Vitamins as excipients in pharmaceutical products.

Excipients are ingredients in pharmaceutical products other than the active ingredient, added to facilitate manufacturing, enhance stability or modulate release and bioavailability. Vitamins are diverse molecules essential for human nutrition that also can fulfil excipient functions. This review focuses on vitamins used as excipients and provides an overview of the functions of vitamins in various pharmaceutical formulations.

Characterization of Silicone from Closed System Transfer Devices and its Migration into Pharmaceutical Drug Products.

Closed System Transfer Devices (CSTDs) are increasingly used in healthcare settings to facilitate compounding of hazardous drugs but increasingly also therapeutic proteins. However, their use may significantly impact the quality of the sterile product. For example, contamination of the product solution may occur by leaching of silicone or particulates from the CSTDs.

Impact of the Design of Different Infusion Containers on the Dosing Accuracy of a Therapeutic Drug Product.

Residual volumes of infusion solutions vary greatly due to container and dimensional variances. Manufacturers use overfill to compensate, but the exact amounts vary significantly. This variability in overfill - when carrier solutions are used to dilute other parenteral preparations - may lead to variable concentrations and dosing, hence, potential risk for patients.

A Survey on Handling and Administration of Therapeutic Protein Products in German and Swiss Hospitals.

Protein products in hospitals often have to be compounded before administration to the patient. This may comprise reconstitution of lyophilizates, dilution, storage, and transport. However, the operations for compounding and administration in the hospital may lead to changes in product quality and possibly even impact patient safety.

N-nitrosamine Mitigation with Nitrite Scavengers in Oral Pharmaceutical Drug Products.

N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of N-nitrosamines in drug products. One strategy to inhibit the formation of N-nitrosamines during the manufacture and storage of drug products involves the incorporation of nitrite scavengers in the formulation.

An Industry Perspective on Compatibility Assessment of Closed System Drug-Transfer Devices for Biologics.

The Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, has identified the increased use of closed system drug-transfer devices (CSTDs) with biologics, without an associated compatibility assessment, to be of significant concern. The use of CSTDs has increased significantly in recent years due to the recommendations by NIOSH and USP that they be used during preparation and administration of hazardous drugs. While CSTDs are valuable in the healthcare setting to reduce occupational exposure to hazardous compounds, these devices may present particular risks that must be adequately assessed prior to use to ensure their compatibility with specific types of drug products, such as biologic drugs, which may be sensitive.

Evaluation of Different Quality-Relevant Aspects of Closed System Transfer Devices (CSTDs).

Purpose: Health care professionals can be exposed to hazardous drugs such as cytostatics during preparation of drugs for administration. Closed sytem transfer devices (CSTDs) were introduced to provide protection for healthcare professional against unintended exposure to hazardous drugs. The interest in CSTDs has significantly increased after USP <800> monograph was issued.

Protein Adsorption to In-Line Filters of Intravenous Administration Sets.

Ensuring compatibility of administered therapeutic proteins with intravenous administration sets is an important regulatory requirement. A low-dose recovery during administration of low protein concentrations is among the commonly observed incompatibilities, and it is mainly due to adsorption to in-line filters. To better understand this phenomenon, we studied the adsorption of 4 different therapeutic proteins (2 IgG1s, 1 IgG4, and 1 Fc fusion protein) diluted to 0.

Freeze-drying of HESylated IFNα-2b: Effect of HESylation on storage stability in comparison to PEGylation.

A comparison of lyophilized PEGylated and HESylated IFNα was carried out to investigate the influence of protein conjugation, lyoprotectants as well as storage temperature on protein stability. Results show that PEG tends to crystallize during freeze-drying, reducing protein stability upon storage. In contrast, HESylation(®) drastically improved the stability over PEGylation by remaining totally amorphous during lyophilization, with and without lyoprotectants while providing a high glass transition temperature of the freeze-dried cakes.

Calculation of injection forces for highly concentrated protein solutions.

Protein solutions often manifest a high viscosity at high solution concentrations, thus impairing injectability. Accordingly, accurate prediction of the injection force based on solution viscosity can greatly support protein formulation and device development. In this study, the shear-dependent viscosity of three concentrated protein solutions is reported, and calculated injection forces obtained by two different mathematical models are compared against measured values.

Influence of particle size, an elongated particle geometry, and adjuvants on dendritic cell activation.

Modern subunit vaccines have many benefits compared to live vaccines such as convenient and competitive large scale production, better reproducibility and safety. However, the poor immunogenicity of subunit vaccines usually requires the addition of potent adjuvants or drug delivery vehicles. Accordingly, researchers are investigating different adjuvants and particulate vaccine delivery vehicles to boost the immunogenicity of subunit vaccines.

Head to head comparison of the formulation and stability of concentrated solutions of HESylated versus PEGylated anakinra.

Although PEGylation of biologics is currently the gold standard for half-life extension, the technology has a number of limitations, most importantly the non-biodegradability of PEG and the extremely high viscosity at high concentrations. HESylation is a promising alternative based on coupling to the biodegradable polymer hydroxyethyl starch (HES). In this study, we are comparing HESylation with PEGylation regarding the effect on the protein's physicochemical properties, as well as on formulation at high concentrations, where protein stability and viscosity can be compromised.

Non-spherical micro- and nanoparticles: fabrication, characterization and drug delivery applications.

Introduction: Micro- and nanoparticles in drug and vaccine delivery have opened up new possibilities in pharmaceutics. In the past, researchers focused mainly on particle size, surface chemistry and the use of various materials to control particle characteristics and functions. Lately, shape has been acknowledged as an important design parameter having an impact on the interaction with biological systems.

Characterization and compatibility of hydroxyethyl starch-polyethylenimine copolymers for DNA delivery.

Hydroxyethyl starch (HES) has been proposed as a biodegradable polymer for shielding of DNA polyplexes, where the feasibility of this approach was shown both in vitro and in vivo. In this study, we report on the physicochemical characterization, the in vitro cytocompatibility and hemotoxicity of HES-decorated polyplexes. For this purpose, various HES molecules were coupled to a 22 kDa linear polyethylenimine (LPEI22) to produce a library of nine different HES-PEI conjugates.

Stability and activity of hydroxyethyl starch-coated polyplexes in frozen solutions or lyophilizates.

Despite their great potential, gene delivery polyplexes have a number of limitations, including their tendency for aggregation in vivo or upon storage. In previous studies, we could show that hydroxyethyl starch (HES)-decoration of polyplexes reduces aggregation in vitro and in vivo. The current study investigates the ability of HES-decoration to improve the stability of polyplexes upon storage as frozen-liquid or lyophilizate, and uses naked polyplexes or PEGylated ones as controls.

Protein HESylation for half-life extension: synthesis, characterization and pharmacokinetics of HESylated anakinra.

Half-life extension (HLE) is becoming an essential component of the industrial development of small-sized therapeutic peptides and proteins. HESylation(®) is a HLE technology based on coupling drug molecules to the biodegradable hydroxyethyl starch (HES). In this study, we report on the synthesis, characterization and pharmacokinetics of HESylated anakinra, where anakinra was conjugated to propionaldehyde-HES using reductive amination, leading to a monoHESylated protein.

Influence of particle geometry and PEGylation on phagocytosis of particulate carriers.

Particle geometry of micro- and nanoparticles has been identified as an important design parameter to influence the interaction with cells such as macrophages. A head to head comparison of elongated, non-spherical and spherical micro- and nanoparticles with and without PEGylation was carried out to benchmark two phagocytosis inhibiting techniques. J774.

Influence of hydroxypropyl-Beta-cyclodextrin on the stability of dilute and highly concentrated immunoglobulin g formulations.

Antibody solutions usually require the addition of suitable excipients-such as surfactants and polyols-to overcome stability problems under mechanical or thermal stress. Because cyclodextrins exhibit weak surface activity (similar to surfactants) and a sugar-based structure (like polyols), they can, in principle, stabilize proteins by a double mechanism. Accordingly, the stabilizing potential of increasing concentrations of hydroxypropyl-beta-cyclodextrin (HPβCD) was investigated for two antibodies in dilute (1.

Quality control of protein crystal suspensions using microflow imaging and flow cytometry.

Protein crystallization is an attractive method for protein processing and formulation. However, minor changes in the crystallization setup can lead to changes in the crystal structure or the formation of amorphous protein aggregates, which affect the product quality. Only few analytical tools for qualitative and quantitative differentiation between protein crystals and amorphous protein exist.

Application of different analytical methods for the characterization of non-spherical micro- and nanoparticles.

Non-spherical micro- and nanoparticles have recently gained considerable attention due to their surprisingly different interaction with biological systems compared to their spherical counterparts, opening new opportunities for drug delivery and vaccination. Up till now, electron microscopy is the only method to quantitatively identify the critical quality attributes (CQAs) of non-spherical particles produced by film-stretching; namely size, morphology and the quality of non-spherical particles (degree of contamination with spherical ones). However, electron microscopy requires expensive instrumentation, demanding sample preparation and non-trivial image analysis.

Weak antibody-cyclodextrin interactions determined by quartz crystal microbalance and dynamic/static light scattering.

In a quest to elucidate the mechanism by which hydroxypropyl β-cyclodextrin (HPβCD) stabilizes antibodies against shaking stress, two heavily debated hypotheses exist, namely that stabilization is due to HPβCD's surface activity, or due to specific interactions with proteins. In a previous study by Serno et al. (Pharm.

The effect of molar mass and degree of hydroxyethylation on the controlled shielding and deshielding of hydroxyethyl starch-coated polyplexes.

PEGylation is currently the gold-standard in shielding cationic DNA-polyplexes against non-specific interaction with blood components. However, it reduces cellular uptake and transfection, in what is known as the "PEG-dilemma". In an approach to solve this problem we developed hydroxyethyl starch (HES)-shielded polyplexes which get deshielded under the action of alpha amylase (AA).

The role of polysorbate 80 and HPβCD at the air-water interface of IgG solutions.

Purpose: To test the hypothesis of surface displacement as the underlying mechanism for IgG stabilization by polysorbates and HPβCD against surface-induced aggregation.

Methods: Adsorption/desorption-kinetics of IgG-polysorbate 80/-HPβCD were monitored. Maximum bubble pressure method was used for processes within seconds from surface formation.

Controlled shielding and deshielding of gene delivery polyplexes using hydroxyethyl starch (HES) and alpha-amylase.

The non-viral delivery of nucleic acids faces many extracellular and intracellular hurdles on the way from injection site to the site of action. Among these, aggregation in the blood stream and rapid elimination by the mononuclear phagocytic system (MPS) represent strong obstacles towards successful development of these promising therapeutic modalities. Even the state-of-the-art solutions using PEGylation show low transfection efficiency due to limited uptake and hindered endosomal escape.