Note: Descriptions are shown in the official language in which they were submitted.
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ACNE-TREATING COMPOSITION
Field of the Invention
The present invention relates to a pharmaceutical
composition that tends to lose its effectiveness prematurely
and to improved means for the effective use of such a
composition. More particularly, the. present invention
relates to the packaging of constituents comprising such a
composition and to an improved form of such composition,
including, for example, a composition for topical
application, such as a topical composition for the treatment
of acne.
Acne is a common inflammatory disease which is very
common at puberty and may continue for many years. It
occurs in facial skin areas where sebaceous glands are the
largest, most numerous, and most active. In its milder
forms, acne is a superficial disorder which is evidenced
by slight, spotty irritations and which can be treated
satisfactorily by ordinary skin hygiene. However, in the
more inflammatory types of acne, bacterial invasion of or
about the pilosebaceous follicles occurs and results in
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the formation of pustules, infected cysts, and, in extreme
cases, canalizing inflamed and infected sacs appear.
These lesions may become extensive and leave permanent,
disfiguring scars.
Therapeutic methods for treating acne are designed to
prevent formation of new lesions and facilitate the
healing of old lesions. Treatments include the systemic
and topical administration of anti-acne agents such as
antibiotics or synthetic Vitamin A analogs. In most
cases, systemic treatment of acne is not desirable because
of the risks of adverse side effects that are experienced
by the user. For this reason, topical acne treatment
compositions have been preferred.
The present invention relates to topical anti-acne
compositions and packages which contain the components of
the composition.
Re~~orted Developments
Topical anti-acne compositions include, for example,
one or more of the following: sulfur, resorcinol,
salicylic acid, benzoyl peroxide, steroids and
antibiotics. Exemplary antibiotics are disclosed in U.S.
Patent No. 3,969,516 (lincomycin family); BR Publication
No..1,594,314 (erythromycin); and U.S. Patent No.
3,952,099 (tetracycline). Preparations containing a
peroxide are reported in U.S. Patent Nos. 3,535,422;
4,056,611; 4,387,107, and British Publication No.
1,594,314 and U.S. Patent No. 4,497,794. Antibiotic-
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containing compositions which also include anti-
inflammatory steroids are disclosed in U.S. Patent No.
4, 1.32, 781 .
Attempts to improve the effectiveness of topical
antibiotic compositions for use in the treatment of acne
have taken a number of approaches. One approach is
reported in U.S. Patent Nos. 3,989,815; 3,989,816,
3,991,203; 4,122,170; 4,316,893; 4,444,762; and EP 27,286,
which disclose skin-penetrating vehicle compositions that
reportedly increase the transdermal absorption of any
physiologically active substance, including antibiotics.
However, some penetrating agents are not compatible with
antibiotics used to treat acne.
A further approach relates to the use of a
composition which utilizes two different active
components, such as erythromycin, clindamycin, Vitamin A
acid or benzoyl peroxide. Compositions including mixtures
of a peroxide and erythromycin are reported in British
Publication No. 1,594,314. Acne-treating compositions
comprising benzoyl peroxide, erythromycin, and
hydroxyethylcellulose have also been disclosed in "The
Formulation and Stability of Erythromycin-Benzoyl Peroxide
in a Topical Gel, Vermeulen et al., International Journal
of Pharmaceutics, 178, 137-141 (1999)". U.S. Patent No.
5,894,019 to Hess et al. discloses a topically applied
pharmaceutical composition that is prepared by mixing a
liquid solution of benzoyl peroxide (or other
pharmaceutically active ingredient) that is dissolved in a
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liquid lipid with a hydrous gel that may also contain a
pharmaceutically active ingredient, such as erythromycin.
The gelling agent used to form the hydrous gel may include
hydroxypropylcellulose. U.S. Patents Nos. 5,466,446 to
Stiefel et al, 5,733,886 to Baroody et al., and 5,767,098
to Klein et al. disclose acne-treating compositions which
contain clindamycin and benzoyl peroxide.
The above compositions comprising a peroxide, such as
benzoyl peroxide, and an antibiotic, such as erythromycin
or clindamycin, may have stability limitations. When the
peroxide and antibiotic are combined, the peroxide can
partially or completely oxidize the antibiotic, rendering
it ineffective. If the peroxide and antibiotic are
provided separately, it is usually necessary to have a
pharmacist combine the component Containing the peroxide
with the component containing the antibiotic to ensure
that the composition is prepared properly, has the correct
final concentrations of the peroxide and antibiotic, and
to maximize the shelf life of the composition by
postponing the mixing of the components until the time of
sale. Another problem with these compositions is that
once mixed, the oxidation reactions of the peroxide not
only degrade the antibiotic, but also result in the
accumulation of undesirable degradative products in the
composition. An additional problem is that unused
portions of certain acne-treating composition must be
refrigerated to minimize degradation until use.
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The present invention relates to improved means for
using effectively anti-acne compositions that tend to lose
their effectiveness prematurely and to improved forms of
anti-acne compositions.
Summary of the Invention
In accordance with the present invention, there is
provided a package comprising components which, upon being
mixed, are capable of forming a pharmaceutical composition
that is effective in treating acne, the composition
tending to degrade prematurely, one of the components
comprising an oxidizing agent and another of the
components comprising an antibiotic which is effective
against acne-associated bacterial species, the components
separated one from the other in the package, one component
having a viscosity within about 500 of the viscosity of
the other component. In preferred
embodiments, the oxidizing agent is benzoyl peroxide, the
antibiotic is selected from the group consisting of
erythromycin and clindamycin, and the package is a dual
packet laminated foil package.
Another aspect of the present invention provides a
package comprising: (A) components which, upon being
mixed, are capable of forming a pharmaceutical composition
that is effective in treating acne, one of the components
comprising a benzoyl peroxide gel and another of the
components comprising a gel of erythromycin and
hydroxypropylcellulose; and (B) containers for holding the
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components in the package separated one from the other;
the components having viscosities such that, upon the
application of a uniform force to the components,
substantially equal volumes of the components are capable
of being dispensed simultaneously from the containers.
Yet another aspect of the present invention is a
composition for the treatment of acne comprising: (A)
benzoyl peroxide; (B) erythromycin; and (C)
hydroxypropylcellulose. Examples of preferred
compositions may further comprise an additional gelling
agent, an agent which inhibits degradative interactions
between benzoyl peroxide and erythromycin, a base which
increases the pH of the composition to a value at which
said composition has an acceptable viscosity, an alcohol
solvent for erythromycin, and a diluent. a
Yet another aspect of the present invention provides
a composition for the treatment of acne comprising: (a)
benzoyl peroxide; (b) erythromycin; (c)
hydroxypropylcellulose; (d) a gelling agent; (e) a surface
active agent; (f) a base; (g) an alcohol; and (h) water.
An example of a preferred gelling agent includes a
hydroxylated vinylic polymer.
An example of a preferred base is sodium hydroxide.
An example of a preferred alcohol used in the composition
is specially denatured ethanol. An example of a surface
active agent is dioctyl sodium sulfosuccinate.
The invention includes also within its scope the
provision of a package containing a first acne-treating
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composition and a second acne-treating composition, the
compositions tending to degrade chemically upon being
mixed with one another, the package comprising a first
chamber containing the first composition and a second
chamber containing the second composition, each of the
chambers having a sealed dispensing orifice, the orifices
positioned adjacent to one another.
Another aspect of the present invention provides a
package containing a first acne-treating composition and a
second acne-treating composition, the compositions tending
to degrade chemically upon being mixed with one another,
the package comprising a first and second packet, the
packets being attached to each other and each of the
packets having a sealed dispensing orif ice, the sealed
dispensing orifices being positioned adjacent to each
other so that, as the compositions are dispensed through
the orifices in unsealed form, they are combined with each
other.
An additional aspect of the present invention
provides a package containing a first acne-treating
composition and a second acne-treating composition, the
compositions tending to degrade chemically upon being
mixed with one another, the package comprising a first and
second packet, each of the packets having a top which
includes a dispensing orifice that has a tear-off tab
seal, a bottom, two sides in a parallel relationship to
one another, and an exterior face and an interior face,
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the first packet containing the first composition and the
second packet containing the second composition, the
interior faces of said packets adjacent to and facing one
another such that the tear-off tabs can be simultaneously
torn off such that the compositions are dispensed and
combined with each other as they exit the packets through
the dispensing orifices.
Description of the Drawings
Figure 1 is a plan view of a dual-packet package.
Figure 2 is a plan view of the package of Figure 1
folded about axis A-A.
Figure 3 is a cross-sectional view of a trilaminate
package.
Figure 4 is an exploded view of a pump for dispensing
the compositions of the present invention.
Figure 5 is a partial sectional view of the assembled
pump depicted in Figure 4.
Detailed Description of the Invention
The acne-treating composition of the present
invention comprises a plurality of components which when
combined tend to degrade prematurely. Degradation is
considered premature when the components are mixed
together and at least one of the components degrades at a
rate faster than the rate at which it degrades (if at all)
in the absence of the other component. As an example, in
acne-treating compositions which contain an oxidizing
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agent and an antibiotic, the oxidizing agent will oxidize
and thereby degrade the antibiotic at a much faster rate
than the antibiotic would degrade in the absence of the
oxidizing agent.
Components that degrade prematurely when combined may
be used in the practice of the present invention and may
be identified using techniques known in the art. Examples
of such components include, but are not limited to,
oxidizing agents, gelling agents, and antibiotics.
The acne-treating composition of the present
invention is provided in a package which maintains the
components separated from each other until the components
are removed in whole or in part from the package. In
preferred form, the package is designed to enable the user
to extract readily from the package amounts of components
which form an effective acne-treating composition.
Use of such a package allows long-term storage of the
components at room temperature without degradation. The
package can be carried conveniently by the patient because
the contents do not require refrigeration. This increases
patient compliance with administration of the composition.
In addition, because the composition is mixed at the time
of application, degradation is minimized. Furthermore,
the proportions of active ingredients in the composition
can be optimized by exact filling of packets and by the
ease with which the patient can empty the packets
simultaneously such that the final composition has the
desired ratios of components.
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The package of the present invention may be made from
any suitable material, for example, paper, plastic, or
metal foil, in laminated or composite form. The material
functions to protect the components from exposure to air,
moisture, light and other environmental factors which
could change the physical and/or chemical nature of the
components and to keep the components from contact with
each other.
In preferred form, the package of the present
invention includes chambers which maintain the components
of the composition in separated form and which accommodate
amounts of the components such that, when the components
are removed from their chambers and brought together, they
form a single effective acne-treating dose of the
composition. For example, in preferred embodiments, the
package contains a sufficient amount of the composition to
apply a thin layer of the composition to the entire
surface of the face (with the exception of the eyes and
mouth) and sufficient amounts of the pharmaceutically
active ingredients to treat effectively any acne present
in the areas to which the composition is applied.
It is believed that the present invention will be
used widely in the packaging of an acne-treating
composition comprising a component which includes an
oxidizing agent and a component which includes an
antibiotic which is effective in treating an acne
condition. As mentioned above, the oxidizing agent in
such a composition tends to oxidize and thereby degrade
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the antibiotic when the two components are brought
together. The present invention may also be used in acne-
treating compositions which include retinoic acid.
A particularly preferred embodiment of the package of
the present invention is shown in Figure 1, in which there
is illustrated a dual-packet, laminated metal foil package
1 comprising a first packet 5 which includes a first
chamber 2 containing a first component of the
pharmaceutical composition and a second packet 7 which
includes a second chamber 3 containing a second component
of the composition.. Each of the chambers 2 and 3 has a
sealed dispensing orifice 9 and 9' with tear-off tabs 11
and 11'. Each packet has a top portion 13 and 13', a
bottom portion 15 and 15', a commonly shared side 17 and a
second side 19 and 19' in parallel relationship to each
other, and an interior face 21 and 21' and an exterior
face (not shown in Figure 1) in opposed relationship to
each other. The first chamber 2 and second chamber 3 may
be of equal or different size.
Figure 2 shows the package of Figure 1 in a form in
which the packets have been folded about axis A and the
interior faces 21 and 21' of the packet are in apposition
to one another and the exterior faces 23 and 23' (not
shown) face outwardly. The tear-off tabs 11 and 11' of
the packets are superimposed upon one another. This
permits them to be removed simultaneously. After removal
of the tabs, the components in chambers 2 and 3 can be
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dispensed and combined with each other as they exit
packets 5 and 7 through the dispensing orifices 9 and 9'.
In preferred embodiments, the packages are comprised
of two packets made of a mufti-layered laminated foil.
Preferably the laminate is a five-layer design consisting
of three main barrier layers and two adhesive layers which
lie between the barrier layers and hold the layers
together. Tn preferred embodiments, the packets have a
first innermost layer comprised of low density
polyethylene. This layer is in contact with the
Composition. The second layer is an adhesive layer
comprised of ethylene-acrylic acid copolymer which binds
the first layer to the third layer. The third layer is a
barrier layer made of aluminum foil. The fourth layer is
comprised of ethylene-acrylic acid copolymer which serves
as an adhesive layer binding the third layer to the fifth
layer. The fifth and final layer is comprised of
polyester which provides durability and tear- and
puncture-resistance to the package. A preferred laminate
for use in the present invention is available from
Reynolds Metals Co.
For exemplary purposes, the use of the package of
Figures 1 and 2 is described in connection with an acne-
treating composition comprising an oxidizing agent and an
antibiotic. Accordingly, one of the chambers of the
package contains the oxidizing agent and the other chamber
contains the antibiotic. To extract the oxidizing agent
and antibiotic from the package, both packets thereof are
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opened simultaneously by tearing off their respective
tear-off tabs. The packets are then squeezed by the user
until the contents of the chambers are emptied
substantially. The contents typically exit their
respective orifices in the form of a ribbon. The
oxidizing agent and the antibiotic component can be mixed
conveniently to form the acne-treating composition by the
user's dispensing the contents into the palm of one hand
and using the fingers of the other hand to mix the
components together by use of a swirling motion. The
composition is then applied to the site or sites in need
of treatment.
The package of Figures 1 and 2 can be characterized
as a single-dose package which contains a sufficient
amount of each component to form a volume of composition
which can be applied as a thin layer to the entire surface
of the face (with the exception of the eyes and mouth)
with a minimal amount of the composition left over. Any
remaining composition may be discarded. Because of the
relatively small amounts of components in the package, the
package can be considered also to be a "single-use"
package which is thrown away after its contents are
emptied.
Figure 3 illustrates a cross-sectional view of
another package embodiment in which there is illustrated a
"trilaminate" package 26 comprising a first packet 27 and
a second packet 29, having a common internal barrier layer
31, preferably a single layer of aluminum foil or other
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suitable material known in the art. This internal barrier
layer 31 is in contact with the first 32 and second 33
compositions within the first 27 and second 29 packets.
The internal barrier layer 31 is sealed along its
perimeter to a first exterior barrier layer 34, and a
second exterior barrier layer 36. Both the first 34 and
second 36 exterior barrier layers are preferably comprised
of a single layer, of aluminum foil or other suitable
material known in the art.
A "multiple use" package is capable of holding
relatively large amounts of components for use in forming
the treating composition. The multiple-use package is
similar to the single-use package in that the components
of the acne-treating composition are kept separate from
one another and mixed when the product is dispensed. In
preferred embodiments, the multiple-use package may
include a dose-metering pump which dispenses an equal
amount of both components of the acne-treatment
composition.
Figure 4 shows an exploded side view of a pump 50 for
dispensing a multi-component fluid formulation, for
example, a topical anti-acne composition. The preferred
pump embodiment shown is designed to accommodate a two-
component formulation, although it is understood that the
design is not limited to use with formulations having only
two components.
Pump 50 is suitable for use with lotions, creams,
oils, gels and liquids and is designed to keep the
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components of the formulation separate while they are
stored in the pump. Mixing of the components occurs only
after they have been dispensed from the pump immediately
before use. This feature is useful to extend the
effective life of formulations, such as the anti-acne
composition, which tend to degrade once the components are
combined. The pump is also designed to dispense the
components of the formulation in the proper relative
amounts which provide maximum effectiveness of the
formulation.
As seen in Figure 4, pump 50 comprises a bottle 52
having two reservoirs 54a and 54b separated from one
another by a bulkhead 56. The reservoirs hold the
different components of the formulation and are attached
to a common neck 58 which provides for attachment of the
other pump components, described below, to the bottle 52.
Neck 58 surrounds and defines two openings 60a and. 60b in
reservoirs 54a and 54b respectively, the openings
permitting the components of the formulation to be loaded
into the reservoirs. A liner 62 engages neck 58 and seals
openings 60a and 60b to prevent premature mixing of the
components within the pump.
Liner 62 has two through openings 64a and 64b through
which dip tubes 66a and 66b extend into reservoirs 54a and
54b respectively. Dip tubes 66a and 66b provide conduits
for drawing the formulation components from the reservoirs
54a and 54b to be dispensed by the pump. Each dip tube is
connected to a respective valve seat 68a or 68b, the valve
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seats being attached to a receptacle 70 which sits atop
neck 58.
As best seen in Figure 5, receptacle 70 has two
cylinders 72a and 72b which are in fluid communication
with dip tubes 66a and 66b through valve seats 68a and 68b
respectively. Housed in each cylinder is a respective
ball 74a or 74b. Balls 74a and 74b are preferably
stainless steel and are sized to seat in respective valve
seats 68a and 68b to form a pair of check valves 76a and
76b which allow components of the formulation to flow in
one direction only, from the respective reservoirs 54a and
54b through the dip tubes 66a and 66b and into cylinders
72a and 72b as described in detail below.
Cylinders 72a and 72b each receive a respective
piston 78a and 78b. The pistons are sized to sealingly
interfit slidably within their respective cylinders and
provide suction and pumping action when they are
reciprocated within the cylinders during pump actuation.
Pistons 78a and 78b have respective piston bores 80a and
80b which provide fluid communication between their
respective cylinders 72a and 72b and a spout 82 attached
to the tops of the pistons. Pistons 78a and 78b are each
biased to a position away from check valves 76a and 76b by
respective springs 84a and 84b housed within cylinders 72a
and 72b between the valve seats 68a and 68b and the
pistons 78a and 78b as shown.
As seen in Figure 5, spout 82 has ducts 86a and 86b
which are in fluid communication with piston bores 80a and
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80b of pistons 78a and 78b respectively. A second set of
valve seats 88a and 88b are provided at the tops of piston
bores 80a and 80b. A second set of balls 90a and 90b are
positioned within ducts 86a and 86b respectively, the
balls being sized to seat on respective valve seats 88a
and 88b and form a second set of check valves 92a and 92b.
Preferably, balls 90a and 90b are made of stainless steel.
Ducts 86a and 86b are in fluid communication with
respective dispensing nozzles 94a and 94b from which the
components held in reservoirs 54a and 54b are dispensed to
be mixed outside of pump 50.
As seen in Figures 4 and 5, most of the pump
components including the spout 82, pistons 78a and 78b,
check valves 76a, 76b, 92a and 92b, springs 84a and 84b,
and receptacle 70 are housed within a retainer 96.
Retainer 96 has a lower portion 98 adapted to engage neck
58 and retain the pump components to the bottle 52.
Attachment of the retainer is preferably by an
interference fit between the retainer inner surface 100
and raised ribs 102 surrounding neck 58. An over cap 104
fits over the retainer 96 and protects the moving parts of
the pump against unintentional pump actuation.
Pump 50 is preferably made from various types of
resilient, flexible plastic materials, such as
polyethylene and polypropylene to cite examples. Plastics
are advantageous because they are inexpensive, easily
molded, substantially unbreakable, and chemically inert
and, thus, will not affect the components of the
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formulation. Parts of the pump, such as the springs for
biasing the pistons arid the balls for the check valves,
for which plastic is not suited are preferably made of
stainless steel. Stainless steel provides a robust,
durable material which also is substantially chemically
inert and, thus, suitable for pump parts which will come
into contact with the components of the formulation during
pump operation.
Operation of the dual dispensing pump 50 is described
with reference to Figure 5. In operation, the user
removes the over cap 104 exposing spout 82. With the pump
50 in an upright position, the user manually depresses
spout 82. This causes the spout and attached pistons 78a
and 78b to move downwardly with respect to the retainer
96, check valves 76a and 76b, liner 62, and bottle 52.
Pistons 78a and 78b move within their respective
cylinders 72a and 72b compressing the formulation
components within the cylinders as well as springs 84a and
84b. Balls 74a and 74b are firmly seated in valve seats
68a and 68b, operating as check valves to prevent the
formulation components in the cylinders from being forced
into respective reservoirs 54a and 54b. The formulation
components are forced upwardly through the piston bores
80a and 80b in each piston respectively, the hydraulic
pressure within each cylinder unseating balls 90a and 90b
from valve seats 88a and 88b at the tops of the piston
bores 80a and 80b. The formulation Components are forced
from the cylinders through the piston bores into ducts 86a
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and 86b in the spout, the components being dispensed from
dispensing nozzles 94a and 94b in the ducts and into the
hand of the user who mixes the components to form the
complete formulation, ready for use.
Upon release of spout 82, springs 84a and 84b push
the pistons 78a, 78b to their biased position spaced away
from check valves 76a and 76b. Upward motion of the
pistons creates a suction within the cylinders 72a and 72b
and the piston bores 80a and 80b. The suction seats balls
90a and 90b on valve seats 88a and 88b to prevent
formulation components in ducts 86a and 86b from being
drawn back into the piston bores 80a and 80b.
Simultaneously, the suction causes balls 74a and 74b to
lift off their respective seats 68a and 68b as the
formulation components are drawn up through dip tubes'66a
and 66b from reservoirs 54a and 54b and into cylinders 72a
and 72b. The pump is then ready to dispense the
formulation components on the next actuation.
As explained above, each component of the formulation
is pumped from its reservoir by its own piston-cylinder
combination. The amount of a particular component
dispensed from the pump is proportional to the volume of
the cylinder swept by its piston, which pumps that
particular component. Since the strokes of both pistons
are equal, the relative amount of component dispensed from
one reservoir in relation to the other reservoir is
determined by the ratio of the cylinder diameters.
Cylinders having equal diameters will have equal swept
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volumes and, thus, dispense equal amounts of formulation
component from each reservoir. If the diameter of one of
the cylinders is made smaller relative to the other
cylinder, then the piston associated with the smaller
cylinder will sweep a smaller volume, and a smaller
amount of component will be dispensed from the respective
reservoir. Thus, the pump can be designed to
automatically dispense formulation components in the
proper relative proportions for maximum effectiveness
simply by having cylinders with different diameters, the
ratio of the diameters being proportional to the desired
ratio of formulation components to be dispensed.
The package embodiments of the present invention are
designed to be used by the lay person who has an acne
condition or a lay person who applies the composition to
the individual with the condition. Accordingly, the
packages are designed so that the user is able to dispense
on a consistent basis effective amounts of the active
ingredients comprising the pharmaceutical composition.
Thus, the need for a pharmacist to prepare the composition
is eliminated. The specific amount of each of the active
ingredients present in the package will depend on the
identity of the active ingredient, taking into account its
known effect on treatment of the acne condition and the
proportion of the ingredients that are desired in the
composition that is formed by mixing the active
ingredients. Also, the package may contain an optimal
dosage of the active ingredients of the composition by
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including in each packet the appropriate volume and
concentration of the active ingredient. For example, in
the use of a peroxide/antibiotic composition, it may be
desired that the peroxide comprises a greater proportion
of the composition than the antibiotic.
It will be appreciated that the packets of the
single-dose package, as described herein, contain
relatively small volumes of the components from which the
composition is formulated. For example, an embodiment of
such a packet contains about 0.425 g of one component and
about 0.425 g of a second component. The dispensed
components are within plus or minus 0.025 g of the 0.425 g
in the packet, allowing for about a 6o tolerance. The
filling of the packets with effective dosage amounts of
the components is essential to providing an effective
acne-treating composition. This is difficult to
accomplish with components that are in a form of the type
described herein, for example, in gel form. In order to
fill the packets with the accurate dosages of components,
it has been found that it is important to rid the
components of air trapped within the Components. To avoid
trapped air, the components are formulated preferably
using a process which avoids the introduction of air into
the components and removes trapped air from the
components. This is accomplished by preparing the
components under a vacuum, for example, about -15 to about
-30 psi. By substantially eliminating trapped air from
the components, it is possible to fill the packets or
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other appropriate containers with a high degree of
accuracy. This, in turn, allows the lay person to prepare
the acne-treating composition within the desired
concentration parameters.
The form of the composition that is applied to the
skin should be such that it adheres to the skin for a
sufficient period of time to allow the active ingredients
to act on the affected area. As an example, for
embodiments which include a peroxide and an antibiotic,
the composition will be in a form which adheres to the
skin for a sufficient period of time for the peroxide to
inactivate extracellular lipases and inhibit the formation
of free fatty acids in the skin and for the antibiotic to
reduce the concentration of acne-associated bacteria in
the affected area. For this purpose, the acne-treating
composition should have a viscosity such that the
composition adheres to the skin. This requires that, when
the components that make up the composition are combined
together, they form a composition which has a viscosity
such that the composition adheres to the skin. The forms
of the components and the viscosities thereof can be
different and vary substantially, provided that they can
be combined to form a composition having the desired
viscosity characteristics. For example, the components
may be in forms ranging from liquids to solids. In
preferred embodiments, as described in detail below, the
component is in a form which has properties intermediate
the liquid and solid states. Examples of such forms
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include gels, lotions, creams, salves, and ointments. In
a particularly preferred embodiment, the components are in
gel form.
The package of the present invention, as exemplified
in Figures 1 and 2, includes the separated components in
dosages which are effective in forming, upon mixing, an
effective acne-treating composition. In preferred form,
the package is designed and the components are formulated
to enable the user to dispense on a consistent basis
substantially all of the contents of the package.
Accordingly, the contents are made available far combining
into an acne-treating composition in which the components
are present in the desired dosage. The preferred means of
accomplishing this is to formulate components which have
viscosities that enable the user to dispense the
components from the package without undue effort. It is
preferred also that the components be in the same form.
For example, if one component is in gel form, it is
preferred that the other component be in gel form. In
addition, it is preferred that the components have similar
viscosities. The term "similar viscosity" means that when
a uniform "dispensing" force is applied to the separated
components, substantially equal amounts of the components
are dispensed simultaneously from their respective
chambers. In a particularly preferred form, the
components have viscosities, as measured by 1V-101
Brookfield Helipath T-F C 1.5 rpm that are within about
50%, preferably within about 25% of each other.
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Standard procedures known in the art may be used to
determine viscosity. To perform the viscosity test, a
test sample was transferred to a 11b jar (89 mm in
diameter and 92 mm in height) while tapping on the jar to
eliminate air. After the transfer, the jar was left to
sit for one hour at 25.0°C. A Brookfield Model LV series
rotational viscometer equipped with a helipath and a T-F
spindle was used to measure the viscosity of the sample.
The spindle of the viscometer was placed in the sample and
the height of the spindle was adjusted so that the
crosspiece of the spindle was Covered by about 1j4" of the
sample. The rotational speed of the spindle was set to
1.5 rpm. The helipath and the viscometer were
simultaneously started. After one minute, the needle lock
was engaged. When the needle was displayed in the window,
the viscometer was shut off. A reading was taken and
recorded on the 0-100 scale. Additional tests may be
performed to obtain additional readings. If additional
tests are performed, the viscometer rotation should be
resumed and at least one rotation allowed prior to the
release of the needle lock. Timing of the additional
sample readings is to be commenced from the time of the
release of the needle lock.
In particularly preferred embodiments, each of the
components is a gel which has a viscosity of about 200,000
cps to about 500,000 cps.
There follows a description of exemplary ingredients
comprising the acne-treating composition of the present
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invention, including a description of exemplary
pharmaceutically active ingredients and exemplary
ingredients that are combined therewith to place the
composition in a suitable form for application to the face
and for dispensing the components of the composition from
the package of the present invention.
In the discussion which follows, the amount of an
ingredient in the acne-treating composition is expressed
in weight percent based on the total weight of the
composition (o w/w - composition). The amount of an
ingredient in ane of the components is expressed in weight
percent based on the total weight of the component (% w/w
- component).
The acne-treating composition includes an antibiotic
which is effective against acne-associated bacterial
species. An antibiotic is effective against acne-
associated bacterial species if it kills or inhibits the
growth of a bacterial population. The term "acne-
associated bacterial species" refers to bacterial species
found at the site of an acne lesion, in particular
Propionibacterium acnes (P. acnes).
Exemplary antibiotics include lincomycin, clindamycin
(a lincomycin derivative), and erythromycin and their
pharmaceutically acceptable salts and esters such as their
hydrochlorides and phosphates.
Lincomycin is a derivative of the amino acid trans-L-
4-a-propyl-hydrinic acid coupled to a derivative of an
octose substituted by a methylmercaptyl group. Lincomycin
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antibiotics are described in U.S. Patent Nos. 3,475,407;
3,509,127; 3,544,551 and 3,513,155.
Clindamycin is the 7-deoxy,7-chloro derivative of
lincomycin, and is otherwise known as methyl 7-chloro
6,7,8,trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)
carbonyl]amino]-1-thio-L-threo-a-D-galacto-octopyranoside.
In the use of clindamycin as the antibiotic, it is
recommended that there be used clindamycin phosphate which
is converted in vivo to active clindamycin.
A preferred antibiotic for use in the present
invention is erythromycin, which is a macrolide antibiotic
produced from a strain of Saccharopolyspora erythraea
(formerly Streptomyces erythreus). It is a base and
readily forms salts with acids. Erythromycin is otherwise
known as [(3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*,
14R*)-4-[(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-
hexopyranosyl)-oxy]-14-ethyl-7,12,13-trihydroxy-
3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-
(dimethylamino)-~-D-xylo-hexopyrano-
syl]oxy]oxacyclotetradecane-2,10-dione].
The antibiotic is present in the composition in a
pharmaceutically effective concentration. Such
concentration will vary depending on the antibiotic used
and the nature of the individual being treated. For
guideline purposes, it is recommended that the antibiotic
be present at a concentration of about 0.5 to about 6% w/w
- composition, preferably about 0.8 to about 5% w/w -
composition. In particularly preferred embodiments of the
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invention utilizing erythromycin, the erythromycin is at a
concentration of about 1.8 to about 4.5% w/w -
composition. In preferred embodiments utilizing
clindamycin, the clindamycin is at a concentration of
about 0.7 to about 2a w/w - composition.
In addition to the antibiotic, the package of the
present invention can include any other active ingredient
that is effective in treating acne and that may be
combined with an antibiotic to form a composition which
tends to degrade prematurely. Examples of such active
ingredients include corticosteroids, tretinoin, antifungal
compounds, alpha-hydroxy acids and beta-hydroxy acids.
In preferred embodiments, the acne-treating
composition preferably includes an antibiotic as described
above and an oxidizing agent which inhibits the formation
of free fatty acids in the skin primarily through
inactivation of extracellular lipase enzymes. Preferably,
the composition includes a "peroxide" oxidizing agent.
The term "peroxide" means an organic compound containing
o~ ~A
an oxygen-oxygen bond capable of cleaving and forming
oxygen free-radicals. A variety of peroxides may be used
in the practice of the present invention. The peroxides
include peroxyacids of carboxylic acids, peroxyesters of
carboxylic acids and the dimeric product of carboxylic
peroxyacids. Exemplary peroxides include t-butyl
peroxyesters of straight and branched chain aliphatic
carboxylic acids, and dimeric peroxides such as lauroyl
peroxide and benzoyl peroxide.
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In. preferred embodiments utilizing a peroxide as the
oxidizing agent, the peroxide should be of high purity and
in the form of finely divided crystalline particles,
preferably micronized particles having a mean average
particle size of less than 35 microns. A preferred
- peroxide for use in the present invention is benzoyl
peroxide, and the most preferred is micronized benzoyl
peroxide 70% hydrous.
The oxidizing agent should be present in the
composition in a pharmaceutically effective concentration.
Such concentration will vary depending on the type of
oxidizing agent used and the nature of the individual
being treated. For guideline purposes, it is recommended
that the composition contain about 1% to about 30o w/w -
composition of oxidizing agent and preferably about 2.5%
to about 15% w/w - composition oxidizing agent. In
especially preferred embodiments, the oxidizing agent is
at a concentration of about 3 to about 6% w/w -
composition.
Active ingredients which are used in formulating the
composition of the present invention and which are
normally in solid form are advantageously converted into a
liquid form in the preparation of the components from
which the composition is made. For example, to prepare a
liquid form of an active ingredient, it is combined with
an appropriate solvent, the identity of which will depend
on the particular active ingredient used. For example, if
the active ingredient is highly soluble in water, then
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water may be used as the solvent. Water may also be added
to the composition~as a diluent. If the active ingredient
has low solubility in water, another appropriate solvent
such as an alcohol may be used as the solvent.
Any pharmaceutically acceptable and suitable material
can be used to impart to the component the desired
viscosity. Viscosity-enhancing agents are well known.
Preferably, a gelling agent is used. The gelling agent
may be selected both as to type and quantity to give
products of desired viscosities.
A variety of gelling agents may be used in the
practice of the invention. Preferred gelling agents are
pure micro-crystalline cellulose, colloidal magnesium-
aluminum silicate, hydroxypropyl methyl cellulose and the
so-called hydroxylated vinyliC polymers, particularly,
those disclosed in U.S. Patent No. 2,798,053. Preferred
hydroxylated vinylic polymers are those described
generally as interpolymers of a monomeric monolefinic
acrylic acid and from about 0.1% to about 10o by weight
based on the total monomer of a monomeric polyether of an
oligosaccharide in which the hydroxyl groups that are
modified are esterified with allyl groups, with said
polyether containing at least two allyl ether groups per
oligosaccharide molecule. Commercially available
interpolymers of this type are known. as "carbomers"
marketed under the trademark Carbopol~. Such
interpolymers are described as being polymers of acrylic
acid cross-linked with about to of a polyallyl ether of
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sucrose having an average of about 5.8 allyl groups for
each sucrose molecule. These polymers have molecular
weight in the order of magnitude of about 1,000,000. Such
polymers are available from the B.F. Goodrich Chemical
Company and are sold under such trademarks as Carbopol~
934, Carbopol° 940, and Carbopol~ 941. A particularly
preferred Carbopol is Carbopol~ 934 NF.
The gelling agent should be present in the
composition at a concentration that provides sufficient
viscosity to the composition to allow the composition to
adhere to the skin for a sufficient period of time to
allow the active ingredients to act on the affected areas.
The effective concentration will depend on the particular
gelling agent used and the nature of the component to be
gelled. In some embodiments, two or more gelling agents
will be present. For guideline purposes, it is
recommended that the gelling agents) comprise about 1 to
about 4% w/w - composition, preferably about 1.5 to about
3% w/w - composition.
In a highly preferred composition of the present
invention, hydroxypropylcellulose is used as a gelling
agent.
In a preferred embodiment, a carbomer such as the
Carbopol~ interpolymers described hereinabove are used as a
gelling agent in the oxidizing agent component and
hydroxypropylcellulose is used as a gelling agent in the
antibiotic Component. Hydroxypropylcellulose is a
propylene glycol ether of cellulose.
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The preferred hydroxypropylcellulose used in the
practice of the invention is available from Aqualon as
Klucel° GF having a weight average molecular weight of
370,000.
A surface active agent may be included in the
composition. The surface active agent functions as a
processing aid which facilitates even distribution of the
oxidizing agent (such as benzoyl peroxide) in the oxidizing
agent component gel. The surface active agent may also
function to retard the degradative interaction between an
oxidizing agent and an antibiotic. Any pharmaceutically
acceptable surface active agent may be used. An example of.
such a surface active agent is dioctyl sodium sulfosuccinate.
The surface active agent is present at a concentration
sufficient to facilitate even distribution of the oxidizing
agent and optionally to retard the aforementioned degradative
interaction. For guideline purposes, it is recommended that
the surface active agent comprise about 0.050 to about 1o w/w
- composition. In preferred embodiments, dioctyl sodium
sulfosuccinate 75% is present at a concentration of about
0.07 to about 0.3% w/w - composition.
The preferred composition includes also a base. The base
is added to neutralize the gelling agent (carbomer). The
preferred pH range for the carbomer containing gels is about
3 to about 7. For guideline purposes, the concentration is
about 0.1 to about to w/w - composition, preferably about
0.15 to about 0.4a w/w - composition. Suitable bases
include, but are not limited to, sodium hydroxide. Other
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bases, including amines and hydroxides, may be used, for
example, triethanolamine, PEG-15 cocamine and potassium
hydroxide. In especially preferred embodiments, sodium
hydroxide is used at a concentration of about 0.2 to about
0.350 w/w - composition.
Examples of other optional ingredients that may be
present in an. acne-treating composition are as follows. The
composition can include a moistening agent (for example,
propylene glycol) at a concentration that functions as a
solvent for methyl- and propylparabens. Preferably the
moistening agent comprises about 0.5 to about 4o w/w -
composition, most preferably about 1.5 to about 2.5% w/w -
composition. The composition may include also an anti-
microbial preservative (for example, methylparaben and
propylparaben) at a concentration sufficient to inhibit
microbial growth in the composition. Preferably, the
composition comprises about 0.01 to about to w/w -
composition, most preferably about 0.03 to about 0.07% w/w -
composition.
As mentioned above, a preferred composition for use in
the practice of the present invention includes
pharmaceutically effective amounts of benzoyl peroxide and
erythromycin and hydroxypropylcellulose. A particularly
preferred form of this composition comprises: (A) benzoyl
peroxide at a concentration of about 2.5 to about 15o w/w -
composition, most preferably about 3 to about 6% w/w -
composition; (B) erythromycin at a concentration of about 0.8
to about 5% w/w -,composition, most preferably about 1.8 to
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about 4.5o w/w - composition; and (C) hydroxypropylcellulose
at a concentration of about 0.5 to about 4% w/w -
composition, most preferably about 1 to about 3% w/w -
composition.
Preferably the composition includes an additional
gelling agent, preferably Carbopol~ 934 at a concentration of
about 0.5 to about 2% w/w - composition, most preferably
about 0.7 to about 1.5o w/w - composition. In this
particularly preferred form of the composition, water is used
to dissolve the benzoyl peroxide at a concentration of about
35 to about 45a w/w - composition, most preferably about 42
to about 44o w/w - composition and an alcohol, preferably
ethanol (SD #40B Alcohol as described in 27 CFR X21.76) is
used to dissolve the erythromycin at a concentration of about
40 to about 48o w/w - composition, most preferably about 43
to about 45o w/w - composition. Optional, but preferred
ingredients, of this particularly preferred form of the
composition comprise sodium dioctyl sulfosuccinate 75% at a
concentration of about 0.05 to about 0.5% w/w - composition,
most preferably about 0.08 to about 0.12% w/w - composition
and sodium hydroxide at a concentration of about 0.05 to
about 0.4o w/w - composition, most preferably about 0.1 to
about 0.3o w/w - composition.
There follows a description of exemplary components
which can be combined to form the acne-treating composition
of the present invention.
Compositions for use in the practice of the present
invention are prepared by combining at least two separate
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active ingredient-containing components. Preferably, a first
component used to prepare the composition contains an
oxidizing agent and the second component contains an
antibiotic. In preferred embodiments of the acne-treating
composition, the oxidizing agent is present in equal or
greater amounts than the antibiotic, preferably the ratio of
oxidizing agent to antibiotic being about 1:1 to about 30:1.
In highly preferred embodiments, the ratio of oxidizing agent
to antibiotic is about 1:1 to about 5:1.
In preferred embodiments of the present invention, the
antibiotic component comprises clindamycin or erythromycin, a
solvent for the antibiotic, and a gelling agent. Additional
ingredients which may be present include moistening agents,
anti-microbial agents and a base.
In a preferred antibiotic component containing
clindamycin ("clindamycin component"), the clindamycin is in
the form of clindamycin phosphate and is present in a
concentration such that the acne-treating composition
includes a pharmaceutically effective concentration of the
clindamycin phosphate. A milligram of clindamycin phosphate
contains approximately 841~g of clindamycin. Accordingly, a
0.7-2% w/w-composition clindamycin will require approximately
0.8-2.3o w/w-composition clindamycin phosphate. Preferably
the clindamycin phosphate concentration comprises about 1.5
to about 3.5o w/w - component. The clindamycin component
includes additionally a solvent for the clindamycin. In
preferred embodiments, the solvent is purified water which
comprises about 88 to about 93o w/w - component. The
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clindamycin component also includes a gelling agent which
imparts thereto a viscosity (about 300,000 to about 500,000
cp) which is similar to the viscosity of the other component
used in the composition (preferably a benzoyl peroxide-
s containing component).. The preferred gelling agent is
Carbopol° 934 which comprises about 1 to about 2o w/w -
component. The clindamycin component can also include a base
for the purpose of neutralizing the carbomer (Carbopol~ 934)
gelling agent. The desired pH range for the carbomer gels is
about 3 to about 7. Preferably the base is sodium hydroxide
in a concentration of about 0.1 to about 0.3 w/w - component.
Other preferred ingredients in the clindamycin component are:
(A) the moistening agent propylene glycol at a concentration
of about 2 to about 6% w/w - component; and (B) the
antimicrobial agents methylparaben and propylparaben at
concentrations of about 0.04 to about 0.2% w/w - component.
In a preferred antibiotic component containing
erythromycin, the erythromycin is present in a concentration
such that the acne-treating composition includes a
pharmaceutically effective concentration of the erythromycin.
Preferably the erythromycin concentration comprises about 5.5
to about 8.5o w/w - component. As erythromycin has limited
solubility in water, the erythromycin is dissolved in
alcohol, preferably SD alcohol #40-B 190 proof, in a
concentration of about 87 to about 92o w/w - component. The
erythromycin component also includes a gelling agent which
imparts to the component a viscosity (about 200,000 cps to
about 400,000 cps) that is similar to the viscosity of the
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other component used in the composition (preferably a benzoyl
peroxide-containing component). Hydroxypropylcellulose is
the preferred gelling agent and is present preferably in a
concentration of about 3 to about 5o w/w - component.
A preferred oxidizing agent component comprises benzoyl
peroxide (for example, 70o hydrous) in a concentration such
that the acne-treating composition contains a
pharmaceutically effective concentration of the benzoyl
peroxide. Preferably the benzoyl peroxide comprises about 8
to about 12o w/w - component. The benzoyl peroxide is
preferably dissolved in water at a concentration of about 80
to about 85o w/w - component. The oxidizing agent component
also includes a gelling agent which imparts to the component
a viscosity (about 200,000 to about 500,000 cp) which is
similar to the viscosity of the other component used to
prepare the acne-treating composition (preferably an
antibiotic component). A preferred gelling agent is
Carbopol~ 934 at a concentration of about 1 to about 3o w/w -
component. The preferred oxidizing agent component comprises
also the surface active agent dioctyl sodium sulfosuccinate
at a concentration of about 0.1 to 0.3% w/w - component.
Another preferred ingredient of the oxidizing agent component
is sodium hydroxide which is present at a concentration of
about 0.3 to 0.5o w/w - component.
Examples
The following examples are illustrative of the present
invention. The term "USP" as used herein refers to chemicals
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that conform to the tolerances set forth in the United States
Pharmacopeia/National Formulary. (The term "NF" refers to
National Formulary standards.) The United States
Pharmacopeia/National Formulary is a compendium of
pharmaceutical formulations widely used as a standard
reference. The term "USP" refers to United States
Pharmacopeia standards. The USP/NF is maintained by the
United States Pharmacopeial Convention, Inc. The USP24/NF19
was issued January, 2000.
Example 1 - Preparation of Benzoyl
Peroxide Gel/Erythromycin Gel Package
(A) BenzoYl Peroxide Gel
A benzoyl peroxide gel containing the following
ingredients was prepared as follows.
Ingredients Weight Percent
Purified Water, USP 82.495
Carbopol~ 934, NF 1.900
Sodium Hydroxide, NF 0.405
Benzoyl Peroxide, USP 700 15.000
Dioctyl Sodium Sulfosuccinate 750 0.200
Purified water was added to a tank (hereinafter, the "Phase A
tank") and sodium hydroxide pellets were added to the water.
The contents of the tank were mixed until the pellets fully
dissolved in the water and the solution cooled to 22-30°C.
25. Purified water was introduced into a second tank
(hereinafter, the "main tank") and the water was Cooled to
22-25°C. Carbopol° 934 was dispensed into the main tank and
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the tank mixed. The contents of the Phase A tank were slowly
added to the contents of the main tank while continuously
mixing the contents of the main tank at a temperature of 22-
30°C.
Purified water was added to a third tank (hereinafter,
the "phase B tank"). The dioctyl sodium sulfosuccinate was
added to the tank, followed by addition of benzoyl peroxide.
The contents of the tank were mixed producing a slurry. The
Phase B tank was connected to the main tank and the benzoyl
peroxide slurry was pumped into the main tank.
The contents of the main tank were mixed under a 10-15"
psi vacuum and transferred to clean and sanitized bulk
storage containers. The resultant gel had a viscosity of
360,000 cps. The viscosity was tested using method 1V-101
Brookfield helipath T-F ~ 1.5 rpm.
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(B) Erythromycin Gel
An erythromycin gel containing the following ingredients
was prepared as follows. ,
Ingredients Weight Percent
S.D. Alcohol #40-B 190 Proof 89.10
Erythromycin, USP 6.90
Hydroxypropylcellulose, NF 4.00
Specially denatured (SD) Alcohol #40-B 190 proof was
added to a vessel. Erythromycin was added while mixing.
Mixing was continued until the erythromycin completely
dissolved. Hydroxypropylcellulose (Klucel~ GF manufactured
by Aqualon) was then added while mixing. Mixing was
performed at -15 to -30 psi to facilitate deaeration. Mixing
may be performed in an open or closed vessel. For commercial
preparations, mixing will be performed in a closed vessel.
After,mixing, the tank was sealed and held for a minimum of
12 hours at room temperature in order to allow any entrapped
air to dissipate and to assure that all of the
hydroxypropylcellulose had gelled. Any evaporated alcohol
was replaced with SD Alcohol #40-B to the target weight and
the mixture was mixed at -15 to -30 psi. Mixing may be
performed in an open or closed vessel. For commercial
preparations, mixing will be performed in a closed vessel.
The mixture was then transferred into clean and sanitized
steel drums. The resultant gel had a viscosity of 360,000
cps. The viscosity was tested using method 1V-101 Brookfield
helipath T-F @ 1.5 rpm.
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(C) Packagina the Gels
The packaging is performed using a Bartelt horizontal,
form-fill-and-seal machine.
The benzoyl peroxide and the erythromycin gels were
transferred to pressure vessels charged by inert gas. A
pressure regulator was used to keep the pressure level
constant. The pressure level was set up to 80 psi for
benzoyl peroxide and up to 40 psi for erythromycin gel. A
vertical linear piston-metering chamber was installed in each
of the gel filling lines. The volume of gel in the chamber
was kept constant by the pressurized vessels continuously
forcing gel into the metering chamber which assures filling
precision and accuracy of viscous gels at high speeds and low
volumes. The stroke of the piston in the metering chamber is
initiated by a programmable logic controller (PLC) signal
synchronized with the movement of the rest of the filling
line. The piston drives the gels to a filling pump. A
horizontal linear positive displacement micro-pump (Hi-Bar
pump), with a packet-dosing chamber, was installed at the
terminal end of the filling line. The dosing chamber was
filled by the action of the metering chamber piston. The
dosing chamber feeds a loop of clear tubing terminating in a
vertical piston, at the filling station.
The gels are packaged in a two-packet laminated foil
package containing the benzoyl peroxide gel in one packet and
the erythromycin gel in the other packet. The benzoyl
peroxide gel (0.425g) was filled into one packet while the
erythromycin gel (0.425g) was simultaneously filled into the
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second packet. The dispensed gels are within. plus or minus
0.0258 of the target weight of 0.4258, allowing for a 6%
tolerance. After each packet was filled and sealed, the
packets were folded and cold-sealed together using a glue
adhesive. The packets are constructed of a laminated foil
consisting of an inner barrier of low-density polyethylene; a
tie layer of ethylene/acrylic acid copolymer; a main barrier
of foil; a tie layer of ethylene/acrylic acid copolymer; and
an outer barrier of polyester.
Combining the benzoyl peroxide gel with the erythromycin
gel provides an acne-treating composition having the
following ingredients by weight%.
INGREDIENT % W/W
COMPOSITION
Purified Water, USP 43.50
Carbopol~ 934, NF 0.95
Sodium Hydroxide, NF 0.20
Benzoyl,Peroxide, 70o Hydrous, USP 5.25
Dioctyl Sodium Sulfosuccinate, DF 0.10
SD Alcohol #40-B/190, DF 44.55
Erythromycin, USP 3.45
H drox ro lcellulose, NF 2.00
Example 2 - Preparation of Benzoyl
Peroxide/Clindamycin Gel Packacre
The benzoyl peroxide gel is prepared as described in
. 25 Example 1.
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A clindamycin gel containing the following ingredients
was prepared as follows.
Ingredients Weight Percent
Purified Water, USP 91.28
Carbomer 934 1.50
Sodium Hydroxide, NF 0.27
Propylene Glycol, USP 4.00
Methylparaben, NF . 0.14
Propylparaben, NF 0.06
Clindamycin Phosphate, USP 2.75
Purified water was added to a tank (hereinafter, the
"Phase A tank") and sodium hydroxide pellets were added to
the purified water and the contents of the tank were mixed
until the pellets fully dissolved in the purified water and
the solution cooled to 22-30°C.
Purified water was added into a second tank
(hereinafter, the "main tank") and Carbomer 934 was dispensed
into the main tank. The contents of the phase A tank were
slowly added to the contents of the main tank while
continuously mixing the contents of the main tank and
deaerating under a vacuum. The temperature was maintained at
22-30°C.
Purified water was added to a third tank (hereinafter,
the "phase B tank"). Clindamycin phosphate was added and
mixed until dissolved. Once the clindamycin phosphate was
completely dissolved, the contents of the tank were pumped
into the main tank and mixed under vacuum.
Purified water and propylene glycol were added to a
fourth tank. The tank was heated to 35-40°C. Methylparaben
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was then added and the contents of the tank were mixed until
all the methylparaben was dissolved. Propylparaben was then
added and the contents of the tank mixed until all the
propylparaben was dissolved. The contents were transferred
into the main tank.
While continuously mixing, a vacuum was turned on and
the mixing continued until the material was homogenous. The
contents of the tank were then transferred to stainless steel
drums. The resultant gel had a viscosity of 370,000 cps.
The viscosity was tested using method IV-101 Brookfield
helipath T-P C~ 1.5 rpm.
The benzoyl peroxide and the erythromycin gels were
transferred to pressure vessels charged by inert gas. A
pressure regulator was used to keep the pressure level
constant. The pressure level was set up to 80 psi for
benzoyl peroxide and up to 40 psi for erythromycin gel. A
vertical linear piston-metering chamber was installed in each
of the gel filling lines. The volume of gel in the chamber
was kept constant by the pressurized vessels continuously
forcing gel into the metering chamber which assures filling
precision and accuracy of viscous gels at high speeds and low
volumes. The stroke of the piston in the metering chamber is
initiated by a PLC signal synchronized with the movement of
the rest of the filling line. The piston drives the gels to
a filling pump. A horizontal linear positive-displacement
micro-pump, with a packet dosing chamber, was installed at
the terminal end of the filling line. The dosing chamber was
filled by the action of the metering chamber piston. The
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dosing chamber feed a loop of clear tubing terminating in a
vertical piston, at the filling station.
For the final packaging step, 0.4258 of a loo benzoyl
peroxide gel was filled into one packet while 0.4258 of a 20
clindamycin gel was simultaneously filled into the second
packet. The dispensed gels are within plus or minus 0.025 g
of the target weight of 0.4258, allowing for a 6% tolerance.
After each pouch was filled and sealed, the pouches were
folded and cold-sealed together.
Combining the benzoyl peroxide gel with the clindamycin
gel provides an acne-treating composition having the
following ingredients by weight%.
INGREDIENT % W/W COMPOSITION
Purified Water, USP 89.14
Carbomer 934, NF 1.70
Sodium Hydroxide, NF 0.34
Propylene Glycol, USP 2.00
Dioctyl Sodium Sulfosuccinate 75%, DF 0.10
Methylparaben, NF 0.07
Propylparaben, NF 0.03
*Clindamycin Phosphate, USP 1.37
H drous Benzo 1 Peroxide, USP 5.25
*The o w/w for the clindamycin phosphate is based solely
on o w/w. The active substance in the product is
clindamycin. Clindamycin phosphate is converted in vitro to
active clindamycin. The actual amount of clindamycin as
clindamycin phosphate is based on several factors including
activity. The actual amount of material added is based on
6.875 kg of clindamycin phosphate.
SUBSTITUTE SHEET (RULE 26)
