Frontiers in drug delivery最新文献

Transcutaneous delivery systems bear several advantages over conventional needle-based injections. Considering the low bioavailability and poor water-solubility of imiquimod, a manufacturing process has been developed to incorporate imiquimod as suspended nanocrystals in different formulations. In this study, three formulations - fast-dissolving microneedle arrays that contain nanocrystalline imiquimod in a poly (vinyl)alcohol matrix and two semisolid preparations-were characterized and compared. The results show that microneedle arrays have an advantage over the semisolid preparations regarding in vitro release and permeation characteristics. Microneedle arrays facilitate ex vivo permeation, thus reducing the applied dose by 93% compared to the semisolid formulations. Additionally, the amount of imiquimod permeated after 24 h maintained the same level even when the contact time of the formulation with the skin is less than 1 hour. In conclusion, our results highlight the great potential of advanced microneedle based delivery systems and foster the further evaluation of this approach.

Therapy of cerebral diseases such as brain metastatic breast cancer is still challenging. Due to the blood-brain barrier (BBB), a tight barrier that protects the brain and prevents the passage of many drugs, therapeutically sufficient drug concentrations in the brain are often not achieved. Therefore, methods and drugs to manipulate the BBB permeability are required. Here we used high-throughput screening (HTS) to identify chemicals that may increase BBB permeability. Human BBB in vitro model derived from hematopoietic CD34⁺ stem cells (differentiated to brain-like endothelial cells, BLECs) was used. BLECs were seeded on 96-well plates coated with biotinylated gelatin, treated with respective chemicals for 24 h followed by addition of FITC-avidin for permeability estimation. Selected substances were further tested in vitro on BLECs. Cell viability, gene and protein expression were measured using CellTiter-Glo^®, qPCR and Western blot, respectively. From 1,278 compounds, we identified 175 substances that cause at least a 50 percent increase in BBB permeability. Two substances from the substance classes used in breast cancer therapy, GW2974 (tyrosine kinase inhibitor) and 4-amino-1,8-naphthalimide (ANI) (PARP inhibitor), were analyzed in more detail. ANI was nontoxic to BLECs, while GW2974 decreased or increased viability depending on the concentration used. Both compounds significantly increased BBB permeability and altered protein and mRNA expression in BLECs. Influencing the BBB permeability in patients with brain metastases could increase the response rate to systemic therapy. Using HTS, we were able to accurately and quickly identify compounds that increase BBB permeability and show that using this type of screening method can be applied to endothelial paracellular permeability testing.

Lipid nanoparticles (LNPs) have emerged as the platform of choice for mRNA delivery. Polyethylene glycol (PEG) is considered a key component of currently approved LNP-based delivery systems as it ensures particle stability and shapes various facets of LNP behavior in biological systems. Whilst PEG has numerous characteristics that are favorable for delivery systems, there is a growing body of evidence that suggests that it is immunogenic. Thus, next-generation mRNA therapeutics are likely to benefit from the identification of PEG alternatives. Towards this end, we have assessed the suitability of poly(2-methyl-2-oxazoline) (PMOZ) for LNP-based mRNA delivery. We compared the properties and bioactivities of PMOZ-containing LNPs to that of a standard composition that includes PEG. Decreasing the percentage of PMOZ in formulations improved transfection efficiency and enhanced the immunostimulatory potential. Reducing the PMOZ density was shown to enhanced antigen-specific T-cell responses in vivo. Interestingly, we found that this was not the case for antibody responses. A direct comparison between LNPs that contain the same amount of PEG or PMOZ strongly suggests that the former induces stronger CD8⁺ T-cell responses while the latter induces superior neutralizing titers. These findings augur well for the further development of PMOZ as a PEG replacement for LNP-based mRNA delivery approaches.

Selective Laser Sintering (SLS) has the potential to offer a more accurate alternative to current-practice manipulation of oral dosage forms for pediatric, geriatric, and dysphagia-suffering patient groups. In order to create the best possible dosage forms for these patient groups, an in-depth look into how a dosage forms geometry impacts the overall properties is essential. In this study, the impact of geometry on SLS manufactured oral dosage forms on the tablet's microstructure, actual-to-theoretical volume, mass deviation, disintegration, and dissolution was investigated. Three different shapes; cylinder, hollow cylinder, and conical frustum with similar surface area (SA), as well as three cylinders with different diameters, were investigated. The results indicate that the geometry has an impact on the mass uniformity, resultant volume, disintegration, and dissolution properties of the tablets. The mass uniformity analysis of the tablets provided the most variation between tablets of different sizes, with more uniformity for tablets with similar SA-to-volume ratio (SA/V). When examining the actual-to-theoretical volume of the tablets, a greater variance between the actual and theoretical volumes for shapes with higher overall SA was observed. The values found are approximately 1.05 for the three differently sized cylinders, 1.23 for the conical frustum, and 1.44 for the hollow cylinder, following this trend. Disintegration data supported a link between SA/V and average disintegration time, observed with the tablet of the highest SA/V disintegrating in 12 s and the tablet with the lowest SA/V disintegrating in 58 s. Dissolution results also indicated a strong dependence on SA/V. Hence, when novel ways to produce oral dosage form tablets become available by additive manufacturing, such as SLS, both geometry and SA/V must be taken into consideration in the tablet design process to ensure appropriate release kinetics and dosing standards.