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Edina Vranić

Full Professor, University of Sarajevo

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University of Sarajevo
Full Professor

Paediatric and geriatric populations, as well as other special patient populations with swallowing problems, require patient-tai-lored dosage forms. One promising dosage form for these specific populations is orodispersible films. When preparing orodispersible films using sodium carboxymethyl cellulose as the film-forming polymer and glycerine as the plasticizer, it is essential to determine the optimal mixing time and mixing speed of the casting solution to achieve the desired transparency/opacity of the orodispersible films. In this paper, the primary focus is on mixing time and mixing speed, and determining how these two parameters can influence optical characteristics. All tested parameters are supported by FTIR anal - ysis. The obtained results show that either a mixing speed of 7000 rpm on a high-shear mixer for 15 min or a mixing speed of 9000 rpm for 5 min can produce films with optimal optical characteristics.

Abstract Four natural sweeteners (sucrose, xylitol, fructose, and isomalt) were selected to examine the influence of their qualities and amounts on the characteristics of orodispersible films. Sodium carboxymethylcellulose (2% w/w) was utilized as the film-forming polymer and 1% w/w glycerol as a plasticizer. Films were produced through the solvent casting method, rendering them suitable for convenient application in community or hospital pharmacy settings. The physicochemical and optical properties of the films were analyzed, and Fourier-transform infrared analysis was carried out. All films exhibited acceptable disintegration time, uniformity of mass, thickness, and optical characteristics, with significant dependence (p<0.05) on both sweetener type and quantity. Disintegration time varied based on the employed method, as well as the characteristics and amount of sweetener. Additionally, all films maintained pH values within the oral cavity range, suggesting no potential irritancy upon administration. Fourier-transform infrared analysis confirmed the formation of the film and demonstrated compatibility between its components.

Although solid oral dosage forms present majority of commonly prescribed drugs, some patients struggle with ingesting them (Awad et al., 2021). Amongst those, a very significant group is the pediatric population. On the other side, questions concerning dosage consistency arise when it comes to liquid oral preparations, particularly for suspensions (Gupta et al., 2021). To avoid the limitations of conventional oral dosage forms, orodispersible films (ODFs) were developed as a promising, patient-tailored therapeutic alternative. After the administration, ODFs are swallowed naturally with saliva, and there is no need for additional water (Yadav et al., 2021). Furthermore, in terms of the pediatric population, the product not only has to be easy to swallow, but it also has to be visually appealing. Therefore, a lot of attention is dedicated to the visual appearance of ODFs, including their color and transparency or opacity (Zamanian et al., 2021). One of the methods used to produce ODFs is the solvent casting of polymer solution/dispersion. The aim of our study was to determine whether high shear mixer heads have an influence on the optical characteristics and disintegration time of the obtained ODFs.

I. Ruseska, Amina Tucak-Smajić, E. Vranić, Andreas Zimmer

Nowadays, nucleic acids are gaining much attention as leading therapeutics. MicroRNAs (miRNAs) are one part of this family of promising tools that can be used in the treatment of numerous diseases. However, the application of miRNAs is limited due to their poor stability and limited cellular uptake. Here, we developed cationic nanostructured lipid carriers (cNLCs) as delivery agents for miRNA. Furthermore, we used human serum album (HSA) as a coat for the cNLCs, to see how it will influence the uptake. These nanoparticles showed favorable physicochemical properties to be used as drug delivery systems, as they successfully complexed miRNA. Therefore, our next goal is to study and understand their cellular uptake. For this purpose, we traced the uptake of the miRNA/cNLCs in two different cell lines (3T3-L1 and MCF-7 cells) under varying experimental conditions.

Amina Tucak-Smajić, I. Ruseska, E. Vranić, Andreas Zimmer

MicroRNAs (miRNAs) are important regulators of gene expression in cells. However, their application in gene therapy is limited by obstacles such as poor cellular uptake and instability (Mendonça et al., 2023). To overcome these limitations, cationic nanostructured lipid carriers (cNLCs) as delivery systems for miRNAs are developed. cNLCs protect and stabilize miRNAs, and also enhance cellular uptake, which results in effective nucleic acid-based therapy. Another approach, found in literature, to enhance cellular uptake is coating particles with human serum albumin (HSA) (Liu et al., 2012). Therefore, the effect of functionalization of miRNA-cNLC complexes with HSA was investigated. The physicochemical properties of uncoated and HSA-coated complexes were compared in terms of particle size, size distribution, surface charge, topography, and cellular uptake in 3T3-L1 mouse embryonic fibroblasts and MCF-7 human breast cancer cells.

Amina Tucak-Smajić, I. Ruseska, I. Letofsky-Papst, E. Vranić, A. Zimmer

Although miRNA-27a has been identified as a promising candidate for miRNA mimic therapy of obesity, its application is limited due to enzymatic degradation and low membrane permeation. To overcome these problems, we developed cationic nanostructured lipid carriers (cNLCs) using high-pressure homogenization and used them as non-viral carriers for the anti-adipogenic miRNA-27a. Cargo-free octadecylamine-containing NLCs and miRNA/cNLC complexes were characterized regarding particle size, size distributions, zeta potential, pH values, particle topography and morphology, and entrapment efficacy. Furthermore, the cytotoxicity and cellular uptake of the miRNA/cNLC complex in the 3T3-L1 cell line were investigated. The investigation of the biological effect of miRNA-27a on adipocyte development and an estimation of the accumulated Oil-Red-O (ORO) dye in lipid droplets in mature adipocytes were assessed with light microscopy and absorbance measurements. The obtained data show that cNLCs represent a suitable DDS for miRNAs, as miRNA/cNLC particles are rapidly formed through non-covalent complexation due to electrostatic interactions between both components. The miRNA-27a/cNLC complex induced an anti-adipogenic effect on miRNA-27a by reducing lipid droplet accumulation in mature adipocytes, indicating that this approach might be used as a new therapeutic strategy for miRNA mimic replacement therapies in the prevention or treatment of obesity and obesity-related disorders.

Merima Šahinović, Alharith A. A. Hassan, K. Kristó, G. Regdon, E. Vranić, T. Sovány

For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: −4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (−0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.

O. Rahić, J. Hadžiabdić, A. Tucak, M. Sirbubalo, Lamija Hindija, A. Elezovic, E. Vranić

OBJECTIVE To examine the influence of vehicles on the stability of extemporaneous suspensions of proton pump inhibitors (PPIs), to single out the formulation most suitable for children, providing appropriate evidence and arguments. METHODS A review was performed of data identified from Medline, Embase, Science Direct, as well as public digital archive PubMed, including reference texts, related to the field of stability testing of extemporaneous PPI suspensions. RESULTS Fourteen selected formulations of extemporaneous suspensions are presented and discussed. Depending on the vehicle and its composition, which was analyzed and explained in detail, the suspensions had various beyond-use dates (BUDs). CONCLUSIONS Selected vehicles and the process of preparation had great influence on the stability of extemporaneous PPI suspensions. The suspension with the longest BUD has been singled out, which is especially suitable for use in newborns. Because an explanation is provided for the influence of individual vehicle components on the stability of the mentioned suspensions, this can aid not only in the selection of an adequate formulation, but also in the development of new ones, which will be suited to individual patients.


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