Effect of natural and synthetic polymers on the properties of candesartan cilexetil matrix tablet prepared by dry granulation

摘要

Objective: Candesartan is widely used in the treatment of cardiovascular diseases primarily hypertension and others like heart failure and myocardial infarction. In spite of candesartan cilexetil is a sa the acid moiety is practically insoluble in water and sparingly soluble in methanol. The solubility in water is less than 5×10 -5 mg/ml. Candesartan was found to have low permeability since it shows less than 90% permeation. Candesartan cilexetil was found to have high permeability since it shows more than 90% permeation. The oral bioavailability of candesartan cilexetil is only 15%.Matrix tablets were used as a promising controlled release drug delivery system to evaluate the properties of candesartan cilexetil in the formulations by using different natural and synthetic polymers. Develop a controlled release matrix tablet of candesartan cilexetil to reduce the frequency of administration, enhance bioavailability and to improve the patient compliance; a once daily sustained release formulation of candesartan cilexetil is desirable. Synthetic polymers like eudragit RS100, sodium carboxy methyl cellulose (Na CMC) and hydroxyl propyl methyl cellulose K100M (HPMC K100M) were used. Natural polymers like xanthan gum, acacia gum and tragacanth were used. Tablet related properties like hardness, friability, swelling, in vitro drug release and others were studied and evaluated. Drug related properties like FT-IR, DSC and X-ray diffraction were evaluated. Methods: Tablets contain candesartan cilexetil were prepared by dry granulation method. The sustained release or controlled release tablets were obtained by using different polymers which control the release property of candesartan cilexetil from each tablet. The prepared tablets from F1 to F24 were evaluated with different evaluation parameters like weight variation, drug content, friability, hardness, thickness and swelling ability. In vitro release for all formulas were studied depends on the type and amount of each polymer, i.e. (16 mg, 32 mg and 48 mg) respectively beside to the combination effect of polymers on the release of the drug from the tablet. Drug characteristics and compatibility were studied using FT-IR, differential scanning calorimetry (DSC) and X-ray diffraction. Results: Angle of repose determination showed excellent and good flow for most of the formulas. Most of the formulas were having good compressibility. Weight variation test for all formulas showed accepted value according to the USP. Drug content measurement showed accepted values. Friability study showed accepted values because the values were less than 1%.Hardness was within the accepted values for all formulas which gave an idea about the sustain type of tablets. Thickness for all tablets complied with pharmacopoeia specifications. The swelling index depends on the polymers used in the study which could be arranged according to the ability to absorb water from the buffer solution from the higher to the lower degree of. In vitro release showed that formula 13 had the faster release (100% after 4 h) which contained acacia (1:1) and the lowest sustain release was showed for F7 (73% after 8 h) which contained HPMC K100M (1:1). Formula 1 was an 89 % release after 8 h which contain eudragit RS100; F4 was a 100 % release after 5 h which contain sodium CMC, F10 was a 100% after 8 h which contain xanthan gum and F16 was a 100 % release after 5 h which contain tragacanth polymer. Formula 9 had a lower release than F7 and F8 respectively. The release of the drug was retarded and controlled from all formulas this due to the effect of polymers in which more than one mechanism of release would involve in the release of drug substance. IR study showed the bands of the drug in the formula (F7) were similar to that of pure drug chromatograms and so there were no drug-excipients interactions. Differential scanning calorimetry thermogram for the most sustain formula (F7) showed endothermic peak of candesartan cilexetil, the characteristic peak corresponding to the drug melting which was appeared with small shifting and reduction in the intensity which indicated that the drug was still in the crystal form. The x-ray diffraction pattern of (F7) showed that peaks in the pure candesartan cilexetil x-ray appeared with reduction in intensity. Kinetic studies showed Koresmeyer-Peppas model combined with zero order in case of F1, F7 and F10 which indicates that the drug release is ruled by both diffusion and dissolution of the tablet matrix system. While F4, F13 and F16 showed Koresmeyer-Peppas model combined with Higuchi model. Conclusion: Formula 7 which contains HPMC K100M can be used for sustain oral drug delivery of candesartan cilexetil while Formula 13 can be used in contrary as fast release tablets for faster response. Controlled drug delivery system is promising for less dosing and higher patient compliance.