DE2748399C2 - Antimicrobial agent for topical use - Google Patents

Description

The invention relates to the anti-microbial agent described in the claims for local use, which contains erythromycin and / or erythromycin compounds. The anti-microbial according to the invention N.ittel is particularly suitable for treating acne.

Acne vulgarls and other types of acne and acne-type skin diseases associated with the hyperplasle of the The sebum glands are often treated with oral antibiotics. The usual remedy of choice was tetracycline, but other antibiotics, like z. B. erythromycin, lincomycin and clindamycin also prescribed for this application. Oral administration of these agents is also common The acne treatment was effective, yet it did oral therapy various aspects. For example, the oral administration of antibiotics continues entire body from the antibiotic, although only that Skin is affected by the acne. In addition, when taken orally, almost all antibiotics have some unwanted side effects.

In contrast to oral administration in the Acne treatment delivers a topical application of antibiotics to the antibiotic. sick place and puts the Into the bloodstream and Into the gastrointestinal tract the amount of antibiotics that is released to a minimum. Undesirable side effects with oral Administration of the agent occur, are greatly reduced, and yet the therapeutic effect is comparable to topical application when administered correctly or even superior to that of oral administration.

Remedies for the topical treatment of acne are known. The US-PS 39 52 099 describes agents for the treatment of acne by topical application of Tetracycline In a skin penetrating vehicle from sucrose monooleate, decylmethylsulfoxide and alcohol.

In US-PS 39 69 516 and In Arch. Dermatol .. Volume 94 (1976). Page 182 is a procedure for local Treatment of acne is described, in which preparations are used that contain various antibiotics in N-MethyI-2-pyrroIldon contain. It is executed that the specified *. Data show that tetracycline in one Penetrating carrier based on pyrrolidone does not effectively treat the inflammatory acne lesions fights. In addition to tetracycline, preparations of erythromycin, erythromycin derivatives and clindamycin were also produced studied in the same institution. The combination of erythromycin and N-methyl-2-pyrrolldon led to Results that were better than those with tetracycline in the same vehicle while taking the antibiotic lincomycin led to superior results in combating the inflamed lesions. Lincomycin does, however known to have serious side effects (e.g. severe colitis) when used systemically. if it has also not yet been established whether such serious side effects also occur with prolonged topical use of Lincomycin should occur so one should be able to do so with Side effects afflicted means nevertheless being preferable to a means that treat acne without also only allows a risk of side effects.

DE-AS 18 04801 describes a means for acne treatment, Vl'amln Α acid as the active ingredient and a mixture of ethanol and liquid polyethylene glycol as a carrier contains. It thus differs from the agent according to the invention both in terms of the active ingredient Also in the carrier as a whole and only contains ethanol as part of the carrier like the one according to the invention Middle.

In Gstlrner, Introduction to Process Engineering Drug Forms, Stuttgart 1973 on page 79 there is the sprinkling Epophilic oils described on the skin, which spread on the skin and penetrate the horny pit and mentions that isopropyl myristate is one of the low viscosity synthetic spreaders. if if it were up to this reference, it would only depend on the spreadability of the carrier and all active ingredients should have the same skin penetration in the same carrier material. But this is just not the case.

An effective skin penetration of the carrier plus active ingredient must be very specific for each particular person Active ingredient should be determined because of the fact that a carrier is an effective penetrant for represents an active pharmaceutical ingredient. In no one Weise says that it could also be useful for the skin penetration of another active ingredient, Irgenwle When assessing skin penetration different Means for topical application It is utterly difficult, if not impossible. Compare With regard to to perform on penetration when different active ingredients are used. For example, decylmethyl sulfoxide is known to be a very effective skin penetrant for tetracycline (see U.S. Patent 3,896,238); however, from Table I of the present application it can be seen that Decylmethylsulfoxld ineffective for erythrocytes than more penetrating through the skin Is the carrier. From the work of R. B. Stoughton in J. Invest. Derm. Vol. 63, (1974). Pp. 305-308 is known that skin penetration is unpredictable Is. In this work it is stated that in the area of percutaneous absorption the theorists unable are to make your predictions more substantive when using human or animal skin, while the attempts of practitioners are more of an art than a science same. Stoughton then states that there are effective systemic agents in many areas which do not appear to be made effective locally

can, while locally effective in other areas Compounds are systemically ineffective. In light of this, it couldn't be considered obvious may be viewed as having a carrier as a skin penetrant for a topical agent a content of erythromycin or erythromycin compounds, as long as this carrier had not yet been proposed as a skin penetrant for an erythromyl compound.

The invention is based on the object of an antimicrobial Means for topical use containing erythromycin and / or erythromycin compounds to provide that the penetration of erythromycin and erythromycin compounds through the Improves skin suitable for topical treatment of acne, particularly acne vulgarls, and the one good stability of the Erythromyclnaktivstoffs guaranteed in the carrier.

According to the invention, this object is achieved by an anti-microbial Dissolved agent for topical application that is pharmaceutically acceptable and penetrates the skin Carrier a mixture of

20 to 80% ethanol,
80 to 20% isopropyl myristate and
Contains 0 to 5% glycerol monooleate.

The agent according to the invention is used in particular Treatment of acne and acne-related skin diseases, e.g. B. Acne vulgarls, by topical application of this Means on the sick place.

The composition of the invention contains a safe and effective amount of erythromycin and / or erythromycin compounds and the above pharmaceutically acceptable skin penetrant carrier.

Under "sick spot" is the skin area ". -h understand that is inflamed, the acne comedos, papules, Pustules and cysts (acne damage), as well as the skin that immediately surrounds this area.

"Carrier material penetrating the skin" is to be understood as meaning the above mixture of 20 to 80% ethanol and 80 to 20% isopropyl myristate, which preferably contains up to 5% glycerol monooleate. In this mixture, other substances that do not affect the penetrating effect of the carrier can be present, such as. B. Perfumes, coloring agents and gelling agents, which make the carrier material more attractive from an athletic point of view. The "penetration" brought about by the use of the carrier substance used according to the invention can, for. This can be observed, for example, by measuring the degree of diffusion of the anti-blot agent through the skin using a device containing a diffusion cell, as further discussed below.

"Pharmaceutically acceptable" is to be understood as meaning that the components are in contact for one application with the skin and the winds of men and women Animals are suitable without any unfavorable physiological response corresponding to an acceptable benefit to risk ratio.

By "safe and effective amount" is meant an amount that is used to relieve inflammation and the damage to acne or acne-like skin disease is effective and yet (at an acceptable level) Ratio of benefit to risk) does not cause any undesirable side effects. For a local Usage Is a dosage range of the agent from about 0.1 mg / cmVday to about 25 mg / cmVday effective. The dosage may depend on such Factors such as the severity of the acne, the frequency of use, the area of the body that is affected is drawn, and the particular erythromycin compound that is used from patient to Patient vary.

Under the term "topical application" is a direct spreading or placing on skin tissue to understand. Application can be by brushing, using medical insoles, or any other in an expedient manner.

Under the term "Erythomycln" is the erythromycln base produced by the strain Streptomyces erythreus to understand. The term includes both the erythromycln base and its hydrated crystals.

The expression "Erytrhormyclnverbindungen" are oils, salts of erythromycin base and acids as well to understand the esters of erythromycin. Examples of erythromycin compounds include, but are not limited to. Erythromycin estolate, the lauryl sulfate salt of the proponic acid ester is of erythromycin; Erythomycin glucoheptonate, which is the glucoheptonic acid salt of erythromycin Is; Erythromycin lactobionate, which is made from the erythromycin base and lactoblono-6-lactone will; Erythromycin proplonate, the propionic acid ester of Erythromycin; Erythromycin stearate, which is both the stearic acid salt of erythromycin and the stearic acid ester comprised of erythromycin; and erythromycin ethyl succinate, by which the ester of erythromycin and ethyl succinic acid is to be understood.

Erythromycin base and compounds or derivatives of erythromycin can be used in the Means can be used alone or in combination.

The expression "glycerol monooleai" (also known in the literature as "monoolein") is understood to mean the monoester of glycerol and oleic acid. The glycerol monooleate employed here can be prepared by any of a wide variety of known processes. The predominant product of these reactions obtained is 1-glycerol monooleate, the remainder being 2-glycerol monooleate. The presence or absence of small amounts of 2-glycerine monooleate does not appear to have any adverse effect on the permeability of the compositions of the invention.
The expression "contains" is intended to express that various other compatible ingredients can be present in the agents according to the invention in such an amount that they do not adversely affect the stability and penetrating effectiveness of the basic compositions.

When in the present description and in the Claims otherwise is not specified. all percentages are based on weight.

With topical administration of antibiotics occurred as the difficulty of the active ingredient In the carrier and the development of a system that allows the active ingredient to penetrate the skin and thus to facilitate the delivery of the antibiotic. Choosing the right carrier for a Anti-blotch agent is critical. Not all delivery systems and penetration aids facilitate diffusion of a given anti-blot agent therethrough the skin barrier. The penetrating carrier must be compatible with the antibiotic; He does not have to be toxic; and the preparation must be permanent.

To get the best penetrating carrier for erythromycin and derivatives of erythromycin too To determine, a diffusion experiment was carried out using the skin of hairless mice. Short

The experiment described mouse skin in a vertical position between two covered dolphin cells appropriate. A calcium 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 tested which is a solution of the untimely agent and the containing penetrating carrier, was adjacent to the skin surface (epidermis) of the mouse skin in the diffuse inner cell introduced. To allow mixing, a small one was placed in each diffusion cell Glass bead given.

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 24 hours.

At the end of this conversation, each diffusion cell was assembled removed from the water bath, and the diffusate from the one adjacent to the underside of the skin The cell was filtered by forcing the liquid through a disposable filter attached to a disposable Plastic canoe was attached. This diffu-

Table I.

Penetration (hairless mouse skin)

10

15th

20 sat was then tested with a microbiological agar diffusion test after the under 21 CF. R. 4,36,105. This attempt provides a measure of the passage of effective erythromycin through the skin.

In Table I below is a representative number of penetrating carriers and theirs Efficacy as μg erythromycin passed through mouse skin penetrate,, per ml ^ g / ml) diffusate compiled. Table I shows the improved penetration of the skin for the agent according to the invention im Compared to

(1) the individual components of the agent and

(2) Penetrants similar to the inventive agent but outside of the claimed one Range (some of these known penetrants being similar to the present invention Agents are inferior to being effective skin penetrants for tetracycline t-rwiesen).

alcohol

Ester

optional penetration improver

Erythromycin effectiveness
^ g erythro-
mycin / ml) 2% 2 175 2% 2 915 4% 1563 2% 1685 4% 750 2% 36.5 2% 140 4% 247 4%
(Ethyl succinate) 174

48% Ethanol 28% Ethanol 40% Ethanol 38.4% Ethanol 60% Ethanol 20% F'hanol 40% Isopropanol 56% Ethanol 75.2% Ethanol 57.9% Ethanol 9 7% 2,2-dimethyl 1,3-dioxoIene 4-methanoI 73% Ethanol 25% Propylene glycol 59% Ethanol

50% isopropyl myristate

70% isopropyl myristate

53% isopropyl myristate 3% glycerol monooleai

57.6% isopropyl myristate, 2% glycerol monooleate

2% glycerol monooleate 34%
98% isopropyl myristate

3% glycerine monooleate 35%

38% diisopropyl adipate, 2% glycerol monooleate

18.3% triethyl citrate, 2% glycerol monooleate

29% isopropyl myristate i, 5% glycerol monooleate 2%

407

58% ethanol

70% isopropanol
25% propylene glycol

0.1% decylmethyl
sulfoxide 39% 2% 5.6 0.1% decyl methyl
sulfoxide 39% 2% 7.3 0.1% decylmethyl
sulfoxide 2% 15.3 0.1% sucrose ester

3% oleic acid

2%

8.3

As shown in the data in the table above. Furthermore, it was also established that the selection of the penetrating carrier- ^{55 is} that the ratio of isopropyl myristate to etha-

very critical substance for erythromycin. Of the combinations tested, mixtures of isopropyl myristate were given and ethanol by far the best permeation oils is critical. However, the solubility of the erythromycin or its compounds in the preparation to ensure. Is it necessary a glitchwrht

to maintain between the isopropyl methylate and ethanol. A mixture of 20 to 80% isopropylmyrlstal with 20 to 80% ethanol is acceptable. A preferred one Mixture contains 45 to 60% isopropyl myristate and 30 to 45% ethanol; a particularly preferred mixture consists essentially of about 60% isopropyl myristate and about 40% ethanol.

The above data show that erythromycin and erythomycin compounds when in a carrier which contains ethanol and isopropylmyrlstat, very effective in penetrating the Are epithelium of excellent hairless mouse skin. In addition, the data show that substances from which Is known to be excellent penetrating agents for tetracycline are not particularly useful with Are erythromycin.

A second experiment, similar to that using mouse skin, was carried out using! TlsnSChÜchcr Abdoniln ^ IhBU? (Π C'ncr * ¹ Carried out in a test. The test system consisted of a sampling cell and a skin sample in contact with a collection cell which contained a phosphate buffer solution at a pH of 8.0 Treated four times with the preparation for 8 or 24 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 analyzed for the amount of erythromycin present.

Tabel II Iso
propyl
myristate (human skin) water Erythro
mycin Effective
speed
^ g / ml) penetration 58% Glycerin
monooleat 0 2% 1.70 * ' Ethyl
alcohol 56% 0 0 4% l, 15 ⁺⁾ 40% 0 0 48% 2% 0.51 ^{+ l} 40% 55% 0 0 2% 6.55 ^{T |} 50% 55% 3% 0 2% 5.50 ** ' 40% 54% 3% 0 4% 5.84 ⁺ *> 40% 0 2% 46% 2% 0.82 ^{++ l} 40% 56% 2% 0 4% 1.87 * ⁺ » 50% 48% 0 0 2% 0.38 ⁺⁺⁾ 40% 0 40%

* 'Test duration 24 hours
~~ 'Test duration 8 hours

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

The preferred vehicle for topical use on human skin is a mixture of 30 to 45% ethanol, 1 to 5% glycerine monooleate and the remainder isopropyl myristate. It is necessary that the glycerol monooleate be limited to an amount up to or below 5% is, well above this concentration glycerol monooleate can cause minor noise damage.

^r> Besides using the Erythromycln base as anllblotlsches means In the above preparations for topical application can also be used other Erythromyclnverblndungen or similar drugs. A preferred erythromyl ether derivative is erythromyl methyl succinate. Other compounds that can be used are erythromyl proplonate, erythromyl proponate, erythromyl lactoblonate, erythromyl proplonate, and erythromyl proplonate lauryl sulfate. Mixtures of these compounds can also be used. The limiting factor in the selection of the erythromycin anti-blotlcum is the solubility and resistance of the compound in the penetrating carriers of ethanol, isopropyl myristate and glyceryl monooleate.

water can be present in the agents according to the invention without adversely affecting the penetration of the antibiotic. The presence of large amounts of water however, causes the erythromycin and the erythromycin compounds with prolonged storage become inconsistent. The preferred compositions of the present invention contain less than 5% water.

The preferred acne treatment of the present invention is to apply to the diseased area safe and effective amounts of the agent on the skin

M for topical application. An effective dosage is 0! up to 25 mg / cm ^{2 of} the anti-blotting agent per day. Preferably, the skin is cleaned before the treatment, for which any soap or cleaning agent that is suitable for washing the skin can be used. Treatment is more effective when topical applications are done two to four times a day.

In one embodiment, the diseased site (the Acne damage and the surrounding and inflamed area). By having a safe and effective amount of an anti-sagging agent containing (1) 0.1 to 10 * one of erythromycin and / or Erythromyclnverblndungen existing antibiotic and (2) a pharmaceutically acceptable, permeable

■ »5 low carrier substance, which (a) 0 to 5% glycerol monooleate, (b) 20 to 80% ethanol and (c) the remainder isopropyl myristate contains, applies to this point.

In a preferred embodiment, the agent contains

(U 2 to 5% erythromycin;

(2) 1 to 5% glycerol monooleate;

(3) 30 to 45% ethanol and

(4) 45 to 60% isopropyl myristate.

The following examples illustrate typical antimicrobial By means of the present invention. All substances used in the funds are available in stores or can be made in the manner described herein.

In a preferred method of making Glycerin monooleate is about 3 moles of methyl oleate with about 11 moles of anhydrous glycerin and about 22 moles Dlmethylacetamide (solvent!) With a content of 80 ml of a 10% Igen slurry of sodium methoxide and 80 ml of xylene mixed. This mixture is stirred at 80 mm HG for two hours heated to about 100 ° C. The product obtained in this reaction consists predominantly (about 90% or more)

from 1-glycerine monooleal, the remainder being made from 2-glycerine monooleal and reactants and by-products not entered into the reaction.

Absolute ethyl alcohol was used in the following examples. (100%) to be used can both absolute ethyl alcohol and 95% ethyl alcohol Lger, both for the present invention acceptable Siik ¹ In the preferred substantially anhydrous mutein absolute ethyl alcohol is used. Denatured ethanol can be used as long as the denaturing agent is pharmaceutically acceptable and does not adversely affect the anti-blotting or penetrating properties of the carrier.

The anti-irritant agents according to the invention can also contain various agents and components, the usual catfish In dermatological and cosmetic Ointments and lotions are used. For example, perfumes, gelling and thickening agents, such as B. Carbaxymethyl cellulose, ethyl cellulose, coloring agents and the like In the invention Means to be present in order to make them more attractive from an aesthetic point of view.

Example I.

The following ingredients were mechanically interrelated mixed to give a flowable mixture suitable for topical application to the Skin was suitable:

component He / thromycln base Glycerol monooleate

Ethanol

Isopropyl myristate

Weight percent 4
3

40
rest

The above mixture improved the penetration of the erythromycin base In and through the skin and was particularly useful in treating acne vulgarls.

One person with acne lesions was treated for six weeks. By making the mixture twice daily in an amount of 3 mg of the anti-microbial Applied to the acne lesions by means of per cm '. At the end of this period, the number of acne lesions was significantly reduced and the inflammation was reduced decreased.

When replacing the erythromycln base with erythromycln ethyl succinate the same results were obtained in the above composition.

Example 2

The following ingredients were mixed together:

Ingredient weight percent Erythromycln base 2 Glycerol monooleate 2

component
Ethanol
Ethyl cellulose
Isopropyl myristate

Weight percent 40
10
rest

The above mixture gave a creamy gel suitable for topical application to the skin packed in a roll pen. This mixture improved the penetration of the Erylhomycln base In and through human skin and settled with excellent Use results for the topical treatment of acne, being that given in Example 1 regular treatment regimen has been applied.

When replacing the erythromycln base used above by erythromyln-ethyl-succinate became the same Get results.

Example 3

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

component
Erythromycln base
Ethanol
Isopropyl myristate

Weight percent 4
40
rest

The product obtained was suitable for topical treatment onset of acne, using it twice a day.

When replacing the Erythromycln base In the above Composition by an equivalent amount of Erythromyclnproplonat or Erythromyclnstearat were equivalent results obtained.

Example 4

The following ingredients were mixed together:

component Erythromycln-ethyl-succinate

Ethanol

Glycerol monooleate Dyes

volume

Isopropyl myristate

Weight percent 4
45
2.5
1

1 to 1.5
rest

First, the dyes of the above composition became a flesh-colored one with each other

so mixed dye mixture. All of the above were then mixed together and with the dye mixture mixed, whereby a flesh-colored tinted cosmetic cream was obtained, which the penetration des Erythromycin-ethyl-succlnates through and into the Acne lesions and inflamed tissues around the lesions improved. The cosmetic The foundation acted as a cover for the sick areas during treatment.

Claims (3)

Patent claims: 1. Anti-microbial agent for topical use with a content of erythromycin and / or erythromycin compounds, characterized in that, that it is a mixture as a pharmaceutically acceptable, skin-penetrating carrier the end 20 to 80% ethanol,
Contains 80 to 20% isopropyl myristate and 0 to 5 * glycerol monooleate. 2. Medium according to claim 1, characterized in that it is 0.1 to 10%, erythromycin and / or Contains erythromycin compounds. 3. Means according to one of claims 1 or 2, characterized characterized in that it contains less than 5% water, and essentially of (1) 2 to 5% erythromycin compound, (2) 1 to 5% glycerine sonccieate, (3) 30 to 45% ethanol and (4) 45 to 60% isopropyl myristate consists.