AAPS PharmSciTech

AbstractThe airway of pediatric patients’ changes through development, presenting a challenge in developing pediatric-specific aerosol therapeutics. Our work aims to quantify geometric variations and aerosol deposition patterns during upper airway development in subjects between 3.5 months–6.9 years old using a library of 24 pediatric models and 4 adult models. Computational fluid–particle dynamics was performed with varying particle size (0.1–10 μm) and flow rate (10–120 Lpm), which was rigorously analyzed to compare anatomical metrics (epiglottis angle (θE), glottis to cricoid ring ratio (GC-ratio), and pediatric to adult trachea ratio (H-ratio)), inhaler metrics (particle diameter, $${d}_{p}$$ d p , and flow rate, Q), and clinical metrics (age, sex, height, and weight) against aerosol deposition. Multivariate non-linear regression indicated that all metrics were all significantly influential on resultant deposition, with varying influence of individual parameters. Additionally, principal component analysis was employed, indicating that $${d}_{p}$$ d p , Q, GC-ratio, θE, and sex accounted for 90% of variability between subject-specific deposition. Notably, age was not statistically significant among pediatric subjects but was influential in comparing adult subjects. Inhaler design metrics were hugely influential, thus supporting the critical need for pediatric-specific inhalable approaches. This work not only improves accuracy in prescribing inhalable therapeutics and informing pediatric aerosol optimization, but also provides a framework for future aerosol studies to continue to strive toward optimized and personalized pediatric medicine. Graphical Abstract

In this study, a nanoemulsion (NE) system was investigated for intravenous delivery of lipophilic and venous irritant drugs. NEs were prepared to deliver diallyl trisulfide (DT) for systemic therapy of bacterial and fungal infection, egg phospholipid was chosen as the main emulsifier, and two co-emulsifiers were also incorporated, including Poloxamer 188 (P188) and Solutol HS 15 (S15). Soybean oil was used as the dispersed phases, forming stable DT NEs with small particle sizes. The venous irritation of DT NEs was evaluated by in vitro human umbilical cord endothelial cells (CRL 1730) compatibility model with the intracellular adenosine triphosphate (ATP) and guanosine triphosphate (GTP) concentrations as the indices. The intracellular ATP and GTP reduction changed with the incorporation of a variety of co-emulsifiers, which varied in a free DT concentration-dependent manner. It was deduced that the free DT concentrations of NEs containing co-emulsifiers were determined by the partition coefficient of DT between oil and surfactant buffer solution. In conclusion, NE was an appropriate delivery system for lipophilic and venous irritant drug, and optimization of the composition of emulsifiers was an effective method to alleviate the venous irritation of DT NEs.

This work aimed to develop and optimize several lipid nanocapsule formulations (LNCs) to encapsulate cisplatin (CDDP) for treatment of hepatocellular carcinoma. By comparing the effect of oil/surfactant ratio, lecithin content, and oil/surfactant type on LNC characteristics, two LNCs were selected as optimal formulations: HS15-LNC (Solutol HS 15/MCT/lecithin, 54.5:42.5:3%, w/w) and EL-LNC (Cremophor EL/MCT/lecithin, 54.5:42.5:3%, w/w). Both LNCs could effectively encapsulate CDDP with the encapsulation efficiency of 73.48 and 78.84%. In vitro release study showed that both LNCs could sustain the release CDDP. Moreover, cellular uptake study showed that C6-labeled LNCs could be effectively internalized by HepG2 cells. Cellular cytotoxicity study revealed that both LNCs showed negligible cellular toxicity when their concentrations were below 313 μg/mL. Importantly, CDDP-loaded LNCs exhibited much stronger cell killing potency than free CDDP, with the IC50 values decreased from 17.93 to 3.53 and 5.16 μM after 72-h incubation. In addition, flow cytometric analysis showed that the percentage of apoptotic cells was significantly increased after treatment with LNCs. Therefore, the prepared LNC formulations exhibited promising anti-hepatocarcinoma effect, which could be beneficial to hepatocellular carcinoma therapy.

The aim of this work was to assess the effect of formulation parameters of a mucoadhesive vaginal gel based on chitosan and lactic acid, and to highlight its release mechanisms. Two molecular weight chitosans were used to prepare gels with 2 lactic acid concentrations. Both chitosan molecular weight and lactic acid concentration had a significant and mutually dependent influence on mucoadhesion, measured on pig vaginal mucosa. Similarly, the lactate release profiles were found to be dependent on lactic acid content and polymer molecular weight. One gel formulation based on the stoichiometric lactate to chitosan ratio was subjected to release test in media with 2 different counterions and increasing ionic strength. This test demonstrated that the lactate release is mainly due to ionic displacement.

The aim of this work was to survey how processing parameters affect the crystal growth of β-sitosterol in suspension. The process variables studied were the cooling temperature, stirring time and stirring rate during recrystallization. In addition, we investigated the effect a commonly used surfactant, polysorbate 80, has on crystal size distribution and the polymorphic form. This study describes the optimization of the crystallization process, with the object of preparing crystals as small as possible. Particle size distribution and habit were analyzed using optical microscopy, and the crystal structure was analyzed using X-ray diffractometry. The cooling temperature had a remarkable influence on the crystal size. Crystals with a median crystal length of ≈23 μm were achieved with a low cooling temperature (<10°C); however, a fairly large number of crystals over 50 μm appeared. Higher cooling temperatures (>30°C) caused notable crystal growth both in length and width. Rapid (250 rpm), continuous stirring until the suspensions had cooled to room temperature created small, less than 50 μm long (median <20 μm), needle-shaped crystals. The addition of surfactant slightly reduced the size of the initially large crystals. Both hemihydrate and monohydrate crystal forms occurred throughout, regardless of the processing parameters. By using an optimized process, it was possible to obtain a microcrystalline suspension, with a smooth texture.

The purpose of this study was to evaluate the effect of topical application of nanoliposomal avocado/soybean unsaponifiables (NANOCEN) on inflammation inhibition and pain relief in mice. NANOCEN was prepared by the injection method and characterized for vesicle size, charge, entrapment efficiency, in vitro release, and 1-month vesicle stability. The analysis of ASU formulation showed that liposomes had an average size of around 146 nm with a surface charge of − 43 mV. SEM and TEM imaging confirmed the spherical shape of the nanovesicles in ASU formulation. Moreover, ASU nanoliposomes had a high entrapment efficiency (96%) and exhibited significantly (p < 0.0001) sustained release of the drug in vitro model. The topical NANOCEN (ASU 2%) showed robust anti-inflammatory (p < 0.01) and analgesic effect (p < 0.01) superior to ibuprofen 5%. The histopathology of the inflamed tissues confirmed that the topical ASU formulation potentially (p < 0.001) inhibited infiltration of inflammatory cells. Our findings suggest that the topical formulation of NANOCEN may have local applications for pain relief in medicine.