Acta Pharmaceutica


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Publications in this journal

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    ABSTRACT: Abstract Crystallization of the drug entacapone from binary solvent mixtures was monitored in situ using a Raman optical probe. The recorded Raman spectra and statistical analysis, which included the principal components method and indirect hard modeling made it possible to estimate the starting point of crystallization, to assess crystallization temperatures and to provide information on the polymorphic content of the mixture. It was established that crystallization temperatures were proportional to the volume content of the solvent in mixtures. The samples were also evaluated off-line via Raman spectroscopy and SWAXS. The collected data showed the presence of forms b and g in all solvent mixtures. In a toluene/methanol 30:70 mixture, in addition to forms b and g, at least one of the forms A, D or a was also indicated by SWAXS. The results have shown that the presence of a particular polymorph is strongly dependent on the nature and portion of the solvent in the binary solvent mixture.
    Acta Pharmaceutica 03/2014; 64(1):1-13.
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    ABSTRACT: Abstract Diclofenac belongs to non-steroidal anti-inflammatory drugs (NSAIDs) and non-selective COX inhibitors. The aim of this study was to examine the effect of diclofenac on endothelial cell proliferation under the influence of hypoxia or inflammatory conditions. Another goal was to check whether diclofenac modulates the secretion of angiogenic factors such as VEGF and bFGF in human microvascular endothelial cells (HMEC-1) in the presence of CoCl2 or lipopolysaccharide (LPS), which could influence the endothelial cells in an autocrine manner or other cells in a paracrine manner. HMEC-1 cells were treated with 0.1 and 0.3 mmol L-1 diclofenac in the presence of 100 μg mL-1 LPS or 200 μmol L-1 CoCl2. Diclofenac decreased cell viability under hypoxia and inflammatory conditions. The stimulation of bFGF secretion by LPS in microvascular endothelial cells (HMEC-1 cell) was attenuated by diclofenac. Diclofenac increased the secretion of VEGF induced by LPS and hypoxia.
    Acta Pharmaceutica 03/2014; 64(1):131-8.
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    ABSTRACT: Abstract Quinone-based fluorophores and enhanced native fluorescence techniques were applied for a fast quantitative analysis of gemifloxacin mesylate (GEM) and linezolid (LIN) in pharmaceutical formulations. For this purpose, three sensitive, accurate and precise spectrofluorimetric methods were developed. GEM, as an n-electron donor, reacts with 7,7,8,8-tetracyanoquinodimethane (method A) and 2,5-dichloro-3,6-dihydroxy-p-benzoquinone (method B) as п-electron acceptors, forming charge transfer complexes that exhibit high fluorescence intensity at 441 and 390 nm upon excitation at 260 and 339 nm, respectively. Method C depends on measurement of enhanced native fluorescence of LIN in phosphate buffer (pH 5) at 380 nm upon excitation at 260 nm. Experimental factors affecting fluorescence intensity were optimized. Linearity was obtained over concentration ranges 50-500, 10-60 and 20-400 ng mL-1 for methods A, B and C, respectively. The developed methods were validated and successfully applied for determination of the cited drugs in tablets.
    Acta Pharmaceutica 03/2014; 64(1):15-28.
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    ABSTRACT: Abstract Alginate vehicles are capable of forming a gel matrix in situ when they come into contact with gastric medium in the presence of calcium ions. However, the gel structure is pH dependent and can break after gastric emptying, leading to dose dumping. The aim of this work was to develop modified in situ gelling alginate formulations capable of sustaining dextromethorphan release throughout the gastrointestinal tract. Alginate solution (2 %, m/m) was used as a vehicle for the tested formulations. Solid matrix of the drug and Eudragit S 100 was prepared by dissolving the drug and polymer in acetone. The organic solvent was then evaporated and the deposited solid matrix was micronized, sieved and dispersed in alginate solution to obtain candidate formulations. The release behavior of dextromethorphan was monitored and evaluated in a medium simulating the gastric and intestinal pH. Drug-polymer compatibility and possible solid-state interactions suggested physical interaction through hydrogen bonding between the drug and the polymer. A significant decrease in the rate and extent of dextromethorphan release was observed with increasing Eudragit S 100 concentration in the prepared particles. Most formulations showed sustained release profiles similar to that of a commercial sustained-release liquid based on ion exchange resin. The release pattern indicated strict control of drug release both under gastric and intestinal conditions, suggesting the potential advantage of using a solid dispersion of drug-Eudragit S 100 to overcome the problem of dose dumping after the rupture of the pH dependent alginate gels.
    Acta Pharmaceutica 03/2014; 64(1):29-44.
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    ABSTRACT: Abstract The aim of this study was to test the hypothesis that glutathione- S-transferase (GST) genotypes were associated with COPD. GSTP1, GSTM1 and GSTT1 genotypes were determined by DNA methods and GST activity spectrophotometrically in older male Caucasian Croats (non- -smokers, ex-smokers, and smokers) with stable COPD (n = 30) and sex/age matched controls (n = 60). The distribution of GSTP1 genotypes and alleles in controls vs. COPD showed a statistical difference (p < 0.05). The odds ratio of CC/CT+TT (wild type GSTP1 exon 6 vs. joint heterozygous and mutant homozygous GSTP1 exon 6) was 10.000 and statistically different (p = 0.002). In this study, the GSTP1 mutant genotype of exon 5 (GG), as well as GSTP1 mutant and heterozygous genotypes of exon 6 (TT and CT), were suggested to be genetic contributors to COPD susceptibility. Null GSTM1, null GSTT1 and joint GSTM1/GSTT1 null genotypes were not disease associated. Serum GST was not associated with GST genotypes and COPD or smoking history in our study subjects. Conclusions drawn from the study should be further supported and clarified by studies with larger sample sizes.
    Acta Pharmaceutica 03/2014; 64(1):117-29.
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    ABSTRACT: Abstract Two randomized, single dose, 2-period, 2-sequence crossover studies were conducted to evaluate the comparative bioavailability of two clopidogrel formulations under fasting and fed conditions. Assessment of bioequivalence was based upon measurement of plasma concentrations of the parent drug, clopidogrel, and its major (inactive) metabolite, clopidogrel carboxylic acid, using improved methanol-free extraction. Bioequivalence of Krka's formulation to the innovator's formulation was demonstrated under both fasting and fed conditions on 205 volunteers. Confidence intervals for AUC0-t, AUC0-inf and Cmax of clopidogrel and its main metabolite were well within the acceptance range of 80.00 to 125.00 %. Food substantially increased the bioavailability of clopidogrel from both formulations, while no effect of food on the extent and rate of exposure to the metabolite was observed. The effect of food was comparable between the two formulations, as indicated by the same direction and rank of food impact on the bioavailability of both formulations.
    Acta Pharmaceutica 03/2014; 64(1):45-62.
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    ABSTRACT: Abstract C57BL/6 mice with dilated cardiomyopathy (DCM) were randomly divided to receive placebo or pitavastatin at a dose of 1 or 3 mg kg-1d-1. After 8 weeks treatment, mice with dilated cardiomyopathy developed serious cardiac dysfunction characterized by significantly enhanced left ventricular end-diastolic diameter (LVIDd), decreased left ventricular ejection fraction (LVEF) as well as left ventricular short axis fractional shortening (LVFS), accompanied with enlarged cardiomyocytes, and increased plasma levels of N-terminal pro-B type natriuretic peptide (NT-proBNP) and plasma angiotensin II (AngII) concentration. Moreover, myocardium sarcoplasmic reticulum Ca2+ pump (SERCA-2) activity was decreased. The ratio of phosphorylated phospholamban (PLB) to total PLB decreased significantly with the down-regulation of SERCA- -2a and ryanodine receptor (RyR2) expression. Pitavastatin was found to ameliorate the cardiac dysfunction in mice with dilated cardiomyopathy by reversing the changes in the ratios of phosphorylated PLB to total PLB, SERCA-2a and RyR2 via reducing the plasma AngII concentration and the expressions of myocardium angiotensin II type 1 receptor (AT1R) and protein kinase C (PKC)b2. The possible underlying mechanism might be the regulation of myocardial AT1R-PKCb2-Ca2+ handling proteins.
    Acta Pharmaceutica 03/2014; 64(1):105-15.
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    ABSTRACT: Abstract Ciprofloxacin bioavailability may be reduced when ciprofloxacin is co-administered with metallic ion containing preparations. In our previous study, physicochemical interaction between ciprofloxacin and ferrous sulphate was successfully simulated in vitro. In the present work, comparative in vitro ciprofloxacin solubility and dissolution studies were performed in the reactive media containing aluminium hydroxide, calcium carbonate or zinc sulphate. Solid phases collected from the dissolution vessel with aluminium hydroxide, calcium carbonate and zinc sulphate were investigated for their properties. The results obtained indicate that different types of adducts may form and retard ciprofloxacin solubility and dissolution. In the case of aluminium, no phase changes were observed. The solid phase generated in the presence of calcium carbonate was identified as hydrated ciprofloxacin base. Similarly to iron, a new complex consistent with Zn(SO4)2(Cl)2(ciprofloxacin)2 × nH2O stoichiometry was generated in the presence of relatively high concentrations of ciprofloxacin hydrochloride and zinc sulphate, indicating that small volume dissolution experiments can be useful for biorelevant dissolution tests.
    Acta Pharmaceutica 03/2014; 64(1):77-88.
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    ABSTRACT: Abstract Eudragit E (EE)-sodium alginate (SA) polyelectrolyte complexes (PECs) were prepared at pH 4 and 5.8 using sodium alginate of high (SAH) and low viscosity (SAL). The optimum EE-SA complexation mass ratio was determined using viscosity measurements. Interactions between EE and SA in PECs were characterized by Fourier transform infra-red spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Diltiazem hydrochloride (DTZ HCl) tablets were prepared using the prepared EE-SA PECs and their physical mixtures at different ratios as matrices. Tablets were evaluated for swelling characteristics and in vitro drug release. Tablets containing EE-SAH physical mixtures of ratios (1.5:1 and 1:3) as matrices were effective in achieving sustained release of DTZ HCl, where the percent drug released was significantly (p < 0.05) decreased compared to that from tablets either containing the same ratios of EE-SAL physical mixtures or the preformed EE- -SAH and EE-SAL PECs.
    Acta Pharmaceutica 03/2014; 64(1):89-104.
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    ABSTRACT: Abstract Sterile thermoreversibly gelling systems based on chitosan- glycerol phosphate were developed for intraperitoneal delivery of the antineoplastic agent 5-FU. The formulation was evaluated for gelling characteristics and in vitro drug release. Drug free gels were evaluated for in vitro cytotoxicity in L-929 mouse fibroblast cells. Drug loaded gels were subjected to acute toxicity studies in Swiss albino mice via intraperitoneal route and efficacy studies via intratumoral injections in subcutaneous colon carcinoma bearing BALB/c mice. The formulations gelled reversibly in 8 min at 37 °C and provided prolonged release of the drug. Drug free systems showed dose dependent cytotoxicity in fibroblast cells, while in vivo studies revealed a 2.8-fold increase in LD50 of 5-FU administered intraperitoneally as the developed system. Tumor volume measurements showed comparable efficacy of 5-FU administered as gel and commercial injection with a greatly improved safety profile of the former as adjudged from mortality and body weight measurements.
    Acta Pharmaceutica 12/2013; 63(4):479-91.
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    ABSTRACT: Abstract Dried buckwheat herb is used in medicinal products whereas fresh green plant parts, especially sprouts, are consumed as a vegetable. The herb contains fagopyrins, which cause sensitivity to light after ingestion. The aim of this study was to investigate the impact of different growing conditions and the development phase on the content of fagopyrin and phenolic compounds in buckwheat sprouts. Total flavonoid and total phenol contents, fagopyrin content and antioxidant activity were determined spectrophotometrically. Fagopyrin and flavonoids were located almost exclusively in cotyledons. Based on a comparison to hypericin toxicity, the recommendable intake of buckwheat sprouts was estimated to be less than 40 g per day.
    Acta Pharmaceutica 12/2013; 63(4):553-60.
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    ABSTRACT: Abstract The aim of this study was to investigate the in vitro and in vivo performance of salbutamol sulfate press-coated tablets for delayed release. The in vitro release behavior of press-coated tablets with the outer layer of PEG 6000/ Eudragit S100 blends (2:1) in pH 1.2 (0.1 mol L-1 HCl) and then pH 6.8 buffer solution was examined. Morphological change of the press-coated tablet during in vitro release was recorded with a digital camera. Release of salbutamol sulfate from press-coated tablets was less than 5 % before 3 h and was completed after 8 h in pH 6.8 phosphate buffer solution. In vivo gamma scintigraphy study carried out on healthy men indicated that the designed system released the drug in lower parts of the GI tract after a lag time of 5 hours. The results showed the capability of the system of achieving delayed release of the drug in both in vitro and in vivo gamma scintigraphy studies.
    Acta Pharmaceutica 12/2013; 63(4):545-51.
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    ABSTRACT: Abstract Many modern drugs are poorly water soluble substances, which causes difficulties in the development of solid dosage forms with sufficient bioavailability. Preparation of liquisolid systems (LSS) is a novel technique for improving solubility, dissolution and bioavailability of such drugs. The basic principle of LSS preparation is conversion of the drug in liquid state into a free-flowing, compressible, dry powder through its absorption into suitable excipients - porous carriers (aluminometasilicates, microcrystalline cellulose), subsequently coated with material having high absorption capacity (silicon dioxide commonly known as colloidal silica). LSS exhibit advantages such as lower production costs compared to soft capsules, simple processing and enhanced drug release. The main benefit is higher bioavailability of the liquid drug, caused by a large surface area available for absorption. The article tries to clarify specific aspects connected with the formulation of LSS: properties of excipients (surface area, absorption capacity), variables related to the processing (solubility, liquid load factor) and dosage form evaluation.
    Acta Pharmaceutica 12/2013; 63(4):447-65.
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    ABSTRACT: Abstract Prevention of skin aging and its treatment is an emerging field for development of new formulations in cosmetics. Accordingly, plant extracts with antioxidant properties are beneficial cosmetic ingredients for this purpose. This study was aimed at developing a stable and easily manufactured emulgel including green tea extract and rose oil that is effective on the barrier function and hydration of the skin. An emulgel formulation containing 20 % green tea extract and 5 % rose oil was designed as a result of pre-formulation studies. Physicochemical characterization, in vitro stability studies, in vivo water content of the stratum corneum and transepidermal water loss studies were carried out afterwards. In vivo studies on ten female subjects were evaluated by using non-invasive skin bioengineering techniques. Finally, a cosmetically acceptable, stable and effective emulgel formulation for skin barrier function with good hydrating properties was obtained for skin hydration, protection and anti-aging purposes.
    Acta Pharmaceutica 12/2013; 63(4):531-44.