B. G. De Geest

Patchiness of Embedded Particles and Film Stiffness Control Through Concentration of Gold Nanoparticles

Patchy particles are fabricated using a method of embedding-into and extracting-from thick, biocompatible, gel-like HA/PLL films. Control over the patchiness is achieved by adjusting the stiffness of films, which affects embedding and masking of particles. The stiffness is adjusted by the concentration of gold nanoparticles adsorbed onto the surface of the films.

Polymer-protein conjugation via a ‘grafting to’ approach – a comparative study of the performance of protein-reactive RAFT chain transfer agents

Efficient polymer-protein conjugation is a crucial step in the design of many therapeutic protein formulations including nanoscopic vaccine formulations, antibody-drug conjugates and to enhance the in vivo behaviour of proteins. Here we aimed at preparing well-defined polymers for conjugation to proteins by reversible addition–fragmentation chain transfer (RAFT) polymerization of both acrylates and methacrylamides with protein-reactive chain transfer agents (CTAs). These RAFT agents contain either a N-hydroxysuccinimide (NHS) or pentafluorophenyl (PFP) ester moiety that can be conjugated to lysine residues, and alternatively a maleimide (MAL) or pyridyl disulfide (PDS) moiety that can be conjugated to cysteine residues. Efficiency of the bioconjugation of these polymers to bovine and avian serum albumin was investigated as a function of stoichiometry, polymer molecular weight and the presence of reducing agents. A large molar excess of polymer was required to obtain an acceptable degree of protein conjugation. However, protein modification with N-succinimidyl-S-acetylthiopropionate (SATP) to introduce sulfhydryl groups onto primary amines, significantly increased conjugation efficiency with MAL- and PDS-containing polymers.

Hydrophilic thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding

Hydrophilic aliphatic thermoplastic polyurethane (Tecophilic™ grades) matrices for high drug loaded oral sustained release dosage forms were formulated via hot melt extrusion/injection molding (HME/IM). Drugs with different aqueous solubility (diprophylline, theophylline and acetaminophen) were processed and their influence on the release kinetics was investigated. Moreover, the effect of Tecophilic™ grade, HME/IM process temperature, extrusion speed, drug load, injection pressure and post-injection pressure on in vitro release kinetics was evaluated for all model drugs. (1)H NMR spectroscopy indicated that all grades have different soft segment/hard segment ratios, allowing different water uptake capacities and thus different release kinetics. Processing temperature of the different Tecophilic™ grades was successfully predicted by using SEC and rheology. Tecophilic™ grades SP60D60, SP93A100 and TG2000 had a lower processing temperature than other grades and were further evaluated for the production of IM tablets. During HME/IM drug loads up to 70% (w/w) were achieved. In addition, Raman mapping and (M)DSC results confirmed the homogenous distribution of mainly crystalline API in all polymer matrices. Besides, hydrophilic TPU based formulations allowed complete and sustained release kinetics without using release modifiers. As release kinetics were mainly affected by drug load and the length of the PEO soft segment, this polymer platform offers a versatile formulation strategy to adjust the release rate of drugs with different aqueous solubility.

Versatile loading of diverse cargo into functional polymer capsules

Polymer microcapsules are of particular interest for applications including self‐healing coatings, catalysis, bioreactions, sensing, and drug delivery. The primary way that polymer capsules can exhibit functionality relevant to these diverse fields is through the incorporation of functional cargo in the capsule cavity or wall. Diverse functional and therapeutic cargo can be loaded into polymer capsules with ease using polymer‐stabilized calcium carbonate (CaCO3) particles. A variety of examples are demonstrated, including 15 types of cargo, yielding a toolbox with effectively 500+ variations. This process uses no harsh reagents and can take less than 30 min to prepare, load, coat, and form the hollow capsules. For these reasons, it is expected that the technique will play a crucial role across scientific studies in numerous fields.

Prilling of fatty acids as a continuous process for the development of controlled release multiparticulate dosage forms

In this study, prilling was evaluated as a technique for the development of multiparticulate dosage forms using the fatty acids, stearic acid, and behenic acid as potential matrix formers to control the release of metoprolol tartrate (MPT), a highly water soluble drug. The in vitro drug release was dependent on the drug load, type of fatty acid, and pH of the dissolution medium. Higher drug loads resulted in faster release with behenic acid releasing drug over longer periods relative to stearic acid. The in vitro drug release was pH-dependent at low drug load with the release being slower at lower pH. Due to ionization of the fatty acid at pH 7.4, drug release was susceptible to the ionic strength at this pH value. Solid state characterization indicated that the crystalline state of the fatty acids was not affected by thermal processing via prilling, while the crystallinity of MPT was decreased. During storage, the amorphous MPT fraction recrystallized in the entire matrix. Drug release from behenic acid matrices was increased during storage at 40 °C; however, no polymorphism of behenic acid was detected. The bioavailability of MPT, after oral administration to dogs as prills containing 30% and 40% MPT using behenic acid as matrix former, was not significantly different from a commercial sustained release reference formulation, although the 40% MPT prills showed a burst release.

Thermoplastic polyurethane-based intravaginal rings for prophylaxis and treatment of (recurrent) bacterial vaginosis

The aim of the present study was to develop thermoplastic polyurethane (TPU)-based intravaginal rings (IVRs) for prophylaxis and treatment of bacterial vaginosis via hot melt extrusion/injection molding. Therefore, different TPU grades were processed in combination with lactic acid or metronidazole, targeting a sustained lactic acid release over a 28day-period and sustained metronidazole release over 4-7days. Hot melt extrusion of lactic acid/TPU combinations required a lower extrusion temperature due to the plasticizing properties of lactic acid, evidenced by the lower glass transition temperature (Tg) and cross-over point (Ttanδ=1) values. NIR-chemical imaging data showed a homogenous distribution of lactic acid in TPU matrices at drug loads up to 30% (w/w). The addition of metronidazole did not lower processing temperatures, as the active pharmaceutical ingredient remained crystalline in the TPU matrix. Hydrophobic TPUs with a low ratio between the soft and hard segments (SS/HS ratio) in the polymer structure were suitable carriers for the lactic acid-eluting device over a 28-day period, while hydrophilic TPUs were needed to achieve the required release rate of metronidazole-eluting IVRs. IVRs manufactured with a TPU grade having a higher SS/HS ratio and lactic acid/TPU ratio exhibited a more elastic behavior. The addition of 25% (w/w) metronidazole did not affect the mechanical properties of the IVRs. Hydrophilic TPUs were most prone to biofilm formation by Candida albicans and Staphylococcus aureus, but the incorporation of metronidazole in the device prevented biofilm formation. Based on the drug eluting performance and mechanical tests, a mixture of lactic acid and Tecoflex™ EG-93A (20/80, w/w) and a combination of metronidazole and Tecophilic™ SP-93A-100 (25/75, w/w) were selected to design IVRs for the prophylaxis and treatment of bacterial vaginosis, respectively. Slug mucosal irritation tests predicted low irritation potency for both devices.

Formulation of poorly water-soluble drugs via coacervation – A pilot study using febantel

In this study, febantel was dissolved under increased temperature in a nonionic surfactant Lutrol L44® and subsequently mixed into an aqueous maltodextrin solution. After 8h under static conditions, coacervation or phase separation took place. (1)H NMR spectra and HPLC analysis showed that the upper phase contained mainly all febantel, while no febantel was detected in the lower phase. Fluorescent microscopy showed that maltodextrin is distributed in the lower phase. Coacervation proved to be a promising formulation technology for certain poorly water-soluble drugs, such as febantel. The coacervate phase showed an increase in in vitro dissolution kinetics, compared to Rintal® granules. These results were confirmed in an in vivo study performed on dogs. Febantel and fenbendazole showed a significant increase in plasma concentration compared to Rintal® granules. Further studies have to be performed to transform coacervates into a solid dosage form and to prove broad applicability to other poorly soluble drugs.

Engineering the immune system with particles, step-by-step

Biomaterials-based strategies to engineer the immune system have gathered considerable attention the past decade and have opened new avenues for vaccine delivery and for modulating the immune system to fight cancer. This review highlights some of these strategies that involve well-defined particle-based delivery systems that are constructed in a multistep fashion. Particular attention is devoted to the design of micro and nanoparticles to deliver antigen and molecular adjuvants to antigen presenting immune cell subsets in lymphatic tissue.