HU217087B - Process for preparing antimycotic synergic pharmaceutical composition - Google Patents

Abstract

The present invention relates to a method for producing a synergistic, anti-keratogenic, anti-steroidal drug composition comprising 40 to 55% by weight of potassium peroxide, 0.1 to 1% by weight of general formula I derivative, wherein X1 and X2 are preferably iodine, and 40-60% by weight of ointment blenders are blended with auxiliary excipients. ŕ

Description

The present invention relates to a novel keratolytic synergistic pharmaceutical composition having antifungal activity.

It is well known that the elimination or treatment of infections, mycoses, due to reduced skin defenses is not an easy task. For the treatment, preparations containing various organic and inorganic active substances and various plant extracts are used. Today's therapy for a single mycosis or corneal disease requires a minimum of 3-4 weeks, but may take several months, even with topical and systemic combination therapy.

Various solutions are known in the art for the preparation of dermatological inhibitors for dermatology, however, these agents are highly aggressive drugs such as natamycin, nystatin, griseofulvin and others, as well as complex synthetic compounds such as terbinaf, to achieve the desired effect.

However, these potent formulations have several unpleasant side effects. Thus, gastrointestinal complaints, protein urination, allergic reactions or photosensitivity have been frequently reported as a side effect of their use. Most of these formulations are unlikely to be used during pregnancy, high doses inhibit cell proliferation and long term use may cause liver and kidney damage. A further disadvantage is that significant results can be observed only at longer application times.

It is therefore an object of the present invention to provide a pharmaceutical composition that reduces or stops the spread of fungal infections even after early, topical treatment and, by virtue of its keratolytic action, softens and cures the infected cornea.

In our initial experiments we tried to cure fungal nail disease and lesions using inorganic iodides. One of these agents, namely potassium iodide, is described in the literature in various ways; thus, according to the data, six

- in arteriosclerosis, it reduces or prevents atherosclerosis by promoting the dissolution of cholesterol in the serum;

- strongly increases bronchial secretion in allergic and spasmodic catarrhs, asthma;

- due to its lipoid colloid solubility, it increases the dispersion of colloids, iodine accumulates in abnormal tissues and promotes their dissolution.

However, according to the literature, potassium iodide is not absorbed through the skin (see Issekutz, B., Pharmacology, 3rd edition, Budapest, Journal of Health, page 473).

Thereafter, our attention turned to various oxyquinoline derivatives. For example, Hungarian Patent Nos. 106,906, 147,445, 149,712, 15,302, and 171,736 disclose various oxyquinoline derivatives substituted with one or more halogen atoms. antifungal effect.

Surprisingly, however, it has been found that potassium iodide, which is otherwise poorly absorbed, is mixed with a quinoline compound of the formula I in which X and X ₂ are halogen, preferably iodine, in a specific weight ratio, supplemented with carriers and carriers to produce an effective composition.

In our experiments, we have found that the weight ratio of potassium iodide to quinoline compound is 100: 0.2-100: 2.

Preferred compounds of formula I are 5-chloro-7-iodo-8-hydroxyquinoline or 5,7-diiodo-8-hydroxyquinoline.

The present invention therefore provides a process for preparing a keratolytic, antifungal, synergistic pharmaceutical composition by:

40-55% by weight of potassium iodide,

0.1 to 1% by weight of a quinoline derivative of the Formula I wherein X ₁ and X _{2 are} halogen, preferably iodine, and

40-60% by weight of a conventional carrier, auxiliary excipient is formulated.

In a preferred embodiment of the invention, weight percent potassium iodide,

0.2% by weight of 5-chloro-7-iodo-8-hydroxyquinoline,% by weight of white petroleum jelly,% by weight of paraffin oil and 9.8% by weight of distilled water are obtained to give an excellent formulation.

In our effect studies, it has been found to be a composition prepared by the process of the present invention

containing 50% by weight of potassium iodide and 0.2% by weight of 5-chloro-7-iodo-8-hydroxyquinoline as active ingredient (see Example 1), 10 to 14 days for onychomycosis of the nails after treatment, the fungal nail area softens and can be removed if desired. The product does not affect the intact nail area. (Naturally, they should not be used by iodine-sensitive people.) Nails that grow at the site of the removed nail are healthy, free from infection.

The treatment was performed on 20 subjects and evaluated according to the following criteria:

- erythema,

- peeling,

- scab formation,

- hydration,

decay and

- itching.

Experiences:

- At the end of the first week, 50% of patients had their nails detached after a brief soak in warm water. In areas where the cream was in contact with intact skin, mild redness was observed in 1 patient.

- By the end of the second week, 100% of the patients had their nails removable. Mild erythema was observed in 15% of patients.

Follow-up: Medial culture from samples of new nail growth from the third week of treatment

Microbiologically negative test results were obtained by weight 28% by weight 7% by weight 5% by weight.

Comparative Experiment 1

The latest and most effective formulation of this type is Lamisilja (active ingredient: terbinafine, chemical name: (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) -hept2-ene-4) from Sandoz. inyl-1-amine hydrochloride, first publication:

European Patent No. 587]. When using Lamisil for onychomycosis when co-administered with an oral tablet, according to our own studies, only 82% of patients will be microbiologically negative by the end of month 3. In contrast, in our experiments, the composition of the invention (Example 1) is microbiologically negative after 3 weeks. 15

Comparative Experiment 2

Verification of synergistic additive effect:

The following experimental set-up was used to treat foot onychomycosis:

Composition: 20 potassium iodide (active ingredient) white petrolatum paraffin oil distilled water

Composition of preparation B:

5-Chloro-7-iodo-8-hydroxyquinoline (active ingredient) white petrolatum paraffin oil 15% w / w distilled water Composition C:

see Example 1.

Fifteen patients were included in the study (syndrome: onychomycosis of the nail); 5-5-5 persons, treated with preparations A, B 35 and C.

Evaluation of results:

For the preparation: By the end of week 2, the patients' nails were removable. In three cases (60%) redness was observed. Treatment 40

Only 60% of the samples from the new nail section growing out after week 3 were negative in culture medium.

For formulation B: The extent of fungal growth decreased by the end of week 4 but did not disappear, so treatment was continued for another 2 weeks. By the end of Week 6, only one patient (20%) had a microbiologically negative specimen taken from the newly removed nail section.

For formulation C: By the end of Week 1, 60% of patients had nails removed. THE 2.

crowd%

By the end of the week, the ratio improved to 100% by 76.5% by weight, 15% by weight, by the end of the week. The grown nails were healthy and 100% microbiologically negative.

It can thus be concluded that there is an additional synergistic effect of preparation C, which was not expected.

The process of the invention is illustrated by the following examples:

Example 1

5-Chloro-7-iodo-8-hydroxyquinoline Potassium iodide White petroleum jelly Paraffin oil Distilled water

Example 2

5,7-diiodo-8-hydroxyquinoline

Potassium iodide White petroleum jelly Paraffin oil Provides distilled water

Example 3

5-Chloro-7-iodo-8-hydroxyquinoline Potassium Iodide White Vaseline Paraffin Oil

0.2 g

50.0 g 32.0 g 8.0 g

To 100.0 g

0.25 g 40.00 g 40.00 g

10.00 g

Made up to 100.00 g

0.30 g

45.00 g 39.70 g 15.00 g

Claims (2)

PATENT CLAIMS A process for the preparation of a synergistic pharmaceutical composition having a keratolytic, antifungal activity, comprising: 40-55% by weight of potassium iodide, 0.1 to 1% by weight of a quinoline derivative of formula I wherein X and X _{2 are} halogen, preferably iodine, and 40-60% by weight of auxiliary excipients conventional in ointment formulation. A process according to claim 1, characterized in that 50% by weight of potassium iodide, 0.2% by weight of 5-chloro-7-iodo-8-hydroxyquinoline, 30% white petroleum jelly, 10% by weight of paraffin oil and 9.8% by weight of distilled water is mixed.