide particle is less than 50
microns in size. Preferably, but not necessarily,
substantially all of the benzoyl peroxide particles in a non-
micronized powder are 150 microns or larger.
As used herein, the term "wetting" refers to the
spreading of a fluid over and through a powder, displacing air
adsorbed thereto, so that the particles of the powder are
individually and discretely encompassed within the fluid. As
is known in the art, a powder is considered to be wetted when
almost all, such as about 80% +/- 10% based on visual
inspection and estimation, of the particles are encompassed
within the fluid. For example, contacting a powder with a
suitable wetting fluid results in what is referred to as
complete wetting even though a minority of the particles,
typically less than about 20% +/- 10% of the particles, does
not become wetted.
As used herein, the term "mechanical agitation"
refers to the application of kinetic energy to a powder
mixture in contact with a liquid in order to facilitate
wetting of the powder mixture within the liquid. Examples of
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mechanical agitation include but are not limited to mixing,
stirring, shearing, shaking, or blending. Other examples
include sonication and vortexing.
As used herein, the term "aqueous gel" with regards
to a pharmaceutical dosage form for topical application means
a single phase semi-solid pharmaceutical dosage form
comprising a carrier or carrier system that is gelled with a
thickening agent such as a polymer wherein the majority of the
carrier or carrier system is water, that is 50% w/w or more.
As used herein, the term "agglomeration" means the
strong physical attraction between small solid particles, such
that a multiplicity of the particles are aggregated into a
single larger mass that appears as a single particle.
In one embodiment, the invention is a method to
obtain a wetted powder containing benzoyl peroxide. According
to the method of the invention, the powder is placed in
contact with a liquid containing water and a water-soluble
organic solvent. The solvent is dissolved in the liquid at a
concentration sufficient to depress the surface tension to
less than 64 dynes/cm at room temperature. In a preferred
embodiment, the solvent is present in the liquid at a
concentration sufficient to depress the surface tension to
less than 62 dynes/cm. In a more preferred embodiment, the
solvent is present in the liquid at a concentration sufficient
to depress the surface tension to less than 61 dynes/cm. In a
most preferred embodiment, the solvent is present in the
liquid at a concentration sufficient to depress the surface
tension to less than 60 dynes/cm. For example, the solvent
may be present in the liquid at a concentration sufficient to
reduce the surface tension to between 55 and 60 dynes/cm or
even to between 50 and 55 dynes/cm or less.
In the description that follows, the method is
described with reference to reducing the surface tension to
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less than 64 dynes/cm. As disclosed in the preceding
paragraph, preferably, the surface tension is decreased to
values even lower than 64 dynes/cm, such as between 50 and 62
dynes/cm or lower.
Non-micronized benzoyl peroxide is available as
Hydrous Benzoyl Peroxide, USP, which is sometimes erroneously
referred to as "wet" benzoyl peroxide. Hydrous Benzoyl
Peroxide contains not less than 65.0% and not more than 82.0 %
benzoyl peroxide, with an average of about 74% benzoyl
peroxide and 26% water, in order to reduce flammability and
shock sensitivity. The benzoyl peroxide in Hydrous Benzoyl
Peroxide is not wetted, as this term is used in the art.
Hydrous Benzoyl Peroxide is not a paste and the benzoyl
peroxide in Hydrous Benzoyl Peroxide is in a microcrystalline
state and behaves as a freely flowing powder. There is no
chemical interaction between water molecules and the benzoyl
peroxide powder and the water does not make the core or the
inside of the benzoyl peroxide powder wet. Thus, commercially
available "wet" benzoyl peroxide is not wetted.
The benzoyl peroxide in the powder may be micronized
or may be non-micronized and, therefore, the description
herein pertaining to non-micronized powders will be understood
to be applicable also to micronized powders. Micronized
benzoyl peroxide powders are often commercially available as a
wetted powder containing benzoyl peroxide and water. An
example of wetted benzoyl peroxide powders are those marketed
under the brand name Benox (Syrgis Performance Initiators,
Inc., Helena, Arkansas). Because powders containing
micronized benzoyl peroxide are already wetted, such powders
are not applicable to the wetting embodiment of the present
invention. However, the use of wetted powders containing
micronized benzoyl peroxide may be applicable to other
embodiments of the invention discussed below.
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In accordance with the method of the invention for
obtaining a wetted benzoyl peroxide powder, a powder
containing benzoyl peroxide is placed in contact with a
suitable wetting fluid, which wetting fluid contains water and
one or more water-soluble organic solvents having a combined
concentration that is sufficient to decrease the surface
tension of water to the desired level. Preferably, the
wetting fluid is free of surfactants. The powder and the
wetting fluid are permitted to remain in contact with one
another for a time sufficient for the benzoyl peroxide to
become wetted by the wetting fluid. If desired, or if
necessary, the powder and the wetting fluid may be
mechanically agitated to facilitate or to hasten or to
complete wetting.
The organic solvent that is suitable for the method
of the invention is one that is "very soluble", "freely
soluble", or "soluble" in water as these terms are defined in
the U.S.P. 23rd Ed. as shown in Table 1.
Parts of water required to
Solubility in water dissolve 1 part of organic
solvent
Very Soluble < 1
Free Soluble 1 - 10
Soluble 10 - 30
Sparingly Soluble 30 - 100
Slightly Soluble 100 - 1000
Very Slightly Soluble 1000 - 10,000
Practically Insoluble or > 10,000
Insoluble
Table 1
Preferably, but not necessarily, the organic solvent
is miscible in water. Examples of organic solvents that are
miscible in water and which are suitable for the method of the
invention include C1_6 alkanols, such as methanol, ethanol, n-
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propanol, isopropanol, n-butanol, sec-butanol, tert-butanol,
n-pentanol, cyclopentanol and cyclohexanol; linear amides,
such as dimethylformamide or dimethylacetamide; ketones and
ketone-alcohols, such as acetone, methyl ethyl ketone,
cyclohexanone and diacetone alcohol; water-miscible ethers,
such as tetrahydrofuran and dioxane; diols, preferably diols
having from 2 to 12 carbon atoms, for example pentane-l,5-
diol, ethylene glycol, propylene glycol, butylene glycol,
pentylene glycol, hexylene glycol and thiodiglycol and oligo-
and poly-alkyleneglycols, such as diethylene glycol,
triethylene glycol, polyethylene glycol and polypropylene
glycol; triols, such as glycerol and 1,2,6-hexanetriol; mono-
C1-4-alkyl ethers of diols, such as mono-C1-4-alkyl ethers of
diols having 2 to 12 carbon atoms, such as 2-methoxyethanol,
2-(2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)-ethanol, 2-[2-
(2-methoxyethoxy)ethoxy]ethanol,2-[2-(2-ethoxyethoxy)-ethoxy]-
ethanol and ethyleneglycol monoallylether; cyclic amides,
preferably 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-
pyrrolidone, caprolactam and 1,3-dimethylimidazolidone; sugar
esters such as dimethyl isosorbide; cyclic esters such as
caprolactone; and sulfoxides, such as dimethyl sulfoxide and
sulfolane.
In addition, the solvent that is suitable for the
method of the invention is capable of being dissolved in water
at a concentration that is sufficient to reduce the surface
tension to less than about 64 dynes/cm at room temperature.
The surface tension of water varies slightly with changes in
temperature as shown below in Table 2.
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Temperature ( C) Surface Tension of
Water
(dynes/cm)
0 75.6
74.9
74.2
73.5
72.8
72.0
71.2
69.6
67.9
66.2
64.4
62.6
100 58.9
Table 2
Preferably, the method of the invention to wet a
benzoyl peroxide powder is performed at about room
5 temperature, that is between 20 and 30 C. Less preferably,
the method of the invention is performed at a temperature
below room temperature, that is between 0 and 20 . Also less
preferably, the method of the invention is performed at a
temperature above room temperature, that is between 30 and
10 50 C. Even less preferable, the method of the invention may
be performed at high temperatures of between 50 and 100 C.
Because one of the advantages of the present invention is the
lack of necessity to apply heat, it is preferable to perform
the method of the invention at room temperature or below.
15 However, if heat is applied and the temperature is elevated
above room temperature, the optimum surface tension for
wetting may be slightly higher than 64 dyne/cm.
The wetting fluid may contain, in addition to the
one or more water soluble organic solvents, additional
20 components that may be additional solvents. Such additional
components are preferably liquid at the temperature at which
the wetting process is performed and are preferably soluble in
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the water soluble organic solvents that are utilized.
Optionally the wetting fluid may contain dissolved solutes
such as additional wetting agents, film-forming agents, or de-
aggregation agents.
It has been surprisingly discovered that a wetting
fluid that is a liquid containing water and one or more water
soluble organic solvents as described above is capable of
wetting a powder containing benzoyl peroxide. The
concentration of the water miscible organic solvent or
solvents in the wetting fluid will vary depending on factors
such as the particular solvent or solvents used, and on the
relative volumes of benzoyl peroxide powder and wetting fluid
used. Generally, the concentration of the water soluble
organic solvent in the wetting fluid is between 1% and 100%
w/w. Preferably, the concentration is about 5% or higher,
more preferably about 10% or higher, and most preferably at
least about 15%. The term "about" in the preceding sentence
is intended to mean an amount that is rounded to be the amount
stated. Thus, about 5% means 4.5% or more, about 10% means
9.5% or higher, and about 15% means 14.5% or higher. The
powder and the wetting fluid may be mechanically agitated to
facilitate, to hasten, or to complete wetting.
In another embodiment, the invention is a wetted
benzoyl peroxide powder that is in combination with a liquid
containing water and one or more water soluble organic
solvents as described above, wherein the concentration of the
water soluble organic solvent in the liquid is sufficient to
decrease the surface tension to less than 64 dynes/cm at room
temperature as described above.
In another embodiment, the invention is a wetted
benzoyl peroxide powder that is in combination with a liquid
containing one or more water soluble organic solvents as
disclosed above, wherein the concentration of the organic
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solvent or solvents in the liquid is sufficient decrease the
surface tension to less than 64 dynes/cm at room temperature.
In another embodiment, the invention is a wetted
benzoyl peroxide powder that is in combination with a liquid
containing one or more water soluble organic solvents as
disclosed above, wherein the concentration of the organic
solvent or solvents in the liquid is sufficient decrease the
surface tension to less than 64 dynes/cm at room temperature
and result in wetting of the benzoyl peroxide powder, thereby
reducing and controlling agglomeration of the benzoyl peroxide
particles, whether micronized or not, during the manufacturing
process of a topical drug product or component thereof.
In another embodiment, the invention is a method for
preparing micronized benzoyl peroxide, such as for use in
making a topical pharmaceutical formulation containing benzoyl
peroxide as an active ingredient. According to this
embodiment of the invention, a wetting fluid containing water
and a water soluble organic solvent at a concentration
sufficient to reduce the surface tension to less than 64
dynes/cm at room temperature is combined with a powder
containing non-micronized benzoyl peroxide. The wetting fluid
is permitted to wet the majority of the benzoyl peroxide
particles in the powder. The wetted benzoyl peroxide is then
subjected to an appropriate micronization procedure to obtain
micronized benzoyl peroxide.
In another embodiment, the invention is a suspension
of benzoyl peroxide. According to this embodiment, the
suspension is a single phase composition containing benzoyl
peroxide at a concentration of between 1% and 30% w/w,
preferably 10% or less, and most preferably 5% or less. The
benzoyl peroxide is suspended in a suspending fluid that
contains one or more water soluble organic solvents at a
concentration sufficient to reduce the surface tension to less
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than 64 dynes/cm at room temperature. The suspending fluid
may contain only the one or more organic solvents.
Alternatively, the suspending fluid may contain one or more
vehicle fluids that are other than a water soluble organic
solvent that is capable of reducing the surface tension to
less than 64 dynes/cm at room temperature.
It is preferred that the suspending fluid contains
only one or more of the above-described water soluble organic
solvents in addition to water. If a vehicle fluid other than
a water soluble organic solvent that is capable of reducing
the surface tension of water to less than 64 dynes/cm at room
temperature is utilized, such vehicle fluid should be
pharmaceutically acceptable and miscible with the one or more
of the water soluble organic solvents used. Further, the
concentration of the one or more water soluble organic solvent
that is capable of reducing the surface tension to less than
64 dynes/cm at room temperature in the suspending fluid should
be that which is sufficient, in the absence of the vehicle
fluid that is other than such water soluble organic solvent,
to wet a benzoyl peroxide powder therewith combined.
The benzoyl peroxide in the suspension may be
micronized or may be non-micronized. If the benzoyl peroxide
is non-micronized, the suspension may be treated by a process
by which the benzoyl peroxide in the suspension becomes
micronized. Suitable micronization processes include milling,
grinding, crushing, cutting, impinging, cavitating, and
shearing the suspension.
Non-micronized benzoyl peroxide, when wetted and
suspended in accordance with the method of the invention, has
a very low tendency to agglomerate or aggregate on the liquid
surface and, therefore, there is little or no problem of
benzoyl peroxide particles becoming stuck in the small
orifices of the micronizing equipment such as a Gaulin mill
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(Delavan, WI). Benzoyl peroxide particles that have been
wetted in accordance with the method of the invention and then
micronized remain in stable suspension and do not agglomerate
or aggregate on the liquid surface to a significant extent
prior to being incorporated into a pharmaceutical formulation
such as a gel, cream or lotion. The stable micro-suspension
obtained according to the invention thus results in good
pharmaceutical homogeneity and optimal non-bolus delivery into
the skin, particularly the pilo-sebaceous apparatus, thus
minimizing irritation potential without compromising efficacy.
In another embodiment, the invention is a method for
preparing micronized benzoyl peroxide, such as for use in
making a topical pharmaceutical formulation containing benzoyl
peroxide as an active ingredient. In accordance with this
method, a benzoyl peroxide powder is wetted and in suspension
as described above, and the benzoyl peroxide suspension is
then subjected to appropriate micronization treatment to
obtain a suspension containing micronized benzoyl peroxide.
In another embodiment, the invention is a suspension
containing micronized benzoyl peroxide, which benzoyl peroxide
has been micronized according to the method described above.
The micronization process and suspension of benzoyl peroxide
of the invention are useful in formulating topical
pharmaceutical products containing benzoyl peroxide as an
active ingredient, especially topical products that are semi-
solid dosage forms. The methods of the invention maintain the
dispersed micronized benzoyl peroxide in a stable non-
agglomerated and non-aggregated state for optimal
pharmaceutical acceptability without a "shake well before
using" label in lotions and other pourable topical dosage
forms and for optimal drug delivery.
In another embodiment, the invention is a
pharmaceutical formulation containing benzoyl peroxide in
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suspension in a liquid containing one or more water-soluble
organic solvents that is, or are in combination, capable of
reducing the surface tension of water to less than 64 dynes/cm
at room temperature, wherein the concentration of the water-
soluble organic solvents together with the water in the
pharmaceutical formulation is sufficient to wet a powder
containing benzoyl peroxide at a concentration of the benzoyl
peroxide present in the formulation in the absence of all
other liquid components of the formulation. Preferably, the
benzoyl peroxide is micronized. Preferably, the benzoyl
peroxide has been micronized according to the present
invention. If desired, the pharmaceutical formulation may
contain one or more additional vehicle fluids, as described
above. The pharmaceutical formulation may further contain
excipients commonly utilized in pharmaceutical formulations,
such as humectants, emollients, pH stabilizing agents,
chelating agents, film forming agents, preservatives, and
anti-oxidants.
The concentration of benzoyl peroxide in the
pharmaceutical formulation is preferably between 1% and 10%
w/w, with a preferred concentration being between 2% to 5%.
If desired, an additional agent that is useful in the
treatment of dermatologic disorders such as acne vulgaris or
acne rosacea may be included in the formulation. Preferably,
the additional anti-acne compound is soluble in the solvent or
multiplicity of solvents and so is dissolved in the
formulation.
One such preferred anti-acne compound is an
antibiotic. Preferred antibiotics include those of the
macrolide family of antibiotics such as erythromycin,
azithromycin, clarithromycin, tilmicosin, and tylosin, and
those of the lincomycin family of antibiotics such as
clindamycin and lincomycin. A particularly preferred
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antibiotic to be used in combination with benzoyl peroxide in
the formulation of the invention is clindamycin, such as
clindamycin hydrochloride or clindamycin phosphate.
Additional topical anti-acne active ingredients that may be
contained in the formulation of the invention, either with or
without the inclusion of an antibiotic, include salicylic
acid, azelaic acid, sulfur, sulfacetamide, resorcinol, alpha-
hydroxy acids such as glycolic acid, niacinamide, urea, and
retinoids such as tretinoin, adapalene, and tazarotene.
The additional anti-acne compound, if present in the
formulation of the invention, is preferably present in a
concentration in which there is a demonstrable anti-acne
effect in the absence of benzoyl peroxide. For example, if
clindamycin is present in the formulation of the invention,
the concentration of the clindamycin is preferred to be at
least 0.5%, such as 1%. Concentrations of clindamycin lower
than 0.5% or higher than 1%, such as 2.5% to 5.0% or higher,
may be utilized in the formulation.
It is preferred, although not required, that the
formulation be in the form of a gel, preferably an aqueous
gel. Accordingly, the formulation of the invention may
contain a gelling or thickening agent. Any gelling agent that
is water-dispersible, is suitable for use on epithelial tissue
such as skin, and forms an aqueous gel of substantially
uniform consistency, is suitable for use in the composition of
the invention. One preferred gelling agent is
hydroxypropylcellulose, such as that sold under the tradename
KLUCEL (Hercules Incorporated, Wilmington, DE, USA) . Another
preferred gelling agent is hydroxyethylcellulose, such as that
sold under the tradename NATROSOL (Hercules Incorporated).
Other suitable gelling agents include carboxyvinyl polymers,
also known as carbomers, such as are sold under the tradename
CARBOPOL 934, 940, 941, 980, and 981 (B.F. Goodrich Co.,
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Akron, OH, USA), ETD 2020''", and ULTREZ (Noveon, Inc. ,
Cleveland, OH, USA). Additional suitable gelling agents are
polyvinyl alcohol, polyethylene oxides, propylene glycol
alginates, methylcellulose, hydroxypropylmethylcellulose and
natural polymeric gums such as xanthan, and carrageenan. The
concentration of gelling agent in the composition may be
varied depending on several factors, including the desired
viscosity of the gel composition. For example, a gel may be
pourable and dispensed from a bottle, such as a plastic
squeeze bottle, or it may be more viscous such that it is
preferably dispensed from a collapsible tube or wide mouth
jar.
If desired, the formulation of the invention may
further include additional pharmaceutically acceptable
excipients typically used in formulations and known to those
skilled in the art. Such excipients include, for example,
humectants, emollients, pH stabilizing agents, chelating
agents, film formers, penetration enhancers, preservatives,
and anti-oxidants.
The semi-solid dosage from of the pharmaceutical
formulation of the invention may also be in the form of an
emulsion, such as a cream or lotion. Preferably, such creams
or lotions are formulated without low molecular weight
surfactants due to the tendency of such surfactants to be
irritating to the skin or to impair the skin barrier function.
Thus, it is preferred that the cream or lotion formulations of
the invention are made with high molecular weight polymeric
emulsifiers which do not exhibit such detrimental effects on
skin, such as disclosed in Dow, U.S. Patent No. 7,368,122, or
with low levels of mild emulsifiers such as poloxamers.
The invention is further described in the following
non-limiting examples. In the examples that follow, the
invention is illustrated primarily with an organic solvent
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that are miscible with water. However, it is understood that
the examples are illustrative and that the invention may be
practiced with water soluble solvents that are not miscible
with water, as described above.
Example 1 - Wetting of a benzoyl peroxide powder utilizing
various water soluble organic solvents
A benzoyl peroxide wettability study was conducted
as follows. 1.5 grams of a benzoyl peroxide powder was spread
on the surface of each of four test fluids contained in glass
beakers having about a 5 cm diameter, containing either 30 ml
of purified water having a surface tension of 72.0 dynes/cm
(Sample A), 30 ml of a fluid composed of 7.5% ethanol and 95%
purified water having a surface tension of 51.4 dynes/cm
(Sample B), 30 ml of a fluid composed of 20% polyethylene
glycol (PEG 200) and 80% purified water having a surface
tension of 51.9 dynes/cm (Sample C),, and 30 ml of a fluid
composed of 20% dimethyl isosorbide (DMI) and 80% purified
water having a surface tension of 50.1 dynes/cm (Sample D).
At the bottom of each beaker was a 12 mm x 8 mm magnetic stir
bar. Each of the fluids, with the benzoyl peroxide powder on
the surface, was stirred at 1200 rpm. After 5 and 10 minutes
of stirring at room temperature, the samples were visually
inspected for the degree of wetting of the benzoyl peroxide.
It was determined that the wetting of the benzoyl peroxide in
Sample A was poor, with little or no visual evidence of
wetting. The wetting of the benzoyl peroxide in each of
Samples B, C, and D was determined to be good, with visual
evidence of wetting of at least 90% of the benzoyl peroxide
powder.
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Example 2 - Effect of various solvents on water surface
tension
Surface tension of a fluid containing water was
determined prior to and after mixing with various
concentrations of various water soluble organic solvents in
water. The study was performed at room temperature and the
results are shown in Table 3. Values for surface tension are
in dynes/cm.
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Conc. of Ethanol Dimethyl
Propylene Hexylene Ethoxy PEG Gly-
Solvent % Glycol (200 Glycol Diglycol 400 Isosor- cerin
w/w proof) bide
0 71.0 72.0 71.9 71.8 72.8 72.8 72.6
1.0 70.8 67.4 60.1 66.2 64.2 66.0
2.5 68.7 62.0 54.2 62.5 60.9 61.7
65.9 55.9 48.9 56.8 56.6 52.8
7.5 63.6 51.4 45.5 55.3 56.0 52.1
61.7 47.8 43.0 53.1 52.5 47.9
12.5 59.7 44.6 41.1 50.4 50.6 46.4
15.0 58.3 42.2 39.4 49.7 49.7 43.5
17.5 56.5 40.2 37.8 47.6 48.1 41.9
55.2 38.0 36.5 43.2 46.2 38.6
22.5 54.1 36.6 35.5 43.1 45.6 40.5
52.8 34.9 34.7 43.8 45.2 41.7 69.8
50.6
50 68.9
75 66.4
100 36.1 22.3 28.6 32.0 45.0 39.3 62.0
Polypro-
Conc. of PEG Poly Isopropyl 1,3 pylene
Solvent % 200 Carbopropylenatnee Alcohol Propanediol Glycol
w/
w
(PPG-9)
0 71.7 71.5 71.9 72.4 72.3
1.0 65.9 68.5 62.1 69.8 50.3
2.5 64.2 63.8 54.2 68.1 47.5
5 61.1 56.8 47.3 64.6 45.2
7.5 58.7 49.6 42.0 64.4 43.6
10 56.1 45.9 38.6 61.2 42.4
12.5 54.8 46.5 35.7 61.1 41.3
15.0 53.0 44.1 33.1 61.0 40.2
17.5 52.2 43.5 31.1 58.9 39.5
20 51.9 29.5 60.4 38.9
22.5 49.9 28.1 58.2 38.3
25 48.7 27.3 58.3 37.5
100 45.4 21.1 32.5
Table 3
5
As shown in Table 3, each of the organic solvents
tested, with the exception of glycerin, decreased the surface
tension of the water-containing fluid to less than 64 dynes/cm
at room temperature. Each of ethanol, hexylene glycol, ethoxy
10 diglycol, polyethylene glycol 400, and dimethyl isosorbide is
suitable for use in the method of the invention in a
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concentration less than 5% w/w and higher, such as at any
.concentration between 1% and 5%. Propylene glycol is shown by
the data of Table 3 to be suitable at a concentration of about
7.5% or higher. Glycerin, by itself, is shown by the data of
Table 3 to be not suitable for the present method.
Example 3 - Wetting benzoyl peroxide powder with a fluid
comprising propylene glycol and water to facilitate the
preparation of a stable micronized suspension to be used in
manufacturing a 3.13% benzoyl peroxide topical gel
A suspension was prepared containing 24.8% w/w
hydrous benzoyl peroxide utilizing a dispersing fluid
containing 9.4% w/w propylene glycol and 90.6% w/w water.
Into a stainless steel tank, 36 kg of purified water and 3.75
kg of propylene glycol were combined. The combination was
agitated with a propeller mixer to form a mixture. While
mixing, 13.12 kg of hydrous benzoyl peroxide (74.5% benzoyl
peroxide) was added. Mixing continued at 1450 rpm for about
10 minutes to wet and disperse the benzoyl peroxide powder at
room temperature and to obtain a benzoyl peroxide suspension.
Upon visual inspection, the suspension appeared to
be smooth and free of lumps, with uniformly wetted benzoyl
peroxide. This suspension was passed through a Gaulin Mill
for micronization using a wet-milling method. The milling
procedure proceeded efficiently and without problems (i.e.,
there was no mill plugging) and a stable micro-suspension was
produced. This suspension was set aside for a short time
before being incorporated into the final topical dosage form,
a 3.13% benzoyl peroxide gel, with the active benzoyl peroxide
drug substance present as a stable micro-suspension without
the use of surfactants.
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This example shows that a concentration of propylene
glycol of about 9% in water is sufficient to provide wetting
of a benzoyl peroxide powder.
The above examples show that a hydrophobic benzoyl
peroxide powder is easily wetted in water containing a water
soluble organic solvent that is capable of reducing the
surface tension of the aqueous fluid to less than 64 dynes/cm.
The wettability of the benzoyl peroxide powder increases with
increased concentrations of the organic solvent and is further
facilitated with mechanical agitation. If desired, the
benzoyl peroxide powder that has been wetted according to the
method of the invention may be effectively and safely
micronized by a wet-milling or other process in order to
manufacture pharmaceutical formulations containing micronized
benzoyl peroxide.
Various modifications of the above described
invention will be evident to those skilled in the art. It is
intended that such modifications are included within the scope
of the following claims.
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