Characterization and Evaluation of
Glibenclamide Transmucosal Drug Delivery System
PS Goudanavar*
, RS Bagali and SM Patil1
K.L.E’s
College of Pharmacy, Nipani,
ABSTRACT
In an
attempt to develop mucoadhesive buccal drug delivery
system, buccal tablets of Glibenclamide were prepared
using polymers such as carbopol-934, Hydroxypropylmethyl
cellulose HPMCK4M, and sodium carboxy methyl
cellulose (Sod. CMC) in various proportions and combinations. The tablets were
evaluated for different physicochemical parameters like weight variation, friability,
hardness, drug content, water absorption studies, bioadhesive
performance, release characteristics and surface pH. Tablets containing
carbopol-934 and sodium CMC showed a maximum in vitro release of 82.27%.
The formulations were subjected to graphical treatments according to Higuchi’s
equation and Peppa’s equation. The best formulation
F1 confirmed that the release mechanism is by diffusion, the rate of release
following first order kinetic model.
KEYWORDS: Buccal tablet, bioadhesive performance, release characteristics, surface
pH,
INTRODUCTION
Glibenclamide
is a second generation sulphonylurea which is widely
used in the treatment of maturity onset diabetes1. Only 50% of
single oral dose of glibenclamide is absorbed,
showing that it is subjected to extensive first pass metabolism2.
In the
present work an attempt has been made to develop a buccal
mucoadhesive dosage form for glibenclamide for
improving and enhancing its bioavailability. The aim of this study was to
prepare and evaluate buccal tablets of Glibenclamide
using bioadhesive polymer in order to over come
bioavailability problems and to reduce dose dependent side effects.
The
physicochemical properties of this drug, i.e. its suitable half life (5-10
hours), low molecular weight (494.00), small dose requirements (2.5-5 mg),
absence of objectionable taste and odour makes it a
suitable candidate for buccal administration3.
Glibenclamide was purchased from Loba Chemicals, Carbopol-934 (CP-934) and carboxymethylcellulose sodium (NaCMC)
from Genuine Chemicals Co. and Hydroxypropylmethylcellulose
K4M (HPMC-K4M) was procured from Loba Chemicals,
Lactose from Samrat Polymers Pvt., Talc and magnesium
stearate were obtained from commercial sources. Other
solvents and materials used in the study were of reagent grade.
Preparation
of Buccal Tablets:
Buccal tablets of
glibenclamide were prepared by wet granulation
technique. The ingredients (Glibenclamide, polymers and diluent
lactose) were weighed accurately and mixed by trituration.
The resultant mixture was wetted with 90% isopropyl alcohol and granulated
through sieve no. 10. Then it is dried at 40° for half an hour in an oven and processed to get
TABLE NO.
1: Effect Of Polymer On Drug Release
And Bioadhesive Strength
|
Composition |
Formulations Code
|
|||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
|
Glibenclamide
(mg) |
10 |
10 |
10 |
10 |
10 |
10 |
|
CP-934 (mg) |
15 |
15 |
50 |
125 |
- |
- |
|
HPMC-K4M (mg) |
- |
125 |
50 |
- |
125 |
- |
|
Sod. CMC-H (mg) |
125 |
- |
- |
- |
- |
125 |
|
Lactose (mg) |
48 |
48 |
88 |
63 |
63 |
63 |
|
Talc (mg) |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
|
Magnesium stearate (mg) |
0.5 |
0.5 |
0.5 |
0.5 |
0.5 |
0.5 |
|
Isopropyl alcohol
(ml) |
q.s |
q.s |
q.s |
q.s |
q.s |
q.s |
|
Cumulative % drug
release |
82.27 |
65.23 |
72.47 |
78.73 |
61.41 |
80.86 |
|
Bioadhesive strength
(gms) |
2.90 |
4.40 |
5.11 |
7.34 |
3.21 |
2.79 |
CP – 934: Carbopol 934, HPMC – K4M: Hydroxypropylmethylcellulose
K4M, Sod. CMC: Sodiumcarboxymethylcellulose – high
viscosity
TABLE NO.
II: Evaluation Of Buccal Tablets Of Glibenclamide For
Pharmacopoeial Specifications.
|
Evaluation
Parameters |
Formulations
|
|||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
|
Diameter n=3 |
9.45 |
9.50 |
9.63 |
9.45 |
9.50 |
9.40 |
|
Hardness kg/cm2 |
4.95 |
5.01 |
5.00 |
4.98 |
4.99 |
5.02 |
|
Friability % |
0.71 |
0.70 |
0.76 |
0.70 |
0.80 |
0.71 |
|
Weight variation
(mg) |
197 |
196 |
190 |
195 |
196 |
201 |
|
% Deviation |
1.5 |
2 |
3.0 |
2.5 |
2.5 |
0.5 |
|
Disintegration time |
9 hrs & 45 min |
12 hrs & 40 min |
9 hrs & 45 min |
6 hrs & 15 min |
13 hrs & 45 min |
9 hrs & 15 min |
|
Content Uniformity
in (%) |
91.95 |
94.6 |
98.68 |
90.52 |
96.34 |
93.03 |
|
Formulation Code |
Regression values of
Higuchi’s Plot |
Slope values of Peppa’s Plot |
Regression values of
Bidah’s Plot |
F1
F2 F3 F4 F5 F6 |
0.9886 0.9746 0.9569 0.9826 0.9652 0.9826 |
0.676 0.827 0.931 0.723 0.065 0.717 |
0.9905 0.9898 0.977 0.9901 0.9887 0.9897 |
The dried granules (
Evaluation of Buccal Tablets:
The buccal tablets were evaluated for general appearance,
diameter, weight variation, hardness, friability and content uniformity. The
tests for weight variation, hardness and friability were performed as per the
United States Pharmacopoeia 20th edition4. Content
uniformity was performed by the method specified in Indian Pharmacopoeia5.
Tablet Disintegration
Test:
The disintegration
pattern of each bioadhesive buccal
tablet was observed by immersing the tablet in a glass petridish
of l cm containing 25ml of water at room temperature (25°C). The morphological
change of each tablet was observed for 20 hours6.
Measurement of surface
pH:
The
surface pH was determined by a method similar to that used by Bottenberg et al. A combined glass electrode was used for
this purpose. The tablets were kept in contact with 0.5ml of distilled water
for 1 hour. pH was noted by bringing, the electrode near the surface of the
formulations and allowing it to equilibrate for 1min7.
Measurement of Bioadhesive Strength:
Bioadhesive strength
was measured using a modified physical balance as described by Gupta et al8.
Water Absorption
Studies:
This was done on 1%
agar gel plates. The tablets were placed with the core facing the gel surface
and incubated for 6 hours at 37°C. The
tablets were weighed before and after standing on the agar plate and examined
for any physical changes9.
In vitro
dissolution studies:
The drug release was
determined using a modified USP dissolution rate test apparatus (No.XXIII). The modification consisted of an internal
compartment made up of 150ml glass beaker (id 40mm) into which was placed a
m-seal block (40mm diameter, 20mm height) having a cavity (13mm diameter, 4mm
depth) on one side. The tablet was inserted into the cavity of m-seal block so
that the core faced the dissolution medium (100ml isotonic phosphate buffer
(IPB) pH 6.6 at 37°C). A
stirrer was lowered so that it remained only l cm above the tablet surface and
stirring was done at 50rpm. Samples (4.5 ml) were withdrawn and replaced by
fresh dissolution medium every half an hour for 6 hours. Filtered samples were
then diluted suitably and absorbance was read at 226mm and cumulative drug
released at various time intervals was calculated10.
Results
and Discussion:
Table 1 gives the
working formula for the tablets. The polymers for the development of glibenclamide buccal tablets were
selected on the basis of bioadhesive property,
non-toxicity, non-irritancy, stability and compatibility with the drug. The
studies revealed that the buccal tablets complied
with the pharmacopoeial specifications for hardness,
friability, weight variation and disintegration time. The surface pH of all the
tablets was within the range of salivary pH i.e. 5.6-7.6.
The measurement of bioadhesive
strength revealed that buccal tablets of F4
containing only carbopol 934 alone showed maximum bioadhesive strength followed by F3 [Carbopol
934 + HPMC K4M (1:1)], F2 [Carbopol 934 + HPMC K4M (
The results of the
water absorption study indicated that the tablets did not show any appreciable
change in their shape during the 6 hr they were kept on the agar plate. The buccal tablets of all formulations showed swelling when
placed in the agar gel plates at the end of 6 hours. Formulations containing carbopol 934 alone i.e. F4 showed maximum gain in weight,
up to 165% due to absorbed water after 6 hours.
The formulation F1
containing 15mg of CP-934 and 125mg of Na-CMC showed a maximum in vitro drug release of 82.27 at the end of
6 hours followed by F6 containing sod. CMC alone, showing an invitro release of 80.86%. Formulations F1 and F6 showed to
be best fitted with first order kinetic model but the remaining formulations
i.e. F2, F3, F4 and F5 showed zero order release pattern.
The in vitro
release data were subjected to Higuchi’s and Peppa’s
plots to determine the mechanism of release. The regression values of Higuchi’s
plot of formulation F1 was found to be 0.9884 which indicates that the drug
release from the matrix is by diffusion. The slope value of Peppa’s
plot was 0.676 for F1 showing that there is a non Fickian
release of the drug. Furthermore the invitro release
data was also subjected to Bidah’s plot to see if the
release pattern fitted into the erosion mechanism. The regression values for F1
also showed the rate of disappearance of the drug from the buccal
tablet of formulation F1 also showed erosion.
Thus it is evident
from the buccal tablets of the best formulation F1,
the mechanism of drug release is diffusion controlled and the rate of diffusion
was by first order kinetics. Rate of disappearance of the drug was found to be
by erosion mechanism.
CONCLUSION:
In conclusion, a mucoadhesive
formulation in the form of erodible buccal tablets of
Glibenclamide was developed to a satisfactory level with respect to drug
release, bioadhesive performance, physical and
mechanical properties and surface pH. Invitro drug
release could be obtained for up to 6 hours with a polymer combination of
CP-934 and SCMC in a ratio of
Further in-vivo
studies need to be carried out for this drug delivery system and in-vitro
correlation need to be established to provide optimum drug levels in the plasma
and to confirm the correctness of statistical results obtained via in-vitro
studies. A high in-vitro -in-vivo
correlation value indicates correctness of the in-vitro method followed and
adaptability of the delivery system to the biological system where it can
release the drug in a concentration dependant factor. Also there is a need for exploring the
possibility of scaling up the method of manufacture in order to make it
suitable for large scale commercial manufacture of buccal
tablets of Glibenclamide to offer an alternative drug delivery system to
conventional therapy.
REFERENCES:
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581-585.
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1990, “Analytical Profile for Drug Substances – Glibenclamide”, Vol. 10,
Academic Press, Inc
4. “United States
Pharmacopoeia”, XX, United States Pharmacopoeial convention,
5. “Indian Pharmacopoeia”, 1996, Ministry of Health and Family
Welfare; Govt. Of
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Received on
08.12.2009
Accepted on
19.01.2010
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Research
Journal of Pharmaceutical Dosage Forms and Technology. 2(1): Jan. –Feb. 2010, 44-46