Optimisation of ultrasound-assisted extraction method of biologically active compounds from Cynara scolymus L.

Drug Technology Department and Department of Pharmacognosy and Pharmaceutical Botany, Nicolae Testemitsanu State University of Medicine and Pharmacy, Chisinau, the Republic of Moldova, Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, RomaniaBackground: Traditionally artichoke has been cultivated as a vegetable for human food in some Mediterranean regions and has been used in folk medicine since Roman times. Biological compounds of artichoke are mostly concentrated in leaves which contain high levels of caffeoylquinic acid derivatives. Obvious interest in this plant with hepatoprotective and cholesterol lowering qualities persuaded artichoke’s introduction in the collection of the Centre for the Cultivation of Medicinal Plants at the NicolaeTestemitsanu State University of Medicine and Pharmacy in 2002. This study is focused on optimized ultrasound-assisted extraction parameters of polyphenols and flavonoids from artichoke leaves without the risk of thermal degradation for their main phytoconstituents. Material and methods: In this study we have investigated the influence of some variables on extraction of polyphenols and flavonoids compounds from artichoke leaves based on ultrasound-assisted method. For this purpose an experimental design with 5 variables and 2 levels was used. The studied variables were: concentration of extraction solvent, temperature, extraction time and also the influence of parameters of ultrasonic processor pulse and amplitude; the total polyphenolic and flavonoid content were dependent variables. Results: The results of composite design indicated that the optimal extraction parameters were as follows: concentration of ethanol solution 70%, temperature 80°C, ultrasound time 30 minutes, with ultrasonic power output and pulse mode factor 100%. Conclusions: The influence of various parameters on the extraction of total flavonoid and polyphenolic content from artichoke’s leaves was studied. The ethanol concentration, the temperature and the time were found to be the most effective in extracting phenolic compouds with ultrasound-assisted method respectively

Low temperature synthesis, magnetic and magnetotransport properties of (La1-xLux)0.67Ca0.33MnO3 (0 < x < 0.12) system

We have been able to synthesize Lu+3 substituted La0.67Ca0.33MnO3 (LCMO) by an auto-combustion method. Synthesis of this compound is not successful by conventional ceramic or other chemical methods. Magnetic and electrical transport properties of the Lu substituted LCMO [(La1-xLux)0.67Ca0.33MnO3 (0 < x < 0.12)] system have been investigated and compared with those of the Y+3, Pr+3, Dy+3 and Tb+3 substituted LCMO systems. All the compounds show a ferromagnetic metal to paramagnetic insulator transition at TC. The tolerance factor reduces from 0.917 for x = 0 to 0.909 for x = 0.12 and for this range all are ferromagnetic metals indicating the dominance of the coupling between spins due to double exchange over the antiferromagnetic superexchange interaction. The transition temperatures and magnetization decrease as the Lu concentration increases. This is satisfactorily accounted for on the basis of transition from ferromagnetic at x = 0 to canted spin order for x > 0. All the samples show higher magnitude of MR compared to that in pure LCMO at 80 kOe field in the temperature range of 5 to 320K. A fairly high value of low field magnetoresistance (LFMR) of about 30% is obtained in all the samples at a field less than 5 kOe.Comment: Total 35 pages of text and figure

Risk assessment and experimental design in the development of a prolonged release drug delivery system with paliperidone

Sonia Iurian, Luana Turdean, Ioan Tomuta Department of Pharmaceutical Technology and Biopharmacy, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania Abstract: This study focuses on the development of a drug product based on a risk assessment-based approach, within the quality by design paradigm. A prolonged release system was proposed for paliperidone (Pal) delivery, containing Kollidon&reg; SR as an insoluble matrix agent and hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), or sodium carboxymethyl cellulose as a hydrophilic polymer. The experimental part was preceded by the identification of potential sources of variability through Ishikawa diagrams, and failure mode and effects analysis was used to deliver the critical process parameters that were further optimized by design of experiments. A D-optimal design was used to investigate the effects of Kollidon SR ratio (X1), the type of hydrophilic polymer (X2), and the percentage of hydrophilic polymer (X3) on the percentages of dissolved Pal over 24 h (Y1&ndash;Y9). Effects expressed as regression coefficients and response surfaces were generated, along with a design space for the preparation of a target formulation in an experimental area with low error risk. The optimal formulation contained 27.62% Kollidon SR and 8.73% HPMC and achieved the prolonged release of Pal, with low burst effect, at ratios that were very close to the ones predicted by the model. Thus, the parameters with the highest impact on the final product quality were studied, and safe ranges were established for their variations. Finally, a risk mitigation and control strategy was proposed to assure the quality of the system, by constant process monitoring. Keywords: pharmaceutical development, quality by design, failure mode effects analysis, Ishikawa diagram, fish-bone diagram, hydrophilic matri

Improvement of skin condition in striae distensae: development, characterization and clinical efficacy of a cosmetic product containing Punica granatum seed oil and Croton lechleri resin extract

Cătălina Bogdan,1 Sonia Iurian,2 Ioan Tomuta,2 Mirela Moldovan1 1Department of Dermatopharmacy and Cosmetics, 2Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania Abstract: Striae distensae are a frequent skin condition associated with pregnancy, weight change or lack of skin elasticity. The aim of this research was to obtain a topical product containing herbal active ingredients with documented antioxidant and anti-inflammatory activity (Punica granatum seed oil and Croton lechleri resin extract) and demonstrate its positive effect on prevention and treatment of striae distensae. First, the cream base formulation was optimized through experimental design. Secondly, the cream containing the two active ingredients was investigated in an interventional nonrandomized clinical trial. The clinical outcome was assessed through biophysical parameters and ultrasonographic evaluation. The state of the skin was evaluated by biophysical measurements and ultrasonography at the beginning of the study and after 3 and 6 weeks. The experimental design was successfully used to set the best ranges for the technological and formulation factors to obtain a cosmetic formulation with optimal characteristics. The study of clinical efficacy on the optimal formulation revealed an increase in the dermis thickness, hydration and elasticity values in both groups after 6 weeks of cream application. The new oil-in-water cream containing P. granatum seed oil and C. lechleri resin extract can be helpful in the prevention or improving of skin changes associated with striae. Keywords: stretch marks, ultrasonography, texture analysis, design of experiments, oil-in-water emulsio

Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach

Lucia Ruxandra Tefas,1 Bianca Sylvester,1 Ioan Tomuta,1 Alina Sesarman,2,3 Emilia Licarete,2,3 Manuela Banciu,2,3 Alina Porfire1 1Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy &ldquo;Iuliu Hatieganu&rdquo;, 2Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, 3Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babeş-Bolyai University, Cluj-Napoca, Romania Abstract: The aim of this work was to use the quality-by-design (QbD) approach in the development of long-circulating liposomes co-loaded with curcumin (CUR) and doxorubicin (DOX) and to evaluate the cytotoxic potential of these liposomes in vitro using C26 murine colon carcinoma cell line. Based on a risk assessment, six parameters, namely the phospholipid, CUR and DOX concentrations, the phospholipid:cholesterol molar ratio, the temperature during the evaporation and hydration steps and the pH of the phosphate buffer, were identified as potential risk factors for the quality of the final product. The influence of these variables on the critical quality attributes of the co-loaded liposomal CUR and DOX was investigated: particle size, zeta potential, drug loading and entrapment efficiency. For this, a 26-2 factorial design was employed to establish a proper regression model and to generate the contour plots for the responses. The obtained data served to establish the design space for which different combinations of variables yielded liposomes with characteristics within predefined specifications. The validation of the model was carried out by preparing two liposomal formulations corresponding to the robust set point from within the design space and one outside the design space and calculating the percentage bias between the predicted and actual experimental results. The in vitro antiproliferative test showed that at higher CUR concentrations, the liposomes co-encapsulating CUR and DOX had a greater cytotoxic effect than DOX-loaded liposomes. Overall, this study showed that QbD is a useful instrument for controlling and optimizing the manufacturing process of liposomes co-loaded with CUR and DOX and that this nanoparticulate system possesses a great potential for use in colon cancer therapy. Keywords: doxorubicin, curcumin, co-loaded long-circulating liposomes, quality by design, design of experiment

Definition and validation of the Design Space for co-milled nasal powder containing nanosized lamotrigine

<p><b>Objective:</b> Design of Experiment (DoE), that is a tool of Quality by Design (QbD) paradigm, with which experiments can be planned more effectively and provide more information, while after Design Space (DS) can be set up, which assure the quality of the desired product. The aim of this study was to find the optimal drug-excipient ratio and the optimal process parameters (milling time, milling speed) of our previously used dry co-milling method and validate the DS.</p> <p><b>Materials and methods:</b> Lamotrigine (LAM), an antiepileptic drug was used as a model API. Poly-vinyl alcohol (PVA) was chosen according to our previous study as a hydrophylic matrix polymer. Milling time, speed, and the API:additive ratio was varied to find out their effect on the product. The optimization was performed on particle size of LAM, its standard deviation and the <i>in vitro</i> dissolution of the samples. Response surface modeling completed the statistical analysis that assessed the effects of independent variables on the responses.</p> <p><b>Results:</b> Due to the DS estimation, a more economical sample preparation method was set up. Finally, the sample that was prepared according to the optimized parameters (1.5 h, 400 rpm, 0.8 PVA:LAM ratio) showed around 100 nm drug particles and 97% drug release in five minutes.</p> <p><b>Conclusion:</b> From the DS generated by the software, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was a useful and effective tool of understanding the parameters that affect the quality of the desired product.</p