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See detailContinuous Production of Itraconazole-based Solid Dispersions by Hot Melt Extrusion: Preformulation, Optimization and Design Space Determination.
Thiry, Justine ULg; Lebrun, Pierre; Vinassa, Chloé et al

in International Journal of Pharmaceutics (in press)

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See detailProtein encapsulation and release from PEO-b-polyphosphoester templated calcium carbonate particles
Ergül, Zeynep ULg; Cordonnier, Thomas; Debuigne, Antoine ULg et al

in International Journal of Pharmaceutics (2016), 513

Calcium carbonate particles are promising candidates as proteins carriers for their controlled delivery in the body. The present paper aims at investigating the protein encapsulation by in situ ... [more ▼]

Calcium carbonate particles are promising candidates as proteins carriers for their controlled delivery in the body. The present paper aims at investigating the protein encapsulation by in situ precipitation of calcium carbonate particles prepared by a process based on supercritical CO2 and using a new type of degradable well-defined double hydrophilic block copolymers composed of poly(ethylene oxide) and polyphosphoester blocks acting as templating agent for the calcium carbonate. For this study, lysozyme was chosen as a model for therapeutic protein for its availability and ease of detection. It was found that by this green process, loading into the CaCO3 microparticles with a diameter about 2 mm can be obtained as determined by scanning electron microscopy. A protein loading up to 6.5% active lysozyme was measured by a specific bioassay (Micrococcus lysodeikticus). By encapsulating fluorescent-labelled lysozyme (lysozyme-FITC), the confocal microscopy images confirmed its encapsulation and suggested a core–shell distribution of lysozyme into CaCO3, leading to a release profile reaching a steady state at 59% of release after 90 min. [less ▲]

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See detailIn vitro and in vivo evaluation of drug-eluting microspheres designed for transarterial chemoembolization therapy
Wang, Y.; Molin, D.; Sevrin, Chantal ULg et al

in International Journal of Pharmaceutics (2016), 503

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See detailDevelopment and evaluation in vitro and in vivo of injectable hydrolipidic gels with sustained-release properties for the management of articular pathologies such as osteoarthritis.
Réeff, Jonathan; Oprenyeszk, Frédéric ULg; Franck, Thierry ULg et al

in International Journal of Pharmaceutics (2015), 490

This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and injectable sustained-release drug delivery systems. The potential pro- and antioxidant activity of the ... [more ▼]

This study aimed to evaluate glycerol monooleate (GMO) as a carrier to develop viscoelastic and injectable sustained-release drug delivery systems. The potential pro- and antioxidant activity of the developed hydrolipidic gels were evaluated by measuring the production of ROS by polymorphonuclear leukocytes (PMNs). In addition, the biocompatibility and effectiveness of two selected gel candidates were evaluated in vivo by evaluating the benefit of a single intraarticular injection of these new treatments in a model of osteoarthritis in rabbits. The in vitro study demonstrated that the carrier F1 did not have a pro-oxidative effect and even protected PMNs against natural auto-activation, regardless of the incorporation of either clonidine chlorhydrate or betamethasone dipropionate. The in vivo study demonstrated that F1 and F1-BDP induced a loss of cartilage quality in comparison to the control and reference groups but that the lesions of cartilage observed were generally mild, with not much full-depth erosion. Moreover, no exacerbating inflammation was observed when considering the synovial membranes and the PGE2 and CRP levels. These results seemed to demonstrate that the sustained-release formulation based on GMO could be well-tolerated after intraarticular injection. Moreover, it could have the potential to prevent inflammatory conditions while sustaining drug activity locally over weeks. [less ▲]

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See detailA Review of Pharmaceutical Extrusion: Critical Process Parameters and Scaling-up
Thiry, Justine ULg; Krier, Fabrice ULg; Evrard, Brigitte ULg

in International Journal of Pharmaceutics (2015), 479(1), 227-240

Hot melt extrusion has been a widely used process in the pharmaceutical area for three decades. In this field, it is important to optimize the formulation in order to meet specific requirements. However ... [more ▼]

Hot melt extrusion has been a widely used process in the pharmaceutical area for three decades. In this field, it is important to optimize the formulation in order to meet specific requirements. However, the process parameters of the extruder should be as much investigated as the formulation since they have a major impact on the final product characteristics. Moreover, a design space should be defined in order to obtain the expected product within the defined limits. This gives some freedom to operate as long as the processing parameters stay within the limits of the design space. Those limits can be investigated by varying randomly the process parameters but it is recommended to use design of experiments. An examination of the literature is reported in this review to summarize the impact of the variation of the process parameters on the final product properties. Indeed, the homogeneity of the mixing, the state of the drug (crystalline or amorphous), the dissolution rate, the residence time, can be influenced by variations in the process parameters. In particular, the impact of the following process parameters: temperature, screw design, screw speed and feeding, on the final product, has been reviewed. [less ▲]

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See detailLow molecular weight poly (2-dimethylamino ethylmethacrylate) polymers with controlled positioned fluorescent labeling: Synthesis, characterization and in vitro interaction with human endothelial cells.
Flebus, Luca ULg; Lombart, François ULg; Sevrin, Chantal et al

in International journal of pharmaceutics (2015), 478(1), 278-287

Poly (2-dimethylamino ethylmethacrylate) (PDMAEMA) is an attractive non-degradable polymer studied as nonviral vector for gene delivery but it can be also adopted for delivery of other biopharmaceutical ... [more ▼]

Poly (2-dimethylamino ethylmethacrylate) (PDMAEMA) is an attractive non-degradable polymer studied as nonviral vector for gene delivery but it can be also adopted for delivery of other biopharmaceutical drugs. As a parenteral carrier, the PDMAEMA free form (FF) might interact with tissues and cells. Few data are available on its selective internalization and efflux from cells, while the majority of studies published have followed the distribution of DNA complexed with PDMAEMA. In order to address polycation safety, the first aim was to synthesize by atom transfer radical polymerisation (ATRP) fluorescent labeled PDMAEMA of low molecular weight (Mw) (below 15kDa), controlling the position and density of fluorescein. The second goal was to analyze the possible difference in uptake and subcellular distribution of this labeled FF polycation between human umbilical vein endothelial cells (HUVEC) and hCMEC/D3 cells. These two cell lines have been chosen in order to detect selectivity towards the blood-brain barrier (BBB). In both cases, polycation was detected along the plasma membrane followed by progressive migration to the peri-nuclear region, where it overlapped with lysosomal structures. The analysis by fluorescence-activated cell sorting (FACS) of the PDMAEMA uptake by hCMEC/D3 cells showed a significant (p<0.05) inhibition (40%) in presence of 2-dexoxy-d-glucose inhibitor, a result supporting an energy-dependence mechanism(s). Cytotoxicity study showed that low Mw PDMAEMA (10kDa) lead to a minor cytotoxicity compared to the higher ones. As main conclusion this study highlights the similitude in cell trafficking of FF PDMAEMA and data previously reported for PDMAEMA/DNA complexes. [less ▲]

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See detailThorough characterization of a Self-Emulsifying Drug Delivery System with Raman hyperspectral imaging: A case study.
Sacre, Pierre-Yves ULg; Netchacovitch, Lauranne ULg; De Bleye, Charlotte ULg et al

in International Journal of Pharmaceutics (2015), 484

Newly developed drugs often have poor bioavailability due to their poor water solubility (BCS class 2 drugs). It is therefore necessary to develop new strategies to enhance their solubility and their ... [more ▼]

Newly developed drugs often have poor bioavailability due to their poor water solubility (BCS class 2 drugs). It is therefore necessary to develop new strategies to enhance their solubility and their activity, among which, Self-Emulsifying Drug Delivery System (SEDDS). The efficacy of the drugs contained in these preparations is mainly affected by the solid state and the particle size of the active pharmaceutical ingredient (API). However, it is quite complex, long and expensive to characterize these parameters with classical techniques such as X-Ray powder diffraction, differential scanning calorimetry or hot stage microscopy. The present article presents, through a case study, the advantages of the Raman hyperspectral imaging in the characterization of such formulations. Indeed, Raman chemical imaging may fully characterize SEDDS with single equipment and operator in a non-destructive way allowing the follow-up of the formulation during stability studies. Raman imaging is therefore a tool of choice in the PAT framework since it increases the knowledge of the formulation and the process. A quantitative multivariate method using Raman hyperspectral imaging to assay the API in the lipid based formulation has been developed and fully validated following the “total error” approach. [less ▲]

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See detailIn vitro study of the specific interaction between poly (2-dimethylamino ethylmethacrylate) based polymers with platelets and red blood cells.
Flebus, Luca ULg; Lombart, François ULg; Martinez-Jothar, L et al

in International Journal of Pharmaceutics (2015), 492

Poly(2-dimethylamino)ethyl methacrylate (PDMAEMA) is an attractive polycation frequently proposed as a non-viral vector for gene therapy. As expected for other cationic carriers, intravenous ... [more ▼]

Poly(2-dimethylamino)ethyl methacrylate (PDMAEMA) is an attractive polycation frequently proposed as a non-viral vector for gene therapy. As expected for other cationic carriers, intravenous administration of PDMAEMA can result in its ionic complexation with various negatively charged domains found within the blood. To gain more insight into this polycation hemoreactivity, we followed the binding kinetics of a free form (FF) of fluorescein labelled PDMAEMA (below 15 kDa) in normal human blood using flow cytometry. This in vitro study highlighted that platelets display higher affinity for this polycation compared to red blood cells (RBCs), with an adsorption isotherm characteristics of a specific saturable binding site. PDMAEMA (1-20μg/mL) exerted a concentration dependent proaggregant effect with a biphasic aggregation of washed platelets. Activation of platelets was also noticed in whole blood with the expression of P-selectin and fibrinogen on platelet surface. Although additional studies would be needed in order to elucidate the mechanism of PDMAEMA mediated activation of platelets, our manuscript provides important information on the hemoreactivity of FF PDMAEMA. [less ▲]

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See detailLinking flowability and granulometry of lactose powders
Boschini, Frédéric ULg; Delaval, Vincent ULg; Traina, Karl et al

in International Journal of Pharmaceutics (2015)

The flowing properties of 10 lactose powders commonly used in pharmaceutical industries have been analyzed with three recently improved measurement methods. The first method is based on the heap shape ... [more ▼]

The flowing properties of 10 lactose powders commonly used in pharmaceutical industries have been analyzed with three recently improved measurement methods. The first method is based on the heap shape measurement. This straightforward measurement method provides two physical parameters (angle of repose αr and static cohesive index σr) allowing to make a first screening of the powder properties. The second method allows to estimate the rheological properties of a powder by analyzing the powder flow in a rotating drum. This more advanced method gives a large set of physical parameters (flowing angle αf, dynamic cohesive index σf, angle of first avalanche αa and powder aeration %ae) leading to deeper interpretations. The third method is an improvement of the classical bulk and tapped density measurements. In addition to the improvement of the measurement precision, the densification dynamics of the powder bulk submitted to taps is analyzed. The link between the macroscopic physical parameters obtained with these methods and the powder granulometry is analyzed. Moreover, the correlations between the different flowability indexes are discussed. Finally, the link between grain shape and flowability is discussed qualitatively. [less ▲]

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See detailInterest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide
Dufour, Gilles ULg; Bigazzi, William ULg; Wong, Nelson et al

in International Journal of Pharmaceutics (2015), 495(2), 869-878

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See detailMicrocrystalline cellulose, a direct compression binder in a quality by design environment—A review
Thoorens, Grégory; Krier, Fabrice ULg; Leclercq, Bruno et al

in International Journal of Pharmaceutics (2014), 473(1-2), 64-72

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See detailCharacterization and optimization of GMO-based gels with long term release for intraarticular administration
Réeff, J.; Gaignaux, A.; Goole, J. et al

in International Journal of Pharmaceutics (2013), 451(1-2), 95-103

Osteoarthritis is characterized by slow degenerative processes in the articular cartilage within synovial joints. It could be interesting to develop a sustained-release formulation that could be effective ... [more ▼]

Osteoarthritis is characterized by slow degenerative processes in the articular cartilage within synovial joints. It could be interesting to develop a sustained-release formulation that could be effective on both pain/inflammation and restoration of mechanical integrity of the joint. Recently, an injectable system based on glycerol monooleate (GMO), containing clonidine as a model hydrophilic analgesic/anti-inflammatory drug and hyaluronic acid as a viscoelastic scaffold, showed promising potential as a biodegradable and biocompatible preparation to sustain the drug activity. However, drug release from the system is relatively fast (complete within 1 week) and the underlying drug release mechanisms not fully understood. The aims of this study were: (i) to significantly improve this type of local controlled drug delivery system by further sustaining clonidine release, and (ii) to elucidate the underlying mass transport mechanisms. The addition of FDA-approved inactive ingredients such as sodium oleate or purified soybean oil was found to be highly effective. The release rate could be substantially reduced (e.g., 50% release after 10 days), due to the increased hydrophobicity of the systems, resulting in slower and reduced water uptake and reduced drug mobility. Interestingly, Fick's second law of diffusion could be used to quantitatively describe drug release. [less ▲]

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See detailDual anticancer drug/superparamagnetic iron oxide-loaded PLGA-based nanoparticles for cancer therapy and magnetic resonance imaging
Schleich, N.; Sibret, Pierre ULg; Danhier, P. et al

in International Journal of Pharmaceutics (2013), 447(1-2), 94-101

We developed dual paclitaxel (PTX)/superparamagnetic iron oxide (SPIO)-loaded PLGA-based nanoparticles for a theranostic purpose. Nanoparticles presented a spherical morphology and a size of 240 nm. The ... [more ▼]

We developed dual paclitaxel (PTX)/superparamagnetic iron oxide (SPIO)-loaded PLGA-based nanoparticles for a theranostic purpose. Nanoparticles presented a spherical morphology and a size of 240 nm. The PTX and iron loading were 1.84 ± 0.4 and 10.4 ± 1.93 mg/100 mg respectively. Relaxometry studies and phantom MRI demonstrated their efficacy as T2 contrast agent. Significant cellular uptake by CT26 cells of nanoparticles was shown by Prussian blue staining and fluorescent microscopy. While SPIO did not show any toxicity in CT-26 cells, PTX-loaded nanoparticles had a cytotoxic activity. PTX-loaded nanoparticle (5 mg/kg) with or without co-encapulated SPIO induced in vivo a regrowth delay of CT26 tumors. Together these multifunctional nanoparticles may be considered as future nanomedicine for simultaneous molecular imaging, drug delivery and real-time monitoring of therapeutic response. [less ▲]

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See detailDrug delivery to inflamed colon by nanoparticles: comparison of different strategies
Coco, Régis; Plapied, Laurence; Pourcelle, Vincent et al

in International Journal of Pharmaceutics (2013), 440(1), 3-12

For inflammatory bowel disease (IBD) treatment, local delivery of molecules loaded in nanoparticles to the inflamed colon could be a promising strategy. The aim of this study was to investigate how drug ... [more ▼]

For inflammatory bowel disease (IBD) treatment, local delivery of molecules loaded in nanoparticles to the inflamed colon could be a promising strategy. The aim of this study was to investigate how drug-loaded polymeric nanoparticles target the site of inflammation and to analyse the influence of different colon-specific delivery strategies. Three different polymeric nanoparticles were formulated using ovalbumin (OVA) as a model drug. pH-sensitive nanoparticles were made with Eudragit® S100. Mucoadhesive nanoparticles were created with trimethylchitosan (TMC). A mix of polymers, PLGA, PEG-PLGA and PEG-PCL, were used to obtain a sustained drug delivery. Furthermore, ligands targeting immune cells (i.e. mannose) or the inflamed colon (i.e. a specific peptide) were grafted on the PEG chain of PCL. Interaction of nanoparticles with the intestinal epithelium was explored using Caco-2 monolayers designed to mimic an inflamed epithelium and then visualized using confocal laser microscopy. TMC nanoparticles had the highest apparent permeability for OVA in the untreated model. However, in the inflamed model, there were no difference between TMC, PLGA-based and Eudragit® nanoparticles. The uptake of nanoparticles in the inflamed mouse colon was assessed in a horizontal diffusion chamber. Mannose-grafted PLGA nanoparticles showed the highest accumulation of OVA in inflamed colon. Based on these results, active targeting of macrophages and dendritic cells may be a promising approach for targeting the colon in IBD. [less ▲]

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See detailPAT tools for the control of co-extrusion implants manufacturing process
Krier, Fabrice ULg; Mantanus, Jérome; Sacre, Pierre-Yves ULg et al

in International Journal of Pharmaceutics (2013), 458

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt ... [more ▼]

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt extrusion: the implant diameter, the quantity of the Active Pharmaceutical Ingredient (API), the homogeneity distribution of API and the thickness of the membrane. We controlled the implant diameter and the quantity of API in-line with a laser measurement, NIR and Raman spectroscopy, respectively. These two different spectroscopic techniques provided comparable results. In fact, the RMSEC and RMSECV were very close in each PAT technique but NIR spectroscopy was easier to use and less sensitive to external changes. For the control of the homogeneity of API distribution and the thickness of the membrane, we used successfully Raman spectroscopy imaging. These PAT tools help reducing analysis time. [less ▲]

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See detailTocol modified glycol chitosan for the oral delivery of poorly soluble drugs
Duhem, Nicolas; Rolland, Julien; Riva, Raphaël ULg et al

in International Journal of Pharmaceutics (2012), 423(2), 452-460

The aim of this study was to develop tocol derivatives of chitosan able (i) to self-assemble in the gastrointestinal tract and (ii) to enhance the solubility of poorly soluble drugs. Among the derivatives ... [more ▼]

The aim of this study was to develop tocol derivatives of chitosan able (i) to self-assemble in the gastrointestinal tract and (ii) to enhance the solubility of poorly soluble drugs. Among the derivatives synthesized, tocopherol succinate glycol chitosan (GC-TOS) conjugates spontaneously formed micelles in aqueous solution with a critical micelle concentration of 2 μg mL−1. AFM and TEM analysis showed that spherical micelles were formed. The GC-TOS increased water solubility of 2 model class II drugs. GC-TOS loading efficiency was 2.4% (w/w) for ketoconazole and 0.14% (w/w) for itraconazole, respectively. GC-TOS was non-cytotoxic at concentrations up to 10 mg mL−1. A 3.4-fold increase of the apparent permeation coefficient of ketoconazole across a Caco-2 cell monolayer was demonstrated. Tocol polymer conjugates may be promising vehicles for the oral delivery of poorly soluble drugs. [less ▲]

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See detailLiposome surface charge influence on skin penetration behaviour
Gillet, Aline ULg; Compère, Philippe ULg; Lecomte, Frédéric ULg et al

in International Journal of Pharmaceutics (2011), 411(1-2), 223-231

Detailed reference viewed: 69 (25 ULg)