Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading

Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers

The prediction of criminal recidivism in male juvenile delinquents

Rezultati dosadašnjh istraživanja su ukazali na jaku vezu između kriminalnog ponašanja maloletnih delinkvenata sa jedne strane i crta ličnosti i odnosa u porodici sa druge strane. Međutim, još uvek se malo zna o tome koliko su odnosi unutar porodice i karakteristike ličnosti povezani sa kriminalnim recidivizmom. Cilj istraživanja bio je da ispita ove odnose koristeći kraću verziju skale Velikih pet + dva (Neuroticizam, Ekstraverzija, Otvorenost za iskustvo, Savesnost, Prijatnost, Pozitivna valenca, Negativna valenca), Skalu kvaliteta porodičnih interakcija (zadovoljstvo porodicom, prihvatanje/odbacivanje od strane majke/oca) i zvanične podatke iz kriminalnih dosija. Istraživanje je sprovedeno na 61 institucionalizovanom delinkventu i 64 ne-delinkventa, uzrasta od 15 do 18 godina. Neuroticizam, Otvorenost za iskustvo, Savesnost, Negativna valenca, prihvatanje od strane oca i odbacivanje od strane majke su statistički značajni prediktori kriminalnog recidivizma maloletnih delinkvenata. Delinkventi su pokazali statistički značajno više skorove na Neuroticizmu, kao i niže na Savesnosti i prihvatanju od strane majke u odnosu na ne-delinkvente.Previous studies have demonstrated a strong association of criminal behavior of juvenile delinquents with delinquents' personality traits and family interactions. However, little is known about the extent to which family interactions and personality traits are associated with criminal recidivism. The present study aimed to examine these relationships, using the Velikih pet plus dva (Big Five Plus Two) - short version (assessing Neuroticism, Extraversion, Openness to experience, Conscientiousness, Aggressiveness, Positive Valence, Negative Valence), the Quality of Family Interaction Scale (Satisfaction with family, Mother and Father Acceptance/Rejection), and official data from criminal records. The study included 61 institutionalized delinquents and 64 non-delinquents, 15 to 18 years of age. Neuroticism, Openness to experience, Conscientiousness, Negative valence, acceptance by father and rejection by mother are statistically significant predictors of criminal recidivism in juvenile delinquents. Delinquents showed higher Neuroticism, lower Conscientiousness and acceptance by mother compared to non-delinquents

Uticaj genotipa i digestata na produktivnost morfološkog pokazatelja silažnog sirka kao visokokvalitetne stočne hrane

Fodder sorghum is used for preparing silage in the phase of milk-wax maturity, when sorghum contains 65-70% water. Sorghum silage is mostly used in the diet of dairy cows. Since sorghum contains a lot of sugar, silage is successfully prepared without the addition of additives. Sorghum forms a large biomass during the year. After each mowing the plants regenerate giving a new swath. The aim of this study is to examine the influence of digestate on sorghum productivity in the conditions of Vojvodina. Digestate had a great influence on plant productivity. Based on the analysis of variance, it is evident that there is a significant difference in the number of leaves per plant in relation to the variant (Fekp = 7.118 *).Krmni sirak se koristi za spremanje silaže u fazi mlečno-voštane zrelosti, kada sirak sadrži 65-70% vode. Silaža od sirka najviše se koristi u ishrani mlečnih krava. Pošto sirak sadrži dosta šećera, silaža se uspešno sprema bez dodavanja aditiva. Sirak formira veliku biomasu tokom godine, posle svake kosidbe biljke se regenerišu dajući novi otkos. Cilj ove studije je da se ispita uticaj digestata na produktivnost sirka u uslovima Vojvodine. Digestat je imao veliki uticaj na produktivnost biljaka. Pokošena biomasa može se spremati kao senaža, sinaža ili se suši. Sveža biomasa sirka za ishranu domaćih životinja može se koristiti kad provene nekoliko sati da bi se razložile štetne supstance. Tokom godine može se dobiti preko 70 t ha-1 sveže biomase sirka

FIRE DYNAMICS IN A BUILDING COMPARTMENT – A NUMERICAL STUDY

Building fires heavy pollute the air and jeopardize human health and life. In this paper, the Large Eddy Simulation method of Fire Dynamics Simulator code has been used to investigate the temperature regime and the pollutant concentrations in a compartment and near a building wall under fire scenario. Numerical results show that the generation of fire products in the compartment is largely dependent on the temperature and the quantity of oxygen available for combustion. The outdoor plume parameters are affected by the temperature difference between the fire flame and plume and the surrounding ambient air

Biometrija sagitalnih otolita tri pridnene vrste riba istočnog Jadrana (Crna Gora)

The otolith morphology, biometry and otolith size and fish length relationship of three demersal fish species: red mullet Mullus barbatus, common pandora Pagellus erythrinus and hake Merluccius merluccius were examined. Based on otoliths relative sizes P. erythrinus and M. merluccius have Large otoliths, while M. barbatus has Small sagittal otoliths. The relationships between otolith variables and fish somatic growth were described by a linear function. All relationships were statistically highly significant (p<0.001). Otolith length (OL) was found to be the variable most strongly related to fish size, with 61.2 – 95.3 % of the variability, while otolith weight had the lowest coefficient of determination (r2). No differences were found neither between left and right otoliths, nor between male and female otoliths in these relationships. For all species studied the relationships of otolith length, height and weight against total fish length were all found to have positive allometry, indicating that the accretion of otoliths is relatively faster than increase in fish body size. The shape indices of form factor (FF), roundness (RD), aspect ratio (AR), circularity (C), rectangularity (R) and ellipticity (E) were calculated and the relationships between otolith length (OL) and shape indices were determined.Ispitana je morfologija otolita, biometrija i odnos veličine otolita i duljine tri pridnene vrste riba: trlja Mullus barbatus, arbun Pagellus erythrinus i oslić Merluccius merluccius. Na temelju relativnih veličina otolita P. erythrinus i M. merluccius imaju velike otolite, dok M. barbatus ima male sagitalne otolite. Odnosi između varijabli otolita i somatskog rasta riba opisani su linearnom funkcijom. Svi odnosi bili su statistički visoko značajni (p<0,001). Utvrđeno je da je duljina otolita (OL) pokazuje najveću povezanost s veličinom ribe, sa 61,2 – 95,3 % varijabilnosti, dok je masa otolita imala najniži koeficijent determinacije (r2). Nisu pronađene razlike ni između lijevog i desnog otolita, niti između muških i ženskih otolita u tim odnosima. Za sve proučavane vrste utvrđeno je da odnosi duljine, visine i mase otolita u odnosu na ukupnu duljinu ribe imaju pozitivnu alometriju, što ukazuje da je nakupljanje otolita relativno brže od povećanja duljine tijela ribe. Izračunati su indeksi oblika faktora forme (FF), zaobljenosti (RD), omjera stranica (AR), kružnosti (C), pravokutnosti (R) i eliptičnosti (E) te su izračunati odnosi između duljine otolita (OL) i indeksa oblika

Oral dosage forms with carvedilol fabricated by selective laser sintering (SLS) 3D printing technique

1. INTRODUCTION When it comes to pharmacy, 3D printing has gained immense popularity in recent years due to its revolutionary use in printing drugs tailored to individual patient needs [1,2]. Selective laser sintering (SLS) is an industrial 3D printing technique which uses a powder bed to build up the 3D object thanks to a laser which binds the powder particles together. Advantages of SLS technique include the fact that it is a solvent-free process and offers relatively fast production. Until today, a limited number of studies investigating the production of drug dosage forms using SLS have been reported [2,3]. 2. MATERIALS AND METHODS 2.1. Materials Carvedilol (CRV) was used as a model substance in this study and it was donated by Hemofarm (Vršac, Serbia). The following excipients used to obtain 3D printing tablets: polyvinyl alcohol (PVA, Merck), mannitol (Parteck® M, Merck), Ludipress® (coprocessed excipient consisting of 93% lactose monohydrate, 3.5% crospovidone (Kollidon® CL) and 3.5% povidone K30 (Kollidon® 30), BASF), talc (Merck) and candurin (Candurin® Gold Sheen, Merck). 2.2. Preparation of formulations The compositions of the formulations are shown in Table 1. Table 1. Composition of the formulations Material Formulation 1 Formulation 2 CRV 10% 10% PVA 55% 55% Parteck® M 30% / Ludipress® / 30% Talc 2% 2% Candurin® Gold Sheen 3% 3% Powder for 3D printing was obtained by mixing all the components of the formulation and sifting through a sieve with a diameter of 180 μm. 2.3. 3D printing of oral dosage forms A cylindrical 3D models of the printed tablets (8.00 mm diameter and 2.00 mm thickness) were designed with Autodesk Fusion 360 software version 2.0.8809 (Autodesk Inc, San Rafael, CA, USA), exported as a stereolithography file (.stl) and printed with Sintratec Kit 3D printer (Sintratec AG, Switzerland). The printing parameters were controlled using Sintratec 3D printer software. After a series of variations in temperature and laser speed, the optimal values of these parameters used in the 3D printing process were established and shown in Table 2. Table 2. SLS 3D printing process parameters Surface Temperature ( ◦C) Chamber Temperature ( ◦C) Laser speed (mm/s) Hatch space 80 ºC 70 ºC 60 250 μm 2.4. Mechanical properties of 3D tablets Tablets (n = 10) were weighed on a Sartorius BP 210 D analytical balance (Sartorius, Goettingen, Germany) and measured (diameter and thickness) using a digital caliper (Vogel, Kevelaer, Germany). 2.5. Powder X-ray diffraction analysis (PXRD) PXRD analysis was performed to assess whether the laser induced amorphization of any of the compounds, especially amorphization of poorly soluble CRV. Samples were collected using a Philips PW-1050 (Philips, The Netherlands) diffractometer, operated at 40 kV and 30 mA, using Ni-filtered Cu Kα radiation. 2.6. Dissolution and Drug Release Analysis Dissolution testing was performed under nonsink conditions using mini paddle apparatus (Erweka DT 600, Germany) with a paddle rotation speed of 50 rpm for 8 h, in 100 ml of phosphate buffer (pH 6.8). The amount of dissolved CRV was determined by HPLC method using Dionex Ultimate 3000 (Thermo Scientific, USA) HPLC system. 3. RESULTS AND DISCUSSION 3.1. 3D printing process It was shown that SLS printer was able to fabricate 3D tablets with CRV, as well as that success of the printing process depended on the used printing parameters. 3.2. Mechanical properties of 3D tablets The dimensions of the obtained 3D tablets were in accordance with the defined values of the created 3D models (F1: 8.10 ± 0.08 mm diameter and 2.10 ± 0.13 mm thickness, F2: 8.13 ± 0.09 mm diameter and 2.10 ± 0.12 mm thickness). Significant variations in tablet weight between formulations were not observed (m1=0.146 ± 0.04; m2=0.136 ± 0.03). 3.3. Powder X-ray diffraction analysis (PXRD) Figure 1. The X-ray powder diffraction of F1 and F2. 3.4. Dissolution and Drug Release Analysis Figure 2. Dissolution profiles of 3D printing tablets 4. CONCLUSION SLA represents a new chapter in 3D printing of solid oral dosage forms and in individualized therapy in particular. By adjusting the formulation and process parameters, it was possible to produce SLS tablets with coamorphous CRV and PVA as a main polymer. Complete drug release was achieved under non sink conditions after 8 hours in phosphate buffer. The tailoring of drug release might be achieved by varying formulation factors as well as process parameters, although it could be governed by the composition of the whole formulation.9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow Ljubljana, Slovenia, 15th-17th September, 202

Functional characterization of microcrystalline cellulose obtained from the crop residues

Crop residues (CR) are usually burned in the field, which causes air pollution, contributes to global warming, hinders nutrient recycling, and negatively affects soil microbes through overheating and carbon loss. There is growing interest in developing processes for isolation of value added components with application in different industries from CR as feedstock. In this study, different procedures for isolation of microcrystalline cellulose (MCC) from wheat, corn and sunflower CR were evaluated, with further testing of functional characteristics of MCC, which are relevant for tablets production.14th Central European Symposium on Pharmaceutical Technology, 28th - 30th September, Ohrid, N. Macedonia, 202

Primena fotopolimerizacione tehnike 3D štampe lekova u izradi dvoslojnih tableta

In recent years, introduction of modern technologies, such as 3D printing, has opened a new chapter and caused a paradigm shift from manufacturing of large-scale to small batches of medicines tailored accordingly to the specific needs of patients (1). The aim of this study was to formulate and fabricate two-layered tablets using digital light processing (DLP) technique, which utilizes light irradiation to create solid objects from photoreactive liquid resin in a layer-by-layer manner. Hydrochlorothiazide (HHT, 5%,w/w) and warfarin sodium (VRN, 5%,w/w) were selected as model drugs, commonly used together in the treatment of cardiovascular diseases. 3D printing process was initiated with 0.10% of photoinitiator, at a constant ratio of poly(ethylene glycol)diacrylate and poly(ethylene glycol) 400, 1:1, with the addition of water (10%,w/w). 3D tablets, with each of the active substances in a separate layer, 8.00 mm in diameter and 1.50 mm thick, as well as combined two-layered tablets with HHT and VRN in individual layers, were successfully printed with Wanhao D8 printer. Dissolution test results showed immediate, but incomplete release of VRN (81.47 ± 1.47%, after 45 min) from individual layers, while the release of HHT was prolonged and complete (98.17 ± 3.11%, after 8 h). Significantly slower and incomplete release of VRN and HHT from combined tablets was observed. The absence of interactions and the presence of a layered structure were confirmed. DLP technique has a potential to provide fast fabrication of combined tablets, while further optimization of formulation factors is necessary in order to achieve complete drug release.Poslednjih godina, uvođenjem savremenih tehnologija, poput 3D štampe, otvorilo se novo poglavlje u načinu proizvodnje lekova i uslovilo razvoj fundamentalnih promena, pri čemu serijska proizvodnja velikih šarži pretenduje da bude zamenjena malim serijama lekova prilagođenih specifičnim potrebama pacijenata (1). Cilj ovog istraživanja bio je da se formulišu i izrade dvoslojne tablete primenom tehnike digitalne obrade svetlosti (DLP) koja omogućava dobijanje objekata mehanizmom nanošenja materijala “sloj po sloj” iz tečne fotopolimerizacione smole pod uticajem svetlosti. Hidrohlortiazid (HHT, 5%, m/m) i varfarin-natrijum (VRN, 5%, m/m) odabrani su kao model lekovite supstance, koje se obično primenjuju zajedno u lečenju kardiovaskularnih bolesti. Proces 3D štampanja sproveden je u prisustvu 0,10% fotoinicijatora, pri konstantnom masenom odnosu poli(etilen glikol)diakrilata i poli(etilen glikola) 400, 1:1, uz dodatak 10% vode. 3D tablete, sa svakom od aktivnih supstanci u posebnom sloju, prečnika 8,00 mm i debljine 1,50 mm, kao i kombinovane dvoslojne tablete sa HHT i VRN u pojedinačnim slojevima, uspešno su odštampane u Wanhao D8 štampaču. Prilikom ispitivanja brzine rastvaranja lekovite supstance iz pojedinačnih slojeva, došlo je do trenutnog (81,47 ± 1,47% nakon 45 min), ali nepotpunog oslobađanja VRN, dok je HHT u potpunosti oslobođen, prateći kinetiku produženog oslobađanja (98,17 ± 3,11%, nakon 8 h). Zapaženo je znatno sporije i nepotpuno oslobađanje VRN i HHT iz kombinovanih dvoslojnih tableta, nakon 8 h. Potvrđeno je odsustvo interakcija i prisustvo slojevite strukture. DLP tehnika ima potencijal da obezbedi brzu izradu kombinovanih tableta, pri čemu je neophodna dalja optimizacija formulacionih faktora u cilju postizanja potpunog oslobađanja lekovite supstance.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis

Introduction: Most of the antipsychotics and antidepressants are metabolized by CYP2C19 and CYP2D6 enzymes. Both CYP2D6 and CYP2C19 genes are polymorphic and metabolic capacity of the enzymes is genotype-determined. Homozygous null allele carriers do not possess active enzyme, and they are referred to as CYP2C19 or CYP2D6 poor metabolizers (PM). Certain genotypes do not abolish the enzyme completely, but they do cause drastic reduction of metabolic capacity and carriers of such genotypes are referred to as intermediate metabolizers (IM). It is known that CYP2C19 and CYP2D6 PM and IM status cause increase in exposure of certain antidepressants and antipsychotics; however, due to small sample size of the previously published studies, the magnitude of this effect still cannot be estimated with sufficient precision. Therefore, the aim of this meta-analysis was to pool all these studies and estimate the magnitude of drug exposure increase caused by CYP2C19 and CYP2D6 PM and IM status, compared with normal metabolizers (NM) to the best possible degree. Methods: The inclusion of the drugs used for the literature survey for meta-analysis was based on the list of new generation antidepressants [1] and antipsychotics [2]. These drugs were screened for inclusion by the PubMed search *DrugName AND (CYP2C19 OR CYP2D6). The studies were included in the meta-analysis if (1) the patients were genotyped for CYP2C19 or CYP2D6; (2) adequate sorting of patients into NM, IM, and PM was possible; (3) the study included at least three patients per subgroup; and (4) drug exposure was measured in representative way by: (a) dose normalized area under plasma level (time) curve, (b) dose normalized steady state plasma levels, or (c) apparent total clearance of the drug from plasma after oral administration (CL/F, reciprocal value represented the drug exposure). Meta-analysis for a specific drug was performed if three or more studies met the inclusion criteria. Drug exposure head-to-head comparisons were made between PM or IM subjects and the NM subject group, which served as a reference. Heterogeneity across the studies was assessed using Cochran's Q test at a given significance level and the percentage of total variability across the studies attributable to heterogeneity was quantified using I2 value. Magnitude of increase is presented as: Odds ratio (95% Confidence interval) Results: Based on the outcome of the literature survey, it was possible to perform meta-analysis for escitalopram, venlafaxine, risperidone, and aripiprazole. Escitalopram exposure was 1.37-fold (1.30-1.44) increased in CYP2C19 IM and 2.44-fold (2.27-2.61) increased in CYP2C19 PM. Venlafaxine exposure was not significantly changed in CYP2D6 PM, 1.10 (0.99-1.22). Risperidone and aripiprazole exposure increased was similar for CYP2D6 IM and PM. Risperidone exposure was 1.42 (1.36-1.51) increased in CYP2D6 IM and PM admixed. Aripiprazole exposure was 1.52 (1.45-1.58) increased in CYP2D6 IM and PM admixed. Conclusions: According to the results, reducing escitalopram dose by 60% in CYP2C19 PM and by 30% in CYP2C19 IM are appropriate dosing decision. Next, reducing risperidone and aripiprazole dose by 30% in CYP2D6 PM is appropriate dosing decision. Finallytract, CYP2D6 metabolizer status is not clinically relevant in venlafaxine dosing.32nd ECNP Congress, 7-10 September 2019, Copenhagen, Denmar

Total Number of Cattle in the Republic of Serbia after an Outbreak of Lumpy Skin Disease

Numerous studies conducted worldwide indicate a tendency towards a continuous decline in number of cattle. Appropriate measures should be taken to prevent the reduction of the number of cattle and to increase the concentration of animals per farm. In this regard, the objective of this study was to analyze the total number of cattle after an outbreak of Lumpy Skin Disease (LSD) in the Republic of Serbia. Due to the occurrence of this highly dangerous infectious disease in the Balkans and Eastern Europe, emergency and preventive vaccination was performed in infected and vulnerable areas in the Republic of Serbia. To prevent the spread of LSD, competent authorities banned public gatherings of cattle at fairs, exhibitions, livestock markets and purchase places, which resulted in economic losses for certain farmers. This disease is believed to have impacted the total number of cattle slaughtered and the number of deaths, as well as the import and export of live cattle, animal products and by-products of animal origin. The comparison between indices for the number of cattle shows a decline in the total number of cattle in the analyzed period across statistical territorial units. Results on the total number of cattle can be used, among other things, to create new and more complex questions arising from current and future farming problems