ANTIMYCOTIC SYNERGISTIC PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THE PREPARATION THEREOF

Abstract: Antimycotic synergistic pharmaceutical compositions comprising nystatine and a 2-lower alkyl-l, 4-naphthoquinone or an addition product thereof in admixture with suitable inert pharmaceutical carriers. The invention also relates to a process for the above compositions by admixing the active ingredients with suitable inert carriers. It is preferred to use 2-methyl-1, -naphthoquinone or the sodium bisulfite adduct thereof. The ratio of the active ingredients is preferably 20.000 to 100.000 IU of nystatine for 1 mg of 2-methyl-1,4-naphthoquinone-sodium bisulfite adduct. The compositions show strong synergism in the treatment of infections caused by Candida albicans and Trichomonas vaginalis and are active against resistant strains too. The compositions may be finished in forms suitable for topical use, such as suppository, aerosol, jelly or vaginal tablets.

Description: ANTTMYCOTIC SYNERGISTIC PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THE PREPARATION THEREOF TECHNICAL FIELD The invention relates to aπti ycotic syπergistic pharmaceutical compositions and a process for the pre¬ paration thereof. BACKGROUND ART It is known that nystatine is an antibiotic having antimycotic effect and produced by the microorganism strain Streptomyces noursei. It is also known that compositions containing nystatine and 8-hydroxy-quinoline possess strong antimycotic activity (British Patent No. 1.143.998). It i3 known furtheroπ that some 1, —naphthoquiπona derivatives exhibit certain antimycotic activity [Br. 0. Pharmac. 40,' 871-770 (1970)]. It is the object of the present invention to provide aπdi ycotic compositions which surpass on the one hand the activity of the known compositions and are active on the other against resistant strains as well. DISCLOSURE OF THE INVENTION The present invention relates to an antimycotic synergistic pharmaceutical composition comprising nystatine and a 2-lower alkyl-l,4-naphthoquinone or an addition product thereof in admixture with suitable inert pharmaceutical carriers. The present invention also relates to a process for the preparation of an antimycotic synergistic pharmaceutical composition which comprises admixing nystatina and a 2-lower alkyl-l,4-naphthoquiπone or an addition product thereof with suitable inert pharmaceutical carriers. The present invention is based on the recognition that there is a synergistic interaction between nystatine and 2-lower alkyl-l,4-naphthoquinone3 which results tnat in the composition of the present invention the active in¬ gredients exert their desired antimycotic effect in a smaller concen ration than when used per se. The term "lower alkyl" used throughout the specification relates to straight or branched chain alkyl groups having 1-4 carbon atoms (e.g. methyl, ethyl, π-propyl, isopropyl, n-butyl, isobutyl etc.). As 2-lower alkyl-l,4-naphthoquinona component preferably the 2-methyl-l,4-naphthoquinone or 2-ethyl- 1,4-naphthoquiπone, particularly the 2-methyl-l,4- πaphthoquinone can be used. The addition product of the ' 2-lower alkyl-1,4- naphthoquinone may be any suitable and conventional adduct formed by carboπyl compounds, particularly a sodium bisulfite adduct. The compositions of the present invention contain preferably from 20.000 to 100.000 IU (international units) of nystatine on 1 mg of 2-methyl-l,4—naphthoquinon or an equivalent amount of an other 2-lower alkyl-1,4- naphthoquinone or an addition product thereof. According to a preferred embodiment of the present invention there are provided antimycotic synergistic compositions.comprising .as active ingredient 1 mg of 2-methyl-l,4-naphthoquinone sodium bisulfite adduct and 20.000-100.000 IU. gf. nystatine. -The .compositions of the present invention can be finished preferably in forms suitable for topical (local) use particularly in the form of suppositories, aerosol, jelly, and. vaginal tabletsj the vaginal tablets proved to be particularly advantageous. The compositions of the present invention are prepared by methods of pharmaceutical industry known per se by using conventional solid or liquid carriers. Suppositories are prepared by using usual suppsitory bases which are soluble in body fluid and melt at body ~ 3 - ture. AΞ soluble in ' body fluids Massa athani iscularly preferred. The composition D repa ' red moulding (casting) method. The Llic suppy base is melt, in a small portion 5 the actiredients are suspended an " d the Ion is do forms in a suitable apparatus i with aated stirrer. The suppositories if the cconal torpedo-shaped- form or ■ d ovula 10 positormeltiπg at body temperature may used, sAdeps solidus (Witepsol 35) or 't ter. "positories can be prepared by the •or presocedurεs by methods known par se . aerosαsitions can also be prepared by 15 , πknown pi With the aid of non-ionic sur- 1 an oilar type emulsion is prepared the itty phaβof being 15-25 - As fatty phase Ulsificaioπicum ( " see VI. Hungarian Pharmaco- pn be us3 active ingrβdents are dispersed 20 isady em The system th ' s obtained, which iof any tations due to he viscosity tl is ' filo ah aerosol flsk and set under tfsure ' ofable " prόpeϊlaπt ' For this purpose c πai " prts " can be used ,g. "the ' haloganated 25 h* fl ons '"' (F ' or Freon 114). "" •' • * vaαiriats contain cϋn ' vrfiσnal carriers (& . rch, 1 auxiliary " age n- etc. • ).- ••* The ta; a n ' be d by dry or wetiranulating methods. Into obttable homόgenei ' r it is ' pr ' eferred to 30 usγ e ett is expedient t add ^ β sintegrating agid auxigents (e.g. talc magneium stearate, ae o thees prior to formng th β tablets. As denting preferably Polyp Jasdon β' L, Esι,g and 1 ' can be used. 35 activeients can also be formers semi- so'positig. ointment). As mineral oil fractions, hydrogenatεd or non-hydrogenated triglycerides and- oils of animal or vegetable origin and jellies of hydrophobic polymers of synthetic or semi-synthetic * origin can be used. The active ingredients are distributed in the carrier by suspending the same. The ointments can be preferably filled in tubes having an elongated discharge opening. According to a preferred embodiment of our invention there are provided pharmaceutical compositions comprising pro 1 g composition 100.000 IE of nystatine and 1,85 mg of 2-methyl-l,4-naphthoquinone or an equivalent amount of an other 2-lower alkyl-l,4-naρhthoquinoπe or an addition product thereof. The compositions of the present invention are suitable for the treatment of leukorrhoea (fluor) and infections caused by Candida albicans and Trichomonas vaginalis. Until the twentieth weak of pregnancy the compositions are active in the treatment of leukorrhoea (fluor), trichomoniasis and oidiomycosis (thrush, soor) and when administered to patients taking oral anri- conceptive pills the compositions of the present inventio stop chronical leukorrhoea (fluor) and eliminate the susceptibility for infections. The synergistic activity of the compositions of the present invention is shown by the following tests: IN V TRO TEST Candida albicans and Trichomonas vaginalis strains are cultured in a liquid nutrient medium. Incubation is carried out at 37 °C for 48 hours. Each nutrient medium (10 ml) is inoculated with 1000 germs pe r ml. The number of germs is determined in a Bϋrker chamber. Dilution series are prepared from the stock inoculum by using a physiological sodium chloride solution. To the mixture of the nutrient medium and 0,5 ml a physiological sodium chloride solution 2-methyl-l,4-naphthoquinoπe, - 5 - nystatine and mixtures thereof are added. It has been found that 2-me hyl-l,4-naphthσσuinoπe inhibits the growth of Candida albicans and Trichomonas vaginalis in a minimal inhibitory concentration of 5 mg/10 ml. When used in a smaller concentration it is completely inactive. The minimal inhibitory concentration of nystatine is determined in the manner disclosed above. 1,25 rng/10 ml of 2-methyl-l,4-naphthoquiπone is added to an amount of nystatine being the one fiftieth (1/50) part of the minimal inhibitory concentration. Complete inhibition of the growth of Candida albicans and Tricho¬ monas vaginalis was observed. This means that 2-methyl-l,4-naphthoquiπoπe, when used in a concentration being completely inactive per se, strongly potentiates the effect of nystatine. IN VIVO TEST Patients suffering of vulvovaginitis candidomyce ica are treated with suppositories according to Example 1. As control suppositories containing no 2-methyl-l,4- πaphthoquinone-sodiu sulfite adduct but nystatine only are used. The results are summarised in the following Table. Number of patients 35. Test compound Recovery in % of the cases 2-methyl-l,4-naphthoquinone- sodium bisulfite adduct + nystatine 88 nystatine 56 INDUSTRIAL APPLICABILITY The compositions according to the present invention can be used in therapy for the treatment of infections caused by Candida albicans and Trichomonas vatiπalis. In clinical tests they proved to show a high synergistic p U' •'* • " • -22 effect in the treatment of vulvovaginitis candido- mycetica. The duration of the treatment depends on various factors e.g. the type of infection, the condition of the patient etc. It can vary between wide ranges and is preferably 10-12 days. BEST MODE OF CARRYING OUT THE INVENTION Further details and the best modes for c ' arrying out the invention are shown in the following Examples without limiting the scope of protection to the said Examples. ExamDle 1 Suppositories of the following composition are prepared: Component Amount Sodium bisulfite adduct of 2-methyl-l,4- naphthoquinone 5 mg Nystatine 100.000 IU Vehiculu • 2.75 g The vehiculum (Massa polyoxyethaπi) i3 melt on a water bath at 45-50 °C. In a small portion of this vehiculum at first the sodium bisulfite adduct of 2- methyl-l,4-naphthoquinona and thereafter the nystatine are suspended and the mixture is quickly poured into forms at the above temperature in a suitable conventional apparatus. ' The casting forms are couled with water. The suppositories are removed from the forms and packed under the exclusion of air. Example 2 Suppositories of the following composition are prepared : Component Amount Sodium bisulϋte adduct of 2-methyl-lV4- naphthoquiπone 5 mg Nystatine 250.000 IU Vehiculum • 2,7 g The vehiculum (cocoa butter) is melt on a water bath at 40 °C and the active ingredients are suspended in a small amount thereof. The suppositories are formulated in an analogous manner to the process described in Example 1. As vehiculum in the place of cocoa butter Adeps solidus (Witepsol 35) can be used too which is malt at a temperature between 40 °C and 45 °C. Examole 3 5 mg of 2-methyl-l,4-naphthoσuinone sodium bisulfite adduct and 200.000 IU of nystatine are continuously admixed with small amounts of cocoa butter. The homogenised mixture is pressed into suppositories with the aid of an Eagler machine. Example 4 An emulsion is prepared from the following components : Component per 100 σemulsion Ung. e ulsificaπs non-ioπicum 20 g Distilled water ad 100 g The composition of the Ung. emulsificaπs non- ionicu is as follows: Sorboxaethanum steariπicum 10 % Liquid paraffine 10 % Cetyl stearyl alcohol 30 % Vaseline album - 8 - The non-ionic e ulsifier is prepared by admixing the components on- a water bath and stirring the mixture until it gets cold: 20 g of a suppository base meeting the requirements of pharmacopoiea and 50 g of water are converted on a water bath into an oil-water type emulsion and cooled to 20 C. The active ingredients (92,5 mg of the sodium bisulfite adduct of 2-methyl-l,4-naphthoquiπone and 5.000.000 IU of nystatine) ars suspended in 20 g of water and the suspension is admixed with the emulsion prepared above. No components precipitate from the viscous sys tern. The mixture thus obtained is filled into an aerosol flask under atmospheric pressure and then set under Freoπ pressure. The propellant used is of the following composition : Frsoπ 12 ~ Freon 114 SO 0/ The composition leaves the flask as a foam. Example 5 Vaginal tablets having the following composition are prepared : Component Amount Sodium bisulfite adduct of 2-msthyl-l,4- naphthoquinone 185 mg Nystatine 10.000.000 IU Lactose 60 g Potato starch 30 g Polyvidoπum 5 g Polyplasdoπ-Xl 1.5 g Talc 3 g Magnesium stearate 2 g Aerosil 1 g - Q _ " granulated with the aid of a sufficient amount of poly- vinyl pyrrolidoπe dissolved in S6 % ethanolj in the said alcoholic solution the active ingredients were previously suspended. The granules are dried at a temperature below 25 C (in a fluidisation drier) and the homogenised and sieved mixture of the other additives (Polyplasdoπ-XL, talc, magnesium stearate and aerosil) is added thereto. The mixture thus obtained is pressed into tablets weighing 2 g. The trade marks and commercial names used throughout the specification relate to the following products: Adeps solidus: a mixture of mono-, di- and triglycerides of saturated carboxylic acids (from C 11 H 23 C00H t0 C T7 H 35 C00H )« (Ph.Hg.VI.) Cocoa butter: this is a mixture of the fatty t iglycerides pressed from the roasted and peeled cocoa grains. (Ph.Hg.VI.) Polyplasdonβ XL = polyvinyl pyrrolidoπe Esmospreng - formaldehyde-caseine Pri ojel = carboxymethyl starch Massa polyoxyethani = ■ polyoxaethanum stearinicum 90 % polyoxaeth. - 4000 5 % polyoxaeth. - 1540 5 % Polyoxaeth. stear. -* polyoxethane stearate H0-CH 2 -(CH 2 -0CH 2 ) n -CH 2 -CO0-(CH^- [s -CH 3 n is an integer between 2 and 40 (average),' (average molecular weight : 2075) Polyoxaethanum-4000-polyoxyethylene-4000 H0-CH 2,-(CH2--0-CH2)π-CH2-OH n β about 90 (average) (molecular weight 3500-4400) Polyoxaeth. 1540 « polyoxyethylene-1540 H0-CH 2 -(CH 2 -0-CH 2 ) n -CH 2 0H n = about 34 (average),* (molecular 21 PCT. ' HU80/0000.-. - 10 - weight 1400-1600). Aerosil » . acidum silicicu colloidale (colloidal silicium dioxide) Polyvidonum β polyviπyl pyrrolidoπe Amylum solaπi «- potato starch The additives and carriers used in the Examples meet the requirements of the VI. Hungarian Pharmacopoea (Ph, Hg. VI.). 'jl' y~ — Λ * U τ '71

Claims: WHAT WE CLAIM IS. 1. Antimycotic synergistic pharmaceutical composition comprising nystatina and a 2-lowar alkyl-1,4- naphthoquinoπe or an addition product thereof in admixture with suitable inert pharmaceutical carriers. 2. Composition according to Claim 1 which comprises 2-methyl-l,4-naphthoquinone as 2-lower alkyl-l,4-naphtho- quinoπe. 3. Composition according to Claim 1 which comprises a sodium bisulfite adduct as addition product. 4. Composition according to any of Claims 1 to 3,- which comprises 20.000 to 100.000 international units (IU) of nystatine for 1 mg of 2-me thyl-l,4-naphthoquinone or an • equivalent amount of an other 2-lower alkyl-l,4-πaphtho- quinone or an addition product thereof. 5. Composition according to any of Claims 1 to 4 which comprises being finished in a form suitable for topical (local) treatment',' preferably suppositories, aerosol, jelly or vaginal tablets. 6. Process for the preparation of antimycotic synergistic pharmaceutical compositions according to Claim 1 which comprises admixing nystatine and a 2-lower alkyl- 1,4-naphthoquinσne or an addition product thereof with suitable inert or liquid pharmaceutical carriers. 7. Process according to Claim 6 which comprises using 2-methyl-l,4-naphthoquiπone as 2-lower alkyl-1,4- naphthoquinoπe . 8. Process according to Claim 5 which comprises using a sodium bisulfite adduct as addition product. 9. Process according to any of Claims 6-8 which comprises using 20.000 to 100.000 IU of nystatine for 1 mg of 2-methyl-1 ' ,4-πaphthoquinone or an equivalent amount of an other 2-lower alkyl-l,4-naphthoquinone or an addition product thereof. . Process according to any of Claims 6-3 which Cθ3 finishing the pharmaceutical compositions in S3uitable for topical (local) administration, ' PDly as suppositories', ' aerosol, jelly or vaginal ta,

Inventors: KOVACS ANDRAS, NEMES JOZSEF, NGYKALDI ATTILA, SZEBENI RUDOLF
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, KOVACS ANDRAS, NEMES JOZSEF, NGYKALDI ATTILA, SZEBENI RUDOLF
Application year: 1980
Main classification: A61K31
IPC codes: A61K31