In current decade, pharmaceutical industries of Bangladesh are giving much emphasize on the formulation of time release preparation to treat various chronic diseases in order to decrease the frequency of administration and to improve patient compliance. Objectives: The objective of this investigation is to design and evaluate sustained release matrix tablet of Gliclazide by direct compression method employing polymers of hydroxypropylmethyl cellulose (HPMC) derivatives (K15M CR and K4M CR) and to select the optimized formulations and compression process by performing a comparative release kinetic study with a reference product, Diamicron MR (one of the worldwide brand of Gliclazide sustain released tablet manufactured by Servier one of the French pharmaceutical company) tablet. Methods: Release kinetics of Gliclazide matrix tablets were determined using USP paddle method at Phosphate buffer (pH 7.4). The release mechanism was explored and explained with zero order, first order, Higuchi and Korsmeyer model. Result: It is found that formulation with lower polymeric concentration follows Higuchi release kinetics and that the formulation with higher concentration best fits with zero order release kinetics. Among the formulations, F1 and F6 show almost similar dissolution profile with Diamicron MR Tablet, which can be suitable candidates for further in-vivo bioequivalence study. Conclusion: Findings of this investigation suggest that F1 and F6 formulations are potential candidates for further bioequivalence study among other formulations.
Matrix systems appear to be a very attractive approach from the economic as well as from the process development and scale-up points of view in modified-release system [
Chemically Gliclazide is 1-(3-azabicyclo [3, 3, 0]oct-3-yl)-3-p-tolylsulphonylurea (
Currently, both conventional and modified release preparation are available. But most of them are failed to give reproducible and desirable drug release profile and there is no evidence of bioavailability and bioequivalence study of such products in Bangladesh. So, a lot of researches are carried out to prepare modified release Gliclazide tablets with pharmacokinetic characteristics suited to the circadian glycemic profile of type II diabetes. This approach will minimize the complications associated with diabetes mellitus [
Individual ingredient was taken according to
The weight variation was determined by taking 10 tablets using an electronic balance (AY120, Shimadzu, Japan). Friability was determined by testing 10 tablets in a friability tester (FTA-20, Campbell Electronics) for 4 minutes at 25 rpm. Tablet thickness, diameter and hardness were determined for 6 tablets using a Sotax HT10.
All dissolution studies were carried out for extended release Gliclazide formulations according to USP XII. Phosphate buffer at pH 7.4 was used as dissolution medium. The amount of Gliclazide was determined by employing UV spectrophotometer to measure the absorbance at the wavelength of maximum 226 nm and 290 nm. For this purpose absorbance of Standard solution against standard blank solution (0.6 ml methanol was diluted to 100 ml by Phosphate buffer (pH 7.4) and absorbance of sample solution against phosphate buffer (at pH 7.4) using 1 cm cell were measured. Differences between these two absorbances (at 226 and 290 nm) were calculated.
All of the studied physical properties were within the acceptable range with narrow variation and complied with the pharmacopoeial specifications for hardness, friability and weight variation. Range of hardness was 9.8 to 10.5 Kpa, friability was below 1.0% and rage was 0.34% to 0.40% and weight variation was 1.4% to 1.8% which is below 5%.
The release profile of Gliclazide was monitored up to 10 hours.
Formulation | Gliclazide | % of Polymer | K15M CR | K4M CR | Lactose | Mg-Stearate |
---|---|---|---|---|---|---|
F1 | 30 | 20 | 36 | - | 113.1 | 0.9 |
F2 | 30 | 25 | 45 | - | 104.1 | 0.9 |
F3 | 30 | 30 | 54 | - | 95.1 | 0.9 |
F4 | 30 | 20 | - | 36 | 113.1 | 0.9 |
F5 | 30 | 25 | - | 45 | 104.1 | 0.9 |
F6 | 30 | 30 | - | 54 | 95.1 | 0.9 |
decreased tortuosity of the path of the drug due to its preferential solubility than Methocel K15 M CR, by its swelling effect; additionally weakened the integrity of the matrix [
The kinetics data are presented in
The release profile of Gliclazide from formulation F4, F5 and F6 were monitored up to 10 hours.
The kinetics data are presented in
Formulation code | Gliclazide release (%) after 10 hrs | Zero order | First order | Higuchi | Korsmeyer | ||||
---|---|---|---|---|---|---|---|---|---|
r2 | K0 | r2 | K1 | r2 | KH | r2 | n | ||
F1 | 64.566 | 0.969 | 5.755 | 0.984 | −0.040 | 0.976 | 20.06 | 0.924 | 0.517 |
F2 | 56.83 | 0.945 | 4.751 | 0.953 | −0.030 | 0.953 | 16.58 | 0.978 | 0.603 |
F3 | 55.293 | 0.974 | 5.051 | 0.953 | −0.032 | 0.922 | 17.07 | 0.938 | 0.645 |
Formulation code | Gliclazide release (%) after 10 hrs | Zero order | First order | Higuchi | Korsmeyer | ||||
---|---|---|---|---|---|---|---|---|---|
r2 | K0 | r2 | K1 | r2 | KH | r2 | n | ||
F4 | 73.07 | 0.885 | 6.266 | 0.958 | −0.054 | 0.978 | 22.89 | 0.936 | 0. 395 |
F5 | 69.26 | 0.961 | 6.414 | 0.988 | −0.049 | 0.979 | 22.50 | 0.970 | 0.565 |
F6 | 65.44 | 0.985 | 6.287 | 0.980 | −0.043 | 0.936 | 21.31 | 0.966 | 0.769 |
good linearity for Korsmeyer plot (r2: 0.991 to 0.936) where Formulation F4 follow Fickian (case I) diffusion (n: 0.395 < 0.45) and others follow Anomalous or non-Fickian transport (n > 0.45 but <0.89).
From
where Rt and Tt are the percent drug dissolved at each time point for the reference and test products, respectively; n is the number of dissolution sample times and t is the time points for collecting dissolution samples.
From the above study, it is seen that among the proposed formulations F1 and F6 are more likely to meet the specification with Diamicron MR in terms of Difference Factor (f1) and Similarity Factor (f2) and their release profile with Diamicron MR (
In the present study, Gliclazide matrix tablets have been prepared by employing polymers K15M CR and K4M CR with good tabletting properties like weight variation, thickness, diameter, hardness and friability (
Formulation | Difference factor, (f1) (0 to 15) | Similarity factor, (f2) (50 to 100) |
---|---|---|
F1 | 5.6 | 72.3 |
F2 | 17.9 | 54.2 |
F3 | 21.6 | 50.7 |
F4 | 34.6 | 41.3 |
F5 | 14.2 | 59.0 |
F6 | 7.3 | 70.6 |
Formulation | Hardness (Kpa) | Thickness (mm) | Diameter (mm) | Friability (%) | Weight Variation |
---|---|---|---|---|---|
F1 | 09.9 ± 0.05 | 3.31 | 10.02 | 0.35 | ±1.8 |
F2 | 10.1 ± 0.08 | 3.32 | 10.01 | 0.37 | ±1.4 |
F3 | 10.5 ± 0.10 | 3.30 | 10.00 | 0.34 | ±1.6 |
F4 | 10.3 ± 0.50 | 3.33 | 10.00 | 0.38 | ±1.6 |
F5 | 10.3 ± 0.50 | 3.34 | 10.01 | 0.38 | ±1.4 |
F6 | 09.8 ± 0.10 | 3.33 | 09.99 | 0.40 | ±1.7 |
transport. Formulation F1 best fits with first order release model indicating concentration dependent drug release where as Formulation F6 best fits with zero order release model indicating that the drug is released from the matrix tablet by both diffusion and erosion. For the further bioequivalence study, these two (F1 & F6) will be more prominent candidates than other formulations.
Authors are thankful to SQUARE Pharmaceuticals Ltd., Bangladesh for proving manufacturing facilities.
The authors declare that they have no conflict of interest to disclose.