Note: Descriptions are shown in the official language in which they were submitted.
~n~ ' .
This invention relates to compositions for topical
application of erythromycin or erythromycin compounds.
O The compositions herein are particularly useful for the
treatment of acne.
Acne vulqaris and other t~pes of acne and
acneiform skin maladies associated with the hyperplasia
of the sebaceous follicle are often treated by the
oral administration of antibiotics. Tetracycline has
bean the traditional drug of choice, but other anti-
; bio~ics such as erythromycin, lincomycin and clinda-
~ycin have also been prescribed for this use. While
oral administration of these drugs is often
' effective in treating acne, oral therapy has several
disadvantages. For example, the oral admin;stration of
antibiotics subjects the entire body to the antibiotic
composition; yet, in acne, only the skin is affected.
Moreover, ~most all antibiotics have some ~u~ndesirable
~5 , side effects when taken orally.
,
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In contrast with oral dosin~ in the treatment of
acne, topical application of antibiotics delivers the
antibiotic to the afflicted situs and minimizes the
antibiotic levels in the circulatory and gastrointestinal
systems. undesirable side effects occurring from oral
administration o-E the drug are greatly reduced, and yet,
properly ~dministered, the therapeutic effect of topical
application is comparable with, or superior to, that
derived by oral administration.
Compositions for topical treatment of acne
are known. Smith, U.S. 3,952,099, issued April 20, 1976,
discloses compositions for treating acne lesions by
topical application of tetracycline antibiotics in a
.
skin penetration vehicle comprising sucrose monooleate,
decyl methyl sulfoxide and alcohol.
Stoughton, U.S. 3,969,516, issued July 13, 1976,
and Arch. Dermatol., 84 182 (1976), discloses a method
for topically treating acne by applying formulations
~ .
containing various antibiotics in ~-methyl-2-pyrrolidone.
~20 - ~ The data presented are said to indicate that tetra-
cycline in a pyrrolidone-based penetrating vehicle does
not effectively control the inflammatory lesions of acne.
In addition to tetracycline, compositions of erythromycin,
erythromycin derivatives and clindamycin in the same
2~5 - ~ehicle were studied. The combination of erythromycin
and N-methyl-2-pyrrolidone gave results which were better
than tetracycline in the same vehicle, wherèas the
antibiotic lincomycin gave superior results in controlling
the inflamed lesions.
In light of the foregoing, it is clear that the
i effectiveness of any particular antibiotic as a topical
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treatment of acneiform skin diseases depends significantly
upon the particular skin penetrating vehicle with which
it is usea.
It is an object of this invention to provide a
topical formulation to enhance the penetration of
erythromycin and erythromycin compounds through skin.
It is another object of this invention to provide
erythromycin compositions which can be usea topically
in the treatment of "acne", especially Acne ~ .
It 1s still another object of this invention to
provide storage-stable compositions comprising
erythromycin antibiotics in a skin-penetrating vehicle
which is especially adapted for the topical treat~ent
Of acne.
These and other objects of this invention are
secured, as will be seen from the following disclosure.
. Sl~MMARY OF THE I~VENTION
The present invention encompasses an antimicrobial
,. ~ - .
composition for topical application, comprising:
20 ~ (l) a safe and effective amount of an antibiotic
; ~ agent selected from the group consisting of
erythromycin and compounds of erythromycin; and
(2) a pharmaceutically acceptable penetrating
carrier, comprising
~25 (a) from about 0% to about 5% glycerol monooleate;
(b) from about 20% to about 80% ethanol; and
.
(c) ~he balance comprising isopropyl myristate.
The invention also encompasses methods for treating
acne and acneiform skin diseases by topically applying
a safe and effective amount of the foregoing type of
i composition to the afflicted situs.
3 ~
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i3
DET.~ILED DESCRIPTION OF TE~ 7ENI ION
This invention relates to antibiotic com-
positions especially adapted for the treatment of Acne
vulqaris and other acneiform skin diseases. The com-
positions herein comprise a safe and effective amount
of erythromycin and/or compounds of erythromycin and a
- pharmaceutically acceptable penetrating carrier comprising
ethanol, isopropyl myristate and, preferably, glycerol
monooleate. The method for treating acne comprises the
topical application of compositions of the foregoing type
to the afflicted situs of the skin of the acne sufferer.
; ` By "afflicted situs" is meant the area of the
skin which is inflamed, the acne comedones, papules,
pustules, and cysts (acne lesions) and the skin
~mmediately surrounding this area.
.
By "antibio~ic agent" is meant erythromycin base
and compounds or derivatives of erythromycin. These
antibiotic agents can be used alone or in combination
; in the present compositions.
y "penetratin~ carrier" is meant a mixture of
- ethanol and isopropyl myristate, and~ preferàbly, glycerol
monooleate. Other materials which will not inter~ere
with the penetrating action caused by thelcarrier
; can be present, and include perfumes, coloring agents
~ 25 and gelling agents to make the carrier aesthetically
~,
~' pleasing. The "penetration" effected through the use
of the carrier of this invention can be observed, for
example, by measuring the amount of diffusion of the
antibiotic agent through skin using a diffusion cell
apparatus, as disclosed hereinafter.
By "pharmaceutically acceptable" is meant that
the ingredients are suitable for use in contact wlth
the skin and tissues of humans and lower animals without
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any untoward physiological response, commensurate with
a reasonable benefit/risk ratio.
By "safe and effective amount" is meant an
amount which is effective to alleviate the inflammation
and the lesions of the acne or acneiform skin disease
and yet cause no undesirable side effects (at a reasonable
benefit/risk ratio). For topical application, a dose
range of antibiotic composition of from about 0.1 mg/cm2
per day to about 25 mg/cm2 per day is effective. The
dosage can vary from patient to patient, depending on
such factors as the severity of the acne, the frequency
of application, the area of the body which is afflicted,
and the particular erythromycin compound being applied.
~ By "topical application" is meant directly
spreading or laying on epidermal tissue. The application
can be made by rubbing, using medicated pads, or by any
other convenient means.
By "erythromycin" is meant erythromycin base
produced by the strain of strePtomYces erYthreus. The
term includes both erythromycin base and/or its hydrated
crystals. By the term "compounds of erythromycin"
is meant the salts between erythromycin base and acids,
as well as the ester derivatives of erythromycin. Non-
limiting examples of compounds of erythromycin include:
erythromycin estolate, which is the lauryl sulfate salt
1 of the propionic acid ester of erythromycin; erythromycin
glucoheptonate, which is the glucoheptonic acid salt
of erythromycin; erythromycin lactobionate, which is
prepared from erythromycin base and lactobiono-~-lactone;
erythromycin propionate, the propionic acid ester of
erythromycin; erythromycin stearate, which includes both
the stearic acid salt of erythromycin and the stearic
S);~S3
acid ester of erythromycin; and erythromycin ethyl
succinate, which is the ester of erythromycin and ethyl
succinic acid.
By ~glycerol monooleate~' (also known in the
literature as "monoolein") is meant the mono-ester of
glycerine and oleic acid. Glycerol monooleate employed
herein can be made by any of a number of methods well
known in the chemical arts. The predominant product
of these reactions is l-glycerol monooleate, the balance
comprising 2-glycerol monooleate. The presence o~ absence
of minor amounts of 2-glycerol monooleate does not
- appear to have any adverse effect on the penetrating
ability of the instant compositions.
By "comprising" is meant that various other
compatible ingredients may be present in th~ compositions
in such a proportion as will not adversely affect the
stability and penetrating effectiveness of the basic
composition. The term "comprising" thus encompasses and
- includes the more restrictive terms "consisting" and
~20 "consisting essentially of" within its scope.
; .
All percentages are by weight, unless otherwise
specified herein.
Skin Penetration Testinq
The problems encountered in the topical administration
"25 of antibiotics have been the stability of the drug in the
carrier or vehicle and the development of a system which
allows the drug to penetrate the skin, thus facilitating
the delivery of the antibiotic. The selection of the
appropriate carrier for an antibiotic agent is critical.
~ot all delivery systems and penetrating aids will
facilitate the aiffusion of a given antibiotic agent
through the skin barrier. The penetrating carrier must
~ - be compatible with the antibiotic; it must be non toxic;
- and the formulation must be stable.
~ 6 ~
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In order to determine the best penetrating carrier
for erythromycin and derivatives o~ erythromycin, a
diffusion study was carried out using the skin of
Xairless mice. Briefly, the study employed mouse skin
which was placed in a vertical position between two
capped diffusion cells. A potassium phosphate buffer
at pH 8 was added to the diffusion cell abutting the
subcutaneous side of the mouse skin and the test com-
position comprising a solution of the antibiotic agent
and the penetrating carrier was added to the diffusion
cell abutting the epidermal side of the mouse skin~
A small glass bead was added to each diffusion cell to
provide mixing.`
This cell assemply was arranged in an oscillating
water bath at about 31C. The diffusion time used for
the test was about 20 to 24 hours.
~ At the end of this time period, each diffusion cell
assembly was removed from the water bath, and the
diffusate from the cell abutting the subcutaneous side
of the skin was filtered by expressing the liquid
through a disposable filter attached to a plàstic
j~ aisposable syringe. This diffusate was then submitted
for microbiological agar diffusion assay done in
accordance with the procedure described at 21 C.F.R.
436.105. This test provides a measure of the passage
of active erythromycin antibiotic through the skin.
Table l lists a representative number of penetrating
carriers and their activity, as micrograms erythromycin
i
i which penetrated through the mouse skin, per milliliter
(=g/ml) of diffusate.
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As can be seen from the data, the selection of
the penetrating carrier for erythromycin is quite critical.
Of the combinations tested, mixtures of isopropyl
myristate and ethanol exhibited by far the best
penetration characteristics. Furthermore, the ratio
of the isopropyl myristate to ethanol was also found to
be critical. However, to ensure the solubility of the
erythromycin or its compounds in the formulation, it is
necessary to maintain a balance between the isopropyl
myristate and ethanol. A mixture of about 20% to about
80% isopropyl myristate with about 20% to about 80%
ethanol is acceptable~ A preferrea mixture comprises
from about 45% to about 60% isopropyl myristate and from
about 30% to about 45% ethanol; a highly preferred mixture
consists essentially of about 60% isopropyl myristate and
about 40% ethanol.
The foregoing data indicate that erythromycin and
compounds of erythromycin when usea in a carrier comprising
- ethanol and isopropyl myristate are very effective in
penetrating the epithelium of excised hairless mouse skin.
; Moxeover, the data indicate that materials which are
known to be excellent penetrants ~or tetracycline are
not particularly useful with erythromycin.
A second study similar to that using the mouse
~5 skin was conductea using human abdominal skin, in an
. .
in vitro model. The test system consisted of a sampling
cell and a skin sample in contact with a collectiDn cell
containing a phosphate buffer at pH 8. The skin surface
was treated with the formulation four times during an
,0 8 or 24 hour period. The sample cell was arranged in
, a water bath at 31~C. At the end of the treatment, the
.. 1 , .
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phosphate buffer was removed from the collection cell
and subsequently analyzed ~or the amount of erythromycin
present.
Table 2 summarizes the data from this study.
The results demonstrate that glycerol monooleate
greatly enhances the penetration of the erythromycin
through human skin. Accordingly, erythromycin formulations
containing glycerol monooleate, ethanol and isopropyl
myristaee are supcrior for ~D an skin ~enetration.
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The preferred carrier for topical application
to human skin is a mixture of from about 30% to about
45% ethanol, about 1% to about 5% glycerol monooleate,
and the remainder being isopropyl myristate. It is
necessary that the slycerol monooleate be limited to
an amount less than 5/O because above that concentratiOn
glycerol monooleate can cause minor skin irritation.
In addition to using erythromycin base as the anti-
microbial agent in the above topical formulations, other
erythromycin compounds or derivatives can be used.
preferred erythromycin derivative is erythromycin ethyl-
succinate. Other compounds which can be used are
erythromycin propionate, erythromycin stearate, erythromycin
lactobionate, erythromycin glucoheptonate, and erythromycin
lS propionate lauryl sulfate. In addition, mixtures of
these compounds can also be used. The limiting factor
in the choice of the erythromycin antibiotic is the
solubility and the stability of the compound in the
ethanol, isopropyl myristate, glycerol monooleate
penetrating carriers.
Water can be present in the compositions of this
invention without deleteriously affecting the penetration
of the antibiotic. However, the presence of large
amounts of water causes the erythromycin and erythromycin
compounds to become unstable on prolonged storage. The
preferred compositions of this invention are substantially
water-free, i.e., they contain less than about 5% water.
The preferred acne treatment of this invention
comprises applying safe and effective amounts of the
topical composition to the afflicted situs on the skin.
An effective dosage is about 0.1 mg/cm2 to about 25 mg/cm2
of the antibiotic composition per day. It is preferred to
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()2~i3
cleanse the skin prior to treatment, and any soap or
detergent compositiOn suitable for washing the skin can
be employed. The treatment is more effective if the
topical applications are made 2 to 4 tLmes per day.
In a method asp~ct of this invention, the
afflicted situs (the acne lesions and surrounding
inflamed area) is treated by applying thereto a safe
and ef~ective amount of an anti-acne composition
comprising:
(1) from about 0.1% to about 10% of an anti-
biotic selectea from the group of erythromycin
and compounds of erykhromycin; and
(2) a pharmaceutically acceptable penetrating
carrier comprising:
(a) from about 0% to about 5% glycerol mono-
oleate;
(b) from about 20% to about 80% ethanol; and
(c) the balance comprising isopropyl myristate~
In a preferred method, the composition comprises:
(l) about 2% to about 5% erythromycin;
(2) about 1% to about 5% glycerol monooleate;
(3) about 30% to about 45% ethanol; and
(4) about 45% to about 60% isopropyl myristate.
The following examples are intended to illustrate
typical antibiotic compositions of this invention, but
are not intended to be limiting thereof. All materials
used in the compositions are commercially available,
or can be prepared in the manner described herein.
In a preferred method of preparation of glycerol
monooleate, about 3 moles of methyl oleate are admixed
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l(~)Z53
with about 11 moles of anhydrous glycerine and about 22
moles of dimethyl acetamide (solvent) containing 80 ml
o a 10% slurry of sodium methoxide and 80 ml xylene.
The mixture is heated to about 100C at 80 mm mercury,
with stirring, for two hours. The product of this
reaction is predominately (ca. 90% or greater)
the l-glycerol monooleate, the balance comprising 2-
glycerol monoaleate ana non-interferring reactants and
by-products.
The following examples employ absolute ethanol. Both
ahsolute (10~%) and 95% ethanol are acceptable for the
practice of this invention. In the preferred substantially
water-free compositions, absolute ethanol is used.
-Denaturea ethanol can be used so long as the denaturant
~is pharmaceutically acceptable and does not adversely
- affect the antibiotic or penetra~ing characteristics
of the~carrier.
The compositions herein can also include various
- agents and ingredients commonly employed in dermatological
and cosmetic ointments and lotions~ For example, perfumes,
gelling and thickening agents such as carboxymethyl cellulose,
ethyl cellulose, coloring agents and the like, can be present
- in the compositions to provide a more pleasing aesthetic
` aspect.
,
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EXAMPLE I
Inqredient Percent (wt.)
Erythromycin base 4%
Glycerol monooleate 3%
Ethanol 40%
Isopropyl myristate Balance
The above ingredients are blended mechanically
and provide a fluid composition adapted for topical
application to skin. The composition of Example I
enhances the penetration of the erythromycin base into
and through skin, and is especially useful in the
treatment of ~cne vulqaris~
; A person afflicted with acne lesions is treated
by topically applying the composition of Example I to
the acne lesions at a rate of 3 mg/cm2 of antibiotic
composition twice a day for 6 weeks. At the end of this
~period, there is a substantial reduction in the number
of acne lesions and the inflammation is reduced-.
Erythromycin ethylsuccinate is substituted for
the erythromycin base of Example I and similar results
are obtained.
- 15 -
EXAMPLE II
Inqredient Percent (wt.)
Erythromycin base 2%
Glycerol monooleate 2%
Ethanol - ~o%
~thyl cellulose ` 10%
Isopropyl myristate Balance
. The above composition provides a creamy gel
base adapted to topical application to skin which can
be packaged in a roll-on bottle. This composition
enhances the penetration of the erythromycin base into
and through human skin~ and is an excellent topical
treatment for acne when used regularly, per the treatment
regimen of Example I.
When erythromycin èthylsuccinate is substituted
for the erythromycin of Example II, similar results are
obtained.
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:
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;3
EXAMPLE III
In~redient Percent (wt.)
Erythromycin base 4%
Ethanol 40%
Isopropyl myristate Balance
.
The above ingredients are mechanically blended
and a fluid product which is suitable for enhancing the
~enetration of erythromycin into and through animal
tissue is provided. The composition is used twice daily
in the topical treatment o~ acne.
In the composition of Example III, the erythromycin
base is replaced by an equivalent amount of erythromycin
: `propionate and erythromycin stearate, respectively, and
equivalent results are secured~
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25;~
~YAMP~E IV
Inqredient Percent (wt.)
Erythromycin ethylsuccinate 4%
Ethanol 45%
Glycerol monooleate 2.5%
Coloring agents 1%
Clay 1 to 105%
Isopropyl myristate Balance
. '
The coloring agents in the above formulation
are blended to provide a flesh colored formulation.
The above ingredients are then mixed and provide a
flesh-toned cosmetic cream which enhances the penetration
of the erythromycin ethylsuccinate through and into
the acne lesion and inflamed tissues around the
lesion. The cosmetic base acts as a cover-up for
the afflicted situs during treabment.
- What is cla~med is: -
'.
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