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Bunker M.,Molecular Profiles Ltd. | Zhang J.,Molecular Profiles Ltd. | Blanchard R.,I Holland Ltd. | Roberts C.J.,Molecular Profiles Ltd.
Drug Development and Industrial Pharmacy | Year: 2011

Purpose: The aim of this study is to develop an atomic force microscopy (AFM) based approach to study the adhesive forces between tabletting punches and model formulation ingredients, that can ultimately be used to understand and predict issues such as sticking during tabletting compression. Methods: Adhesive interactions were studied between single lactose particles and coated tablet punches. The adhesion was measured at varying relative humidities (RHs) and the influence of surface roughness was investigated. Roughness parameters were measured with AFM imaging and a modeling approach used to predict the influence of roughness on adhesion. Results: Surface roughness was found to play a significant role in the observed lactose-punch adhesion and the variation of this adhesion across the punch surface. Such differences between punches can be correlated to observations from industrial use. Adhesion forces were spatially mapped to indentify "hot spots" of high adhesion. A modeling approach can predict the relative adhesion of different surfaces from roughness data. The adhesion was also significantly affected by RH, for one type of punch causing a greater than 3×-increase in adhesion between 30 and 60% RH. Interestingly, different punches showed different RH-adhesion behavior, relating to their hydrophilicity. Conclusions: The work introduces a new method for screening tablet punch materials and tabletting conditions. Important factors to be considered when evaluating adhesive interactions in tablet compression have been highlighted. Correlations are observed between AFM adhesion results and tabletting behavior during manufacture. This provides a promising basis for a predictive approach toward combating tabletting issues. © 2011 Informa Healthcare USA, Inc.


Colombo S.,Copenhagen University | Cun D.,Shenyang Pharmaceutical University | Remaut K.,Ghent University | Bunker M.,Molecular Profiles Ltd. | And 6 more authors.
Journal of Controlled Release | Year: 2015

Understanding the delivery dynamics of nucleic acid nanocarriers is fundamental to improve their design for therapeutic applications. We investigated the carrier structure-function relationship of lipid-polymer hybrid nanoparticles (LPNs) consisting of poly(dl-lactic-co-glycolic acid) (PLGA) nanocarriers modified with the cationic lipid dioleoyltrimethyl-ammoniumpropane (DOTAP). A library of siRNA-loaded LPNs was prepared by systematically varying the nitrogen-to-phosphate (N/P) ratio. Atomic force microscopy (AFM) and cryo-transmission electron microscopy (cryo-TEM) combined with small angle X-ray scattering (SAXS) and confocal laser scanning microscopy (CLSM) studies suggested that the siRNA-loaded LPNs are characterized by a core-shell structure consisting of a PLGA matrix core coated with lamellar DOTAP structures with siRNA localized both in the core and in the shell. Release studies in buffer and serum-containing medium combined with in vitro gene silencing and quantification of intracellular siRNA suggested that this self-assembling core-shell structure influences the siRNA release kinetics and the delivery dynamics. A main delivery mechanism appears to be mediated via the release of transfection-competent siRNA-DOTAP lipoplexes from the LPNs. Based on these results, we suggest a model for the nanostructural characteristics of the LPNs, in which the siRNA is organized in lamellar superficial assemblies and/or as complexes entrapped in the polymeric matrix. © 2015 Elsevier B.V. All rights reserved.


Cun D.,Copenhagen University | Jensen D.K.,Copenhagen University | Maltesen M.J.,Copenhagen University | Maltesen M.J.,Novo Nordisk AS | And 5 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2011

Poly(dl-lactide-co-glycolide acid) (PLGA) is an attractive polymer for delivery of biopharmaceuticals owing to its biocompatibility, biodegradability and outstanding controlled release characteristics. The purpose of this study was to understand and define optimal parameters for preparation of small interfering RNA (siRNA)-loaded PLGA nanoparticles by the double emulsion solvent evaporation method and characterize their properties. The experiments were performed according to a 25-1 fractional factorial design based on five independent variables: The volume ratio between the inner water phase and the oil phase, the PLGA concentration, the sonication time, the siRNA load and the amount of acetylated bovine serum albumin (Ac-BSA) in the inner water phase added to stabilize the primary emulsion. The effects on the siRNA encapsulation efficiency and the particle size were investigated. The most important factors for obtaining an encapsulation efficiency as high as 70% were the PLGA concentration and the volume ratio whereas the size was mainly affected by the PLGA concentration. The viscosity of the oil phase was increased at high PLGA concentration, which explains the improved encapsulation by stabilization of the primary emulsion and reduction of siRNA leakage to the outer water phase. Addition of Ac-BSA increased the encapsulation efficiency at low PLGA concentrations. The PLGA matrix protected siRNA against nuclease degradation, provided a burst release of surface-localized siRNA followed by a triphasic sustained release for two months. These results enable careful understanding and definition of optimal process parameters for preparation of PLGA nanoparticles encapsulating high amounts of siRNA with immediate and long-term sustained release properties. © 2010 Elsevier B.V. All rights reserved.


Jayapaul J.,RWTH Aachen | Jayapaul J.,University of Heidelberg | Jayapaul J.,Leibniz Institute for Molecular Pharmacology | Arns S.,RWTH Aachen | And 6 more authors.
Nano Research | Year: 2016

Riboflavin (Rf) receptors bind and translocate Rf and its phosphorylated forms (e.g. flavin mononucleotide, FMN) into cells where they mediate various cellular metabolic pathways. Previously, we showed that FMN-coated ultrasmall superparamagnetic iron oxide (FLUSPIO) nanoparticles are suitable for labeling metabolically active cancer and endothelial cells in vitro. In this study, we focused on the in vivo application of FLUSPIO using prostate cancer xenografts. Size, charge, and chemical composition of FLUSPIO were evaluated. We explored the in vitro specificity of FLUSPIO for its cellular receptors using magnetic resonance imaging (MRI) and Prussian blue staining. Competitive binding experiments were performed in vivo by injecting free FMN in excess. Bio-distribution of FLUSPIO was determined by estimating iron content in organs and tumors using a colorimetric assay. AFM analysis and zeta potential measurements revealed a particulate morphology approximately 20–40 nm in size and a negative zeta potential (–24.23 ± 0.15 mV) in water. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry data confirmed FMN present on the USPIO nanoparticle surface. FLUSPIO uptake in prostate cancer cells and human umbilical vein endothelial cells was significantly higher than that of control USPIO, while addition of excess of free FMN reduced accumulation. Similarly, in vivo MRI and histology showed specific FLUSPIO uptake by prostate cancer cells, tumor endothelial cells, and tumor-associated macrophages. Besides prominent tumor accumulation, FLUSPIO accumulated in the liver, spleen, lung, and skin. Hence, our data strengthen our hypothesis that targeting riboflavin receptors is an efficient approach to accumulate nanomedicines in tumors opening perspectives for the development of diagnostic and therapeutic systems.[Figure not available: see fulltext.] © 2015 The author(s)


Crean B.,University of Nottingham | Crean B.,Astrazeneca | Parker A.,Molecular Profiles Ltd. | Roux D.L.,Molecular Profiles Ltd. | And 6 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2010

X-ray micro-computed tomography (XMCT) was used in conjunction with confocal Raman mapping to measure the intra-granular pore size, binder volumes and to provide spatial and chemical maps of internal granular components in α-lactose monohydrate granules formulated with different molecular weights of polyvinyl pyrrolidone (PVP). Infrared spectroscopy was used to understand the molecular association of binder domains. Granules were prepared by high-shear aqueous granulation from α-lactose monohydrate and PVP K29/32 or K90. XMCT was used to visualise the granule microstructure, intra-granular binder distribution and measure intra-granular porosity, which was subsequently related to intrusion porosimetry measurements. Confocal Raman microscopy and infrared microscopy were employed to investigate the distribution of components within the granule and explore the nature of binder substrate interactions. XMCT data sets of internal granule microstructure provided values of residual porosity in the lactose:PVP K29/32 and lactose:PVP K90 granules of 32.41 ± 4.60% and 22.40 ± 0.03%, respectively. The binder volumes of the lactose:PVP K29/32 and lactose:PVP K90 granules were 2.98 ± 0.10% and 3.38 ± 0.07%, respectively, and were attributed to PVP-rich binder domains within the granule. Confocal Raman microscopy revealed anisotropic domains of PVP between 2 μm and 20 μm in size surrounded by larger particles of lactose, in both granule types. Raman data showed that PVP domains contained various amounts of lactose, whilst IR microscopy determined that the PVP was molecularly associated with lactose, rather than residual water. The work shows that XMCT can be applied to investigate granular microstructure and resolve the porosity and the excipient and binder volumes. Combining this technique with vibrational techniques provides further structural information and aids the interpretations of the XMCT images. When used complementarily, these techniques highlighted that porosity and binder volume were the most significant microstructural differences between the α-lactose monohydrate granules formulated with the different grades of PVP. © 2010 Elsevier B.V.

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