DE2557431C2 - Topically applicable antimicrobial preparation - Google Patents

Description

Acne and acne vulgaris are inflammatory diseases of the sebum glands. Acne vulgaris is one common inflammatory skin disease that generally first appears in early adolescentia. It is believed that endocrinological factors are primarily responsible for the formation of hyperactivity the sebum glands are responsible, which then leads to the disease state. Acne lesions contain no pathogenic organisms, even if pus is present. Sebum (skin sebum), a fluid secretion of the The sebum glands contain an irritant factor that leads to the formation of comedones, which are part of the disease represent. Corynebacterium acnes, generally a component of the normal flora of the Skin, is found in significant abundance in certain acne lesions. Some researchers believe that Corynebacterium acnes plays a role in the pathogenesis of acne lesion. For example, it is known to use oral administration of antibiotics, such as B. Tetracycline, which reduces the development of Corynebacterium acnes in the skin. Numerous therapeutic methods for treating acne have been tried. Hexachlorophene was applied as a topical antibacterial agent The application of tetracycline and clindamycin as systemic antibiotics are known. While treatment with systemic antibiotics are effective, In contrast, the treatments with the previously topically applied antibacterial agents show no effective success.

Systemic treatment for acne is because of the side effects due to the enforcement of the entire body with antibiotics and the fact that only the affected skin get treated needs, not particularly cheap.

Despite the longstanding need to treat acne topically, antibiotics are common so far it has only been used systemically against acne.

Griseofulvin is known as a treatment for fungal infections of the skin and nails. So far is Griseofulvin was administered orally. However, it has long been known that oral administration because of the side effects from the penetration of the whole body with griseofulvin and the fact that only the outer layers of the affected skin need to be treated is not advantageous is. Because fungal infections are generally infections of the skin and nails, it would be beneficial to To be able to apply griseofulvin topically. Despite a long-standing desire to take the antibiotic To be used topically, griseofulvin has only been used orally for the treatment of localized fungal diseases given because no formulation was known that could be safely applied topically and one gives adequate griseofulvin retention in the skin suitable for therapeutic treatments.

From B. Helwig, Moderne Arzneimittel, a specialty customer based on indication areas for doctors and Apotheker, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 1972, pp. 470-471, it is known that gentamycin represents a highly effective, locally applicable antibiotic. However, it is not devoid of undesirable effects Side effects, for example with previously damaged kidneys. On p. 824 of the same book are about treatment of skin diseases Ichthoseptal ® -preparations indicated that as active ingredient besides chloramphenicol Contain sodium bituminosulfonate.

According to US-PS 25 55 353 N-alkylpyrrolidones are therapeutically suitable, without a special field of 1 is called herapie. In the context of the present invention, however, it has been shown that these pyrrolidones in use on their own against acne shows practically no effectiveness. A penetration-increasing effect of 2-pyrrolidones in topically applicable preparations was not previously known.

DE-OS 23 41 742 discloses the use of organic and inorganic pyroglutamic acid salts (Salts of 2-pynolidone-5-carboxylic acid) and their derivatives for strengthening antibiotics that can be administered internally such as extractive penicillins, semi-synthetic penicillins, cephalosporins, oligosaccharides,

Tetracyclines and sulfamethylthiadiazoles are known. About comparable effects of 2-pyrrolidone and of N-alkyl-2-pyrrolidones are not reported. For topical applications are pyroglutamic acid and theirs Derivatives are unsuitable because of their ionic character.

Clindamycin and its salts are in medicinal products for the therapeutic treatment of human Body has been used for internal administration (cf. Negwer, Organisch-Chemische Arzneimittel und their Syno- ||

nyma, Akademie-Verlag Berlin 1971, Volume I, p. 515). A topically effective application of clindamycin [j |

In contrast, nothing is known. jt

The object of the invention is to provide for the topical application of certain antimicrobial agents f ^{; i}

to provide a suitable preparation that enables the effective topical application of griseofulvin and of [ '■;

Antibiotics of the lincomycin and erythromycin families and thus the previous systemic treatment

Development on the way of inner gifts with the associated disadvantages and side effects superfluous!: <

power. f:

To solve this problem, the preparation specified in claim 1 with the jf specified in claim 2;

preferred composition suggested. ψ

The invention preferably claims the use of clindamycin for the production of this topically applicable antimicrobial preparations.

The subject of the invention are antimicrobial preparations containing 0.1 to 10% by weight griseofulvin or an antibiotic of the lincomycin or erythromycin family and 5 to 99.9% by weight of 2-pyrrolidione or N-alkyl-2-pyrrolidone contain. S.

"Lincomycin family antibiotic" refers to a class of antibiotics originally developed by an Actinomycete Streptomyces lincolnensis were formed. These connections and the procedures too their preparation is described in US Patents 3,086,912 and 3,155,580. Lincomycin has the the following structural formula:

CH ₃

CH ₃ I.

HIGH

r CONHCH

CH ₃ CH ₂ CH ₂ -I ι _ο

HO— <9 ^Η \ -SCH ₃

Lincomycin OH

Clindamycin is the 7-deoxy-7-chloro derivative of lincomycin. To typical examples of antibiotics the Lincomycin family includes lincomycin, mirincamycin, clindamycin, N-demethylclindamycin and the pharmaceutically acceptable salts thereof, e.g. B. the clindamycin free base, clindamycin phosphate and clindamycin · HCl.

"Erythromycin-family antibiotic" refers to a class of antibiotic substances that originally formed from a strain of Streptomyces erythreus. To typical examples of antibiotics the erythromycin family includes erythromycin, erythromycin ethyl carbonate, erythromycin stearate, Erythromycin estolate, erythromycin lucepat, erythromycin propionate, erythromycin ethyl succinate and erythromycin lactobionate. These compounds and the processes for their preparation are described in US patents 2823 203, 3000874, 2852429, 2761 859, 2993833 and 2862921.

The amount of the antibiotic of the lincomycin family to be used in the preparation of the invention Erythromycin family ranges from 0.1 to 10% by weight, and preferably from about 0.5 to about 5% by weight of the preparation.

An effective amount of the preparation is to be understood as that amount which is necessary for the desired treatment, ζ. B. acne, is therapeutically effective. The preparation is generally administered once to four times a day ^ Usual amounts used, i.e. in amounts that lead to the formation of a thin coating on the attacked

si areas are sufficient. Treatment will continue until or after all symptoms of the treated

Disease state have disappeared.

Besides treating acne, the antibiotic preparations are also used to provide temporary relief from the Signs and symptoms of skin infections applied topically caused by organisms against which the antibiotics of the lincomycin or erythromycin family are effective. The preparations of the invention can therefore be used for the topical treatment of skin disease states which

! associated with the appearance of microorganisms, such as. B. impetigo, and pyodermias by secondary

Eczema formed by infections.

The amount of griseofulvin to be used to treat fungal diseases is somewhat different Fungus and the place where it has settled, but the amounts generally range from about 0.1 to about 10% and more suitably from about 0.5 to about 5% by weight.

The active therapeutic agents described herein can be in a suitable topical formulation dissolved and applied to the affected skin areas in any usual form, such as. B. as a cream, lotion, spray, Solution and the like.

The 2-pyrrolidori and the N-alkyl-2-pyrrolidones are commercially available and can after a series known methods such as those described in U.S. Patents 2,555,353 and 2,267,757 described procedure. The N-alkyl-2-pyrrolidones include those with straight or branched alkyl groups having 1 to 12 and preferably 1 to 4 carbon atoms. N-methyl-2-pyrrolidone is preferred.

The amount of 2-pyrrolidone or N-alkyl-2-pyrrolidone to be employed in the preparation of the invention is sufficient from 5 to 99.9% and preferably from 10 to 50% of the weight of the preparation.

Particularly useful formulations of the preparation of the invention in which N-methyl-2-pyrrolidone as Penetration aids used contain about 0.5 to about 5 wt .-% clindamycin phosphate combined with about 10 to about 50% by weight of N-methyl-2-pyrrolidone and those based on erythromycin about 0.5 to about 5% by weight of an erythromycin together with about 10 to about 50% by weight of N-methyl-2-pyrrolidone.

Other ingredients that may be included in the formulations of the invention include conventional ones Formulation components, such as fluorinated hydrocarbons, ethyl alcohol, isopropyl alcohol, acetone, Polyvinylpyrrolidone, propylene glycol, fragrances, gel-forming materials, mineral oil, water, stearyl alcohol, Stearic acid, whale rat or spermacet, sorbitan monooleate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate, Sorbitol solutions (sorbitol solutions) and methyl cellulose. Preferred ingredients are alcohols.

example 1

A series of clinical and microbiological tests was carried out to determine the effectiveness of the preparation of the invention for the treatment of Ame. 5 to 6 people with acne vulgaris were diagnosed with

S mung used Formulations A to D (Table I) were applied to the face of each patient ^{twice a day in an amount of about 0.5 cm 3 per day.} Comedones were removed with an extractor and placed in a gelatin capsule. The capsule was dissolved in warm phosphate buffer, and equal proportions were applied to a special medium in dilutions and cultured anaerobically for 7 days. The numerical values of Corynebacterium acnes were in the form of the number of Corynebacterium acnes per mg

10 Commission material expressed. The results of the test sequence are given in Tables II and Ul below specified.

Table I.

! 5 components of ABCD

preparation Evaluation duration, 2 Weeks 4th X 10 ⁶ 6th X 10 ⁶ 8th X 10 ⁷ 0 1 X 3 X 10 ³ 6th X 10 ' 3 X 10 ¹ A. 3 X 10 ⁷ 2 X 10 ⁷ 2 X 10 ⁵ 2 X 10 ⁶ 3 X 10 ⁷ B. 3 X 10 ⁶ 3 X 10 ⁵ 7th X 10 ⁶ 2 X 10 ⁵ 3 X 10 ⁵ C. 2 XlO ⁶ 4 X 10 ⁶ 1 3 2 D. 4 XlO ⁶ 10 ⁶

Tetracycline HCl 1 - - -

20 clindamycin phosphate - 1 - -

Erythromycin - - 1

N-methyl-2-pyrrolidone 99 99 100 99

Table II

Evaluation of the antibacterial effectiveness of against Corynebacterium acnes active antibiotics in the treatment of acne

³⁰ comedone bacteria count (number of Corynebacterium acnes), per / mg

Table III

Clinical evaluation in the treatment of acne ^a )

·) The evaluation was based on the following value scale:
0 = no response 3 = very good improvement

60 1 = slight improvement 4 = extremely good improvement

2 = get well soon

The results of the above tests show that formulation A (tetracycline), like formulation C

65 (penetrating vehicle alone) is essentially ineffective. However, the results show an extreme Get well soon using Formulation B (a clindamycin along with a penetrating Vehicle) and get well soon using Formulation D (an erythromycin together with a penetrating carrier).

preparation Evaluation duration, weeks 4th 6th 8th 0 2 1.0 0.8 1.1 A. 0.7 3.1 3.5 3.5 B. 2.2 0.7 0.9 C. 0.5 2.1 2.2 D. 1.5

ι ~

Example 2

Further attempts have been made with clindamycin compounds and a compound to increase the percutaneous absorption carried out. Each of the formulations listed in Table IV were clinically indicated Tested 15 acne patients over an 8 week period.

Table IV

component

Formulation (%) 1.3 B. _ A. - 1 34 34 100 100

Clindamycin phosphate clindamycin base

N-methyl-2-pyrrolidone

Adjuvant solvent, topical solution in an amount up to

The experiments showed that in most of the patients there was a considerable improvement, like that Tables V and VI below can be found in. In Table V the results of the clinical Assessment given by the patient.

Table V

Clinical evaluation: beginning vs. end

■ »pcci» rt fllpirh Vprcrjilprhtprt

formulation Improved acceptance
except for 0 Same Worsened A. 13th 2 0 B. 13th 2 0 Table VI Bacteria count formulation No decrease
except for 0

A 11 3

B 6 9

The experiments given above demonstrate the effectiveness of the tested formulations for treatment from acne.

Example 3

The experiments of Example 2 were carried out using clindamycin · HCl, lincomycin, N-demethylclindamycin and mirincamycin repeated in place of clindamycin phosphate. Comparable results were received.

Example 4

The experiments of Example 1 were carried out using erythromycin ethyl carbonate, erythromycin stearate, Erythromycin estolate, erythromycin glucepat, erythromycin propionate, erytrhomycin ethyl succinate and eryihromycin lactobionate instead of erythromycin repeated. Comparable results were received.

Example 5

Examples 3 and 4 were repeated with the exception, however, that N-methyl-2-pyrrolidone by a of the compounds 2-pyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-isobutyl-2-pyrrolidone, N-hexyl-2-pyrrolidone, N-octyl-2-pyrrolidone and N-decyl-2-pyrrolidone was replaced. Comparable results were received.

Example 6

This example shows the radius of inhibition of griseofulvin when used in the preparations of the invention in comparison with the use of griseofulvin in conventional vehicles. The inhibition radius gives the Radius of a spot on a culture in which there is a complete inhibition of the specified growth Organism is achieved when a piece of skin treated with the griseofulvin is placed on the culture. Of the Inhibition radius shows the amount of material that has escaped from the skin and into the surrounding culture medium migrates into it and is directly proportional to the amount of griseofulvin left in the skin after the treatment. T.mentagrophytes is inhibited when treated with the specified formulations has taken place. The values obtained are given in Table VII.

Table VII

Inhibition radius of griseofulvin

Human skin Mouse hairless skin 1% griseofulvin in mm mm 1) N-methyl-2-pyrrolidone 6th 9 2) N-methyl-2-pyrrolidone 50%
and acetone 50% 6 ' 8th 3) Sperm Acet Cream
(cooling ointment) 0 0 4) ethyl alcohol 0 0 Example 7

Experiments were conducted to determine if the preparations of the invention were therapeutic effective amounts of griseofulvin are retained in the human stratum corneum. A row of Test trials were carried out using 1% griseofulvin in the specified vehicle on areas of the skin was applied to the upper arms of people for 15 minutes and then these areas of skin with a solution of normal soap in water and then rinsed with tap water. Samples from the stratum corneum were taken prior to treatment and after various tests shown in Table VIII hours to determine the growth of T.mentagrophytes on these samples. T.mentagrophytes growth was rated on a 0 to 3 scale, with 0 being no growth corresponded. Table VIII shows the summed total values of 6 people with two samples each specified.

Table VIII

Stratum corneum retention by griseofulvin

1% griseofulvin in

Hours 0

24

48

N-methyl-2-pyrrolidone 23 6th 7th 9 Sperm Acet Cream 25th 23 27 25th 95% ethanol 22nd 21 23 22nd acetone 24 23 23 24 Ointment base 26th 23 27 22nd

It can be seen from Table VIII that griseofulvin applied in the form of conventional topical preparations does not is retained by the epidermis while griseofulvin applied in the form of the preparation of the invention is retained by the skin in therapeutically effective amounts.

Example 8

The retention of griseofulvin was also determined in vitro by applying preparations containing radioactive griseofulvin to samples of human skin on the legs. The samples were treated in such a way that areas 3 cm ^{2 in} diameter were covered with 0.01 cm ^{3 of} the specified preparations; after 15 minutes the samples were washed with soap and water in the normal manner, followed by the

Radioactivity was determined using a gas flow ^{skin counter which measures C 14} in the stratum corneum of the epidermis. After washing, the remaining amount of radioactive carbon was measured. The data obtained are given in Table IX.

Table IX

Percentage of griseofulvin retention in the stratum corneum after washing

0.1% C ¹⁴ griseofulvin

After washing

in N-methyl-2-pyrrolidone 12.2% in ethyl alcohol 0.0%

in spermacet cream 0.8%

This example shows that no or only insignificant amounts of griseofulvin from the epirdermis when used of a conventional topical preparation, while significant amounts of griseofulvin are withheld retained on the skin when the preparation of the invention is used.

Example 9

Example 8 was repeated with 1% griseofulvin instead of 0.1%; the experiment lasted 72 hours. In the results of this experiment are given in Table X below.

Table X

Percentage of 1% griseofulvin retention in the stratum corneum after washing

1% C ¹⁴ griseofulvin in

Immediately

8 hours 24 hours 72 hours

N-methyl-2-pyrrolidone 18.5 14.2 7.1 Sperm Acet Cream 1.3 0.2 0.0 Ethyl alcohol 0.9 0.3 0.0

4.1
0.0
0.0

Example 10 The following cream formulations were prepared:

Cream 0 - 4) B. - C. - D. - E. 1 A. 1 1 1 1 - Griseofulvin 25th 20th 34 42 34 Clindamycin 12th - - 10 - N-methyl-2-pyrrolidone - 19th 18th 6th 18th Searyl alcohol 7.5 - 2 4th 2 Stearic acid 1.0 - - - - synthetic spermacet 5.5 - - - - Sorbitan monooleate - 3.5 3.5 3.5 3.5 Polyoxyethylene (20) sorbitan
monooleat - 3.5 3.5 3.5 3.5 Polyoxyethylene (20) sorbitan
monostearate 5.5 19.4 14th 10.5 14.0 Sorbitan mnostearate - 2 - - - Sorbitol solution - 0.2 0.2 0.2 0.2 mineral oil Hydroxypropyl methyl cellulose

continuation

Cream (%) ABCD

Fragrances 0.2 -

Sodium citrate 0.5 -

¹⁰ water up to 100 100 100 100

Example 15 The following solution formulations were prepared:

35 Formulation E was tested on people with fungal infections of the feet or hands. The patients indicated that the formulation stopped the itching and eliminated the fungus, namely at daily use within 2 to 4 weeks.

example

An aerosol form of Formulations A and E of Example 11 was prepared to make the following Mixture produced:

Solutions{ [%) C. D. E. A. B. - 1 - Clindamycin phosphate 1 - - - - Mirincamycin - 1 20th - 1 Griseofulvin 10 15th - 25th 25th N-methyl-2-pyrrolidone - - 5 - 5 Isopropyl myristate 5 5 - 33 - Propylene glycol - - 0.1 0.1 0.1 Fragrance 0.1 0.1 acetone Isopropyl Isopropyl Adjuvant solvent Ethanol Isopropyl alcohol alcohol up to 100% alcohol

45

Formulation A or E

Mixture of 1,2-dichloro

1,1,2,2-tetrafluoroethane and

Dichlorodifluoromethane

Example ₅₅ The following gel formulations were prepared:

Gel (%) _ B. _ C. 1 A. 1 - - Griseofulvin - 1 - Lincomycin base 1 - - Clindamycin phosphate - 0.75 0.75 Carboxyl vinyl polymer, MW about 500,000 25th 25th 20th Carboxyl vinyl polymer, MW approx. 4 · 10 ⁶ N-methyl-2-pyrrolidone

25th continuation 57 431 Gel (%) B. C. A. 25th 50 25th 2 2 Ethanol - 0.5 0.5 Polyoxyethylene (16) lanolin alcohol - 0.5 - Diethanolamine - 100 100 Di-2- (ethylhexyl) amine 100 Water except for

Claims (2)

Patent claims: 1. Topically applicable antimicrobial preparation, characterized in that it is used in combination 0.1 to 10% by weight of an antibiotic from the group of the erythromycin or lincomycin family or griseofulvin and 5 to 99.9% by weight of 2-pyrrolidone or N-alkyl-2-pyrrolidone with straight or branched chains Contains alkyl groups of 1 to 12 carbon atoms 2. Topically applicable antimicrobial preparation, characterized in that it is clindamycin as an antibiotic contains