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Nottingham, United Kingdom

Keles H.,Sheffield Hallam University | Naylor A.,Critical Pharmaceuticals | Clegg F.,Sheffield Hallam University | Sammon C.,Sheffield Hallam University
Analyst | Year: 2014

For the first time, we report a series of time resolved images of a single PLGA microparticle undergoing hydrolysis at 70 °C that have been obtained using attenuated total reflectance-Fourier transform infrared spectroscopic (ATR-FTIR) imaging. A novel partially supervised non-linear curve fitting (NLCF) tool was developed to identify and fit peaks to the infrared spectrum obtained from each pixel within the 64 × 64 array. The output from the NLCF was evaluated by comparison with a traditional peak height (PH) data analysis approach and multivariate curve resolution alternating least squares (MCR-ALS) analysis for the same images, in order to understand the limitations and advantages of the NLCF methodology. The NLCF method was shown to facilitate consistent spatial resolution enhancement as defined using the step-edge approach on dry microparticle images when compared to images derived from both PH measurements and MCR-ALS. The NLCF method was shown to improve both the S/N and sharpness of images obtained during an evolving experiment, providing a better insight into the magnitude of hydration layers and particle dimension changes during hydrolysis. The NLCF approach facilitated the calculation of hydrolysis rate constants for both the glycolic (kG) and lactic (kL) acid segments of the PLGA copolymer. This represents a real advantage over MCR-ALS which could not distinguish between the two segments due to colinearity within the data. The NLCF approach made it possible to calculate the hydrolysis rate constants from a single pixel, unlike the peak height data analysis approach which suffered from poor S/N at each pixel. These findings show the potential value of applying NLCF to the study of real-time chemical processes at the micron scale, assisting in the understanding of the mechanisms of chemical processes that occur within microparticles and enhancing the value of the mid-IR ATR analysis. © the Partner Organisations 2014.

Keles H.,Sheffield Hallam University | Naylor A.,Critical Pharmaceuticals | Clegg F.,Sheffield Hallam University | Sammon C.,Sheffield Hallam University
Vibrational Spectroscopy | Year: 2014

Attenuated total reflection-Fourier transform infrared (ATR-FTIR) imaging has been applied for the first time to monitor the redistribution and release of hGH from a range of PLGA/PLA microparticles during a set of dissolution experiments at 37 C in D2O. The effect of gamma-irradiation, a common sterilisation method, on hGH release kinetics from such systems has been demonstrated. Increasing the gamma dose was shown to have a profound influence on the nature of the release mechanism, with higher gamma doses leading to a dramatic increase in the initial burst release followed by a retardation in the sustained release and a lower total level of hGH release over the dissolution experiment. These changes were shown to be the result of a combination of factors; firstly, via scanning electron microscopy (SEM), gamma-irradiation was shown to strongly influence the morphology of the PLGA/PLA microparticles; reducing their overall porosity and reducing the available surface area, whilst forcing some of the entrapped hGH to the microparticle surface. Secondly, from FTIR measurements, gamma-irradiation was shown to increase the number of oxygenated components in the Poloxamer 407 excipient, by a process of chain scission, thereby increasing the strength of interaction between the microparticle and the entrapped hGH.©2014 Published by Elsevier B.V.

Casettari L.,University of Nottingham | Casettari L.,Urbino University | Vllasaliu D.,University of Nottingham | Mantovani G.,University of Nottingham | And 4 more authors.
Biomacromolecules | Year: 2010

The aim of the present work is to investigate if conditions can be devised where PEGylation of chitosan would reduce its toxicity toward the nasal mucosa while maintaining its ability to open the cellular tight junctions and, consequently, produce an enhancement of macromolecular permeability. A series of mPEG-g-chitosan copolymers with varying levels of mPEG substitution, mPEG molecular weight, and chitosan molecular weight were synthesized by grafting carboxylic acid-terminated mPEGs (Mw 1.9 and 5.0 × 10 3 g mol-1) to chitosans (Mw 28.9 and 82.0 × 103 g mol-1) using a NHS/EDC coupling system. The synthesized mPEG-g-chitosans were fully characterized using a number of techniques, including FT-IR, 1H NMR, and SEC-MALLS and their physicochemical properties were analyzed by TGA and DSC. Thereafter, the conjugates were tested for their cytotoxicity and tight junction modulating property in a relevant cell model, a mucus producing Calu-3 monolayer. mPEG-g-chitosan conjugates exhibited reduced toxicity toward cells, as compared to unmodified chitosan counterparts. Furthermore, the conjugates demonstrated a dramatic effect on cell monolayer transepithelial electrical resistance (TEER) and enhancement of permeability of model macromolecules. TEER and permeability-enhancing effects, as measurable indicators of tight junction modulation, were found to be pH-dependent and were notably more pronounced than those exhibited by unmodified chitosans. This work therefore demonstrates that conditions can be contrived where PEGylation improves the toxicity profile of chitosan, while preserving its effect on epithelial tight junctions in the nose. © 2010 American Chemical Society.

Agency: GTR | Branch: BBSRC | Program: | Phase: Training Grant | Award Amount: 75.28K | Year: 2010

The project will evaluate a novel absorption promoter system - CriticalSorb for the nasal delivery of drugs. The project will focus on four key areas: evaluation of the physico-chemical properties of the formulations and identify essential characteristics, investigate its mechanisms of action using appropriate cell culture models, identify synergistic effects with other known absorption promoters and the final part of the project will look at developing a robust in vitro cell culture model in order to replace animal models when evaluating the nasal absorption of drugs. Background The nasal route of delivery can be exploited for the systemic delivery of drugs such as small molecular weight polar drug, peptides and proteins that are not easily administered via other routes than by injection. Despite the large surface area of the nasal cavity and extensive blood supply absorption of polar molecules, peptides and proteins is low but can be greatly improved if administered in conjunction with an absorption promoting agent. The enhancer systems work by a number of mechanisms however; animal studies have shown that most often there is a direct correlation between the absorption enhancing effect obtained and the damage caused to the nasal membrane. It is therefore important to discover and evaluate new absorption promoter systems. Critical Pharmaceuticals is a small specialty pharmaceutical company and have developed a nasal drug delivery platform based on an absorption promoter called CriticalSorb which has shown to be non-toxic to the nasal membrane in repeat dosing studies Task1. Physico-chemical characterisation of the formulations The first stage of the project will evaluate at the physico-chemical characterization of formulations containing CriticalSorb and a model drug in the form of a peptides or a protein. The CriticalSorb aqueous solutions form micelles and experiments will be carried out to determine the position of drug within such the micellar solutions, as well as the micellar properties. It will apply a combination of routine and state of the art nanotechnology analytical techniques including: particle size and distribution, dye incorporation, morphology (cryo-TEM). Task 2. Evaluation of CriticalSorb mechanism of action The second stage of the project will study and describe the mechanism of action of the absorption enhancing effect of CriticalSorb and its principal components. This will focus on cell culture monolayers of either Calu-3 cells or HBEC (human bronchial epithelial) cells lines and will assess the mechanism of transport across the mucosal membrane, potentially transcellular or paracellular route. Specific mechanism of action will be investigated, such as the tight junction opening, clathrin or calveolin cellular pathway and effect on the 170 kDa membrane bound P-glycoprotein. Task 3. Potential synergistic effects of CriticalSorb with other known absorption enhancers CriticalSorb will be combined with other known absorption enhancers with alternative modes of action such as the typically investigated bioadhesive polysaccharide Chitosan to determine potential synergistic effects between the enhancers. Task 4. In vitro - in vivo correlation of absorption enhancing effect The final stage of the project will include comparisons of absorption enhancing effect from in vitro cell culture models with the in vivo data presently available, and those that will be created in animal studies by Critical Pharmaceuticals through another project. Wagner-Nelson modeling of the data will be carried out to determine the in vitro-in vivo correlation and the suitability of the in vitro cell culture model.

Critical Pharmaceuticals | Date: 2015-11-20

A process for preparing microparticles comprising a biologically active material and a polymer and having a mean particle size expressed as the volume mean diameter (VMD) of from 10 to 500 m, wherein the biologically active material is substantially insoluble in the polymer, which process comprises: a. contacting a mixture of the biologically active material or a precursor thereof, the polymer or a precursor thereof and a processing aid with a supercritical fluid which is capable of swelling the polymer under temperature and pressure conditions necessary to maintain the fluid in a supercritical state; b. allowing the supercritical fluid to penetrate and liquefy the polymer, whilst maintaining the temperature and pressure conditions so that the fluid is maintained in a supercritical state; c. releasing the pressure to precipitate microparticles comprising the biologically active agent and the polymer.

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