Authors: Andrea Peštálová¹, Sylvie Pavloková¹, Jan Gajdziok¹

¹ Department of Pharmaceutical Technology, Faculty of Pharmacy, Masaryk University

e-mail: pestalova@mail.muni.cz

Key words: microparticles, spray drying, ciprofloxacin, cystic fibrosis

Background: Inhalation therapy of cystic fibrosis using a dry powder inhaler (DPI) is currently being studied in many clinical trials. One possible treatment option is the administration of fluroqinolones in the treatment of P. aeruginosa infections and have been proven to reduce the bacterial load in the lungs and improve patients’ lung function. In order for antibiotic therapy to be effective, the formulation should focus on the parameters particles should have, especially their size and shape, porosity or aerosolisation properties. For the formulation of dry powders, the most common are spray technologies and also the addition of excipients such as porogens or substances from the amino acid group can modify the resulting properties.

Methods: In the scope of the experiment, particles consisting of carriers (mannitol, chondroitin-sulfate and their mixture), a constant amount of leucine (15 %) and ammonium-bicarbonate (1 %) were prepared by spray drying. The aim was to optimize the drying conditions to produce aerodynamically suitable particles. In the next step, particles containing ciprofloxacin (1:1 ratio to the carrier) were formulated. The resulting particles were evaluated in terms of morphology, flow properties and geometric or aerodynamic diameter respectively.

Results: The obtained results showed that aerodynamically suitable particles (aerodynamic diameter (MMAD) < 5 µm, fine particle fraction > 50 %) were achieved by increasing the drying temperature and reducing the spray nozzle diameter. For all particles containing ciprofloxacin MMAD ranged from 4.87 µm (carrier mixture) to 5.43 µm (mannitol as carrier). Moreover, due to the addition of porogen, the internal porosity of the particles was up to 79.57 %, which is also related to the relatively low bulk density (0.41–0.45 g/cm³). The shape of the mannitol-based particles was mainly spherical, whereas the chondroitin-based particles were mostly wrinkled.

Conclusion: Based on the measured results, we were able to prepare microparticles containing ciprofloxacin meeting the requirements for inhalable powder particles and in a sufficient dose for pulmonary delivery by DPI.

The study was supported by Specific research MUNI/A/1140/2021.

Authors: Hana Hořavová¹, Barbara Sterle Zorec², Alenka Pobirk Zvonar²

¹ Department of Pharmaceutical technology, Faculty of Pharmacy, Masaryk University

² Department of Pharmaceutical technology, Faculty of Pharmacy, University of Ljubljana

e-mail: 422926@muni.cz

Key words: liposomes, spray drying, protectants

Liposomes are very potent modern delivery system, however, their physical and chemical instability in aqueous dispersions can be problematic.¹ Converting the dispersions into liposomal dry powders (by spray drying) could be a solution. To achieve good stability of liposomes during this process, it is important to find a suitable protective material.² This study aimed to optimize the preparation process of liposomes and to investigate the ability of different protectant materials to maintain the size of liposomes during the spray drying process.

Liposomes were prepared by the hydration of a thin film formed by evaporation of chloroform solution. For hydration Milli-Q water was used at a temperature of 65 °C. For size homogenization a sonication probe was used. Liposome DLS size measurements were performed using the Zeta sizer. After optimization 5 thin films were hydrated with an aqueous solution containing lactose, trehalose, maltodextrin, sucrose, or sorbitol respectively. Optimally prepared the dispersions were spray dried and DLS measurement was performed with the rehydrated products.

A higher number of sonication cycles leads to better homogenization. It is possible to increase the sonication volume, but preferably not more than 6 ml to keep the polydispersity index (PI) acceptable. With higher hydration medium volume, the size of liposomes and PI decrease. The changes in liposome size with lactose, trehalose and sucrose were minimal (+14.7%, -2.2%, and +7.2% respectively) and the PI was very low. The size of liposomes in maltodextrin increased significantly (by more than 2-fold) and the system was polydisperse. Spray drying of the sorbitol dispersion did not result in particles under the used conditions.

We were able to prepare optimal liposomal dispersions and find suitable carbohydrates to protect liposomes from stress during spray drying, for possible future drug incorporation.

References

1 Guimarães, D.; Cavaco-Paulo, A.; Nogueira, E. Design of liposomes as drug delivery system for therapeutic applications. Int. J. Pharm. 2021, 601, 120571.

2 Hořavová, H.; Gadziok J.; Vetchý, D. Typy a příprava lipozomálních přípravků pro plicní podání. Chem. listy. 2020, 114, 322 - 328.

Authors: Martin Veselý¹, Jan Elbl¹, Natália Janigová¹, Jan Gajdziok¹

¹ Department of Pharmaceutical Technology, Faculty of Pharmacy, Masaryk University

e-mail: 460848@muni.cz

Key words: 3D print, porous films, semi-solid extrusion, porogens

The most beneficial aspect of 3D print lies in the possibility of defining the size, number of different layers and composition of various dosage forms.¹ That plays a crucial role in the treatment of patients with special needs such as pediatric or geriatric patients as they might experience certain swallowing problems which makes some dosage forms (e. g. tablets or capsules) inappropriate for administration.² Orodispersible films (ODFs) present one path that could overcome these difficulties as they are passed through easily.³ To prepare ODFs solvent casting is mostly utilized. Punching individuals films out of bigger piece and the hazard of breaking the films contribute to the downsides of this method.⁴ Semi-solid extrusion (SSE) 3D print is a sensible alternative as it diminishes all previously mentioned method disadvantages.

The aim of this study was to prepare porous ODFs using SSE 3D printing method as a novel technique for preparation of a suitable carrier for subsequently 2D printed medicine. Multilayered ODFs with the bottom layer contributing to film mechanical properties and top layer increasing the porosity level were successfully prepared.

Several porogen agents acted as porosity enhancers in two types of the top layer and their impact on the film properties was compared. Films were evaluated on weight and thickness variability, handling and mechanical properties, disintegration time, porosity level and appearance using scanning electron microscope (SEM).

The study was supported by Masaryk University (project number MUNI/A/1151/2021).

References

1 Planchette, C.; Pichler, H.; Wimmer-Teubenbacher, M.; Gruber, M.; Gruber-Woelfler, H.; Mohr, S.; Tetyczka, C.; Hsiao, W.-K.; Paudel, A.; Roblegg, E.; et al. Printing Medicines as Orodispersible Dosage Forms: Effect of Substrate on the Printed Micro-Structure. Int. J. Pharm. 2016, 509, 518–527.

2 Roden, D.F.; Altman, K.W. Causes of Dysphagia Among Different Age Groups: A Systematic Review of the Literature. Otolaryngol. Clin. North Am. 2013, 46, 965–987.

3 Sjöholm, E.; Sandler, N. Additive Manufacturing of Personalized Orodispersible Warfarin Films. Int. J. Pharm. 2019, 564, 117–123.

4 Genina, N.; Janßen, E.M.; Breitenbach, A.; Breitkreutz, J.; Sandler, N. Evaluation of Different Substrates for Inkjet Printing of Rasagiline Mesylate. Eur. J. Pharm. Biopharm. 2013, 85, 1075–1083.

Authors: Eliška Marková ^1,2, Kateřina Horská ^1,2

¹ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University Brno ² Department of Clinical Pharmacy, Hospital Pharmacy, University Hospital Brno

e-mail: 436724@mail.muni.cz

Key words: voriconazole, TDM, therapeutic drug monitoring, pharmacokinetic models

Background and Objective: Therapeutic drug monitoring (TDM) is becoming an increasingly important (and common) tool for achieving efficient and safe anti-infective therapy. Based on guidelines, TDM of voriconazole should be performed for most patients. To perform TDM in routine clinical practice and fully use its potential, precise and possibly subpopulation-specific pharmacokinetic models are required. Our study aims to assess the interindividual variability in voriconazole pharmacokinetics, target specific subpopulations of patients, and relevant comorbidities. Correspondingly, we aim to evaluate the reliability of currently available pharmacokinetic models.

Setting and Method: A retrospective cohort study in 28 patients treated with voriconazole. Data collected: measured voriconazole plasma levels, descriptive patient data, and basic biochemical parameters. Analysis of the data in the context of the target reference range and comparison between voriconazole plasma levels predictions by the pharmacokinetic model (MWPharm Online, Mediware a.s.) and the measured levels were performed.

Results: Based on our experiences and preliminary results, the inter (and even intra-)- individual variability in pharmacokinetics is wide. At steady state, only 62% of voriconazole levels are within the target therapeutic range, 27% are subtherapeutic, and 11% are supratherapeutic (total n=70). When a minimal target through concentration is considered 2 mg/l, as newly recommended, one-half of measurements are subtherapeutic; on-label dosing frequently led to subtherapeutic measured levels. The effect of C-reactive protein and body weight on voriconazole levels, recently discussed in the literature, was also assessed in our study; these variables considerably impact voriconazole levels. Moreover, we evaluate the precision of prediction of an available pharmacokinetic model; the mean difference between predicted and measured levels is 5,23 mg/l (SD=4,17), minimal and maximal differences 0,10 and 19,68 mg/l, respectively. More than half of the predictions are higher than measured levels.

Conclusion: Our preliminary data support the urgent need for precise and subpopulation-specific pharmacokinetic models for higher clinical utility of voriconazole TDM. These data clearly demonstrate the importance of routine voriconazole TDM and raise the question of standard dosing recommendation adjustments.