Balázs, János

Erős, István

Péter, I.

Tacsi, M.

English

Balázs János

Erős István

Tacsi M.

Péter I.

University of Szeged

Acta Ph.ys. et Chem. Szeged 34 121-133 (1988) 121 DRUG-CONTAINING MULTIPLE-PHASE EMULSIONS By J. BALÄZS1, I. ERÖS2, M. TACSI2 and I. PÉTER1 ' Department of Colloid Chemistry, József Attila University Szeged, Hungary 2 Department of Pharmaceutical Technology, Albert Szent-Györgyi Medical University, Szeged, Hungary (Received 15 June 1988) We studied the effectiveness of the formation (of w/o/w emulsions as a function of composition and mixing time. We found that concentration of emulsifier I, the concentration and HLB of emulsifier 2, the viscosity of the oil phase and the external water phase as well as the mixing time in step two of making the emulsion characteristically influence the ef-fectiveness of emulsification and the stability of the emulsions. Introduction The "complex" emulsions (multiple phase emulsions, dop-pelte Emulsionssysteme) are disperse systems in which the disperse phase contains droplets of the external (coherent) phase. Two types are known:' "water-in-oil-in-water" (w/o/w) and "oil-in-water-in oil" (o/w/o) [1]. INDEX As concerns the structure of w/o/w emulsions, water droplets in an oil coating are present in a coherent water phase (w2 phase, "external" water phase) [2,3] (Fig. 1). The prospective uses of these systems justify investiga-tions of their formation, properties and stability. Hungarian research in this field began only recently [4,5]. So far, the chemical industry, the food industry and the drug industry apply complex emulsions [1]. Their use as drug delivery systems seems especially important and promising. pnmoryldispersedj aqueous phase oil phase oil layer emulsifiei I-ernulsifier t l outer/continuous) aqueous phase 1st step 2nd ¿tep Figure 1.: Two-step procedure for emulsification and struc-ture of w/o/w emulsions [3]. Their application in pharmaceutics is based on their follow-ing favourable properties [6-8]: - protection of an agent dissolved in an internal water (or oil) phase is ensured, - a prolonged effect can be achieved, - in cases of overdosing, they have a detoxicating effect. w/o/w and o/w/o emulsions have so far been used with more or less success.in the formulation of vaccines, anal-getics and antiphlogistics, hormone preparations, antitumour INDEX agents, antibiotics and morphine antagonists [6-12]. For the production of stable w/o/w emulsions, the fol-lowing are necessary: - a non-ionic emulsifier with a low HLB value in a relatively high concentration (in order to form a w/o emulsion), - an emulsifier with a high HLB value in a relatively low concentration (ensuring dispersion of the w/o emulsion in the coherent water phase), - a suitable volume of the w/o emulsion withing the complex emulsion [2, 3., 12]. The aim of our investigations was to develop a stable w/o/w emulsion. Our primary task was to elucidate the rela-tionship between the composition, and especially the con-centrations of the two emulsiflers, and the result of emulsi-fication. We set out to improve the stability (at the optimum composition) by increasing the viscosity Of the external water phase and by thickening the oil phase. A further aim was to learn, whether a stable w/o/w emulsion is suitable as a drug delivery system. At what rate and in what quantities is the active substance liberated from the complex emulsions? The present paper reports on studies concerning the ef-fectiveness of production of w/o/w emulsions. Materials and methods w/o/w emulsions were made from liquid petrolatum (Paraffinum liquidum, satisfying Ph.Hg.VI), Span 80, Span 20 and Tween 80 (Atlas GmbH, FRG). The viscosity of the external water phase was improved with hydroxyethyl-cellulose (Cellosize QP, Union INDEX Carbide, USA). The oil phase was thickened with ceresine. Emulsions were prepared in a two-step procedure [2,3]. In the first step. Span 80 (lipophilic emulsifier) was dissolved in liquid paraffin, after which water was emulsified in it by mechanical stirring at an even rate. The internal water phase of the model emulsions was a 10 ' mol dm 3 potassium chloride solution; the drug-containing emulsions contained 1 mass per cent of ephedrinlum chloride solution. In the second step, the w/o emulsion obtained in this way was emulsified in an aqueous solution of Tween 80 (hydrophilic emulsifier) or a Tween 80-Span 20 mixture. Investigation of "efficiency" of formation of emulsions The efficiency of formation of the complex emulsion was determined as the proportion of chloride ions added to the internal water phase which penetrated into the external water phase: c . - measured h r efficiency (%) = — 100 (1) CKC1 Chloride ion concentration was measured with a Radelkis 0P-CI-0711 P membrane electrode and a Radelkis OR-205/1 preci-sion pH and voltage-meter immediately after emulsification and after different periods of waiting. INDEX Investigation of drug release The liberation of ephedrinium chloride dissolved in the internal water phase was studied by the membrane dialysis method (leading to equilibrium). A synthetic membrane was attached to one end of the dialysing tube, and a constant volume of emulsion was measured on it. The tube was placed in a flask containing 20.0 ml distilled water at body tempe-rature. The membrane just touched the surface of the water. This apparatus was placed in a thermostat at 305 K. The amount of ephedrinium chloride that passed through the mem-brane was measured with a Spektromom 195 spectrophotometer at 290 nm. Examination of the liberation of the agent was also found .to be suitable for numerical characterization of the efficiency of emulsification. In agreement with the lit-erature, a linear correlation was obtained between the amount of ephedrinium chloride measured in the dialysis liquid (Q) and the square root of the time of dialysis (t) [14]: Q = a /t. (2) a is the rate of liberation of the agent. We determined the rates of liberation of the drug from the w/o emulsion and from a w/o/w emulsion that contained ephedrinium chloride in the external water phase. If the two steps of emulsification were perfect, then the rate of dialysis would be rate of liberation of drug from the w/o emulsion. If no w/o/w emul-sion was formed in step 2, but all of the agent passed into the external water phase, then the rate of drug release would be that of a w/o/w emulsion in which the agent was al-ready dissolved in the external water. Therefore, if we con-sider the first 100 and the latter 0 % emulsifications, with INDEX a known rate constant of dialysis, we can determine the ef-ficiency of the emulsion formation by means of a nomogram (calibration line, Fig. 2)-. Figure 2.: Efficiency of emulsification determined via rate of dialysis Rheological examinations Rheological measurement (leading to flow and viscosity curves) were made with a Rheotest-2 and a Hôppler rheovisco-simeter at 298 K. Results and discussion 1. Effect of composition on effectiveness of emulsification The effectiveness of formation of w/o/w emulsions is mainly influenced by the amount of lipophilic emulsifier [1-3]. In the studies on the production of stable emulsions, INDEX the amount of lipophilic emulsifier was varied at constant amount of hydrophilic emulsifier and volume ratio. It can be seen from Fig. 3 that the effectiveness of emulsification increased with the concentration of emulsifier 1, but even in the presence of 20 % lipophilic emulsifier only 70 % com-plex emulsion was formed. Figure 3. shows the correlation between the volume ratio.and effectiveness. The effectiveness of emulsification increased with increase of the volume of the o/w emulsion. Figure 3.: Effects of concentration of lipophilic emulsi-fier (I) and volume fraction (II) on formation of w/o/w emulsions In the next phase, the concentration of the second emulsi-fier (Tween 80) was also changed. Figure 4 shows an inter-esting phenomenon. In the presence of 0.1 % hydrophilic emulsifier, emulsification was complete, but then not a liquid emulsion, but a cream-like substance with a specific structure was formed.' An increase of the amount of the hydro-philic emulsifier sharply reduced the effectiveness of emulsification until a minimum was reached. Further increase of the concentration led to a maximum in the graph of the function. On increase of the concentration of the lipophilic INDEX Figure 4.: Effect of emulsifier 2 concentration on forma-tion of w/o/w emulsions emulsifier, the maximum is situated at lower and lower con-centrations of emulsifier 2. The HLB value of the hydrophilic emulsifier also in-fluences the effectiveness of emulsification: the correla-tion between HLB and effectiveness exhibited a maximum. With' increase of the concentration of emulsifier 1, the optimum HLB shifted towards higher values. Figure 5.: Effect of HLB on formation of w/o/w emulsions INDEX 2. Drug release from w/o/w emulsions. Evaluation of ef-fectiveness of emulsification via.rate of dialysis The emulsion deemed most suitable on the basis of its effectiveness was used to prepare a drug-containing emulsion. One mass per cent of ephedrinium chloride was dissolved in either the internal or the external water phase. TKfe process of liberation of the agent was studied (Fig. 6). In this series of experiments the stability of the emulsions and the effectiveness of emulsification were closely connected: the rate constant of the 8-hour dialysis was determined and used to calculate the effectiveness of emulsification via Fig. 2. The effectiveness determined in this was characterized the stability. If the rate of dialysis was low (i.e. not higher than the rate of the w/o emulsion), then emulsification was successful and the emulsion remained stable for 8 hours. T—| I I—I—I—I—I—I—r ; j t i » 2o Time iHourst Figure 6.: Drug release from w/o/w emulsions INDEX The effectiveness of emulsification was found to fc>6 in-creased considerably by an increase of the viscosity of the oil phase (addition of ceresine). Increase of the viscosity of the continuous water phase with hydroxyethyl-cellulose had less effect .on the stability. The duration of emulsifica-tion was of vital importance: mixing for a longer time than optimum "or just necessary destroyed the w/o/w emulsion (Tab-le I) . Investigation of the relationship between the stability values calculated on the basis of dialysis and the results of ion-selective membrane electrode examinations is continuing. Table I Effectiveness of formation of w/o/w emulsions COMPOSITION EFFICIENCY (%) Base 10 g Span 80 in 100 g w/o 'emulsion emulsion 1 g Tween 80 in 100 g w/o/w emulsion 67,9 0,4 volime fraction (w/o in w/o/w) Increase of 0 t ceresine 67,9 viscosity 5 % ceresine 78,0 of oil phase 10 % ceresine 79,9 Increase of 3 % HEC 75,9 viscosity of 4 % HEC 74,3 continuous 5 % HEC 75,4 w phase Time of 1 minute 80,9 2nd step 3 minutes 63,3 (mixing time) 5 minutes 40,4 INDEX 3. Rheologiaal investigation of w/o/w emulsions The development of w/o/w emulsions from w/o emulsions involves important rheological changes. From the structurally viscous w/o emulsion with high viscosity, ideally viscous systems with much lower viscosity are formed (Fig. 7). 1600-1400-1200-£ £ iooo-too-a l> 5 6 oo-<00-200 \ w / o emulsion ToTo Ho ib Shearing stress (Po ) w/o/w emulsion o o — o — 0 10 20 JO <0 S Jo i Shearintj stress IPo) Figure 7.: Viscosity curves of w/o and w/o/w emulsions Dissolution of the polymer in the external water phase increases the viscosity of w/o/w emulsions (Fig. 8). Comparison of the viscosity curves of the emulsions made with different mixing times (Fig. 9) proved our assump-tion that, during a long mixing time, w/o/w emulsions under go transformation into simple o/w emulsions. The viscosity INDEX K co-1710-1000-o £ eoo-o 600-i00-200-~I0 To To i'O 50 S % HSC o < v. use 3 •/. HEC ^ Shearing stnrss {Po Jt Figure 8.: Effect of hydroxyethyl-cellulose (HEC) content on viscosity of w/o/w emulsions 10 -h jt & 3o i0 7b Shearing stress i P o j Figure 9.: Effect of mixing time (2nd step) on viscosity of w/o/w emulsions of a w/o/w emulsion made by mixing for 5 minutes is about half that of an emulsion made by mixing for 1 minute. INDEX References [1] Attuood, D. and A.T. Florence: Surfactant Systems. Their Chemistry, Pharmacy and Biology. Chapman and Hall, Lon-dón. New-York, 1983. pp. 509-519. [2] Matsumoto, S., Y. Koh and A. Michiura: J. Dispers. Sei. Technol. 6, 507 (1985). [3] Matsumoto, S Y . Kita and D. Yonezawa: 1. Coll. Inter-face Sei. 57, 353 (1976). [4] Balázs, J., I. Erős, M. Tacsi and I. Péter: 1st Interna-tional Congress on Cosmetics and Household Chemicals 1 Abstracts 108, Budapest, 1987. [5] Erős, I.j J. Baldze and Sz. Mueztafa: ibid 104 [6] Brodinj A.F., D.R. Kavaliunae and S.G. Frank: Acta Pharm. Suec. J15, 1 (1978). [7] Brodin, A.F. and S.G. Frank: ibid 15, 111 (1978). [8] Mcrimotoj Y., K. Sugibajashi and Y. Yamaguchi: Chem. Pharm. Bull. 27, 3188 (1979). [9] Schichiri, M.j Y. Shimuzu: Diabetologica 1_0, 317 (1974). [10] Murani8hi, S.j Y. Takahashi, M. Ha$hida and H. Sezaki: J. pharm. Dyn. 2, 383 (1979). [11] Tomitaj W.j Y. Abe and T. Kondo: J. pharm. Sei. 71̂ , 332 (1982). [12] Abd-Elbary, A., S.A. Noyr and F.F. Mansour: Pharm. Ind. 46, 964 (1984). 3 [13] Mat8umoto, M. : Formation and Stability of Water-in-Oil--in-Water Emulsions. In Macro and Microemulsions: Theory and Applications (Ed.s D.O. Shah). American Chemical Society, 1985. pp. 415-436. [14] Thoma, K.: Dermatika. Werbe- und Vertriebgesellschaft Deutscher Apotheker m.b.H. München, 1983. INDEX ДРОГ-СОДЕРЖАЩИЕ МНОГОКРАТНЫЕ ЭМУЛЬСИИ Я. Балаж, И. Эреш, М. Тачи и И. Петер Изучена эффективность образования эмульсий в/м/в в зависимости от состава и времени перемешивания. Показано, что на эффективность образования многократных эмульсий и на их стабильность оказывают определяющее влияние концент-рация эмульгатора 1, концентрация и ГЛБ эмульгатора 2, вязкость масляной и водной фаз, а также время перемешива-ния во второй ступени приготовления эмульсии. 

Drug-containing multiple-phase emulsions

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Drug-containing multiple-phase emulsions

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