CA1090253A - Anti-acne composition - Google Patents

Abstract

ANTI-ACME COMPOSITION
Edward David Thompson Stephen Beauregard Carter Gary Lee Manring ABSTRACT OF THE DISCLOSURE
Compositions for topical application of erythromycin and derivatives of erythromycin comprising ethanol, iso-propyl myristate, glycerol monooleate and the erythromycin compounds are especially useful as a treatment for acne.

Description

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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.

, 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 ~.(~(~Z~3 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.

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~c 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.
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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 :,1' " ' , ' '.

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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.

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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.
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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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- 8a -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 ()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 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.

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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;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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~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: -'.

Claims (8)

1. An antimicrobial composition for topical application comprising:
(1) 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:
(a) from about 0% to about 5% glycerol monooleate;
(b) from about 20% to about 80% ethanol; and (c) the balance comprising isopropyl myristate.

2. The composition of Claim 1 which comprises from about 0.1% to 10% of the antibiotic agent.

3. The composition of claim 2 wherein the anti-biotic agent is erythromycin.

4. The composition of claim 3 which comprises from about 2% to about 5% erythromycin.

5. The composition of claim 2 wherein the anti-biotic agent is an organic ester derivative of erythromycin.

6. The composition of Claim 5 wherein the organic ester derivative of erythromycin is erythromycin ethyl-succinate.

7. The composition of Claim 2 wherein the derivative of erythromycin is selected from the group consisting of erythromycin propionate and erythromycin stearate.

8. A substantially water-free antimicrobial composition according to Claim 1 which consists essentially of:

(1) from about 2% to about 5% erythromycin;
(2) from about 1% to about 5% glycerol monooleate;
(3) from about 30% to about 45% ethanol; and (4) about 45% to about 60% isopropyl myristate.