Formulation and Optimization of Sustained Release Floating Matrix Tablet of Salbutamol Sulphate Using Xanthan Gum and Hydroxypropyl Methylcellulose Polymer Blend
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Date
2014-06
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Addis Ababa University
Abstract
Salbutamol sulphate is a directly acting sympathomimetic agent with selective action on
ß2-receptors. It is used as bronchodilator in the management of disorders involving
reversible airways obstruction and in chronic obstruction pulmonary diseases. Oral
salbutamol sulphate has site-specific absorption in the stomach and upper part of the
small intestine. Its bioavailability is about 40% due to extensive hepatic first pass
metabolism, sulphonation in intestinal fluid, degradation in colon and narrow absorption
window. The aim of this study was to formulate and optimize a sustained release floating
tablet of salbutamol sulphate using xanthan gum (XG) and hydroxypropyl
methylcellulose (HPMC) as release retarding agents and sodiumbicarbonate (NaHCO3)
as floating aid in order to improve bioavailability, reduce dosing frequency, and increase
patient compliance.
The sustained release floating tablets of salbutamol sulphate was prepared by wet
granulation technique using XG and HPMC as release retarding polymers. The effects of
formulation variables: percentage of polymer (XG, HPMC, or XG/HPMC) and
percentage of sodium bicarbonate on response variables: floating lag time, floating
duration, cumulative release within 1 hr, and release rate were investigated. Preliminary
studies revealed that the percentage of sodium bicarbonate, percentage of polymer (XG,
HPMC, or XG/HPMC) significantly affected the floating lag time, cumulative release
within 1 hr and release rate (P < 0.05), but not floating duration. Among the polymers
used, the one with 1:3 (XG:HPMC) ratio was selected for further optimization purpose
due to that it contains relatively high amount of HPMC, which has low hydration power
than XG, that can release enough amount of drug in the first 1 hr which can be used as
bolus dose for rapid relief of asthma. The effect of formulation variables on floating lag
time was significant, but all formulations floated below 10 seconds and not considered
during optimization. The effects of percentage of NaHCO3 and percentage of XG/HPMC
(1:3) were studied and optimized for maximum desired output of drug release rate and
cumulative release within 1 hr using central composite design statistical approach.
Design-Expert 8.0.7.1 software was employed to carry out the experimental design,
statistical analysis, and numerical and graphical optimization.
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Linear and quadratic models were developed as best fit models for release rate and
cumulative release at 1 hr, respectively. The analysis of variance (ANOVA) of the
models showed that the linear effects of both parameters were significant for the linear
model of release rate; and all the linear, interaction and quadratic effects were significant
for the quadratic model of cumulative release at 1 hr. The effect of percentage of
XG/HPMC was more pronounced than the effect of percentage of NaHCO3 on both
models. Finally, simultaneous optimization of cumulative release at 1 hr and release rate
was performed and the most desirable representative optimal point was obtained to have
release rate of 28.49 hr-1/2 and cumulative release at 1 hr of 24% at corresponding levels
of 24.79% of XG/HPMC and 5% of NaHCO3 with desirability of 0.756. The validity of
this optimal point was confirmed by the low magnitude of percent prediction error.
Evaluation of the optimized formulation showed successful formulation of the floating
tablets with excellent granule and tablet property. Comparison of the release profiles of
three different batches of the optimized formulation by dissolution efficiency revealed
that there was no statistically significant difference (p > 0.05) in release profiles of the
formulations. In addition, drug release kinetics and drug release mechanism studies
indicated that the optimized formulation followed Higuchi square root kinetic model with
non Fickian diffusion release mechanism. In conclusion, this study has come up with an
optimum formulation for the development of floating tablet of salbutamol sulphate that
could remain buoyant and release the drug over a period of 12 hr in a sustained manner in
vitro.
Keywords: GRDFs; Floating tablet; Salbutamol sulphate; Xanthan gum; HPMC;
Optimization
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Keywords
GRDFs; Floating tablet; Salbutamol sulphate; Xanthan gum; HPMC; Optimization