1. Inclusion Complexes of Piroxicam with B-Cyclodextrin Derivatives
In-Vitro and In-Vivo Drug Availability
Bushra T. Al-Quadeib, Seham A. Alkheshen, and Sayed M. Ahmed
Dept. of pharmaceutics, college of Pharmacy, King Saud University
INTRODUCTION
RESULTS
CONCLUSION
It is well established that the rate-determining step in the absorption process for poorly water soluble drugs is the dissolution rate of such drugs in the gastrointestinal fluids rather than the rapidity of their diffusion across the gut wall. Consequently, the dissolution rate enhancement is one of the most commonly used approaches to improve the bioavailability of such drugs. Piroxicam (PIR) is practically insoluble in water. Recently, chemically modified CDs (Hepta-kis-[2,6-di-O-methyl]--Cyclode-xtrin “DM--CD” and Hydroxypropyl -- Cyclodextrin “HP--D”), have become more interesting because their physiochemical properties. Most of these CDs are highly water soluble and can therefore improving water solubility and increase the bioavailability of the guest molecules.
Table 1: Percentage drug content (%DC) and percentage piroxicam complexed (%PC) in different PIR-CD system
The results of In-Vitro dissolution study showed that the most significant improvement effect on the dissolution rate and extent was due to the method of preparation (FD > COPPTs > PMs) followed by the PIR-to-CDs molar ratios (1:2.5 > 1:1) and finally the different CDs types (DM--CD > HP--CD > -CD).
All PIR-CDs systems improved the dissolution rate of the drug but FD products at 1:2.5 molar ratio showed the superior effect.
The 95% confidence interval of the mean value of DE% of PIR-DM--CD FD of 1:2.5 molar ratio was completely and significantly separated from those of PIR-HP--CD and PIR--CD.
The results of In-Vivo bioavailability study showed that administration of PIR-DM--CD “FD” “1:2.5 MR” is characterized by a highly significant oral absorption rate and extent than that of the marketed Feldene® and higher absorption rate but not extent than Brexin®.
A good to excellent In-Vitro- In-Vivo correlation between the dissolution parameters and the In-Vivo bioavailability data, was observed which indicates that the main effect of DM-  -CD on PIR bioavailability enhancement was based on its of dissolution improvement effect.
CDs type PM
COPPT FD
%DC
PIR-to- -CD
1:1
1:2.5
PIR-to- DM--CD
PIR-to- HP--CD
Figure 1: In-Vitro-In-Vivo correlation of the dissolution parameters and the absorption data in absence of formula-A parameters.
Table 3: Pharmacokinetic parameters of PIR (mean +) following a single oral dose administration to six rabbits under fasting conditions
Pharmacokinetic parameters
Feldene®
Brexin®
PIR-DM--CD “FD”
Cmax (g/ml)
3.60
+ 0.41
4.03
+ 0.70
6.99
+ 1.33
tmax (h)
3.67
+ 0.52
2.50
+ 0.55
1.33
AUC0-96h (g.h/ml)
108.01
146.47
179.84
AUC0- ∞ (g.h/ml)
120.16
219.13
261.62
AUMC0-96h (g.h2/ml)
AUMC0- ∞ (g.h2/ml)
MRT (h)
42.29
+ 6.28
78.88
78.52
+ 9.98
K el (h –1)
0.025
0.015
0.014
t 1/2el (h)
28.39
+ 4.06
51.92
48.56
+ 7.11
Frel-1
---- %
Frel-2
----- %
AIM OF THE WORK
To investigate the effect of PIR inclusion complexes with two modified CDs “DM--CD” and “HP--CD” on the dissolution and the bioavailability of the drug. While -CD has been used for comparison.
Note: Theoretical drug content for PIR--CD at 1:1= 22.59%, at 1:2.5 = 10.46%; for DM--CD at 1:1= 21.13%, at 1:2.5 = 9.68% and for HP--CD at 1:1= 20.09%, at 1:2.5 = 9.14%.
METHODS
REFERENCES
For In-Vitro dissolution:
Inclusion complexes of (PIR) with each of the selected CDs in molar ratios of 1:1 and 1:2.5 (PIR-to-CDs), were prepared using coprecipitation (COPPTs) and freeze drying (FD) processes. Physical mixtures (PMs) have been also prepared for comparison. Then the dissolution rates of PIR from different CD systems were determined according to the USP rotating paddle method. A sample of 10 mg or its equivalent of the CD system were used.
2. For In-Vitro dissolution:
A modified method of Wanwi-
molruk et al., (1991). A protein
precipitation technique, using
U.V. spectrophotometer detector
at 365 nm. Single dose oral
study has been performed. An
equivalent to 5mg drug/kg body
weight of rabbits was calculated
and filled into empty gelatin
Capsules then administered
orally.
Table 2: Dissolution efficiency (DE%) of piroxicam from piroxicam cyclodextrin systems (calculated based on 60 minutes)
1. Acerbi, D., Bovis, G., Carli, F., et al.,
Dr. Invest., 2 (supplement 4): 29-36
(1990).
2. Betageri, G.V. and Makarla, K.R.,.
Int. J. of Pharm., 126:
(1995).
3. Deroubaix, X., Stockis, A., Allemon,
A.M., et al., Eur. J. of Clin. Pharma.,
47: (1995).
4. Elkheshen, S.A., Ahmed, S. M., Al-
Quadeib, B. T., et al., Pharm. Ind. 64,
612 (2002).
5. Uekama, K. and Otagiri, M. CRC Cri.
Rev. in Ther Drug Car. Sys. 3:1-40
(1987).
6. Wanwimolruk, S., Wanwimolruk, S.Z. and Zoest, A.R. J. L. Chrom. , 4(12): (1991).
Composition
(molar ratio)
Initial dissolution rate (IDR)
( % dissolved / min)
Time required for 50% (t50%) of the drug to be dissolved (min)
Extent of dissolution
after 60 minutes (%)
PIR
PMs
COPPTs FD
PIR-to--CD
1:1
0.92
+0.06
1.88
+ 0.09
4.95
+ 0.07
109.73
+ 6.26
63.11
+ 4.33
7.77
+ 0.21
33.48
+ 1.65
44.97
+ 1.93
82.78
+ 1.28
1:2.5
1.23
+0.07
2.83
+ 0.06
6.00
98.92
+ 7.64
32.65
+ 1.33 ND
<2.5 min
36.88
+ 1.73
62.70
+ 1.43
94.38
+ 1.94
PIR-to-DM--CD
1.57
4.07
5.68
+ 0.03
87.74
+ 4.79
13.62
+ 0.47
4.27
+ 0.17
40.59
+ 2.66
63.45
+ 0.73
95.08
+ 1.61
2.26
+0.11
4.36
7.13
+ 0.01
79.55
+ 5.91
10.03
+ 0.51
48.10
+ 1.92
78.34
98.98
+ 0.68
PIR-to-HP--CD
1.19
2.57
+ 0.04
5.22
101.05
45.48
+ 2.09
6.52
+ 0.14
36.73
+ 1.53
51.68
+ 1.24
86.84
+ 1.18
1.45
3.02
6.46
89.46
28.64
+ 127
40.37
+ 2.15
64.866
+ 1.51
97.16
+ 0.49
ACKNOWLEDGMENT
ND: Not detectable.
Special thanks to King Abdulaziz City for Science and Technology.