DE2557431A1 - TOPICAL ANTIMICROBIAL PREPARATIONS - Google Patents

Description

Nelson Research & Development Company Irvine, Calif., V.St. A.

Topical antimicrobial preparations

The invention relates in general terms to topical antimicrobial preparations. In the more specific relates the invention relates to preparations which are used for topical use of griseofulvin and antibiotics of the lincomycin and Erythromycin families can be used.

Acne is the commonly used term for an inflammatory disease of the sebum glands; likewise Acne vulgaris. Acne vulgaris is a common inflammatory skin disorder that is common in the early Adolescentia occurs for the first time. It is believed that endocrinological factors are primarily responsible for the Formation of hyperactivity of the sebum glands responsible

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which then leads to the disease state. Acne lesions do not contain any pathogenic organisms, even if pus is present. Sebum, a liquid secretion the sebum, contains an irritant factor that leads to the formation of comedones, the one Represent part of the disease. Corynebacterium acnes, generally a component of normal Skin flora is found in significant abundance in certain acne lesions. Some researchers take it suggest that Corynebacterium acnes plays a role in the pathogenesis of the acne lesion. For example, it is known that oral administration of antibiotics such as tetracycline, the development of Corynebacterium acnes decreased in the skin.

Numerous therapeutic methods of treating acne have been tried, including application topical antibacterial agents such as hexachlorophene and systemic antibiotics such as tetracycline and clindamycin. While treatments with systemic antibiotics are effective, treatments with topical ones are antibacterial agents have not been effective.

It has long been known to have systemic treatment for acne because of the side effects due to the enforcement the entire body with antibiotics and the fact that only the affected skin get treated needs, is not preferable. Despite the long-standing

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_r . , Z 3 O ■ '= "t O

When there is a need to be able to treat acne topically, antibiotics are generally only used systemically Treatment of acne has not been applied because previously it had been believed that antibiotics could be used effectively in the topical treatment of acne.

Grisiofulvin is known as the drug of choice for treating fungal infections of the skin and nails. Until now Griseofulvin has been administered orally. However, it has long been known that oral administration because of the side effects from the penetration of griseofulvin all over the body and the fact that only the outer layers of the affected skin need to be treated is not beneficial. because Fungal infections are generally infections of the skin and nails, so it would be beneficial to use griseofulvin to be able to apply topically. Despite the long-standing wish to be able to apply griseofulvin topically, Griseofulvin for the treatment of localized fungal diseases has only been administered orally because so far no formulation was known which can be safely applied topically and one for a therapeutic one Treatment will result in adequate griseofulvin retention in the skin.

The subject of the invention are antimicrobial preparations containing 0.1 to about 10% by weight of griseofulvin or an antibiotic the lincomycin or erythromycin families and about 5 to

ORIGINAL INSPECTED

about 99.9% by weight of 2-pyrrolidone or N-alkyl-2-pyrrolidone contain.

The term "lincomycin family antibiotic" relates based on a class of antibiotics originally formed by an Actinoycte Streptomyces lincolnensis became. These compounds and the processes for their preparation are described in U.S. Patents 3,086,912 and 3 155 58o. Lincomycin has the following structural formula: CH-j

HIGH

, CH, '^, -CONHCH

) H / SCH ₃

Lincomycin OH

Clindamycin is the 7-deoxy-7-chloro derivative of lincomycin. Typical examples of lincomycin family antibiotics include lincomycin, mirincamycin, clindamycin, N-demethylclindamycin and the pharmaceutically acceptable salts thereof, such as clindamycin free base, clindamycin phosphate, Clindamycin · HCL and the like.

The term used here "antibiotic of the erythromycin family" refers to a class of antibiotic substances originally from a strain of Streptomyces erythreus were formed.

Typical examples of antibiotics of the erythromycin

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ORIGINAL INSPECTED

2 5 5 7 Λ 31

family include erythromycin, erythromycin ethyl carbonate, erythromycin stearate, erythromycin estolate, erythromycin lucepat, Erythromycin propionate, erythromycin ethyl succinate and erythromycin lactobionate. These connections and the Processes for their preparation are described in U.S. Patents 2,823,2o3, 3,000,874, 2,852,429, 2,761,859, 2,993,833 and 2,862,921.

The amount of the antibiotic of the lincomycin family or erythromycin family to be employed in the preparation of the invention ranges from about 0.1 to about 10% by weight and is preferably from about 0.5 to about 5 % by weight of the preparation.

An effective amount of the preparation should be understood here to mean that amount of the preparation which is necessary for the desired treatment, e.g. acne, is therapeutically effective. The preparation is generally used once to Applied four times a day in the usual amounts, i.e. in amounts that allow the formation of a thin film on the attacked Areas are sufficient. Treatment will continue until or after all symptoms of the disease condition being treated Have disappeared.

Besides treating acne, the antibiotic preparations can also be used to temporarily relieve the signs and symptoms of skin infections are 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 conditions associated with the appearance of microorganisms such as impetigo, pyodermias and eczema formed by secondary infections.

The amount of griseofulvin to be used in the preparation of the invention is such that it can be used to treat fungal diseases of the type in which griseofulvin is known is suitable, is therapeutically effective, i.e. this amount must be used for temporary relief of signs and symptoms fungal diseases that are known to be treated with griseofulvin are sufficient. Typical therapeutic Amounts are somewhat dependent on the fungus in question and the place where it has settled, but these amounts generally range from about 0.1 to about 10 percent, and preferably from about 0.5 to about 5 percent by weight.

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

The 2-pyrrolidone and the N-alkyl-2-pyrrolidones are commercially available and can be prepared by a number of known methods, such as those disclosed in U.S. patents 2 555 353 and 2 267 757 described

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255743

travel. The N-alkyl-2-pyrrolidones include those with straight or branched alkyl groups with 1 to 12 and preferably 1 to k 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 ranges from about 5 to about 99.9 % and preferably from 10 to 50 % of the weight of the preparation.

Other ingredients that may be included in these formulations include common formulation components, such as the Freon types, ethyl alcohol, isopropyl alcohol, acetone, polyvinylpyrrolidone, propylene glycol, Fragrances, gel-forming materials, mineral oil, water, stearyl alcohol, stearic acid, spermacet, sorbitan monooleate, Polysorbate 80, Tween 6o, sorbitol solutions (sorbitol solutions), methyl cellulose. Preferred ingredients are alcohols.

The following specific examples illustrate the effectiveness of various embodiments of the invention.

example 1

A series of clinical and microbiological tests were carried out to determine the effectiveness of the preparation of the invention to show how to treat acne. 5 to 6 people

- ο -

Acne vulgaris were used in each determination. Formulations A through D (Table 1) were used twice applied daily to the face of each patient in an amount of about 0.5 cm per day. Comedones were removed with an extractor and placed in a gelatin capsule. The capsule was in warm phosphate buffer dissolved, and equal proportions were applied to a special medium in dilutions and anaerobically for 7 days cultivated. The numerical values of Corynebacterium acnes were expressed in the form of the number of Corynebacterium acnes per mg of comedone material. The results of the test sequence are given in Tables 2 and 3 below.

Table 1

Ingredients ^ BCD

Tetracycline ^ HCL 1% -

Clindamycin phosphate - Λ%

Erythromycin - - - 1 %

N-methyl-2-pyrrolidone 99% 99% 100 % 99 %

Table 2

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

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Comedone bacteria count (number of Corynebacterium acnes),

■ '"- - ■" / -
Evaluation duration, weeks 3x10 ⁷ 2 Preparation 0 3x10 ⁶ 1x10 ⁷ A. 2x10 ⁶ 2x10 ⁵ B. 4x10 ⁶ 3x10 ⁶ C. 4x10 ⁶ D.

3x1 0 2x10 ^: 7x1 0-

1x10 ¹

6x10 ^c
2x1 θ '
2x10 *
3x10 ^f

3x10 '3x10 ¹ 3x1 θ''

2x10-

Table 3

Clinical evaluation in the treatment of acne evaluation duration, weeks

preparation

2 4th 6th 8th 0.7 1.0 0.8 1.1 2.2 3.1 3.5 3.5 0.5 0.7 0.9 1.5 2.1 2.2

The evaluation was based on the following value scale:

* no response 3 = very good improvement = slight improvement 4 »extremely good (" dramatic ")

= get well well soon

The results of the above tests show that the formulation A (tetracycline) is essentially ineffective,

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- 1ο -

like formulation C (a penetrating vehicle) alone. The results of the above tests show however, extremely good improvement using Formulation B (a clindamycin along with a penetrating Carrier) and get well soon using Formulation D (an erythromycin together with a penetrating carrier).

Example 2

Further attempts have been made with clindamycin compounds containing a compound to increase percutaneous absorption carried out. Each of the formulations given in Table 4 was clinically used on 15 acne patients within tested over an 8 week period.

Table 4 component Formulation (%) A. 34 B. Clindamycin phosphate 1.3 - Clindamycinbas e - 1 N-methyl.-2-pyrrolidone 100 34 Adjuvant solvent topical solution in an amount up to 100

The results of the tests showed that most The patient experienced a significant improvement, as was the case

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can be found in Tables 5 and 6 below. Table 5 shows the results of the clinical Assessment given by the patient.

Tabel 5 Clinical evaluation: Beginning vs. at the end to Worsened > Same 0
0 formulation Improved 2
2 A.
B. 13th
13th

Tabel 6th Bacteria count
to 0 No decrease formulation acceptance until except for 0 3
9 A.
B. 11
6th

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

Example 3

The experiments of Example 2 were carried out using clindamycin * HCL, lincomycin, N-demethylclindamycin and

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Mirincamycin repeated instead of clindamycin phosphate. Similar results were obtained.

Example 4

The experiments of Example 1 were carried out using erythromycin ethyl carbonate, erythromycin stearate, erythromycin estolate, Erythromycin lucepat, erythromycin propionate, erythromycin ethyl succinate and erythromycin lactobionate instead repeated by erythromycin. Similar results were obtained.

Example 5

Examples 3 and 4 were repeated with the exception however, that N-methyl-2-pyrrolidone by one 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. Similar results were obtained.

Example 6

This example shows the inhibition radius of griseofulvin when used in the preparations of the invention in comparison with an application of griseofulvin in conventional carriers. The radius of inhibition indicates the radius of a spot on a culture in which a complete inhibition of the

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Growth of the specified organism is achieved when a piece of skin treated with the griseofulvin is placed on the Culture is laid. The radius of inhibition shows the amount of material that is flowing out of the skin and into the surrounding area Culture medium migrates into it and is directly related to the amount of griseofulvin remaining in the skin after the treatment proportional. T.mentagrophytes is inhibited when a Treatment with the specified formulations has taken place. The values obtained are shown in the table specified.

Table 7 Inhibition radius of griseofulvin Human skin hairless skin

the mouse

196 griseofulvin in

1) N-methyl-2-pyrrolidone 6 mm 9 µm

2) N-methyl-2-pyrrolidone 50 % and

Acetone 50 % 6mm 8mm

3) Cold Cream (cooling fatty ointment) according to the US Pharmacopoeia 0 mm 0 mm

4) ethyl alcohol 0 mm 0 mm

Example 7

Experiments were conducted to determine whether the compositions of the invention were therapeutically effective in amounts

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Griseofulvin can be retained in the human stratum corneuni. A series of tests was carried out in which 1 % griseofulvin in the specified vehicle was applied to areas of skin on the upper arms of individuals for 15 minutes and then these areas of skin were washed with a solution of normal soap in water and then rinsed with tap water. Samples from the stratum corneum were taken before the treatment and after various hours indicated in Table 8 in order to determine the growth of T. mentagrophytes on these samples. T.mentagrophytes growth was rated on a 0 to 3 scale, where 0 corresponded to no growth. Table 8 shows the total values of 6 people with two samples each.

Table 8

Stratum corneum retention 0 8th by Griseofulvin 48 1 % griseofulvin in 23 6th hours 9 24 N-methyl-2-pyrrolidone 25th 23 7th 25th Cold Cream according to US 22nd 21 22nd Pharmacopoeia 24 23 27 24 95% ethanol 26th 23 23 22nd acetone 23 Ointment base 27

Table 8 shows that in the form of usual to-

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Griseofulvin applied to pischer preparations is not retained by the epidermis while in the form of the preparation griseofulvin applied to the invention is retained by the skin in therapeutically effective amounts.

Example 8

The retention of griseofulvin was also increased by applying preparations containing radioactive griseofulvin, determined in vitro on samples of human skin from legs. The samples were treated in such a way that

2 ^

areas 3 cm in diameter were covered with 0.01 cnr of the indicated preparations; and after 15 minutes were the samples are washed off in the normal way with soap and water, after which the radioactivity is removed by means of a gas

14th

the C in the stratum corneum of the epidermis. After washing, the remaining amount of radioactive carbon became measured. The data obtained are given in Table 9.

Table 9

Percent retention of griseofulvin in the stratum corneum after washing

14th
0.1 % C -Griseofulvin After washing

in N-methyl-2-pyrrolidone 12.2%

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in ethyl alcohol 0.0 %

in cold cream according to the US Pharmacopoeia 0.8 %

This example shows that no or only insignificant amounts of griseofulvin from the epidermis when using a usual topical preparation, while significant amounts of griseofulvin are retained by the skin upon application of the preparation of the invention are retained.

Example 9

Example 8 was repeated with the exception, however, that 1 % griseofulvin was used instead of 0.1 % and the experiment was carried out for 72 hours. The results of this experiment are given in Table 10 below.

Table 1o

Percent retention of 1 % Griseofulvin in the stratum corneum after washing

1% C ¹ ^ -Griseofulvin in N-methyl-2-pyrrolidone

Cold Cream according to the US Pharmacopoeia

Ethyl alcohol

Immediately 8th Hours. 24 Hours. 72 Hours. 18.5 % 14th Q (kl
, C. / O 7, A η /
I / ν 4, * t ο /.
I / D 1.3 % 0 f C. / D ο, O % ο, O? 6 0.9 % 0 • χ η / ο, O% ο, O %

6Ü9826 / U9b4

Example 10

The following cream formulations were made:

cream

A. B. 5 C. D. 5 E. 5 Griseofulvin - - 5 - - 5 1 5 Clindamycin 1 1 4th 1 1 5 - 0 N-methyl-2-pyrrolidone 25th 20th 34 42 34 Stearyl alcohol 12th - 2 - 10 2 - 2 Stearic acid - 19th 18th 6th 18th synthetic spermacete 7.5 - 2 4th 2 Sorbitan monooleate 1.0 - - - - Polysorbate 80 5.5 - - - - Tween 60 - 3, 3.5 3, 3, Arlacel 60 - 3, 3.5 3, 3, Sorbitol solution 5.5 19 14th 10, 14, mineral oil - 2 - - - Methocel 90 HG-100 - O, 0.2 0, O, Fragrances 0.2 - - - - Sodium citrate 0.5 - - - - Water except for 100 100 100 100 100

Example 11 The following solution formulations were prepared:

N-demethylclindamycin Clindamycin phosphate

Mirincamycin

Griseofulvin

N-methyl-2-pyrrolidone isopropyl myristate

Propylene glycol

Fragrance

Adjuvant solvent up to 100 %

10

0.1

solutions

20th

0.1

33
0.1

25 5

0.1

Etha- isopro- acetone isopro- isorponol pylal- pylal- pyl alcohol alcohol get

Formulation E was tested on people with fungal infections of the feet or hands. The patients left recognize that the formulation stopped the itching and got rid of the fungus, with daily use within 2 to 4 weeks.

Example 12

An aerosol form of Formulations A and E of Example 11 was prepared to make up the following mixture manufactured:

Formulation A or E Freon

'Freon was 7/25 Freon 114/12.

25 %
75 %

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Example 13 The following gel formulations were prepared:

gel (%)

ABC

Griseofulvin 1

Lincomycin base 1

Clindamycin phosphate 1

Carbonpol 934 1

Carbon pole 94o - 0.75 0.75

N-methyl-2-pyrrolidone 25 25 20

Ethanol 25 25 50

Ethoxyl 16R 2 2

Diethanolamine - 0.5 0.5

Di-2- (ethylhexyl) amine - 0.5

Water up to 100 100 100

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Claims (16)

Claims 1. A topical antimicrobial preparation, characterized in that it contains about 0.1 to about 10 of an antimicrobial agent selected from an antibiotic of the griseofulvin or erythromycin or Lincomycinfamilien, together with about 5 to about 99.9 wt -.% Of a compound selected from 2-pyrrolidone or an N-alkyl-2-pyrrolidone. 2. For topical treatment of fungal infections of the skin and nails suitable preparation, characterized in that it contains about 0.1 to about 10 wt -.% Griseofulvin, together with about 5 to about 99.9 wt .- ^ a compound selected from the of 2-pyrrolidone and an N-alkyl-2-pyrrolidone group. 3. Preparation according to claim 2, characterized in that the N-alkyl substituent has 1 to 4 carbon atoms. 4. A preparation according to claim 2, characterized in that the N-alkyl substituent has 1 to 12 carbon atoms. 5. For topical treatment of fungal infections of the skin and nails suitable preparation, characterized in that it contains about 0.1 to about 10 wt .-% griseofulvin, together with about 5 to about 99.9 wt -.% N-methyl-2- contains pyrrolidone. 60982b / U9b4 6. Preparation suitable for the treatment of acne, thereby characterized in that it contains about 0.1 to about 10 weight percent of one Lincomycin family antibiotic along with about 5 to about 99.9% by weight of a compound selected from consisting of 2-pyrrolidone and an N-alkyl-2-pyrrolidone Group, contains. 7. A preparation according to claim 6, characterized in that the N-alkyl substituent of the compound is 1 to 12 carbon has atoms. 8. A preparation according to claim 6, characterized in that the N-alkyl substituent of the compound is 1 to 4 carbon has atoms. 9. A preparation according to claim 6, characterized in that the compound is N-methyl-2-pyrrolidone. 10. A preparation, characterized in that it is about 0.5 to contains about 5 wt .-% clindamycin phosphate together with about 10 to about 50 wt .-% N-methyl-2-pyrrolidone. 11. preparation, characterized in that it contains about 0.1 to about 10 parts by weight of an antibiotic of the 9ό Erythromycinfamilie together with about 5 to about 99.9 wt -.% Of a compound selected from the group consisting of 2-pyrrolidone and an N -Alkyl-2-pyrrolidone consisting group contains. 609826 / U9o k 12. A preparation according to claim 11, characterized in that the N-alkyl substituent of the compound has 1 to 12 carbon atoms Has. 13. Preparation according to claim 11, characterized in that the N-alkyl substituent of the compound has 1 to 4 carbon atoms Has. 14. Preparation according to claim 11, characterized in that the compound is N-methyl-2-pyrrolidone. 15. A preparation according to claim 11, characterized in that the antibiotic of the erythromycin family Erythromycinglucepat or erythromycin ethyl carbonate or erythromycin propionate or erythromycin stearate or erythromycin ethyl succinate or erythromycin estolate or erythromycin lactobionate is. 16. A preparation, characterized in that it contains about 0.5 to about 5% by weight of an erythromycin together with about 10 contains up to about 50% by weight of N-methyl-2-pyrrolidone. 609826 / UbA