GB2189392A

GB2189392A - Stable erythromycin-based anti-acne composition

Info

Publication number: GB2189392A
Application number: GB08709017A
Authority: GB
Inventors: Jean-Pierre Laugier; Beatrice Renault
Original assignee: LOreal SA
Current assignee: LOreal SA
Priority date: 1986-04-16
Filing date: 1987-04-15
Publication date: 1987-10-28
Anticipated expiration: 2007-04-15
Also published as: CH670567A5; LU86393A1; JPS62289520A; FR2597342A1; FR2597342B1; DE3712758C2; DE3712758A1; GB8709017D0; GB2189392B; IT1206778B; IT8720140A0; BE1000153A4

Description

GB 2 189 392 A 1

SPECIFICATION

Stable Erythromycin-based Anti-acne Composition The present invention relates to a stable erythromycin-based composition suftable for the topical treatment of acne, especially acne in which the papular and pustular lesions predominate and polymorphic acne having an inflammatory component. 5 Acne, which especially affects 14 to 30 year old subjects, can be seen by the appearance of pimples, blackheads or pustules on the face, neck and, possibly, the back and chest of the subject.

Acne results from the hyperkeratinization of the duct of the sebaceous glands, causing a narrowing of the passage in such a way that the sebum cannot flow freely. This forms a medium which supports bacterial proliferation. 10 Bacteria are not generally considered to perform a fundamental role in the origin of acne, but they are capable of disrupting the ducts of the sebaceous glands, thereby liberating irritant fatty acids which cause local inflammation. As a result of the bacterial action it has already been proposed to use different antibiotics, including erythromycin, in topical preparations.

The topical application of erythromycin is effective against acne since it inhibits the lipolytic enzymes 15 produced by the main microorganisms responsible for acne, especially Corynebacterium acnes and Propionibacterium granulosum, which are present on the surface of the skin.

By inhibiting the lipolytic enzymes, the hydrolytic cleavage of the normal triglycerides of the sebum is avoided, and the formation of long- chain fatty acids, which are the source of the typical inflammation phenomena of acne lesions, may be avoided. 20 Erythromycin, as compared with other antibiotics, has the advantage of not normally giving rise to allergic phenomena when applied topically. Nevertheless, two difficulties arise from the topical use of erythromycin. Firstly, it has poor penetration through the skin and, secondly, it lacks stability in solution.

Erythromycin in solution is rapidly degraded at room temperature to produc6 erythromycin A enol ether andlor anhydroerythromycin. These degradation products encourage the formation of erythromycin- 25 resistant strains.

Various attempts have been made in recent years to improve the stability and the penetration of erythromycin.

Thus, British Patent No. 1,152,644 describes stable compositions of erythromycin in an oil, whose molecules have from 8 to 18 carbon atoms having an iodine number of less than 42. 30 While such compositions in a lipophilic base have better stability, they are not completely satisfactory since the antibiotic cannot be released in an appropriate manner. Moreover, the use of fatty excipients is not particularly desirable in the therapeutic treatment of acne.

US Patent No, 4,000,263 describes a solution of erythromycin in propylene glycol, ethyl alcohol and polyoxyethylenated laury] alcohol. This solution has good storage stability. 35 French Patent No. 77107,785 describes compositions, for the local treatment of acne, containing erythromycin and an excipient to promote penetration. This excipient is dimethyl sulphoxide, chloroform or an alkyl esterto which a moisturizing compound, such as glycerin, a glycol or another polyhydric alcohol, has been added.

French Patent No. 77132,761 and European Patent Application No. 80120,929 (Publication No. 0,027,286) 40 describe antimicrobial compositions in the treatment of acne wherein erythromycin is combined with a penetrating agent which is a fatty alcohol or a fatty acid ester. The composition contains, in addition, an alcohol, preferably ethanol, and optionally glycerol monooleate.

US Patent No. 4,469,684 describes a pharmaceutical composition for topical application which is stable on storage and contains erythromycin in the form of its zinc salt in t- butanol. 45 The solutions which have been proposed either improve the stability of the composition or promote penetration, but have not provided a topical composition having good stability over time, good penetration and good cutaneous tolerability.

We have surprisingly found that these objectives may be achieved by using either propylene glycol monomethyl ether or dipropylene glycol monomethyl ether as the vehicle of the composition. 50 Thus the present invention provides a stable erythromycin-based anti-acne composition suitable for topical application which comprises an erythromycin base in a pharmaceutically acceptable vehicle comprising from 20 to 99.5% by weight of propylene glycol monomethyl ether or dipropylene glycol monomethyl ether relative to the total weight of the composition.

Propylene glycol monomethyl ether, or fnethoxypropanol, can occur in two isomeric forms, the a form 55 (1-methoxy-2-propanol) and the P form (2-methoxy-l-propanol).

The industrial methods of preparation generally lead to a mixture of these isomers in which the a isomer predominates by a wide margin, generally more than 90%, the remainder consisting of the P isomer.

The commercial product sold by Dow Chemical under the name "Dowanol PM" (Trade Mark), which is 60 a mixture of at least 95% by weight of the a isomer, is especially suitable.

The physical properties of Dowanol PM are:

Boiling point: 119-1200C Density at 25C: 0.917-0.919 2 GB 2 189 392 A 2 Refractive index (25'C): 1.402 Viscosity: 1.86 centistokes (1.86 x 10-6 m21s) at 250C.

A preferred dipropylene glycol monomethyl ether is the commercial product sold by Dow Chemical under the name "Dowanol DW' (Trade Mark), which is a mixture of isomers in which the following isomer is predominant: 5 CH:-O-CH:2-CH-O-CH2-CH-CH, 1 1 LP13 UM The physical properties of Dowanol DPM are: Boiling point: 188-1900C Density at 25'C: 0.948-0.951 Refractive index (25'C): 1.419 10 Viscosity: 3.57 centistokes (3.57X106m21s) at 250C The stabilizing effect of propylene glycol monomethyl ether and dipropylene glycol monomethyl ether can be shown by performing many stability trials, in different solvents, using high performance thin layer chromatography (HPTLC) on silica plates.

These stability studies showthat, in contrast to ethylene ethers and diethylene glycol ethers, and in 15 contrastto propylene glycol itself, propylene glycol monomethyl ether and dipropylene glycol monomethyl ether provide stable erythromyin solutions which have, moreover, excellent cutaneous tolerability.

The concentration of erythromycin base in the compositions according to the present invention depends on the nature of the acne lesions to be treated. It is generally from 0.5 to 6%, preferably from 1.5 to 5%, by weight relative to the total weight of the composition. 20 Although propylene glycol monomethyl ether or dipropylene glycol monomethyl ether may be used as the only vehicle, it is preferred to use them mixed with at least one Cl- C, aliphatic alcohol, preferably a Cl-C4 aliphatic alcohol such as ethanol or isopropanol.

A preferred composition comprises:

0.5 to 6% of erythromycin, 25 to 79.5% of a Cl-C6 aliphatic alcohol, and to 80% of propylene glycol monomethyl ether or dipropylene glycol monomethyl ether all the above percentages being by weight relative to the total weight of the composition.

The vehicle may additionally comprise at least one triglyceride of fatty acids or a polyoxyethylenated glyceride of fatty acids. Thus another preferred composition comprises: 30 0.5 to 6% of erythromycin, to 69.5% of a Cl-C6 aliphatic alcohol, to 40% of a triglyceride of fatty acids andlor a polyoxyethylenated glyceride of fatty acids, and to 74.5% of propylene glycol monomethyl ether or dipropylene glycol monomethyl ether, all the above percentages being by weight relative to the total weight of the composition. 35 The triglyceride of fatty acids is preferably a triglyceride of saturated fatty acids of plant origin having from 6 to 12 carbon atoms.

The distribution of the fatty acids in the triglyceride is preferably as follows, wherein the percentages are expressed by weight relative to the total weight of the triglyceride:

Caproic acid (C,,): <3% 40 Caprylic acid (C8): 50 to 80% Capric acid (C,,): 15 to 45% Lau ric acid (C,,): <5%.

Preferred triglycerides of fatty acids are sold by Dynamit Nobel under the names "Miglyof 81 W' (Trade Mark) and "Miglyol 812" (Trade Mark). 45 Preferred polyoxyethylenated glycerides of fatty acids, which can be used instead of the triglycerides of fatty acids or mixed with them, are sold by Gattefosse under the following Trade Marks:

---LabrafilWL 1318 CS" (polyoxyethylenated isostearic glycerides) "Labrafii M 1944 CW (polyoxyethylenated oleic glycerides) "Labrafil M 1980 CW or---LabrafilM 2700 CW (polyoxyethylenated oleic glycerides) 50 "Labrafil M 2125 CS" (polyoxyethylenated oleic and linoleic glycerides) -Labrafil WL 2609 BW (polyoxyethylenated ofeic/linoleic glycerides) "Labrafil M 2130 CW (polyoxyethylenated lauric/palmitic/stearic glycerides), and "Labrasol" (polyoxyethylenated glycerides of Cg-Clo acid).

The compositions according to the invention are usually anhydrous, and generally take the form of 55 more or less fluid lotions which are easy to apply on the acne lesions.

If it is desired to obtain gels, from 0.1 to 5% by weight, relative to the weight of the composition, of a thickening agent, such as a cellulose derivative, for example methylcel 1 u lose, hydroxymethylcel 1 u lose, hyd roxyethylcel lu lose or hydroxypropylcel 1 u lose, can be added.

Various other ingredients can also be included in the composition, for example oils, waxes and other 60 3 GB 2 189 392 A 3 ingredients used in compositions for topical application, so long as they do not affect the stability of the composition or the penetration of the erythromycin.

The invention will now be further described in the following Examples, wherein all of the percentages are expressed by weight.

EXAMPLES 5

1. Lotions A) Erythromycin base 2% Methoxypropanol 49% lsopropanol 49% B) Erythromycin base 2% 10 Methoxypropanol 20% Triglycerides of caprylic and capric acids "Miglyol 812" 20% Isopropanol 58% C) Erythromycin base 2% Dipropylene glycol monomethyl ether 20% 15 PolVoxyethylenated lauric/paimitic/stearic glycerides "Labrafil M 2130 CS" 20% Ethanol 58% The lotions obtained above are fluid and are produced by mixing the ingredients using mechanical agitation.

When they are applied to acne lesions in an amount of approximately 2 to 5 M 91CM2, tWo to threetimes 20 per day for 5 to 10 weeks, a distinct reduction of the number of acne lesions and the inflammation phenomena was observed.

The lotions are especially stable overtime and do not require special storage conditions.

2. Gels D) Erythromycin base 2% 25 Methoxypropanol 36.5% Hyd roxypropylcel 1 u lose 1.5% Absolute ethanol 60% E) Erythromycin base 2% Methoxypropanol 25.5% 30 Triglycerides of caprillic and capric acids "Miglyol 812" 23% Hydroxypropylcellulose 1.5% Absolute ethanol 48% The above gels are obtained by mixing the ingredients with agitation. As a result of their consistency, these gels are suitable fora limited application to only those areas where there are acne lesions to be 35 treated.

These gels have great stability, no appreciable reduction in activity being observed after more than six months'storage at room temperature (20-25OC).

Aftertreatment of acne lesions atthe rate of two applications per day for approximately three months, the virtually complete disappearance of the acne lesions was observed. 40 Prior to the application of the composition of the present invention, it is desirable to wash the skin lightly with a non-alkaline soap having low detergency.

Claims

1. A stable erythromycin-based anti-acne composition suitable for topical application which comprises an erythromycin base in a pharmaceutically acceptable vehicle comprising from 20 to 99.5% by weight of 45 propylene glycol monomethyl ether or dipropylene glycol monomethyl ether relative to the total weight of the composition.

2. A composition according to Claim 1 which comprises from 0.5 to 6% by weight of erythromycin relative to the total weight of the composition.

3. a composition according to Claim 2 which comprises from 1.5 to 5% by weight of erythromycin 50 relative to the total weight of the composition.

4. A composition according to Claim 2 or 3 which comprises:

0.5 to 6% of erythromycin, to 79.5% of a C,-C, aliphatic alcohol, and 20 to 80% of propylene glycol monomethyl ether or dipropylene glycol monomethyl ether 55 all the above percentages being by weight relative to the total weight of the composition.

4 GB 2 189 392 A 4

5. A composition according to Claim 4 which comprises:

0.5 to 6% of erythromycin, to 69.5% of a Cl-Ce aliphatic alcohol, 10 to 40% of a triglyceride of fatty acids andlor a polyoxyethylenated glyceride of fatty acids, and 20 to 74.5% of propylene glycol monomethyl ether or dipropylene glycol monomethyl ether, 5 all the above percentages being by weight relative to the total weight of the composition.

6. A composition according to Claim 4 or 5 wherein the Cl-C6 aliphatic alcohol is ethanol or isopropanol.

7. A composition according to any one of the preceding claims which additionally comprises a thickening agent in an amount of from 0.1 to 5% by weight relative to the total weight of the composition. 10

8. A composition according to Claim 7, wherein the thickening agent is hydroxypropylcell u lose.

9. A composition according to Claim 1 substantially as hereinbefore described in any one of the Examples.

10. A composition as defined in Claim 1 for use in a method of treatment of the human or animal body by therapy. 15

11. A composition as defined in Claim 1 for use in a method of treatment of acne.

Printed for Her Majesty's Stationery Office by Courier Press, Leamington Spa. 1011987. Demand No. 8991685. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.