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Ajps2010,5 (1) 1
Ajps2010,5 (1) 1
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Abstract
Purpose:The aim of this study was to prepare inclusion complexes and solid dispersions of ketoconazole to improve its dissolution
rate and hence its antifungal properties for the effective therapy of candidaiasis. Methods: The solvent evaporation method was used
to prepare ketoconazole inclusion complexes in -cyclodextrin with different molar ratios of drug to carrier (1: 1, 1: 2.5 and 1: 5). In
addition, solid dispersions of ketoconazole in polyvinylpyrrolidone k-17 with different weight ratios of drug to carrier (1: 1, 1: 5 and
1: 10) were prepared. Moreover, the effect of the molecular weight of polyvinylpyrrolidone was also investigated. A phase solubility
method was used to evaluate the effect of the tested carriers on the aqueous solubility of ketoconazole. The dissolution of all the
preparations was tested using the USP paddle method. The interaction of ketoconazole with the carriers was evaluated by differential
scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The selected ketoconazole inclusion complex or ketoconazole solid
dispersion was incorporated in different topical bases by trituration and compared with the pure drug and the commercial ketoconazole
cream for in-vitro drug release and antifungal activity. Results: According to the results of this investigation, the solubility and
dissolution rates of ketoconazole were significantly increased by solid dispersions and cyclodextrin complexes as well as their physical
mixtures. However, the dissolution enhancement of ketoconazole was dependent on the carriers used and the nature of presentation
of ketoconazole in the carriers (physical mixture/solid dispersion/molecular inclusion). The ketoconazole-beta cyclodextrin inclusion
complex at 1: 5 molar ratio showed the highest dissolution of all the preparations (DE%=71.11.9). The results from DSC and XRPD
indicated the presence of ketoconazole in an amorphous form in both the inclusion complex and solid dispersion, accounting for the
occurrence of a strong interaction between ketoconazole and beta cyclodextrin/or polyvinylpyrrolidone in the solid state. Improved
drug release was found with topical formulations containing ketoconazole in the form of a solid dispersion or inclusion complex.
However, hydroxypropylmethyl cellulose gel base showed maximum drug release compared with the other topical bases. The antifungal
data agreed with the in vitro results and proved the superiority of the prepared vaginal gel (ketoconazole/-cyclodextrin complex in
hydroxypropylmethyl cellulose gel) to the commercial ketoconazole cream. Conclusion: An increased solubility and dissolution rate of
ketoconazole can be achieved by complexation with beta cyclodextrin and solid dispersion formation with polyvinylpyrrolidone k-17.
Keywords:Ketoconazole; -cyclodextrin; Polyvinylpyrrolidone; Topical activity; Antifungal activity
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1. Introduction
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
2.1. Materials
Ketoconazole (KET), polyvinyl pyrrolidone k-17 (PVP
k-17), (PVP k-25) and (PVP k-30) were obtained as
gifts from Memphis Co. (Cairo, Egypt). - Cyclodextrin (CD) (Mw 1135), hydroxypropylmethyl cellulose (50 cp)
and sabouraud's dextrose agar were purchased from
Sigma-Aldrich (St Louis, MO, USA). Methanol, ethanol,
white petrolatum, liquid paraffin, bees wax, olive oil,
borax, stearic acid, cirtic acid, sodium hydroxide, hydrochloric acid and sodium lauryl sulphate were purchased
from El-Gomhoria Co. (Cairo, Egypt). A semipermeable
cellophane membrane 30/32 was supplied by (Fischer
Scientific Co., London, England).
2.2. Phase solubility studies
Solubility studies were performed according to the
method described by Higuchi and Connors [26]. An
excess of drug (10 mg) was added to 10 ml water or
aqueous carrier solutions of different concentrations
(01.8% for -CD or 1%20% for PVP polymers)
in 25-ml stopper conical flasks and shaken at 25C in a
thermostatically controlled water bath (Julabo SW 20C,
Osaka, Japan). At equilibrium after 4 d (for -CD) or
2 d (for PVP polymers), aliquots were withdrawn, filtered
(0.22 m pore size, Whatman UK), suitably diluted with
methanol and the drug content spectrophotometrically
assayed at 260 nm (Shimadzu UV-160A Spectrophotometer, Shimadzu, Japan). Each experiment was carried
out in triplicate.
The apparent 1:1 stability constant was calculated
from the solubility data using the following formula:
Slope
____________
S0 (1Slope)
Where S0 is the intrinsic solubility of ketoconazole.
K1:1 =
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
molar ratios, 1:1, 1:2.5 and 1:5 [27]. KET and -CD
were dissolved at 40C in the lowest volume of 50%
ethanol (which is necessary to obtain solution) and
stirred for 30 min. Then, the solvent was evaporated
in a vacuum oven at 50C until complete drying was
obtained as shown by constant weight.
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
solution [38]. Moreover, it was suggested that PVP polymers might form soluble complexes with KET [13, 39].
The stability constant of KET with PVP k-17, PVP
k-25 and PVP k-30 was found to be 141, 179 and 191 M-1,
respectively, indicating that the ketoconazole and the
carrier dispersions are sufficiently stable. In fact, the
values of the obtained stability constants were always
within the range 1001000 M-1, which is believed to be
ideal. Actually, smaller values of the stability constant
indicate too weak an interaction between drug and carrier,
while higher values are symptomatic of an incomplete
drug release from the complex [40]. So the values we
obtained are considered ideal and are expected to be
stable.
Solubility (g/ml)
1600
1200
800
400
0
0
0.2
1.4
1.6
PVP k-17
Solubility (g/ml)
2500
PVP k-25
PVP k-30
2000
1500
1000
500
0
0
10
12 14
16
18
20
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
KET
1: 2.5 PM
1: 1 IC
1: 5 IC
120
100
KET released (%)
1: 1 PM
1: 5 PM
1: 2.5 IC
80
60
40
20
0
0
15
30
45
60
75
90
105
120
Time (min)
Fig. 3. Dissolution profiles of KET from its different systems
with -CD in distilled water at 37C.
120
100
KET
1: 1 PM
1: 5 PM
1: 1 SD
1: 10 PM
1: 5 SD
1: 10 SD
80
60
40
20
0
0
15
30
45
60
75
90
105
120
Time (min)
KET
PVP k-17
100
PVP k-25
PVP k-30
80
60
40
20
0
0
15
30
45
60
75
90
105
120
Time (min)
Fig. 5. Effect of PVP molecular weight on the dissolution
behavior of KET.
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
Table 2
Dissolution parameters (SEM) of KET from different ketoconazole- -CD physical mixtures and inclusion complexes in
distilled water.
Table 3
Dissolution parameters (SEM) of KET from different
ketoconazole-PVP physical mixtures and solid dispersions in
distilled water.
Q30 (%)
Q120 (%)
DE (%)
3.1
15.24.2
5.61.7
1:1
51.29.5
7.40.4
1:2.5
77.6
10.4
KET
1:5
75.2
12.1
System
KET
KET- -CD (PM):
Q30 (%)
Q120 (%)
DE (%)
3.1
15.24.2
5.61.7
1: 1
27.35.2
9.20.4
System
17.13.8
49.410
25.56.2
1: 5
10.53.6
44.63.3
19.33.2
8.2
34.2
15.62.5
1: 10
3411.5
90.77.6
41.78.1
66.31.04
95.510.6
71.11.9
100
50.83.4
1: 1
1: 5
33.210.1 10013.8
43.910
1: 10
31.610.1 10012.3
494.7
43.812.4
8.5
35.94.8
7.71.6
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
1: 5 IC
('HKET = 1.89 J/g )
('HE-CD = 154.26 J/g)
1: 5 PM
Endotherm
50
100
150
Temperature (C)
Fig. 6. DSC curves of KET and binary systems with -CD.
1: 1 SD
Endotherm
1: 1 PM
('HKET = 46.46 J/g)
('HPVP = 104.44 J/g)
PVP k-17
('H = 164.57 J/g)
KET
('H = 90.72 J/g)
50
100
150
Temperature (C)
Fig. 7. DSC curves of KET and binary systems with PVP k-17.
Fig. 7: DSC curves of KET and binary systems with PVP k-17.
1: 5 IC
1: 1 SD
1: 5 PM
Intensity
Intensity
1: 1 PM
-CD
PVP k-17
KET
20
10
30
KET
10
40
20
2 ()
40
30
20
10
0
20
10
02
0
3
4
1 (h) 2
Time
Oleaginous
40
HPMC gel
O/W cream
30
W/O cream
5
6
3
4
Time (h)
(B)
Oleaginous
HPMC gel
O/W cream
W/O cream
(B)
5
3
6
4
30
20
10
0
10
02
0
3
4
1 (h) 2
Time
(D)
40
10
3
4
1
Time (h) 2
10
0
20
0 2
0
40Fig. 9: X-rayOleaginous
(C)of KET and binary systems with PVP k-1
diffraction patterns
40 gel
Oleaginous
(C)
HPMC
HPMC
gel
O/W cream
30
O/W cream
30 cream
W/O
W/O
cream
of 20
KET and binary systems
with
-CD.
20
KET released (%)
10
(A)
40
KET released (%)
20
(A)
Oleaginous
HPMC gel
O/W cream
W/O cream
30
Oleaginous
40 HPMC gel
O/W cream
W/O cream
30
40
40
30
2 ()
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
5
6
3
4
Time (h)
(D)
30
20
10
10
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
References
3.8. Influence of cyclodextrin complex and solid dispersion formation on the anti-candidal activity of KET
The inhibiting capability of KET on the growth of
Candida albicans is shown in Table 4. It was observed
that KET was more readily released from HPMC gel
base containing cyclodextrin complex than from the same
vehicle with PVP solid dispersion or KET alone. Moreover, KET complexed with cyclodextrin exhibited significant antifungal activity (larger zone of inhibition indicating prolonged antifungal activity) compared to the
marketed formulation. The activity ranking agrees with
both the solubility and drug release ranking observed
for these formulations. Similar results were obtained by
Van Doorne et al. [48] and Perdomo-Lpez et al. [49].
Table 4
Inhibition zones in mm for the antifungal activity of various
formulations against Candida albicans.
Formulations
Test
Control
Net diameter*
HPMC gel/KET
25
10
15
40
10
30
30
10
20
Commercial cream
35
15
20
4. Conclusion
This study clearly showed that the addition of carriers
especially -CD and PVP k-17 to KET improved its
dissolution rate. Solvent evaporation method proved to
be an efficient and simple method for the preparation
of ketoconazole- cyclodextrin complexes. The present
study also showed that incorporation of the drug as -CD
inclusion complex in bioadhesive gel (HPMC) might
be further developed for safe, convenient and effective
treatment of vaginal candidasis.
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Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences 2010, 5(1):1-12
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