Quality by Design-Driven Zeta Potential Optimisation Study of Liposomes with Charge Imparting Membrane Additives.

Liposomal formulations, as versatile nanocarrier systems suitable for targeted delivery, have a highly focused role in the therapy development of unmet clinical needs and diagnostic imaging techniques. Formulating nanomedicine with suitable zeta potential is an essential but challenging task. Formulations with a minimum ±30 mV zeta potential are considered stable. The charge of the phospholipid bilayer can be adjusted with membrane additives. The present Quality by Design-derived study aimed to optimise liposomal formulations prepared via the thin-film hydration technique by applying stearylamine (SA) or dicetyl phosphate (DCP) as charge imparting agents. This 32 fractional factorial design-based study determined phosphatidylcholine, cholesterol, and SA/DCP molar ratios for liposomes with characteristics meeting the formulation requirements. The polynomials describing the effects on the zeta potential were calculated. The optimal molar ratios of the lipids were given as 12.0:5.0:5.0 for the SA-PBS pH 5.6 (optimised sample containing stearylamine) and 8.5:4.5:6.5 for the DCP-PBS pH 5.6 (optimised sample containing dicetyl phosphate) particles hydrated with phosphate-buffered saline pH 5.6. The SA-PBS pH 5.6 liposomes had a vesicle size of 108 ± 15 nm, 0.20 ± 0.04 polydispersity index, and +30.1 ± 1.2 mV zeta potential, while these values were given as 88 ± 14 nm, 0.21 ± 0.02, and -36.7 ± 3.3 mV for the DCP-PBS pH 5.6 vesicles. The prepared liposomes acquired the requirements of the zeta potential for stable formulations.

Pharmaceutical Development and Design of Thermosensitive Liposomes Based on the QbD Approach.

This study aimed to produce thermosensitive liposomes (TSL) by applying the quality by design (QbD) concept. In this paper, our research group collected and studied the parameters that significantly impact the quality of the liposomal product. Thermosensitive liposomes are vesicles used as drug delivery systems that release the active pharmaceutical ingredient in a targeted way at ~40-42 °C, i.e., in local hyperthermia. This study aimed to manufacture thermosensitive liposomes with a diameter of approximately 100 nm. The first TSLs were made from DPPC (1,2-dipalmitoyl-sn-glycerol-3-phosphocholine) and DSPC (1,2-dioctadecanoyl-sn-glycero-3-phosphocholine) phospholipids. Studies showed that the application of different types and ratios of lipids influences the thermal properties of liposomes. In this research, we made thermosensitive liposomes using a PEGylated lipid besides the previously mentioned phospholipids with the thin-film hydration method.

An Updated Risk Assessment as Part of the QbD-Based Liposome Design and Development.

Liposomal formulation development is a challenging process. Certain factors have a critical influence on the characteristics of the liposomes, and even the relevant properties can vary based on the predefined interests of the research. In this paper, a Quality by Design-guided and Risk Assessment (RA)-based study was performed to determine the Critical Material Attributes and the Critical Process Parameters of an "intermediate" active pharmaceutical ingredient-free liposome formulation prepared via the thin-film hydration method, collect the Critical Quality Attributes of the future carrier system and show the process of narrowing a general initial RA for a specific case. The theoretical liposome design was proved through experimental models. The investigated critical factors covered the working temperature, the ratio between the wall-forming agents (phosphatidylcholine and cholesterol), the PEGylated phospholipid content (DPPE-PEG2000), the type of the hydration media (saline or phosphate-buffered saline solutions) and the cryoprotectants (glucose, sorbitol or trehalose). The characterisation results (size, surface charge, thermodynamic behaviours, formed structure and bonds) of the prepared liposomes supported the outcomes of the updated RA. The findings can be used as a basis for a particular study with specified circumstances.

Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration.

The present study aimed to develop n-propyl gallate (PG)-encapsulated liposomes through a novel direct pouring method using the quality-by-design (QbD) approach. A further aim was to coat liposomes with hyaluronic acid (HA) to improve the stability of the formulation in nasal mucosa. The QbD method was used for the determination of critical quality attributes in the formulation of PG-loaded liposomes coated with HA. The optimized formulation was determined by applying the Box-Behnken design to investigate the effect of composition and process variables on particle size, polydispersity index (PDI), and zeta potential. Physiochemical characterization, in vitro release, and permeability tests, as well as accelerated stability studies, were performed with the optimized liposomal formulation. The optimized formulation resulted in 90 ± 3.6% encapsulation efficiency, 167.9 ± 3.5 nm average hydrodynamic diameter, 0.129 ± 0.002 PDI, and -33.9 ± 4.5 zeta potential. Coated liposomes showed significantly improved properties in 24 h in an in vitro release test (>60%), in vitro permeability measurement (420 µg/cm2) within 60 min, and also in accelerated stability studies compared to uncoated liposomes. A hydrogen-peroxide-scavenging assay showed improved stability of PG-containing liposomes. It can be concluded that the optimization of PG-encapsulated liposomes coated with HA has great potential for targeting several brain diseases.

A Proposed Methodology for a Risk Assessment-Based Liposome Development Process.

The requirements of a liposomal formulation vary depending on the pharmaceutical indication, the target patient population, and the corresponding route of administration. Different preparation methods require various material attributes (MAs) (properties and characteristics of the components) and process parameters (PPs) (settings of the preparation method). The identification of the quality target product profile for a liposome-based formulation, the critical quality attributes of the liposomes, and the possible MAs and PPs that may influence the key characteristics of the vesicles facilitates pharmaceutical research. Researchers can systematise their knowledge by using the quality by design (QbD) approach. The potential factors that influence the quality of the product can be collected and studied through a risk assessment process. In this paper, the requirements of a liposome formulation prepared via the thin-film hydration preparation technique are presented; furthermore, the possible factors that have an impact on the quality of the final product and have to be considered and specified during the development of a liposomal formulation are herein identified and collected. The understanding and the application of these elements of QbD in the pharmaceutical developments help to influence the quality, the achievements, and the success of the formulated product.

Quality by Design Based Formulation Study of Meloxicam-Loaded Polymeric Micelles for Intranasal Administration.

Our study aimed to develop an "ex tempore" reconstitutable, viscosity enhancer- and preservative-free meloxicam (MEL)-loaded polymeric micelle formulation, via Quality by Design (QbD) approach, exploiting the nose-to-brain pathway, as a suitable tool in the treatment of neuroinflammation. The anti-neuroinflammatory effect of nose-to-brain NSAID polymeric micelles was not studied previously, therefore its investigation is promising. Critical product parameters, encapsulation efficiency (89.4%), Z-average (101.22 ± 2.8 nm) and polydispersity index (0.149 ± 0.7) and zeta potential (-25.2 ± 0.4 mV) met the requirements of the intranasal drug delivery system (nanoDDS) and the targeted profile liquid formulation was transformed into a solid preservative-free product by freeze-drying. The viscosity (32.5 ± 0.28 mPas) and hypotonic osmolality (240 mOsmol/L) of the reconstituted formulation provides proper and enhanced absorption and probably guarantees the administration of the liquid dosage form (nasal drop and spray). The developed formulation resulted in more than 20 times faster MEL dissolution rate and five-fold higher nasal permeability compared to starting MEL. The prediction of IVIVC confirmed the great potential for in vivo brain distribution of MEL. The nose-to-brain delivery of NSAIDs such as MEL by means of nanoDDS as polymeric micelles offers an innovative opportunity to treat neuroinflammation more effectively.

Directional coupling in spatially distributed nanoreactors.

Silica based hollow nanospheres filled with a reactant solution act as nanoreactors. A close packed ensemble of the nanoshells comprise a porous medium through which a chemical front can propagate. The front velocity decreases as the chemical signal, in the shape of a reaction-diffusion front, is transmitted from one sphere to the other due to the high curvature at the contact points. Experiments reveal that front propagation occurs through the cavity of the nanoshells because surface activity of filled nanoparticles itself cannot support chemical front across the medium.

Interaction between amino-functionalized inorganic nanoshells and acid-autocatalytic reactions.

Amino-functionalized inorganic silica nanoshells with a diameter of 511 ± 57 nm are efficiently used as hydrogen ion binders with a base dissociation constant of (1.2 ± 0.1) × 10-4. The hydrogen removal has been shown to produce reaction-diffusion fronts of constant propagation velocity in the autocatalytic chlorite-tetrathionate reaction when it is run in thin planar slices of nanoshell-containing agarose gel to exclude all convection related effects. By controlling the exact amount of amino-functionalized hollow nanospheres in the gel matrix it is possible to finely tune the propagation velocity of the chemical front in the 0.1-10 cm h-1 range. Remarkably, this can be achieved with very low amino-functionalized hollow inorganic nanosphere loadings between 0.1-0.01 (m V-1)%. The front width has also been determined experimentally, which increases by a factor of two with one magnitude decrease in the front velocity.

Photoelectrochemistry by Design: Tailoring the Nanoscale Structure of Pt/NiO Composites Leads to Enhanced Photoelectrochemical Hydrogen Evolution Performance.

Photoelectrochemical hydrogen evolution is a promising avenue to store the energy of sunlight in the form of chemical bonds. The recent rapid development of new synthetic approaches enables the nanoscale engineering of semiconductor photoelectrodes, thus tailoring their physicochemical properties toward efficient H2 formation. In this work, we carried out the parallel optimization of the morphological features of the semiconductor light absorber (NiO) and the cocatalyst (Pt). While nanoporous NiO films were obtained by electrochemical anodization, the monodisperse Pt nanoparticles were synthesized using wet chemical methods. The Pt/NiO nanocomposites were characterized by XRD, XPS, SEM, ED, TEM, cyclic voltammetry, photovoltammetry, EIS, etc. The relative enhancement of the photocurrent was demonstrated as a function of the nanoparticle size and loading. For mass-specific surface activity the smallest nanoparticles (2.0 and 4.8 nm) showed the best performance. After deconvoluting the trivial geometrical effects (stemming from the variation of Pt particle size and thus the electroactive surface area), however, the intermediate particle sizes (4.8 and 7.2 nm) were found to be optimal. Under optimized conditions, a 20-fold increase in the photocurrent (and thus the H2 evolution rates) was observed for the nanostructured Pt/NiO composite, compared to the benchmark nanoparticulate NiO film.