DE2748399A1 - ANTIMICROBIAL AGENT FOR LOCAL USE - Google Patents

Description

The invention relates to an antimicrobial agent for topical Application containing erythromycin or erythromycin compounds. The antimicrobial agent according to the invention is suitable especially used to treat acne.

Acne vulgaris and other types of acne and acne-like skin diseases associated with hyperplasia of the sebum gland, are often treated with oral antibiotics. The usual drug of choice was tetracycline, but other antibiotics, such as erythromycin, lincomycin, and clindamycin, were used also prescribed for this application. Although oral administration of these agents is common in the treatment of acne was effective, oral therapy has several disadvantages. For example, the oral administration of antibiotics continues The entire body is removed from the antibiotic, although only the skin is affected by the acne. In addition, almost all of them have antibiotics some undesirable side effects if taken orally.

In contrast to oral administration for acne treatment A topical application of the antibiotics delivers the antibiotic to the sick place and places them in the bloodstream and in the The amount of antibiotics entering the gastrointestinal tract is reduced to a minimum. Undesirable side effects with oral administration of the remedy occur are greatly diminished, and yet the therapeutic effect of the topical application is, with correct use,

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administration comparable to or even superior to that of oral administration.

Means for the local treatment of acne are known. the U.S. Patent 3,952,099 describes agents for treating acne by topical application of tetracycline in a skin penetrating agent Carrier made from sucrose monooleate, decyl methyl sulfoxide and Alcohol.

In US Pat. No. 3,969,516 and Arch. Dermatol., Vol. 84 (1976), page 182, a method for the topical treatment of acne is described in which preparations are used which contain various antibiotics in N-methyl-2-pyrrolidone contain. It states that the data presented show that tetracycline in a pyrolytic vehicle based on pyrrolidone is not effective in combating inflammatory acne lesions. Besides tetracycline, preparations of erythromycin, erythromycin derivatives and clindamycin were also studied in the same vehicle. The combination of erythromycin and N-methyl-2-pyrrolidone produced results that were better than those with tetracycline in the same vehicle, while the antibiotic lincomycin produced superior results in combating the inflamed lesions.

In light of the foregoing, it should be apparent that the effectiveness of any particular antibiotic in a topical treatment of acne-like skin diseases will depend to a significant extent on the particular skin-penetrating vehicle with which the antibiotic is administered.

It is an object of the invention to provide an antimicrobial agent for topical use which improves the penetration of erythromycin and erythromycin compounds through the skin, which is suitable for topical treatment of acne, in particular acne vulgaris, and which is shelf stable.

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According to the invention, this object is achieved by an antimicrobial agent for topical application which has the following components contains:

(1) a safe and effective amount of an antibiotic consisting of erythromycin and / or erythromycin compounds By means of and

(2) a pharmaceutically acceptable, permeable carrier comprising (a) 0 to about 5 % glycerol monooleate. (b) contains about 20 to about 80 % ethanol and (c) the balance isopropyl myristate.

The agent according to the invention is used in particular for the treatment of acne and acne-like skin diseases through topical application a safe and effective amount of this agent on the diseased area.

The invention relates to antimicrobial agents, the antibiotics and are particularly suitable for the treatment of acne vulgaris and other acne-like skin diseases Agents contain a safe and effective amount of erythromycin and / or erythromycin compounds and one pharmaceutically acceptable penetrating carrier containing ethanol, isopropyl myristate and preferably glycerol monooleate contains. The agent according to the invention is used in particular for the treatment of acne, it being applied locally is applied to the diseased area of the skin.

The "diseased area" is the area of the skin that is inflamed, the acne comedos, papules, pustules and cysts (Acne damage), as well as the skin surrounding this area immediately surrounds.

Under "antibiotic agent" are the erythromycin base as well To understand compounds or derivatives of erythromycin. These antibiotic agents can be used in the agents according to the invention can be used alone or in combination.

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“Penetrating carrier” is to be understood as meaning a mixture of ethanol and isopropyl myristate, which preferably continues to be Contains glycerol monooleate. In this mixture, other substances that do not have the penetrating effect of the carrier substance can also be used affect, such as perfumes, coloring agents and gelling agents that affect the carrier from the aesthetic Make point of view more attractive. The "penetration" brought about by the use of the carrier material used according to the invention can be observed, for example, by measuring the extent of diffusion of the antibiotic agent through the skin using a device containing a diffusion cell measures, as will be explained in more detail below.

By "pharmaceutically acceptable" is meant that the ingredients are suitable for use in contact with the skin and tissues of humans and lower animals, without any adverse physiological response, with an acceptable benefit to risk ratio.

By "safe and effective amount" is meant an amount such that which is effective in relieving the inflammation and damage caused by acne or acne-like skin disease and yet (with an acceptable ratio of benefit to risk) does not cause any undesirable side effects. For topical use is an antibiotic agent dosage range of

2 2

about 0.1 mg / cm / day to about 25 mg / cm / day effective. The dosage may vary depending on such factors as the severity of the Acne, the frequency of use, the area of the body that is affected and the particular erythromycin compound, which is used will vary from patient to patient.

Under the term "topical application" is a direct strike or to understand laying on skin tissue. It can be applied by brushing, using medical insoles or in any other appropriate manner.

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The expression "erythromycin" is to be understood as meaning the erythromycin base produced by the strain Streptomyces erythreus. The term includes both the erythromycin base and its hydrated crystals. The expression "erythromycin compounds" is to be understood as meaning the salts of erythromycin base and acids and the esters of erythromycin. Examples of erythromycin compounds include erythromycin estolate, which is the lauryl sulfate salt of the propioric acid ester of erythromycin; Erythromycin glucoheptonate, which is the glucoheptonic acid salt of erythromycin; Erythromycin lactobionate, which is produced from the erythromycin base and lactobiono / lactone; Erythromycin propionate, the propionic acid ester of erythromycin; Erythromycin stearate, which comprises both the stearic acid salt of erythromycin and the stearic acid ester of erythromycin; and erythromycin ethyl succinate, which is understood to mean the ester of erythromycin and ethyl succinic acid.

Under the term "glycerol monooleate" (also known in the Literature as "monoolein") is to be understood as the monoester of glycerol and oleic acid. The glycerol monooleate used here can be made by any of a wide variety of methods known in the art. Most of the product obtained from these reactions is the i-glycerol monooleate, with the remainder consisting of 2-glycerol monooleate. The presence or absence of small amounts of 2-glycerol monooleate does not appear to have any adverse effect on the penetrability of the agents according to the invention.

The expression "containing" or "contains" is intended to mean the expression be brought that in the agents according to the invention various other compatible ingredients can be present in such an amount that they the resistance and penetrating Do not adversely affect the effectiveness of the basic composition. The term "containing" therefore also includes the terms "consisting of "and" consisting essentially of ".

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Unless stated otherwise in the present description and claims, all percentages relate to on weight.

Difficulties in topical administration of antibiotics have been the persistence of the active ingredient in the vehicle and the development of a system that would allow the active ingredient to penetrate the skin and thus deliver the Antibiotic to make it easier on. The selection of the appropriate carrier for an antibiotic agent is critical. not all delivery systems and penetration aids facilitate diffusion of a given antibiotic agent through the skin barrier. The penetrating carrier must be compatible with the antibiotic; it doesn't have to be toxic; and the preparation must be constant.

In order to determine the best permeable carrier for erythromycin and derivatives of erythromycin, a diffusion test was carried out carried out using skin of hairless mice. Briefly described in the experiment, mouse skin was attached in a vertical position between two covered diffusion cells. A potassium phosphate buffer solution with a pH of 8.0 was introduced into the diffusion cell adjacent to the underside of the skin of the mouse, and the composition to be examined, the containing a solution of the antibiotic agent and the penetrating vehicle, became adjacent to the top of the skin (Epidermis) of the mouse skin introduced into the diffusion cell. One was placed in each diffusion cell to allow mixing given small glass bead.

This cell assembly was placed in a water bath with oscillating water at about 31 ° C. The diffusion time used for the test was about 20 to 2k hours.

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At the end of this diffusion period, each diffusion cell was assembled removed from the water bath, and the diffusate from the cell adjacent to the underside of the skin was filtered, by forcing the liquid through a disposable filter, attached to a disposable plastic cannula. This Diffusate was then a microbiological agar diffusion test according to the under 21 CF. R «436 105 subject to the procedure described. This test provides a measure of the passage of effective erythromycin through the skin.

In Table I below is a representative number of penetrating carriers and their effectiveness as a / ig erythromycin, which penetrate the mouse skin, pro ml (yug / ml) diffusate compiled.

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Table I.

Penetration (skin of the hairless mouse)

O
(O
OO

alcohol % Ethanol 50 % 48 % Ethanol 70 % 28 % Ethanol 53 % 40 4 % ethanol 57.6 38, % Ethanol 60 98 % % Ethanol 20th % Isopro 40 panol % Ethanol 38 % 56 2 % ethanol 18.8 75

Ester

optional penetration improver

Isopropyl myristate
Isopropyl myristate
Isopropyl myristate
% Isopropyl myristate

Isopropyl myristate

Diisopropyl adipate
% Triethyl citrate

3 % glycerol monooleate, 2 % glycerol monooleate

2 % glycerol monooleate

3 % glycerol monooleate

2 % glycerol monooleate, 2 % glycerol monooleate

57.9% ethanol
9.7 % 2,2-dimethyl-1,3-di-
oxolene-4-methanol

% Ethanol
% Propylene glycol

% Ethanol
% Ethanol

% Isopropanol
% Propylene glycol

% Isopropyl myristate 1.5 % glycerol monooleate

0.1 % decyl methyl sulfoxide

0.1 % decylmethyl-sulf-

oxide
0.1% decylmethyl-sulf-

oxide
0.1 % sucrose ester

3 % oleic acid

water

%

%
%

effectiveness

Erythromycin (pg Erythro my c in / ml)

2
2
4th
2
4th
2

4 %
(Ethyl succinate)

2 %

2 %

2 %

2 %

2 %

2175 2915 1563 1685 750

36.5 140

247 174

407 5.6

7.3

15.3 oo CO CO

As can be seen from the data in the table above, the selection of the penetrating carrier for erythromycin is very critical. Of the combinations tested, mixtures of isopropyl myristate and ethanol gave by far the best penetration properties. It was also found that the ratio of isopropyl myristate to ethanol is also critical. However, in order to ensure the solubility of the erythromycin or its compounds in the preparation, 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 preferred mixture contains about 15 to about 60 % isopropyl myristate and about 30 to about 15 % ethanol; a particularly preferred mixture consists essentially of about 60 % isopropyl myristate and about 10 % ethanol.

The above data indicate that erythromycin and erythromycin compounds, when used in a vehicle containing ethanol and isopropyl myristate, are very effective in penetrating the epithelium of excised hairless mouse skin. In addition, the data indicate that substances known to be excellent penetrants for tetracycline are not particularly useful with erythromycin.

A second experiment, similar to that using mouse skin, was carried out using human abdominal skin in an in vitro experiment. The test system consisted of a sampling cell and a skin sample in contact with a collection cell containing a phosphate buffer solution at pH 8.0. The skin surface was treated four times with the preparation during a test duration of 8 or 21 hours. The sampling cell was placed in a water bath at 31 ° C. At the end of the treatment, the phosphate buffer solution was removed from the collection cell and then applied to the

Analyzed the amount of erythromycin present.

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Table II summarizes the data from this experiment. The results show that glycerol monooleate greatly improves the penetration of erythromycin through human skin. Therefore are erythromycin preparations, which contain glycerol monooleate, ethanol and isopropyl myristate, for the penetration of human Skin superior.

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Table II Penetration (human skin)

Ethyl alcohol Isopropyl myristate Glyeerin monooleate water Erythromycin Potency (µg / ml) 40 % 58 % 0 0 2 % 1.70 ⁺ 40 % 56 Jf 0 0 4 X 1.15 ⁺ 50 % 0 0 48 % 2 Jt 0.51 ⁺ 0 » 40 % 55 % 3 % 0 2 * 6.55 ⁺ O 40 % 55 * 3 * 0 2 JC 5.50 ⁺⁺ IF 40 % 54 * 2 X 0 4 % 5.84 ⁺⁺ (D 50 * 0 2 * 46 % 2% 0.82 ⁺⁺ 40 % 56> 0 0 4 JC 1.87 ⁺⁺ «Ο 40 9 48 % 0 0 $ 2 0.38 ⁺⁺

⁺ Test duration 24 hours test duration 8 hours

OO Ca> CO CO

-IU-

The preferred vehicle for topical application to human skin is a mixture of about 30 to about M5 % ethanol, about 1 to about 5 % glycerol monooleate, and the balance isopropyl myristate. It is necessary that the glycerol monooleate is limited to an amount up to or below 5 % , because above this concentration glycerol monooleate can cause minor skin damage.

Besides using the erythromycin base as an antibiotic Other erythromycin compounds or derivatives can also be used in the above preparations for topical use will. A preferred erythromycin derivative is erythromycin ethyl succinate. Other compounds that can be used are erythromycin propionate, erythromycin stearate, erythromycin lactobionate, Erythromycin lauryl sulfate and erythromycin propionate lauryl sulfate. It is also possible to use mixtures of these compounds. The restrictive factor in the Selection of the erythromycin antibiotic is based on the solubility and persistence of the compound in the penetrating carrier from ethanol, isopropyl myristate and glycerol monooleate.

Water can be present in the agents according to the invention without adversely affecting the penetration of the antibiotic. However, the presence of large amounts of water causes the erythromycin and the erythromycin compounds to become unstable upon prolonged storage. The preferred compositions of the present invention are essentially anhydrous, that is, they contain less than about 5 % water.

The preferred acne treatment of the present invention is in applying safe and effective amounts of the topical agent to the diseased area of the skin.

p An effective dosage is from about 0.1 to about 25 mg / cm

of antibiotic per day. Preferably the skin

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Cleaned before treatment, including any soap or detergent suitable for washing the skin. Treatment is more effective when local Applications can be done two to four times a day.

In one embodiment, the diseased site (the acne lesions and the surrounding and inflamed area) is treated by adding a safe and effective amount of an anti-acne drug containing (1) about 0.1 to about 10 % of one consisting of erythromycin and / or erythromyein compounds containing antibiotic and a pharmaceutically acceptable penetrating carrier (2), the (a) 0 to about 5% glycerol monooleate, (b) about 20 to about 80% ethanol and (c) the balance isopropyl myristate, applying to this position.

In a preferred embodiment, the agent contains

(1) about 2 to about 5 % erythromycin}

(2) about 1 to about 5 % glycerol monooleate;

(3) about 30 to about * 5 % ethanol and

(4) about Ί5 to about 60 % isopropyl myristate.

The following examples illustrate typical antimicrobial Means of the present invention. All substances used in the funds are commercially available or can be applied to the catfish described here are produced.

In a preferred method for preparing glycerol monooleate, about 3 moles of methyl oleate are mixed with about 11 moles of anhydrous glycerin and about 22 moles of dimethylacetamide (solvent) containing 80 μl of a 10 slurry of sodium methoxide and 80 ml of xylene. This mixture is for two hours heated to about 100 ° C. for a long time with stirring at 80 Hg. The product obtained in this reaction consists predominantly (about 90 % or more) of 1-glycerol monooleate, with the remainder

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from 2-glycerol monooleate and not included in the implementation Reactants and by-products consists.

Absolute ethyl alcohol was used in the following examples. Both absolute ethyl alcohol (100 %) and 95% ethyl alcohol can be used, both of which are acceptable for the present invention. Absolute ethyl alcohol is used in the preferred essentially anhydrous compositions. Denatured ethanol can be used as long as the denaturant is pharmaceutically acceptable and does not adversely affect the antibiotic or penetrating properties of the carrier.

The antimicrobial agents of the present invention can also be various Contain agents and ingredients that are commonly used in dermatological and cosmetic ointments and lotions will. For example, perfumes, gelling and thickening agents, such as carboxymethyl cellulose, ethyl cellulose, Coloring agents and the like be present in the agents according to the invention in order to improve them from the aesthetic point of view To give attraction.

example 1

The following ingredients were mechanically mixed together, resulting in a flowable mixture suitable for topical application to the skin:

Ingredient weight percent erythromycin base 4

Glycerol monooleate 3

Ethanol MO

Isopropyl myristate 'remainder

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The above mixture improved the penetration of the erythromycin base into and through the skin and was special useful for treating acne vulgaris.

A person with acne lesions was treated for six weeks by taking the mixture in an amount twice a day of 3 mg of the antimicrobial agent per cm applied to the acne lesions. At the end of this period was the number the acne damage is significantly reduced and the inflammation reduced.

When the erythromycin base was replaced by erythromycin ethyl succinate in the above composition, the same became Get results.

Example 2 The following ingredients were mixed together:

Ingredient weight percent erythromycin base 2

Glycerol monooleate 2

Ethanol MO

Ethyl cellulose 10 Isopropyl myristate remainder

The above mixture gave a creamy gel that was suitable for topical Application to the skin was suitable and could be packaged in a roll-on-bottle. This mixture improved the Penetration of the erythromycin base into and through the human skin and can be applied locally with excellent results Use treatment of acne using the regular treatment regimen given in Example 1.

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When replacing the erythromycin base used above with Erythromycin ethyl succinate Similar results were obtained.

Example 3

The following ingredients were mechanically mixed together, whereby a flowable product was obtained which is used to improve the penetration of erythromycin into and through animal skin was suitable:

Ingredient weight percent

Erythromycin base 4

Ethanol 40

Isopropyl myristate remainder

The product obtained could be used for the topical treatment of acne, being applied twice a day.

When replacing the erythromycin base in the above composition equivalent results were obtained by using an equivalent amount of erythromycin propicnate or erythromycin stearate.

Example 4

The following ingredients were mixed together: Ingredient weight percent

Erythromycin ethyl H succinate Ethanol 45 Glycerol monooleate 2.5 Dyes 1 volume 1 to 1.5 Isopropyl myristate Rest

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First, the dyes were of the above composition mixed together to form a flesh-colored mixture of dyes. Then all of the above components were mixed with one another and with mixed with the dye mixture, whereby a flesh-colored tinted cosmetic cream was obtained, which the penetration of the Erythromycin-ethyl-succinates improved through and into the acne lesions and inflamed tissues around the lesions. The cosmetic base acted as a cover for the diseased areas during treatment.

For: The Procter & Gamble Company Cincinnati! OM / Lo, V.St.A.

Dr H.J. Wolff Lawyer

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Claims (8)

FRANKFURT AM MAIN 80 2748399 Patent claims: 1. Topical antimicrobial agent containing (1) a safe and effective amount of one of erythromycin and / or erythromycin compounds and antibiotic agents (2) a pharmaceutically acceptable, permeable carrier which (a) 0 to about 5 % olycerol monooleate; (b) about 20 to about 80 % ethanol and (c) the remainder contains isopropyl myristate. 2. Agent according to claim 1, characterized in that it contains the antibiotic agent in an amount of about 0.1 to 10 % . 3. Means according to claim 1 or 2, characterized in that it contains erythromycin as an antibiotic. ¹ year agent according to claim 3, characterized in that it contains about 2 to about 5 % erythromycin. 5. Means according to claim 1 or 2, characterized in that it an organic ester of erythromycin as an antibiotic agent contains. 6. Agent according to claim 5, characterized in that it contains erythromycin ethyl succinate as the organic ester of erythromycin. 7. Composition according to claim 5, characterized in that it contains erythromycin propionate or erythromycin stearate as the erythromycin derivative. 8. Agent according to one of claims 1 to 4, characterized in that that it is practically anhydrous and essentially off 809819/0760 ORIGINAL INSPECTED (1) about 2 to about 5 % erythromycin, (2) about 1 to about 5 % glycerol monooleate, (3) about 30 to about 45 % ethanol and ( ¹ O consists of about ^ 5 to about 60 % isopropyl myristate. 809819/0760