Barbara J. Forbes

Long-term stability, biocompatibility and oral delivery potential of risperidone-loaded solid lipid nanoparticles

A solid lipid nanoparticles (SLN) formulation to improve the oral delivery of risperidone (RISP), a poorly water-soluble drug, was designed and tested. Initially, lipid-RISP solubility was screened to select the best lipid for SLN preparation. Compritol(®)-based formulations were chosen and their long-term stability was assessed over two years of storage (at 25 °C and 4 °C) by means of particle size, polydispersity index (PI), zeta potential (ZP) and encapsulation efficiency (EE) measurements. SLN shape was observed by transmission electron microscopy (TEM) at the beginning and end of the study. The oxidative potential (OP) of the SLN was measured and their biocompatibility with Caco-2 cells was evaluated using the (4,5-dimethylthiazol-2-yl)2,5-dyphenyl-tetrazolium bromide (MTT) assay. In vitro drug release and transport studies were performed to predict the in vivo release profile and to evaluate the drug delivery potential of the SLN formulations, respectively. The RISP-loaded SLN systems were stable and had high EE and similar shape to the placebo formulations before and after storage. Classical Fickian diffusion was identified as the release mechanism for RISP from the SLN formulation. Biocompatibility and dose-dependent RISP transport across Caco-2 cells were observed for the prepared SLN formulations. The viability of SLN as formulations for oral delivery of poorly water-soluble drugs such as RISP was illustrated.

Temporal dependence of ectopeptidase expression in alveolar epithelial cell culture : implications for study of peptide absorption

There is little data available regarding the extent of peptide metabolism encountered following inhalation to the lung. We have studied the activity of five ectopeptidases in primary rat alveolar epithelial cells, A549 cells and pulmonary macrophages. Peptidase activity was assayed in the plasma membrane fractions (PMF) of primary type II alveolar epithelial cells (ATII cells) after 2 days in culture and after 7 days in culture when they had formed monolayers of type I-like cells (ATI-like cells). Dipeptidyl peptidase IV (DPP) activity fell from 36.65 mU/mg protein to 16.29 mU/mg protein between day 2 and day 7 in culture, aminopeptidase N (AMN) activity increased from 16.16 mU/mg protein to 23.99 mU/mg protein, angiotensin-converting enzyme (ACE) activity was lost (4.29 mU/mg protein at day 2, not detected at day 7), and carboxypeptidase M (CPM) activity was acquired (not detected at day 2, 5.20 mU/mg protein at day 7). The profile of exopeptidase expression in A549 cells was similar to that of primary rat alveolar cells at day 7 in culture (DPP 24.24 mU/mg protein, AMN 47.74 mU/mg protein, CPM 4.28 mU/mg protein, ACE not detected). Macrophages expressed high levels of aminopeptidases (DPP 46.85 mU/mg protein, AMN 28.28 mU/mg protein) but carboxypeptidase activity was not detected. Low neutral endopeptidase 24.11 (NEP) activity was found in all cell types studied (0.96-2.41 mU/mg protein). The qualitative and quantitative changes in the peptidase activity of primary cultured rat alveolar cells between day 2 and day 7 in culture has implications for the use of alveolar cell monolayers as drug absorption models to investigate peptide absorption from the lung. Ectopeptidase activity in cultured alveolar cells can be used to infer the peptide-metabolising capacity of the surface of the alveolar epithelium. The aminopeptidase activity in particular, if representative of enzyme activity in vivo, would offer a significant metabolic barrier to systemic delivery of peptides via the lung.

Inverse potential scattering in duct acoustics

The inverse problem of the noninvasive measurement of the shape of an acoustical duct in which one-dimensional wave propagation can be assumed is examined within the theoretical framework of the governing Klein-Gordon equation. Previous deterministic methods developed over the last 40 years have all required direct measurement of the reflectance or input impedance but now, by application of the methods of inverse quantum scattering to the acoustical system, it is shown that the reflectance can be algorithmically derived from the radiated wave. The potential and area functions of the duct can subsequently be reconstructed. The results are discussed with particular reference to acoustic pulse reflectometry.

The vocal‐tract ‘‘potential function:’’ Many‐to‐one mappings and compensatory articulations in speech production

A fully quantitative, mathematical framework for the analysis of compensatory articulations is described. It is shown that the physics of speech production is best described by a spatial ‘‘potential function,’’ which, unlike cylindrical n‐tube approximations, accounts for dispersive wave phenomena in regions of rapidly varying cross section. It is demonstrated that many possible area functions, and hence articulatory configurations, correspond to a single potential function, and so it is claimed that the potential‐function descriptor is a both more accurate and more compact basis for the scientific investigation of phonetic systems. This work demonstrates that a 27‐vowel system may be simulated from just 8 binary, potential‐function parameters. The acoustic correlates of the individual ‘‘bits’’ are discussed, and it is found that they characterize the main vowel classes in a transparent way. Transformations from high to mid, and from mid to low, vowels are obtained, along with those involving the tense–la...

Pulse reflectometry as an acoustical inverse problem: Regularization of the bore reconstruction

The theoretical basis of acoustic pulse reflectometry, a noninvasive method for the reconstruction of an acoustical duct from the reflections measured in response to an input pulse, is reviewed in terms of the inversion of the central Fredholm equation. It is known that this is an ill‐posed problem in the context of finite‐bandwidth experimental signals. Recent work by the authors has proposed the truncated singular value decomposition (TSVD) in the regularization of the transient input impulse response, a non‐measurable quantity from which the spatial bore reconstruction is derived. In the present paper we further emphasize the relevance of the singular system framework to reflectometry applications, examining for the first time the transient bases of the system. In particular, by varying the truncation point for increasing condition numbers of the system matrix, it is found that the effects of out‐of‐bandwidth singular functions on the bore reconstruction can be systematically studied.