IE41720B1

IE41720B1 - Fungicidal and fungistatic compositions

Info

Publication number: IE41720B1
Application number: IE2058/75A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1974-09-20
Filing date: 1975-09-19
Publication date: 1980-03-12
Also published as: NL7511001A; IE41720L; AT339471B; SU607534A3; ZA755632B; SE7510429L; CU34348A; BE833589A; DD122023A5; AU8456875A; FR2285133A1; LU73422A1; ATA719775A; DE2540799A1; AU476206B2; IL48039A0; GB1472046A; HU172247B

Abstract

1472046 Fungicidal compositions F HOFFMANN-LA ROCHE & CO AG 19 Sept 1975 [20 Sept 1974] 38528/75 Heading A5B Fungicidal and fungistatic compositions comprise a) 5-fluoro-cytosine and b) nystatin, candicidin or trichomycin in a free, esterified or N-glycosylated form or a water-soluble, physiologically tolerable salt thereof. The compositions are suitable for combating infections by fungi and yeasts of the skin, muccous membranes and gastrointestinal and genital tracts, e.g. vaginitis.

Description

The present invention is concerned with a fungicidal and fungistatic composition, a process for the manufacture thereof, pharmaceutical preparations containing same and a process for the manufacture of said preparations.

The fungicidal and fungistatic composition in accordance with the invention contains a) 5-fluorooytosine and b) nystatin, candicidin or trichomycin in a free, esterified or N-glycosylated form of a water-soluble, physiologically tolerable salt thereof.

The invention further provides a pharmaceutical preparation with fungicidal action containing such a composition together with a compatible pharmaceutical carrier material.

-Fluorocytosine is a known compound with a fungistatic and fungicidal action. Similarly, nystatin, candicidin and trichomycin are known compounds with a fungistatic and fungicidal action from the class of the polyene macrolide antibiotics. While 5-fluorocytosine is synthetically available and is obtainable in high purity with good reproducibility, nystatin, candicidin and trichomycin are obtained from biological material, i.e. from culture filtrates of various micro-organisms, especially from the genus Streptomyces (e.g. Str. noursei, Str. albulus, Str. griseus or Str. Hachijoensis). Depending on the methods of isolation or purification, the nystatin, candicidin or trichomycin are obtained with a diverse purity or biological activity they can thus have activities which, depending on origin, deviate considerably not only above but also below an official biological standard of 100% and values of, for example, over 200% can be readily attained.

Apart from being in a free form (i.e. in the naturally occurring form), the antibiotic components nystatin, candicidin and trichomycin can also be present in the form of an ester (especially a C1 to Cg alkyl ester; preferably the methyl ester) or in the form of a water-soluble, physiologically tolerable acid addition salt of such an ester. For the salt formation, there may be used the usual, physiologically tolerable organic and inorganic acids, preferably hydrohalic acids and especially hydrochloric acid. Not only the esters but also their salts possess approximately the same fungistatic and fungicidal activity as the corresponding antibiotic components in a free form and also have a better water solubility than same. The esterification of the carboxyl group of the said antibiotic components and their salt formation can be effected in a simple and known manner. The methyl ester can be manufactured, for example, by reaction with diazomethane.

Furthermore, the antibiotic components nystatin, candicidin and trichomycin can also be present in N-glycosylated form (i.e. in the form of an N-glycoside) or in the form of a water-soluble, physiologically tolerable salt of such an N-glycoside. Suitable N-glycosides include, for example, those obtained from mannose, fructose, ribose, maltose, glucuronic acid and, in particular, glucose. Inorganic or organic bases can be used for the salt formation.

The N-glycosides and their salts also possess approximately the same fungistatic and fungicidal activity as the corresponding antibiotic components in a free form and also have a better water solubility than same.

The N-glycosides and their salts can be obtained ' according to methods known per se c.f., for example, The Journal of Antibiotics 28 (1975), pp 244-245 and the literature references cited therein , Due to their fungistatic and fungicidal action, the compositions in accordance with the invention are suitable for combating infections which are caused by fungi and yeasts, for example of the genera Candida, Cryptococcus, Sporotrichum, Aspergillus or Saccharomyces. They are especially active against Candida species such as Candida albicans and are suitable principally for the local therapy or surface infections of the skin, the mucous membranes, the gastrointestinal tract and the genital tract, for example vaginitis, especially when caused by Candida. The preferred form of application is local and thus the active substance combinations can be used as pharmaceutical preparations in the form of salves, cones, suppositories, ovula or other suitable forms. 41730 The composition of the present invention is manufactured by a process which comprises mixing the two components in a manner known per se. Pharmaceutical preparations containing the active substance combination in accordance with the invention can also be manufactured in a manner known per se from the composition or the individual ingredients and with addition of customary organic or inorganic inert carrier materials and/or adjuvants such as water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure or buffers.

In general terms the process for the- manufacture of a pharmaceutical preparation according to the present invention comprises mixing a composition of the present invention or the individual ingredients thereof with a compatible pharmaceutical carrier material and bringing the resulting mixture into a suitable pharmaceutical dosage form.

Preferred compositions in accordance with the invention contain nystatin or candicidin in a suitable form and especially preferred are such containing candicidin in a suital form. In contrast to the individual components, the compositions are distinguished by a surprising synergism of the fungistatic action and fungicidal action. Thus, for example, a salve with a content of 10 mg/g of 5-fluorocytosine and 0.03 mg/g of candicidin has a significantly better chemotherapeutic influence on an experimental vaginal candidiasis of the rat than a salve with 30 mg/g of 5fluorocytosine or 0.1 mg/g of candicidin. A further surprising advantage of the compositions of the invention is that they provide a decrease in the frequency of resistance against 5-fluorocytosine.

The weight ratio of the two active components of the composition can be varied within wide limits. With 5-fluorocytosin/candicidin or a candicidin derivative, it can amount to 40-4000:1, preferably 100-400 (based on NF5 activity of candicidin); with 5-fluorocytosine/nystatin or a nystatin derivative, it can amount to 10-1000:1, preferably 20-80:1 (based on an activity of 3 u/pg for nystatin and with 5-fluorocytosine/trichomycin or a trichomycin derivative, it can amount to 20-2000:1, preferably 50-200:1 (based on an activity of 8 u/pg for trichomycin).

The d'-sage is ascertained by individual requirements, but a daily application of 1-2 tablets prepared -- according to the following Examples 1-3 for a few days represents a preferred dosage.

, The following Examples illustrate the present invention: - -.

; Example 1 Vaginal tablets containing: Candicidin (NF-activity 5 mg 2.5 mg 5-Fluorocytosine 1000 mg 500.0 mg Secondary calcium phosphate dihydrate 300 mg 400.0 mg STA-RX 1500 (directly pressable starch) 203 mg 261.5 mg Lactose (spray-dried) 100 mg 400.0 mg Polyvinylpyrrolidone K 90 30 mg 25.0 mg Citric acid (anhydrous) 5 mg 5.0 mg Magnesium stearate 7 mg 6.0 mcr 1650 mg 1600.0 mg can be prepared according to well-known methods.

Example 2 Vaginal tablets containing: Nystatin (activity 3 u/pg) 25 mg 12.5 mg 5-Fluorocytosine 1000 mg 500.0 mg Secondary calcium phosphate dihydrate STA-RX 1500 (directly pressable starch) Lactose (spray dried) 280 mg 203 mg 100 mg 390.0 mg 261.5 mg 400.0 mg Polyvinylpyrrolidone K 90 30 mg 25.0 mg Citric acid (anhydrous) 5 mg 5.0 mg Magnesium stearate 7 mg 6 .0 mg 1650 rag 1600.0 mg can be prepared according to well-known methods. Example 3 Vaginal tablets containing: Trichomycin (activity 8 u/qg) 5 mg 5-Pluorocytosine 500 mg Secondary calcium phosphate dihydrate 300 mg STA-RX 1500 (directly pressable starch) 208 mg Lactose 550 mg Polyvinylpyrrolidone 25 mg Citric acid (anhydrous) 5 mg Magnesium stearate .., ...2..311.¾ 1600 mg can be prepared according to well-known methods. Example 4 A salve for vaginal application containing: Candicidin methyl ester hydrochloride 0.25 g 5-Fluorocytos ine 10.00 g Cetyl alcohol 3.60 g Lanolin 9.00 g Petroleum jelly (white) 70.00 g Paraffin oil 7.35 g 100.20 g can be prepared according to well-known methods.

Claims

CLAIMS:

1. A fungicidal and fungistatic composition containing a) 5-fluorocytosine and b) nystatin, candicidin or trichomycin in a free, esterified or N-glycosylated form or a water-soluble, physiologically tolerable salt thereof.

2. A composition according to claim 1, containing a) 5-fluorocytosine and b) nystatin, candicidin or trichomycin in a free or esterified form or a water-soluble, physiologically tolerable salt thereof.

3. A composition according to claim 2, containing 5-fluorocytosine and nystatin.

4. A composition according to claim 2, containing 5-fluorocytosine and nystatin methyl ester.

5. A composition according to claim 2, containing 5-fluorocytosine and nystatin methyl ester hydrochloride.

6. A composition according to claim 2, containing 5-fluorocytosine and candicidin.

7. A composition according to claim 2, containing 5-fluorocytosine and candidicin methyl ester.

8. A composition according to claim 2, containing 5fluorocytoslne and candicidin.methyl ester hydrochloride.

9. A phannaceutical preparation with fungicidal action containing a composition according to claim 1, together with a compatible pharmaceutical carrier material.

10. A pharmaceutical preparation with fungicidal action containing a composition according to any one of claims 2 to 8 inclusive, together with a compatible pharmaceutical carrier material.

11. A process for the manufacture of a composition according to claim 1, wherein the two ingredients are mixed with one another in a manner known per se. - 8 41720

12. A process for the manufacture of a composition according to any one of claims 2 to 8 inclusive, wherein the two ingredients are mixed with one another in a manner known per se. 5

13. A process for the manufacture of a preparation according to claim 9, wherein a composition according to claim 1 or the individual ingredients thereof are mixed with compatible pharmaceutical carrier material and the resulting mixture is brought into a suitable pharmaceutical 10 dosage form.

14. A process for the manufacture of a preparation according to claim 10, wherein a composition according to any one of claims 2 to 8 inclusive or the individual ingredients thereof are mixed with compatible pharmaceutical

15. Carrier material and the resulting mixture is brought into a suitable pharmaceutical dosage form.