Development and characterisation of fast release bioadhesive suppository system containing diclofenac sodium
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Date
2009
Authors
Wai Hau, Tung
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Abstract
The migration of suppository towards the upper rectum has always posed a
problem in rectal bioavailability. Only drug absorbed from suppositories retained
at the lower rectum can bypass the strongly metabolising liver, while drug
absorbed from the upper rectum will experience first-pass metabolism. A
bioadhesive suppository system was developed to localise the suppository onto
the lower rectum by using fatty and water-soluble bases, hydrophilic polymers
of Carbopol 934P (CP) and Polyvinylpyrrolidone K90 (PVP) and diclofenac
sodium .(DeNa) as model drug. Of all the bases evaluated, ChocExa,
Supercocofat HS and Supercocofat resembled Cocoa Butter with comparable
base hardness, short softening time and similar melting range, bioadhesive
properties and biphasic drug release profiles. CP was a better bioadhesive
polymer than PVP. The presence of CP at 2 % w/w yield considerable
bioadhesive properties, but higher amount of CP prolonged DeNa release in
distilled water with higher value of initial drug release constants, k1 and longer
time to achieve 50% of drug release (Tso%). By employing CP at 2% w/w in the
ChocExa with DeNa, three different designs. of suppositories, namely the
conventional, hollow and double-layered suppositories were developed. Three
different DcNa-CP mixtures were also evaluated, namely the physical mixture,
co-grinding and wet granulations of DcNa-CP. The hollow and double-layered
suppositories released DeNa faster than the conventional design but with less
base hardness values and shorter softening time. On the other hand, all
designs of suppository containing granules of DcNa-CP were released faster
than physical mixture and co-grinding of DcNa-CP. Both FTIR and DSC profiles
of co-grinding preparation showed an intermediate profile of the physical
mixture and granulation preparation. Prior to the in vivo study, a simple, specific
and sensitive isocratic HPLC-UV method was validated for the quantification of
DeNa in rabbit plasma. An in vivo study of three-way crossover design was
performed on six rabbits for conventional suppository containing DcNa-CP
granules (B) and hollow suppository containing DcNa-CP granules (C) in
comparison to conventional suppository containing DeNa granules without CP
(A). The rate and extent of absorption (AUC0 ... ) and the maximum drug plasma
concentration (Cmax) for B and C were found to be significantly higher than A.
However, the AUC0 ... and Cmax between B and C were not significantly different,
although the AUC0 ... for C appeared to be higher than B. In conclusion, a
bioadhesive suppository system that could be retained on the lower rectum was
successfully prepared. The newly developed bioadhesive formulations resulted
in an improvement of bioavailability, hence offering advantages over the
conventional suppository.
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Keywords
Bioadhesive suppository , Diclofenac sodium