Search

Protein-based drugs often require targeted drug delivery for optimal therapy. A successful strategy to increase the circulation time of the protein in the blood is to link the therapeutic protein with an albumin-binding domain. In this work, we characterized such a protein-based drug, GA-Z. Using asymmetrical flow field-flow fractionation coupled with multi-angle light scattering (AF4-MALS) we investigated the GA-Z monomer-dimer equilibrium as well as the molar binding ratio of GA-Z to HSA. Using small angle X-ray scattering, we studied the structure of GA-Z as well as the complex between GA-Z and HSA. The results show that GA-Z is predominantly dimeric in solution at pH 7 and that it binds to monomeric as well as dimeric HSA. Furthermore, GA-Z binds to HSA both as a monomer and a dimer, and thus, it can be expected to stay bound also upon dilution following injection in the blood stream. The results from SAXS and binding studies indicate that the GA-Z dimer is formed between two target domains (Z-domains). The results also indicate that the binding of GA-Z to HSA does not affect the ratio between HSA dimers and monomers, and that no higher order oligomers of the complex are seen other than those containing dimers of GA-Z and dimers of HSA. [ABSTRACT FROM AUTHOR]

This work investigates the stability of emulsions prepared by using octenyl succinic anhydride (OSA)-modified waxy maize starch in the form of granules, dissolved starch, and non-solvent precipitated starch as Pickering emulsion stabilisers. The aim of this study was to investigate the effects of different forms of starches on the stability of emulsion using light microscopy, light scattering, and static multiple light scattering. All starch samples were hydrophobically modified with 3% (w/w) n-octenyl succinyl anhydride (OSA). Starch polymer solutions were prepared by dissolving OSA- modified starch in water in an autoclave at 140°C. Non-solvent precipitates were obtained through ethanol precipitation of dissolved waxy maize. The stability of the oil/water emulsions were different for the three forms of starches used. The granule-based emulsions were unstable, with only a small proportion of the granules adsorbed onto oil droplets, as viewed under a light microscope. The emulsions were observed to cream after 2 hours. The dissolved starch and non-solvent precipitate-based emulsions were stable towards creaming for months, and they had almost 100% emulsifying index (EI = 1) by visual observation and EI ~ 0.9 by multiple light scattering measurements. The results from light microscopy and multiple light scattering measurements indicated the occurrence of coalescence for all three types of emulsions. The coalescence was fastest within days for the granule stabilised system while it was slower both for the dissolved starch and non-solvent precipitate-based emulsions. The latter demonstrated the least degree of coalescence over time. Thus, it was concluded that differences in starch particle size and molecular structure influenced the emulsion droplet size and stability. A decreased particle size correlates to a decrease in droplet size, thus increasing stabilisation against creaming. However, stability towards coalescence was low for the large granules but was best for the non-solvent precipitate starch indicating that there is a window of optimal particle size for stability. Thus, best emulsifying properties were obtained with the non-solvent precipitates (~ 120 nm particle size) where the emulsions remained stable after one year of storage. In conclusion, this study illustrated the potentiality of non-solvent precipitated starch as emulsion stabilizers. [ABSTRACT FROM AUTHOR]

The emulsifying ability of OSA-modified and native starch in the granular form, in the dissolved state and a combination of both was compared. This study aims to understand mixed systems of particles and dissolved starch with respect to what species dominates at droplet interfaces and how stability is affected by addition of one of the species to already formed emulsions. It was possible to create emulsions with OSA-modified starch isolated from Quinoa as sole emulsifier. Similar droplet sizes were obtained with emulsions prepared at 7% (w/w) oil content using OSA-modified starch in the granular form or molecularly dissolved but large differences were observed regarding stability. Pickering emulsions kept their droplet size constant after one month while emulsions formulated with OSA-modified starch dissolved exhibited coalescence. All emulsions stabilized combining OSA-modified starch in granular form and in solution showed larger mean droplet sizes with no significant differences with respect to the order of addition. These emulsions were unstable due to coalescence regarding presence of free oil. Similar results were obtained when emulsions were prepared by combining OSA-modified granules with native starch in solution. The degree of surface coverage of starch granules was much lower in presence of starch in solution which indicates that OSA-starch is more surface active in the dissolved state than in granular form, although it led to unstable systems compared to starch granule stabilized Pickering emulsions, which demonstrated to be extremely stable. [ABSTRACT FROM AUTHOR]

A large part of new pharmaceutical substances are characterized by a poor solubility and high hydrophobicity, which might lead to a difference in drug adsorption between fasted and fed patients. We have previously evaluated the release of hydrophobic drugs from tablets based on Pemulen TR2 and showed that the release can be manipulated by adding surfactants. Here we further evaluate the possibility to use Pemulen TR2 in controlled release tablet formulations containing a poorly soluble substance, griseofulvin. The release is evaluated in simulated intestinal media that model the fasted state (FaSSIF medium) or fed state (FeSSIF). The rheology of polymer gels is studied in separate experiments, in order to gain more information on possible interactions. The release of griseofulvin in tablets without surfactant varied greatly and the slowest release were observed in FeSSIF. Addition of SDS to the tablets eliminated the differences and all tablets showed a slow linear release, which is of obvious relevance for robust drug delivery. Comparing the data from the release studies and the rheology experiment showed that the effects on the release from the different media could to a large extent be rationalised as a consequence of the interactions between the polymer and the surfactants in the media. The study shows that Pemulen TR2 is a candidate for controlled release formulations in which addition of surfactant provides a way to eliminate food effects on the release profile. However, the formulation used needs to be designed to give a faster release rate than the tablets currently investigated. [ABSTRACT FROM AUTHOR]