Transcript Suppositories containing 200 mg of mebeverine hydrochloride were

Suppositories containing 200 mg of mebeverine hydrochloride were prepared using
different suppository bases namely: Cocoa butter, Witepsol H15, Suppocir AP, Estaram
Formula
H15, and polyethylene glycol (PEG)1000:4000 mixture in a ratio of 3:1, respectively. The
Correlation coefficients of
different release models
K ± SD*
t50% ± SD*
Zero
First
Higuchi
PEG suppositories
0.997
0.989
0.974
8.497 ± 0.44a
5.88 ± 0.28
Witepsol H15 suppository bases among the other tested bases. The effect of type and
Witepsol H15 suppositories
0.974
0.988
0.974
0.055 ± 0.003b
12.60 ± 0.65
concentration of different enhancers: Brij 35, sodium lauryl sulfate, urea and L- lysine
Estaram H15 suppositories
0.898
0.987
0.984
0.025 ± 0.001b
27.72 ± 1.65
0.988
0.014 ±
in-vitro release rate of mebeverine HCl was optimum from
polyethylene glycol and
Suppocir AP suppositories
The increase in the release rate from Witepsol H15 base was found to be optimum upon the
Cocoa Butter suppositories
0.919
0.946
0.989
3.291 ± 0.19c
209.05 ± 10.00
Duspatalin® Tablets
0.997
0.947
0.924
1.443 ± 0.12a
34.65 ± 3.20**
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
0.997
49.50 ± 1.97
hydrochloride on the rate of drug release from Witepsol H15 suppositories was studied.
addition of 10% urea as compared to other enhancers. The in-vivo study of mebeverine
0.908
0.001b
*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).
5000
Mean plasma concentration (ng/ml)
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.
8%
Oral tablet
Witepsol supp.
PEG supp
Witepsol supp.+ 2% Brij 35
Witepsol supp.+10% urea
4000
3000
21%
29% 19%
2000
1000
Oral tablet
PEG suppositories
Witepsol H15 suppositories
Witepsol supp. + 2% Brij 35
Witepsol supp. + 10% urea
0
0
2
Time (hr)
4
6
23%
8
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.
due to partial avoidance of first-pass metabolism in the liver.
Mebeverine is a musculotropic antispasmodic agent which is rapidly and completely
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.
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.
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.
0.1
-1
First -order release rate constant
It was reported that mebeverine undergoes rapid and extensive first-pass metabolism
(min )
absorbed after oral administration in the form of tablets or suspensions.
0.08
Control Witepsol supp.
Control + 0.5% w/w SAA
Control + 1% w/w SAA
Control + 2% w/w SAA
0.055
0.111
0.104
0.04
0.02
0.071
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 .
% Drug Released
120
100
Polyethylene glycol
suppositories
206.27 ± 38.33%
41.26 ± 10.13%
Control Witepsol H15
suppositories
167.52 ± 27.15%
26.30 ± 6.64%
Witepsol H15 suppositories
containing 2% Brij 35
253.96 ± 58.32%**
59.72 ± 15.83%**
Witepsol H15 suppositories
containing 10% urea
187.23 ± 16.70%
34.45 ± 6.89%**
* compared to that of Duspatalin® -135 mg sugar coated tablets.
** significantly different (p ≤ 0.05 ) from control Witepsol H15 suppositories.
0
Sodium Lauryl
Sulfate
Brij 35
0.06
Witepsol H15 suppositories
Witepsol supp. + 0.75% lysine HCl
Witepsol supp. + 1.5% lysine HCl
Witepsol supp. + 3% lysine HCl
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.
Mebeverine HCl suppositories (200 mg / 1g suppository), with or without enhancers,
The dissolution tests of different suppositories of mebeverine HCl were performed in
fnh ± SD
0.058 0.055
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.
were prepared adopting the melting method.
Frel * ± SD
Formula
0.085
Witepsol H15 suppositories
Witepsol supp. + 1% urea
Witepsol supp. + 4% urea
Witepsol supp. + 10% urea
0.06
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.
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).
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 .
The authors would like to thank Mr. Abubakr El-Gorashi in the Department of Pharmaceutics for
the generous assistance in the animal work.
80
60
Witepsol H15
Estraram H15
Suppocir AP
Cocoa butter
Duspatalin® tablets
Polyethylene glycol
40
20
0
0
20
40
60
80
100
120
140
Time (min)
1. Connel A.M.; Br, Med. J., 2: 848-851, (1965).
Four male albino rabbits weighing 3.5-4.5 kg were treated with either an oral dose equivalent
2. Dickinson, R.G., Baker, P.V., Franklin, M.E. et al.; J. Pharm. Sci., 80 (10): 952-957, (1991).
to 67.5 mg of the drug administered in a slurry form, or with half suppository containing 100
3. Tulich L.J., Randall, J.L., Kelm, G.R. et al. ; J. Chromatog. Biomed. Appl., 682: 273-281, (1996).
mg of the drug inserted into the rectum (Latin Square method, washout period of one week).
4. Hosny, E.A and Al-Gohary, O.M.N.; Drug Dev. Ind. Pharm., 20(16): 2593-2605, (1994).
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).
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.
The pharmacokinetic parameters were calculated from the plasma level data obtained.
5. Al-Angary, A.A., Khidr, S.H., Abd-Elhady, S.S., et al. ; Anal. Lett., 25(7): 1251-1260, (1992).
6. Tokada, K., Yoshikawa, H. and Muranishi, S.; Int. J. Pharm.; 25: 155-163, (1985).