Advanced Pharmaceutical Bulletin
Volume:1 Issue: 1, Jun 2011

We report the synthesis of novel 1,4-dihydropyridine derivatives containing biphenyl-2''-tetrazole moieties. We hypothesized that merging the key structural elements present in an AT1 receptor antagonist with key structural elements in 1,4-dihydropyridine calcium channel blockers would yield novel analogs with potential dual activity for both receptors. This strategy led to the design and synthesis of dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[2΄-(1H-tetrazole-5-yl) biphenyl -4-yl] methyl] imidazole-4(or 5)-yl]- 3, 5-pyridinedicarboxylate analogs. These compounds were obtained by two methods starting from biphenyltetrazolyl-4-(or 5)-imidazolecarboxaldehyde intermediates employing in classical Hantzsch condensation reaction. In the first method, triphenylmethyl protecting group of 4- or 5-carboxaldehyde intermediate was first removed in acidic media and then classical Hantzsch reaction was employed in order to obtain the final products. In the second method, without further deprotection process, protected 4- or 5-carboxaldehyde intermediate directly was used in Hantzsch reaction. The second method was more efficient than the first method since the deprotection and ring closure reaction occurs simultaneously in one pot. Eight novel dihydropridines analogs were synthesized using classic Hantzsch condensation reaction. Chemical structures of the compounds were characterized by 1H NMR, infrared and mass spectroscopy.

DHPEE is a newly synthesized compound by merging the key structural elements in an angiotensin receptor blocker (Telmisartan) with key structural elements in 1,4- dihydropyridine calcium channel blocker (Nifedipine). In this study, we examined dual calcium channel blocking and AT1 antagonist activity for DHPEE. The functional inhibitory characteristics of DHPEE were studied in vitro in rat thoracic aorta preparations precontracted by phenylephrine (1µM) or KCl (80µM) or Ang II in normal or calcium-free solutions. Concentration–dependent significant relaxation was observed in aortic rings precontracted with phenylephrine, KCl or Ang II. The tension increment produced by increasing external calcium was also reduced by DHPEE. DHPEE caused a marked decrease in the maximal contractile response of the vasoactive agents and shifted their concentration-response curves to the right. DHPEE possesses dual characteristics and cause vasorelaxation by blocking the L-type calcium channels and blocking Ang II receptors (AT1) in rat aortic smooth muscle.

The purpose of this investigation was to evaluate microencapsulated controlled release preparation of theophylline using Eudragit RS 100 as the retardant material with high entrapment efficiency. Microspheres were prepared by the emulsion-solvent evaporation method. A mixed solvent system consisting of methanol and acetone and light liquid paraffin as oily phase were chosen. Sucrose stearate was used as the surfactant to stabilize the emulsification process. The prepared microspheres were characterized by drug loading, Fourier-transform infrared spectroscopy (FTIR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release studies were performed at pH 1.2 and 7.4 aqueous medium. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release rate. The drug loading microparticle Eudragit RS100 (1:6) showed 60-75% of entrapment and mean particle size 205.93-352.76 µm. The results showed that, an increase in the ratio of polymer: drug (F5, 6: 1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The release of theophylline is influenced by the drug to polymer ratio and particle size. Drug release is controlled by diffusion and the best-fit release kinetic is Higuchi model.

The percolation theory studies the critical points or percolation thresholds of the system, where onecomponent of the system undergoes a geometrical phase transition, starting to connect the whole system.The application of this theory to study the release rate of hydrophilic matrices allows toexplain the changes in release kinetics of swellable matrix type system and results in a clear improvement of the design of controlled release dosage forms. In this study, the percolation theory has been applied to multi-component hydroxypropylmethylcellulose (HPMC) hydrophilic matrices.Matrix tablets have been prepared using phenobarbital as drug,magnesium stearate as a lubricant employing different amount of lactose and HPMC K4M as a fillerandmatrix forming material, respectively.Ethylcelullose(EC) as a polymeric excipient was also examined. Dissolution studies were carried out using the paddle method.In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to thevolumetric fraction of HPMC at time zero, was studied. In both HPMC/lactose and HPMC/EC/lactose matrices, from the point of view of the percolation theory, the optimum concentration for HPMC, to obtain a hydrophilic matrix system for the controlled release of phenobarbital is higher than 18.1% (v/v) HPMC. Above 18.1% (v/v) HPMC, an infinite cluster of HPMC would be formed maintaining integrity of the system and controlling the drug release from the matrices. According to results, EC had no significant influence on the HPMC percolation threshold. This may be related to broad functionality of the swelling hydrophilic matrices.

Tetracyclines (TCs) are widely used in animal husbandry and their residues in milk may resultinharmful effects on human. The aim of this study was to investigate the presence of TCs residues in various bovine milk samples from local markets of Ardabil, Iran. One hundred and fourteen pasteurized, sterilized and raw milk samples were collected from markets of Ardabil. Tetracycline, Oxytetracycline and Chlortetracycline (TCs) residues extraction carried out by Solid Phase Extraction method. Determination of TCs residues were performed by high performance liquid chromatography (HPLC) method using Fluorescence detector. The mean of total TCs residues in all samples (114 samples) was 97.6 ±16.9ng/g and that of pasteurized, sterilized and raw milk samples were 87.1 ± 17.7, 112.0 ± 57.3 and 154.0 ± 66.3ng/g respectively. Twenty five point four percent of the all samples, and24.4%, 30% and 28.6% of the pasteurized, sterilized and raw milk samples, respectively had higher TCs residues than the recommended maximum levels (100ng/g). This study indicates the presence of tetracycline residues more than allowed amount. Regulatory authorities should ensure proper withdrawal period before milking the animals and definite supervisions are necessary on application of these drugs.

In this work, the use of β-cyclodextrine (β-CD)-modified dendrimers as a nanocapsule with a biocompatible shell have studied. β-CD-modifieddendrimers have designed and synthesized to enhance the loading capacity of the final dendrimers with encapsulation properties. To achieve β-CD-modified dendrimers, first citric acid dendrimers were synthesized and then the end functional groups of dendrimers were grafted to β-CD through ester linkages. The molecular structures of resulted dendrimers were verified using common spectroscopic methods such as 1H NMR, FT-IR and the diameters of obtained nanocarriers were evaluated with using dynamic light scattering (DLS) experiments. The isolated dendrimers were utilized as the drug delivery agents and the encapsulation and the controlled release of guest drug molecule Naltrexone (NLX) was investigated in different pH’s using UV spectroscopy method. It was established that the loading capacity of dendrimers depend on several factors such as their generation and the structure and number of conjugated modifier end groups. Increasing in the number of branches and the size of interior voids and number of conjugated β-CDs cause to enhance the loading capacity.

Prednisolone is a class II substance according to the Biopharmaceutics Classification System. It is a poorly water soluble agent. The aim of the present study was to improve dissolution rate of a poorly water-soluble drug, prednisolone, by a solid dispersion technique. Solid dispersion of prednisolone was prepared with PEG 6000 or different carbohydrates such as lactose and dextrin with various ratios of the drug to carrier i.e., 1:10, 1:20 and 1:40. Solid dispersions were prepared by coevaporation method. The evaluation of the properties of the dispersions was performed using dissolution studies, Fourier-transform infrared spectroscopy and x-ray powder diffractometery. The results indicated that lactose is suitable carriers to enhance the in vitro dissolution rate of prednisolone. The data from the x-ray diffraction showed that the drug was still detectable in its solid state in all solid dispersions except solid dispersions prepared by dextrin as carrier. The results from infrared spectroscopy showed no well-defined drug–carrier interactions for coevaporates. Solid dispersion of a poorly water-soluble drug, prednisolone may alleviate the problems of delayed and inconsistent rate of dissolution of the drug.