CA1148469A

CA1148469A - Anti-acne composition

Info

Publication number: CA1148469A
Application number: CA000362256A
Authority: CA
Inventors: Wilmer L. Luedders
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1979-10-12
Filing date: 1980-10-10
Publication date: 1983-06-21
Also published as: JPS5699416A; EP0027286A3; JPH0118883B2; EP0027286A2; EP0027286B1; DE3066507D1; US4299826A

Abstract

ABSTRACT
Compositions for topical application of erythromycin and derivatives of erythromycin, com-prising an erythromycin compound and diisopropyl sebacate, are especially useful as a treatment for acne.

Description

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ANTI-~CNE CO`I~OSlTION
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Wilmer Louis Luedders TECHNIC~L FIEL~
Acne vulgaris and other types of acne and acneiform skin maladies associated with the hyperplasia of the sebaceous follicle are often treated by ~he oral administration of antibiotics. Tetracycline has been the traditional drug of choice J but other antibiotics such as erythromycin, lincomycin and clindamycin have also been prescribed for this u~e. While oral administration of these drugs is often effective ln treating acne, oral therapy has several disadvantages. ~or example, the oral administration of antibiotics subjects the entire body to the antibiotic composition; yet, in acne, only - the skin is affected. Moreover, almost all antibiotics have some undesirable side effects when taken orally.
In contrast with oral dosing in the trea~ment of acne, topical application of antibiotics delivers the antibiotic to the afflicted situs and minimi~es the antibiotic levels in the circulatory and gastrointestinal systems. Undesirable side effects occurring from oral administration of the drug are grea~ly reduced, and yet, properly administered in the manner disclosed herein, the therapeutic benefits of topical application are comparable with, or superior to, those derived by oral administration.
A problem with this approach is that the effectiveness of any particular antibiotic as a topical treatment of acneiform skin diseases depends significantly upon the particular skin penetrating vehicle with which it is used.
One agent, isopropyl myristate, has been used with some success in enhancing the percutaneous penetratlon of erythromycin. However, isopropyl myristate has the undesirable characterlstic of promoting the formation of comedones, or blackheads. Thus, it would be desirable to develop new, mo)re dermatologically acceptable pene~ra~ion enhancers for , erythromycin.
Unfortunately, the field of percutaneous absorption remains hlghly empirical. A leader in this field, Dr. Richard B. Stoughton, has aptly summari~ed the problem: There arP two rather distinct groups of researchers in the field of percutaneous absorption. They are probably best class:ified as the theoreticians and the practitioners.
The theoreticians are primarily physical chemists who establish strict mathematical relationships of penetration based on general theory and observations of simple membrane structures. ~n general, they try to avoid working wi~h human or animal skin because these perverse models generally fail to substantiate their predictions based on simpler systems and theoretical models.
The practitioners have to admit to their studies being more an art than a science but they have the responsibility (and the great advantage) of working with a live, functioning model.
Without detailed knowledge of higher mathe~atics or physical ~ chemistry? these practitioners are best described as belongin~
to the "apply and observe" school. (Dr. R. B. Stoughton, J.
Invest. Derm., 63 (4):305-305 (1974)) This invention relates to erythrorQycin-containing compositions which have been empirically determined to cause erythromycin to penetrate skin when applied topically.

BACKGROUND ART
French 2,383,667, S. Desjonqueres, bearing the legend "Date de la mise a la dispositiGn du public de la demande...
B.O.P.I. - "Listes" n. 41 du L3-10-1978" describes topical erythromycin compositions in which rapid penetration of the antibiotic into the sebaceous follicles is achieved. The excipient bases include alkyl esters of fatty acids such as lauric, linoleic, myristic and oleic acids.
Compositions for topical treatment of acne are known.
10 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 N-methyl-2-pyrrolidone. The data presented are said to indicate that tetracycline ln a pyrrolidone-based penetrating vehicle does not effectively control the inflammatory lesion of acne. In addition to tetracycline, ` compositions of erythromycin, erythromycin derivatives and clindamycin in the same vehicle were studied. ~he combination of erythromycin and N-methyl-2-pyrrolidone gave results which were assertedly better than tetracycline in the same vehicle, whereas the antibiotic lincomycin gave superior results in controlling the inflamed lesions.

-D I S CLOSURE OF THE I NVENT I ON
This invention relates to antibiotic compositions especially adapted for the treatment of skin disorders and dermatoses of bacterial origin, including ~cne vulgaris and other acneiform skin diseases (hereater "acne"). The compositions herein comprise a safe and effective amount of erythromycin and/or compounds of erythromycin and a pharmaceutically acceptable penetrating carrier comprising (a) a penetration enhancing amount of diisopropyl sebacate;
and (b) the balance comprising a dermatologically accept-able alcohol, or mixture thereof. A method for treating acne and bacterial dermatoses comprises the topical app-lication of compositions of the foregoing type to the afflicted situs of the skin of a human or lower animal in need of such treatment.
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 immediately sur-rounding this area.
By "antibiotic agent" is meant erythromycin base and derivatives of erythromycin. These antibiotic agents can be used alone or in combination in the present compositions.
By "pharmaceutically acceptable" and "dermato-logically acceptable" is meant that the ingredients are suitable for use in contact with the skin and tissues of humans and lower animals without any untoward physio-logical 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 dermatological condition and yet cause no undesirable side effects (at a reasonable benefit/risk ratio). For topical application, a dose range of anti-biotic composition of from about 0.1 mg/cm2 per day to r ~

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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 disease, the frequency of application, the area of the body which is afflicted, and the particu-lar erythromycin compound being applied.
By "topical application" is meant directly spread-ing or laying on epidermal tissue. The application can be made by rubbing, by 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 "derivatives of erythromycin" is meant the salts between erythromycin base and acids, as well as the ester derivatives of erythromycin. Non-limiting examples of derivatives of erythromycin include:
erythromycin estolate, which is the lauryl sulfate salt 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 lactobiano- -lactone; erythro-mycin stearate, which includes both the stearic acid salt of erythromycin and the stearic acid ester of erythromycin;
and erythromycin ethyl succinate, which is the ester of erythromycin and ethyl succinic acid.
By "penetration-enhancing amount" of the penetrat-ing carriers described herein is meant an amount sufficient to deliver clinically effective amounts of erythromycin or a derivative of erythromycin through intact skin within 18 hours. Penetration enhancing amounts of the penetration enhancers disclosed herein can be determined by the skin penetration testing techniques described hereinafter.
By "skin disorders and dermatoses of bacterial origin" is meant both primary infectious (pyogenic) pro-cesses, and secondary cutaneous manifestions of infectionelsewhere in the body. Among the primary pyodermas are ~;

included impetigo, such as impetigo contagiosa and impetigo bullosa; deep and superficial folliculitis, including follicular impetigo, sycosis barbae, pyoderma faciale and folliculitis decalvans; furuncles and carbuncles; parony-chial infections; ecthyma; erysipelas; cellulitis;lymphangitis; and erythrasma. Typical secondary bacterial infections include those caused by burns, eczematous dermatitis, including exfoliative erythrodermas; chronic ulcers; dermatophytosis; traumatic lesions; and vesicular or bullous eruptions such as varicella and pemphigus.
Other distinctive clinical dermatologic entities include secondary folliculitis such as acne conglobata or hidra-denitis suppurativa; infectious eczematoid dermatitis;
intertrigo; pilonidal and sebaceous cysts; infections gangrene; and necrotizing ulcers. Unusual cutaneous infections include cutaneous diphtheria; listeriosis;
bartonellosis; and animal-borne diseases.
A more detailed description of the diagnosis and antibiotic therapy of the foregoing and related diseases can be found in Dermatology ln General Medicine, Fizpatrick, et. al., eds., pages 1679 et seq. (1971).
By "comprising" is meant that various other compatible ingredients may be present in the compositions in such a proportion as will not adversely affect the ~5 stability and penetrating effectiveness of the basic composition. The term "comprising" thus encompasses and includes the more restrictive terms "consisting"
and "consisting essentially of" within its scope.
All percentages are by weisht, unless otherwise specified herein.

BEST MODE
The compositions of the present invention comprise (1) a minor proportion of an antibiotic agent selected from the group consisting of erythromycin and derivatives of erythromycin; and (2) a major proportion of pharma-ceutically-acceptable penetrating carrier, comprising:
(a) a penetration-enhancing amount of diisopropyl sebacate;
and (b) the balance comprising a dermatologically acceptable alcohol.
In general, the penetration enhancers are effec-tive in concentrations of from about 20% to about 80%, and above. Preferably, the compositions will contain sufficient penetration enhancer to promote penetration of the erythromycin, and sufficient dematologically acceptable alcohol to provide a conveniently usable and esthetically acceptable liquid, lotion, gel, or the like.
Thus, the compositions of the present invention preferably contain from about 30% to about 60% of the penetration enhancer, most preferably about 30%, and from about 40%
to about 70% of the alcohol.
Of course, optional ingredients may be added, including pigments and perfumes to provide cosmetic accept-ability, emollients, humectants, and natural oils to provide skin conditioning benefits, and thickening, gelling, and film forming agents such as carboxymethyl cellulose, polyethylene glycols, carbomers, and "CarbosetsTM". Preservatives, such as the "parabens"
(methyl, ethyl, propyl and butyl esters of parahydroxy-benzoic acid), and benzyl alcohol can be used to provide protection against contamination by fungi and non-susceptible bacteria.
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,, ,, "~ , The foregoing compositions preferably comprise ~rom about 0.1% to about 10% of the antibiotic agcnt, more preferably from about 2~ to about 5% erythromycin. Most preferable, from the standpoint of efficacy, stability, and safety, is a concentration of erythromycin or erythromycin derivative which provides about 4% erythromycin base equivalent.
Preferred antibiotic agents are erythromycin base and organic ester derivatives of erythromycin, especially erythromycin ethyl succinate. Also preferred are erythromycin derivatives selected from the group consisting of erythromycin propionate, erythromycin estolate, and erythromycin stearate.
Selection of an antibiotic agent from a~ong erythromycin and derivatives of erythromycin will depend in many cases on the solubility of erythromycin or the erythromycin derivative in the particular penetrating vehicle being used. In some cases, limited solubility of the antibiotic agent in the vehicle selected will determine the maximum concentration of antibiotic that can be used.
Among the penetrating carrier materials, diisopropyl sebacate is especially preferred because of its known safety and compatibility in compositions for topical application to skin. An especially preferred composition containing diisopropyl sebacate comprises (1) about 4% erythromycin; (2) about 30% diisopropyl sebacate; and (3) about 66% ethanol.
Dermatologically acceptable alcohols can be selected from the simple short-chain alcohols and the toxicologically safe polyols. Examples include ethanol, isopropanol, propylene glycol, and glycerol. Especially prefered is a member selected from the group consisting of ethanol, isopropanol, and mixtures thereof. While the examples herein employ absolute ethanol, it is to be understood that both absolute (100~) and g5% ethanol are acceptable for the practice of thi~ invention. Denatured ethanol can be used so long as the denaturant is toxiologicslly acceptable and does not affect the stability of the antibiotic or its efficacy, or the penetratin~ characteristics of the vehicle.

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Water can be present in the compositions of this invention ~7ithout deleteriously affe~ting the penetration of the antibiotic agent. However, the presence of substantial amounts of water causes erythromycin and erythromycin derivatives to become unstable on prolonged storage. Thus, the preferred compositions of this invention are substantially water-free or contain less than about 5~ water. In light of this, the preferred compositions which contain ethanol as a detmatologically acceptable alcohol will employ absolute ethanol.
Use When the compositions of the present invention are used in the treatment of skin disorders and dermatoses of bacterial origin, the amount of composition topically applied and ; treatment regimen wlll vary, depending upon the particular disease being treated and the susceptibility of the causativ~
organisms to erythromycin antibiotics, the patient, the severity of the disease state, and like factors which must be considered by ~he attending physician.
When the compositions of this invention are used in the topical treatment of acne, the preferred treatment will comprise applying a safe and effective amount of the composltion 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 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 topical applicatiolls are =ade 2 to 4 time; per day.

., . la ~r INDUSTRIAL A~PLICABIIITY
The problems encountered in the topical administration of antibiotics have been the stability of the drug in the carrier or vehicle and the development of a carrier vehicle 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 cri~ical. Not all delivery systems and penetrating aids will facilitate the difusion of a given antibiotic agent through the skin barrier. The 1~ penetrating carrier must be compatible with the antibiotic; it must be non toxic; and the formulation must be stable.
Skin Penetration Testing In order to determine the best penetrating carriers for erythromycin and derivatives of erythromycin, a diffusion study was carried out using the skin of hairless mice. Briefly, the ~ study employed mouse skin which was placed in a vertical positlon between a lower, capped, diffusion cell and an upper, _ open cell. A normal saline solution was added to the lower diffusion cell, abutting the subcutan~ous side of the mouse skin, and the test composition 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 the lower diffusion cell to provide mixing.
This cell assembly was kept in a constant-temperature room at about 31 C. The diffusion time used for the test was about 18 hours.
At the end of this time period, each diffusion cell assembly was opened and the diffusate from the cell abutting the subcutaneous side of the skin was filtered by expressing the liquid through a disposal filter attached to a plastic disposable 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 passa~e of active erythromycin `antibiotic through the skin.

Table 1 lists a representative number of penetrating carriers and other tested materials and their activity~ as ~icrograms erythromycin which penetrated through the mouse s'~in, per milliliter (mcg/ml) of diffusate.

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Table 1 Test Material Hrs.Penetration-mcg./ml.
Propylene glycol dipelargonate 18 248 Polyoxypropylene 15 stearyl ether 18 95*
Standamul HE~(Polyol fatty acid ester) 18 0*
Propylene glycol 18 0*
Benzyl alcohol 18 0*
Carbowax'~ kOO 18 0*
Octyl alcohol 18 132*
1,2-Butanediol 18 0*

2,3-Butanediol 18 0*
1,3-Butanediol 18 0*
POE ester of oleyl alcohol 18 121*
15 Phenethyl alcohol 18 0*
Oleyl alcohol ` 18 197 Cyclohexanol 18 0*
2-Phenoxyethanol 18 0*
Lauryl alcohol 18 254 Dioctyl adipate 18 234 Diethyl adiyate 18 0*
Dicapryl adipate 18 235 Diisopropyl adipate 18 103*
; Diisopropyl sebacate 18 268 Dibutyl sebacate 18 207 Diethyl sebacate 18 158 Di~ethyl sebacate 18 91*

Dioctyl sebacate 18 181 Dibenzyl sebacate 18 132*
30 Diethyl suberate 18 ; 0*
Dibutyl suberate 18 36*
Dioctyl azelate 18 180 Dibutyl azelate 18 86*
Dimethyl azelate 18 64*
*Does not represent acceptable delivery O*indicates that no readable zone was produced at the dilution tested.
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~3 Table 1 (continued) Dibutyl succinate 18 73*
Diethyl succinate 18 0*
Dibutyl phthalate 18 227 Dimethyl phthalate 18 0*
Didecyl phthalate 18 55*
Ethyl myristate 18 ~96 Butyl myristate 18 243 Isopropyl palmitate 18 285 Ethyl laurate 18 243 Decyl oleate 18 126 2-ethyl-hexyl pelargonate 18 228 Isopropyl isostearate 18 204 Butyl laurate 18 214 Benzyl benzoate 18 230 Butyl benzoate 7 177 Ethyl benzoate 18 0*
Benzyl 2-aceto~y benzoate 18 0*
Hexyl laurate 18 201 Rthyl caprate 18 236 Ethyl caprylate 18 162 Ethyl caproate 18 66*
Butyl stearate 18 198 Benzyl salicylate 18 236 Ethyl salicylate 18 131*
20% ~enzyl benzoate+20% Ethyl laurate 18 253 10% Benzyl salicylate ~
40X Ethyl laurate 18 269 40% Dibutyl sebacate ~
10% Benzyl salicylate 18 241 - *Does not represent acceptable delivery 0* indicates that no readable zone was produced at the dilution tested.
In addition, the following ~aterials were tested in the foregoing malmer and ~ere not found to deliver clinically effective concentrations of erythromycin.

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1~' Squalane Castor oil N-methyl-2-pyrrolidone Ethyl lactate 2,4~pentanedione Silicone 344 Cyclohexanone Salicylic acid + isopropyl myristate " " ~ propylene glycol ' + dibutyl sebacate " " ~ propylene glycol dipelargonate Solketal~ + Propylene glycol dipelargonate Propylene glycol dipelargonate + lactic acid " " " + ethyl lactate Dimethyl s~tlfoxide ~ Propylene glycol + monoolein The following Examples illustrate the practice of this inver.tion9 withou~ in~ending to te limiting thereof.

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Ingredient Weight Y
O
Erythromycin base 4~
Ethanol 66Z
~iisopropyl sebacate 30~
The above ingredients are blended mechanically to provide a fluid composition suitable for topical application to skin. In the composition cf Example I, the diisopropyl sebacate markedly enhances the skin penetration of the erythromycin.
The composition of Example I is especially useful in the treatment of common acne (acne vulgaris) and similar . _ acneiform bacterial dermatological conditions.
A person afflicted with acne lesions is treated by topically applying the composition of Exa~ple I to the afflicted areas of skin (typically the face, neck and shoulders) - at a rate of 3 mg./cm of antibiotic co~position twice a day for 6 weeks. At the end of this per~od, there is a snbstantial redu;tion in the number of acne lesions, and ~he illflamQtationtis reduced.
Erythromycin ethylsuccinate can be substituted for the erythromycin base, in an amount which provides 4Z erythromycin base equivalent, with equivalent results.

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E~ample 11 Ingredient Welght %
Erythromycin lactobionate 10%
- Isopropyl alcohol 40%
S Ethyl laurate 50%
The above ingredients are blended mechanically to provide a.fluid composition suitable for topical application to skin. In the composition of Example II, the ethyl laurate markedly enhances the skin penetration of the erythromycin.
This composition is especially useful in the treatment of impetigo and similar dermatologic disorders caused by Staph.
aureus and/or group A Streptococci, when applied topically at a rate of from about 0.1 mg/cm to about 25 mg./cm per day.
Erythromycin propionate can be substituted for the erythromycin lactobionate, in an amount which provides 10%
~ erythromycin lactobionate equivalent, with equivalent results.
_ Oleyl alcohol, dibutyl sebacate, or dioctyl sebacate !
can be substituted for the ethyl laurate in the composition of Example II, with equivalent results.

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t''` " ~,~ /~;7 Example lLI
Ingredient We~ght %
Erythromycin estolate 0.5%
Ethanol ~ 15%
Isopropyl Alcohol 24.5%
~ioctyl Adipate 60%
The above ingredients are blended mechanically to provide a fluid composi~ion suitable for topical application to skin. In the composition of Example III, the dioctyl adipate markedly ~nhances the skin penetration of the erythromycin.
This composition i5 especially useful in the treatment of folliculitis, including follicular impetigo, sycosis barbae, pyoderma faciale, and folliculitis decalvans. The treatment regimen described in Example I is especially suitable.
When used topically in the manner disclosed hereln, the topical use of erythromycin estolate offers marked advantages over the systemic administration of the same compound, in that the erythromcin estolate exerts its antihiotic action primarily at the site of topical application, with minimal systemic exposure to the drug. In so doing, the hepatotoxicity sometimes noted with syste~ic administration of erythromycin estolate is avoided.
Erythromycin stearate can be substituted for the erythromycin estolate~ in an amount which provides equivalent ~o 0.5% erythromycin estolate, ~ith equivalent results.
Dioctyl azelate, hexyl laurate, and ethyl caprate can be substituted for the dioctyl adepate of the composition of ; Exa=ple 111, aith eqaivalene resales.

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Example IV
Ingredient Weight %
Erythromycin glucoheptonate 0.1%
Ethanol 40,%
Ethyl cellulose 10%
Dibutyl sebacate Balance ~ his composition provides a creamy gel base adapted to topical application to skin via, for example, a rGll-on bottle.
The penetrating vehicle for the erythromycin glucoheptonate makes this composition especially suitable for the treatment of deep bacterial skin di.sorders such as fur-mcles and carb~mcles.
Erythromycin laurate 0.170 can be substituted for the erythromycin glucoheptonate, with equal effect.
The composition of Example IV can be applied topically to cattle, sheep, horses and other domestic animals in the treatmcnt of infccted insect bites, mange, and other skin diseases and dermatoses of bacterial origin.

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' Example V
Ingredient Weight %
Erythromycin, hydrated crystals 5%
Carbopol~ 940 0.1%
Triethanolamine 0.5%
Propy]ene glycol dipelargonate 25%
Flesh-tone pigment q.s Ethanol bal.
The composition is mechanical]y blended at low shear (to avoid excessive entrainment of air), with the triethanolamine added last, forming a gel suitable for use in the treatment of eczematous dermatitis, dermatophytosis, and ecthyma, and most common bacterial skin disorders.
Lauryl alcohol can be substltuted for the propylene glycol dipelargonate, with equivalent enhancement of erythromycin penetration;

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Example VI
Ingredient Weight %
Erythromycin base 5%
Isopropyl alcohol 50%
Propylene glycol dipelargonate 20%
Butyl laurate 25%
~ he co~position of Example VI is formulated as a fluid composition suitable for topical administration by simple mechanical mixlng of the components.
Other blends of penetration enhancers which can be used in lieu of the propylene glycol dipelargonate-butyl laurate vehicle include 3:1 isopropyl palmita.e and isopropyl isostearate, 1:1 butyl and ethyl myristate; 2:1 butyl iaurate and butyl stearate; and 1:2 benzyl benzoate and benzyl salicylate. In each instance, equivalent results are obtained.

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Example VII
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Ingrediellt W _ght Erythromycin estolate 2%
2-ethyl-hexyl pelargonate 30Z
Flesh-tone pigment q.s.
Perfume r~l . 5 .
Carboset 514~ 0.25%
NaOH q.s.
Isopropyl alcohol ~al.
The formulation of Example VII is prepared by mixing the irlgredients at low shear, to avoid excessive air entrainment, with the sodium hydroxide added last.
The composition of Example VII, with the appropriate pigment and perfume, provides a highly effective medicated make-up base for use in the treatment of acne.
In the composition of Example VII, butyl benzoateprovides equivalent results when substituted for the 2-ethyl-hexyl pelargonate.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
l. A composition for topical application to skin in the treatment of skin disorders and dermatoses of bacterial origin, comprising:
(1) a minor proportion of an antibiotic agent selected from the group consisting of erythromycin and derivatives of erythromycin; and (2) a pharmaceutically-acceptable penetrating carrier comprising (a) a penetration enhancing amount of diisopropyl sebacate; and (b) the balance comprising a dermatologically acceptable alcohol, or mixture thereof.
2. A composition according to Claim 1 wherein the dermatologically acceptable alcohol is a member selected from the group consisting of ethanol, isopropanol, and mixtures thereof.
3. A composition according to Claim 1 which comprises from about 0.1% to about 10% of the antibiotic agent.
4. A composition according to Claim 2 wherein the antibiotic agent is erythromycin.
5. A composition according to Claim 3 which comprises from about 2% to about 5% erythromcyin.
6. A composition according to Claim 2 wherein the antibiotic agent is an organic ester derivative of erythromycin.
7. A composition according to Claim 6 wherein the organic ester derivative of erythromycin is erythromycin ethyl succinate.
8. A composition according to Claim 3 wherein the derivative of erythromycin is selected from the group consisting of erythromycin propionate, erythromycin estolate, and erythromycin stearate.
9. A composition according to Claim 5, comprising:
(1) about 4% erythromycin;
(2) about 30% diisopropyl sebacate; and (3) about 66% ethanol.