DE3321487A1 - LOCALLY APPLICABLE MEDICINES WITH ANTISEPTIC AND ANTI-INFLAMMATORY EFFECT - Google Patents

Abstract

The invention relates to topically applicable medicaments with antiseptic and anti-inflammatory effects, which a) 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene -3,20-dione and b) 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride and / or -digluconate in a weight ratio of a) to b) of 1: 1 to 1:50 as active ingredients, optionally together with 1 or more pharmaceutically customary carrier and / or auxiliary substance (s). The medicaments according to the invention are for the topical treatment of primary and secondary infections with adjuvant inflammation, especially for the therapy of dermatoses , extremely suitable.

Description

The invention relates to stable, topically applicable medicaments with antiseptic and increased anti-inflammatory effects, ie a double effect, in particular for external use, which are suitable for the treatment of primary or secondary infections, ie for the therapy of skin diseases accompanied by inflammation.

Ointments, the antibiotics for example 2,2-dichloro-N - {(small alpha R, small beta R) -small beta-hydroxy-small alpha-hydroxymethyl-4'-nitrophenethyl} -acetamide [chloramphenicol], 5-hydroxytetracycline [ Oxytetracycline], neomycin or gentamycin, or antiseptics, for example 5-chloro-8-hydroxy-7-iodo-quinoline [clioquinol] or 2,2'-dihydroxy-3,3 ', 5,5', 6,6 ' -hexachloro-diphenyl-methane {2,2'-methylene-bis- (3,4,6-trichlorophenol)} [hexachlorophene], contained as an active ingredient, are widely used for the therapy of various skin infections. However, these preparations only inhibit the bacteria that cause the infection themselves and are ineffective against the secondary inflammation.

In the treatment of skin inflammation, especially in chronic cases, antibacterial therapy is supplemented with anti-inflammatory ointments, mainly containing corticosteroids.

The use of combination ointments that contain an antibacterial or antiseptic agent and also a corticosteroid, for example a combination ointment with the antibacterial ingredient 2,2-dichloro-N - {(small Alpha R, small Beta R) -small beta-hydroxy- small alpha-hydroxymethyl-4'-nitrophenäthyl} -acetamide [chloramphenicol] and the

Corticosteroid component 11 small beta, 17,21-trihydroxy-4-pregnen-3,20-dione [hydrocortisone] <Chlorocid-H [high] (R)>, a combination ointment with the antibacterial component 5-hydroxytetracycline [oxytetracycline] and the corticosteroid component 11 small beta, 17,21-trihydroxy-4-pregnen-3,20-dione [hydrocortisone] <tetran-hydrocortisone [high] (R)> or a combination ointment with the antibacterial component 5-chloro-8- hydroxy-7-iodo-quinoline {clioquinol} and the corticosteroid component 11 small beta, 17,21-trihydroxy-1,4-pregnadiene-3,20-dione [prednisolone] {prednisolone j [high] (R)}, or which contain an antifungal agent and a corticosteroid, for example from a combination ointment with the antifungal component pimaricin and the corticosteroid component 11 small beta, 17,21-trihydroxy-4-pregnen-3,20-dione [hydrocortisone] <pimafucort [high ] (R)> or a combination ointment with the antifungal component 1- {2 ', 4'-dichloro-small beta (2 ", 4" -di <chlor> -benzyloxy) -ph enäthyl} -imidazol {Miconazol} and the corticosteroid component 21-deoxy-21- [4 '- (methyl) -piperazino] -prednisolone hydrochloride <Micosolon [high] (R)>, is used in the treatment of skin inflammations and other skin diseases, For example, eczema, to be regarded as a great advance, even if these dual-purpose combinations could not solve the basic problems of one-component therapy satisfactorily. These problems are summarized as follows:

The antibacterial spectrum of most of the antibiotics in these preparations is quite narrow. So is the 5-hydroxytetracycline component [oxytetracycline component] of the above-mentioned second ointment against such gram-negative bacteria as the Pseudomonas, Proteus and Klebsiella strains, and gram-positive bacteria such as the strains Staphylococcus aureus and Streptococcus, and the 2,2-dichloro-N - {(small alpha R, small beta R) - small beta-hydroxy-small alpha-hydroxymethyl-4'-nitrophenethyl} -acetamide component [chloramphenicol component] of the The first ointment mentioned above is nowhere near active enough.

In addition, when all dermatological preparations containing an antibiotic are used, resistance is promptly developed, with the result that not only does the patient fail to cure, but also promotes the growth or proliferation of resistant pathogenic bacteria (Antibiotics and Chemotherapy, Churchill Livingstone Press, London, 1981, p. 306).

Since these preparations are rather weak antimycotics, their use can also lead to increased growth or proliferation of the dermatological mycotic population or population (guidelines for the regulation of pharmaceutical preparations, Medicina Verl., Budapest, 1980, page 479). Skin allergy can often be observed after using such preparations.

The antibacterial spectrum of aminoglycoside antibiotics, for example neomycin and gentamycin, is relatively broader, but again they are much more toxic than the earlier preparations, they attack the kidneys and the hearing sense, which can be proven even when large amounts are used locally .

As far as the dermatological use of antiseptics, such as 5-chloro-8-hydroxy-7-iodo-quinoline (clioquinol), a broad-spectrum agent, is concerned, it is due to its skin irritation or skin irritation and allergy-causing properties due to its iodine content are limited, it cannot be administered to iodine-sensitive or iodine-sensitive patients at all (Martindale: Extra Pharmacopoea, The Pharmaceutical Press, London, 1977, pages 27, 72 and 823;

JAMA 201 [1967], p. 1009; JAMA 202 [1967], p. 710; Arch. Derm. 106 [1972], p. 335) and it also stains clothes and linen. The side effects of antiseptics, which are mostly quite toxic, cannot be ignored either, as skin adsorption is to be expected. It has recently been found that 2,2'-dihydroxy-3,3 ', 5,5', 6,6'-hexachlorodiphenylmethane [hexachlorophene] can seriously damage the nervous system (JAMA 240 [1973], p. 513; J Clin. Pathol. 34 [1981], page 25; Lancet 1982/1, pages 87 and 91). It is another unfavorable property of antibiotics and other antibacterial agents, such as of 2,2'-dihydroxy-3,3 ', 5,5', 6,6'-hexachlorodiphenylmethane [hexachlorophene], iodine and mercury (II) - Compounds that they cause allergies and skin inflammation as a side effect. This danger is all the more pronounced as eczematous patients are much more sensitive to allergic inflammation (polysensitization).

Ointments containing antifungal agents are generally quite weak antibacterial agents, both alone and in combination (like the combination ointments mentioned above as the penultimate and last mentioned combination ointments), so that their antibacterial spectrum is much narrower confirm the mycotic infection can be administered.

In dermatological ointments, the anti-inflammatory ingredients are mostly corticosteroids. When administered topically, they are excellent therapeutics, but unfortunately they weaken the skin's resistance to bacteria, fungi and viruses, which sooner or later leads to secondary infections, pustules and suppuration processes when applied to the inflamed skin. In addition, due to the high corticoid content, there are also systemic side effects, characteristic of synthetic steroids.

The above-mentioned dermatological combination preparations are also not up-to-date because in most of them the activity of the steroids used is weaker than that of the recently synthesized compounds and their use is only appropriate if the pathogenic microorganism has been identified beforehand . Since dermatological treatment is generally carried out on an outpatient basis, breeding or cultivation is rarely carried out and consequently the success of a treatment can never be predicted. In hypersensitivity cases, all of the above preparations can cause itching, hives or urticaria, skin irritation, burning skin and maculopapular rash. hydroxy-small alpha-hydroxymethyl-4'-nitrophenethyl} -acetamide [chloramphenicol] and the corticosteroid component 11 small beta, 17,21-trihydroxy-4-pregnen-3,20-dione [hydrocortisone] {chlorocide-H [high ] (R)}> (Guidelines for the Regulation of Pharmaceutical Preparations, Medicina Verlag, Budapest, 1980, page 128).

The invention is based on the object, while eliminating the disadvantages of the prior art, stable, topically applicable drugs with antiseptic and increased anti-inflammatory action, which have an effect that is superior to the action of the known drugs and also in those cases in which the known drugs failed, Can be used with success as well as create fewer unwanted side effects.

It has now surprisingly been found that the antiseptic and anti-inflammatory effects of topical drugs, which 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4- diene-3,20-dione

<Triamcinolone acetonide> and 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride and / or -digluconate [1,1'-hexamethylene-bis- {5" - (4 "'-chlorphenyl) -biguanid}] <Chlorhexidine dihydrochloride and / or -digluconate> are significantly higher than the effect of the known drugs and that they are successful in the treatment of primary and secondary dermatoses with adjuvant inflammation, such as eczema nummulare, microbiale, mycoticum cruris, impetiginosum, dyshidrosis, intertrigo and pemphigus vulgaris, as well as superinfections or reinfections, such as contact dermatitis, can be used.

The invention therefore relates to topically applicable medicaments with antiseptic and anti-inflammatory effects, which are characterized in that they

a) 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <triamcinolone acetonide>

and

b) 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride and / or -digluconate [1,1'-hexamethylene-bis- {5" - (4 "' -chlorphenyl) -biguanide}] <chlorhexidine dihydrochloride and / or digluconate>

in a weight ratio (weight to weight) of a) to b) of 1: 1 to 1:50 as active ingredients, optionally together with 1 or more pharmaceutically customary carrier and / or auxiliary substance (s).

The active ingredients of the medicaments according to the invention are known compounds, 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione

[Triamcinolone acetonide] can according to the method described in Hungarian patent specification 163 145 and 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride and 1,6-bis- {5' - [4 "- (chlor) -phenyl] -biguanido} -hexanedigluconate <Chlorhexidine dihydrochloride and -digluconate> can be prepared according to the process described in the Hungarian patent specification 175,371.

The medicaments according to the invention are more active than the known medicaments with the same direction of action and are safer and simpler. Because of the broader antibacterial spectrum of these drugs, resistance will not develop during treatment. As far as the possible side effects of the medicaments according to the invention are concerned, they are far weaker than those of the commercial preparations with the same direction of action.

On the basis of the clinical test reports, the medicaments according to the invention enable the successful dermatological treatment of patients who have been either uncured or only partially cured with the previous conventional treatments. By reducing the number of bacteria on the main surface in combination with a secondary anti-inflammatory effect, 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexane <chlorohexidine> inhibits the development of an adjuvant bacterial infection in chronic skin inflammation cases and consequently it ensures more favorable anti-inflammatory conditions of action for 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione < Triamcinolone acetonide> on the eczematous skin surface.

The medicaments according to the invention preferably contain the 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <triamcinolone acetonide>

[Component a)] in amounts of 0.05 to 0.25% by weight and that or the 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride and / or -digluconate <chlorhexidine dihydrochloride and / or -digluconate> [component (s) b)] in amounts of 0.25 to 2.5% by weight.

It is also preferred that the medicaments according to the invention contain an ointment base.

The medicaments according to the invention can expediently be prepared in such a way that 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3.20- dion <triamcinolone acetonide> [component a)] and 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride and / or digluconate <chlorhexidine dihydrochloride and / or digluconate> [component (e) b)] in a weight ratio of a) to b) of 1: 1 to 1:50 and, if necessary, by means of 1 or more carriers and / or auxiliaries commonly used in pharmacy according to known drug manufacturing processes in pharmaceuticals Ready-made products such as ointments, syrups, vaginal tablets and various other preparations are transferred, preferably working in such a way that pharmaceutical preparations containing the 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy ) -pregna-1,4-diene-3,20-dione <Triam cinolone acetonide> [component a)] in amounts of 0.05 to 0.25% by weight and that or the 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride and / or digluconate <chlorhexidine dihydrochloride and / or digluconate> [component (s) b)] in amounts of 0.25 to 2.5% by weight.

For the production of ointments it is advisable to proceed as follows: 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <Triamcinolone acetonide>

[Component a)] and 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexane dihydrochloride and / or digluconate <chlorhexidine dihydrochloride and / or -digluconate> [component (s) b )] are mixed in the specified weight ratio and their mixture with 1 or more carrier and / or auxiliary substance (s) customary in pharmacy and before, at the same time with and / or afterwards with an ointment base emulsion of the oil in water type and afterwards known drug manufacturing processes is processed into pharmaceutical finished products.

According to one embodiment of the ointment production, the 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <triamcinolone acetonide> [ Component a)] used in the form of a micronized powder.

According to a further embodiment of the ointment production, the 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride <chlorhexidine dihydrochloride> [component b)] with a particle size of 0.05 to 0 , 07 mm, in particular 0.062 mm, is used.

According to yet another embodiment of the ointment production, the 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexane digluconate <Chlorhexidine digluconate> is in the form of a, preferably 15 to 30 wt. % strength, in particular 20% strength by weight, aqueous solution is used.

Preferably 0.05 to 0.25% by weight, in particular 0.05 to 0.15% by weight, of the micronized powder of 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha- (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <triamcinolone acetonide> [component a)], based on the finished ointment, with 0.25 to 2.5% by weight, in particular 0.5 to 2.0 wt%, 1,6-bis- {5 '- [4 "- (chloro) -phenyl] -biguanido} -hexane dihydrochloride

<Chlorhexidine dihydrochloride> [component b)], also based on the finished ointment, in particular with a particle size of 0.062 mm (230 mesh), homogenized.

For the production of ointments which contain 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexane digluconate <chlorhexidine digluconate>, this is preferably in the form of a 15 to 30 wt. % strength, in particular 20% strength by weight, advantageously commercially available, solution is introduced into the amount of water required for the ointment production at 60 ° C. and the oily melt of the ointment base, which has been prepared according to the procedure described below, is introduced into this aqueous solution added with constant stirring, after which the whole thing cooled, then homogenized with the preservative (s) and then with the appropriate amount of the micronized 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidendioxy) -pregna-1,4-diene-3,20-diones <Triamcinolonacetonides> is processed into a homogeneous ointment.

The ointment base emulsion of the oil in water type can advantageously be prepared in such a way that 10% by weight of paraffin oil, with a viscosity of at least 100 mPa, based on the finished ointment, and 25% by weight of the emulsifying wax cetomacrogol (BP 1973, page 91) are heated until the mixture has melted, the melt is introduced into 60 to 65 wt .-% water, advantageously at a temperature of 60 ° C, and stirred until the ointment base has cooled to room temperature and then this cold ointment base is homogenized with 1% by weight of a solution containing 1 or more preservatives, based on the finished ointment. Various benzoic acid derivatives, such as methyl p-hydroxybenzoate and / or n-propyl p-hydroxybenzoate.

The effectiveness of the medicaments according to the invention was tested on an ointment containing 0.1% by weight of 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4- diene-3,20-dione <triamcinolone acetonide> and 1% by weight 1,6-bis- {5 '- [4 "- (chloro) -phenyl] -biguanido} -hexanedihydrochloride <chlorhexidine dihydrochloride> and according to example 1 has been established.

1st clinical trial

a) Open preliminary investigation

Number of patients studied: 17

Diagnosis: eczema dyshidrosiform (11 cases)

Pemphigus vulgaris (6 cases).

Previous conventional therapy was unsuccessful in the patients.

Evaluation: There were no refractory cases, the effect was prompt, visible (apparent) and progressed to a completely symptom-free state of the patient. No side effects were detectable. b) Double-blind clinical trial

The comparative ointment contained only 0.1% by weight of 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <Triamcinolone acetonide>. Both ointments, i.e. the one that contains 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <triamcinolone acetonide> and 1,6-bis- {5 '- [4 "- (chloro) -phenyl] -biguanido} -hexanedihydrochloride <chlorhexidine dihydrochloride>, {ointment according to the invention} as well as that which only 9 small alpha-fluoro-11 small beta , 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <triamcinolone acetonide> were prepared with identical ointment bases and designated with a code number neither the doctor nor the patient who was used by the two ointments. The code number was only revealed after the end of the trial. The ointments were used for the treatment of skin infections that were symmetrical on the body. A lot was drawn, to decide which of the two sides should be treated with which ointment.

Number of patients studied: 30

Diagnosis: Eczema nummulare (19 cases),

Eczema mycoticum (3 cases),

Eczema impetiginosum (3 cases),

Dyshidrosis (5 cases).

The test results were evaluated using the segmental procedure. The data that are combination ointment according to the invention were achieved were significant compared to those with commercial ointments (p = 0.05).

No side effects were detectable.

Evaluation: Both the open and the double-blind examination showed the ointment according to the invention, which contained 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4 -diene-3,20-dione <triamcinolone acetonide> and 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedihydrochloride <chlorhexidine dihydrochloride> contained as therapeutically valuable, even at Dermatoses for which conventional therapy was unsuccessful.

Neither side effects nor allergizing effects were detectable, not even in individual cases.

In the opinion of the investigators, the ointment according to the invention can be used in the following range of indications: In all eczema in which bacterial and mycotic factors are of primary and secondary importance, for example in eczema nummulare, microbiale, mycoticum cruris, impetiginosum, dyshidrosis, intertrigo and pemphigus vulgaris . The combination ointment according to the invention is more modern and has more favorable properties than preparations of similar indication areas, such as the combination ointment with the antibacterial component 5-chloro-8-hydroxy-7-iodo-quinoline {clioquinol} and the corticosteroid component

11 small beta, 17,21-trihydroxy-1,4-pregnadiene-3,20-dione [prednisolone] {prednisolone j [high] (R)}, the combination ointment with the antibacterial component 5-hydroxytetracycline [oxytetracycline] and the corticosteroid - Ingredient 11 small beta, 17,21-trihydroxy-4-pregnen-3,20-dione [hydrocortisone] <Tetran-Hydrocortisone [high] (R)>, the combination ointment with the antibacterial ingredient 2,2-dichloro-N- {(small alpha R, small beta R) - small beta-hydroxy-small alpha-hydroxymethyl-4'-nitrophenäthyl} -acetamide [chloramphenicol] and the corticosteroid component 11 small beta, 17,21-trihydroxy-4-pregnen- 3,20-dione [hydrocortisone] <Chlorocid-H [high] (R)> and the combination ointment with the antifungal ingredient 1- {2 ', 4'-dichloro-small beta (2 ", 4" -di- < chlorine> -benzyloxy) -phenäthyl} -imidazole {Miconazole} and the corticosteroid component 21-deoxy-21- [4 '- (methyl) -piperazino] -prednisolone hydrochloride <Micosolon [high] (R)>.

2nd clinical trial

The said ointment according to the invention was dermatologically and clinically tested on a total of 71 patients. The distribution of the subjects subjected to the trial according to their diagnosis was as follows:

Eczema bacteriale 18

Eczema mycoticum 13

Eczema contactum 6

Eczema endogenous 1

Eczema ronicosum 2

Candida balanoposthitis 3

Leg ulcer 5

Pustular acne 7

Dyshidrosis mani 7

Dyshidrosis pedis 8

Intertriginous dermatitis 1

Breeding (cultivation) or microscopic tests were carried out in 20 of 71 cases and the following pathogens or pathogens were detectable: Staphylococcus aureus, Klebsiella, Pseudomonas aeruginosa, Proteus mirabilis, Escherichia coli, Candida albicans and Epidermophyta fungi. The patients had previously been treated with known preparations, which failed in 53 of the 71 cases (74.6%).

The individual test results obtained with conventional commercial preparations prior to treatment with the combination ointment according to the invention are shown in Table 1 below and those obtained with the combination ointment according to the invention are summarized in Table 2 below. In the latter, the 5 main symptoms, namely crust formation, suppuration, hyperemia, pain and itching, are identified with the following ratings obtained by assessment, which characterize their severity:

1 = symptom-free, 2 = weak,

3 = medium, 4 = difficult.

In these experiments, control examinations were carried out before, during and after the treatment. For the individual symptom assessments, their percentage occurrence (incidence) before treatment, at the control during treatment and after the end of treatment is given in Table 2 below, which also shows the change in their percentage occurrence from that before treatment to that after treatment has ended .

Table 1

Pretreatment with commercial products

Table 1 continued Table 1 continued Table 1 continued Table 1 continued Table 1 continued Table 1 continued

*) Formulas Normales (Fo-No., V. Hungarica, Medicina Verlag, Budapest, 1967)

When the above 71 patients were treated with the combination ointment according to the invention, this was successful in most cases (95%).

Table 2

Treatment with the combination ointment according to the invention

Table 2 continued

Table 2 above shows that after the treatment with the combination ointment according to the invention had ended, the 5 representative symptoms, namely crust formation, suppuration, hyperemia, pain and itching, were considerably alleviated or eliminated in most of the patients treated (95.3%) ( 95.3% = average of the sums of the weak forms of the representative symptoms + the symptom-free cases from the ratings of the 5 symptoms mentioned).

Side effects were observed in only 3 patients, namely in 2 mild skin drying and in 1 pustules.

The effectiveness of the combination ointment according to the invention can best be measured by the fact that while only 25.4% of the patients reacted to the conventional therapy with the known agents, the condition of 95.3% of the same patients improved considerably when they were treated with the invention Combination ointment were treated.

The invention is explained in more detail with reference to the following examples.

example 1

Manufacture of a pharmaceutical ointment

The following ingredients were used.

1,6-bis- {5 '- [4 "- (chloro) phenyl] -

biguanido} hexane dihydrochloride

<Chlorhexidine dihydrochloride> 1.0 g

9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha

(isopropylidenedioxy) -pregna-1,4-

diene-3,20-dione

<Triamcinolone acetonide> 0.1 g

Paraffin oil (viscosity at least

100 mPa) 10.0 g

Cetomacrogol emulsifying wax °)

(B.P. 1973, p.91) 25.0 g

Preservative solution °°)

(Pharmacopoea Hungarica VI.

Page 1 314) 1.0 g

Distilled water 62.9 g

°) Composition of the cetomacrogol emulsifying wax:

Cetostearyl alcohol 20.0 g

Polyethylene glycol-1000-

monoacetyl ether 5.0 g

°°) Composition of the preservative solution:

p-oxybenzoic acid-n-

propyl ester 30.0 g

p-oxybenzoic acid methyl

ester 70.0 g

Alcohol concentratissi-

mus 900.0 g

The ointment was prepared from the above ingredients using the following procedure.

10 g of paraffin oil and 25 g of cetomacrogol emulsifying wax were heated to 60 ° C. on a water bath and the melt was slowly poured into 62.9 g of warm water (at 60 ° C.) with constant stirring. Stirring was continued until the oil-in-water emulsion had cooled to room temperature. This cold emulsion was homogenized with 1 g of the preservative solution, left to stand for 24 hours, then passed through 3 press cylinders and repeatedly stirred. Separately, 1 g of 1,6-bis- {5 '- [4 "- (chloro) -phenyl] -biguanido} -hexane dihydrochloride was ground to a particle size of 0.062 mm (230 mesh) and then 0.1 g of micronized 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione <triamcinolone acetonide> mixed thoroughly and the mixture was mixed The above ointment base was added in portions and then the entire mixture was homogenized to form a uniform ointment.

Example 2

Manufacture of a pharmaceutical ointment

1,6-bis- {5 '- [4 "- (chloro) phenyl] -

biguanido} hexane dihydrochloride

<Chlorhexidine dihydrochloride> 2.0 g

9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha

(isopropylidenedioxy) -pregna-1,4-

diene-3,20-dione

<Triamcinolone acetonide> 0.05 g

Paraffin oil (viscosity at least

100 mPa) 10.0 g

Cetomacrogol emulsifying wax °)

(B.P. 1973, p.91) 25.0 g

Preservative solution °°)

(Pharmacopoea Hungarica VI.

Page 1 314) 1.0 g

Distilled water 61.95 g

°) and °°) see the explanation of symbols in example 1

The ointment was prepared by following the procedure of Example 1 from the above ingredients.

Example 3

Manufacture of a pharmaceutical ointment

1,6-bis- {5 '- [4 "- (chloro) phenyl] -

biguanido} hexane dihydrochloride

<Chlorhexidine dihydrochloride> 1.50 g

9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha

(isopropylidenedioxy) -pregna-1,4-

diene-3,20-dione

<Triamcinolone acetonide> 0.15 g

Paraffin oil (viscosity at least

100 mPa) 10.0 g

Cetomacrogol emulsifying wax °)

(B.P. 1973, p.91) 25.0 g

Preservative solution °°)

(Pharmacopoea Hungarica VI.

Page 1 314) 1.0 g

Distilled water 62.35 g

°) and °°) see the explanation of symbols in example 1

The ointment was prepared by following the procedure of Example 1 from the above ingredients.

Example 4

Manufacture of a pharmaceutical ointment

1,6-bis- {5 '- [4 "- (chloro) phenyl] -

biguanido} hexane dihydrochloride

<Chlorhexidine dihydrochloride> 0.50 g

9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha

(isopropylidenedioxy) -pregna-1,4-

diene-3,20-dione

<Triamcinolone acetonide> 0.20 g

Paraffin oil (viscosity at least

100 mPa) 10.0 g

Cetomacrogol emulsifying wax °)

(B.P. 1973, p.91) 25.0 g

Preservative solution °°)

(Pharmacopoea Hungarica VI.

Page 1 314) 1.0 g

Distilled water 63.3 g

°) and °°) see the explanation of symbols in example 1

The ointment was prepared by following the procedure of Example 1 from the above ingredients.

Example 5

Manufacture of a pharmaceutical ointment

1,6-bis- {5 '- [4 "- (chloro) phenyl] -

biguanido} hexanedigluconate

<Chlorhexidine digluconate>

in 20% by weight aqueous

Solution 5 ml

9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha

(isopropylidenedioxy) -pregna-1,4-

diene-3,20-dione

<Triamcinolone acetonide> 0.1 g

Paraffin oil (viscosity at least

100 mPa) 10.0 g

Cetomacrogol emulsifying wax °)

(B.P. 1973, p.91) 25.0 g

Preservative solution °°)

(Pharmacopoea Hungarica VI.

Page 1 314) 1.0 g

Distilled water 58.9 g

°) and °°) see the explanation of symbols in example 1

The ointment was prepared from the above ingredients using the following procedure:

5 ml of the 1,6-bis- {5 '- [4 "- (chlor) -phenyl] -biguanido} -hexanedigluconate solution <chlorhexidine digluconate solution> 58.9 ml of warm distilled water (at 60 ° C.) were added. The combined Components of the lipoid phase, namely 10 g of paraffin oil (liquid paraffin) and 25 g of cetomacrogol emulsifying wax, were also heated to 60 ° C. on a water bath and the 1,6-bis- {5 '- [4 "- ( chloro-phenyl] -biguanido} -hexanedigluconate <Chlorhexidindigluconat> containing aqueous phase added. Stirring was continued until the mixture had cooled to room temperature, then 1 g of the preservative solution was homogenized with this ointment and the whole mixture was added in portions of the above amount of 0.1 g of micronized 9 small alpha-fluoro-11 small beta, 21 -dihydroxy-16 small alpha, 17 small alpha (isopropylidendioxy) -pregna-1,4-diene-3,20-dione <Triamcinoloneacetonid> added and to homogenized with a uniform ointment. This was left to stand for 24 hours and then passed through a three-cylinder press.

Claims (3)

1.) Topically applicable drugs with antiseptic and anti-inflammatory effects, characterized in that they a) 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione and b) 1,6-bis- {5 '- [4 "- (chloro) -phenyl] -biguanido} -hexanedihydrochloride and / or -digluconate in a weight ratio of a) to b) of 1: 1 to 1:50 as active ingredients, optionally together with 1 or more conventional pharmaceutical carrier and / or auxiliary substance (s). 2.) Medicament according to claim 1, characterized in that it has the 9 small alpha-fluoro-11 small beta, 21-dihydroxy-16 small alpha, 17 small alpha (isopropylidenedioxy) -pregna-1,4-diene-3, 20-dione [component a)] in amounts of 0.05 to 0.25% by weight and that or the 1,6-bis {5 '- [4 "- (chlor) -phenyl] -biguanido} - hexane dihydrochloride and / or digluconate [component (s) b)] in amounts of 0.25 to 2.5% by weight. 3.) Medicaments according to claim 1 or 2, characterized in that they also contain an ointment base.