Gökhan Ertan

Transdermal Delivery of Diclofenac Sodium Through Rat Skin From Various Formulations

The aim of this study was to evaluate and compare the in vitro and in vivo transdermal potential of w/o microemulsion (M) and gel (G) bases for diclofenac sodium (DS). The effect of dimethyl sulfoxide (DMSO) as a penetration enhancer was also examined when it was added to the M formulation. To study the in vitro potential of these formulations, permeation studies were performed with Franz diffusion cells using excised dorsal rat skin. To investigate their in vivo performance, a carrageenan-induced rat paw edema model was used. The commercial formulation of DS (C) was used as a reference formulation. The results of the in vitro permeation studies and the paw edema tests were analyzed by repeated-measures analysis of variance. The in vitro permeation studies found that M was superior to G and C and that adding DMSO to M increased the permeation rate. The permeability coefficients (Kp) of DS from M and M+DMSO were higher (Kp=4.9×10−3±3.6×10−4 cm/h and 5.3×10−3±1.2×10−3 cm/h, respectively) than the Kp of DS from C (Kp=2.7×10−3±7.3×10−4 cm/h) and G (Kp=4.5×10−3±4.5×10−5 cm/h). In the paw edema test, M showed the best permeation and effectiveness, and M+DMSO had nearly the same effect as M. The in vitro and in vivo studies showed that M could be a new, alternative dosage form for effective therapy.

Extended release lipophilic indomethacin microspheres: formulation factors and mathematical equations fitted drug release rates

Extended release liphophilic microspheres of indomethacin were prepared using cetostearyl alcohol (CsA), stearyl alcohol (SA) and cetyl alcohol (CA) in the various drug-lipid ratios. The release of indometacin was studied on the basis of USP criteria and the effects of drug-lipid ratio, the size of microspheres and carboxymethylcellulose sodium (CMC-Na) added as a hydrophilic polymer on the drug release were investigated. In vitro dissolution studies were performed using USP XXIII apparatus I at pH 6.2. Release profiles were evaluated according to first order, Higuchi square root of time and Hixson-Crowell cube root models. The best fit was found with the square root of time model (r2=0.991) for the microspheres (125-250 microm) prepared in 1:4:1 drug-lipid-copolymer ratio using stearyl alcohol. With a further regression analysis, an excellent equation (Release%=-10.721+42.549*square root of (t)-4.027*t) was developed for empirical drug estimation (r2=0.998).

Preparation and in vitro–in vivo evaluation of ofloxacin loaded ophthalmic nano structured lipid carriers modified with chitosan oligosaccharide lactate for the treatment of bacterial keratitis

The objective of this study was to explore the potential of the nanostructured lipid carriers (NLCs) modified with chitosan oligosaccharide lactate (COL) for topical ocular application. Ofloxacin (OFX) loaded NLCs were prepared by microemulsion or high shear homogenization methods. For combination of NLCs Compritol HD5 ATO was used as solid lipid, oleic acid as liquid lipid, Tween 80 as surfactant, ethanol as co-surfactant. The optimum NLCs was modified with 0.75% COL. The properties of NLCs in the absence or presence of OFX (0.3%) were characterized as zeta potential, particle size, viscosity and pH, TEM, drug loading, encapsulation efficiency and anti-microbial properties. Ex-vivo penetration/permeation studies were performed with rabbit cornea in Franz-diffusion cells. The penetration rate of OFX from NM-COL4OFX and NH-COL4OFX were significantly higher than commercial solution. Based on the selected formulations, in vivo tests were carried out by eye-drop instillation of NLCs in rabbit. The addition of COL improved the preocular residence time, controlled the drug release and enhanced the corneal bioavailability. In conclusion, OFX COL modified NLCs prepared by high shear homogenization method could be offered as a promising strategy for ocular drug delivery.

Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: Preparation, rheological, textural, mucoadhesive and release properties

This study developed and examined the characterization of Benzidamine hydrochloride (BNZ) bioadhesive gels as platforms for oral ulcer treatments. Bioadhesive gels were prepared with four different hydroxypropylmethylcellulose (HPMC) types (E5, E15, E50 and K100M) with different ratios. Each formulation was characterized in terms of drug release, rheological, mechanical properties and adhesion to a buccal bovine mucosa. Drug release was significantly decreased as the concentration and individual viscosity of each polymeric component increased due to improved viscosity of the gel formulations. The amount of drug released for the formulations ranged from 0.76 ± 0.07 and 1.14 ± 0.01 (mg/cm2 ± SD). Formulations exhibited pseudoplastic flow and all formulations, increasing the concentration of HPMC content significantly raised storage modulus (G′), loss modulus (G″), dynamic viscosity (ŋ′) at 37°C. Increasing concentration of each polymeric component also significantly improved the hardness, compressibility, adhesiveness, cohesiveness and mucoadhesion but decreased the elasticity of the gel formulations. All formulations showed non-Fickian diffusion due to the relaxation and swelling of the polymers with water. In conclusion, the formulations studied showed a wide range of mechanical and drug diffusion characteristics. On the basis of the obtained data, the bioadhesive gel formulation which was prepared with 2.5% HPMC K 100M was determined as the most appropriate formulation for buccal application in means of possessing suitable mechanical properties, exhibiting high cohesion and bioadhesion.

Modeling of theophylline release from different geometrical erodible tablets

The aim of this study is to reveal statistically how various geometrical shapes such as triangle, cylinder, half-sphere affect the release rate of the active substance called theophylline in erodible hydrogel matrix tablets. We have tried to indicate these changes in the release rate of theophylline by supporting our aim with the mathematical equations developed by Hopfenberg and Katzhendler et al. The model developed by Hopfenberg assumes that drug release occurs from the primary surface area of the device but Katzhendler et al. (I. Katzhendler, A. Hoffman, A. Goldberger, M. Friedman, Modelling of drug release from erodible tablets, J. Pharm. Sci. 86 (1997) 110-115), described a situation where the erosion rates of the tablet are different in the radial and axial directions. Hydrogel matrix tablets were prepared with hydroxypropylmethylcellulose (HPMC E(50)) possessing different geometrical shapes as triangular, cylindrical and half-spherical using experimental design. When the dissolution results have been evaluated, it has been observed theophylline release from different geometrical erodible tablets fitted with that of the Katzhendler et al., equation. This equation which was suggested for cylindrical tablets was also used to interpret half-spherical and triangular tablets. According to the above stated equation, n has been determined as 4 for triangular tablets and 1.5 for half-spherical tablets and we have also suggested that, these n values could be used in the kinetic programs.

A new approach to the treatment of recurrent aphthous stomatitis with bioadhesive gels containing cyclosporine A solid lipid nanoparticles: in vivo/in vitro examinations

Aim To develop a suitable buccal bioadhesive gel formulation containing cyclosporine A solid lipid nanoparticles (CsA SLNs) for the treatment of recurrent aphthous stomatitis. Methods The suitability of the prepared formulations for buccal application was assessed by means of rheological studies, textural profile analysis, and ex vivo drug-release studies. Plastic flows, typical gel-like spectra, and suitable mechanical properties were obtained from prepared formulations. The retention time was explored in in vivo distribution studies and the effect of the gel containing CsA SLNs on the healing of oral mucosal ulceration was investigated in an animal model. In vivo distribution studies are a very important indicator of the retention time of formulations at the application site. Results Distribution studies showed that 64.76% ± 8.35% of the formulation coded “F8+SLN” remained on the buccal mucosa 6 hours after application. For the second part of the in vivo experiments, 36 rabbits were separated into three groups: the first group was treated with the gel formulation without the active agent; the second group with the gel formulation containing CsA SLNs; and the third group, used as the control group, received no treatment. Wound healing was established by scoring of the rate of wound healing on Days 3, 6, 9, and 12. Histological observations were made on the same days as the scoring studies. The bioadhesive gel formulation that included CsA SLNs increased the rate of mucosal repair significantly. Conclusion This study has shown that the bioadhesive gel formulation containing CsA SLNs reported here is a promising candidate for the topical treatment of recurrent aphthous stomatitis.

Micromeritic studies on nicardipine hydrochloride microcapsules

Abstract In this study, nicardipine hydrochloride (N.HCl) microcapsules were prepared by means of coacervation phase separation technique using ethylcellulose (EC) as a coating material. Micromeritic investigations were carried out on nicardipine hydrochloride, ethylcellulose and nicardipine hydrochloride microcapsules in order to standardize the microcapsule product and to optimize the pilot production of dosage forms prepared with these microcapsules. Microcapsules we prepared had the ratio of 2:1 core:wall and then by sieving, were divided into two groups according to their particle sizes which were > 840 μm and 476–840 μm. The bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, particle size distribution, density and porosity of nicardipine hydrochloride, ethylcellulose and nicardipine hydrochloride microcapsules were studied. To determine flowability, Hausner ratio and Consolidation index were also calculated from the results obtained. The findings of the study suggested that the micromeritic properties of the crude materials were significantly changed by the microencapsulation process. In addition, it was shown by scanning electron microscopy, that the changes were due to changes in the physicochemical properties of drug particles.

An anti-inflammatory drug (mefenamic acid) incorporated in biodegradable alginate beads: development and optimization of the process using factorial design.

The objective of this study was to prepare and evaluate biodegradable alginate beads as a controlled-release system for a water-insoluble drug, mefenamic acid (MA), using 3 × 22 factorial design by ionotropic gelation method. Therefore, the mefenamic acid dispersion in a solution of alginate was dropped into the cross-linking CaCl2 solution and a fairly high yield (71–89%) of MA-alginate beads were obtained. Their encapsulation efficiencies were in the range of 79.3–98.99%. The effect of drug:polymer ratio, CaCl2 concentration, and curing time on the time for 50% of the drug to be released (t50%), and the drug entrapment efficiency were evaluated with factorial design method. It was found that drug:polymer ratio and interaction of drug:polymer ratio and curing time had an important effect on the drug to be released (t50%). The effect of CaCl2 concentration is also important on the drug release. On the other hand, all factors except CaCl2 concentration were effective on the drug entrapment efficiency. The swelling properties of beads were also studied. The release mechanism was described and found to be non-Fickian, Case II, and Super Case II transport for the formulations. This study suggested a new mefenamic acid alginate bead formulation for oral delivery of nonsteroidal anti-inflammatory drugs, which cause gastric irritation.

Sustained release bioadhesive effervescent ketoconazole microcapsules tabletted for vaginal delivery

Microcapsules of ketoconazole with 1:1 and 1:2 core-wall ratios were prepared by means of the phase separation technique using sodium carboxymethylcellulose as a coating material. The microcapsules were mixed with effervescent granules and were tabletted. Dissolution studies of microcapsules, tabletted microcapsules and commercial ovules were carried out with a new basket method (horizontal rotating basket). A good sustained action was obtained with tablets. Micromeritic investigations were carried out on microcapsules in order to standardize the microcapsule product and to optimize the pilot production of the dosage forms prepared with these microcapsules. Bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, relative deviation, particle size distribution, density and porosity values of the microcapsules were determined. In addition, to evaluate whether some kind of glidant will be needed during tabletting of microcapsules, the Hausner ratio and consolidation index were also calculated and it may be concluded that microcapsules do not need any glidant.

Novel ofloxacin-loaded microemulsion formulations for ocular delivery.

PURPOSE The aim of this study was to prepare a novel oil-in-water microemulsion of ofloxacin (OFX) for topical ocular application. METHODS Pseudo-ternary phase diagrams were constructed for combination of oleic acid as oil phase, Tween 80 as surfactant, ethanol as co-surfactant, and 0.5 N NaOH solutions as aqueous phase. The optimum microemulsion was modified with 0.75% chitosan oligosaccharide lactate (COL). The properties of microemulsions in the absence or presence of OFX (0.3%) were measured, such as electrical conductivity, droplet size, viscosity, and pH. The in vitro release study was carried out using the dialysis bag method. Ex vivo permeability studies were performed with rabbit cornea in Franz-diffusion cells. Sterility, minimum inhibition concentration (MIC), and antibacterial activity studies were conducted microbiologically. The preocular residence time and efficacy against bacterial keratitis was compared with a commercial (C) solution via in vivo studies. RESULTS M2OFX modified with 0.75% COL showed slower release than M1OFX, which does not contain COL. The permeation rate of OFX from M1OFX was significantly higher than M2OFX and the C solution. The formulations were sterile and MIC values were the same for both. M2OFX, which contains 0.75% COL, performed higher antibacterial activity than M1OFX. The preocular residence time was improved by microemulsion in comparison to solution; the addition of COL did not make a significant difference. In total, 8 rabbits gave better results with M1OFX, whereas 4 gave similar scores to commercial solution-applied rabbits. CONCLUSION In conclusion, OFX microemulsions could be offered as a promising strategy for ocular drug delivery.