Itraconazolepoloxamer188 system/Asian Journal of Pharmaceutical Sciences 2006, 1 (3-4): 213-221

Increasing solubility and dissolution rate of drugs via eutectic mixtures: itraconazolepoloxamer188 system
Dan Liua, Xueping Feib, Siling Wanga, *, Tongying Jianga, Desen Sua
a

School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China b Nursing Department, the Fourth Hospital, China Medical University, Shenyang 110032, China
Received 23 October 2006; Revised 24 November 2006; Accepted 2 December 2006

_____________________________________________________________________________________________________________

Abstract
Purpose: The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug itraconazole. Methods: Cooling curve method was used to determine the eutectic point of drug-poloxamer 188 mixture and the phase diagram of the binary system was constructed. Solid dispersions of itraconazole were prepared by the hot melt method and characterized by differential scanning calorimetry (DSC). Solubility and dissolution studies in various media were conducted with pure itraconazole, a physical mixture and solid dispersions. Results: Solubility studies indicated that poloxamer 188 increased signicantly the solubility of itraconazole in water (range 33.40- to 176.8-fold increases). The eutectic mixture resulted in highest increases in drug dissolution rate. The cumulative release of itraconazole from solid dispersions within 60 min was 4.66 times higher than the pure drug in 0.1 mol/l HCl. The dissolution of itraconazole from solid dispersions in poloxamer 188 with a eutectic composition reached a satisfactory level (above 90%) after 20 min in both water (0.5% SDS) and pH 6.58 PBS buffer (0.5% SDS). Conclusion: An increased solubility and dissolution rate of itraconazole can be achieved by forming a eutectic mixture using poloxamer 188 as a carrier. The drug dissolution rate was highest at a drug-to-polymer ratio of 5: 95 (w/w). Keywords: Eutectic mixture; Itraconazole; Poloxamer 188; Solubility; Dissolution _____________________________________________________________________________________________________________

1. Introduction
Itraconazole (ITZ) is a potent broad-spectrum triazole antifungal drug with activity against cryptococcus, aspergillus, candida, blastomycosis, onychomycosis, and histoplasmosis organisms [1-4]. The compound is insoluble in water (S 50 ng/ml at neutral pH and S = 1.2 g/ml in 0.1mol/l HCl), and has an ionization constant of 3.7 and a very high n-octanol/water partition coefcient (logP >5) [5]. The chemical structure is shown in Fig. 1. According to the biopharmaceutical classication system (BCS), itraconazole is an extreme example of a class II compound meaning that its oral bioavailability is determined by its dissolution rate in the GI tract [6-8]. Consideration of the modied Noyes-Whitney equation provides some hints as to how the dissolution rate of very poorly soluble compounds might be improved to
__________ *Corresponding author. Address: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China. Tel.: +86-24-23986348; fax: +86-24-23986348. E-mail: silingwang@hotmail.com

minimize the limitations to their oral availability. There have been numerous efforts to improve drug dissolution rates. These include (a) reducing the particle size to increase the surface area; (b) using water-soluble carriers to form inclusion complexes; (c) solubilization in surfactant systems; (d) using pro-drugs and drug derivatization; and (e) manipulation of the solid state of drug substances to improve the drug dissolution i.e. by reducing the crystallinity of drug substances through formation of solid dispersions. However, there are practical limitations to these techniques [9]. Although particle size reduction is commonly used to increase the dissolution rate, there is a practical limit to the size reduction that can be achieved by such commonly used methods as controlled crystallization and grinding. The use of very ne powders in a dosage form may also be problematic because of handling difculties and poor wettability. Salt formation is not feasible for neutral compounds and the synthesis of appropriate salt forms of drugs which are weakly acidic or weakly basic may often not be practical. Even when salts can be prepared,

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Itraconazolepoloxamer188 system/Asian Journal of Pharmaceutical Sciences 2006, 1 (3-4): 213-221

N N CH3 H3 C N N N O N N N O H Fig. 1. Chemical structure of itraconazole. O O Cl Cl

an increased dissolution rate in the gastrointestinal tract may not be achieved in many cases because of the reconversion of salts into aggregates of their respective acid or base forms. The solubilization of drugs in organic solvents or in aqueous media by the use of surfactants and cosolvents leads to liquid formation that is usually undesirable from the viewpoints of patient acceptability and marketing [10]. Solid dispersions have been widely used to enhance the solubility, dissolution rate, and bioavailability of poorly soluble drugs [11-14]. There are different types of solid dispersion systems categorized according to the physical states of the drug and the carrier in the systems. It may be a molecular solid solution, a dispersion of amorphous or crystalline drug particles in an amorphous carrier matrix, or a combination of a solution and dispersion of solids. A simple eutectic mixture consists of two compounds which are completely miscible in the liquid state but only to a very limited extent in the solid state. When a mixture of I and II with an appropriate composition is cooled, I and II crystallize out simultaneously, whereas when other compositions are cooled, one of the components starts to crystallize out before the other [15, 16]. Solid eutectic mixtures are usually prepared by rapid cooling of a co-melt of two compounds in order to obtain a physical mixture of very ne crystals of the two components. Sekiguchi and co-workers [11, 17] have proposed that when the eutectic mixture is exposed to the gastrointestinal uids, the soluble carrier dissolves rapidly, leaving the insoluble drug in an extremely ne state

of subdivision. The large surface area of the resulting suspension should result in an enhanced dissolution rate and, consequently, improved bioavailability. The aim of the present study was to improve the solubility and dissolution rate of itraconazole by a simple eutectic mixture using poloxamer 188 as the carrier. The physical characteristics, solubility and in vitro dissolution rate of the solid dispersions are presented in this report. This study was part of a preformulation study to develop an oral formulation of itraconazole.

2. Materials and methods

2.1. Materials Itraconazole were purchased from Tianjin Lisheng Pharmaceutical Co. Ltd., Polyoxyethylene-polyoxypropylene copolymer (poloxamer 188) was purchased from Shenyang Pharmaceutical Co. Ltd. All other materials were of analytical regent grade. 2.2. Preparation of solid dispersions Solid dispersions of itraconazole were prepared by the hot melt method. The mixture of Itraconazole and poloxamer 188 was heated to a liquid state, and cooled in an ice bath immediately, leading to rapid solidication [9]. The weight ratio of the drug to poloxamer 188 was 5: 95, 1: 9, 1: 5, 1: 4, 3: 7, 3.5: 6.5 and 1: 1 (Fsd 0.05, Fsd 0.1, Fsd 0.167, Fsd 0.2, Fsd 0.3, Fsd 0.35, Fsd 0.5, respectively).

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2.3. Preparation of physical mixtures Physical mixtures were prepared by mixing itraconazole and the polymer in a mortar for 5 min and then sieving (< 355 m). 2.4. Screening the eutectic point Equal quantities (1 g) of carrier and drug, employing blends of itraconazole and the polymer in the following weight ratios: 0.05: 0.95, 0.1: 0.9, 0.2: 0.8, 0.3: 0.7, 0.4: 0.6, 0.5: 0.5, 0.6: 0.4, 0.7: 0.3, 0.8: 0.2, 0.9: 0.1, were physically mixed and placed along with a thermometer in test tubes [17-19]. The tubes were immersed into a temperature controlled oil bath, preset to the melting point of the lower melting component (58.3C). The mixture was constantly stirred to facilitate distribution of the heat and the temperature of the oil bath was slowly raised to fusion point, and the temperature of the melt was allowed to rise to about 10C above the itraconazole melting point 169.2C. The tubes were then removed and left at ambient temperature. During the cooling process, the following observations were made: (a) the temperature at which the mixture started to precipitate; (b) the temperature at minute intervals; (c) the temperature at which the point was constant; and (d) the temperature at which precipitation was complete [17]. The phase diagram of itraconazole-poloxamer188 was constructed using the cooling curve method. During the cooling process, the temperature was plotted versus time, and two discontinuities in the curve were noted. The rst change of slope (at the higher temperature) was comparable with the melting point of that component in the mixture which was in excess of the eutectic composition, and the second change in slope (at the lower temperature) corresponds to the eutectic temperature. Then a phase diagram was constructed by plotting the two temperatures versus the ratio of the components (percentage w/w).

2.5. Differential scanning calorimetry (DSC) analysis The thermal characteristics of the pure materials, the physical mixtures and the solid dispersions were determined by differential scanning calorimetry (DSC-60, SHIMADZU). The scanning rate was 10C/min, and the scanning temperature range was between 30C and 300C. Samples of about 5 mg were sealed into aluminum pans. [20] 2.6. Determination of solubility Drug solubility was determined by adding excess amounts of itraconazole and solid dispersions to water and 0.1mol/l HCl at 37 0.5C, respectively. The suspensions formed were equilibrated under continuous agitation for 48 h and passed through a 0.8 m membrane lter to obtain a clear solution. The absorption of the samples wasmeasured in a UV spectrophotometer (WFZ 800-D2, Beijing Second Telescope Factory) at 261 nm and the concentrations in g/ml were determined. Each sample was determined in triplicate. 2.7. In vitro dissolution Itraconazole powder alone, itraconazole/poloxamer 188 physical mixtures and solid dispersions equivalent to 20 mg itraconazole were directly added to 500 ml 0.1 mol/l HCl, water (0.5% SDS) and pH 6.58 PBS (0.5% SDS) at 37C, respectively. Dissolution studies were performed according to CP (2005 Edition). The rotation speed of the paddle was adjusted to 100 r/min. Dissolution samples were collected at 5, 10, 15, 20, 30, 45 and 60 min through a 0.8 m lter and analyzed by direct UV spectrophotometry (WFZ800-D2, Beijing Second Telescope Factory) at 261 nm [10]. The cumulative amount of drug released was calculated and plotted versus time. Standards were prepared by dissolving itraconazole in 10 ml methanol and diluting with the dissolving media [21].

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180 160 140 Temperature (C) 120 100 80 60 40 20 0 0 10 20 30 40 50 60 70 80 90 100 Poloxamer 188 (100C)

- -Temperature T1 - -Tamperature T2

Itraconazole (100C)

Fig. 2. Pseudo-binary phase diagram of itraconazole-poloxamer 188 with a eutectic point.

T1 represents the temperature at which the mixture started to precipitate. T2 represents the temperature at which the point was constant.

3. Results and discussion

3.1. Pseudo-binary phase diagram of itraconazolepoloxamer 188 Fig. 2 shows the phase diagram and it can be seen that itraconazole and poloxamer 188 have a eutectic point of 40C at which the composition was 5% itraconazole and 95% poloxamer 188. However, the phase diagram revealed the existence of a pseudo-binary system which was not close to a theoretical simple eutectic mixture. Between an itraconazole composition of 5% to 40%, the precipitation temperature increased on increasing the itraconazole concentration. However, above a composition of 50%, the temperature decreased. The precipitation temperature of the 40% composition was higher than any other composition. It was presumed that itraconazole and the polymer might form a new compound, and this will need to be conrmed in a future study. At an itraconazole composition of below 40%, itraconazole and the new compound had a eutectic point of about 40C. In our study, we found that above a composition of 40%, the new compound and poloxamer 188 did not have a visible eutectic point.

3.2. Differential scanning calorimetry (DSC) analysis DSC curves obtained for pure material, solid dispersions, and their corresponding physical mixtures are displayed in Fig. 3. In the thermogram of poloxamer 188, a sharp peak (58.3C) was observed, which was associated with the endothermic melting of poloxamer 188. Pure itraconazole had a sharp endothermic peak at 169.2C that corresponded to the melting point of itraconazole. As the amount of poloxamer 188 increased, the size of the itraconazole endothermic peak was reduced (Fig. 3). At a ratio of 0.2 with poloxamer 188, a small but shifted itraconazole endothermic peak was observed at 151.24C. Also, the two melting transitions in the system made up of itraconazole and poloxamer 188 indicated that both materials formed a separate phase [20]. It was found that itraconazole was in a crystalline state in the solid dispersions. The position of the melting peak of poloxamer 188 remained largely unchanged, while that of itraconazole shifted depending on the concentration. At a ratio of 0.167 and below, the endothermic peak of itraconazole was no longer observed (Fig. 3). This could be because itraconazole was molecularly or amorphously dispersed in the phases [22]. The physical

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Itraconazolepoloxamer188 system/Asian Journal of Pharmaceutical Sciences 2006, 1 (3-4): 213-221

mixtures of itraconazole and poloxamer 188, on the other hand, showed an apparent endothermic peak of itraconazole at 166.88C. The eutectic temperature measured using the cooling curve method was found to be somewhat lower than the temperature observed by DSC. The small discrepancy in eutectic composition between the two methods was attributable to differences in the scanning rate. This proved that the cooling curve method was more accurate due to its lower increase and cooling rate. 3.3. Solubility studies The solubility of itraconazole in water and in 0.1 mol/l HCl is shown in Table 1. The solubility of itraconazole in water at 37C was found to be 50 ng/ml and 1.2 g/ml in 0.1 mol/l HCl. These results show that the solubility of itraconazole increased on increasing the concentration. The solubility of itraconazole from the solid dispersion was signicantly higher than that from the physical mixture, when the solid dispersion and physical mixture contained the same weight ratio of itraconazole (10%). It was about 39.87 times higher than that from physical mixtures in water and 25.34 times higher in 0.1 mol/l HCl. It reached a maximum when the ratio of itraconazole to poloxamer 188 was that of the eutectic composition. The higher solubility of itraconazole from solid dispersions may due to the increased surface area and the highly dispersed state of the drug in the system for the wetting effect and solubilizing effect of the carrier [23]. The extent of the increase in solubility was marked, about a 33.40- to 176.8-fold increase in water and a 7.91- to 39.25-fold increase in 0.1 mol/l HCl, respectively. 3.4. Dissolution studies The dissolution curves of itraconazole in different media from the various pseudo-binary systems examined are shown in Fig. 46. The release rate proles were plotted as the percentage itraconazole dissolved from the solid dispersions, physical mixture and pure itracon-

azole versus time. Fig. 4 shows the dissolution proles of itraconazole with poloxamer 188 at different drug-tocarrier (w/w) ratios, the corresponding physical mixture 1: 9 and itraconazole alone in 0.1 mol/l HCl. It was evident that the rate of dissolution of pure itraconazole was slow, less than 10% of the itraconazole being dissolved within 60 min. Compared with that of pure itraconnazole, the dissolution rate of itraconazole from its physical mixtures appeared faster. The cumulative release of itraconazole from solid dispersions was more rapid than from pure itraconazole and the physical mixtures. It was 45.03% at the eutectic composition, which was 4.66 times that of the pure drug and 2.96 times that of the physical mixtures. Fig. 56 shows the dissolution proles of itraconazole with poloxamer 188 solid dispersions, the corresponding physical mixture 1: 9 and itraconazole alone in water (0.5% SDS) and pH 6.58 PBS buffer (0.5% SDS). The dissolution of itraconazole from poloxamer 188 with the eutectic composition reached a satisfactory level (above 90%) after 20 min in both media, which was an enormous increase compared with the physical mixture and the drug alone. Release was complete after 45 min. There was a signicant difference in the drug release between the solid dispersion and physical mixture. The increase in dissolution from the physical mixtures was probably due to the wetting and solubilizing effect of the carrier, which could reduce the interfacial tension between the itraconazole and the dissolution medium, thus leading to a higher dissolution rate. When a eutectic mixture, consisting of a slightly soluble drug and a highly water-soluble carrier, was dissolved in an aqueous medium, the carrier would dissolve rapidly, leaving the insoluble drug in an extremely ne state of subdivision. The large surface area of the resulting suspension should result in an enhanced dissolution rate and thereby improve the bioavailability. 3.5. Effect of surfactant on itraconazole dissolution from solid dispersions The cumulative release of the eutectic mixture was

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57.11 C

1: 19 (Fsd 0.05)

57. 48 C

1: 9 (Fsd 0.1) 1: 5 (Fsd 0.167)

57.16 C Heat flow (mW) Endo up 151.24 C 57.62 C

1: 4 (Fsd 0.2)

55.78 C

155.83 C

3: 7 (Fsd 0.3) 1: 1 (Fsd 0.5)

53.19 C

162.85 C

199.20 C

itraconazole poloxamer 188

58.03 C 166.88 C PM 1: 9 (Fsd 0.1)

60.13 C

Temperature (C) Fig. 3. DSC curves of itraconazole, poloxamer 188, physical mixtures (PM) and solid dispersions. The numbers indicate the composition (wt. ratio) of itraconazole. Fsd represents the solid dispersions of itraconazole prepared with poloxamer 188. Table 1 Solubility of ITZ solid dispersion at different ratios of poloxamer 188 in water and 0.1 mol/l HCl. Weight ratio (ITZ/poloxamer 188) SD (1: 19) SD (1: 9) SD (1: 5) SD (1: 4) SD (1: 3) SD (1: 2.3) SD (1: 1) SD (1: 0.43) SD (1: 0.11) Concentration of ITZ in water (g/ml) 8.841 7.974 7.35 6.333 5.872 2.944 2.281 1.92 1.67 Concentration of ITZ in 0.1 mol/l HCl (g/ml) 47.1 40.55 36.98 35.22 34.88 33.61 32.12 14.69 9.497 Solubilized times in water 176.8 159.5 147.0 126.7 117.4 58.88 45.62 38.4 33.4 Solubilized times in 0.1 mol/l HCl 39.25 33.79 30.82 29.35 29.07 28.01 26.77 12.24 7.914

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50 45 40 Dissolution (%) 35 30 25 20 15 10 5 0 0 10 20 30 Time (min) Fig. 4. Dissolution proles of itraconazole, ITZ/poloxamer 188 physical mixtures and solid dispersions at different drug-to-carrier (w/w) ratios in 0.1 mol/l HCl. () ITZ: poloxamer 188 = 5: 95; () ITZ: poloxamer 188 = 1: 9; () ITZ: poloxamer 188 = 3: 7; () ITZ: poloxamer 188 = 1: 1; () ITZ: poloxamer 188 = 7: 3; () ITZ/poloxamer PM; () pure ITZ. 40 50 60

120 100 80 60 40 20 0 0 10 20 30 Time (min) Fig. 5. Dissolution proles of itraconazole, ITZ/poloxamer 188 physical mixtures and solid dispersions at different drug-to-carrier (w/w) ratios in water (0.5% SDS). () ITZ: poloxamer 188 = 5: 95; () ITZ: poloxamer 188 = 1: 9; () ITZ: poloxamer 188 = 3: 7; () ITZ: poloxamer 188 = 1: 1; () ITZ: poloxamer 188 = 7: 3; () ITZ/poloxamer PM; () pure ITZ. 40 50 60

Dissolution (%)

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120 100 80 60 40 20 0 0 10 20 30 Time (min) Fig. 6. Dissolution proles of itraconazole, ITZ/poloxamer 188 physical mixtures and solid dispersions at different drug-to-carrier (w/w) ratios in pH 6.58 PBS buffer (0.5% SDS). () ITZ: poloxamer 188 = 5: 95; () ITZ: poloxamer 188 = 1: 9; () ITZ: poloxamer 188 = 3: 7; () ITZ: poloxamer 188 = 1: 1; () ITZ: poloxamer 188 = 7: 3; () ITZ/poloxamer PM; () pure ITZ. 40 50 60

Dissolution (%)

lower than 50% in 0.1 mol/l HCl. As the concentration of poloxamer 188 increased, a gel might be formed in the media [24]. During the dissolution experiments, it was noticed that solid dispersions formed a viscous block which prevented the dissolution of itraconazole. Also, during dissolution in aqueous media, there could be a tendency for the drug to precipitate out in the diffusion layer adjacent to the dissolving solid surface because use of its low aqueous solubility. However, when SDS was added, its cumulative release was nearly complete. Based on these observations, a mechanism can be postulated for the inuence of SDS on the dissolution of drug from the solid dispersion. Since the solubilizing effect of SDS was high, a concentrated drug solution would be formed in the diffusion layer, which would retard drug precipitation in both the diffusion layer and bulk dissolution medium. Such a potential difference in the kinetics of drug precipitation in the diffusion layer might be a possible reason why the solid dispersion containing SDS resulted in ner particles and satisfactory dissolution [25].

4. Conclusion
In this paper, an increased solubility and dissolution rate of itraconazole were achieved by forming a eutectic mixture using poloxamer 188 as a carrier. The drug dissolution rate was highest at the drug-to-polymer ratio of 5: 95(w/w). The solid dispersion technique used in our study involves relatively simple preparation steps and can be used for preparing granules, tablets, capsules and creams. Further study is warranted to examine if the bioavailability of itraconazole is increased for solid dispersions with enhanced dissolution characteristics.

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