Influence of Glycerol on the polymorphic Behavior of solid Triglyceride Nanoparticles stabilized with Poly(vinyl Alcohol)

Colloidal dispersions of lipids, e.g. triglycerides, are under intensive investigation as drug delivery systems. Solid triglyceride nanoparticles exist in different polymorphic modifications. The aim of this study was to investigate the effects of the addition of glycerol, which can be used for the isotonization of such dispersions, on the polymorphic behavior of poly(vinyl alcohol)-stabilized tripalmitin nanoparticles. Glycerol was added to the nanoparticle dispersions at different concentrations in the heat. The dispersions were investigated for their thermal behavior and storage stability with regard to particle size and polymorphic transitions of the triglyceride matrix, using photon correlation spectroscopy, differential scanning calorimetry and X-ray diffraction. The addition of glycerol led to a decreasing crystallization temperature of the nanoparticles and slowed down the polymorphic transition into the stable β-modification

Parameters influencing Ostwald ripening of Nanoemulsions produced by Premix Membrane Emulsification

Premix membrane emulsification is a promising method to produce colloidal lipid carrier systems, e.g. triglyceride nanoemulsions, with small particle sizes and narrow particle size distributions for intravenous administration. The stability of these systems can be affected by Ostwald ripening. The process of Ostwald ripening in emulsions of medium chain triglycerides stabilized with sucrose laurate was monitored by particle size measurements with photon correlation spectroscopy. Two different preparation methods were used and the concentration of free emulsifier measured to learn more about the influencing parameters. The concentration of free sucrose laurate turned out to be the main influencing parameter and should be about zero to minimize Ostwald ripening in the emulsions

Formulation of Cannabidiol in Lipid Carriers

Substances extracted from Cannabis varieties are of increasing interest, especially cannabidiol as a non-psychoactive drug with various pharmacological effects. Formulation of cannabidiol is, however, challenging due to its low water solubility. In this study, different types of lipid carriers were investigated as formulation options for cannabidiol to enable parenteral or oral application. The study included self-dispersing lipid formulations, nanoemulsions and liposomes. With regard to parenteral application, a higher load of cannabidiol was obtained in nanoemulsions than in liposomes. Lipid nanoemulsions are thus a very promising formulation option for parenteral formulations with a high drug load. Also in formulations intended for oral use a notably higher amount of cannabidiol could be incorporated in oil-containing self-dispersing formulations than in liposomes

Release of TGF-β3 from Surface-Modified PCL Fiber Mats Triggers a Dose-Dependent Chondrogenic Differentiation of Human Mesenchymal Stromal Cells

The design of implants for tissue transitions remains a major scientific challenge. This is due to gradients in characteristics that need to be restored. The rotator cuff in the shoulder, with its direct osteo-tendinous junction (enthesis), is a prime example of such a transition. Our approach towards an optimized implant for entheses is based on electrospun fiber mats of poly(ε-caprolactone) (PCL) as biodegradable scaffold material, loaded with biologically active factors. Chitosan/tripolyphosphate (CS/TPP) nanoparticles were used to load transforming growth factor-β3 (TGF-β3) with increasing loading concentrations for the regeneration of the cartilage zone within direct entheses. Release experiments were performed, and the concentration of TGF-β3 in the release medium was determined by ELISA. Chondrogenic differentiation of human mesenchymal stromal cells (MSCs) was analyzed in the presence of released TGF-β3. The amount of released TGF-β3 increased with the use of higher loading concentrations. This correlated with larger cell pellets and an increase in chondrogenic marker genes (SOX9, COL2A1, COMP). These data were further supported by an increase in the glycosaminoglycan (GAG)-to-DNA ratio of the cell pellets. The results demonstrate an increase in the total release of TGF-β3 by loading higher concentrations to the implant, which led to the desired biological effect

Formulation of Cannabidiol in Colloidal Lipid Carriers

In this study, the general processability of cannabidiol (CBD) in colloidal lipid carriers was investigated. Due to its many pharmacological effects, the pharmaceutical use of this poorly water-soluble drug is currently under intensive research and colloidal lipid emulsions are a well-established formulation option for such lipophilic substances. To obtain a better understanding of the formulability of CBD in lipid emulsions, different aspects of CBD loading and its interaction with the emulsion droplets were investigated. Very high drug loads (>40% related to lipid content) could be achieved in emulsions of medium chain triglycerides, rapeseed oil, soybean oil and trimyristin. The maximum CBD load depended on the type of lipid matrix. CBD loading increased the particle size and the density of the lipid matrix. The loading capacity of a trimyristin emulsion for CBD was superior to that of a suspension of solid lipid nanoparticles based on trimyristin (69% vs. 30% related to the lipid matrix). In addition to its localization within the lipid core of the emulsion droplets, cannabidiol was associated with the droplet interface to a remarkable extent. According to a stress test, CBD destabilized the emulsions, with phospholipid-stabilized emulsions being more stable than poloxamer-stabilized ones. Furthermore, it was possible to produce emulsions with pure CBD as the dispersed phase, since CBD demonstrated such a pronounced supercooling tendency that it did not recrystallize, even if cooled to −60 °C

ELISA- and Activity Assay-Based Quantification of BMP-2 Released In Vitro Can Be Biased by Solubility in “Physiological” Buffers and an Interfering Effect of Chitosan

Chitosan nanogel-coated polycaprolactone (PCL) fiber mat-based implant prototypes with tailored release of bone morphogenic protein 2 (BMP-2) are a promising approach to achieve implant-mediated bone regeneration. In order to ensure reliable in vitro release results, the robustness of a commercially available ELISA for E. coli-derived BMP-2 and the parallel determination of BMP-2 recovery using a quantitative biological activity assay were investigated within a common release setup, with special reference to solubility and matrix effects. Without bovine serum albumin and Tween 20 as solubilizing additives to release media buffed at physiological pH, BMP-2 recoveries after release were notably reduced. In contrast, the addition of chitosan to release samples caused an excessive recovery. A possible explanation for these effects is the reversible aggregation tendency of BMP-2, which might be influenced by an interaction with chitosan. The interfering effects highlighted in this study are of great importance for bio-assay-based BMP-2 quantification, especially in the context of pharmaceutical release experiments

Stabilized Production of Lipid Nanoparticles of Tunable Size in Taylor Flow Glass Devices with High-Surface-Quality 3D Microchannels.

Nanoparticles as an application platform for active ingredients offer the advantage of efficient absorption and rapid dissolution in the organism, even in cases of poor water solubility. Active substances can either be presented directly as nanoparticles or can be integrated in a colloidal carrier system (e.g., lipid nanoparticles). For bottom-up nanoparticle production minimizing particle contamination, precipitation processes provide an adequate approach. Microfluidic systems ensure a precise control of mixing for the precipitation, which enables a tunable particle size definition. In this work, a gas/liquid Taylor flow micromixer made of chemically inert glass is presented, in which the organic phases are injected through a symmetric inlet structure. The 3D structuring of the glass was performed by femtosecond laser ablation. Rough microchannel walls are typically obtained by laser ablation but were smoothed by a subsequent annealing process resulting in lower hydrophilicity and even rounder channel cross-sections. Only with such smooth channel walls can a substantial reduction of fouling be obtained, allowing for stable operation over longer periods. The ultrafast mixing of the solutions could be adjusted by simply changing the gas volume flow rate. Narrow particle size distributions are obtained for smaller gas bubbles with a low backflow and when the rate of liquid volume flow has a small influence on particle precipitation. Therefore, nanoparticles with adjustable sizes of down to 70 nm could be reliably produced in continuous mode. Particle size distributions could be narrowed to a polydispersity value of 0.12

Protective Filtration for Microfluidic Nanoparticle Precipitation for Pharmaceutical Applications

Microfluidic processes are of great interest for the production of nanoparticles with reproducible properties. However, in real systems, it is difficult to completely exclude incidental production of larger particles, which can contaminate the product or clog downstream process modules. A class of microfluidic filters was devised for eliminating particulate contamination in multistage continuous‐flow processes. To achieve high throughput and filtration efficiency, a high‐surface‐area filter with an application‐adapted bonding method was developed. As a model application, the filtration efficiency was analyzed for lipid nanoparticles made by microfluidic antisolvent precipitation and the results were compared with requirements of the European and US guidelines

Influence of Formulation Parameters on Redispersibility of Naproxen Nanoparticles from Granules Produced in a Fluidized Bed Process

The particle size reduction of active pharmaceutical ingredients is an ecient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient’s convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the influence of several formulation parameters (i.e., type of carrier material, type and amount of additional polymeric drying excipient in the nanosuspension) on the redispersibility of naproxen nanoparticle-loaded granules produced in a fluidized bed process was investigated. The dissolution rate of the carrier material (i.e., sucrose, mannitol, or lactose) was identified as a relevant material property, with higher dissolution rates (sucrose > mannitol > lactose) resulting in better redispersibility of the products. Additionally, the redispersibility of the product granules was observed to improve with increasing amounts of polymeric drying excipient in the nanosuspension. The redispersibility was observed to qualitatively correlate with the degree of nanoparticle embedding on the surface of the corresponding granules. This embedding was assumed to be either caused by a partial dissolution and subsequent resolidification of the carrier surface dependent on the dissolution rate of the carrier material or by resolidification of the dissolved polymeric drying excipient upon drying. As the correlation between the redispersibility and the morphology of the corresponding granules was observed for all investigated formulation parameters, it may be assumed that the redispersibility of the nanoparticles is determined by their distance in the dried state

Structural and functional stabilization of bacteriophage particles within the aqueous core of a W/O/W multiple emulsion: a potential biotherapeutic system for the inhalational treatment of bacterial pneumonia

The increase of antibiotic-resistant bacteria is growing every day, most likely associated with the indiscriminate use of these antimicrobials or even with evolutionary adaptability of bacteria to their environment. This situation brings a need to develop new alternatives to conventional antibiotics, and thus the application of strictly lytic bacteriophages has been proposed as an alternative (or complement) to the former, allowing release of the natural predators of bacteria directly where they are needed the most: the infection site. The main advantages of bacteriophages to treat infections is the maintenance of a high concentration of bacteriophage particles in the action site while any viable target bacteria still exist, coupled to the production of enzymes that hydrolyze the polymeric matrix of bacterial biofilms promoting penetration and antibacterial action. In the research effort entertained herein, the potential for protection and stabilization of strictly lytic bacteriophages with broad spectrum capable of infecting Pseudomonas aeruginosa, so as to maintain their structure and functionality, was investigated via encapsulation within the aqueous-core of lipid nanodroplets integrating a W/O/W multiple emulsion system, aiming at developing isotonic derivative solutions thereof for administration by nebulization.Project funding by FAPESP (São Paulo, Brazil; Refs. No. 2013/ 03181-6 (Project PneumoPhageKill), 2016/08884-3 (Project PneumoPhageColor) and 2016/12234-4 (Project TransAppIL)), is hereby gratefully acknowledged. This work also received support from CNPq, in the form of a Research Productivity (PQ)fellowship granted to Victor M. Balcão (Ref. No. 306113/2014-7). The authors are grateful to the LME facility at LNNano/CNPEM (Campinas, Brazil) for the use of the TEM microscope. The authors have no conflicts of interest whatsoever to declare.info:eu-repo/semantics/publishedVersio