1. In-Vitro and In-Vivo Evaluation of Mebeverine Hydrochloride From Different Suppository Bases
Basmah N. Al-Dossary, M.S., Omaimah M.N. Al-Gohary, PhD., and Manal M. El-Khawaas, PhD.
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O.Box 22452, Riyadh (Saudi Arabia)
Abstract
Table 1: The correlation coefficients; the release rate constant, (K); and the time (min) at which 50% of mebeverine HCl is released (t50%) from different suppository bases and commercial Duspatalin® tablets.
Suppositories containing 200 mg of mebeverine hydrochloride were prepared using different suppository bases namely: Cocoa butter, Witepsol H15, Suppocir AP, Estaram H15, and polyethylene glycol (PEG)1000:4000 mixture in a ratio of 3:1, respectively. The in-vitro release rate of mebeverine HCl was optimum from polyethylene glycol and Witepsol H15 suppository bases among the other tested bases. The effect of type and concentration of different enhancers: Brij 35, sodium lauryl sulfate, urea and L- lysine hydrochloride on the rate of drug release from Witepsol H15 suppositories was studied. The increase in the release rate from Witepsol H15 base was found to be optimum upon the addition of 10% urea as compared to other enhancers. The in-vivo study of mebeverine HCl availability from selected suppositories, in rabbits, revealed a significant increase in plasma concentrations, compared to oral Duspatalin® tablets. This result is thought to be due to partial avoidance of first-pass metabolism in the liver.
t50% ± SD*
K ± SD*
Correlation coefficients of different release models
Formula
Higuchi
First
Zero
5.88 ± 0.28
8.497 ± 0.44a
0.974
0.989
0.997
PEG suppositories
12.60 ± 0.65
0.055 ± 0.003b
0.988
Witepsol H15 suppositories
27.72 ± 1.65
0.025 ± 0.001b
0.984
0.987
0.898
Estaram H15 suppositories
49.50 ± 1.97
0.014 ± 0.001b
0.908
Suppocir AP suppositories
± 10.00
3.291 ± 0.19c
0.946
0.919
Cocoa Butter suppositories
34.65 ± 3.20**
1.443 ± 0.12a
0.924
0.947
Duspatalin® Tablets
Figure 4: Mean plasma levels of mebeverine HCl in rabbits following oral administration of crushed commercial Duspatalin® tablets and selected rectal suppositories.
Figure 5: The area under the plasma concentration – time curve (AUC0-) of mebeverine HCl following rectal administration of selected suppositories to rabbits, as compared to oral Duspatalin® tablets.
*SD: Standard Deviation.
** significantly different (p ≤ 0.05 ) from Witepsol H15 and polyethylene glycol suppositories.
a : Zero-order release rate constant (mg.ml-1.min-1).
b : First-order release rate constant (min-1).
c : Diffusion release rate constant (mg.ml-1.min-1/2).
The formula prepared from Witepsol H15 was selected as a control formula for further study of the effect of addition of different enhancers on the release rate of the drug, since it exhibited the highest release rate of the drug compared to the other fatty suppository bases.
Table 2 :The percentage relative bioavailability (Frel) and the fraction of the dose of mebeverine HCl that avoided first-pass metabolism in the liver (fnh) following rectal administration of selected suppositories to rabbits.
Introduction
fnh ± SD
Frel * ± SD
Formula
41.26 ± 10.13%
± 38.33%
Polyethylene glycol suppositories
26.30 ± 6.64%
± 27.15%
Control Witepsol H15 suppositories
59.72 ± 15.83%**
± 58.32%**
Witepsol H15 suppositories containing 2% Brij 35
34.45 ± 6.89%**
± 16.70%
Witepsol H15 suppositories containing 10% urea
Mebeverine is a musculotropic antispasmodic agent which is rapidly and completely absorbed after oral administration in the form of tablets or suspensions.
It was reported that mebeverine undergoes rapid and extensive first-pass metabolism following oral administration. The plasma concentrations of the main metabolites were determined in human plasma after oral administration of mebeverine HCl commercial tablets.
Mebeverine HCl was reported to be well absorbed rectally by a mechanism that is not different from that in the upper part of the gastrointestinal tract.
* compared to that of Duspatalin® -135 mg sugar coated tablets.
** significantly different (p ≤ 0.05 ) from control Witepsol H15 suppositories.
Objectives
Conclusions
To formulate mebeverine hydrochloride in suppository dosage form for better targeting of the drug in the treatment of irritable bowel syndrome.
To obtain optimal availability of the drug from suppositories, by avoiding the portal circulation.
The rectal absorption of mebeverine HCl from different formulated suppositories resulted in a significant increase in the systemic availability of the drug, in comparison with that after oral administration of tablets.
This may be due to the partial avoidance of hepatic first-pass metabolism. The extent of avoidance of first-pass metabolism was found to be dependent on the type of the base and the enhancer used.
The results of this study have implications for the development of suppositories as a rectal dosage form of mebeverine HCl that is not commercially available .
Figure 2: The first-order release rate constant (K, min-1) of mebeverine HCl from Witepsol H15 suppositories containing different concentrations of surface active agents (SAA); sodium lauryl sulfate and Brij 35.
Figure 3: The first-order release rate constant (K, min-1) of mebeverine HCl from Witepsol H15 suppositories containing different concentrations of urea and L-lysine HCl.
Methods and Results
1. In-vitro study
Mebeverine HCl suppositories (200 mg / 1g suppository), with or without enhancers, were prepared adopting the melting method.
The dissolution tests of different suppositories of mebeverine HCl were performed in Sorensen,s phosphate buffer pH (6.8), using the rotating basket dissolution apparatus.
Dissolution test of commercial Duspatalin® tablets was performed in 0.1 M HCl pH (1.2).
Samples were assayed for its drug content spectrophotometrically .
Suppositories selected for in-vivo study:
Polyethylene glycol suppositories (a reasonable value of t50% without any release enhancer).
Witepsol H15 suppositories (the highest release rate of the drug compared to the other fatty bases).
Witepsol H15 suppositories containing 2% Brij 35 (superior to the other suppositories containing surfactants).
Witepsol H15 suppositories containing 10% urea (the highest release rate constant among the other tested formulae, compatible with body fluids).
Acknowledgements
The authors would like to thank Mr. Abubakr El-Gorashi in the Department of Pharmaceutics for the generous assistance in the animal work.
References
2. In-vivo study
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Four male albino rabbits weighing kg were treated with either an oral dose equivalent to 67.5 mg of the drug administered in a slurry form, or with half suppository containing 100 mg of the drug inserted into the rectum (Latin Square method, washout period of one week).
Plasma samples were analyzed for the drug using the reversed phase High Performance Liquid Chromatographic (HPLC) method previously established by Al-Angary et al. (1992).
The pharmacokinetic parameters were calculated from the plasma level data obtained.
Figure 1 : In-vitro release of Mebeverine HCl from different suppository bases (in phosphate buffer pH 6.8) and commercial Duspatalin® tablets (in 0.1 M HCl pH 1.2) at 37 ± 0.5 oC.