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Belgrade, Serbia

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Belgrade, Serbia

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Maric L.B.,Galenika Ad | Jovic B.D.,University of Novi Sad | Petrovic S.D.,University of Belgrade | Nikolic A.M.,University of Novi Sad | Homsek I.J.,Galenika Ad
Journal of the Serbian Chemical Society | Year: 2014

This paper reports the use of near infrared (NIR) spectroscopy as a process analytical technology (PAT) tool for monitoring the metformin (N,N- -dimethylimidodicarbonimidic diamide) hydrochloride and poly(vinyl pyrrolidone) (PVP) mixing process, which is the first stage in tablet production. Blend homogeneity was tested using the non-invasive NIR spectroscopy method and the partial least squares (PLS) regression model was applied for the analysis of the obtained spectra. Simultaneously, the critical parameter (metformin hydrochloride content) was monitored by a classical analytical technique, the validated HPLC method, commonly used for this purpose. Based on the high sensitivity of the model developed in this study, as well as the established correlation among the results obtained by different methods, it could be concluded that the proposed rapid and non-invasive technique could be an effecttive tool for the monitoring of one of the critical manufacturing steps in the production solid dosage forms. © 2014 Copyright SCS.


Kocic I.,Galenika Ad | Homsek I.,Galenika Ad | Dacevic M.,Galenika Ad | Grbic S.,University of Belgrade | And 4 more authors.
Biopharmaceutics and Drug Disposition | Year: 2012

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright © 2012 John Wiley & Sons, Ltd.


Trisovic N.P.,University of Belgrade | Bozic B.D.,University of Belgrade | Petrovi S.D.,University of Belgrade | Tadic S.J.,Galenika a.d. | Ivic M.L.A.,University of Belgrade
Hemijska Industrija | Year: 2014

The anodic behaviour of carbamazepine (CBZ), an anticonvulsant drug, has been studied on gold electrode in 0.1 mol dm-3 phosphate buffer of pH 7.0 by using cyclic voltammetry. It has been found that the value of the oxidative current of pure CBZ at 0.90 V vs. SCE is a linear function of the concentration in a range from 1.0×10-7 to 1.0×10-4 mol dm-3. The detection of CBZ in the concentration of 1.0×10-8 mol dm-3 is among the lowest that have been reported for this drug using voltammetric techniques. CBZ as a content of tablet Galepsine® has been quantitatively determined. It has also been demonstrated that the modification of gold electrode with bovine serum albumin (BSA) results in a decrease of the oxidative peak current due to the binding of the drug to BSA.


Seatovic S.L.,Galenika A.d. | Jovanovic Novakovic J.S.,Galenika A.d. | Zavisic G.N.,Galenika A.d. | Radulovic Z.C.,Galenika A.d. | And 2 more authors.
Journal of the Serbian Chemical Society | Year: 2011

The aim of this study was the partial characterization of the antimicrobial peptide bacteriocin G2 produced by probiotic bacteria Lactobacillus plantarum G2, which was isolated from a clinical sample of a healthy person. Antimicrobial substance was secreted in the supernatant of an L. plantarum G2 culture, and showed a diverse spectrum of antimicrobial activity of all the tested strains of the genera Lactobacillus and the pathogenic bacteria Staphylococcus aureus and Salmonella ?bony. Isoelectric focusing revealed that bacteriocin G2 is a cationic peptide (pI about 10) with a molecular mass of 2.2 kDa according to tricine-sodium dodecyl sulphate-polyacrylamide gel electrophoresis, SDS-PAGE. The antimicrobial activity of bacteriocin G2 was diminished by the proteolytic action of trypsin and proteinase K. Bacteriocin G2 preserved its biological activity in the temperature range 40-60 °C (15 min), which was lost at 80 °C. Bacteriocin G2 was stable in the pH range 2-9, while treatment with 1 % Tween 80 and 1 % urea resulted in increased antimicrobial activity. The probiotic strain L. plantarum G2 produces the antimicrobial substance proteinaceous in nature with bacteriocin characteristics. Bacteriocin production is one of the key properties of probiotic bacteria with clinical potential as antiinfective agents, which will increase the likelihood of its in vivo efficacy.


Pjanovic R.,University of Belgrade | Bo.skovic-Vragolovic N.,University of Belgrade | Veljkovic-Giga J.,Galenika A.d. | Garic-Grulovic R.,University of Belgrade | And 2 more authors.
Journal of Chemical Technology and Biotechnology | Year: 2010

BACKGROUND: The mass transfer of model drugs Lidocaine hydrochloride and Dihydroquercetin from hydrogels (the usual carriers for topical drugs), and hydrogels containing liposomes, as novel drug vehicles,was studied. Diffusion experiments were performed using a Franz diffusion cell. Experimental data were used to calculate drug diffusion coefficients acrossmembranes, and their effective diffusion coefficients from hydrogels and liposome containing hydrogels. For the first time the diffusion resistance of all drug carriers was determined from corresponding diffusion coefficients. The main aim of this work was the study of drug diffusion coefficients from liposomes and their comparison with related diffusion coefficients from hydrogels to find how liposomes contribute to prolonged and controlled drug release. RESULTS: Drug diffusion coefficients were: 1.38 • 10-8m2 s-1 for Lidocaine hydrochloride and 5.96 • 10-9m2 s -1 for Dihydroquercetin, while corresponding effective diffusion coefficients from hydrogels were: 7.82 • 10-10m2 s-1 and 7.98 • 10-10m2 s-1, respectively. Effective diffusion coefficients from liposome-containing hydrogels were:4.82 • 10-10m2 s-1 (Lidocaine hydrochloride) and 4.305 • 10-10m2 s -1 (Dihydroquercetin). Diffusion resistances for the two hydrogels were almost the same. Very similar values of diffusion resistances for all liposome dispersions were obtained. CONCLUSION: Calculated diffusion coefficients and resistances demonstrate that liposomes, as drug carriers, significantly affect diffusion rates. The results obtained could be used whenever diffusion-controlled drug release is required. © 2010 Society of Chemical Industry.


PubMed | ORGENTEC GmbH, University of Belgrade, Galenika AD and University College London
Type: Journal Article | Journal: Journal of neurochemistry | Year: 2015

Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D2 /5-HT1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]-picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), in experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation. Both compounds (10mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D2 and 5-HT1A receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM-CSF, TH 1 cytokine IFN-, TH 17 cytokine IL-17, as well as the signature transcription factors of TH 1 (T-bet) and TH 17 (RORt) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The invitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic protein-activated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation. Arylpiperazine dopaminergic/serotonergic ligands reduce neurological symptoms of acute autoimmune encephalomyelitis in rats without affecting the activation of autoreactive immune response, through mechanisms involving a decrease in CNS immune infiltration, as well as direct protection of CNS from immune-mediated damage. These data indicate potential usefulness of arylpiperazine-based compounds in the treatment of neuroinflammatory disorders such as multiple sclerosis.


Djukic-Cosic D.,Farmaceutski fakultet Univerziteta u Beogradu | Stanojevic A.,Galenika a.d | Djekic-Ivankovic M.,Institute za medicinska istrazivanja | Curcic M.,Farmaceutski fakultet Univerziteta u Beogradu | And 3 more authors.
Vojnosanitetski Pregled | Year: 2011

Background/Aim. The beneficial effects of medicinal plants are well-known from the ancient times. However, expansion of phytopharmacy and phytotherapy occured during the last decades. Medicinal plants can absorb environmental contaminants from the ground and consequently may cause harmful effects on human health. Quality control usually comprises standard methodology which includes macroscopic identification and examination of active ingredients. Additionaly, there is a permanent need to control the level of pollutants in herbs, with a particular attention to the level of toxic metals. In this study we estimated the level of contamination by determining the content of cadmium (Cd) in the herbs of Hypericum perforatum and Thymus serpyllum collected from the different localities of the mountains Rtanj and Ozren. Methods. Herbs of investigated plants were collected during July 2005 from various localities of Rtanj and Ozren mountains. After drying, homogenization and mineralization, Cd content was determined by atomic absorption spectrophotometry. Results. The obtained results show that Cd content varies significantly in Hypericum perforatum samples collected. The lowest Cd level was found in samples from the one of Rtanj localities (0.25 mg Cd/kg), while the highest was observed in Hypericum perforatum from Ozren locality (1.24 mg/kg). Levels of Cd in the three of four investigated localities were higher than proposed by WHO (0.3 mg/kg dried herb material). In all investigated samples of Thymus serpyllum herbs Cd levels were below the limit of detection of analytical method (0.2 mg Cd/kg dried materials). Conclusion. This work contributes to the issue of Cd content in Hypericum perforatum and Thymus serpyllum grown in localities of Rtanj and Ozren, and implies the importance for systemic control of Cd content in Hypericum species in order to provide safety of their preparations. Furthermore, regarding Cd toxicity, maximal permissible level of Cd in plant material should be evaluated and established concerning national legislative frame.


In this study, we collected and analyzed information on the importance of drug packaging quality to end users and pharmaceutical industry, as an indicator of the process of traceability and originality of drugs. Two surveys were conducted: one among the end users of drugs (252 patients) and the other among professionals working in seven pharmaceutical companies in Serbia. For most end users (82.5%), the quality of the packaging was important, but only 41.8% of them thought that the appearance of the packaging could be an indicator of genuinity of drugs. The existence of the control marks (KM) on drug packaging was not of great importance, since most of the users (86.9%) know its function, but the majority (60.2%) would nevertheless decide to buy the drug without KM. Regarding the experts from the pharmaceutical industry, more then two thirds (68.4%) believed that the existance of KM did not contribute to efficient operations. Although a great number of pharmaceutical industry professionals (84.2%) answered that the introduction of GS1 DataMatrix system would allow for complete traceability of the drug from the manufacturer to the end user, only 22.2% of them introduced this system to their products. This study also showed that domestic producers did not have a great interest for additional protection (special inks, holograms, special graphics, smart multicolor design, watermark, chemically labeled paper and cardboard, etc.) on their products, given that only 15.8% of them had some kind of additional protection against counterfeiting. Monitoring drug traceability from a manufacturer to end user is achieved by many complex activities regulated by law. A high percentage of responders said they were satisfied with the functionality of traceability systems used in their companies. As a way to increase the quality of drug packaging and business performance, most responders saw in the continuous improvement of the system of traceability within the company's overall quality management system. For them, a big financial investment in the complete traceability chain was not feasible because of the inability to achieve competitive prices in the market. Since only three of the surveyed companies were part of international chains, these findings open the path for new research that would include more multinational drug manufacturers from the region, in order to fully comprehend the importance of investing in the drug chain traceability and protection against counterfeiting, as a part of total quality management process in the pharmaceutical industry.


PubMed | Galenika ad
Type: Clinical Trial | Journal: Biopharmaceutics & drug disposition | Year: 2012

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets.


The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products.

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