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INTRODUCTION Epilepsy requires a rapid and effective treatment, targeting the brain. In this area, the intranasal administration of lipid nanosystems, such as nanostructured lipid carriers (NLC) was suggested as a promising strategy. This route allows drug passage directly from the nose to the brain, bypassing the blood-brain barrier [1]. However, nasal administration faces some physiological barriers, such as the mucociliary clearance, which decreases the residence time of the formulation in the nasal cavity, reducing drug absorption. To circumvent this limitation, the use of ion sensitive polymers, such as pectin, which interacts with the calcium ions of the nasal mucus, increases the residence time of the NLC formulation within the nasal cavity [2]. The aim of this work was to develop an ion sensitive in situ hydrogel containing an optimized diazepam- loaded NLC formulation and to study its nasal deposition using a 3D nasal cavity model. The experiments started with the determination of the in situ hydrogel gelation time and the spray cone angle, using two types of pectin, at different concentrations. Subsequently, the nasal deposition in a 3D nasal cavity model was evaluated at with an airflow of 0 L/min and different administration angles. EXPERIMENTAL Preparation and characterization of in situ hydrogels containing diazepam-loaded NLC Costa et al. [3] previously optimized the diazepam-loaded NLC composition and preparation method. For the in situ hydrogels preparation, pectin CF005 and pectin CF025 were added at concentrations of 0.6% and 1.2% to the aqueous phase of the diazepam-loaded NLC, under continuous stirring, at 20.0±0.5ºC. Evaluation of the gelation time The gelation time of the in situ hydrogels was determined by the oscillatory gelation time test (Modular Compact Rheometer 102, Anton Paar GmbH, Austria) after mixing the diazepam-loaded NLC suspension containing pectin with simulated nasal fluid, in a volume ratio of 1:1. For this test, changes in the storage modulus (G´) and loss modulus (G´´) were recorded. The experiment was performed at 34ºC, using a parallel plate 50 (PP50) measuring system. The defined measuring position was 0.5 mm and the angular frequency was fixed at 6.28 rad s-1. Three replicate measurements were conducted for each formulation and the results are presented as mean values ± standard deviation (SD). Spray cone angle determination The spray cone angle was measured using a virtual protractor, after spraying the formulation against a dark background. The formulation was first placed in a Spray Pump 3K (Aeropump, Germany) and sprayed three times. A camera recorded the emitted plume and the spray cone angle was analyzed for each sample. Evaluation of the formulation deposition profile in a 3D nasal cavity model The 3D nasal cavity model was carried out using a computed tomography (CT) scan of a 62-year old patient with healthy nasal passages airways, obtained from the database of University Hospital Center “Sestre milosrdnice” (Ethics Committees approval codes: EP-9941/19-3 class: 003-06/21- 02/001, registry number:251-29- 11/1-21-01-1 ; PEER class: 643-02/21-03/01, registry number 251-62-03- 21-8) [4]. The nasal model is divided in (Figure 1): anterior region, turbinate region with detachable olfactory part, septum with detachable olfactory part, and nasopharynx. For the nasal deposition profile, the 3D nasal model was covered with Sar-gel®, which turns purple in contact with water and has calcium ions that induce pectin gelation. The administration of the formulations was performed on the right nostril of the 3D model. The fractional spray deposition pattern was determined weighting the amount of deposited formulation in all the nasal regions. Three replicates were conducted for each formulation and the results are presented as mean values ± SD. RESULTS Evaluation of the gelation time For both concentrations of pectin CF025, the G´ was higher than G´´ during the entire measuring period, which indicates that the gelation occurred immediately after the contact with the nasal fluid. The same was not observed with the formulations with pectin CF005. For this reason, further experiments were only performed with pectin CF025. Spray cone angle determination The spray cone angle of the in situ hydrogels was 34.3±0.2º and 16.3±0.4º for the formulation with 0.6% and 1.2% of pectin, respectively, which shows that spray cone angle decreased with the increase of pectin concentration. It was reported that narrow cone angles could increase the drug deposition on the olfactory region. However, if the angle is too narrow, the impact of the sprayed jet might cause patient discomfort. For this reason, only the formulation with 0.6% pectin was chosen for the nasal deposition studies [5]. Evaluation of the formulation deposition profile in a 3D nasal cavity model The deposition in the olfactory region (olfactory part of septum + olfactory part of turbinates) at different administration angles, from the vertical plane (0 and 20º) and horizontal plane (60 and 75º) are shown in Table 1. Table 1. Deposition profile of the in situ hydrogels containing diazepam-loaded NLC in the 3D nasal cavity model, administered at angles of 0 and 20° from the vertical plane and 60 and 75° from the horizontal plane. AHP: angle from horizontal plane ; AVP: angle from vertical plane OS: olfactory part of septum ; OT: olfactory part of turbinates ; R: recovery. Based on the results of Table 1, it was concluded that the angles of administration from the horizontal and vertical planes affect the nasal deposition in the olfactory region. The highest olfactory deposition was obtained for the administration angles of 75º from the horizontal plane and 0º from the vertical plane, with 28.10% of the formulation found in the olfactory region (Figure 2). In addition, it was observed that olfactory deposition increases with the increase of the administration angle from the horizontal plane and with the decrease of administration angle from the vertical plane. CONCLUSION The in situ hydrogel containing diazepam-loaded NLC with 0.6% of pectin CF025 presented an adequate gelation time and provided a suitable spray cone angle. About 28% of the formulation was deposited in the olfactory region, which is considered high. From the results of this study, we conclude that angles of administration from horizontal and vertical planes have impact on olfactory deposition. Currently, more factors that may also interfere, including the presence of airflow and the use of different nasal devices, are being studied by our research group. ACKNOWLEDGEMENTS This work was supported by Fundação para a Ciência e a Tecnologia (FCT) (SFRH/136177/2018, Portugal), by the Applied Molecular Bio-sciences Unit-UCIBIO, which is financed by national funds from FCT (UIDP/04378/2020 and UIDB/04378/2020) and CIBB (FCT reference: UIDB/04539/2020). Also, this work has been supported in part by Croatian Science Foundation under the project UIP-2017-05-4592". REFERENCES 1. Costa, C. et al. Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis, Journal of Controlled Release. 187-200 (2019). 2. Nižić, L. et al. Innovative sprayable in situ gelling fluticasone suspension: Development and optimization of nasal deposition. International Journal of Pharmaceutics. 563, 445-456 (2019). 3. Costa, C.P. et al. Quality by design (QbD) optimization of diazepam-loaded nanostructured lipid carriers (NLC) for nose-to-brain delivery: Toxicological effect of surface charge on human neuronal cells. International Journal of Pharmaceutics. 607, 120933 (2021). 4. Nižić Nodilo, L. et al. A Dry Powder Platform for Nose-to-Brain Delivery of Dexamethasone: Formulation Development and Nasal Deposition Studies. Pharmaceutics. 13, 795 (2021). 5. Maaz, A. et al. In Vitro Evaluation of Nasal Aerosol Depositions: An Insight for Direct Nose to Brain Drug Delivery. Pharmaceutics. 13, 1079 (2021).

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Medication adherence is a growing concern for public health and poor adherence to therapy has been associated with poor health outcomes and higher costs for patients. Interventions for improving adherence need to consider the characteristics of the individual therapeutic regimens according to the needs of the patients. In particular, geriatric and paediatric populations as well as dermatological patients have special needs/preferences that should be considered when designing drug products. Patient Centric Drug Product Pharmaceutical Design (PCDPD) offers the opportunity to meet the needs and preferences of patients. Packaging, orodispersible formulations, fixed dose combinations products, multiparticulate formulations, topical formulations and 3D printing are of particular relevance in a PCDPD process. These will be addressed in this review as well as their impact on medication adherence.